Clinical trial NCT04321343
Conditions: NASH - Nonalcoholic Steatohepatitis
Sponsor: Poxel SA
Start date: 2020-09-01; Completion date: 2022-06-20
Enrollment: 117 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the effect of 3 doses of PXL065 versus placebo on liver fat content in NASH patients after 36 weeks of treatment

Detailed description:
The study will be performed in patients with NASH. The primary endpoint will be the assessment of the change in the percentage of liver fat content (assessed by MRI-PDFF).

Arms: arm 1: PXL065 Dose 1 arm 2: PXL065 Dose 2 arm 3: PXL065 Dose 3 arm 4: Placebo oral tablet
Interventions: intervention 1: PXL065 intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: PXL065 oral tablet intervention 2: Placebo oral tablet

Protocol documents:
Prot_000.pdf: 
PXL065 / Study No. PXL065-003 / DESTINY 1 
Protocol Version 5.0 / 17th December 2020 
 
 
 
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CLINICAL TRIAL PROTOCOL 
Trial Protocol Number 
PXL065-003 
Study Full Title 
A 36-week, randomized, double-blind, placebo-
controlled, parallel group trial to assess the efficacy 
and safety of PXL065 versus placebo in 
noncirrhotic, 
biopsy-proven 
Nonalcoholic 
Steatohepatitis (NASH) patients 
Study Short Title 
DESTINY 1 
Program Acronym 
DESTINY 
Deuterium-stabilized 
R-pioglitazone 
(PXL065) 
Efficacy and Safety Trial In NASH 
Phase 
Phase 2 
Authors 
Julie Dubourg, MD  
Pascale Fouqueray, MD, PhD 
Carole Thang, PharmD 
IND Number 
144089  
EudraCT Number 
N/A 
Coordinating investigator 
Stephen Harrison, MD 
Pinnacle Clinical Research 
5109 Medical Dr Ste 200 
San Antonio, TX 78229 
United States 
Sponsor 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon 
France 
Sponsor’s Legal Representative (EU) N/A 
Trial Protocol Version 
Version 5.0 / 17th December 2020 
Replaces Trial Protocol Version 
Version 4.0 / 19th August 2020 
Current Protocol Amendment 
#4 
Previous Protocol Amendments 
#3 
NCT04321343 
Corporate confidential information 


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Signature Page 
 
Lead responsible for designing the clinical study: 
 
I approve the design of the study. 
 
 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Jean-Marie GROUIN  
Statistics consultant for POXEL S.A. 
 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Julie DUBOURG, MD 
Vice President - Medical Operations, Biometry and Safety 
POXEL S.A.  
 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Carole THANG, PharmD 
Associate Medical Director, Clinical Development 
POXEL S.A.  
 
 
 
 
 
 
 
Corporate confidential information 


PXL065 / Study No. PXL065-003 / DESTINY 1 
Protocol Version 5.0 / 17th December 2020 
 
 
 
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Lead responsible for reviewing the clinical study protocol: 
 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Emeline KIEKEN 
Clinical Project Manager 
POXEL S.A. 
 
 
Corporate confidential information 


PXL065 / Study No. PXL065-003 / DESTINY 1 
Protocol Version 5.0 / 17th December 2020 
 
 
 
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Investigator Signature 
Study Full Title  
A 
36-week, 
randomized, 
double-blind, 
placebo-
controlled, parallel group trial to assess the efficacy and 
safety of PXL065 versus placebo in noncirrhotic, 
biopsy-proven Nonalcoholic Steatohepatitis (NASH) 
patients 
Study Short Title  
DESTINY 1 
Program Acronym   
DESTINY 
(Deuterium-stabilized 
R-pioglitazone 
(PXL065) Efficacy and Safety Trial In NASH) 
Protocol Version / Date 
Version 5.0 / 17th December 2020 
Study site Number  
__________________________________________ 
Investigator (full name, title and academic degree) ____________________________ 
 
__________________________________________ 
 
Address: ___________________________________ 
 
Phone: _____________________________________ 
 
Fax: _______________________________________ 
 
Email: _____________________________________ 
 
I, the undersigned, am responsible for the conduct of the study at this study site and affirm 
that: 
• I understand and will conduct the study according to the protocol, any approved protocol 
amendments, International Council for Harmonization (ICH) Good Clinical Practice 
(GCP) and all applicable Regulatory Authority requirements and national laws. 
• I will not deviate from the protocol, except where necessary to prevent immediate 
danger to patients. 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
 


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List of Abbreviations 
A2M 
Alpha-2-macroglobulin 
AASLD 
American Association for the Study of Liver Diseases 
Adipo-IR 
Adipose tissue insulin resistance 
 
ADL 
Activities of daily living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AERP 
Adverse Event Reporting Plan 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
ALP 
Alkaline Phosphatase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
AUCinf 
Area under the concentration time curve extrapolated to infinity 
BA 
Bone area 
β-HCG 
Human Chorionic Gonadotropin 
BMC 
Bone mineral content 
BMD 
Bone mineral density 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CABG 
Coronary Artery Bypass Graft 
CD 
Choline-deficient 
CGM 
Continuous Glucose Monitoring 
CHI3L1 
Chitinase-3-like protein 1 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease – Epidemiology Collaboration 
Cmax 
Maximum concentration 
Cpre 
Predose concentration 
CRA 
Clinical Research Associate 
CRC 
Clinical Research Coordinator 
CRN 
Clinical Research Network 
CRO 
Contract Research Organization  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DILI 
Drug-Induced Liver Injury 
DXA 
Dual-energy X-ray absorptiometry 
EC 
Ethics Committee 
ECG 
Electrocardiogram 


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eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EDC 
Electronic Data Capture 
e.g. 
exempli gratia 
ELF 
Enhanced Liver Fibrosis 
EoS 
End-of-Study Visit 
EoT 
End-of-Treatment Visit 
ET 
Early Termination Visit 
FCS 
Fully conditional specification 
FDA 
Food and Drug Administration 
FFA 
Free Fatty Acids 
FIB-4 
Fibrosis 4 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GLP1-RA 
Glucagon-Like Peptide 1 – Receptor Agonist 
GMP 
Good Manufacturing Practice 
HA 
Hyaluronic acid 
HbA1c 
Glycated hemoglobin 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HDL-c 
High-Density Lipoprotein cholesterol 
HF 
Heart Failure 
HIV 
Human Immunodeficiency Virus 
HOMA-IR 
Homeostasis Model Assessment of Insulin Resistance 
HOMA-β 
Homeostasis Model Assessment of β-cell function 
HR 
Heart Rate 
hsCRP 
High-sensitivity C-Reactive Protein 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
i.e. 
id est 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT(S) 
Intention-To-Treat (Set) 
IWRS 
Interactive Web Response System 
LDL-c 
Low-Density Lipoprotein cholesterol 
LFC 
Liver Fat Content 


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LSM 
Least Square Mean 
MATE 
Multidrug and Toxin Extrusion 
MCD 
Methionine/choline-deficient 
MedDRA 
Medical Dictionary for Regulatory Activities 
miR-34a 
microRNA-34a 
MPC 
Mitochondrial pyruvate carrier 
MR 
Metabolite-to-parent ratio 
MRI 
Magnetic Resonance Imaging 
MRS 
Magnetic Resonance Spectroscopy 
NAFL 
NonAlcoholic Fatty Liver 
NAFLD 
NonAlcoholic Fatty Liver Disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic Steatohepatitis 
NFS 
NAFLD Fibrosis Score 
NOAEL 
No-observed-adverse-effect level 
NYHA 
New York Heart Association 
OAT 
Organic Anion Transporter 
OCT 
Organic Cation Transporter 
PDFF 
Proton Density Fat Fraction 
PIIINP 
Amino-terminal propeptide of type III procollagen 
PK 
Pharmacokinetic(s) 
PPARγ 
Peroxisome proliferator-activated receptor γ 
PPS 
Per Protocol Set 
Pro-C3 
N-terminal type III collagen propeptide 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
QD 
Once a day (Quaque die) 
QUICKI 
Quantitative Insulin Sensitivity Check Index 
RNA 
Ribonucleic Acid 
RS 
Randomized Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SGLT2-I 
Sodium-Glucose-Co-Transporter-2 Inhibitor 
SMBG 
Self-Monitoring Blood Glucose  
SOC 
System Organ Class 
SS 
Safety Set 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T2DM 
Type 2 Diabetes Mellitus 
TBL 
Total bilirubin 


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TEAE 
Treatment-Emergent Adverse Event 
TIMP-1 
Tissue inhibitor of metalloproteinases 1 
TMF 
Trial Master File 
TSH 
Thyroid Stimulating Hormone 
TZD 
Thiazolidinediones 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organization 
 
 


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Table of Contents 
1 
SYNOPSIS............................................................................................................ 13 
2 
BACKGROUND INFORMATION ................................................................... 30 
2.1 
SCIENTIFIC RATIONALE .............................................................................................................. 30 
2.2 
PXL065 ...................................................................................................................................... 31 
2.2.1 
Non-clinical Information ....................................................................................................... 31 
2.2.2 
Clinical Information .............................................................................................................. 32 
2.2.2.1 
DRX-065-001: Single Ascending Dose Phase 1 study ............................................................... 32 
2.2.2.2 
PXL065-002: Multiple Ascending Dose Phase 1 study .............................................................. 33 
2.3 
RESEARCH HYPOTHESIS ............................................................................................................. 35 
3 
STUDY OBJECTIVES ....................................................................................... 36 
3.1 
PRIMARY OBJECTIVE .................................................................................................................. 36 
3.2 
SECONDARY OBJECTIVES ........................................................................................................... 36 
4 
STUDY DESIGN ................................................................................................. 37 
4.1 
STUDY DESIGN AND SCHEDULE .................................................................................................. 37 
4.2 
RATIONALE FOR STUDY DESIGN, DOSES AND CONTROL GROUP ................................................ 37 
5 
STUDY POPULATION ...................................................................................... 39 
5.1 
INCLUSION CRITERIA .................................................................................................................. 39 
5.2 
EXCLUSION CRITERIA ................................................................................................................. 40 
5.3 
RESCREENING ............................................................................................................................. 43 
5.4 
RETESTING DURING THE SCREENING PERIOD .............................................................................. 43 
5.5 
RESTRICTIONS DURING THE STUDY ............................................................................................ 43 
5.6 
PATIENTS INCORRECTLY RANDOMIZED ...................................................................................... 44 
5.7 
CRITERIA FOR SCREEN-FAILURE ................................................................................................. 44 
5.8 
CRITERIA FOR WITHDRAWAL FROM THE STUDY FOR RANDOMIZED PATIENTS DURING THE 
DOUBLE-BLIND TREATMENT PERIOD ......................................................................................... 45 
5.8.1 
Criteria for withdrawal from the study ................................................................................. 45 
5.8.2 
Procedure for withdrawal from the study ............................................................................. 46 
5.9 
DISCONTINUATION OF THE STUDY .............................................................................................. 46 
5.10 
REPLACEMENT POLICY ............................................................................................................... 47 
6 
INVESTIGATIONAL MEDICINAL PRODUCT AND OTHER DRUGS 
USED IN THE TRIAL ........................................................................................ 48 
6.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT ........................................................ 48 
6.2 
DOSAGE AND ADMINISTRATION ................................................................................................. 48 
6.2.1 
Double-blind Treatment Period ............................................................................................ 49 
6.2.2 
Follow-up Period .................................................................................................................. 49 
6.3 
TREATMENT ASSIGNMENT AND BLINDING ................................................................................. 50 
6.3.1 
Patient Numbering ................................................................................................................ 50 
6.3.2 
Treatment Assignment or Randomization ............................................................................. 50 
6.3.3 
Treatment Blinding ................................................................................................................ 51 
6.3.3.1 
Method of Blinding .................................................................................................................... 51 
6.3.3.2 
Emergency Unblinding ............................................................................................................... 51 
6.4 
CONCOMITANT MEDICATIONS AND THERAPIES .......................................................................... 52 
6.5 
NON-PERMITTED MEDICINES ...................................................................................................... 53 
6.6 
PACKAGING AND LABELING ....................................................................................................... 53 
6.7 
MANAGEMENT OF IMP ............................................................................................................... 54 
6.7.1 
Shipment of IMP .................................................................................................................... 54 
6.7.2 
Supply and Receipt of IMP .................................................................................................... 54 
6.7.3 
Storage of IMP ...................................................................................................................... 54 
6.7.4 
Dispensing, Accountability and Compliance of IMP ............................................................ 55 
6.7.5 
Return and Destruction of IMP ............................................................................................. 56 
6.8 
OVERDOSE PREVENTION ............................................................................................................. 56 
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7 
STUDY PROCEDURES ..................................................................................... 58 
7.1 
SCREENING PERIOD .................................................................................................................... 58 
7.2 
DOUBLE-BLIND TREATMENT PERIOD .......................................................................................... 59 
7.2.1 
Visit 1: Randomization Visit (Day 1) .................................................................................... 59 
7.2.2 
Visit 2: Week 3 ...................................................................................................................... 60 
7.2.3 
Visit 3: Week 6 ...................................................................................................................... 60 
7.2.4 
Visit 4: Week 12 .................................................................................................................... 61 
7.2.5 
Visit 5: Week 18 .................................................................................................................... 62 
7.2.6 
Visit 6: Week 24 .................................................................................................................... 62 
7.2.7 
Visit 7: Week 30 .................................................................................................................... 63 
7.2.8 
Visit 8: End-of-Treatment Visit (EoT-Week 36) .................................................................... 64 
7.3 
FOLLOW-UP PERIOD, VISIT 9: END-OF-STUDY VISIT (EOS) ........................................................ 65 
7.4 
EARLY TERMINATION VISIT (ET) ............................................................................................... 65 
8 
STUDY ASSESSMENTS .................................................................................... 67 
8.1 
BLOOD VOLUME ......................................................................................................................... 67 
8.2 
EFFICACY ASSESSMENT .............................................................................................................. 67 
8.2.1 
Liver fat mass content assessed by MRI-PDFF – Central imaging core laboratory ............ 67 
8.2.2 
Liver biopsy ........................................................................................................................... 68 
8.2.3 
Other Efficacy Parameters .................................................................................................... 69 
8.3 
SAFETY ....................................................................................................................................... 70 
8.3.1 
Physical Examination ............................................................................................................ 70 
8.3.2 
Pitting edema assessment ...................................................................................................... 70 
8.3.3 
Vital Signs and Body Measurements ..................................................................................... 71 
8.3.4 
Patient Diary ......................................................................................................................... 71 
8.3.5 
Supine 12-Lead electrocardiogram (ECG) ........................................................................... 72 
8.3.6 
Laboratory Assessments ........................................................................................................ 72 
8.3.6.1 
Standard Safety Laboratory Panel (Blood and Urine) ................................................................ 73 
8.3.6.2 
Viral Infection Screen Panel ....................................................................................................... 73 
8.3.6.3 
eGFR .......................................................................................................................................... 74 
8.3.6.4 
Serum and Urine Pregnancy Tests .............................................................................................. 74 
8.3.7 
Bone mineral density ............................................................................................................. 74 
8.3.8 
Adverse Events ...................................................................................................................... 75 
8.3.8.1 
Adverse Event Definitions ......................................................................................................... 75 
8.3.8.1.1 
Adverse Event (AE) .............................................................................................................. 75 
8.3.8.1.2 
Adverse Drug Reaction (ADR) ............................................................................................. 76 
8.3.8.1.3 
Serious Adverse Event (SAE) ............................................................................................... 76 
8.3.8.1.4 
Adverse Event of Special Interest (AESI) ............................................................................. 78 
8.3.8.2 
Definition of the AE Reporting Period ....................................................................................... 80 
8.3.8.3 
Methods of Recording and Assessing Adverse Events ............................................................... 80 
8.3.8.4 
Sponsor immediate notification and Regulatory Reporting ........................................................ 81 
8.3.8.4.1 
Sponsor Immediate Notification ........................................................................................... 81 
8.3.8.4.2 
Reporting to Regulatory Authorities (Expedited Reporting), Investigators and Independent 
Ethics Committees/Institutional Review Boards .................................................................. 82 
8.3.8.5 
Monitoring of Patients with Adverse Event ............................................................................... 82 
8.3.9 
Overdose ............................................................................................................................... 83 
8.3.10 
Pregnancy and In Utero Drug Exposure .......................................................................... 83 
8.3.11 
Special Recommendations for Hypoglycemia................................................................... 84 
8.4 
PHARMACOKINETICS .................................................................................................................. 85 
8.5 
BIOBANKING SAMPLES FOR POST-HOC ASSESSMENTS ................................................................ 85 
9 
STATISTICAL METHODS ............................................................................... 86 
9.1 
GENERAL CONSIDERATIONS ........................................................................................................ 86 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................... 86 
9.3 
RANDOMIZATION ........................................................................................................................ 87 
9.4 
ANALYSIS SETS .......................................................................................................................... 87 
9.4.1 
Screened Set .......................................................................................................................... 87 
9.4.2 
Safety Set ............................................................................................................................... 88 
9.4.3 
Efficacy Analyses .................................................................................................................. 88 
9.4.3.1 
Randomized Set (RS) ................................................................................................................. 88 
9.4.3.2 
Intention-to-treat Set (ITTS) ....................................................................................................... 88 


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9.4.3.3 
Per Protocol Set (PPS) ................................................................................................................ 88 
9.4.4 
PK Population ....................................................................................................................... 88 
9.5 
EFFICACY ANALYSIS ................................................................................................................... 88 
9.5.1 
Primary Endpoint: relative change in liver fat content (LFC) .............................................. 88 
9.5.2 
Secondary Endpoints ............................................................................................................. 90 
9.5.2.1 
Absolute Change in liver fat content (LFC) ............................................................................... 90 
9.5.2.2 
Analysis of responders ............................................................................................................... 90 
9.5.2.3 
Other Secondary Endpoints ........................................................................................................ 91 
9.5.3 
Safety Analysis ...................................................................................................................... 91 
9.5.3.1 
Adverse Events ........................................................................................................................... 91 
9.5.3.2 
Concomitant Medications ........................................................................................................... 91 
9.5.3.3 
Physical Examination, Pitting Edema, Vital signs and Body measurements, Bone mineral 
density and ECG ........................................................................................................................ 92 
9.5.3.4 
Clinical Laboratory Data ............................................................................................................ 92 
9.5.3.5 
Withdrawals of study .................................................................................................................. 92 
9.5.4 
Exploratory Endpoints .......................................................................................................... 92 
9.5.5 
Analysis of Further Endpoints ............................................................................................... 93 
9.6 
INTERIM ANALYSIS ..................................................................................................................... 93 
10 
ETHICAL AND REGULATORY ASPECTS .................................................. 94 
10.1 
ETHICS AND GOOD CLINICAL PRACTICE ..................................................................................... 94 
10.2 
PATIENT INFORMATION AND INFORMED CONSENT ..................................................................... 94 
10.3 
PATIENT IDENTIFICATION AND PRIVACY .................................................................................... 95 
10.4 
EMERGENCY MEDICAL SUPPORT AND PATIENT EMERGENCY CARD ........................................... 95 
10.5 
PATIENT INSURANCE AND COMPENSATION TO PATIENTS ........................................................... 96 
10.6 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE ................................................................ 96 
10.7 
REGULATORY AUTHORITIES ....................................................................................................... 97 
11 
STUDY MANAGEMENT .................................................................................. 98 
11.1 
DATA COLLECTION AND CRF MANAGEMENT .............................................................................. 98 
11.2 
HANDLING OF PROTOCOL DEVIATIONS ....................................................................................... 99 
11.3 
SOURCE DATA AND PATIENT FILES ............................................................................................ 99 
11.4 
INVESTIGATOR SITE FILE AND ARCHIVING ............................................................................... 100 
11.5 
MONITORING, QUALITY ASSURANCE AND INSPECTION BY AUTHORITIES ................................. 100 
11.6 
CHANGES TO THE PROTOCOL .................................................................................................... 101 
11.7 
CLINICAL STUDY REPORT AND PUBLICATION POLICY .............................................................. 101 
11.7.1 
Clinical Study Report ..................................................................................................... 101 
11.7.2 
Publication ..................................................................................................................... 102 
11.7.3 
Disclosure and Confidentiality ....................................................................................... 102 
12 
REFERENCES .................................................................................................. 103 
13 
ANNEX 1. SPONSOR, COORDINATING INVESTIGATORS AND STUDY 
ADMINISTRATIVE STRUCTURE ............................................................... 106 
14 
ANNEX 2. SERIOUS ADVERSE EVENT CONTACT INFORMATION .. 110 
 
 
 
 


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Index of Tables 
Table 1. Visit Schedule Chart ........................................................................................... 26 
Table 2. Treatments to be administered in the 4 treatment groups ................................... 49 
Table 3. Pitting edema scale .............................................................................................. 70 
 
Index of Figures 
Figure 1. Diagram of Study Design .................................................................................. 25 
Figure 2. Screening period examination flow ................................................................... 29 
 
 


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1 Synopsis 
Protocol Number 
PXL065-003 
Study Full Title 
A 
36-week, 
randomized, 
double-blind, 
placebo-
controlled, parallel group trial to assess the efficacy and 
safety of PXL065 versus placebo in noncirrhotic, biopsy-
proven Nonalcoholic Steatohepatitis (NASH) patients 
Study Short Title 
DESTINY 1 
Program Acronym 
DESTINY 
Deuterium-stabilized R-pio (PXL065) Efficacy and 
Safety Trial In NASH 
Sponsor 
POXEL S.A. 
Trial under IND  
 yes 
 no 
FDA "covered trial" 
 yes 
 no 
Study site(s)/Country 
United States (US)  
Planned Trial Period  
(first patient screened-last patient 
out) 
Study start: Q3 2020 
Study end: Q1 2022 
Trial Objectives 
Primary objective 
• To assess the effect of 3 doses of PXL065 (7.5 mg 
QD, 15 mg QD and 22.5 mg QD) versus placebo on 
liver fat content (LFC) in NASH patients after 36 
weeks of treatment 
Secondary objectives 
• To assess the safety and tolerability of 3 doses of 
PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg QD) 
versus placebo in NASH patients after 36 weeks of 
treatment 
• To assess the effect of 3 doses of PXL065 (7.5 mg 
QD, 15 mg QD and 22.5 mg QD) versus placebo on 
metabolic and non-metabolic parameters in NASH 
patients after 36 weeks of treatment 
• To assess the effect of 3 doses of PXL065 (7.5 mg 
QD, 15 mg QD and 22.5 mg QD) versus placebo on 
histological changes in liver biopsy in NASH 
patients after 36 weeks of treatment 
• To assess the effect of 3 doses of PXL065 (7.5 mg 
QD, 15 mg QD and 22.5 mg QQ) versus placebo on 
histological changes in liver biopsy analyzed (by 
automated digital images analysis) in NASH patients 
after 36 weeks of treatment 
• To describe PXL065 pre-dose plasma concentrations 
during the course of the treatment and the pre- and 
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post-dose concentrations in NASH patients after 36 
weeks of treatment 
Trial Design and Plan 
(Design description in Figure 1 
and schedule of visits in Table 1) 
Phase 2, multi-center, double-blind, placebo-controlled, 
randomized study with 4 parallel groups in noncirrhotic, 
biopsy-proven NASH patients. 
There will be a total of 3 study periods, as follows: 
• Screening Period: maximum of 8 weeks 
• Double-blind treatment period: 36 weeks  
• Follow-up period: 2 weeks   
Patients will be randomized in a 1:1:1:1 ratio to receive 
either: 
• PXL065 7.5 mg oral QD 
• PXL065 15 mg oral QD 
• PXL065 22.5 mg oral QD 
• Placebo oral QD 
Randomization will be stratified according to type 2 
diabetes mellitus (T2DM) status (T2DM patients versus 
non-T2DM patients) and the NASH Clinical Research 
Network (CRN) fibrosis score (F1 versus F2/F3).  
Planned Number of Patients 
120 patients to be randomized in order to obtain at least  
96 evaluable patients (24 patients per treatment group) 
accounting for a 20% drop-out rate.  
Diagnosis and main Inclusion and 
Exclusion Criteria  
Inclusion criteria 
1. Capable of providing written informed consent. 
Male or female patients must have given written 
informed consent before any study-related activities 
are carried out 
2. Age: ≥ 18 to ≤ 75 years at informed consent 
signature 
3. Body mass index (BMI) ≤ 50 kg/m² during 
Screening Period  
4. Estimated 
glomerular 
filtration 
rate 
(eGFR)  
≥ 45 mL/min/1.73m² during Screening Period 
calculated by the Chronic Kidney Disease – 
Epidemiology collaboration (CKD-EPI) formulae 
5. Either T2DM or non-T2DM patients (after 50% non-
T2DM patients have been randomized, only T2DM 
patients will be eligible).  
If T2DM patients: 
a. Glycated hemoglobin (HbA1c) ≤ 9.5% during 
Screening Period  


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b. If treatment-naïve: patients must be diagnosed 
and under diet and exercise for the last 6 
months prior to Randomization Visit (V1) 
c. If currently treated: patients must be on stable 
mono- or bi-therapy (i.e. same doses and same 
drug(s)).  
Permitted antidiabetic drugs are:  
• Metformin, sitagliptin, alogliptin: stable for 
at least 3 months prior to Randomization 
Visit (V1) 
• Empagliflozin, canagliflozin, dapagliflozin:  
stable for at least 6 months prior to 
Randomization Visit (V1) 
All other antidiabetic drugs are not allowed 
6. Liver fat content (LFC) ≥ 8% measured with 
magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF) during the Screening Period 
7. Noncirrhotic, biopsy-proven NASH patients with: 
- Histological evidence of NASH based on liver 
biopsy with a NonAlcoholic Fatty Liver 
Disease (NAFLD) Activity Score (NAS) ≥ 4 
(at least 1 point in each histological feature: 
steatosis, 
lobular 
inflammation 
and 
hepatocellular ballooning) 
- Histological evidence of liver fibrosis defined 
as NASH CRN System fibrosis score F1, F2 or 
F3. F1 patients must have at least one of these 
risk factors: T2DM, BMI ≥ 30 kg/m², and/ or 
ALT > 1.5 x ULN. After 35% of patients with 
a fibrosis score of F1 have been randomized 
only patients with F2 and F3 will be eligible 
8. Qualifying liver biopsy must be obtained within 6 
months prior to Randomization Visit (V1). If there is 
no available liver biopsy within this period, a liver 
biopsy must be performed during the Screening 
Period 
9. Women of child-bearing potential (e.g. not 
surgically sterile or not postmenopausal) must have 
a negative serum pregnancy test during Screening 
Period and a negative urine pregnancy test at 
Randomization Visit (V1) and must use an adequate 
method of contraception or be sexually abstinent. 
Adequate method of contraception includes, but is 
not limited to: oral, intramuscular, or implanted 
hormonal contraception, sexual partner with non-
reversed vasectomy (with azoospermia in 2 tests), 2 
barrier methods (e.g. condom, diaphragm, or 
spermicide), intrauterine device  


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10. Male patients must have agreed on an effective 
method of contraception with their female partner 
 
Exclusion criteria 
Patients must not enter in the study and will not be 
randomized in the study if they fulfill any of the following 
exclusion criteria: 
1. Involvement in the planning and/or conduct of the 
study (applies to POXEL, COVANCE and 
SUMMIT staff and/or the study site staff)  
2. Participation in another clinical study with intake of 
an investigational product during the last 3 months 
prior to Screening Period  
3. Participation in another NASH clinical study with 
intake of an active investigational product during the 
last 6 months prior to qualifying liver biopsy (i.e. 
screen-failure patients or patients treated with 
placebo do not meet this exclusion criterion) 
4. Previous participation in any clinical study with 
PXL065 intake  
Target disease exclusions 
5. Evidence of another form of active liver disease 
including but not limited to viral hepatitis, 
autoimmune hepatitis, alcoholic disease, cholestatic 
liver disease, Wilson’s disease, Alpha-1-antitypsin 
deficiency, hemochromatosis or drug induced liver 
injury (DILI) 
6. Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) > 200 IU/L during 
Screening Period 
7. Evidence of hepatic impairment during Screening 
Period as defined by any of the following 
parameters: 
a. Total bilirubin (TBL) ≥ 1.3 mg/dL unless 
diagnosis of Gilbert’s disease 
b. Serum albumin < 3.5 g/dL 
c. International Normalized Ratio (INR) ≥ 1.3, 
except for patients under anticoagulant 
treatment 
d. Platelets < 150 G/L 
e. Hemoglobin < 11 g/dL in females or < 12 g/dL 
in males 
f. Evidence of portal hypertension (e.g. ascites, 
esophageal varices) 
8. Bariatric surgery of any kind at any time prior to 
Randomization Visit (V1)  


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9. Change in body weight greater than 5% within the 
last 6 months prior to Randomization Visit (V1) 
10. Positive serologic evidence of current infectious 
liver disease including hepatitis B surface antigen 
(HBsAg), and/or hepatitis C virus antibody (anti-
HCV) with detected circulating ribonucleic acid 
(RNA) during Screening Period.  
11. History of excessive alcohol intake defined by ≥ 21 
units of alcohol/week in males and ≥ 14 units of 
alcohol/week in females for 2 years prior to 
Randomization Visit (V1), where a unit of alcohol is 
equal to 10 g pure alcohol.  
Medical History and Concurrent Disease Exclusions 
Cardiovascular diseases 
12. Any of the following disease within 6 months prior 
to Randomization Visit (V1): 
- Myocardial infarction 
- Cardiac revascularization surgery (coronary 
artery bypass graft / percutaneous transluminal 
coronary angioplasty (CABG / PTCA)) 
- Unstable angina 
- Transient 
ischemic 
attack, 
stroke 
or 
cerebrovascular disease 
13. Any history of heart failure (HF) 
14. Unstable or undiagnosed arrhythmias, long QT 
syndrome, short QT syndrome, history of drug-
induced Torsade de Pointe 
15. Uncontrolled high blood pressure (BP): diastolic BP 
≥ 100 mmHg or systolic BP ≥ 160 mmHg with or 
without antihypertensive treatment during Screening 
Period and/or at Randomization Visit (V1). BP 
measurement is the mean of 3 measurements and can 
be repeated 
once. 
If currently treated 
for 
hypertension: patients must be on stable therapy (i.e. 
same doses and same drugs) for the last 1 month 
prior to Randomization Visit (V1) 
16. Lipid-lowering drug treatment modified (doses 
and/or drugs) during the past month prior to 
Randomization Visit (V1)   
Hematological and oncological diseases 
17. Active malignance or malignancy with a complete 
remission date within 2 years prior to Randomization 
Visit (V1) (with the exception of treated basal cell 
carcinoma or treated squamous cell carcinoma of the 
skin)  


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18. Any history of bladder cancer or unexplored 
macroscopic hematuria  
19. History of haemoglobinopathies (e.g., sickle cell 
anemia or thalassemia, sideroblastic anemia) 
Endocrinological disease 
20. Diabetes other than T2DM 
21. Uncontrolled hypothyroidism (thyroid stimulating 
hormone (TSH) > 2 x the upper limit of normal 
(ULN) during Screening Period) 
Other exclusion conditions 
22. Any recent (<1 year prior to Randomization Visit 
(V1)) history of bone fracture 
23. Postmenopausal women with a bone mineral density 
(BMD) T-score ≤ -2.5 SD (osteoporosis) measured 
by standard dual-energy X-ray absorptiometry 
(DXA) within 6 months prior to Randomization Visit 
(V1) or if not available, during the screening period. 
Postmenopausal women with a T-score between -1 
and -2.5 SD can be included if they are treated 
according to standards of care for osteopenia 
24. Immunocompromised patients such as patients that 
underwent organ transplantation or are diagnosed 
with human immunodeficiency virus (HIV) 
25. Any other known serious disease (such as major 
infection, clinically significant gastrointestinal 
disorder, major autoimmune disease) or other 
disease which in the Investigator’s opinion would 
exclude the patient from the study 
26. Any recent (< 5 years) or current drug addiction  
27. Mental handicap, limited capacity of recognition, 
inability to follow the study procedures as evaluated 
by the Investigator, or any history of clinically 
important emotional and/or psychiatric illness  
28. Anorexia or bulimia 
29. Known hypersensitivity to any of the constituents or 
excipients of the investigational medicinal product 
(IMP) or pioglitazone, or history of relevant drug 
and/or 
food 
allergies 
(e.g. 
anaphylactic, 
anaphylactoid reactions) 
30. Use of non-permitted concomitant medication within 
6 months prior to Randomization Visit (V1) (A 
transient intake < 2 weeks may be allowed with the 
approval of the COVANCE Medical Monitor and the 
POXEL Medical Representative): 
a. Any medication containing pioglitazone (e.g. 
Actos®, Actoplus Met®, Duetact®, Oseni®) or 


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other 
approved 
or 
experimental 
thiazolidinediones (TZDs) (e.g. rosiglitazone 
(Avandia®), leriglitazone (MIN-102), MSDC-
0602K), or peroxisome proliferator-activated 
receptor γ (PPARγ) agonists  
b. Any other antidiabetic drug except those 
permitted in inclusion criterion #5 (metformin, 
sitagliptin, 
alogliptin, 
empagliflozin, 
canagliflozin, and dapagliflozin) 
c. Topiramate, amiodarone, bile salt chelators, 
methotrexate, equal or more than 800 U of 
vitamin E per day, chronic use (> 2 consecutive 
weeks) of corticosteroids with a systemic effect 
at doses ≥10 mg/day of oral prednisone (or 
equivalent), orlistat, obeticholic acid or any 
other medications (including vitamins, herbal 
and dietary supplements) known to affect liver 
function/steatosis at the Investigator’s discretion 
31. Use of non-permitted medications related to the risk 
of drug-drug interaction at randomization visit. 
a. Inducer of CYP2C8 (i.e. rifampicin) 
b. Strong and moderate inhibitors of CYP2C8 
(i.e. gemfibrozil, clopidogrel, letermovir, 
deferasirox, teriflunomide) 
c. Strong inhibitors of OAT1, and OAT3 (i.e. 
darolutamide, tenofovir)  
Those medications should be stopped or switched if the 
patient is eligible for randomization based on all other 
inclusion/exclusion criteria. 
32. Contraindications to MRI 
- Such as patients with pacemakers, metallic 
cardiac valves, magnetic material such as 
surgical clips, implanted electronic infusion 
pumps or other conditions that would preclude 
proximity to a strong magnetic field 
- History of extreme claustrophobia 
- The patient cannot fit inside the magnetic 
resonance scanner cavity 
33. Pregnancy or lactation  
Investigational Medicinal 
Product(s) (IMP): dose / dosing 
schedule / mode of administration 
PXL065 tablets (7.5 mg or 15 mg) orally 
Placebo tablets (matched for each PXL065 dosage) orally 
One intake per day in the morning 
Treatments to be administered in the 4 treatment groups: 
• PXL065 7.5 mg + Placebo (matching PXL065 15 mg 
tablet) 
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• Placebo (matching PXL065 7.5 mg tablet) + PXL065 
15 mg 
• PXL065 7.5 mg + PXL065 15 mg  
• Placebo (matching PXL065 7.5 mg tablet) + Placebo 
(matching PXL065 15 mg tablet) 
Planned Study Duration per 
Patient 
Study duration per patient (from Screening Period up to 
End-of-Study Visit (V9)) 
• Minimum: 40 weeks  
• Maximum: 46 weeks 
Assessments for Efficacy 
Primary endpoint: 
Relative change in the percentage of LFC (assessed by 
MRI-PDFF) from baseline to Week 36 (V8-EoT) 
Secondary endpoints: 
• Absolute change in the percentage of LFC (assessed 
by MRI-PDFF) from baseline to Week 36 (V8-EoT) 
• Response defined as an absolute reduction in LFC ≥ 
5% from baseline to Week 36 (V8-EoT) 
• Response defined as a relative reduction in LFC ≥ 
30% from baseline to Week 36 (V8-EoT) 
• Response defined as a relative reduction in LFC ≥ 
50% from baseline to Week 36 (V8-EoT) 
• Response defined as a LFC value at Week 36 (V8-
EoT) that is normalized, i.e. ≤5% 
• Change in the following parameters from baseline to 
Week 36 (V8-EoT): 
- Liver enzymes: ALT, AST, gamma-glutamyl 
transferase (GGT), alkaline phosphatase (ALP) 
- Percentage of responders as defined by the 
percentage of patient with normalization of liver 
enzymes in the subset of patients with increased 
baseline value 
- Measured glycemic parameters: Fasting plasma 
glucose (FPG), HbA1c, serum insulin, C-peptide 
- Insulin resistance indexes: Homeostasis model 
assessment of insulin resistance (HOMA-IR), 
Quantitative insulin sensitivity check index 
(QUICKI), Homeostasis model assessment of β-
cell function (HOMA-β) and Adipose tissue insulin 
resistance (Adipo-IR) 
Exploratory endpoints 
Change from baseline in the following parameters at 
Week 36 (V8-EoT): 


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• Adiponectin 
• Lipids: total cholesterol, low-density lipoprotein 
cholesterol 
(LDL-c), 
high-density 
lipoprotein 
cholesterol (HDL-c), triglycerides, free fatty acids 
(FFA) 
• Biomarker of inflammation: High-sensitivity C-
reactive protein (hsCRP) 
• Biomarkers of fibrosis: N-terminal type III collagen 
propeptide (pro-C3), NAFLD Fibrosis score (NFS) 
and Fibrosis 4 (FIB-4) score and Enhanced Liver 
Fibrosis (ELF) score  
• Histological change in liver biopsy: 
- Change in NAS, in each component of NAS 
(steatosis, ballooning and inflammation) and in 
NASH CRN fibrosis score 
- Improvement in each component of NAS 
(steatosis, lobular inflammation and hepatocellular 
ballooning) by ≥ 1 point without worsening of 
fibrosis  
- Improvement in NAS by ≥ 2 points without 
worsening of fibrosis 
- Improvement in NASH CRN fibrosis score by ≥ 1 
point  
- NASH resolution (NAS score of 0-1 for 
inflammation, 0 for ballooning, and any value for 
steatosis) 
- NASH resolution (NAS score of 0-1 for 
inflammation, 0 for ballooning, and any value for 
steatosis) with improvement in NASH CRN 
fibrosis score by ≥ 1 point 
- NASH resolution (NAS score of 0-1 for 
inflammation, 0 for ballooning, and any value for 
steatosis) with no worsening in NASH CRN 
fibrosis score 
- NASH resolution (NAS score of 0-1 for 
inflammation, 0 for ballooning, and any value for 
steatosis) and improvement in NAS by ≥ 2 points 
with no worsening in NASH CRN fibrosis score 
• Histological 
changes 
(steatosis, 
inflammation, 
ballooning and fibrosis) quantified by automated 
digital images analysis  
Assessments for Safety 
Safety and tolerability will be assessed on the following 
parameters: 
• Adverse events (AEs) 
Corporate confidential information 


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• Physical examination 
• Weight, waist and hip circumferences, and BMI 
• Vital signs: systolic BP, diastolic BP, heart rate (HR) 
• Pitting edema assessment 
• 12-lead electrocardiogram (ECG) 
• Bone mineral density in postmenopausal women 
• Biological parameters: biochemistry, hematology, 
coagulation 
• eGFR (CKD-EPI formula) 
• Urinalysis 
Pharmacokinetics (PK) 
One pre-dose blood sample will be drawn just before the 
IMP daily intake at Week 12, Week 24 and Week 36 
(visits V4, V6, and V8-EoT) and one sample between 1h 
and 4h post-dose at Week 36 (last IMP intake, V8-EoT).  
Other Assessment 
Blood samples will be drawn in all patients for extra-
samples at Randomization Visit (V1) and Week 36 (V8-
EoT) to allow post-hoc testing of any additional safety and 
efficacy parameters or any potential biomarkers related to 
liver, cardiovascular, or metabolic diseases in relation 
with the drug target.  
The blood samples will be frozen and stored centrally, and 
will be destroyed within 2 years after clinical study report 
finalization. 
Statistical Methods 
Sample size calculation 
Sample size determination is based on the primary 
objective, i.e. to demonstrate that at least one dose of 
PXL065 is superior to placebo in terms of the primary 
endpoint, i.e. the relative percent change in LFC (assessed 
by MRI-PDFF) from baseline to Week 36 (V8-EoT). 
120 patients (30 per am) need to be randomized to achieve 
a 90% power for this primary objective, assuming an 
expected difference of 30% between at least one dose of 
PXL065 and placebo, a 1-sided nominal alpha level of 
0.025 for each comparison vs placebo, a common standard 
deviation of 30% and an expected drop-out rate of about 
20%. 
Statistical methods 
Analyses will be further detailed in the Statistical Analysis 
Plan (SAP), which will be finalized prior to the unblinding 
and locking of the clinical database. 
Analyses sets 
• Screened Set: all patients who were screened for 
inclusion into the study  


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• Randomized Set (RS): all patients randomized and 
considered as randomized regardless of the treatment 
actually received. 
• Safety Set (SS): all randomized patients having 
received at least one dose of the IMP (either PXL065 
or placebo) and considered as-treated. Primary set for 
safety analyses and tolerability will be analyzed on the 
Safety Set. 
• Intention-to-treat Set (ITTS): all patients having 
received at least one dose of the IMP (either PXL065 
or placebo) and considered as randomized. Primary set 
for efficacy analyses. 
• Per Protocol Set (PPS): ITT patients without any 
major violations. 
• PK population: all patients from the SS who have been 
treated with PXL065 according to the protocol and 
have provided at least one pre-dose assessment during 
the study with sufficient plasma to derive the Cpre. 
Efficacy analyses 
Primary Endpoint:  
The relative change in LFC from baseline to Week 36 
(V8-EoT) will be analyzed on the ITTS in an analysis of 
covariance (ANCOVA) model adjusting for treatment 
(PXL065 doses of 7.5 mg QD, 15 mg QD and 22.5 mg 
QD, and placebo), for stratification factors, i.e. T2DM 
Status (T2DM patients versus non-T2DM patients) and 
NASH CRN fibrosis scoring system (F1 versus F2/F3), 
and for the baseline LFC as a continuous covariate. The 
Least Square Means (LSMs) of the primary endpoint for 
treatment groups and pairwise difference in LSMs will be 
estimated along with p-values and 95% confidence 
intervals. 
Sensitivity analyses will be performed and detailed in the 
SAP. 
Secondary Endpoints:  
• Absolute change in the percentage of LFC from 
baseline to Week 36 (V8-EoT): this will be analyzed in 
the same analysis of covariance (ANCOVA) model as 
for the primary endpoint.  
• Responders (as defined above) will be analyzed with 
a 
stratified 
Cochran-Mantel-Haenszel-based 
approach. In addition, a logistic regression model 
adjusting for the same factors as for the primary 
analysis will be provided. Pairwise differences 
between PXL065 doses and placebo will be estimated 
in this model as odds ratio along with their p-values 
and 95% confidence intervals. A secondary approach 
described in Ge, et al., 2011 [1] will also be proposed.  


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Other secondary and exploratory Endpoints:  
The analysis of these other secondary and exploratory 
endpoints will be fully detailed in the SAP.   
Safety Endpoints:  
Safety endpoints will be analyzed with usual descriptive 
methods. 
PK Endpoints: 
Pharmacokinetic data (PXL065 concentrations) will be 
analyzed using a Population PK model. PK parameters 
will be listed and summarized by treatment groups and by 
visits/timepoints. 


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Figure 1. Diagram of Study Design 
 
 


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Table 1. Visit Schedule Chart 
The visit schedule chart is the master representation of the clinical trial. In case of (apparent) inconsistencies in the clinical trial protocol, the information provided here is the binding one. 
Screening 
Period 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ET 
Randomization 
Week 3 
Week 6 
Week 12 
Week 18 
Week 24 
Week 30 
Week 36 EoTWeek 38 EoS 
- 
Timeframe 
-8 weeks max
Day 1 
Day 22 
Day 43 
Day 85 
Day 127 
Day 169 
Day 211 
Day 253 
Day 267 
- 
Time windows 
- 
Within 8W after 
ICF signature 
 
3W after V1 
± 4 days 
6W after V1 
± 4 days1 
12W after V1 
± 6 days1 
18W after V1 
± 6 days1 
24W after V1 
± 6 days1 
30W after V1 
± 6 days1 
36W after V1 
± 6 days1 
2W after V8 
± 3 days 
Within 8 days 
after IMP 
discontinuation 
General Activities 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
IWRS log-on 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Emergency Card dispensing 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
IMP dispensing 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
IMP compliance 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Diary dispensing  
 
X 
 
X 
X 
X 
X 
X 
 
 
 
SMBG dispensing2 
 
X 
 
 
 
 
 
 
 
 
 
Diary review (+SMBG review if T2DM) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AASLD lifestyle guidance3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History and Clinical Investigations 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete phys ex.4 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Limited phys ex.4 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Pitting edema assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and body measurements5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
DXA6 
X 
 
 
 
 
 
 
 
X 
 
 
Central Laboratory 
MRI-PDFF7 
X  
 
 
 
 
 
 
 
X  
 
X 
Liver Biopsy8 
X 
 
 
 
 
 
 
 
X 
 
 
Viral screen lab9 
X 
 
 
 
 
 
 
 
 
 
 
Safety lab10 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
eGFR 
X 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy test11 
X 
X 
 
 
 
X 
 
 
 
X 
X 
FPG  
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
HbA1c 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Measured metabolic param12 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Insulin resistance indexes13 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Fibrosis biomarkers14 
 
X 
 
 
 
 
 
 
X 
 
 
Biobanking sampling 
 
X 
 
 
 
 
 
 
X 
 
 
PK sampling15 
 
 
 
 
X 
 
X 
 
X 
 
 


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AASLD: American Association for the Study of Liver Diseases; AE: adverse event; DXA: dual-energy X-ray absorptiometry; ECG: electrocardiogram; eGFR: estimated glomerular 
filtration rate; EoS: End-of-Study Visit; EoT: End-of-Treatment Visit; ET: Early Termination Visit; FPG: Fasting Plasma Glucose; HbA1c: glycated hemoglobin; hsCRP: High-
sensitivity C-Reactive Protein; ICF: informed consent form; IMP: Investigational medicinal product; IWRS: Interactive Web Response System; lab: laboratory; MRI-PDFF: 
Magnetic Resonance Imaging - Proton Density Fat Fraction; param.: parameters; phys ex.: physical examination; PK: pharmacokinetics;  SMBG: self-monitoring blood 
glucose;T2DM: Type 2 Diabetes mellitus V: visit; W: week(s) 
 
1: The interval between two on-site visits must not exceed 48 days. 
2: SMBG device dispensed to T2DM patients only. SMBG devices to be brought back to the study site at each visit for measurement review. SMBG device 
will be kept by the patient after the end of his/her study participation. Continuous Glucose Monitoring (CGM) is accepted and no SMBG device needs to 
be dispensed in this case. 
3: Investigators will explain AASLD guidance regarding diet and exercise at Randomization Visit (V1). Investigators will collect the compliance to this 
guidance at each subsequent visit. 
4: The complete physical examination will include head, ears, eyes, nose, mouth, skin, cardiovascular and lung examinations, lymph nodes, gastrointestinal, 
musculoskeletal and neurological systems. The limited physical examination will be focused on general appearance, the cardiovascular system as well as 
towards patient reported symptoms. 
5: Vital signs and body measurements include: heart rate and 3 blood pressure measurements in supine or sitting position, and, height (during Screening 
Period only), body weight, BMI, waist and hip circumferences. 
6: Postmenopausal women must have BMD T-score results assessed by standard DXA testing within 6 months prior to Randomization Visit (V1). If there 
is no available BMD T-score within this period, a DXA testing must be performed during the Screening Period only after receiving confirmation of 
eligibility on history, clinical examination and labs. DXA testing must also be performed before (within 8 days) or on the day of Week 36 (V8-EoT). 
7: MRI-PDFF must be performed only after receiving confirmation of eligibility on history, clinical examination and labs during Screening Period. MRI-
PDFF must also be performed before (within 8 days) or on the day of Week 36 (V8-EoT). MRI-PDFF must also be performed at Early termination Visit 
(ET) only for patients who withdraw from the study at or after Week 12 (V4) and only when the IMP was discontinued less than 14 days before the ET 
Visit. 
8: Eligibility is to be confirmed based on all assessments before performing liver biopsy and/or sending material to histopathology central laboratory. A 
qualifying liver biopsy is required within 6 months prior to the Randomization Visit (V1). If no appropriate historical liver biopsy material is available, a 
liver biopsy must be performed during Screening Period. A second liver biopsy must be performed before (within 8 days) or on the day of Week 36 (V8-
EoT). 
9: The viral infection screen panel includes hepatitis screening (hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV) and in case of 
positive result, reflex test of HCV circulating ribonucleic acid (RNA), anti-human immunodeficiency virus (HIV) 1 and 2) 
10: The standard safety laboratory panel (blood and urine) includes hematology, biochemistry, coagulation and urinalysis. Refer to Section 8.3.6.1 Standard 
Safety Laboratory Panel (Blood and Urine) 
11: For female patients of child-bearing potential only. Serum pregnancy test (Human Chorionic Gonadotropin (β-HCG)) during Screening period, End-
of-study Visit (V9) and Early termination Visit (ET) and urine pregnancy test at Randomization Visit (V1) and Week 18 (V5). 


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12: Measured metabolic parameters include serum insulin, C-peptide, adiponectin, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-
density lipoprotein cholesterol (HDL-c), triglycerides, free fatty acids (FFA) 
13: Insulin resistance indexes include Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index 
(QUICKI), Homeostasis Model Assessment of β-cell function (HOMA-β) and Adipose tissue Insulin Resistance (Adipo-IR) 
14: Fibrosis biomarkers include: N-terminal type III collagen propeptide (pro-C3), Nonalcoholic Fatty Liver Disease (NALFD) Fibrosis Score (NFS), 
Fibrosis 4 (FIB-4) score and Enhanced Liver Fibrosis (ELF) score  
15: One pre-dose blood sample will be drawn just before the IMP daily intake at Week 12, Week 24 and Week 36 (visits V4, V6 and V8-EoT) and one 
sample between 1h and 4h post-dose at Week 36 (last IMP intake, V8- EoT).  
 
 


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Figure 2. Screening period examination flow  


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2 Background Information 
2.1 Scientific Rationale 
Nonalcoholic fatty liver disease (NAFLD) is one of the most prominent forms of chronic liver 
disease worldwide and is defined as the presence of ≥ 5% of hepatic steatosis in the absence of 
competing liver disease etiologies, use of medications that induce steatosis, and other chronic liver 
diseases. Within the general population, the overall global prevalence of NAFLD is estimated to 
be 25% [2]. NASH is a subset of NAFLD which is associated with inflammation and hepatocyte 
injury (with or without accompanying fibrosis). The prevalence of NASH in the general population 
is approximately 1.5% to 6.5% [2]. Multiple comorbidities are associated with NAFLD and/or 
NASH, including obesity, insulin resistance and/or T2DM, dyslipidemia, hypertriglyceridemia, 
hypertension, liver cirrhosis, hepatic impairment, and hepatocellular carcinoma [2]. Both 
cardiovascular and liver mortality are significantly elevated in patients with NAFLD, and these 
mortalities rise dramatically as the disease progresses to more advanced stages of fibrosis and 
scarring. In fact, NASH cirrhosis is currently the primary etiology for dual liver kidney 
transplantation and is estimated to become the number one indication for liver transplant by 2020 
[3]. The striking prevalence of NAFLD and NASH paired with their profound complications 
underscore the critical need for safe and effective therapies [3]. However, there are no medications 
currently approved by the Food and Drug Administration (FDA) for the treatment of NASH. 
Pioglitazone was first approved in the United States in 1999 and has been prescribed extensively for 
the treatment of T2DM. As of 2014, it was estimated that there were over 29 million patient years of 
exposure data available for pioglitazone [4].  Pioglitazone has been studied in humans as well as 
animal models for indications other than T2DM, including NASH. The safety profile of 
pioglitazone has been established via numerous animal toxicology studies, human clinical studies, 
and through its extensive use as an active ingredient in approved drugs. The efficacy of 
pioglitazone in both nondiabetic and diabetic NASH patients has been demonstrated in randomized 
controlled studies [5] and the use of pioglitazone in nondiabetic or diabetic biopsy-proven NASH 
patients is recommended by the practice guidance of the American Association for the Study of 
Liver Diseases (AASLD) [6] and of the European Association for the Study of the Liver [7].  
However, in the United States, pioglitazone is prescribed by only about 14% of gastroenterologists 
and hepatologists to their biopsy-proven NASH patients, due primarily to its propensity to induce 
weight gain [8, 9].  
Pioglitazone is a member of the class of compounds known as thiazolidinediones (TZDs). TZDs are 
known to be PPARγ activators. However, while PPARγ activation has been shown to result in positive 
pharmacological effects, PPARγ activation can also explain many of the side-effects observed in 
patients treated with TZDs. Specifically, PPARγ activation has been linked to weight gain [10], fluid 
retention [11], and bone loss [12, 13]. Recently, pioglitazone and other TZDs have been reported to 
exert pharmacological activity through additional, non-PPARγ-related mechanisms of action including 


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inhibition of mitochondrial pyruvate carrier (MPC) [14]. MPC inhibition, as opposed to PPARγ 
activation, is predicted to provide the treatment benefits for NASH patients [15]. 
All TZDs, including pioglitazone, are mixtures of stereoisomers with at least one chiral center at 
the 5-position of the TZD moiety. However, these stereoisomers chemically interconvert in solution 
and in vivo due to the chemical instability of the 5-position. Because of this chemical interconversion, 
information on the potential contribution of each enantiomer of pioglitazone to the overall 
pharmacological effects of the racemic mixture (1:1 mixture of (R)- and (S)-enantiomers) has not been 
previously reported. Replacement of hydrogen with deuterium at the chiral center of pioglitazone 
stabilized the chiral center and enabled characterization of each enantiomer. Deuterium is a 
naturally occurring, non-radioactive isotope of hydrogen broadly used in medicine to facilitate the 
tracing of compounds in vivo or to alter metabolism. Humans can tolerate high exposure to 
deuterium in body fluids, as no evident toxicity was observed upon acute exposure to levels of 
15% to 23% deuterium replacement in whole body plasma [16]. Deuterated compounds that 
exemplify metabolic switches, i.e. stabilization against metabolism, have been extensively studied 
in nonclinical and clinical settings and the first deuterated drug, Austedo®, was approved by the 
FDA in 2017. Several applications of deuterium labeling in therapeutic research and development 
have been or are being pursued [17]. 
PXL065 is the deuterium-stabilized (R)-enantiomer of pioglitazone. PXL065 is stabilized against 
inversion of configuration by deuterium substitution at the chiral center of pioglitazone. This minor 
chemical change stabilizes the enantiomer by slowing, through a deuterium kinetic isotope effect, 
the formation of a planar intermediate, which leads to the formation of a mixture of the (R)- and 
(S)-enantiomers of pioglitazone. PLX065 is anticipated to have similar or better efficacy with less 
side effects than pioglitazone. 
2.2 PXL065 
2.2.1 Non-clinical Information 
The nonclinical development program of PXL065 aimed to demonstrate the in vitro and in vivo 
separation of the pharmacological effects of racemic pioglitazone between its two enantiomers. 
This evaluation was enabled by the stabilization of the enantiomers of pioglitazone against 
racemization through the use of deuterium-enabled chiral switching, producing the deuterium-
stabilized (R)- and (S)-enantiomers (PXL065 and PXL064, respectively).  
Importantly, PXL065 was shown to have limited PPARγ agonist activity in vitro, compared to 
pioglitazone, while the (S)-enantiomer was a strong PPARγ agonist. Additionally, PXL065, as well 
as the (S)-enantiomer of pioglitazone, were shown in vitro to act like pioglitazone, the protonated 
racemate (1:1 mixture of (R)- and (S)-enantiomers), as mitochondrial function modulators, likely 
through inhibition of the MPC. In vivo in a db/db mouse model of T2DM, PXL065, like 
pioglitazone, reduced plasma glucose and lipid levels and had anti-inflammatory effects while 
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PXL064 showed no anti-inflammatory effects. In an ob/ob obesity mouse model, pioglitazone and 
PXL065 improved basal glycemia and glucose tolerance as well as insulin secretion, although the 
strongest effects were observed after PXL065 treatment. Additionally, PXL065 did not exhibit the 
PPARγ-related side effect of weight gain in a C57BL/6 mouse model as well as the ob/ob mouse 
model (except at the highest dose of 30 mg/kg), while pioglitazone and PXL064 significantly 
increased body weight. 
The NASH efficacy of PXL065 was evaluated in 2 diet-induced models of NASH: the choline-
deficient (CD) and methionine/choline-deficient (MCD) diet models.  In the MCD diet model, 
PXL065 exhibited at least the same efficacy as pioglitazone at reducing the components of NAS 
(hepatic steatosis, ballooning, and inflammation) and hepatic fibrosis.  In the CD diet model, 
PXL065 was equal to or better than pioglitazone at alleviating the NASH phenotype as well as 
other hepatic measures (eg, FFAs, triglycerides, cholesterol). By contrast, also in this model, 
PXL064 only showed an effect on hepatic fibrosis similar to that of pioglitazone and PXL065, 
although none of the compounds had any effect on ballooning. 
Two bridging single-species toxicity studies with PXL065 (28-day and 13-week oral toxicity 
studies in beagle dogs) demonstrated no novel toxicities relative to pioglitazone.     
The observed effects of PXL065 on red blood cell mass parameters, liver enzyme activities, and 
heart weight at PXL065 15 mg/kg/day were consistent with those observed in dogs administered 
pioglitazone at 10 mg/kg/day, as shown in the 13-week oral toxicology study in beagle dogs. 
Toxicity findings seemed to be mainly driven by exposure to total (S)-pioglitazone, as exposure to 
total (S)-pioglitazone after 15 mg/kg/day PXL065 was found to be equivalent to the exposure 
observed after 10 mg/kg/day pioglitazone, whereas exposure to total (R)-pioglitazone was 6.1-fold 
higher than the one observed after 10 mg/kg/day pioglitazone.   
In addition, in vitro genotoxicity testing of PXL065 in bacterial reverse mutation and mammalian 
gene mutation assays did not show any evidence of mutagenicity and the potential for drug-drug 
interaction of PXL065 was shown to be similar to that of pioglitazone through in vitro cytochrome 
P 450 and transporter assays. 
Collectively, these data support the development of PXL065 for the treatment of NASH. 
 
2.2.2 Clinical Information 
2.2.2.1 DRX-065-001: Single Ascending Dose Phase 1 study 
The first clinical study (DRX-065-001) was an open-label, single dose study in healthy subjects to 
assess the safety, tolerability, and PK of PXL065 versus pioglitazone (Actos). 
Subjects were randomly allocated to receive a single dose of PXL065 (7.5 mg, 22.5 mg, or 30 mg 
capsules; 6 subjects per dose group), or Actos 45 mg (6 subjects). PXL065 showed a favorable 
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safety and tolerability profile with no serious adverse events (SAEs) at all three doses.  In all three 
PXL065 dose groups, the exposure of (R)-pioglitazone (sum of deuterated and protonated (R)-
pioglitazone) was higher than for (S)-pioglitazone (sum of deuterated and protonated (S)-
pioglitazone), indicating limited deuterium/hydrogen exchange and enantiomerization of (R)-
pioglitazone to (S)-pioglitazone. Additionally, the maximum plasma concentration (Cmax) and 
AUC0-∞ R/S ratios were higher for all PXL065 doses than they were following Actos treatment.   
The total pioglitazone exposure (sum of protonated and deuterated (R)- and (S)-enantiomers) 
following 22.5 mg of PXL065 was approximately 87% of the total pioglitazone exposure following 
45 mg of Actos. Nearly equivalent total pioglitazone exposure was achieved with half of the 
pioglitazone dose.  
It is known that the major metabolites of pioglitazone, M-III and M-IV, exhibit higher exposures 
than pioglitazone, with M-IV exposure being highest. For both M-III and M-IV, the metabolite-to-
parent AUC ratios were lower following 22.5 mg of PXL065 than 45 mg of Actos. Total M-III and 
M-IV exposures (sum of AUC0- ∞ for deuterated and protonated isotopomers) following 
PXL065 22.5 mg intake were approximately 60% and 50%, respectively, of the exposure 
following Actos 45 mg. 
2.2.2.2 PXL065-002: Multiple Ascending Dose Phase 1 study 
Study PXL065-002 was a Phase 1b, double-blind, randomized, placebo-controlled study in healthy 
subjects to assess the safety, tolerability, pharmacokinetics of repeated doses of PXL065 
versus Actos, food effect, dose proportionality and intra-individual variability. 
In this study, subjects received a single oral dose of PXL065 (7.5 mg, 15 mg, or 30 mg tablets; 
6 subjects per dose group) or matching placebo (2 subjects on placebo for each placebo dose group) 
or Actos 45 mg (6 subjects) under fasting conditions on Day 1. Subjects then received repeated 
daily administrations of the appropriate study medication for 7 days, from Day 3 to Day 9. All 
study medications were dosed under fasting conditions, except for PXL065 15 mg and its matching 
placebo on Day 3, to assess the potential for food effects. 
Overall, the study medication was well tolerated with no SAE. 
In all three PXL065 groups, exposure to PXL065 was higher than exposure to protonated (R)-
pioglitazone, protonated (S)-pioglitazone or deuterated (S)-pioglitazone. The accumulation of 
exposure (Cmax and AUC0-24) of the enantiomers between Day 1 and Day 9 in the PXL065 groups 
was limited.  
The percentages of (R)-pioglitazone and (S)-pioglitazone accounting for the total pioglitazone 
exposure (Cmax and AUC) were similar in the Actos 45 mg group representing 55% and 45%, 
respectively, regardless of the day. By contrast, the percentage of (R)-pioglitazone was higher in 
the PXL065 groups accounting for around 90% by Cmax and 80% by AUC of the total pioglitazone 
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exposure. This demonstrates the stabilization of the (R)-enantiomer in vivo in humans after 
administration of PXL065 with a limited formation of the (S)-enantiomer. The dose of 15 mg of 
PXL065 gave an exposure to (R)-pioglitazone similar to 45 mg of Actos whereas the exposure to 
the (S)-enantiomer was 4.65-fold lower.  
Dose-proportionality assessed using a power model. For each of the species evaluated (d-(R)-
pioglitazone, total (R)-pioglitazone, and total (S)-pioglitazone), the dose-proportionality analysis 
led to an estimate of the power parameter around 1, regardless of the parameter or the day. 
However, the bounds of the reference interval calculated according to Smith criteria (0.8390; 
1.1610) did not entirely include the 90% confidence intervals (CIs). Consequently, 
dose-proportionality could not be statistically accepted nor rejected, according to the Statistical 
Analysis Plan-defined criteria.  As a graphical exploration did not suggest departure from dose 
proportionality, and because the power estimate was close to 1, with 90% CI including 1, the more 
powerful extended intervals according to the less strict Hummel criteria were presented for 
supportive purposes.  Using Hummel criteria, the reference intervals included all the 90% CIs, 
supporting the likelihood of dose-proportionality for Cmax and AUC for PXL065. 
The effect of food was assessed by comparing the PK parameters (Cmax and AUC0-24) of PXL065 
15 mg A decrease of both Cmax and AUC0-24 was observed when PXL065 was administered with a 
high fat and high calorie breakfast. However this decrease was only approximately 15% and this 
is not considered as clinically relevant.   
The intra-individual variability was assessed for PXL065 at doses of 7.5 mg and 30 mg. The intra-
individual variability was around 22% for Cmax regardless of the analyte and 16.1% for AUC0-24 
for PXL065. 
In the PXL065 groups, exposure (Cmax,ss and AUC) of metabolites M-III, d-M-III, M-IV, and d-M-
IV) increased with the dose level. After dosing PXL065, exposure to the d-M-III and d-M-IV 
metabolites was lower and elimination was faster compared with the protonated M-III and M-IV 
metabolites. In the Actos 45 mg group, M-III and M-IV exposure was higher than in all three 
PXL065 groups. Across the PXL065 groups, mean metabolic ratio (metabolite/parent) for AUC0-
24 for total M-III (sum of deuterated and protonated metabolite M-III) and total M-IV (sum of 
deuterated and protonated metabolite M-IV) ranged from 0.73 to 0.95 and 1.80 to 2.10, 
respectively.  As in Study DRX-065-001, mean metabolic ratios in the PXL065 groups were lower 
than those observed in the Actos group.  Total M-III and M-IV for the Actos 45 mg group were 
1.11 and 1.80, respectively.  These findings indicate lower exposure of M-III compared with 
pioglitazone and higher exposure of M-IV compared with pioglitazone in subjects treated with 
PXL065.  
No new major metabolites were identified following dosing of PXL065 
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of PXL065, please refer to the latest version of the Investigator's Brochure (IB) for 
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PXL065. The term of "POXEL" used throughout the protocol refers to the Sponsor entities 
listed in the Contact Information page(s), which will be provided in Annex 1. Sponsor, 
Coordinating Investigators and Study Administrative Structure. 
2.3 Research Hypothesis  
After 36 weeks of double-blind treatment, we aim to show superiority in LFC reduction, assessed 
by MRI-PDFF, achieved with PXL065 compared to placebo in noncirrhotic biopsy-proven NASH 
patients. 
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3 Study Objectives 
3.1 Primary Objective 
To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg QD) versus placebo 
on LFC in NASH patients after 36 weeks of treatment 
3.2 Secondary Objectives 
• To assess the safety and tolerability of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 
22.5 mg QD) versus placebo in NASH patients after 36 weeks of treatment 
• To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg QD) 
versus placebo on metabolic and non-metabolic parameters in NASH patients after  
36 weeks of treatment 
• To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg QD) 
versus placebo on histological changes in liver biopsy in NASH patients after 36 weeks 
of treatment 
• To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg QQ) 
versus placebo on histological changes in liver biopsy analyzed by automated digital 
images analysis in NAH patients after 36 weeks of treatment 
• To describe PXL065 pre-dose plasma concentrations during the course of the treatment 
and the pre- and post-dose concentrations in NASH patients after 36 weeks of treatment 
 
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4 Study Design 
4.1 Study Design and Schedule 
This study is a Phase 2, multi-center, double-blind, placebo-controlled, randomized study with  
4 parallel groups in noncirrhotic, biopsy-proven NASH patients. 
There will be a total of 3 study periods, as follows: 
• Screening Period: maximum of 8 weeks 
The screening period can be exceptionally extended after approval of the COVANCE medical 
monitor and the POXEL medical representative, if there is no more than 10 weeks between MRI-
PDFF and Randomization Visit (V1). 
• Double-blind treatment period: 36 weeks  
• Follow-up period: 2 weeks   
 
Patients will be randomized in a 1:1:1:1 ratio to receive either: 
• PXL065 7.5 mg oral QD 
• PXL065 15 mg oral QD 
• PXL065 22.5 mg oral QD 
• Placebo oral QD 
 
Randomization will be stratified according to T2DM status (T2DM patients versus non-T2DM 
patients) and the NASH Clinical Research Network (CRN) fibrosis scoring system (F1 versus 
F2/F3). This study will have to include at least 50% of T2DM patients and a maximum 35% of F1 
patients. 
The diagram of the study design is shown in Figure 1 and the visit schedule is tabulated in Table 
1.  
The duration of study for each patient from the first visit for the informed consent signature (ICF) 
up to the end of the Follow-up period will be between 40 and 46 weeks.  
The end of study (EoS) is defined as the date of last visit of last patient participating in the study.  
4.2 Rationale for Study Design, Doses and Control Group 
This study is a Phase 2, multicenter, double-blind, placebo-controlled, randomized, parallel group, 
dose-ranging trial in noncirrhotic, biopsy-proven NASH patients to assess the efficacy, safety and 
tolerability of PXL065 administered as monotherapy. 


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The design of the study is based upon the known safety and efficacy of pioglitazone in clinical 
practice and in NASH patients (assessed by liver biopsy) [18-20]. PXL065 is the deuterium-
stabilized (R)-enantiomer of pioglitazone and is anticipated to have similar or better efficacy with 
less side effects than pioglitazone.  The goal of this phase 2 study is to evaluate the dose(s) to be 
used for the confirmatory Phase 3 study, using a surrogate marker for LFC (MRI-PDFF) (primary 
endpoint), with histologic evaluation of the liver (secondary endpoints) to support the effect on 
NASH and to guide the SAP for the Phase 3 study. The patient population will include both non-
T2DM and T2DM patients. The duration of the study is 36 weeks to assess the primary efficacy 
endpoint (MRI-PDFF) and secondary and exploratory endpoints based on liver histology with 
sufficient time between liver biopsies. The primary efficacy endpoint is based on emerging data 
that supports the use of MRI-PDFF as a noninvasive, quantitative, and accurate measure of LFC 
to assess treatment response in Phase 2 NASH trials [21] and reduction in LFC observed with 
pioglitazone by MRI or magnetic resonance spectroscopy (MRS) in biopsy-proven NASH patients 
[19, 22]. The assessment of weight as a secondary safety endpoint will seek to confirm the 
reduction in PPARγ activity and related weight gain seen with pioglitazone. The three doses of 
PXL065 (7.5 mg, 15 mg and 22.5 mg) were selected based on preclinical and Phase 1 studies 
combined with the product label of the listed drug, Actos.  Since the highest approved dose of 
Actos is 45 mg QD and the Phase 1b Study of PXL065 demonstrated dose proportionality up to 30 
mg QD, 22.5 mg PXL065 is the highest dose to be tested. The 15 mg dose of PXL065 is predicted 
to have efficacy similar to Actos 45 mg with little or no weight gain. The 7.5 mg dose of PXL065 
is predicted to be the minimally efficacious dose without weight gain. 
 


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5 Study Population 
Each patient must meet all the applicable inclusion criteria and none of the exclusion criteria for 
this study. No waiver will be granted to this rule. Rescreening will be allowed once (see Section 
5.3) 
5.1 Inclusion Criteria 
1. Capable of providing written informed consent. Male or female patients must have given 
written informed consent before any study-related activities are carried out 
2. Age: ≥ 18 to ≤ 75 years at informed consent signature 
3. Body mass index (BMI) ≤ 50 kg/m² during Screening Period  
4. Estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m² during Screening Period 
calculated by the Chronic Kidney Disease – Epidemiology collaboration (CKD-EPI) 
formulae 
5. Either T2DM or non-T2DM patients (after 50% non-T2DM patients have been randomized, 
only T2DM patients will be eligible).  
If T2DM patients: 
a. Glycated hemoglobin (HbA1c) ≤ 9.5% during Screening Period  
b. If treatment-naïve: patients must be diagnosed and under diet and exercise for the 
last 6 months prior to Randomization Visit (V1) 
c. If currently treated: patients must be on stable mono- or bi-therapy (i.e. same 
doses and same drug(s)).  
Permitted antidiabetic drugs are:  
• Metformin, sitagliptin, alogliptin: stable for at least 3 months prior to 
Randomization Visit (V1) 
• Empagliflozin, canagliflozin, dapagliflozin:  stable for at least 6 months prior 
to Randomization Visit (V1) 
All other antidiabetic drugs are not allowed 
6. Liver fat content (LFC) ≥ 8% measured with magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF) during the Screening Period 
7. Noncirrhotic, biopsy-proven NASH patients with: 
- Histological evidence of NASH based on liver biopsy with a NonAlcoholic Fatty Liver 
Disease (NAFLD) Activity Score (NAS) ≥ 4 (at least 1 point in each histological 
feature: steatosis, lobular inflammation and hepatocellular ballooning) 
- Histological evidence of liver fibrosis defined as NASH CRN System fibrosis score F1, 
F2 or F3. F1 patients must have at least one of these risk factors: T2DM, BMI ≥ 30 
kg/m², and/ or ALT > 1.5 x ULN. After 35% of patients with a fibrosis score of F1 have 
been randomized only patients with F2 and F3 will be eligible 
8. Qualifying liver biopsy must be obtained within 6 months prior to Randomization Visit (V1). 
If there is no available liver biopsy within this period, a liver biopsy must be performed during 
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9. Women of child-bearing potential (e.g. not surgically sterile or not postmenopausal) must 
have a negative serum pregnancy test during Screening Period and a negative urine pregnancy 
test at Randomization Visit (V1) and must use an adequate method of contraception or be 
sexually abstinent. Adequate method of contraception includes, but is not limited to: oral, 
intramuscular, or implanted hormonal contraception, sexual partner with non-reversed 
vasectomy (with azoospermia in 2 tests), 2 barrier methods (e.g. condom, diaphragm, or 
spermicide), intrauterine device  
10. Male patients must have agreed on an effective method of contraception with their female 
partner 
5.2 Exclusion Criteria 
Patients must not enter in the study and will not be randomized in the study if they fulfill any of 
the following exclusion criteria: 
1. Involvement in the planning and/or conduct of the study (applies to POXEL, COVANCE and 
SUMMIT staff and/or the study site staff)  
2. Participation in another clinical study with intake of an investigational product during the last 
3 months prior to Screening Period  
3. Participation in another NASH clinical study with intake of an active investigational product 
during the last 6 months prior to qualifying liver biopsy (i.e. screen-failure patients or patients 
treated with placebo do not meet this exclusion criterion) 
4. Previous participation in any clinical study with PXL065 intake  
Target disease exclusions 
5. Evidence of another form of active liver disease including but not limited to viral hepatitis, 
autoimmune hepatitis, alcoholic disease, cholestatic liver disease, Wilson’s disease, Alpha-
1-antitypsin deficiency, hemochromatosis or drug induced liver injury (DILI) 
6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 200 IU/L during 
Screening Period 
7. Evidence of hepatic impairment during Screening Period as defined by any of the following 
parameters: 
a. Total bilirubin (TBL) ≥ 1.3 mg/dL unless diagnosis of Gilbert’s disease 
b. Serum albumin < 3.5 g/dL 
c. International Normalized Ratio (INR) ≥ 1.3, except for patients under anticoagulant 
treatment 
d. Platelets < 150 G/L 
e. Hemoglobin < 11 g/dL in females or < 12 g/dL in males 
f. Evidence of portal hypertension (e.g. ascites, esophageal varices) 
8. Bariatric surgery of any kind at any time prior to Randomization Visit (V1)  
9. Change in body weight greater than 5% within the last 6 months prior to Randomization Visit 
(V1) 


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10. Positive serologic evidence of current infectious liver disease including hepatitis B surface 
antigen (HBsAg), and/or hepatitis C virus antibody (anti-HCV) with detected circulating 
ribonucleic acid (RNA) during Screening Period.  
11. History of excessive alcohol intake defined by ≥ 21 units of alcohol/week in males and ≥ 14 
units of alcohol/week in females for 2 years prior to Randomization Visit (V1), where a unit 
of alcohol is equal to 10 g pure alcohol.  
Medical History and Concurrent Disease Exclusions 
Cardiovascular diseases 
12. Any of the following disease within 6 months prior to Randomization Visit (V1): 
- Myocardial infarction 
- Cardiac revascularization surgery (coronary artery bypass graft / percutaneous 
transluminal coronary angioplasty (CABG / PTCA)) 
- Unstable angina 
- Transient ischemic attack, stroke or cerebrovascular disease 
13. Any history of heart failure (HF) 
14. Unstable or undiagnosed arrhythmias, long QT syndrome, short QT syndrome, history of 
drug-induced Torsade de Pointe 
15. Uncontrolled high blood pressure (BP): diastolic BP ≥ 100 mmHg or systolic BP 
≥ 160 mmHg with or without antihypertensive treatment during Screening Period and/or at 
Randomization Visit (V1). BP measurement is the mean of 3 measurements and can be 
repeated once. If currently treated for hypertension: patients must be on stable therapy (i.e. 
same doses and same drugs) for the last 1 month prior to Randomization Visit (V1) 
16. Lipid-lowering drug treatment modified (doses and/or drugs) during the past month prior to 
Randomization Visit (V1)   
Hematological and oncological diseases 
17. Active malignance or malignancy with a complete remission date within 2 years prior to 
Randomization Visit (V1) (with the exception of treated basal cell carcinoma or treated 
squamous cell carcinoma of the skin)  
18. Any history of bladder cancer or unexplored macroscopic hematuria  
19. History of haemoglobinopathies (e.g., sickle cell anemia or thalassemia, sideroblastic anemia) 
Endocrinological disease 
20. Diabetes other than T2DM 
21. Uncontrolled hypothyroidism (thyroid stimulating hormone (TSH) > 2 x the upper limit of 
normal (ULN) during Screening Period) 
Other exclusion conditions 
22. Any recent (<1 year prior to Randomization Visit (V1)) history of bone fracture 
23. Postmenopausal women with a bone mineral density (BMD) T-score ≤ -2.5 SD (osteoporosis) 
measured by standard dual-energy X-ray absorptiometry (DXA) within 6 months prior to 
Randomization Visit (V1) or if not available, during the screening period. Postmenopausal 


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women with a T-score between -1 and -2.5 SD can be included if they are treated according 
to standards of care for osteopenia 
24. Immunocompromised patients such as patients that underwent organ transplantation or are 
diagnosed with human immunodeficiency virus (HIV) 
25. Any other known serious disease (such as major infection, clinically significant 
gastrointestinal disorder, major autoimmune disease) or other disease which in the 
Investigator’s opinion would exclude the patient from the study 
26. Any recent (< 5 years) or current drug addiction  
27. Mental handicap, limited capacity of recognition, inability to follow the study procedures as 
evaluated by the Investigator, or any history of clinically important emotional and/or 
psychiatric illness  
28. Anorexia or bulimia 
29. Known hypersensitivity to any of the constituents or excipients of the investigational 
medicinal product (IMP) or pioglitazone, or history of relevant drug and/or food allergies 
(e.g. anaphylactic, anaphylactoid reactions) 
30. Use of non-permitted concomitant medication within 6 months prior to Randomization Visit 
(V1) (A transient intake < 2 weeks may be allowed with the approval of the COVANCE 
Medical Monitor and the POXEL Medical Representative): 
a. Any medication containing pioglitazone (e.g. Actos®, Actoplus Met®, Duetact®, Oseni®) 
or other approved or experimental thiazolidinediones (TZDs) (e.g. rosiglitazone 
(Avandia®), leriglitazone (MIN-102), MSDC-0602K), or peroxisome proliferator-
activated receptor γ (PPARγ) agonists  
b. Any other antidiabetic drug except those permitted in inclusion criterion #5 (metformin, 
sitagliptin, alogliptin, empagliflozin, canagliflozin, and dapagliflozin) 
c. Topiramate, amiodarone, bile salt chelators, methotrexate, equal or more than 800 U of 
vitamin E per day, chronic use (> 2 consecutive weeks) of corticosteroids with a systemic 
effect at doses ≥10 mg/day of oral prednisone (or equivalent), orlistat, obeticholic acid 
or any other medications (including vitamins, herbal and dietary supplements) known to 
affect liver function/steatosis at the Investigator’s discretion 
31. Use of non-permitted medications related to the risk of drug-drug interaction at randomization 
visit. 
a. Inducer of CYP2C8 (i.e. rifampicin) 
b. Strong and moderate inhibitors of CYP2C8 (i.e. gemfibrozil, clopidogrel, letermovir, 
deferasirox, teriflunomide) 
c. Strong inhibitors of OAT1, and OAT3 (i.e. darolutamide, tenofovir)  
Those medications should be stopped or switched if the patient is eligible for randomization based 
on all other inclusion/exclusion criteria. 
32. Contraindications to MRI 
- Such as patients with pacemakers, metallic cardiac valves, magnetic material such as 
surgical clips, implanted electronic infusion pumps or other conditions that would 
preclude proximity to a strong magnetic field 
- History of extreme claustrophobia 
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- The patient cannot fit inside the magnetic resonance scanner cavity 
33. Pregnancy or lactation 
5.3 Rescreening 
Re-screening is permitted once with the approval of the COVANCE Medical Monitor and the 
POXEL Medical Representative if a subject has not met the eligibility criteria within the screening 
period with the following exception:  
• If a subject fails screening due to Inclusion Criterion #7 in Section 5.1, re-screening is not 
permitted. 
Patients are only allowed to be re-screened once; the entire screening process (including informed 
consent signature) must be repeated except MRI-PDFF only if the investigator can ensure that there 
will be maximum 10 weeks between MRI-PDFF and Randomization Visit (V1). 
5.4 Retesting during the Screening Period 
If the investigator is not able to assess patient’s eligibility for any of the laboratory or imaging 
eligibility criteria in cases of technical malfunction (e.g. loss of laboratory specimen) or an 
indeterminate result (e.g. out of stability sample, breathing motion artifact during the MRI) should 
be retested. 
If there is reason to believe the assessment result may be inconsistent (i.e. contradicts recent result 
for the same parameter), the test may be repeated once within the screening period only with the 
approval of the COVANCE Medical Monitor and the POXEL Medical Representative. If the 
original result was exclusionary and is confirmed by repeat testing, then the patient is to be 
considered a screen failure; these subjects may be rescreened as described in Section 5.3. 
5.5 Restrictions during the Study 
Investigators will explain to the patients at Randomization Visit (V1) the AASLD guidance [6] 
regarding diet and exercise. Investigators will collect the compliance to this guidance at each 
subsequent visit. Patients must make every effort to maintain the same diet/exercise treatment 
through the study. They will be asked about their compliance to this guidance at every visit. 
Answers will be documented in source documents and reported in the electronic Case Report Form 
(eCRF).  
Patients must be in a fasting condition for at least 10 hours (during which only water is permitted) 
prior to all study visits. 
To respect Inclusion criteria #9, women of child-bearing potential must immediately contact the 
Investigator if they suspect they might be pregnant or if they have changed, or plan to change their 
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Effective contraception (as detailed in the Inclusion criterion #9) or abstinence should be used 
during the study and for at least 7 days after the last dose of study drug for both males and females 
of child-bearing potential. 
Patients should not donate blood or blood products, sperm or oocytes during the study.   
Any modifications or deviations regarding these restrictions must be documented in the patient 
file. 
5.6 Patients Incorrectly Randomized 
Patients who fail to meet the inclusion/exclusion criteria must not, under any circumstances, enter 
the double-blind treatment period.  
If a patient who does not meet the inclusion/exclusion criteria mistakenly enters the double-blind 
treatment period, a discussion should occur between the POXEL Medical Representative, the 
COVANCE Medical Monitor and the Investigator regarding whether to continue or discontinue 
the IMP, based on patient’s safety and study’s consideration. In situations where an agreement 
cannot be reached, the patient should be withdrawn from the study. In such case, patients will be 
considered as withdrawn from the study due to protocol deviation. 
5.7 Criteria for Screen-failure 
Patients who are withdrawn from the study between the Screening Period and the Randomization 
Visit (V1) will be considered as screen failure. 
Patients must be screen-failed in the event of any of the following: 
1. Target LFC (MRI-PDFF) not met (as defined in Section 5.1 Inclusion Criteria, Inclusion 
Criteria #6) 
2. Target liver histology criteria not met (as defined in Section 5.1 Inclusion Criteria, Inclusion 
Criteria #7) 
3. Cap reached for patients with NASH CRN fibrosis F1 (see Section 4.1 Study Design and 
Schedule) 
4. Other Inclusion criteria not met (as defined in Section 5.1 Inclusion Criteria) 
5. Occurrence of an AE or SAE which is clinically relevant and affects patient’s safety, if 
withdrawal from the study is considered necessary by the Investigator or POXEL Medical 
Representative 
6. Occurrence of pregnancy 
7. Important protocol deviation if withdrawal from the study is considered necessary by the 
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8. Intake of non-permitted drug (as defined in Section 6.5 Non-permitted Medicines) if 
withdrawal from the study is considered necessary by the Investigator or POXEL Medical 
Representative/designee 
9. Occurrence of any other Exclusion criteria (as defined in Section 5.2 Exclusion Criteria)  
10. Withdrawal of patient informed consent  
11. Lost to follow-up  
The reason for screen failure must be documented in source documents and reported in the eCRF 
and interactive web response system (IWRS). If more than one reason is given, the Investigator 
should make all efforts to establish the main reason. 
The Investigator will verify AE and concomitant medications. This information will be recorded 
in the patient file and in the eCRF, including screen-failure reason and date.  
Patients will then be referred to their physician for the pursuit of routine medical care. 
5.8 Criteria for Withdrawal from the Study for Randomized Patients during 
the Double-blind Treatment Period 
5.8.1 Criteria for withdrawal from the study 
Patients may withdraw from the study at any time at their own request.  
The Investigator must temporarily interrupt or permanently discontinue the IMP if 
continued administration of the IMP is believed to be detrimental to the patient well-being. 
IMP should be discontinued and the patient should be withdrawn from the study in the event 
of any of the following: 
1. Occurrence of an AE or SAE which is clinically relevant and affects patient’s safety 
(Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher AE related 
to the drug OR CTCAE grade 4 or higher regardless of attribution to the study drug), if 
discontinuation of the IMP is considered necessary by the Investigator or POXEL Medical 
Representative  
2. Occurrence of pregnancy 
3. Important protocol deviation if discontinuation of IMP is considered necessary by the 
Investigator or POXEL Medical Representative/designee 
4. Intake of non-permitted drug (as defined in Section 6.5 Non-permitted Medicines) if 
discontinuation of IMP is considered necessary by the Investigator or POXEL Medical 
Representative/designee 
5. Requirement of an emergency unblinding (as described in Section 6.3.3.2 Emergency 
Unblinding)  
6. Withdrawal of patient informed consent  


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7. Lost to follow-up  
8. Sponsor decision (as defined in Section 5.9 Discontinuation of the Study) 
 
In case of temporary interruption of the IMP, the decision to resume the IMP should be taken in 
agreement by the Investigator, POXEL Medical Representative and COVANCE Medical Monitor. 
5.8.2 Procedure for withdrawal from the study 
In the case of discontinuation of IMP for any reason listed in Section 5.8.1 Criteria for 
withdrawal from the study except SAE leading to death and lost to follow-up, patients will be 
asked to perform an Early Termination Visit within 8 days after the IMP discontinuation. 
At the Early Termination Visit, patients will be considered as withdrawn patients. This visit 
will allow the Investigator to check the medical status of the patient and the patient to return all the 
IMP kits (used and unused), his/her patient diary and the self-monitoring blood glucose (SMBG) 
device for review if applicable. The SMBG device will be kept by the patient after the end of 
his/her study participation if applicable. The reason and date for withdrawal from the study must 
be documented in source documents, and reported in the eCRF and in the IWRS. If more than one 
reason of study withdrawal is given, the Investigator should make all efforts to establish the main 
reason. 
If there is any medical reason for withdrawal from the study, the patient will remain under the 
supervision of the Investigator until resolution or stabilization of the medical condition. The 
Investigator must make every effort to collect the information related to the outcome of the event, 
as described in Section 8.3.8.5. This information is recorded in the part of eCRF dedicated to AEs. 
If the IMP is discontinued as a result of a SAE/AESI/Overdose/Pregnancy, the procedure described 
in Section 8.3.8.4 is to be implemented. 
If patients are lost to follow-up, all reasonable means of contact must be used. In addition, a letter 
must be sent to the patient and a copy filed in the patient file (if allowed by site’s Standard 
Operating Procedures). All the attempts (at least 3 by telephone by the Investigator or Clinical 
Research Coordinator (CRC) at study site) must be recorded in the patient file; last contact date 
will be reported in the eCRF.  
Any withdrawal from the study, irrespective of the reason, is to be notified immediately to the 
COVANCE Medical Monitor and POXEL Medical Representative. 
5.9 Discontinuation of the Study 
The whole study may be discontinued by POXEL in the event of any of the following: 
• New information leading to unfavorable risk-benefit ratio of IMP, e.g. due to: 


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▪ Occurrence of significant previously unknown adverse reactions or unexpectedly 
high severity or incidence of known adverse reactions, or 
▪ Other unfavorable safety findings 
• POXEL’s decision that continuation of the study is unjustifiable for medical or ethical 
reasons 
• Poor enrollment of patients making completion of the study within an acceptable time frame 
unlikely 
• Discontinuation of development of the POXEL’s IMP  
The study will be paused if any of the following occurs: 
• Three patients develop the same Grade 3 CTCAE classified as related to study drug  
• Two patients develop the same Grade 4 CTCAE classified as related to study drug  
• One patient develops a grade 5 CTCAE classified as related to study drug 
In case the study is paused, the Sponsor will organize an ad hoc global safety board according to 
Sponsor’s Standard Operating Procedures. This global safety board will assess the benefit/risk ratio 
in order to decide whether the study should be stopped or can be continued. This 
assessment/conclusion will be sent to Competent Authorities. 
Competent Authorities and Institutional Review Boards/Ethics Committees (IRB/EC) will be 
informed about the discontinuation of the study in accordance with applicable regulations. 
The study may be terminated or suspended upon request of Competent Authorities. 
5.10 Replacement Policy 
Patients who withdrew from the study for any reason will not be replaced. 


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6 Investigational Medicinal Product and Other Drugs Used in the 
Trial 
According to the Article 2(d) of Directive 2001/20/EC, the definition of an “Investigational 
Medicinal Product (IMP)” is a pharmaceutical form of an active substance or placebo tested or 
used as a reference in a clinical trial, including products already with a marketing authorization but 
used or assembled (formulated or packaged) in a way different from the authorized form, or when 
used for an unauthorized indication, or when used to gain further information about the authorized 
form” [23]. 
In this study, the terminology IMP refers both to PXL065 (any dosage) or placebo. 
All IMPs will be produced in accordance with Good Manufacturing Practice (GMP) and Annex 
13 of GMP dedicated to IMP. 
6.1 Description of Investigational Medicinal Product 
PXL065 tablets contain 7.5 mg or 15 mg of PXL065 plus the excipients. The active pharmaceutical 
ingredient is the single, mono-deuterated (R)-enantiomer of pioglitazone, which is isolated as a 
hydrochloride salt. Placebo tablets will contain excipients alone. PXL065 tablet of each dosage 
strength has the same shape, size and appearance (including the same color, smell and taste) as its 
respective placebo tablet.  
The IMP administered are white to off-white, round, biconvex, immediate release tablets. They are 
presented in 2 dose proportional strengths: 7.5 mg and 15 mg, and their corresponding placebos, 
with a diameter of 6 mm and 8 mm, respectively. The tablets are packaged in blisters. The 
qualitative composition of PXL065 tablets is given in the IB [24]. 
6.2 Dosage and Administration 
PXL065 and/or placebo tablets will be taken once daily (QD) in the morning with a glass of water. 
Patients will take 2 tablets at each administration. For one administration, tablets should be taken 
together or one after the other. An optimal interval between the daily IMP intakes would be 24 ± 
2 hours.  
No IMP should be taken in the morning at home before each visit. IMP will be taken at study 
site after all visit assessments are performed as specified in Table 1 and intake date/time will be 
recorded in the patient file by delegated staff. 
Patients will be provided with the patient diary (paper format) as specified in Table 1. All IMP 
intakes (date and time) will be documented by the patients in the patient diary.  
 
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The patient diary is to be returned at each visit together with the IMP kit(s) (used and unused). This 
also applies to Week 3 (V2), where the patient diary and IMP kits dispensed at Randomization 
Visit (V1) will be used until Week 6 (V3).  
6.2.1 Double-blind Treatment Period 
The double-blind treatment period starts at the time the first IMP dose is taken by the patient, on 
the day of the Randomization Visit (V1), in the morning, following randomization to one of the 4 
double-blind treatment groups in this study.  
To ensure a double-blind design, regardless of the treatment group, all patients will take an oral 
dose of 2 tablets QD of either placebo and/or PXL065 7.5 mg or 15 mg depending on the group 
they have been allocated to: 
Table 2. Treatments to be administered in the 4 treatment groups 
Treatment Group 
Number of Tablets (Total = 2 Tablets/Day) 
PXL065 7.5 mg QD (7.5 mg/day) 
1 tablet of PXL065 7.5 mg  
+ 1 tablet of placebo (matching PXL065 15 mg tablet) 
PXL065 15 mg QD (15 mg/day) 
1 tablet of placebo (matching PXL065 7.5 mg tablet) 
+ 1 tablet of PXL065 15 mg  
PXL065 22.5 mg QD (22.5 mg/day) 
1 tablet of PXL065 7.5 mg  
+ 1 tablet of PXL065 15 mg  
Placebo 
1 tablet of placebo (matching PXL065 7.5 mg tablet) 
+ 1 tablet of placebo (matching PXL065 15 mg tablet) 
 
The double-blind treatment period will last for 36 weeks after Randomization Visit (V1). 
The first dose from the new IMP kit dispensed during the visit should be taken on-site during the 
visit, as detailed in Section 7.2 Double-blind Treatment Period. 
The last IMP intake will be at study site on the day of End-of-Treatment Visit (V8-EoT) (morning 
time; after completion of all pre-dose assessments). 
6.2.2 Follow-up Period 
The Follow-up period starts at the end of the 36-week double-blind treatment period. At the End-
of-Treatment Visit (V8-EoT), patients will not receive an IMP kit and consequently they will not 
take IMP during the follow-up period.  


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The Follow-up period will last for 2 weeks. 
6.3 Treatment Assignment and Blinding 
Allocation of patients to treatment groups will proceed through the use of an IWRS and will be 
performed according to the IWRS manual. 
6.3.1 Patient Numbering 
Patients will be identified during the whole study (Screening Period to V9) by a patient number 
assigned upon ICF signature at the start of Screening Period. 
The patient number consists of a unique 9-digit number using the schema AAA-XYY-ZZZ. The 
first 3 digits (AAA) indicate the study number (065). The 3 digits (XYY) indicate the pre-defined 
site number that consists of one-alphabetic letter and 2-digit number. The last 3 digits (ZZZ) 
identify the patient within the site. The first patient entered in a site will be assigned the number 
001, the second will be assigned the number 002, and so on. For example, patient 065-S04-001 
will be the first patient screened at site S04.  
Upon ICF signature by the patient and the Investigator, the Investigator (or designee) will register 
the patient in the IWRS. The patient number will be created and allocated automatically by the 
IWRS. In case of rescreening, the Investigator (or designee) will register the patient again in the 
IWRS (as he/she was a new patient). A new patient number will be created and allocated 
automatically by the IWRS. 
6.3.2 Treatment Assignment or Randomization 
Double-blind treatment period 
At Randomization Visit (V1), after confirming the eligibility criteria, the Investigator (or designee) 
will log on to the IWRS to confirm the eligibility and enter the patient into the double-blind 
treatment period. Patients will be randomized in a 1:1:1:1 ratio to receive either PXL065 doses of 
7.5 mg QD, 15 mg QD and 22.5 mg QD or placebo for 36 weeks.  
Randomization will be stratified according to T2DM status (T2DM patients versus non-T2DM 
patients) and NASH CRN fibrosis scoring system (F1 versus F2/F3).  
Patients will be assigned a unique randomization number at the Randomization Visit (V1) by 
IWRS. This randomization number identifies which record in the randomization list and therefore 
which treatment will be allocated to the patient.  


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The randomization list will be generated and kept by the COVANCE statistical department by a 
statistician independent of the project team. A copy will be provided to the CRO in charge of 
medication packaging and logistics, and to the bioanalytical laboratory in charge of the PK 
assessments on samples from patients receiving PXL065. 
During the double-blind treatment period, at each visit (except at Week 3 (V2)), after all visit 
assessments and safety evaluation are performed, the Investigator (or designee) will log on to the 
IWRS for IMP kit allocation.  
All confirmation reports generated by IWRS must be stored at least in the patient file. 
6.3.3 Treatment Blinding 
6.3.3.1 Method of Blinding 
The study will be conducted using a double-blind design with placebo tablets that have the same 
shape, size and appearance (including the same color, smell and taste) as the corresponding 
PXL065 tablets. Whatever the dose group they will be assigned to, patients will receive the same 
number of tablets (PXL065 and/or placebo) in order to keep the blind during the double-blind 
treatment period. 
PXL065 and placebo tablets will be identical in packaging, labelling, schedule of administration 
and appearance. Traceability of the IMP kit content is ensured by the IMP kit number and the 
randomization list.  
Blinded IMP will be assigned according to a computerized randomization list using the IWRS. The 
IWRS will assign IMP kits containing blinded medication for each patient at each visit requiring 
IMP kit dispensation.  
6.3.3.2 Emergency Unblinding 
Only in case of emergency, the Investigator is authorized to access the IWRS’s randomization 
system using the randomization code break provided at the beginning of the study. 
Code-breaking can be accessed via internet. The exact description of the treatment assigned to the 
individual patient will be accessible. A code-break can thus be made for any patient without 
affecting the double-blind nature of the study. Patients IMP information may only be accessed in 
the event of an emergency and out of necessity to know the identity of the allocated IMP in order 
to institute appropriate therapeutic management. The Investigator is obliged to make every effort 
to discuss the code-break with POXEL and COVANCE before code breaking. Once the code is 
broken for a patient, this patient must discontinue IMP, perform Early Termination Visit 
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In the event that a code-break is performed, the Investigator will receive a confirmation by email 
from IWRS. The Investigator must document on the confirmation printout the reason for the code-
break, and sign the document. The document has to be kept in a safe place until the end of the 
study. Once a code has been broken, the Investigator must confirm the unblinding to the Clinical 
Research Associate (CRA), the COVANCE Medical Monitor and the POXEL Medical 
Representative within 24 hours in writing. 
POXEL designee (UBC, Safety Provider) will also receive an authorization to access IWRS 
randomization information and will be attributed a specific access code that can be used if a 
suspected Serious Adverse Reaction (SAR) occurs, to assess the expectedness of the reaction. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) need to be reported according to 
regulatory requirements (see Section 8.3.8.4). 
6.4  Concomitant Medications and Therapies 
The use of any systemic medication will be restricted during the study, with the exception of 
ongoing authorized medications, and/or potential medications that could be required for the 
patient’s welfare, apart from contra-indicated medications as listed in Section 6.5 Non-permitted 
Medicines.  
As far as possible, no change should be made to the dosing of these concomitant medications from 
the ICF signature (Screening Period) to the End-of-Study Visit (V9-EoS). This is of particular 
importance for all concomitant medications which may affect the assessment of the efficacy 
endpoints (e.g. antidiabetic drugs, lipid lowering drugs); the dose(s) and drug(s) must remain stable 
during the whole study. Patients must not take any unlicensed medication, i.e. other investigational 
drugs except PXL065 or placebo, during their participation in the study.  
Medications taken within 28 days prior to ICF signature and stopped before or on ICF signature 
date will be considered as prior medication. 
Medications that are ongoing before and continue after the ICF signature will be considered as 
concomitant medication. 
Medications that will be prescribed during the study (from the ICF signature to End-of-Study Visit 
(V9-EoS) will be considered as new medication. 
Any prior, concomitant and new medication must be recorded in the corresponding section of the 
eCRF, its dose, dosage form, frequency, date of onset and stop date of the medication, indication, 
reason and route used. Patients should inform the Investigator of any change in their usual 
treatment and any change should be recorded. All patients will be questioned about concomitant 
medication at each study visit. 


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6.5 Non-permitted Medicines 
Patients must not take any of the following licensed medications from the Randomization Visit 
(V1) up to Week 38 (V9-EoS): 
▪ Any medication containing pioglitazone (e.g. Actos, Actoplus Met, Duetact, Oseni) or other 
approved or experimental TZD (e.g. rosiglitazone (Avandia), leriglitazone (MIN-102), 
MSDC-0602K), or PPARγ agonists  
▪ Any other antidiabetic drug except those permitted in the inclusion criterion #5 (Section 5.1 
Inclusion Criteria, metformin, sitagliptin, alogliptin, empagliflozin, canagliflozin, and 
dapagliflozin) 
▪ Topiramate 
▪ Amiodarone 
▪ Bile salt chelators 
▪ Methotrexate 
▪ Chronic corticosteroids (> 2 consecutive weeks) with a systemic effect (e.g. oral or 
intravenous administrations) at doses ≥10 mg/day of oral prednisone (or equivalent) 
▪ Equal or more than 800 U of vitamin E per day 
▪ Orlistat 
▪ Obeticholic acid 
▪ Any other medications (including vitamins, herbal and dietary supplements) known to affect 
liver function/steatosis at the Investigator’s discretion 
▪ Inducer of CYP2C8 (i.e. rifampicin) 
▪ Strong and moderate inhibitors of CYP2C8 (i.e. gemfibrozil, clopidogrel, letermovir, 
deferasirox, teriflunomide) 
▪ Strong inhibitors of OAT1 and OAT3 (i.e. darolutamide, tenofovir) 
If, during the study, the administration of a non-permitted concomitant drug occurs or becomes 
necessary, e.g. because of AE, the Investigator together with the POXEL Medical Representative 
and COVANCE Medical Monitor will decide whether the patient can continue the IMP. 
6.6 Packaging and Labeling 
PXL065 and placebo tablets will be packaged in appropriate blister and will be labeled in English 
with respect to the regulatory requirements in the United States. 
Two tablets, one of each size for the two dosages of PXL065 (15 mg and 7.5 mg, or their respective 
placebo), should be taken at each intake. The patient must strictly follow these indications. 
IMP kit: An IMP kit contains 96 tablets (48 days), corresponding to 6 weeks of treatment with 6 
additional daily doses to cover time-window between visits; and will be dispensed at each 
dispensing visit during the double-blind treatment period. 
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IMP kit numbering: The IMP kit number will identify medication packs.  
6.7 Management of IMP 
The Investigator (or designee) will be responsible for the IMP storage, dispensing, stock inventory, 
accountability and return in the view of destruction of all remaining IMP kits. 
6.7.1 Shipment of IMP 
The depot will store and supply IMPs to the study sites. The shipments will contain the IMP kits 
as agreed upon for the timely completion of the clinical study, once the necessary regulatory 
documents have been received. 
6.7.2 Supply and Receipt of IMP 
Upon receipt of IMP, the Investigator (or designee) will check for accurate delivery, data logger 
temperature records and any damage to the IMP. The Investigator (or designee) will then 
acknowledge receipt via IWRS. The receipt and inventory of IMP in the study site is tracked in 
IWRS. Furthermore, IMP stock at study site must be followed and documented by the Investigator 
(or designee) on a Site Drug Inventory Log throughout the whole duration of the study. 
IMP resupply will be managed automatically through the IWRS.  
6.7.3 Storage of IMP 
The Investigator (or designee) will ensure that all IMPs are stored under recommended storage 
conditions in accordance with applicable US regulatory requirements and the pharmacy manual. 
IMP must be carefully and safely stored at the study site, separately from other drugs, in a locked 
area under the responsibility of the Investigator (or designee). Only the Investigator (or designee) 
will have access to this room.  
The storage condition of IMP will be indicated in the pharmacy manual. 
The Investigators (or designee) are reminded to check temperature daily (e.g. manually) before the 
first dispensation of the day, at least on every working day (i.e. manually) and ensure that 
thermometers are working correctly as required for proper storage of IMP. Any temperature 
excursions should be addressed according to the procedures described in the pharmacy manual.  
Under no circumstances is the Investigator allowed to use IMP in conditions other than described 
in the protocol and the pharmacy manual otherwise the insurance coverage will become null and 
void. 


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It must be ensured at the study site that IMP is not dispensed to a patient with an expiry date prior 
to the date of the patient’s next visit. The IMP expiry date might be extended after the drug stability 
has been re-analyzed.  
Instructions in case of expiration date extension and further details of procedures will be described 
in the pharmacy manual. 
6.7.4 Dispensing, Accountability and Compliance of IMP 
IMP dispensing 
Only the IMP kit number assigned by the IWRS will be dispensed to the patient. The dispensing 
of the IMP will be carefully recorded on the appropriate drug accountability logs provided by 
COVANCE.  
IMP accountability 
The Investigator (or designee) must maintain an accurate record as follows: 
▪ Site Drug Inventory Log recording IMP receipt, dispensing and return by the CRA to the 
depot for destruction. The global stock at study site level must be carefully tracked and 
documented on this log. The Investigator (or designee) should ensure that this stock is 
consistent with the inventory described in IWRS. 
▪ Subject Dispensing Log recording IMP dispensing and IMP return by patient detailed in 
terms of number of tablets.    
For both logs, dates, quantities, dose, batch numbers, expiry dates and initials of the Investigator 
(or designee) must be recorded.  
The supplies, inventory and accurate IMP documentation must be available for monitoring visit, 
audit by the designated representatives of POXEL or inspection by regulatory authorities, upon 
request.  
Any unused IMP must not be discarded or used for any other purpose than the present study. IMP 
that has been dispensed to a patient must not be re-dispensed to the patient neither to a different 
patient. 
IMP compliance 
Compliance will be calculated by the Investigator (or designee) at each visit except Week 3 (V2), 
from Randomization Visit (V1) to End-of-Treatment Visit (V8-EoT), for the double-blind 
treatment period based on the patient diary and IMP kits returned by the patient.  


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The Investigator (or designee) must document the IMP compliance in source document. In case of 
inconsistency between data in the patient diary and IMP returned, the Investigator (or designee) 
should question the patient and the reported compliance will be based on Investigator judgment.  
The compliance will be calculated using the following formula based on the medication returned: 
Number of tablets taken×100 
Theoretical number of tablets to be taken during the period (based on visit days)  
The acceptable compliance will be within 80% - 120% (≥80 % - ≤120%). If at any visit the 
compliance does not fall within this range, unless due to temporary interruption requested by the 
Investigator (e.g. due to AE), it must be reported as a protocol deviation and the Investigator must 
remind the patient to follow the IMP instructions.  
Though no IMP compliance calculation is recorded at Week 3 (V2), the Investigator will still 
ensure that the patient takes IMP according to instructions. 
6.7.5 Return and Destruction of IMP 
The Investigator (or designee) will reconcile tablets returned by the patients with the Subject 
Dispensing Log. The CRA will verify and confirm this reconciliation by checking IMP 
accountability logs and all IMP returns (both unused and used kits). Thereafter, the CRA will place 
IMP kits in sealed containers to be sent to a predefined location designated by POXEL, for interim 
storage. The description of IMP kits returned will be recorded on a form completed by the CRA 
and signed by the Investigator (or designee). The allowed number of sealed container returns by 
the study site is described in the pharmacy manual.  
Upon clinical database hard lock and after green light from POXEL, the company in charge of IMP 
destruction will proceed with IMP kits destruction (both unused and used). They should provide 
certificates of destruction including but not limited to destruction dates, quantities and batch 
numbers. 
6.8 Overdose prevention 
The packaging has been designed to prevent any overdose with a clear indication on the blisters of 
the dose to be taken per day. Moreover, to limit the risk of overdosing while still allowing some 
flexibility in the double-blind treatment period duration, only 1 extra daily dose is available per 
week. In total, 6 extra daily doses are provided between 2 visits (6 weeks). For Week 3 (V2, 3 
weeks after randomization), patients will have to come at the visit with the IMP kit but no other 
kit will be provided. Patients will continue to use the IMP kit provided at Randomization Visit 
(V1) until Week 6 (V3, 6 weeks after randomization). 


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In the event of an overdose, please refer to Section 8.3.9 Overdose. 


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7 Study Procedures 
At each visit, it will be recommended to perform the assessments in the following order: Body 
measurements, ECGs, vital signs, blood samplings and IMP intakes (when applicable). Patients 
must be in a fasting condition for at least 10 hours (during which only water is permitted) prior to 
all study visits to allow for PK assessments and other labs. 
7.1 Screening Period 
Patients will be informed about the study in detail and sign the ICF prior to any study-related 
procedure. Rescreening will be allowed once (see Section 5.3) 
The Screening Period starts from the date of ICF signature. Screening evaluations to determine 
patient eligibility will be conducted within 8 weeks prior to Randomization Visit (V1). The 
screening period can be exceptionally extended after approval of the COVANCE medical monitor 
and the POXEL medical representative, if there is no more than 10 weeks between MRI-PDFF and 
Randomization Visit (V1). 
The following procedures should be performed: 
▪ Obtain ICF signature 
▪ Register the patient in the IWRS to retrieve his/her patient study number 
▪ Dispense patient emergency card 
▪ Review Inclusion and Exclusion criteria 
▪ Obtain demography  
▪ Obtain complete medical history (including liver disease history, diabetes history, history 
of drug abuse, alcohol and tobacco consumption) 
▪ Collect AE 
▪ Obtain complete prior and concomitant medication history of all prescription or 
nonprescription drugs, dietary and herbal supplements taken within 28 days prior to ICF 
signature 
▪ Conduct complete physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Perform standard supine single 12-lead ECG 
▪ Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
Viral infection screen panel 
- 
Standard safety laboratory panel (blood and urine) 


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- 
eGFR calculation using CKD-EPI formula 
- 
Serum pregnancy test (if applicable) 
- 
FPG 
- 
HbA1c 
▪ Perform MRI-PDFF  
▪ If no available historical BMD T-scores, perform standard DXA for postmenopausal 
women only 
▪ Check if a qualifying liver biopsy is available and send the slides to the histopathology 
central laboratory to confirm eligibility 
▪ If no available historical liver biopsy material, perform liver biopsy and send the slides to 
the histopathology central laboratory to confirm eligibility 
The Screening Period can last up to 8 weeks in order to organize procedures and receive results to 
assess patient’s eligibility. The screening period can be exceptionally extended after approval of 
the COVANCE medical monitor and the POXEL medical representative, if there is no more than 
10 weeks between MRI-PDFF and Randomization Visit (V1). 
Procedures should follow the sequence as shown in Figure 2. Screening period examination flow, 
to avoid unnecessary examinations for screen-failure patients.  
7.2 Double-blind Treatment Period 
7.2.1 Visit 1: Randomization Visit (Day 1) 
Randomization Visit (V1) will take place within a maximum of 8 weeks after ICF signature. 
The following procedures will be completed:  
▪ Review Inclusion and Exclusion criteria (including MRI-PDFF and liver biopsy criteria) 
▪ Log on to IWRS to confirm patient eligibility and retrieve IMP kit number assigned by the 
system 
▪ Dispense IMP kit for 6 weeks of treatment 
▪ Dispense patient’s diary 
▪ Dispense SMBG device only for T2DM patients 
▪ Provide AASLD lifestyle guidance  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct complete physical examination 
▪ Complete pitting edema assessment 


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▪ Record vital signs and body measurements 
▪ Perform standard supine single 12-lead ECG 
▪ Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
Standard safety laboratory panel (blood and urine) 
- 
eGFR calculation using CKD-EPI formula 
- 
Urine pregnancy test (if applicable) 
- 
FPG 
- 
HbA1c 
- 
Measured metabolic parameters 
- 
Insulin resistance indexes  
- 
Fibrosis biomarkers 
- 
Biobanking sampling 
▪ Ensure patient takes IMP daily dose on site 
7.2.2 Visit 2: Week 3  
Week 3 (V2) will take place 3 weeks (± 4 days) after Randomization Visit (V1).  
The following procedures will be completed:  
▪ Log on to IWRS to register patient visit date 
▪ Ensure appropriate IMP intakes and review patient diary (no data to record at this visit, no 
new dispensation) 
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct limited physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Ensure patient takes IMP daily dose on site 
7.2.3 Visit 3: Week 6 
Week 6 (V3) will take place 6 weeks (± 4 days) after Randomization Visit (V1).  


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The following procedures will be completed:  
▪ Log on to IWRS to retrieve IMP kit number assigned by the system 
▪ Calculate and record IMP compliance from Randomization Visit (V1) to Week 6 (V3) and 
review corresponding patient diary 
▪ Dispense IMP kit for 6 weeks, according to IWRS, and patient diary 
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct limited physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Ensure patient takes IMP daily dose on site 
7.2.4 Visit 4: Week 12  
Week 12 (V4) will take place 12 weeks (± 6 days) after Randomization Visit (V1). The interval 
between V3 and V4 must not exceed 48 days. 
The following procedures will be completed:  
▪ Log on to IWRS to retrieve IMP kit number assigned by the system 
▪ Calculate and record IMP compliance from previous to current visit and review 
corresponding patient diary 
▪ Dispense IMP kit for 6 weeks, according to IWRS, and patient diary 
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct limited physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
Standard safety laboratory panel (blood and urine) 


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- 
FPG 
- 
HbA1c 
- 
Measured metabolic parameters 
- 
Insulin resistance indexes  
- 
PK sampling (before IMP intake) 
▪ Ensure patient takes IMP daily dose on site 
7.2.5 Visit 5: Week 18  
Week 18 (V5) will take place 18 weeks (± 6 days) after Randomization Visit (V1). The interval 
between V4 and V5 must not exceed 48 days. 
The following procedures will be completed:  
▪ Log on to IWRS to retrieve IMP kit number assigned by the system 
▪ Calculate and record IMP compliance from previous to current visit and review 
corresponding patient diary 
▪ Dispense IMP kit for 6 weeks, according to IWRS, and patient diary 
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct limited physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Perform standard supine single 12-lead ECG 
▪ If applicable, collect urine specimens for urine pregnancy test 
▪ Ensure patient takes IMP daily dose on site 
7.2.6 Visit 6: Week 24 
Week 24 (V6) will take place 24 weeks (± 6 days) after Randomization Visit (V1). The interval 
between V5 and V6 must not exceed 48 days. 
The following procedures will be completed:  
▪ Log on to IWRS to retrieve IMP kit number assigned by the system 


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▪ Calculate and record IMP compliance from previous to current visit and review 
corresponding patient diary 
▪ Dispense IMP kit for 6 weeks, according to IWRS, and patient diary 
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct limited physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
Standard safety laboratory panel (blood and urine) 
- 
FPG 
- 
HbA1c 
- 
Measured metabolic parameters 
- 
Insulin resistance indexes 
- 
PK sampling (before IMP intake) 
▪ Ensure patient takes IMP daily dose on site 
7.2.7 Visit 7: Week 30  
Week 30 (V7) will take place 30 weeks (± 6 days) after Randomization Visit (V1). The interval 
between V6 and V7 must not exceed 48 days. 
The following procedures will be completed:  
▪ Log on to IWRS to retrieve IMP kit number assigned by the system 
▪ Calculate and record IMP compliance from previous to current visit and review 
corresponding patient diary 
▪ Dispense IMP kit for 6 weeks, according to IWRS, and patient diary 
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 


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▪ Conduct limited physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Ensure patient takes IMP daily dose on site 
7.2.8 Visit 8: End-of-Treatment Visit (EoT-Week 36) 
End-of-Treatment Visit (V8-EoT) will take place 36 weeks (± 6 days) after Randomization Visit 
(V1). The interval between V7 and V8-EoT must not exceed 48 days. 
The following procedures will be completed:  
▪ Log on to IWRS to register patient visit date  
▪ Calculate and record IMP compliance from previous to current visit and review 
corresponding patient diary 
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct complete physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Perform standard supine single 12-lead ECG 
▪ Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
Standard safety laboratory panel (blood and urine) 
- 
eGFR calculation using CKD-EPI formula 
- 
FPG 
- 
HbA1c 
- 
Measured metabolic parameters 
- 
Insulin resistance indexes  
- 
Fibrosis biomarkers 
- 
Biobanking sampling 
- 
PK sampling (before IMP intake and between 1h and 4h after IMP intake). The 
morning meal time after IMP intake should be collected. 


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▪ Ensure patient takes the last IMP daily dose on site, in accordance with PK sampling schedule 
▪ Perform MRI-PDFF, before (within 8 days) or on the day of Week 36 (V8-EoT) 
▪ For postmenopausal women only, perform standard DXA testing, before (within 8 days) or 
on the day of Week 36 (V8-EoT) 
▪ Perform liver biopsy, before (within 8 days) or on the day of Week 36 (V8-EoT),  
7.3 Follow-up Period, Visit 9: End-of-Study Visit (EoS) 
End-of-Study Visit (V9-EoS) will take place 2 weeks (± 3 days) after End-of-Treatment Visit (V8-
EoT). 
The following procedures will be completed:  
▪ Log on to IWRS to register patient visit date  
▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct complete physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Perform standard supine single 12-lead ECG 
▪ Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
Standard safety laboratory panel (blood and urine) 
- 
Serum pregnancy test (if applicable) 
- 
FPG 
▪ Refer patient to his/her previous physician for the pursuit of his/her routine medical care 
7.4 Early Termination Visit (ET) 
The following procedures will be completed during a visit within 8 days after the IMP 
discontinuation: 
▪ Log on to IWRS to register patient withdrawal date  
▪ Calculate and record IMP compliance from previous to current visit and review 
corresponding patient diary 


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▪ For T2DM patients, review SMBG measurements (or CGM recording) according to the 
Investigator (or designee) recommendation 
▪ Record AASLD lifestyle guidance compliance as reported by patient  
▪ Collect AE 
▪ Collect concomitant medications 
▪ Conduct complete physical examination 
▪ Complete pitting edema assessment 
▪ Record vital signs and body measurements 
▪ Perform standard supine single 12-lead ECG 
▪ Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
Standard safety laboratory panel (blood and urine) 
- 
Serum pregnancy test (if applicable) 
- 
FPG 
- 
HbA1c 
- 
Measured metabolic parameters 
- 
Insulin resistance indexes  
▪ Perform MRI-PDFF, before or on the day of Early Termination Visit, if study withdrawal 
occurs at or after Week 12 (V4) and only when the IMP was discontinued less than 14 days 
before the ET Visit 
▪ Refer patient to his/her previous physician for the pursuit of his/her routine medical care 


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8 Study Assessments 
Every effort should be made to ensure that protocol-required tests and procedures are completed 
as described.  
8.1 Blood Volume 
The total blood sampling volume for individual patients in this study will be described in the central 
laboratory manual.  
Additional blood samples may be taken for safety assessments at times specified by the 
Investigator (in case of safety issue for example) with the agreement of POXEL Medical 
Representative. 
8.2 Efficacy Assessment 
8.2.1 Liver fat mass content assessed by MRI-PDFF – Central imaging core laboratory 
The primary evaluation of efficacy will be based on MRI-PDFF. This primary endpoint will be the 
relative change in the percentage of LFC (assessed by MRI-PDFF) from baseline to Week 36 (V8-
EoT). 
MRI-PDFF is deemed a non-invasive, quantitative, and accurate measure of LFC to identify the 
study population and assess the treatment response in subjects with NASH. MRI-PDFF will be 
performed using a standardized imaging protocol and the results will be analyzed by a central 
reader. The central reader for this study will train the local imaging centers for this study and will 
provide imaging manual. 
MRI-PDFF reports for Screening Period received by the central core imaging laboratory will be 
source data to confirm eligibility based on Inclusion criterion #6.  
MRI-PDFF will be performed as planned in Table 1. MRI-PDFF must be performed only after 
receiving confirmation of eligibility on history, clinical examination and labs during Screening 
Period. MRI-PDFF must also be performed before (within 8 days) or on the day on the day of 
Week 36 (V8-EoT). MRI-PDFF must also be performed at Early termination Visit (ET) only for 
patients who withdraw from the study at or after Week 12 (V4) and only when the IMP was 
discontinued less than 14 days before the ET Visit. 
MRI-PDFF will be exclusively used for assessment of LFC. The image acquisition technique and 
programmable sequences used for MRI-PDFF in the study will restrict the obtainable diagnostic 
information to liver fat quantity and will not support its use for other clinical purposes. 


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Please refer to central imaging core laboratory manual for further details. 
8.2.2 Liver biopsy 
All patients must have a qualifying liver biopsy within 6 months prior to Randomization Visit 
(V1). If no available liver biopsy at screening, a liver biopsy must be performed during Screening 
Period (see Inclusion criterion #7). All patients will have a liver biopsy at Week 36 (V8-EoT). 
Histopathological examination of the liver biopsy specimen by a central reader will confirm the 
diagnosis and provide the staging for the disease. Scores for total NAS, steatosis, ballooning, 
lobular inflammation, and portal inflammation, as well as fibrosis stage will be evaluated. 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the 
biopsy, and the risks to the patient should not outweigh the potential benefits. 
The platelet count and INR (or additional blood test) of the patient may be checked at a local 
clinical laboratory prior to the percutaneous liver biopsy according to local guidelines. If the 
conditions are not all respected, a safer option would be to perform the liver biopsy by trans-jugular 
route, when available. 
Anticoagulants should be suspended around the time of liver biopsies to reduce hemorrhagic risk, 
according to local practices.  
Sedation is recommended to be given for percutaneous liver biopsy and should be given with 
caution in liver disease. 
The recommended biopsy procedure is as following: 
- 
Needle core biopsy 
- 
16 or lower gauge needle 
- 
Tissue core ≥ 2 cm long (≥ 10 portal tracts) represents optimal biopsy length 
- 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for the 
qualifying biopsy, a left lobe biopsy should be used for future biopsy at Week 36 
(V8-EoT). 
If the liver biopsy fragment is too small or of bad quality, precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested of 
the site.  
 
It is recommended that the patient should remain in the hospital consistent with the standard of 
care of that institution after the percutaneous biopsy. 
Liver biopsy report for Screening Period received by the histopathology central laboratory will be 
source data to confirm eligibility based on Inclusion criterion #7.  


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Liver biopsies will be performed as planned in Table 1, please refer to Liver biopsy manual for 
further details. 
In addition to the central reading, histology of the liver biopsy specimen will be assessed by 
automated digital images analysis by Biocellvia. 
Results from central assessment of liver biopsy should be exclusively used for the purpose of 
this clinical trial and should not be used for the purpose of patient standard of care. 
8.2.3 Other Efficacy Parameters 
The following parameters will be also determined at various timepoints to further assess efficacy:  
• Liver enzymes: ALT, AST, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) 
• Measured metabolic parameters: fasting plasma glucose (FPG), HbA1c, serum insulin, C-
peptide, adiponectin, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-
density lipoprotein cholesterol (HDL-c), triglycerides and free fatty acids (FFA) 
• Insulin resistance indexes: Homeostasis model assessment of insulin resistance (HOMA-IR), 
Quantitative insulin sensitivity check index (QUICKI), Homeostasis model assessment of β-
cell function (HOMA-β) and Adipose tissue insulin resistance (Adipo-IR) 
HOMA-IR, QUICKI, and HOMA-ß will be calculated using the fasting C-peptide and FPG values 
at visits specified in Table 1. Adipo-IR will be calculated using the fasting insulin and FFA values 
at visits specified in Table 1. 
The HOMA-IR is calculated as [25]:  
Serum C-peptide (ng/mL) × FPG (mg/dL) / 405 
The QUICKI is calculated as [26]:  
1 / (log (FPG (mg/dL)) ＋ log (C-peptide (ng/mL))) 
The HOMA-ß is calculated as [25]:  
(Serum C-peptide (ng/mL) × 360) / (FPG (mg/dL) – 63) 
The Adipo-IR is calculated as [27]: 
Fasting serum FFA (mmol/L) x Fasting serum insulin (µIU/mL) 
• Biomarker of inflammation: hsCRP (assessed as part of Section 8.3.6.1 Standard Safety 
Laboratory Panel (Blood and Urine) 
• Biomarkers of fibrosis: N-terminal type III collagen propeptide (pro-C3), NAFLD Fibrosis 
score (NFS), Fibrosis 4 (FIB-4) score and Enhanced Liver Fibrosis (ELF) score 
The NFS is based on a combination of clinical and laboratory measurements (i.e. age, glycemia, 
BMI, platelet, albumin and AST/ALT ratio). This score has been validated in a large cohort of 
patients with biopsy-proven NAFLD (> 700 patients) [28].  
NFS is calculated as [28]:  
Corporate confidential information 


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1.675 + 0.037 x age (years) + 0.094 x BMI (kg/m²) + 1.13 x Impaired Fasting Glucose or 
Diabetes (yes =1; no=0) + 0.99 x AST/ALT ratio – 0.013 x platelet (109/L) – 0.66 x 
albumin (g/dL)  
The FIB-4 score is based on a combination of clinical and laboratory (i.e. age, platelets, AST, 
ALT). This score has been created and validated in different cohorts of patients [29, 30].  
FIB-4 score is calculated as [29]:    
(Age (years) x AST (IU/L))/ (platelet (109/L) x √(ALT (IU/L))) 
ELF score is an extracellular matrix marker set consisting of tissue inhibitor of metalloproteinases 
1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) 
showing good correlations with fibrosis stages in chronic liver disease [31]. 
8.3 Safety 
8.3.1 Physical Examination 
Physical examination must be conducted by the Investigator.  
A complete physical examination will include head, ears, eyes, nose, mouth, skin, cardiovascular 
and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. 
The limited physical examination will be focused on general appearance, the cardiovascular system 
as well as towards patient reported symptoms.  
Any new clinically significant abnormal findings or worsening of conditions previously recorded 
as medical history should be documented in the source documents and reported in the eCRF as AE. 
8.3.2 Pitting edema assessment 
At each visit, an assessment of pitting edema will be performed. 
The pitting edema will be assessed following this procedure:  
- 
Place your index finger over the patient’s tibia, 10 cm above the lateral malleolus 
- 
Exert pressure for 5 seconds 
- 
Any depression that does not resume its original contour almost immediately is a 
sign of pitting edema 
 
If the presence of pitting edema is confirmed, the following scale should be used to grade it. 
Table 3. Pitting edema scale 
Grade 
Physical Characteristics 
1+ 
No visible change in shape of the extremity 


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Pitting ≤ 2 mm 
Pit disappears rapidly 
2+ 
No marked change in the shape of the extremity 
2 mm < pitting ≤ 5 mm 
Pit usually disappears in 10-15 seconds 
3+ 
Noticeable swollen extremity 
5 mm < pitting ≤ 10 mm 
Pit may persist for about a minute 
4+ 
Very swollen and distorted extremity 
Very deep pit > 10 mm 
Pit may persist 2 – 5 minutes 
 
The presence or absence of edema will be recorded at each visit (Yes/No). If there is a pitting 
edema, a grade will be recorded for the edema according to the pitting edema scale. 
8.3.3 Vital Signs and Body Measurements 
Body measurements will be taken, before vital signs measurement. Weight should be measured 
with a scale having an appropriate resolution.  The scale should be placed on a stable and flat 
surface. Patients are to be weighed in similar attire (only light clothing) and without shoes at each 
visit. Height will be recorded only during Screening Period. Waist and hip circumferences will be 
measured at each visit as planned in Table 1. All these data have to be recorded in the source 
documents and reported in the eCRF 
One HR measurement will be taken after the patient has been resting in supine or sitting position 
for at least 10 minutes and before blood samples are taken. The HR measurement will be followed 
by 3 BP measurements, using a standardized cuff adapted to the size of the patient’s arm. BP 
readings will be taken with patients comfortably in a supine or sitting position with the arms raised 
to the level of the heart and in a supported position. All readings should be recorded as accurately 
as possible and the same BP device and the same patient’s arm (preferentially the left arm) should 
be used for all assessments for a given patient. 
All 3 readings have to be recorded in the source documents and reported in the eCRF. For analysis, 
the average of the 3 BP readings will be used. 
Any new clinically significant abnormal findings or worsening of conditions previously recorded 
as medical history should be documented in the source documents and reported in the eCRF as AE. 
8.3.4 Patient Diary 
Patient diary will be dispensed according to Table 1.  


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Patients will be asked to report their IMP intakes (date + dose + time). Any new AE or concomitant 
medications should be reported by the patient on the diary.  
At each visit, the Investigator will review the patient diary dispensed at the previous visit. The 
review will be documented in the source documents and the Investigator will have to sign and date 
the previous patient diary and keep it in the patient file. At each visit, except Week 3 (V2) where 
no IMP/patient diary dispensation occurs, the appropriate data have to be reported in the eCRF.  
8.3.5 Supine 12-Lead electrocardiogram (ECG) 
A 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) will be performed at the visits shown in the 
Visit Schedule Chart in Table 1 after the patient has been lying down resting for at least 10 minutes. 
Standard 12-lead digital ECGs will be recorded as single measurement. The ECG printout or 
electronic record will be evaluated by the Investigator and reported as “Normal” or “Abnormal” in 
the source documents and in the eCRF. If the ECG is evaluated as “Abnormal”, the Investigator 
should document in the source documents as well as in the eCRF, the specific abnormality and if 
this abnormality is “clinically significant” or “not clinically significant”. ECG printouts or 
electronic record will include date, time, patient number, and date/signature of the Investigator 
who reviewed the ECG. The ECG printouts or electronic records will be kept in the patient file. 
Any new clinically significant findings or worsening of abnormalities previously recorded as 
Medical History on the ECG will be reported as AEs, and followed up and/or treated locally until 
the AE has resolved or the condition has stabilized.  
8.3.6 Laboratory Assessments 
All laboratory measurements will be performed by a central laboratory using samples collected at 
the visits shown in the Visit Schedule Chart in Table 1. However, if judged necessary for the safety 
of the patients, the Investigator or POXEL may request unscheduled central laboratory 
assessments.  
Blood samples will be collected, handled and stored according to the instructions described in the 
central laboratory manual. 
A list of normal reference ranges will be provided by the central laboratory to POXEL and the 
Investigators before the study start. Any change in the normal reference ranges during the study 
will be forwarded by the central laboratory to POXEL and the Investigators, who will have to keep 
it in the Trial Master File (TMF) and respectively, in the Investigator Site File (ISF).   
Central laboratory reports must be reviewed by the Investigator as soon as received. Each 
parameter must be assessed by the Investigator and the clinical significance of the abnormal 


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parameters must be documented. To confirm the review, the Investigator will have to sign and date 
the report and keep it in the patient file. 
Any new clinically significant findings or worsening of laboratory abnormalities previously 
recorded as Medical History will be reported as AEs, and followed up and/or treated locally until 
the AE has resolved or the condition has stabilized. The CTCAE criteria, version 5.0, will be used 
to determine severity. 
The following panel will be evaluated. 
8.3.6.1 Standard Safety Laboratory Panel (Blood and Urine) 
Hematology 
Biochemistry 
Urinalysis 
Erythrocytes 
Hemoglobin 
Hematocrit 
Red Blood Cell Morphology 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Leucocytes 
Differential blood count 
(lymphocytes, monocytes, 
eosinophils, basophils, 
neutrophils/ absolute values 
and percentages should be 
given) 
Thrombocytes 
 
Blood Urea Nitrogen   
Creatinine 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
Inorganic phosphate 
Total protein  
Albumin 
Uric acid 
Creatine phosphokinase 
AST 
ALT 
GGT 
TBL 
ALP 
hsCRP 
TSH (during Screening Period only) 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Nitrites 
Urobilinogen 
Blood 
Leucocytes 
If the dipstick result is 
abnormal: microscopic 
examination of the 
sediment for blood cells, 
cylinders, etc. 
Coagulation 
aPTT 
PT 
INR 
8.3.6.2 Viral Infection Screen Panel 
Hepatitis screening 
HIV screening 
HBsAg 
Anti-HIV 1 and 2 


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anti-HCV, and in case of positive result, reflex test of 
HCV circulating RNA 
8.3.6.3 eGFR  
eGFR will be calculated using the CKD-EPI formula, as follows [32]:  
141 x min(Scr/κ,1)α x max(Scr/κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] 
 
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. 
8.3.6.4 Serum and Urine Pregnancy Tests 
For female patients of child-bearing potential only, a serum β-HCG test or a urine pregnancy test 
will be performed at the visits shown in the Visit Schedule Chart in Table 1. 
Additional serum pregnancy testing should be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
All pregnancy tests performed should be recorded in the source documents and reported in the 
eCRF.  
If a pregnancy occurs during the study, refer to Section 8.3.10 Pregnancy and In Utero Drug 
Exposure. 
8.3.7 Bone mineral density 
For postmenopausal women only, a standard DXA testing will be performed at the visits shown in 
the Visit Schedule Chart in Table 1. 
If possible, all DXA testing for a given patient (historical testing or testing performed during 
Screening Period and Week 36 (V8-EoT)) should be performed at the same facility and using the 
same procedure.  
DXA reports must be reviewed by the Investigator as soon as received. To confirm the review, the 
Investigator will need to sign and date the report and retain it in the patient file. 
Any new clinically significant abnormal findings or worsening of conditions previously recorded 
in the medical history should be documented in the source documents and reported in the eCRF as 
an AE. 


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8.3.8 Adverse Events  
Comprehensive assessment of AE experienced by the patient will be performed throughout the 
course of the study, from the time of the patient’s ICF signature till the EoS (V9).  
It is of the utmost importance that all staff involved in the study is familiar with the content 
of this section. The Investigator is responsible for ensuring this. 
8.3.8.1 Adverse Event Definitions 
8.3.8.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal, whether or not considered related to the medicinal product. 
The official definition also extends to AEs occurring under placebo or in a reference group 
receiving drug or non-drug therapy. Because of regulatory requirements, events occurring during 
drug-free and pre- and post-treatment periods should also be designated as AEs. 
Therefore, safety surveillance applies to the time when the patient is included into the study (date 
of ICF signature) until the End-of-Study Visit (V9-EoS) performed two weeks after the End-of-
Treatment Visit (V8-EoT). 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. 
The Investigator is required to grade the severity/intensity of each AE according to CTCAE:  
- 
CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated  
- 
CTCAE Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL) 
- 
CTCAE Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL 
- 
CTCAE Grade 4 (Life threatening): life-threatening consequences; urgent intervention 
indicated 


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- 
CTCAE Grade 5 (Death): death related to AE 
8.3.8.1.2 Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered ADR. 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility e.g., the relationship cannot be 
ruled out.  
The following judgments of the causality to IMP or study procedures will be used: 
- 
Unrelated: IMP cannot be reasonably suspected, a reasonable explanation must be 
given 
- 
Related: 
IMP 
can 
be 
reasonably 
suspected. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the IMP. 
8.3.8.1.3 Serious Adverse Event (SAE) 
A SAE is an AE occurring during any study phase (i.e., Screening, Treatment, Follow-up), that 
fulfils one or more of the following criteria: 
▪ Results in death 
▪ Is immediately life-threatening 
NOTE: The term “life-threatening” in this definition refers to an event in which the patient 
is at risk of death at the time of the event; it does not refer to an event that hypothetically 
might cause death if it were more severe  
▪ Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled or 
planned before signing of ICF. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AE and assessed for 
seriousness. 
Admission to the hospital for social or situational reasons (e.g. no place to stay, live too far 
away to come for hospital visits) will not be considered inpatient hospitalizations.  
▪ Results in persistent or significant disability/incapacity 
▪ Is a congenital anomaly/birth defect 
▪ Is otherwise considered as medically important 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered as SAE when, based upon appropriate medical judgment, they may jeopardize 


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the patient or may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such events include: 
▪ allergic bronchospasm requiring intensive treatment in an emergency room or at home 
▪ angioedema not severe enough to require intubation but requiring intravenous hydrocortisone 
treatment 
▪ blood dyscrasias (e.g. neutropenia or anemia requiring blood transfusion, or convulsions that 
do not result in inpatient hospitalization) 
▪ development of drug dependency or drug abuse 
Events that do not meet the definition of an SAE 
Elective hospitalizations to simplify study treatment or study procedures are not considered as 
SAE. However, all events leading to unplanned hospitalizations or unplanned prolongation of an 
elective hospitalization (e.g. undesirable effects of any administered treatment) must be 
documented and reported as SAE. 
Events not to be considered as AE/SAE 
Medical conditions present prior to ICF signature that do not worsen in severity or frequency 
during the study are defined as baseline medical conditions and are NOT to be considered as AEs. 
Abnormal laboratory findings and other abnormal investigational findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG tracing) 
should not be reported as AE unless they are associated with clinical signs and symptoms, lead to 
IMP discontinuation or are considered otherwise medically important by the Investigator. If an 
abnormality fulfills these criteria, the identified medical condition (e.g. anemia, pancreatitis) must 
be reported as the AE rather than the abnormal value itself. 
NOTE: To ensure no confusion or misunderstanding of the difference between the terms "serious" 
and "severe," which are not synonymous, the following note of clarification is provided: The term 
"severe" is often used to describe the intensity (severity) of a specific event (as in mild, moderate, 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This is not the same as "serious," which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a 
patient's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 


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8.3.8.1.4 Adverse Event of Special Interest (AESI) 
An AE of Special Interest (AESI, serious or non-serious) is one of scientific and/or medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the Sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial Sponsor to other parties (e.g., regulators) might also be 
warranted.  
Even if non-serious, AESI are managed with the same process than SAE: 
- 
notification to the Sponsor within 24h following investigator awareness 
- 
case to be created and processed in the safety database (including narrative writing) by 
Safety Provider. 
In this study, the following AEs are considered as AESI: 
• Heart failure. In case of any event of heart failure, whatever the cause, patients should 
be referred to a cardiology specialist. 
• Pitting edema. In case of occurrence of pitting edema with presence of other suspected 
signs and/or symptoms of heart failure, patients should be referred to a cardiology 
specialist.  
• Bladder cancer 
• Bone fracture 
• Drug-induced liver injury (DILI) 
 
Below are specific recommendations for the management of elevated liver transaminases 
and/ or total bilirubin to detect and monitor a possible DILI, following FDA guidelines: 
▪ For patients with normal liver transaminases and total bilirubin at baseline 
(Randomization Visit (V1)):  
If patients with normal baseline (Randomization Visit (V1)) liver indices develop new elevations 
of AST or ALT >3  ULN or TBL >2  ULN values during the study, repeat testing should be 
performed within 48 to 72 hours. Investigators should also ask the patient if he/she has symptoms. 
If there are persistent elevations (ALT or AST >3  ULN or TBL >2  ULN) upon repeat testing, 
then close observation (as described below) should be implemented and discontinuation of drug 
should be considered. 
Drug should be discontinued, and the patient followed until resolution of symptoms or signs in the 
following situations:  
- 
ALT or AST >8  ULN 
- 
ALT or AST >5  ULN for more than 2 weeks. 


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- 
ALT or AST >3  ULN and (TBL >2  ULN or INR >1.5, except for patients on 
anticoagulant treatment) 
- 
ALT or AST >3  ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
▪ For patients with elevations in liver transaminases or total bilirubin at baseline 
(Randomization Visit (V1)):  
If patients with abnormal baseline liver indices develop elevations of AST or ALT >2  baseline 
or TBL >2  baseline values during the study, repeat testing should be performed within 48 to 72 
hours. Investigators should also ask to the patient if he/she has symptoms. 
If there are persistent elevations (ALT or AST >2  baseline or TBL >2  baseline values) upon 
repeat testing, then close observation (as described below) should be implemented and 
discontinuation of drug should be considered. 
Drug should be discontinued, and the patient followed until resolution of symptoms or signs in the 
following situations:  
- 
If baseline measurements were <2  ULN, discontinue if ALT or AST increases to >5  
baseline measurements.  
- 
If baseline measurements 2  ULN (≤200 IU/L as per eligibility requirements), 
discontinue if ALT or AST increases to >3  baseline measurements. 
- 
If baseline measurements 5  ULN (≤200 IU/L as per eligibility requirements), 
discontinue if ALT or AST increases to >2  baseline measurements. 
- 
Discontinue if ALT or AST increase >2  baseline measurements AND the increase is 
accompanied by a concomitant increase in TBL to >2  baseline measurements or the 
INR concomitantly increases by >0.2, except for patients on anticoagulant treatment. 
- 
For any patients who present with a constellation of syndromes indicative of liver disease 
as per the Investigator’s overall assessment (i.e. fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia [>5%]). 
▪ Close observation for suspected DILI includes the following:  
- 
Repeating liver enzyme (ALT, AST, and ALP) and TBL tests 2 or 3 times weekly. The 
frequency of repeat testing can decrease to once a week or less if abnormalities stabilize 
or the IMP has been discontinued and the patient is asymptomatic. 
- 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
- 
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
- 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 
- 
Obtaining a history of exposure to environmental chemical agents. 


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- 
Obtaining additional tests to evaluate liver function, as appropriate (e.g. INR, direct 
bilirubin). 
- 
Considering gastroenterology or hepatology consultations. 
Only confirmed DILI should be reported as AESI. 
8.3.8.2 Definition of the AE Reporting Period 
The AE reporting period for safety surveillance begins when the patient is included into the study 
(ICF signature date) and continues through the end of the study’s post-treatment follow-up period, 
defined as EoS (V9). AEs will be recorded on an ongoing basis in EDC. In case any AE occurs, 
the Investigator will follow up the patient within the AE reporting period until the event has 
resolved or the condition has stabilized. For SAEs, regardless of their relatedness to the IMP, the 
follow-up period might be extended, see Section 8.3.8.5.  
All SAEs that the Investigator considers related to IMP occurring after the post-treatment follow-
up period (V9-EoS, or Early Termination Visit) must be reported to POXEL as well as to Safety 
Provider UBC (see contact details in Section 14. Annex 2. Serious Adverse Event Contact 
Information). 
Only events that occur after the first intake of IMP of the double-blind treatment period 
(Randomization Visit (V1)) or if they were present prior to the first intake of IMP of the double-
blind treatment period and increased in severity or relationship to IMP after the first intake of IMP 
of the double-blind treatment period will be considered as treatment-emergent AEs (TEAEs).  
8.3.8.3 Methods of Recording and Assessing Adverse Events 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined above in Section 8.3.8.2) will be reported on an ongoing basis in the appropriate 
section of the eCRF.  
The following aspects must be recorded for each event in the source documents and in the eCRF 
for AE:  
▪ A description of the AE in medical terms, not as reported by patients (AE verbatim) 
▪ The date and time of onset (start date and time) 
▪ The date and time of recovery (stop date and time) 
▪ The severity grade (CTCAE Grade 1-5)  
▪ Seriousness: yes or no 
▪ The causal relationship to IMP as assessed by the Investigator; the decisive factor in the 
documentation is the temporal relation between the AE and the IMP. The following 
judgments of the causality to IMP or study procedures are to be used: 


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- 
Unrelated: IMP cannot be reasonably suspected, a reasonable explanation must be 
given 
- 
Related: 
IMP 
can 
be 
reasonably 
suspected. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the IMP 
▪ Action taken on IMP (no change, temporary interruption, permanent discontinuation, not 
applicable) 
▪ Other actions (none, corrective treatment, hospitalization or prolongation of hospitalization, 
other) 
▪ The outcome and date of outcome according to the following definitions: 
- 
Recovered/resolved (AE disappeared) 
- 
Recovering/resolving (patient is recovering)  
- 
Not recovered/not resolved (AE remains without signs of improvement) 
- 
Recovered/resolved with sequelae 
- 
Fatal 
- 
Unknown (only applicable if patient has been lost to follow-up) 
The following aspects must be recorded in the source documents and in the eCRF for SAE: 
▪ All the above information listed for AEs 
▪ Additional information: 
- 
A SAE medical term 
- 
A description of the SAE in medical terms, not as reported by patient; only the 
term(s) that fulfills the seriousness criteria should be listed (including sequence of 
events, symptoms, diagnosis, treatment and any other relevant information) 
- 
The seriousness criteria (as described in Section 8.3.8.1.3) 
If a patient experienced the same AE several times during his/her participation in the study, then 
this AE must be documented and assessed as a new AE each time. 
Each AE will be classified using the version of the Medical Dictionary for Regulatory Activities 
(MedDRA®) available at the start of the study. 
8.3.8.4 Sponsor immediate notification and Regulatory Reporting  
8.3.8.4.1 Sponsor Immediate Notification 
The Investigator must report immediately (within 24 hours of the Investigator’s awareness) to 
POXEL as well as to Safety Provider (UBC) all SAE/AESI/Overdose/Pregnancy occurring from 


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the date of ICF signature to the End-of-study Visit (V9-EoS) or to the last study visit performed in 
case of premature discontinuation.  
For SAE, AESI, overdose and pregnancy, the study site must complete the corresponding eCRF 
page with as much available information within 24 hours of knowledge of the event. 
Manual Back-Up Reporting Procedures 
This study is utilizing an Electronic Data Capture (EDC) system for data entry. In the event that 
the EDC system is unavailable for electronic reporting, the manual back-up reporting procedures 
below should be followed: 
▪ Complete a SAE or Pregnancy/Overdose Form 
▪ Email the form to POXEL as well as to Safety Provider UBC (fax can be used as second 
option), contact details in Section 14. Annex 2. Serious Adverse Event Contact Information. 
When the EDC system becomes available, the EDC system should be updated with all previously 
reported information. 
8.3.8.4.2 Reporting to Regulatory Authorities (Expedited Reporting), Investigators and 
Independent Ethics Committees/Institutional Review Boards 
SUSARs and other safety information requiring expedited reporting will be reported to 
Investigators, Ethics Committees as well as Competent Authorities in agreement with applicable 
guidelines and US regulations. 
In accordance with ICH GCP guidelines, POXEL/COVANCE will inform the Investigator of 
“findings that could adversely affect the safety of patients, impact the conduct of the study or alter 
the IRB/EC’s approval/favorable opinion to continue the study.” In particular, and in line with 
respective US regulations, POXEL will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (SUSARs). The 
Investigator should place copies of these safety reports in the ISF. National regulations with regard 
to safety report notifications to Investigators will be considered. 
8.3.8.5 Monitoring of Patients with Adverse Event 
Any AE that occurs during the course of a clinical trial and is possibly related to IMP must be 
monitored and followed up until the event is resolved or stabilized, unless patients are documented 
as “lost to follow-up”. Reasonable attempts to obtain this information must be made and 
documented. It is the responsibility of the Investigator to ensure that any necessary additional 
therapeutic measures and follow-up procedures are performed. 


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For SAEs, regardless of their relatedness to the IMP, follow-up of the outcome might be extended 
until the clinical database hard lock if not resolved or stabilized before, in agreement by the 
Investigator, POXEL Medical Representative and COVANCE Medical Monitor. 
8.3.9 Overdose 
Preclinical data showed that daily administration of PXL065 was well tolerated in the dog for 13 
weeks at doses up to 15 mg/kg/day. 
Clinical data available so far with PXL065 showed a good safety and tolerability profile in healthy 
subjects after single and repeated administrations of PXL065 up to 30 mg QD. The dose of 30 mg 
QD is the maximal dose tested in humans. 
Overdose is defined as any dose greater than the daily dose prescribed, equivalent to the intake of 
3 or more capsules per day, in any of the cohorts.  
Any suspicion of overdose, whether or not associated with a AE must be reported to POXEL and 
Safety Provider (UBC) immediately (within 24 hours of the Investigator’s awareness) (contact 
details in Section 14. Annex 2. Serious Adverse Event Contact Information). Details of overdose 
and any AE associated with this will be reported by the Investigator in the eCRF system also.  
These events will be managed, followed up and reported as any other SAE. 
No specific antidote is currently available for PXL065 and only symptomatic therapy is possible. 
Conclusion on overdose will be included in the final clinical study report. 
8.3.10 Pregnancy and In Utero Drug Exposure  
All pregnancies with an estimated conception date after the date of ICF signature until the End-of-
Study Visit (V9-EoS) must be reported to POXEL and Safety Provider (UBC) immediately (within 
24 hours of the Investigator’s awareness) (contact details in Section 14. Annex 2. Serious Adverse 
Event Contact Information).  
In case of pregnancy, patients will discontinue the IMP and withdraw from the study. The 
Investigator must actively follow up, document and report on the outcome of these pregnancies. 
Any abnormal outcome: 
1. Spontaneous abortion includes abortion or missed abortion 
2. Induced abortion 
3. Stillbirth 
4. Death of newborn 


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5. Congenital anomaly 
6. Delivery within appropriate pregnancy terms, but congenital abnormalities in the newborn  
should be reported first to Safety Provider (UBC) with 24 hours of the Investigator’s awareness.  
Newborns should be followed up for at least 8 weeks for any potential congenital anomalies. 
Pregnancy and pregnancy outcome of female partners of male trial patients need to be reported in 
the same way after obtaining written consent from the pregnant partner.  
8.3.11 Special Recommendations for Hypoglycemia  
Patients with T2DM should be reminded of symptoms of hypoglycemia i.e. increased sweating, 
palpitation, trembling, shaky feeling, headaches, anxiety, poor concentration, confusion, dizziness, 
irritability, hunger or pale skin.  
Patients with T2DM should check their glucose levels, using SMBG devices at least twice a week 
(unless CGM is used). The investigator will be responsible to ensure the clinical assessment of 
hypoglycemic events. The investigator might decide to reduce the dose and / or to discontinue the 
background glucose lowering therapy in order to reduce recurrence of hypoglycemia. 
Patients are requested to immediately perform a finger stick glucose measurement with the SMBG 
device provided for this study (unless CGM is used) if any symptoms occur that may be related to 
hypoglycemia and to avoid any delay in treating these symptoms. After the recovery of the 
symptoms, patients may report all the symptoms, date and time, dietary intake states, time of the 
recovery in the patient diary as well as blood glucose values if available. Only symptoms and / or 
plasma glucose concentration values deemed by the Investigator to meet the definition of 
hypoglycemia should be reported in the eCRF. Hypoglycemia will be reported as recommended 
by the FDA guidance [33]: 
- 
Hypoglycemia evidenced only by symptoms without blood glucose measurement will be 
reported as probable symptomatic hypoglycemia. 
- 
Hypoglycemia evidenced only by plasma glucose concentration of less than 70 mg/dL 
(3.9 mmol/L) will be reported as asymptomatic hypoglycemia. In case of asymptomatic 
hypoglycemia observed on SMBG, it should be reported using the verbatim of 
asymptomatic hypoglycemia (with the glucose value) reported from SMBG. 
- 
Hypoglycemia evidenced both by typical symptoms and plasma glucose concentration 
of less than 70 mg/dL (3.9 mmol/L) will be reported as documented symptomatic 
hypoglycemia. 
- 
Hypoglycemia requiring assistance of another person to administer carbohydrate or 
glucagon or other procedure will be reported as severe hypoglycemia. 


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Therefore, there might be values coming from the SMBG device (or CGM) under the threshold for 
hypoglycemia without any associated symptoms. In such case, it is important for the Investigator 
to judge whether this has to be reported or not as an AE of hypoglycemia, depending on the clinical 
context and the overall glycemic control. 
In case of hypoglycemia, the Investigator should query the patient to understand the clinical context 
that may have explained a low glucose value (exercise, missing meal, timing of IMP intake and 
SMBG…). 
8.4 Pharmacokinetics  
During this study, pre-dose and post-dose plasma concentration of PXL065 will be assessed as 
indicated in Table 1.  
The assays of PXL065 will only be carried out in patients who have received the active drugs. 
Thus, the laboratory responsible for PK bioanalysis will be provided with a randomization list. 
Under no circumstances will this list be brought to the attention of the Investigators, or to the 
project team members. 
Pre-dose and post-dose plasma samples for PK bioanalysis will be collected at study sites and 
forwarded to Central laboratory. For the determination of PXL065, blood samples will be taken by 
an indwelling catheter or direct venipuncture, as appropriate. 
Please refer to the central laboratory manual for further explanations. 
8.5 Biobanking Samples for Post-hoc Assessments 
Blood (total, plasma and serum) samples for supplementary tests will be collected at visits shown 
in Table 1 to enable post-hoc testing of any additional efficacy and safety parameters or any 
potential biomarkers related to liver, cardiovascular diseases or metabolic diseases in relation with 
the drug target. The samples will be stored until further use. All the biobanking samples will be 
destroyed within 2 years after the final study report is issued. 
No genetic testing will be performed. 
Please refer to the central laboratory manual for further explanations. 


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9 Statistical methods 
Statistical analysis will be performed by COVANCE under the supervision of POXEL. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Full details of analyses will be provided in the SAP, which will be finalized prior to the 
unblinding and locking of the clinical database. 
9.1 General considerations 
In general, summary tabulations will be presented by treatment arm and will display the number 
of patients/observations, mean, standard deviation, median, 25% and 75% percentiles, minimum, 
and maximum for continuous variables, and the number and percent per category for categorical 
data.   
Unless stated otherwise, tests will be performed at the nominal alpha two-sided level of 0.05 along 
with 95% two-sided confidence intervals.  
Given the early stage of development (i.e. a Phase 2 trial for internal decision), no adjustment for 
multiplicity will be considered. Hence, pairwise comparisons between PXL065 doses 
(PXL065 doses of 7.5 mg QD, 15 mg QD and 22.5 mg QD) vs placebo and pairwise comparisons 
between PXL065 active doses will be tested at the two-sided nominal level of significance of 0.05. 
The primary endpoint will be the relative change LFC (assessed by MRI-PDFF) from baseline to 
Week 36 (V8-EoT). 
The primary set for efficacy analysis will be the ITTS. 
No interim analysis is planned for this study. 
Sensitivity methods to handle missing data will be further detailed in the SAP. 
9.2 Sample Size Determination 
The sample size determination is based on the primary endpoint, i.e. the relative change in LFC 
(assessed by MRI-PDFF) from baseline to Week 36 (V8-EoT) ([LFCW36 – LFCbaseline] / LFCbaseline) 
and the primary objective, i.e. to demonstrate the superiority of at least one PXL065 dose to 
placebo as tested by the following null hypothesis (H0) versus the alternative hypothesis (Ha): 
H0: PXL065 - placebo   =  0  versus  Ha: PXL065 - placebo   <  0 
Where placebo and PXL065 denote the mean relative change in the percentage of LFC from baseline 
to Week 36 in the PXL065 and placebo groups respectively.  


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The following assumptions will be considered for the sample size determination:  
• No adjustment for multiple comparisons between PXL065 doses and placebo will considered 
and the usual nominal 1-sided alpha level of 0.025 (or equivalently the 2-sided level of 0.05) 
will be considered for each PXL065 dose vs placebo comparison 
• A power of 90% 
• An expected difference PXL065 - placebo of -30% for at least one PXL065 dose vs placebo 
comparison 
• A standard deviation (SD) of the primary endpoint equal to 30%, as estimated from previous 
published data [34]  
• With these assumptions, a sample size of 23 patients per arm is needed to achieve 90% power 
for at least one PXL065 dose vs placebo comparison. 
Assuming a dropout rate of 20%, around 30 patients per arm (120 = 4 x 30 patients in total) are 
needed to be randomized. 
9.3 Randomization 
A statistician independent of POXEL will prepare the randomization list. Each patient will be 
assigned to one of four treatments in a 1:1:1:1 ratio: 
• Group 1: PLX065 7.5 mg QD 
• Group 2: PXL065 15 mg QD 
• Group 3: PXL065 22.5 mg QD  
• Group 4: Placebo 
 
Randomization will be stratified according to T2DM status (T2DM patients versus non-T2DM 
patients) and NASH CRN fibrosis scoring system (F1 versus F2/F3).  
See Section 6.3.2 Treatment Assignment or Randomization for further details of the 
randomization procedures to be applied. 
9.4 Analysis Sets 
9.4.1 Screened Set 
The Screened Set is defined as all patients who were screened for inclusion into the study. 


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9.4.2 Safety Set 
The Safety Set (SS) comprises all randomized patients having received at least one dose of the 
IMP (either PXL065 or placebo) and considered as-treated. Safety and tolerability will be analyzed 
on the safety set.  
9.4.3 Efficacy Analyses  
All primary and secondary efficacy endpoints will be analyzed using the ITTS. The PPS will be 
used only for the analysis of the primary endpoint to assess the robustness of the primary analysis. 
9.4.3.1 Randomized Set (RS)  
All patients considered as-randomized regardless of the treatment actually received. 
9.4.3.2 Intention-to-treat Set (ITTS) 
The ITTS consists of all as-randomized patients having received at least one dose of the IMP (either 
PXL065 or placebo). Patients will be assigned to the treatment group as-randomized regardless of 
the treatment actually received. The ITTS will be considered as the primary set for efficacy 
analyses. 
9.4.3.3 Per Protocol Set (PPS)  
The PPS consists of all ITTS patients without any important violations of study procedures. 
Important protocol violations will be identified prior to breaking the blind. Protocol deviations will 
be reviewed and classified as important and non-important during a data review meeting that will 
be held before clinical database hard lock and breaking the blind.   
9.4.4 PK Population 
The PK population corresponds to the SS and includes all randomized patients who have been 
treated with PXL065 according to the protocol and have provided at least one pre-dose assessment 
during the study with sufficient plasma to derive the Cpre. 
9.5 Efficacy analysis 
9.5.1 Primary Endpoint: relative change in liver fat content (LFC) 
The primary analysis of efficacy will be performed on the ITTS. 
 
No adjustment for multiplicity will be considered. 


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Primary method to handle missing data: the LFC will be assessed at baseline and Week 36 (V8-
EoT) only. For patients who withdraw from the study at or after Week 12 (V4), the LFC will be 
assessed at Early Termination Visit (ET) as far as possible. With the assumption that the LFC 
assessed at or after Week 12 (V4) reflects what could have been observed at Week 36 (V8-EoT), 
the missing LFCs at Week 36 (V8-EoT) will be estimated by this value. For patients who withdraw 
before Week 12 (V4) or withdraw at or after Week 12 (V4) but without any LFC assessment on 
treatment, LFC missing values at Week 36 (V8-EoT) will be imputed using a multivariate 
imputation approach by fully conditional specification (FCS) regression method assuming Missing 
At Random Mechanism. The set of variables included in the multiple imputation model will be 
further specified in the SAP.  
Primary analysis: 
The primary endpoint, i.e. expressed as the relative change in the percentage of LFC (assessed by 
MRI-PDFF) from baseline to Week 36 (V8-EoT), will be analyzed in an analysis of covariance 
(ANCOVA) model adjusting for treatment (PXL065 doses of 7.5 mg QD, 15 mg QD and 22.5 mg 
QD and placebo) and for stratification factors, i.e. T2DM status (T2DM patients versus non-T2DM 
patients) and NASH CRN fibrosis scoring system (F1 versus F2/F3), and for the baseline LFC as 
a continuous covariate. 
The LSMs of the primary endpoint for treatment groups and pairwise differences in LSMs will be 
estimated along with p-values and 95% confidence intervals.  
The validity of the ANCOVA model will be checked (studentized residuals will be plotted against 
predicted values, etc.).   
Sensitivity analyses: 
Pairwise Wilcoxon tests stratified according to T2DM status and NASH CRN fibrosis scoring 
system will be performed. Hodges-Lehmann estimates along with their 95% confidence intervals 
will also be provided.    
The primary and sensitivity analyses will be repeated on the PPS. 
Other sensitivity analyses to handle missing data will be further detailed in the SAP. 
Subgroup analyses: 
Subgroup if interest will be analyzed for the primary endpoint. 
Subgroup analyses will be displayed with a forest plot to check consistency of the treatment effect 
across subgroups. Tests for subgroup by treatment interaction at the nominal alpha level of 0.10 
will be provided and further detailed in the SAP: 
• baseline age group (<65 years, ≥65 years) 
• BMI (<median and ≥ median) 
• Sex (female and male) 


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• T2DM status (T2DM patients versus non-T2DM patients) 
• NASH CRN fibrosis scoring system (F1 versus F2/F3) 
• Baseline LFC (assessed by MRI-PDFF) (<median and ≥ median) 
• Pooling site. Before unblinding, the rule of pooling site according to geographical area or 
other rationale shall be discussed by study team and documented in SAP. 
9.5.2 Secondary Endpoints 
9.5.2.1 Absolute Change in liver fat content (LFC)   
The absolute change in LFC (assessed by MRI-PDFF) from baseline to Week 36 (V8-EoT) will 
be analyzed in ANCOVA model adjusting for treatment, T2DM status (T2DM patients versus non-
T2DM patients), and NASH Fibrosis CRN histological scoring system (F1 versus F2/F3) and for 
baseline LFC as a continuous covariate. Least square means of the primary endpoint for treatment 
groups (PXL065 doses of 7.5 mg QD, 15 mg QD, 22.5 mg QD and placebo) and pairwise 
differences in LSMs will be estimated along with their p-values and 95% confidence intervals.  
Validity of the ANCOVA model will be checked (studentized residuals will be plotted against 
predicted values, etc.).  
The same sensitivity analyses proposed for the primary endpoint will be performed.  
9.5.2.2 Analysis of responders    
Four types of responders will be proposed and analyzed. 
- 
Response defined as an absolute reduction in LFC ≥ 5% from baseline to Week 36 (V8-
EoT) 
- 
Response defined as a relative reduction in LFC ≥ 30% from baseline to Week 36 (V8-
EoT) 
- 
Response defined as a relative reduction in LFC ≥ 50% from baseline to Week 36 (V8-
EoT) 
- 
Response defined as a LFC value at Week 36 (V8-EoT) that is normalized, i.e. ≤5% 
For each type of response, responder rate will be provided within each treatment group. 
Binary endpoints will be primarily analyzed with a stratified Cochran-Mantel-Haenszel approach 
and further detailed in the SAP. 
Additional analyses will be proposed: 
- 
The binary response will be analyzed in a logistic regression model adjusting for 
treatment (PXL065 doses of 7.5 mg QD, 15 mg QD, 22.5 mg QD and placebo),  
stratification factors, i.e. T2DM status (T2DM patients versus non-T2DM patients), 


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NASH CRN fibrosis scoring system (F1 versus F2/F3), and for the baseline LFC as a 
continuous covariate. Pairwise differences in treatment groups will be estimated in this 
model as odds ratios along with their p-values and 95% confidence intervals. 
- 
The binary response will be analyzed based on the approach proposed by Ge, et al., 2011 
[1] and further detailed in the SAP. 
9.5.2.3 Other Secondary Endpoints 
The analysis of these secondary endpoints will be provided and fully detailed in the SAP.   
Other efficacy secondary endpoints are as follows:  
• Liver enzymes: ALT, AST, GGT, ALP 
• Percentage of responders as defined by the percentage of patient with normalization of liver 
enzymes in the subset of patients with increased baseline value 
• Measured glycemic parameters: FPG, HbA1c, serum insulin, C-peptide 
• Insulin resistance indexes: HOMA-IR, QUICKI, HOMA-β, Adipo-IR 
 
The timepoints for collection of each of these are given in detail in Section 7 Study Procedures 
and in Table 1. 
9.5.3 Safety Analysis 
The analysis of safety parameters will be based on the safety analysis set. In general, missing safety 
data will not be replaced. Standard safety analysis will be performed and fully detailed in the SAP. 
Safety parameters are as follows: 
9.5.3.1 Adverse Events  
AEs will be coded using the most recent version available of the MedDRA at the start of the study. 
The frequency and incidence of TEAEs will be presented by System Organ Class (SOC) and 
preferred term for PXL065 treatment groups and placebo (number and percentage of patients 
experiencing at least one AE per preferred term as well as the number of observed events per 
preferred term). Separate tables will be presented by severity and by relationship. All AEs will be 
presented in a full and comprehensive listing including patient number, treatment, severity, 
seriousness, action taken, outcome, relationship to treatment, onset/stop and duration. Details of 
SAEs and AEs leading to permanent discontinuation of IMP or to death will be listed separately.  
9.5.3.2 Concomitant Medications 
Previous, concomitant and new medications will be coded using the World Health Organization 
(WHO) Dictionary.  


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Previous, concomitant and new medication will be tabulated and summarized by treatment groups. 
9.5.3.3 Physical Examination, Pitting Edema, Vital signs and Body measurements, Bone 
mineral density and ECG 
Physical examination, pitting edema assessment, vital signs and body measurements, bone mineral 
density and ECG parameters will be summarized descriptively by treatment and timepoint. 
Similarly, changes from baseline will be summarized. 
Physical examination results will be listed by patients and body system. 
9.5.3.4 Clinical Laboratory Data 
Laboratory findings will be evaluated using central laboratory’s normal reference ranges. 
Clinically relevant values will be flagged (please refer to central laboratory manual). Descriptive 
statistics will be derived for quantitative laboratory parameters for each treatment group and 
timepoint. Similarly, changes from the baseline will be summarized. 
Values outside the normal range (N) will be categorized as H (above the normal range) or L (below 
the normal range) based on the central laboratory’s normal reference range. Shift tables will be 
presented at each post-baseline visit showing the number of patients per treatment group with N, 
H or L. 
9.5.3.5 Withdrawals of study 
Patients who withdraw from the study will be summarized by treatment group according to their 
reason of withdrawal. 
9.5.4 Exploratory Endpoints 
Efficacy exploratory endpoints are as follows:  
• Adiponectin 
• Lipids: total cholesterol, LDL-c, HDL-c, triglycerides, FFA 
• Biomarker of inflammation: hsCRP 
• Biomarkers of fibrosis: pro-C3, NFS, FIB-4 and ELF score  
• Histological change in liver biopsy: 
• Change in NAS, in each component of NAS (steatosis, ballooning and 
inflammation) and in NASH CRN fibrosis score 
• Improvement in each component of NAS (steatosis, lobular inflammation and 
hepatocellular ballooning) by ≥ 1 point without worsening of fibrosis 
• Improvement in NAS ≥ 2 points without worsening of fibrosis 
• Improvement in NASH CRN fibrosis score by ≥ 1 point  


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• NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) 
• NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) with improvement in NASH CRN fibrosis score by ≥ 1 point 
• NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) with no worsening in NASH CRN fibrosis score 
• NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) and improvement in NAS ≥ 2 points with no worsening in 
NASH CRN fibrosis score 
• Histological changes (steatosis, inflammation, ballooning and fibrosis) quantified by 
automated digital images analysis 
9.5.5 Analysis of Further Endpoints 
Pharmacokinetic data (PXL065 concentrations) will be analyzed using a Population PK model. PK 
parameters will be listed and summarized by treatment groups and by visits/timepoints. 
9.6 Interim Analysis 
No interim analysis is planned. 
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10 Ethical and Regulatory Aspects 
10.1 Ethics and Good Clinical Practice 
The Investigator will ensure that this study is conducted in full compliance with the principles of 
the ‘Declaration of Helsinki’ (as amended in Tokyo, Venice, Hong Kong, Somerset West, 
Edinburgh and Seoul), and with the laws and regulations of the country in which the clinical 
research is conducted.  
Study staff must follow ICH GCP Guidelines and local regulations. Investigators will strictly 
ensure adherence to the stated provisions.  
For any study site staff member responsible for performing a critical task, ICH GCP training must 
be documented on the Curriculum Vitae and/or evidence of training provided. Any study site staff 
member not familiar with or having conducted an ICH GCP training more than 2 years prior to the 
study initiation or start of involvement in the study will have to be trained before the start of the 
study. 
10.2 Patient Information and Informed Consent 
It is the responsibility of the Investigator to obtain informed consent according to GCP and local 
regulations from each individual participating in this study. 
An unconditional prerequisite for patients’ participation in the study is their written informed 
consent. The patient’s written informed consent to participate in the study must be given before 
any study-related activities are carried out. 
Adequate information must therefore be given to the patient by the Investigator before informed 
consent is obtained. A patient information sheet prepared in accordance with the Note for Guidance 
on GCP (ICH E6) will be provided by COVANCE and validated by POXEL for the purpose of 
obtaining informed consent. In addition to providing this written information to a potential patient, 
the Investigator (or his/her designate) will inform the patient verbally of all pertinent aspects of the 
study. The Investigator (or his/her designate) must provide adequate explanation of the methods, 
objectives and potential hazards of the study. The language used in doing so must be chosen so 
that the information can be fully and readily understood by laypersons. The Investigator (or his/her 
designate) must explain to patients that they are completely free to refuse to enter the study, or to 
withdraw from it at any time for any reason. 
The ICF must be signed and dated by the patient in person at study site and the person obtaining 
consent in person at study site. The signed and dated declaration of informed consent will remain 
at the Investigator’s site and must be safely archived by the Investigator so that the forms can be 


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retrieved at any time for monitoring, auditing and inspection purposes. A copy of the signed and 
dated ICF should be provided to patients prior to participation. The whole consenting process must 
be clearly documented in the patient file. 
The patient information leaflet and ICF will be provided in the local language. 
Whenever important new information become available that may be relevant to the patient’s 
consent, the written patient information sheet and any other written information provided to 
patients will be revised by POXEL and be submitted again to the IRB/EC for review and favorable 
opinion. The agreed, revised information will be forwarded to each patient in the study. The 
Investigator (or his/her designate) will explain the changes to the previous version and patient will 
be asked to sign the new version. 
The patient identification log must be maintained for all patients who consented to participate in 
the study, whether or not they were randomized.  
10.3 Patient Identification and Privacy 
A unique patient number (see Section 6.3.1 Patient Numbering) will be assigned to each patient 
upon ICF signature, at the start of Screening Period. This number will serve as the patient’s 
identifier in the study as well as in the clinical study database. 
The patient’s data collected in the study will be stored under this number. The identification list, 
to link the patient’s study data to the patient, will be kept at the study site with restricted access 
under the Investigator’s responsibility. The patient’s original medical data that are reviewed versus 
eCRF data (source data verification process) at the study site during routine monitoring, audits and 
authority inspections will be kept strictly confidential. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing patient data. Patients will be informed accordingly and will be requested to give their 
consent on data handling procedures in accordance with US regulations. 
10.4 Emergency Medical Support and Patient Emergency Card 
Patients included in this study will be provided with a Patient Emergency Card upon ICF signature 
at the start of Screening Period. The Patient Emergency Card is based on the need to provide 
patients with a way of identifying themselves as participating in this study, and subsequently to 
give health care providers access to the information about this participation that may be needed to 
determine the course of the patient’s medical treatment. 
This card is designed to provide information to health care providers who are not part of the clinical 
study. The Investigators, who are already aware of the protocol and treatment, have other means 


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of accessing necessary medical information for the management of emergencies occurring in their 
patients. 
The first point of contact for all emergencies will be the Investigator caring for the affected patient. 
The Investigator agrees to provide his or her emergency contact information on the card for this 
purpose. If the Investigator is available when an event occurs, he/she will answer any questions. 
Any subsequent action (e.g. unblinding) will follow the standard processes established for the 
Investigators. 
10.5 Patient Insurance and Compensation to Patients 
Insurance coverage shall be provided in line with the regulations. Coverage will be provided from 
the time a patient has been screened in the study, i.e. from the time the patient has given written 
informed consent.  
In the event that a patient is injured as a direct result of study participation, POXEL will reimburse 
for treatment of such injuries, as long as those costs are not covered by the patient’s health care 
payer. However, if the patient has not complied with the study procedures, has not followed the 
instructions of the Principal Investigator or if the injury is a result of a medical condition not related 
to the IMP, the patient’s health care payer will be responsible for the costs of diagnosing and 
treating the condition.  
10.6 Institutional Review Board/Ethics committee 
Prior to commencement of the study at a given study site, the study protocol will be submitted 
together with its associated documents (Patient Information and Consent Form, IB) and any other 
relevant information (e.g. patient diary, patient emergency card) to the responsible IRB/EC for its 
favorable opinion/approval. The written favorable opinion/approval of the IRB/EC will be filed in 
the ISF, and a copy will be filed in the TMF at COVANCE. 
The study must not start at a study site before POXEL has obtained written confirmation of 
favorable opinion/approval from the concerned IRB/EC. The IRB/EC will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the study, the protocol version and the Patient Information 
and Consent Form version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained. Amendments to the protocol will also be submitted for favorable 
opinion/approval to the concerned IRB/EC, before implementation in case of substantial changes 
(see Section 11.6 Changes to the Protocol). Relevant safety information will be submitted to the 
IRB/EC during the course of the trial in accordance with national regulations and requirements. 


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10.7 Regulatory Authorities 
The protocol and any applicable documentation will be notified to the Food and Drug 
Administration (FDA) in US. 


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11 Study Management 
11.1 Data collection and CRF management 
In this study, an eCRF data will be captured via EDC using RAVE (Medidata), a web-based tool. 
An eCRF will be completed for each screened patient. 
Patient diary, specifically designed for the clinical trial by POXEL and provided to the study sites 
will be given to the patients. Data collected in this patient diary are detailed in Section 8.3.4. 
The data in the eCRF should be consistent with the relevant source documents as verified by 
COVANCE’s CRA during monitoring visits. The data will be processed, evaluated, and stored in 
anonymous form in accordance with the data-protection regulations. 
The Investigator must ensure that any document associated with an eCRF forwarded to POXEL 
contains no mention of any patient names. 
The eCRFs will be reviewed by the Investigator for completeness and accuracy. Each patient’s 
eCRF must be signed electronically by the Investigator to document correctness and accuracy of 
data contained. Any amendments and corrections necessary must be undertaken and countersigned 
electronically by the Investigator, stating the date of the amendment/correction. The Investigator 
must state his/her reasons for the correction of important data. Electronic errors will be captured 
by the audit trail within the collection system. Details on eCRF completion will be given in the 
eCRF completion guidelines.  
The eCRFs are regulatory documents and must be suitable for submission to authorities. 
The Investigator or designee will be responsible for entering study data in the eCRF provided by 
COVANCE. It is the Investigator’s responsibility to ensure the accuracy of the data entered in the 
eCRFs. The eCRF information need to be completed as soon as possible after each patient’s visit 
(but no later than 5 business days after the patient’s visit). 
In addition to eCRF, other external data are collected:  
• MRIs performed during the study will be sent to a centralized imaging core laboratory. 
Results will be electronically transferred to the COVANCE Data Management Department.  
• A portion of the slides prepared from liver biopsies collected during the study will be sent to 
a centralized pathologist. Results will be communicated to the centralized laboratory for data 
entry into the laboratory database and data will then be electronically transferred to the 
COVANCE Data Management Department. 
• A portion of the slides prepared from liver biopsies collected during the study will be sent to 
BIOCELLVIA. Results will be electronically transferred to the POXEL Data Management 
Department. 
 
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• Laboratory blood and urine samplings will be sent to the centralized laboratory and results 
will be transferred electronically to COVANCE Data Management Department. 
• PK samplings will be sent to Charles River Saint-Nazaire for analysis and results will be 
transferred electronically to COVANCE Data Management Department. 
Reconciliation of all centralized data will be done by COVANCE before final transfers and clinical 
database hard lock.  
All the data collected during the trial will be integrated into a validated clinical database. 
COVANCE will be responsible for data processing, in accordance with COVANCE’s data 
management procedures. Clinical database lock will occur once quality assurance procedures have 
been completed. Patient Data Reports, recorded on CD or DVD, will be provided to the 
Investigators at the completion of the study. Each patient data report will contain all the data for a 
particular patient in the same format as the eCRF pages as well as audit trails and indexed 
comments. 
During the study, SAE/Overdose/Pregnancy/AESI (reported on the respective forms in eCRFs) 
will be shared with POXEL and the Safety Provider (UBC) within 24h following Investigator 
awareness. Each SAE will be processed into the POXEL global safety database hold by UBC and 
according to UBC Adverse Event Reporting Plan (AERP). Each case will be assigned a safety 
database case identification number. Each case will be reviewed by POXEL before being reported 
to the relevant Competent Authorities as required. SAE/Overdose/Pregnancy/AESI from the safety 
database will be reconciled with those of the clinical database. 
11.2 Handling of Protocol Deviations 
In the event of a significant deviation from the protocol due to an emergency, accident, or mistake 
(e.g. violation of informed consent process, IMP dispensing or patient dosing error, treatment 
assignment error, patient enrolled in violation of eligibility criteria, or concomitant medication 
criteria), the Investigator (or designee) will contact POXEL (or its designee) at the earliest possible 
time by telephone or by email. The Investigator and POXEL (or its designee) will come as quickly 
as possible to a joint decision regarding the patient’s continuation in the trial. This decision will be 
documented by the Investigator and POXEL (or its designee) and reviewed by the CRA. 
11.3 Source Data and Patient Files 
The Investigator must keep a patient file (medical file, original medical records) on paper or 
electronically for every patient included in the study. This file will contain the available 
demographic and medical information for the patient and should be as complete as possible.  
It should be possible to verify the inclusion and exclusion criteria for the study from the available 
data in this file. 


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It must be possible to identify each patient by using this patient file. 
Printouts of electronic patient file documents as stated above must be signed and dated by the 
Investigator and kept with the Investigator’s copy of the document. 
Additionally, any other documents with source data, especially original printouts of data that were 
generated by technical equipment or printouts have to be filed in the patient files. This includes 
e.g. ECG recordings, BP monitoring, laboratory value listings, patient diary, etc. All these 
documents have to bear at least the patient number, study number, scheduled time and the printing 
date printed by the recording device to indicate to which patient and to which study procedure the 
document belongs. The medical evaluation of such records should be documented as necessary 
and signed/dated by the Investigator (or his/her designee).  
11.4 Investigator Site File and Archiving 
The Investigator will be provided with an ISF upon initiation of the study. This file will contain all 
documents necessary for the conduct of the study and will be updated and completed throughout 
the study. It must be available for review by the CRA, must be ready for inspection by Competent 
Authorities during and after the study, and must be safely archived for at least 15 years after the 
end of the study. The documents to be thus archived include the Patient Identification List and the 
signed patient ICFs. If archiving of the Investigator Site File is no longer possible at the study site, 
the Investigator must notify POXEL. 
All original patient files (medical records) must be stored at the study site (hospital, research 
institute, or practice) for the longest possible time permitted by the applicable regulations, and/or 
as per ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that 
no destruction of medical records is performed without the written approval of POXEL. 
11.5 Monitoring, Quality Assurance and Inspection by Authorities 
This study will be monitored in accordance with the ICH Note for Guidance on GCP (ICH E6). 
The CRA will perform visits to study site at regular intervals. 
During monitoring visits, the CRAs will review: 
• the conformity of ICFs with the applicable regulation 
• the compliance of patient inclusion with protocol Inclusion/Exclusion criteria 
• that the data management is adequate: source data verification, queries resolution, SAEs/ 
AEs reporting, protocol deviations reporting 
• ISF (e.g. Protocol & Amendments and Regulatory sections, delegation list and training 
records) 
• that IMP handling is compliant with the protocol requirements 


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• the compliance of centralized procedures management (e.g. central laboratory and central 
imaging) by study site staff 
• the adequacy of facilities, equipment and material management 
In line with ICH GCP guidelines, monitoring will include verification of data entered in the eCRF 
against original patient’s records. This verification will be performed by direct access to the 
original patient records, and POXEL guarantees that patient confidentiality will be respected at all 
times. Participation in this study will be taken as agreement to permit direct source data 
verification. 
Representatives of appropriate POXEL personnel or its designee(s), as well as Competent 
Regulatory Authorities, must be permitted to inspect all study-related documents and other 
materials at study site, including the ISF, the completed eCRFs, IMP and the patients’ original 
medical records/files. 
The protocol, each step of the data capture procedure, and the handling of the data, as well as the 
eventual clinical study report, will be subject to independent Clinical Quality Assurance. Audits 
may be conducted at any time during or after the study to ensure the validity and integrity of the 
study data. 
11.6 Changes to the Protocol 
Changes to the protocol will be documented in written protocol amendments. Major (substantial, 
significant) amendments will usually require submission to the competent authorities and to the 
relevant IRB/EC for approval or favorable opinion. In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained. 
Minor (non-substantial) protocol amendments, including administrative changes, will be submitted 
to the relevant IRB/EC or to competent authorities only where requested by pertinent regulations. 
Any amendment that could have an impact on the patient’s agreement to participate in the study 
requires the patient’s informed consent prior to implementation (see Section 10.2 Patient 
Information and Informed Consent) 
11.7 Clinical Study Report and Publication Policy 
11.7.1 Clinical Study Report 
After completion of the study, a clinical study report according to ICH E3 will be written by 
COVANCE under the direction of POXEL.  


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11.7.2 Publication 
In accordance with standard editorial and ethical practice, the results of the study will be published. 
Results from multi-center studies must be published or presented at congress only in their entirety 
and not as individual study site data, except for ancillary studies.  
The coordinating Investigator will have the opportunity to review the analysis of data and to discuss 
with POXEL the interpretation of the study prior to publication.  
Any study-related article or abstract written independently by Investigators must be submitted to 
POXEL for review at least 60 days prior to submission for publication or presentation. POXEL is 
entitled to delay publication in order to protect intellectual property rights. 
The list of authors of any formal publication or presentation of study results may include, as 
appropriate, representatives of POXEL, and will be determined by mutual agreement. 
11.7.3 Disclosure and Confidentiality 
By signing this protocol, the Investigator agrees to keep all information provided by POXEL in 
strict confidence, and to request similar confidentiality from his or her staff and the IRB/EC. Study 
documents (including IB, protocol, eCRF and other protocol-related documents) will be stored 
appropriately to ensure their confidentiality. The information provided by POXEL to the 
Investigator may not be disclosed to others without direct written authorization from POXEL, 
except to the extent necessary to obtain ICF patients who wish to participate in the study. 


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12 References 
1. 
Ge, M., et al., Covariate-adjusted difference in proportions from clinical trials using 
logistic regression and weighted risk differences. Drug Information Journal, 2011. 45: p. 
481-493. 
2. 
Younossi, Z.M., et al., Global epidemiology of nonalcoholic fatty liver disease-Meta-
analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016. 64(1): p. 
73-84. 
3. 
Konerman, M.A., J.C. Jones, and S.A. Harrison, Pharmacotherapy for NASH: Current and 
emerging. J Hepatol, 2018. 68(2): p. 362-375. 
4. 
Takeda, Takeda announces completion of the postmarketing commitment to submit data to 
the FDA, the EMA, and the PMDA for pioglitazone-containing medicines including 
ACTOS. 2014. 
5. 
Musso, G., et al., Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic 
Steatohepatitis: A Meta-analysis. JAMA Intern Med, 2017. 177(5): p. 633-640. 
6. 
Chalasani, N., et al., The diagnosis and management of nonalcoholic fatty liver disease: 
Practice guidance from the American Association for the Study of Liver Diseases. 
Hepatology, 2018. 67(1): p. 328-357. 
7. 
EASL-EASD-EASO, 
EASL-EASD-EASO Clinical Practice Guidelines for 
the 
management of non-alcoholic fatty liver disease. J Hepatol, 2016. 64(6): p. 1388-402. 
8. 
Rinella, M.E., et al., Practice patterns in NAFLD and NASH: real life differs from 
published guidelines. Therap Adv Gastroenterol, 2016. 9(1): p. 4-12. 
9. 
Sanyal, A.J., et al., Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N 
Engl J Med, 2010. 362(18): p. 1675-85. 
10. 
Shah, P. and S. Mudaliar, Pioglitazone: side effect and safety profile. Expert Opin Drug 
Saf, 2010. 9(2): p. 347-54. 
11. 
Guan, Y., et al., Thiazolidinediones expand body fluid volume through PPARgamma 
stimulation of ENaC-mediated renal salt absorption. Nat Med, 2005. 11(8): p. 861-6. 
12. 
Wan, Y., PPARgamma in bone homeostasis. Trends Endocrinol Metab, 2010. 21(12): p. 
722-8. 
13. 
Fukunaga, T., et al., An insulin-sensitizing thiazolidinedione, which minimally activates 
PPARgamma, does not cause bone loss. J Bone Miner Res, 2015. 30(3): p. 481-8. 
14. 
Divakaruni, A.S., et al., Thiazolidinediones are acute, specific inhibitors of the 
mitochondrial pyruvate carrier. Proc Natl Acad Sci U S A, 2013. 110(14): p. 5422-7. 


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15. 
McCommis, K.S. and B.N. Finck, Treating Hepatic Steatosis and Fibrosis by Modulating 
Mitochondrial Pyruvate Metabolism. Cell Mol Gastroenterol Hepatol, 2019. 7(2): p. 275-
284. 
16. 
Harbeson, S. and R. Tung, Deuterium in drug discovery and development. Annual Reports 
in Medicinal Chemistry, 2011. 46: p. 403-417. 
17. 
Pirali, T., et al., Applications of Deuterium in Medicinal Chemistry. J Med Chem, 2019. 
62(11): p. 5276-5297. 
18. 
Promrat, K., et al., A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. 
Hepatology, 2004. 39(1): p. 188-96. 
19. 
Belfort, R., et al., A placebo-controlled trial of pioglitazone in subjects with nonalcoholic 
steatohepatitis. N Engl J Med, 2006. 355(22): p. 2297-307. 
20. 
Cusi, K., et al., Long-Term Pioglitazone Treatment for Patients With Nonalcoholic 
Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann 
Intern Med, 2016. 165(5): p. 305-15. 
21. 
Caussy, C., et al., Noninvasive, Quantitative Assessment of Liver Fat by MRI-PDFF as an 
Endpoint in NASH Trials. Hepatology, 2018. 68(2): p. 763-772. 
22. 
Kim, C.W., et al., Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but 
Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. 
Cell Metab, 2017. 26(2): p. 394-406.e6. 
23. 
Council, E.P.a.o.t., Official Journal Of the European Communities. Directive 2001/20/EC 
of the Europea Parliament and of the Council of 4 april 2001, in Article 2(d). 2001. 
24. 
POXEL Investigator's Brochure Version 4. 0 / 31 Mar 2020. 
25. 
Wallace, T.M., J.C. Levy, and D.R. Matthews, Use and Abuse of HOMA Modeling. 
Diabetes Care, 2004. 27(6): p. 1487-1495. 
26. 
Katz, A., et al., Quantitative insulin sensitivity check index: a simple, accurate method for 
assessing insulin sensitivity in humans. J Clin Endocrinol Metab, 2000. 85(7): p. 2402-10. 
27. 
Lomonaco, R., et al., Effect of adipose tissue insulin resistance on metabolic parameters 
and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology, 
2012. 55(5): p. 1389-97. 
28. 
Angulo, P., et al., The NAFLD fibrosis score: a noninvasive system that identifies liver 
fibrosis in patients with NAFLD. Hepatology, 2007. 45(4): p. 846-54. 
29. 
Sterling, R.K., et al., Development of a simple noninvasive index to predict significant 
fibrosis in patients with HIV/HCV coinfection. Hepatology, 2006. 43(6): p. 1317-25. 


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30. 
Verlinden, W., et al., Validation of APRI and FIB-4 score in an Antwerp cohort of chronic 
hepatitis C patients. Acta Gastroenterol Belg, 2015. 78(4): p. 373-80. 
31. 
Lichtinghagen, R., et al., The Enhanced Liver Fibrosis (ELF) score: normal values, 
influence factors and proposed cut-off values. J Hepatol, 2013. 59(2): p. 236-42. 
32. 
Levey, A.S., et al., A new equation to estimate glomerular filtration rate. Ann Intern Med, 
2009. 150(9): p. 604-12. 
33. 
FDA, Guidance for Industry. Diabetes mellitus: developping drugs and therapeutic 
biologics for treatment and prevention. 2008. 
34. 
Harrison, S.A., et al., NGM282 for treatment of non-alcoholic steatohepatitis: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet, 2018. 
391(10126): p. 1174-1185. 
 


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13 Annex 1. Sponsor, Coordinating Investigators and Study 
Administrative Structure 
 
Study Sponsor  
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Phone: +33 4 37 37 20 10 
Fax: +33 4 37 70 88 15 
 
EVP, Clinical Development & Regulatory at POXEL 
Pascale Fouqueray, MD, PhD 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 6 98 01 71 03 
Fax: +33 4 37 70 88 15 
E-mail: pascale.fouqueray@poxelpharma.com 
 
Vice President - Medical Operations, Biometry and Safety at POXEL  
Julie Dubourg, MD 
Clinical Development Department 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 6 63 49 37 53 
Fax: +33 4 37 70 88 15 
E-mail: julie.dubourg@poxelpharma.com 
 
Associate Medical Director, Clinical Development at POXEL 
Carole Thang, PharmD 
Clinical Development Department 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 7 63 12 45 53 
Fax: +33 4 37 70 88 15 
E-mail: carole.thang@poxelpharma.com 
 
Corporate confidential information 


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Senior Manager, Clinical Development at POXEL 
Caroline Reilhac, PhD 
Clinical Development Department 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 6 98 23 05 52 
Fax: +33 4 37 70 88 15 
E-mail: caroline.reilhac@poxelpharma.com 
 
Clinical Project Manager at POXEL  
Emeline Kieken 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 6 63 49 38 26 
Fax: +33 4 37 70 88 15 
E-mail: emeline.kieken@poxelpharma.com 
 
Senior Clinical Project Manager at POXEL  
Béatrice Jacolin-Maffei 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 6 65 77 94 82  
Fax: +33 4 37 70 88 15 
E-mail: beatrice.jacolin-maffei@poxelpharma.com 
 
Clinical Data Manager at POXEL  
Cécilia Bergounioux 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 6 65 92 86 96 
Fax: +33 4 37 70 88 15 
E-mail: cecilia.bergounioux@poxelpharma.com  
 
CRO information and vendors: 
 
Corporate confidential information 


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Project Manager II at Covance  
Andrea Myers, PhD,  
Covance Clinical Development GmbH,  
Carl-Wery-Straße 42  
81739 Munich, Germany Mobile: +49 173 356 3071 
E-mail: Andrea.Myers@covance.com 
Senior Medical Monitor at Covance 
Friedrich Mittermayer, MD, MSc 
Clinical Development Services, Covance GmbH 
Herrengasse 1-3, 1010 Vienna, Austria  
Mobile: +43 664 8825 2422  
Fax: +43 1 928 1845 
E-mail: Friedrich.Mittermayer@covance.com 
Data Manager at Covance 
Lynne Girdwood  
Osprey House, 1 Maidenhead Office Park,  
Westacott Way, Maidenhead, SL6 3QH 
Mobile: +44 (0) 7970 372 548 
Phone: +44 (0) 1506 815 675 
E-mail: Lynne.Girdwood@covance.com 
Biostatistician at Covance 
Mark Senior, BSc (Hons) MSc GradStat 
Covance Clinical and Periapproval Services Limited 
Osprey House, 1 Maidenhead Office Park,  
Westacott Way, Maidenhead, SL6 3QH 
Phone: +44 (0)20 8680 9723  
E-mail: Mark.Senior@covance.com 
Clinical central laboratory- Cerba Research 
Daryl Doblados 
Laboratory Project Manager, Europe  
Industriepark Zwijnaarde 3 
9052 Ghent, Belgium 
Mobile: +44 (0) 7538766305 
E-mail : ddoblados@cerbaresearch.com 
BioTel Imaging Core Laboratories 
One Preserve Parkway, Suite 600 
Rockville, MD, 20852 
Corporate confidential information 


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Phone: +1 919 349 2264 
Website: gobio.com/clinical-research 
IxRS- EndPoint Clinical 
55 Francisco Street, Suite 200 
San Francisco, CA, 92133 
Phone: +1 848 213 3133 
Website: www.endpointclinical.com  
 
Digital Imaging analysis for biopsy 
Biocellvia 
10 rue Grignan 
13001 Marseille 
 
IMP Kit and Supply Chain Management 
Fisher Clinical Services UK Limited  
Langhurstwood road 
Horsham 
RH12 4QD – United Kingdom 
 
Bioanalytical laboratory & PK sampling Dosing 
Charles River Saint- Nazaire 
1, rue Graham Bell 
ZI de Brais, BP 40309 
44605 Saint Nazaire, France 
 
Coordinating Investigator 
Stephen Harrison, MD 
Pinnacle Clinical Research 
5109 Medical Dr Ste 200 
San Antonio, TX 78229 
United States 
 
Study Sites and Investigators 
List of Study Sites and Investigators will be attached separately. 
 
Corporate confidential information 


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14 Annex 2. Serious Adverse Event Contact Information 
In case of a SAE/AESI/Overdose/Pregnancy (see Section 8.3.8.4.1), the Investigator will share the 
information immediately and no later than within 24 hours of awareness to below email addresses: 
 
POXEL PV Provider 
United Biosource Company (UBC) 
E-mail: POXELPV@ubc.com  
Fax: +1 877 778 0204 
POXEL safety generic mailbox: safety@poxelpharma.com  
 
Keeping in the loop below POXEL Team members email IDs: 
- 
Pharmacovigilance (PV) and Safety Manager at POXEL 
Claire Boutron, PharmD 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Fax: +33 (0) 437 70 88 15/Mobile: +33 (0) 666 09 56 84 
E-mail: claire.boutron@poxelpharma.com   
 
- 
Vice President – Medical Operations, Biometry and Safety at POXEL  
Julie Dubourg, MD 
E-mail: julie.dubourg@poxelpharma.com 
 
- 
Associate Medical Director, Clinical Development at POXEL  
Carole Thang, PharmD 
E-mail: carole.thang@poxelpharma.com  
 
Corporate confidential information 

SAP_001.pdf: 
 
 
CONFIDENTIAL 
Page 1 of 56 
Document Date: 12AUG2022 
 
ST-AD-008 version 05 
Statistical Analysis Plan 
 
POXEL 
PXL065-003 
 
 
Labcorp Drug Development Study ID: 000000197965 
Document Version: Final v3.0 
Document Date: 12AUG2022 
 
Author: Mark Senior 
 
 
 
 
 
 
Labcorp Drug Development Limited 
 
Table of Contents 
1. 
Source Documents ............................................................................ 10 
2. 
Protocol Details ................................................................................. 10 
2.1 
Study Objectives ............................................................................ 10 
2.2 
Overall Study Design Per Protocol ..................................................... 10 
2.3 
Sample Size and Power ................................................................... 13 
2.4 
COVID-19 ..................................................................................... 13 
3. 
Efficacy and Safety Variables .............................................................. 14 
3.1 
Primary Efficacy Endpoint ................................................................ 14 
3.2 
Secondary Efficacy Endpoints ........................................................... 14 
3.3 
Safety Variables ............................................................................. 15 
Corporate confidential information 
Corporate confidential information 


Statistical Analysis Plan 
Sponsor Name: Poxel 
Sponsor Protocol ID: PXL065-003                     Labcorp Drug Development Study ID: 000000197965 
 
 
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Document Date: 12AUG2022 
 
ST-AD-008 version 05 
 
4. 
Pharmacokinetic Variables .................................................................. 15 
5. 
Analysis Populations .......................................................................... 15 
5.1 
Screened Set ................................................................................. 16 
5.2 
Screened Set with Site 065-S22 ........................................................ 16 
5.3 
Randomized Set (RS) ...................................................................... 16 
5.4 
Randomized Set with Site 065-S22 (RS-w-065-S22) ............................ 16 
5.5 
Safety Set (SS)  ............................................................................. 16 
5.6 
Safety Set with Site 065-S22 (SS-w-065-S22) .................................... 16 
5.7 
Intent-to-treat Set (ITTS)  ............................................................... 17 
5.8 
Intent-to-treat Set with Site 065-S22 (ITTS-w-065-S22)  ..................... 17 
5.9 
Per-Protocol Set (PPS) ..................................................................... 17 
5.10 Important Protocol Deviations Leading to Exclusion from the PP Analysis . 17 
5.10.1 
Failure of Inclusion/Exclusion Criteria ................................................................................ 18 
5.10.2 
Prohibited Medications ....................................................................................................... 18 
5.10.3 
Accidental or Emergency Unblinding During Treatment Period ......................................... 19 
5.10.4 
Errors in Treatment Allocation During Treatment Period .................................................. 19 
5.10.5 
Adequate Study Medication Compliance ........................................................................... 19 
5.10.6 
Assessment of Important Protocol Deviations ................................................................... 19 
6. 
DATA Handling.................................................................................. 20 
6.1 
Time Points and Visit Windows .......................................................... 20 
6.2 
Handling of Dropouts ...................................................................... 22 
6.3 
Handling of Patients from Site 065-S22 .............................................. 22 
6.4 
Handling of Rescreened Patients ....................................................... 22 
6.5 
Handling of Missing Data ................................................................. 22 
6.5.1 
Safety Variables ................................................................................................................... 22 
6.5.2 
Laboratory Values ............................................................................................................... 23 
6.5.3 
Type 2 Diabetes Diagnosis .................................................................................................. 23 
7. 
Statistical Methods ............................................................................ 24 
7.1 
General Principles ........................................................................... 24 
7.2 
Patient Disposition and Data Sets Analyzed ......................................... 25 
7.3 
Protocol Deviations ......................................................................... 26 


Statistical Analysis Plan 
Sponsor Name: Poxel 
Sponsor Protocol ID: PXL065-003                     Labcorp Drug Development Study ID: 000000197965 
 
 
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ST-AD-008 version 05 
 
7.4 
Demographics and Other Baseline Characteristics ................................ 26 
7.4.1 
Medical History ................................................................................................................... 27 
7.4.2 
Previous and Concomitant Medications ............................................................................. 28 
7.5 
Measurements of IMP Treatment Compliance ...................................... 28 
7.6 
Efficacy ......................................................................................... 29 
7.6.1 
Primary Endpoint ................................................................................................................ 29 
7.6.1.1 
Primary Analysis .......................................................................................................... 29 
7.6.1.2 
Sensitivity Analysis for the Primary Analysis ............................................................... 31 
7.6.1.3 
Other Analyses for the Primary Endpoint ................................................................... 31 
7.6.1.4 
Subgroup Analysis ....................................................................................................... 31 
7.6.2 
Secondary Endpoints .......................................................................................................... 31 
7.6.2.1 
Absolute Change in LFC ............................................................................................... 31 
7.6.2.2 
Analysis of Responders ............................................................................................... 32 
7.6.2.3 
Other Secondary Continuous Endpoints ..................................................................... 33 
7.6.2.4 
Other Secondary Categorical Endpoint ....................................................................... 34 
7.6.2.5 
Subgroup Analysis ....................................................................................................... 34 
7.6.3 
Exploratory Endpoints ......................................................................................................... 35 
7.7 
Safety .......................................................................................... 37 
7.7.1 
Extent of Exposure .............................................................................................................. 37 
7.7.2 
Adverse Events .................................................................................................................... 37 
7.7.2.1 
Hypoglycemia .............................................................................................................. 39 
7.7.3 
Laboratory Evaluations ....................................................................................................... 39 
7.7.3.1 
Standard Safety Laboratory Panel .............................................................................. 40 
7.7.3.2 
eGFR ............................................................................................................................ 41 
7.7.3.3 
Viral Infection Screen Panel ........................................................................................ 41 
7.7.3.4 
Serum and Urine Pregnancy Test ................................................................................ 42 
7.7.4 
Bone Mineral Density .......................................................................................................... 42 
7.7.5 
Vital Signs and Body Measurements ................................................................................... 42 
7.7.6 
Electrocardiograms ............................................................................................................. 43 
7.7.7 
Physical Examination ........................................................................................................... 43 
7.7.8 
Pitting Edema ...................................................................................................................... 43 


Statistical Analysis Plan 
Sponsor Name: Poxel 
Sponsor Protocol ID: PXL065-003                     Labcorp Drug Development Study ID: 000000197965 
 
 
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Document Date: 12AUG2022 
 
ST-AD-008 version 05 
 
7.7.9 
Other Safety Variables ........................................................................................................ 43 
7.8 
Interim Analysis ............................................................................. 44 
8. 
Changes in Planned Analysis ............................................................... 44 
9. 
Data Issues ...................................................................................... 45 
10. 
References ....................................................................................... 46 
11. 
Appendix A: Visit Schedule Chart ......................................................... 48 
12. 
Appendix B: Sample SAS® code for analyses of efficacy endpoints ............ 51 
13. 
Appendix C: Ge et al. code ................................................................. 53 
 
 
 


Statistical Analysis Plan 
Sponsor Name: Poxel 
Sponsor Protocol ID: PXL065-003                     Labcorp Drug Development Study ID: 000000197965 
 
 
CONFIDENTIAL 
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ST-AD-008 version 05 
 
Reviewers 
The following reviews of the SAP were conducted: 
Name and Title  
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
Adrien Michon 
Senior Manager, 
Statistical Programming 
Final v3.0 
Poxel 
Carole Thang 
Director Medical 
Operations 
Final v3.0 
Poxel 
Emeline Kieken 
Senior Project Manager 
Final v3.0 
Poxel 
Malika Ammar 
Consultant, Data 
Management 
Final v3.0 
Poxel 
Jean-Marie Grouin 
Statistical Consultant 
Final v3.0 
JM Grouin 
Conseil 
Pascale Fouqueray 
EVP Clinical Development 
and Regulatory Affairs 
Final v3.0 
Poxel 
Shubha Lakshmi 
Statistical Programmer 
Final v3.0 
Labcorp 
Adrien Michon 
Senior Manager, 
Statistical Programming 
Final v2.0 
Poxel 
Carole Thang 
Director Medical 
Operations 
Final v2.0 
Poxel 
Emeline Kieken 
Senior Project Manager 
Final v2.0 
Poxel 
Cecilia Bergounioux 
Director Biometry 
Final v2.0 
Poxel 
Jean-Marie Grouin 
Statistical Consultant 
Final v2.0 
JM Grouin 
Conseil 
Pascale Fouqueray 
EVP Clinical Development 
and Regulatory Affairs 
Final v2.0 
Poxel 
Shubha Lakshmi 
Statistical Programmer 
Final v2.0 
Labcorp 
Adrien Michon 
Senior Manager, 
Statistical Programming 
Sponsor draft 1.1 
Poxel 
Carole Thang 
Director Medical 
Operations 
Sponsor draft 1.1 
Poxel 
Emeline Kieken 
Senior Project Manager 
Sponsor draft 1.1 
Poxel 
Cecilia Bergounioux 
Director Biometry 
Sponsor draft 1.1 
Poxel 
Grazina Binkauskiene  
Lead Programmer 
Sponsor draft 1.1 
Labcorp 
Jean-Marie Grouin 
Statistical Consultant 
Sponsor draft 1.1 
JM Grouin 
Conseil 
Pascale Fouqueray 
EVP Clinical Development 
and Regulatory Affairs 
Sponsor draft 1.1 
Poxel 
Shubha Lakshmi 
Statistical Programmer 
Sponsor draft 1.1 
Labcorp 
Mark Senior 
Lead Statistician 
Sponsor draft 1.1 
Labcorp 
Julie Dubourg  
Medical Director 
Final v1.0 
Poxel 
Corporate confidential information 


Statistical Analysis Plan 
Sponsor Name: Poxel 
Sponsor Protocol ID: PXL065-003                     Labcorp Drug Development Study ID: 000000197965 
 
 
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Table of Tables 
Table 1 - Visit window groups ...................................................................... 20 
Table 2 - Visit windows .............................................................................. 21 
Table 3 - Imputation Rules for Incomplete Dates for AE and Concomitant Medication
 .............................................................................................................. 23 
 
Table of Figures 
Figure 1 Diagram of Study Design ................................................................ 12 
 
 
 
 
 
 
 
 
Jean-Marie Grouin 
Statistical Consultant 
Final v1.0 
JM Grouin 
Conseil 
Carole Thang 
Associate Medical 
Director 
Final v1.0 
Poxel 
Cecilia Bergounioux 
Clinical Data Manager 
Final v1.0 
Poxel 
Pascale Fouqueray 
EVP Clinical Development 
and Regulatory Affairs 
Final v1.0 
Poxel 
David Dolling 
Peer Review Statistician 
Sponsor draft 0.2 
Labcorp 
Grazina Binkauskiene 
Lead Programmer 
Internal draft 0.1 
Labcorp 
Friedrich Mittermayer 
Senior Medical Director 
Internal draft 0.1 
Labcorp 
Caroline Herbert 
Medical Writer 
Internal draft 0.1 
Labcorp 
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Glossary of Abbreviations 
Abbreviation 
Term 
AASLD 
American Association for the Study of Liver Diseases 
Adipo-IR 
Adipose tissue insulin resistance 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Anti-HCV 
Hepatitis C virus antibody 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BDRM 
Blinded data review meeting 
BMI 
Body Mass Index 
CGM 
Continuous glucose monitoring 
CI 
Confidence Interval 
CKD-EPI  
Chronic Kidney Disease – Epidemiology Collaboration  
CMH 
Cochran-Mantel-Haenszel  
COVID-19 
Coronavirus Disease 
CRF 
Case report form 
CRN 
Clinical Research Network 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR  
Estimated Glomerular Filtration Rate  
ELF 
Enhanced liver fibrosis 
EoS 
End-of-Study 
EoT 
End-of-Treatment 
ET  
Early termination 
FCS 
Fully conditional specification 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
FIB4 
Fibrosis 4 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase (GGT) 
HbA1c 
Glycated hemoglobin  
HBsAg 
Hepatitis B antigen 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Anti-human immunodeficiency virus  
HOMA-IR 
Homeostasis model assessment of insulin resistance 
HOMA-β 
Homeostasis model assessment of β-cell function 
HR 
Heart Rate 
hsCRP 
High-sensitivity C-reactive protein 


Statistical Analysis Plan 
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ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional review board 
ITTS 
Intent-to-treat set 
IWRS 
Interactive Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LFC 
Liver Fat Content 
LKAD 
Last known assessment date 
LLOQ 
Lower limit of quantification  
LSMs 
Least Square Means 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MRI-PDFF 
Magnetic Resonance Imaging – Proton Density Fat Fraction 
NAFLD 
Non Alcoholic Fatty Liver Disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic Steatohepatitis 
NFS 
NAFLD Fibrosis Score 
OAT 
Organic Anion Transporter 
OR 
Odds ratio 
PD 
Protocol deviation 
PDLC 
Predefined Limits of Change 
PK  
Pharmacokinetic(s) 
PPS 
Per-protocol Set 
pro-C3 
N-terminal type III collagen propeptide 
PT 
Preferred term 
QA 
Quality Assurance 
QD 
Quaque die 
QTcF 
Fridericia corrected QT interval 
QUICKI 
Quantitative insulin sensitivity check index 
RNA 
Ribonucleic acid 
RS 
Randomized Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard Deviation 
SEM 
Standard error of the mean 
SI 
International system of units 
SMBG 
Self-Monitoring Blood Glucose 
SOC 
System Organ Class 
SS 
Safety Set 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TFLs 
Tables, Figures and Listings 
TSH 
Thyroid-stimulating hormone 
TZD 
Thiazolidinedione 
ULN 
Upper Limit of Normal 


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ULOQ 
Upper limit of quantification 
WHO 
World Health Organization 
β-HCG 
Serum B Human Chorionic Gonadotropin 
 
 
 


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1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following documentation: 
Document 
Date 
Version 
Protocol 
17th December 
2020 
5.0 
eCRF 
24th Jan 2022 
5.01 
COVID-19 Memo 
19th August 2020 
1.0 
Note to file – Handling for patients at 
site 065-S22 
29th April 2022 
1.0 
2. Protocol Details 
2.1 Study Objectives 
Primary Objective  
• 
To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg 
QD) versus placebo on liver fat content (LFC) in nonalcoholic steatohepatitis 
(NASH) patients after 36 weeks of treatment. 
Secondary Objectives 
• 
To assess the safety and tolerability of 3 doses of PXL065 (7.5 mg QD, 15 mg 
QD and 22.5 mg QD) versus placebo in NASH patients after 36 weeks of 
treatment 
• 
To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg 
QD) versus placebo on metabolic and non-metabolic parameters in NASH 
patients after 36 weeks of treatment 
• 
To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg 
QD) versus placebo on histological changes in liver biopsy in NASH patients after 
36 weeks of treatment 
• 
To assess the effect of 3 doses of PXL065 (7.5 mg QD, 15 mg QD and 22.5 mg 
QD) versus placebo on histological changes in liver biopsy analyzed by 
automated digital images analysis in NASH patients after 36 weeks of treatment 
• 
To describe PXL065 pre-dose plasma concentrations during the course of the 
treatment and the pre- and post-dose concentrations in NASH patients after 36 
weeks of treatment 
2.2 Overall Study Design Per Protocol 
This study is a Phase 2, multi-center, double-blind, placebo-controlled, randomized study 
with 4 parallel groups in noncirrhotic, biopsy-proven NASH patients. 
There will be a total of 3 study periods, as follows: 
• 
Screening Period: maximum of 8 weeks 
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The screening period can be exceptionally extended after approval of the Labcorp medical 
monitor and the POXEL medical representative, if there is no more than 10 weeks 
between MRI-PDFF and Randomization Visit (V1). Screen failure patients may be eligible 
for re-screening once approval is provided by the Labcorp medical monitor and Poxel 
representative. Patients may only be re-screened once.  
• 
Double-blind treatment period: 36 weeks 
• 
Follow-up period: 2 weeks 
Patients will be randomized in a 1:1:1:1 ratio to receive either: 
• 
PXL065 7.5 mg oral QD 
• 
PXL065 15 mg oral QD 
• 
PXL065 22.5 mg oral QD 
• 
Placebo oral QD 
Randomization will be stratified according to type 2 diabetes mellitus (T2DM) status 
(T2DM patients versus non-T2DM patients) and the NASH Clinical Research Network 
(CRN) fibrosis score (F1 versus F2/F3).  
The diagram of the study design is shown in Figure 1 and the visit schedule is displayed 
in Appendix A. 
The duration of study for each patient from the first visit for the informed consent 
signature up to the end of the Follow-up period will be between 40-46 weeks. The 
end-of-study (EoS) is defined as the date of last visit of the last patient participating in 
the study.  
 
 
 
 
 
 
 
 
 
 


 
 
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Figure 1 Diagram of Study Design 
 
 
 


 
 
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2.3 Sample Size and Power 
The sample size determination is based on the primary endpoint, i.e. the relative change 
in LFC (assessed by magnetic resonance imaging – proton density fat fraction [MRI-PDFF] 
from baseline to Week 36 (V8-End of Treatment [EoT]) ([LFCW36 – LFCbaseline] / LFCbaseline) 
and the primary objective, i.e. to demonstrate the superiority of at least one PXL065 dose 
to placebo as tested by the following null hypothesis (H0) versus the alternative 
hypothesis (Ha):  
 
H0: µPXL065 - µplacebo = 0 versus Ha: µPXL065 - µplacebo < 0 
 
Where µplacebo and µPXL065 denote the mean relative change in the percentage of LFC from 
baseline to Week 36 in the PXL065 and placebo groups respectively.  
 
The following assumptions will be considered for the sample size determination:  
• 
No adjustment for multiple comparisons between PXL065 doses and placebo will 
considered and the usual nominal 1-sided alpha level of 0.025 (or equivalently 
the 2-sided level of 0.05) will be considered for each PXL065 dose vs placebo 
comparison  
• 
A power of 90%  
• 
An expected difference µPXL065 - µplacebo of -30% for at least one PXL065 dose vs 
placebo comparison  
• 
A standard deviation (SD) of the primary endpoint equal to 30%, as estimated 
from previous published data   
• 
With these assumptions, a sample size of 23 patients per arm is needed to 
achieve 90% power for at least one PXL065 dose vs placebo comparison.  
Assuming a dropout rate of 20%, around 30 patients per arm (120 = 4 x 30 patients in 
total) are needed to be randomized. 
2.4 COVID-19  
The COVID-19 memo provided alternative processes relative to those described in the 
protocol that may be used to conduct the study if needed to ensure subject safety and/or 
minimize impact on study integrity during the COVID-19 pandemic. For example, the 
screening window according to the memo can be extended from 8 weeks to 12 weeks. 
The visit window for Visit 2 and 3 can also be extended from +/- 4 days to 6 days. In 
addition, laboratory assessments can also be done locally if they cannot be collected for 
central laboratory testing and visits can be done virtually by phone or telehealth calls. 
However, if there are two consecutive virtual visits then the next one needs to be on-
site.  
Additional data related to COVID-19 will now also be collected for example, patients 
discontinuing due to COVID, patients failing screening due to COVID, patients missing 
visits due to COVID, interruption of study treatment due to COVID and missed visits due 
to COVID. This data will be presented in tables and listings. 
 


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Sponsor Protocol ID: PXL065-003                     Labcorp Drug Development Study ID: 000000197965 
 
 
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3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoint 
• 
Relative change in the percentage of LFC (assessed by MRI-PDFF) from baseline 
to Week 36 (V8-EoT) 
3.2 Secondary Efficacy Endpoints 
• 
Absolute change in the percentage of LFC (assessed by MRI-PDFF) from baseline 
to Week 36 (V8-EoT) 
• 
Response defined as an absolute reduction in LFC ≥ 5% from baseline to Week 
36  
(V8-EoT) 
• 
Response defined as a relative reduction in LFC ≥ 30% from baseline to Week 36  
(V8-EoT) 
• 
Response defined as a relative reduction in LFC ≥ 50% from baseline to Week 36  
(V8-EoT) 
• 
Response defined as a LFC value at Week 36 (V8-EoT) that is normalized, i.e. 
≤5% 
• 
Change in the following parameters from baseline to Week 36 (V8-EoT): 
− 
Liver enzymes: Alanine aminotransferase (ALT), Aspartate aminotransferase 
(AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) 
− 
Percentage of responders as defined by the percentage of patient with 
normalization of liver enzymes in the subset of patients with increased baseline 
value 
− 
Measured glycemic parameters: Fasting plasma glucose (FPG), Glycated 
hemoglobin (HbA1c), serum insulin, C-peptide 
− 
Insulin resistance indexes: Homeostasis model assessment of insulin 
resistance (HOMA-IR), Quantitative insulin sensitivity check index (QUICKI), 
Homeostasis model assessment of β-cell function (HOMA-β) and Adipose tissue 
insulin resistance (Adipo-IR) 
 
Exploratory endpoints 
Change from baseline in the following parameters at Week 36 (V8-EoT): 
• 
Adiponectin  
• 
Lipids: 
total 
cholesterol, 
low-density 
lipoprotein 
cholesterol 
(LDL-c), 
high-density lipoprotein cholesterol (HDL-c), triglycerides, free fatty acids 
(FFA) 
• 
Biomarker of inflammation: High-sensitivity C-reactive protein (hsCRP) 
• 
Biomarkers of fibrosis: N-terminal type III collagen propeptide (pro-C3), 
NAFLD Fibrosis score (NFS) and Fibrosis 4 (FIB-4) score and Enhanced Liver 
Fibrosis (ELF) score  
• 
Histological change in liver biopsy: 
o 
Change in NAFLD Activity Score (NAS), in each component of NAS 
(steatosis, ballooning and inflammation) and in NASH CRN fibrosis score 
o 
Improvement in each component of NAS (steatosis, lobular inflammation 
and hepatocellular ballooning) by ≥ 1 point without worsening of fibrosis 
o 
Improvement in NAS by ≥ 2 points without worsening of fibrosis 
o 
Improvement in NASH CRN fibrosis score by ≥ 1 point 


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o 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and 
any value for steatosis) 
o 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and 
any value for steatosis) with improvement in NASH CRN fibrosis score by 
≥ 1 point 
o 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and 
any value for steatosis) with no worsening in NASH CRN fibrosis score 
o 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and 
any value for steatosis) and improvement in NAS by ≥ 2 points with no 
worsening in NASH CRN fibrosis score 
• 
Histological changes (steatosis, inflammation, ballooning and fibrosis) 
quantified by automated digital images analysis. 
3.3 Safety Variables 
Safety and tolerability will be assessed on the following parameters: 
• 
Adverse events (AEs) 
• 
Physical examination 
• 
Weight, waist and hip circumferences, and BMI 
• 
Vital signs: systolic blood pressure (SBP), diastolic blood pressure (DBP), 
heart rate (HR) 
• 
Pitting edema assessment 
• 
12-lead electrocardiogram (ECG) 
• 
Bone mineral density in postmenopausal women 
• 
Biological parameters: biochemistry, hematology, coagulation 
• 
Estimated Glomerular Filtration Rate (eGFR) (Chronic Kidney Disease – 
Epidemiology Collaboration [CKD-EPI] formula) 
• 
Urinalysis 
4. Pharmacokinetic Variables 
Pharmacokinetics (PK) analysis will be done separately and consequently not reported in 
this SAP.  
5. Analysis Populations 
The analysis populations have been adapted due to data integrity being compromised at 
site 065-S22. Indeed, due to several ICH-GCP (International Council for Harmonisation 
– Good Clinical Practice) non-compliance and protocol deviations during the monitoring 
visits, LabCorp quality assurance (QA) issued a quality report and performed an on-site 
quality control visit. Following this visit, LabCorp QA advised Poxel QA to perform an on-
site audit to which the auditor reported six critical observations. Based on these 
observations, the site was put on-hold and Poxel notified the institutional review 
board (IRB) and the Food and Drug Administration (FDA). The site was then early 
terminated by Poxel. Despite several attempts to finalize the monitoring and perform the 
close-out visit, the site consistently refused to give access to the source data to LabCorp 
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monitoring team. As a result, the data recorded in EDC are partially source data verified 
and will not be signed by the principal investigator. Due to the criticality of the 
observations, the complete lack of trust in the principal investigator and site director, the 
lack of monitoring and absence of principal investigator signature (which could attest that 
the data entered in the eCRF and submitted to the sponsor are attributable, legible, 
original, accurate, complete, and contemporaneous), data integrity and quality of this 
site were judged as compromised. For these reasons, Poxel considers it is not possible to 
rely on these data. As a consequence, patients from site 065-S22 are excluded from 
principal analysis. Primary and some secondary endpoints will be analyzed including 
patients from site 065-S22 in a sensitivity analysis. Details of tables which will include 
site 065-S22 will be described in each dedicated part. In addition, site 065-S22 patients 
that did not complete the study will have treatment exposure end date coded as 23rd 
December 2021, corresponding with the site early termination date. This change will 
impact some derivations e.g., treatment-emergent AEs, duration of exposure, etc. Details 
of the quality issue and data handling at site 065-S22 are available in the note to file.  
5.1 Screened Set 
All patients except patients from site 065-S22, who were screened for inclusion into the 
study will be included in the screened set. Patients who are rescreened will be considered 
once utilizing their most recent subject identifier. 
5.2 Screened Set with Site 065-S22 
All patients who were screened for inclusion into the study will be included in the screened 
set with site 065-S22. Patients who are rescreened will be considered once utilizing their 
most recent subject identifier. 
5.3 Randomized Set (RS)  
All patients except patients from site 065-S22, considered as-randomized regardless of 
the treatment actually received. 
5.4 Randomized Set with Site 065-S22 (RS-w-065-S22)  
All patients including patients from site 065-S22, considered as-randomized regardless 
of the treatment actually received.  
5.5 Safety Set (SS)  
All randomized patients except patients from site 065-S22, having received at least one 
dose of the IMP (either PXL065 or placebo) and considered as-treated will be included in 
the Safety set. The Safety set will be considered as the primary set for safety and 
tolerability analyses. Safety patients are analyzed according to their actual treatment 
received. 
5.6 Safety Set with Site 065-S22 (SS-w-065-S22) 
All randomized patients including patients from site 065-S22 having received at least one 
dose of the IMP (either PXL065 or placebo) and considered as-treated will be included in 
the Safety set with site 065-S22. The Safety set with site 065-S22 will be considered as 
the secondary set for some safety and tolerability analyses. Safety patients are analyzed 
according to their actual treatment received. 
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5.7 Intent-to-treat Set (ITTS) 
The ITTS consists of all as-randomized patients excluding patients from site 065-S22, 
having received at least one dose of the IMP (either PXL065 or placebo). Patients will be 
assigned to the treatment group as-randomized regardless of the treatment actually 
received. The ITTS will be considered as the primary set for efficacy analyses. 
5.8 Intent-to-treat Set with Site 065-S22 (ITTS-w-065-S22)  
The ITTS-w-065-S22 consists of all as-randomized patients including patients from site 
065-S22, having received at least one dose of the IMP (either PXL065 or placebo). 
Patients will be assigned to the treatment group as-randomized regardless of the 
treatment actually received. The ITTS-w-065-S22 will be considered for the sensitivity 
analyses of the primary and secondary efficacy endpoints. 
5.9 Per-Protocol Set (PPS) 
The PPS consists of all ITTS-w-065-S22 patients without any important deviation of study 
procedures some of which include but are not limited to the following: 
• 
Inclusion/Exclusion criteria likely to affect the primary efficacy endpoint satisfied 
• 
Absence of relevant protocol violations with respect to factors likely to affect the 
primary efficacy endpoint where the nature of protocol violation will be defined 
before breaking the blind 
• 
Adequate study medication compliance (80-120%) for the overall treatment 
period where patient has passed Week 12. 
• 
Adequate measurement of the primary variable 
The above criteria for the PPS are described in further detail in Section 5.10. Important 
protocol deviations (PDs) will be identified prior to breaking the blind. All important 
protocol deviations will be assessed for exclusion from the PPS during the blinded data 
review meeting (BDRM).  
Patients in the PPS will be analyzed based on treatment actually received and actual 
strata rather than randomized.  
5.10 Important Protocol Deviations Leading to Exclusion from 
the PP Analysis 
All important and non-important protocol deviations are defined in a separate 
documentation where each PD’s detection methods are indicated by monitoring or 
programming. 
Only those important protocol deviations considered to have a major effect on the primary 
efficacy endpoint will lead to complete exclusion of the patient from the PPS. 
The following criteria have been identified as important protocol deviations leading to 
exclusion from the PPS as it is considered that the occurrences of any of these criteria 
might have an important influence on the primary efficacy endpoint.  
Note: Emergency unblinding may lead to a patient being removed from PPS even if it is 
not included as a PD.  


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5.10.1 
Failure of Inclusion/Exclusion Criteria 
Non-compliance with Inclusion / Exclusion criteria leading to exclusion from PPS will be 
described in the BDRM minutes.    
Per protocol, if a patient who does not meet the inclusion/exclusion criteria mistakenly 
enters the double-blind treatment period, a discussion should occur between the POXEL 
Medical Representative, the Labcorp Medical Monitor and the Investigator regarding 
whether to continue or discontinue the IMP, based on patient’s safety and study’s 
consideration. In situations where an agreement cannot be reached, the patient should 
be withdrawn from the study. In such case, patients will be considered as withdrawn from 
the study due to protocol deviation (GCP non-compliance) and may be excluded from 
PPS. 
5.10.2 
Prohibited Medications 
Prohibited medications leading to exclusion from PPS will be described in the BDRM 
minutes. Per protocol, patients must not take any of the following licensed medications 
from the Randomization Visit (V1) up to Week 38 (V9-EoS): 
• 
Any medication containing pioglitazone (e.g. Actos®, Actoplus Met®, Duetact®, 
Oseni®) or other approved or experimental TZD (e.g. rosiglitazone (Avandia®), 
leriglitazone (MIN-102), MSDC-0602K), or PPARγ agonists  
• 
Any other antidiabetic drug except those permitted in the inclusion criterion #5 
(Protocol Section 5.1 Inclusion critera: Metformin, sitagliptin, alogliptin, 
empagliflozin, canagliflozin, and dapagliflozin) 
• 
Topiramate 
• 
Amiodarone 
• 
Bile salt chelators 
• 
Methotrexate 
• 
Chronic corticosteroids (> 2 consecutive weeks) with a systemic effect (e.g. oral 
or intravenous administrations) at doses ≥10 mg/day of oral prednisone (or 
equivalent) 
• 
Equal or more than 800 U of vitamin E per day 
• 
Orlistat 
• 
Obeticholic acid 
• 
Any other medications (including vitamins, herbal and dietary supplements) 
known to affect liver function/steatosis at the Investigator’s discretion 
• 
Inducer of CYP2C8 (rifampicin) 
• 
Strong and moderate inhibitors of CYP2C8 (gemfibrozil, clopidogrel, letermovir, 
deferasirox, teriflunomide) 
• 
Strong inhibitors of OAT1 and OAT3 (darolutamide, tenofovir) 
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5.10.3 
Accidental or Emergency Unblinding During Treatment 
Period 
If the treatment code for a patient is inadvertently revealed to one or more site staff or 
project team members who should have remained blind until database lock, this will lead 
to patient exclusion from the PPS. 
If it becomes necessary for the investigator to unblind a specific patient in an emergency 
because of a safety concern, this will exclude the patient from the PPS. 
5.10.4 
Errors in Treatment Allocation During Treatment Period 
Some patients may have received the wrong IMP treatment at one or more study visits 
due to randomization, packaging or dispensing errors. 
If the wrong treatment was received at all or most visits, then the patient should be 
assigned to the actual or predominant treatment received in the PPS analysis at all visits 
(in contrast to the randomized treatment for the ITTS-w-065-S22 /ITTS analysis). 
If the wrong treatment was received at a single visit, then the patient should be assigned 
to the randomized treatment in the PPS analysis at all visits, possibly with exclusion of 
the patient from the PPS if this is considered of sufficient concern for key efficacy 
conclusions. 
Impact of incorrect IMP administration on efficacy analysis will be discussed and decided 
prior to database lock and unblinding at the BDRM. 
5.10.5 
Adequate Study Medication Compliance 
The acceptable overall compliance will be within 80% - 120% (≥80% - ≤120%). If at 
any visit the compliance does not fall within this range, it must be reported as a protocol 
deviation (if it occurs anytime during treatment period), however, this may not necessary 
mean that the patient will be excluded from the PPS and will be reviewed by the study 
team at the BDRM. 
5.10.6 
Assessment of Important Protocol Deviations 
Important protocol deviations which require clinical or medical monitoring interpretation 
will be reviewed periodically during the protocol deviations review by the team. 
All-important protocol deviations leading to exclusion from the PPS occurring during the 
study will be reviewed and approved by Poxel prior to unblinding during the BDRM. 
Should additional important protocol deviations leading to exclusion from the PPS, not 
anticipated at the time of preparing this SAP, be identified during the study (and prior to 
unblinding) they will be documented in a SAP amendment/updated Important Protocol 
Deviations Designation and Escalation document and included in all relevant protocol 
deviation reviews and approvals. 
 


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6. DATA Handling 
6.1 Time Points and Visit Windows 
Day 1 is defined as the day of randomization. Relative days after Day 1 are calculated as 
(assessment date – Day 1 date) + 1.  Relative days prior to Day 1 are calculated as 
(assessment date – Day 1 date).  The day prior to Day 1 is Day -1.  
To maximize the data available for analysis, where possible, results from ET and 
Unscheduled Visits will be allocated to scheduled visit according to the following rules and 
visit windows described in Table 2.  
• 
If a valid value exists for the scheduled visit to which the ET/Unscheduled Visit has 
been allocated then the value from the scheduled visit will be used in the analysis, 
otherwise the values from the ET/Unscheduled Visits will be used in the analysis 
for the particular scheduled visit.  
• 
If more than one ET/Unscheduled Visit is allocated to the same scheduled visit 
(and no valid value from the scheduled visit is available) then the closest visit 
value will be used in the analysis for the scheduled visit. 
Visit Windowing rules are defined according to parameters groups in Table 1Table 1 - 
Visit window groups and the windows in Table 2. 
Double-blind treatment period is defined as the period between the randomization visit 
(V1) and the EoT visit (V8). Follow-up period is defined as the period between the EoT 
visit (V8) and the EoS visit (V9). 
Table 1 - Visit window groups 
Visit window group 
Visits 
Parameters 
Group 1 
All visits 
Pitting edema assessment, vital signs and body 
measurements, physical examination 
Group 2 
Screening, V1, V4, V6, V8 
HbA1c 
Group 3 
Screening, V1, V4, V6, V8, V9 
Safety lab, FPG 
Group 4 
Screening, V1, V5, V8, V9 
ECG 
Group 5 
Screening, V8 
DXA, MRI-PDFF, Liver biopsy 
Group 6 
Screening, V1, V8 
eGFR 
Group 7 
Screening, V1, V5, V9 
Pregnancy test 
Group 8 
V1, V4, V6, V8 
Measured metabolic parameters, insulin resistance 
indexes 
Group 9 
V1, V8 
Fibrosis biomarkers, biobanking sampling 
 
 
 
 


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Table 2 - Visit windows 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Relative to the date of randomization (Day 1)  
 
Visits 
Study 
day a 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Group 6 
Group 7 
Group 8 
Group 9 
Screening 
N/A 
-∞ to -1 
-∞ to -1 
-∞ to -1 
-∞ to -1 
-∞ to -1 
-∞ to -1 
-∞ to -1 
 
 
Randomiz
ation 
1 
1 to 12 
1 to 43 
1 to 43 
1 to 64 
 
1 to 127 
1 to 64 
1 to 43 
1 to 127 
Week 3 
22 
13 to 33 
 
 
 
 
 
 
 
 
Week 6 
43 
34 to 64 
 
 
 
 
 
 
 
 
Week 12 
85 
65 to 106 
44 to 127 
44 to 127 
 
 
 
44 to 127 
 
Week 18 
127 
107 to 148 
 
65 to 190 
 
 
65 to 197 
 
 
Week 24 
169 
149 to 190 
128 to 211 
128 to 211 
 
 
 
 
128 to 211 
 
Week 30 
211 
191 to 232 
 
 
 
 
 
 
Week 36 
253 
233 to 260 
212 to ∞ 
212 to 260 
191 to 260 
79 to ∞ 
128 to ∞ 
 
212 to ∞ 
128 to ∞ 
Week 38 
267 
261 to ∞ 
 
261 to ∞ 
261 to ∞ 
 
198 to ∞ 
 
 


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6.2 Handling of Dropouts 
A patient who discontinues study participation prematurely for any reason after 
randomization is defined as a “dropout”. Patients who drop out will not be replaced. 
A patient who, for any reason (e.g., failure to satisfy the selection criteria), terminates 
the study before the time point used for the definition of “dropout” in this study is 
regarded a screen failure. 
In all cases, the reason for withdrawal must be entered in the eCRF and in the patient’s 
medical records. 
6.3 Handling of Patients from Site 065-S22 
Patients included at site 065-S22 will be presented in all listings and in specific tables of 
interest.  
6.4 Handling of Rescreened Patients 
Patients who are rescreened will be presented once in summary tables utilizing the most 
recent subject identifier. Both new and old subject identifier will be presented in listings.  
6.5 Handling of Missing Data 
In order to achieve the goal of a well conducted clinical trial according to International 
Council on Harmonization Good Clinical Practice, every effort should be made to collect 
all data (i.e., if a patient misses a scheduled assessment, the site personnel should 
contact the patient and request him/her to come to the clinic for the visit). However, 
despite best efforts, it may be inevitable that missing or incomplete data are reported. 
All missing or partial data will be presented in the patient data listings, as they were 
recorded on the eCRF. 
6.5.1 Safety Variables 
Incomplete adverse event start or stop dates and concomitant medication start or stop 
dates will be imputed to determine treatment-emergent AE and concomitant medication 
as described in Table 3. Missing or partial dates will be presented in the patient data 
listings as they were recorded on the CRFs. 
 
 
 
 
 
 
 


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Table 3 - Imputation Rules for Incomplete Dates for AE and Concomitant 
Medication 
 Note: If first dose date is missing, use randomization date for the imputation. 
          If the imputed start date is after the stop date, the start date will be imputed to  
        equal the stop date. 
          If the imputed stop date is before the start date, the stop date will be imputed to  
        equal the start date. 
 
6.5.2 Laboratory Values 
For laboratory values below the lower limit of quantification (LLOQ) like “<xxx” or “≤xxx”, 
or above the upper limit of quantification (ULOQ) like “>xxx” or “≥xxx”, LLOQ or ULOQ 
(xxx) will be used for calculation of descriptive statistics. The original laboratory values 
(“<xxx”, “≤xxx”, “>xxx” or “≥xxx”) are presented in the listing. 
6.5.3 Type 2 Diabetes Diagnosis 
Partial dates for diagnosis of type 2 diabetes will be handled in the following way, 
• 
Missing day only: Impute using the last day of the month 
• 
Missing day and month: Impute using the last day of the year 
  
Missing 
Scenario 
Imputation 
Start date  
(AE, 
concomitant 
medication) 
Day 
Event month&year < 
month&year of first dose 
last day of the month 
Event month&year = 
month&year of first dose 
first dose date 
Event month&year > 
month&year of first dose 
first day of the month 
Day / 
Month 
Event year < year of first 
dose 
December 31 
Event year = year of first 
dose 
first dose date 
Event year > year of first 
dose 
January 01 
Complete 
missing 
AE: first dose date 
Conmed: no imputation 
Stop date  
(AE, 
concomitant 
medication) 
Day 
Event month&year < 
month&year of last known 
assessment date (LKAD) 
last day of the month 
Event month&year = 
month&year of LKAD 
date of LKAD 
Event month&year > 
month&year of LKAD 
no imputation 
Day / 
Month 
Event year < year of LKAD 
December 31 
Event year = year of LKAD 
date of LKAD 
Event year > year of LKAD 
no imputation 
Complete 
missing 
  
date of LKAD 


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If the imputed date goes beyond the informed consent date, then impute to the 
date of informed consent.  
7. Statistical Methods 
7.1 General Principles 
All data processing, summarization and analyses will be performed using Labcorp’s SAS 
Environment / Version 9.4 (or later) of the SAS statistical software package. 
The following principles will be applied to all tables, figures and listings (TFLs) unless 
otherwise stated: 
Principle 
Value 
Significant tests 
Two-sided and use a 5% significance level for main effect 
Treatment group labels 
and order presented 
PXL065 7.5mg QD 
PXL065 15 mg QD 
PXL065 22.5mg QD 
Placebo 
Visit labels presented 
Tables and Figures: 
     Week XX 
Listings: 
Screening 
Randomization (V1) 
Week 3 (V2) 
Week 6 (V3) 
… 
Week 36 (V8-EoT) 
End of Study (V9-EoS) 
Early termination 
Unscheduled 
Tables 
Data in summary tables presented by treatment group, 
assessment (where applicable) and analysis visit (where 
applicable).  
Listings 
All data collected presented by treatment group, patient, 
nominal visit, Date unless otherwise specified.  
Descriptive summary 
statistics for continuous 
variables 
Number of patients/observations (N) 
Mean 
SD 
standard error of the mean (SEM), median 
interquartile range (25th percentile, 75th percentile) (Q1, Q3)  
minimum and maximum 
Descriptive summary 
statistics for categorical 
variables 
Frequency counts and percentages: 
n (%) 
Denominator for 
percentages 
Number of patients in the analysis population, unless stated 
otherwise in table shell(s). 
Include “Missing” as 
category 
Yes, when the number missing is greater than zero for at 
least one treatment group.  


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Principle 
Value 
Display for 0 
percentages 
Leave blank 
Display to one more 
decimal place than 
collected value 
Mean 
SEM 
Mean Difference 
Median 
Interquartile range (Q1, Q3) 
Display to 2 more 
decimal places than 
collected value 
SD 
Confidence Intervals (CI) 
Limit of precision for 
displays 
3 decimal places 
Date Format for the 
presentation in the 
listings 
DDMMMYYYY 
 
The baseline value is defined as last scheduled or unscheduled value collected prior to 
the first dose of IMP treatment, scheduled on Randomization Visit (V1). Assessments 
carried out on day of first treatment administration are considered to have taken place 
before the IMP administration, if the corresponding times have not been recorded. 
7.2 Patient Disposition and Data Sets Analyzed 
Patient disposition will be listed and summarized (for screened set and screened set with 
site 065-S22) by treatment group and overall and will include the number and percentage 
of patients: 
• 
Screened; 
o 
Discontinued during screening period; 
 
Discontinued during screening period due to COVID-19 
• 
Randomized into double-blind period 
o 
Randomized but did not receive a dose of IMP  
o 
Randomized and received at least one dose of IMP; 
 
Randomized but discontinued IMP/Study; 
• 
Patients whose primary reason for withdrawal was due to 
COVID-19 pandemic circumstances; 
• 
Patients who had study treatment temporarily interrupted due 
to COVID-19 pandemic circumstances 
• 
Randomized but not completed due to Site Early Termination; 
 
Completed double-blind period 
• 
Patients who had study treatment temporarily interrupted due 
to COVID-19 pandemic circumstances 
• 
Entered into follow-up period 


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o 
Discontinued during follow-up period; 
 
Patients whose primary reason for withdrawal was due to COVID-19 
o 
Completed follow-up period 
In addition, the number and percentage of patients who discontinue early, including a 
breakdown of the primary reasons for discontinuation from study, will be presented. 
A summary of the reasons for screen failure will be produced. 
A summary table of randomized patients by site and treatment group will be provided for 
the randomized set.  
A summary table of patients included in each study population (RS, Safety, ITT, PPS) will 
be produced for the Randomized set and Randomized set with site 065-S22. A listing of 
patients included from each population will be produced, for the Randomized set with site 
065-S22.  
In addition, a summary table and listing will be produced for discrepancies between the 
stratification factors in the database and Interactive Web Response System (IWRS). 
A listing of IMP kit numbers and assignments will be produced for the Randomized set 
with site 065-S22.  
7.3 Protocol Deviations 
All protocol deviations (important and non-important) will be listed by treatment group 
for the Randomized set with site 065-S22. 
All-important protocol deviations leading to exclusion from the PPS (see Section 5.10) 
will be listed for the ITTS-w-065-S22 and summarized by treatment group for the ITTS. 
The protocol deviations will be identified before data are unblinded near database lock. 
7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed for the ITTS-w-065-S22 and 
summarized by treatment group and overall for the ITTS. Standard descriptive statistics 
will be presented for: 
• 
Sex; 
• 
Race (American Indian or Alaska Native, Asian, African American, Native 
Hawaiian or Other Pacific Islander, White, Other); 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, not stated, unknown); 
• 
Age (years) at screening (derived on eCRF); 
• 
Age group (years) at screening (<65 years, ≥ 65 years) ; 
• 
Height (cm) at screening visit; 
• 
Weight (kg) at baseline; 
• 
Body mass index (BMI) (kg/m2) (derived on eCRF) at baseline; 
• 
BMI (<median, ≥ median) at baseline; 


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• 
Child-bearing potential (yes, no, not applicable); 
• 
Randomization strata of T2DM status (T2DM patients, non-T2DM patients); 
• 
Randomization strata of NASH CRN fibrosis scoring system (F1, F2/F3); 
• 
Baseline LFC (%) (<median, ≥ median); 
• 
Baseline LFC (%); 
• 
Baseline ALT (U/L); 
• 
Baseline HbA1c (%); 
• 
Baseline FPG (mmol/L); 
• 
Previously diagnosed with type 2 diabetes mellitus (Yes, No); 
• 
Diabetes duration (Years); 
• 
Patient currently treated for diabetes (Yes, No); 
• 
Alcohol status (Never, former, current); 
• 
If former or current, alcohol units consumed per week; 
• 
Habitual cigarette smoking status (Never, former, current); 
• 
If former or current, number of cigarettes per day; 
• 
Other habitual tobacco or nicotine use (Never, former, current); 
• 
Any history of drug abuse (Yes, No); 
• 
Site pooling (Investigators speciality [Hepatologist, Others]);  
The demographic and baseline characteristics table will be repeated in 4 additional 
populations in the ITTS: Diabetic patients, non-diabetic patients, F1 patients and F2/F3 
patients. All of these populations will be based on the randomization strata. The derivation 
of the medians for BMI and LFC will be based on the subset populations.  
For randomization strata, the stratification factors as used in the IWRS randomization will 
be summarized. 
No formal tests of statistical significance will be performed on the demographic and 
baseline data.  
Other baseline measurements, such as vital signs and ECG, will be summarized by 
treatment group with post-baseline measurements.  
Demographic and baseline characteristics table will also be repeated in ITTS-w-065-S22. 
7.4.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 23.0].  
All medical history will be listed for Safety set with site 065-S22, and the number and 
percentage of patients with any medical history will be summarized for Safety set by 
system organ class (SOC) and preferred term (PT) for each treatment group sorting by 
descending overall frequency of SOC, and within SOC by descending incidence of PT. 
 


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7.4.2 Previous and Concomitant Medications 
Medications received prior to or concomitantly with IMP treatment will be coded by 
Labcorp using the World Health Organization (WHO) Drug Dictionary [Version WHODrug 
Mar 2020], Anatomical Therapeutic Chemical (ATC) Classification codes.  
Prior medications and concomitant medications are defined as follows: 
Prior medications are defined as medications taken within 28 days prior to informed 
consent form (ICF) signature and stopped before or on ICF signature date. 
Concomitant medications are medications that are ongoing before and continue after the 
ICF signature 
New medications are medications that are prescribed during the study (Starting after ICF 
signature). 
If a medication cannot be classed as prior or concomitant after applying imputation rules 
for missing/incomplete dates, it will be classed as concomitant. 
Prior, concomitant and new medications will be listed for the Safety set with site 065-S22 
and summarized separately for the Safety set, with summary tables displayed by 
treatment group.  
The number and percentage of patients using each medication will be displayed together 
with the number and percentage of patients using at least one medication within each 
indication, WHO ATC-Level 1, WHO ATC-Level 3, therapeutic class, and PT. The number 
and percentage of patients using medication for each different indication will also be 
displayed.  
7.5 Measurements of IMP Treatment Compliance 
 
7.5.1 Compliance 
Overall compliance based on IMP accountability will be presented for the double-blind 
treatment period by treatment group. 
Compliance will be calculated using the following formula based on accountability records 
on the eCRF: 
Number of tablets taken ×100 
Theoretical number of tablets to be taken during the period (based on visit days) 
Compliance as recorded in the eCRF will also be presented for each visit: 
• 
Randomization Visit (V1) to V3, V3 to V4, V4 to V5, V5 to V6, V6 to V7 and V7 to 
V8 
Percentage compliance will be listed for the Safety set with site 065-S22 and summarized 
descriptively by treatment group for the ITTS and Safety set. 
The following percentage compliance categories will also be presented: 


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• 
<80.0% 
• 
≥80.0% and ≤120.0% 
• 
>120.0% 
7.5.2 Overdose 
This study will be blinded during the treatment period. Since the daily dose received will 
be unknown up to the end of the study, an overdose can only be identified relying on the 
number of tablets administered over a defined period of time. 
An overdose is defined as any dose greater than the daily dose prescribed, equivalent to 
the intake of 3 or more tablets per day, in any of the treatment groups.  
Overdose events will be listed for the Safety set with site 065-S22. 
Cases of overdose may constitute AEs or serious adverse events (SAEs) and will also be 
presented in the relevant AE/SAE summaries and listings, see Adverse Events (section 
7.7.2) below. 
7.6 Efficacy 
7.6.1 Primary Endpoint 
7.6.1.1 
Primary Analysis 
The primary evaluation of efficacy will be based on MRI-PDFF. The primary endpoint will 
be the relative change in the percentage of LFC from baseline to Week 36 (V8-EoT) in 
the ITTS.  
For patients who withdraw from the study at or after Week 12 (V4), the LFC will be 
assessed at ET as far as possible. With the assumption that the LFC assessed at or after 
Week 12 (V4) reflects what could have been observed at Week 36 (V8-EoT), the missing 
LFCs at Week 36 (V8-EoT) will be estimated by this value. For patients who withdraw 
before Week 12 (V4) or withdraw without any LFC assessment at or after Week 12 (V4), 
LFC missing values at Week 36 (V8-EoT) will be imputed using a multivariate imputation 
approach by fully conditional specification (FCS) regression method assuming missing at 
random (MAR) mechanism. The set of variables included in the multiple imputation model 
will be randomized treatment, type 2 diabetes mellitus status (T2DM patients versus non-
T2DM patients), NASH CRN fibrosis scoring system (F1 versus F2/F3), and baseline LFC. 
The number of imputed datasets generated will be 1000 with the burn-out iterations set 
at 100. A minimum value of 0 and a maximum value of 50 will also be applied to restrict 
imputed LFC values, see  
 
 
 
 
 
 
 


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Appendix B: Sample SAS® code for analyses of efficacy endpoints for example SAS code. 
Each of the complete datasets after imputation will then be analyzed in an analysis of 
covariance (ANCOVA) model adjusting for treatment and for randomization stratification 
factors, i.e. T2DM status (T2DM patients versus non-T2DM patients) and NASH CRN 
fibrosis scoring system (F1 versus F2/F3), and for the baseline LFC as a continuous 
covariate in the ITTS. Results from each complete dataset will be combined using Rubin’s 
rule to provide the least square means (LSMs) for treatment groups at Week 36, standard 
error of the LSM, pairwise differences (PXL065 7.5 mg QD, 15 mg QD and 22.5 mg QD 
versus placebo) in LSMs, p-values and 95% CIs, see  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix B: Sample SAS® code for analyses of efficacy endpoints for example SAS code. 
The ANCOVA model validity will be checked using appropriate plots (studentized residuals 
vs predicted values, etc.). 
In addition, descriptive statistics on the non-imputed LFC and percentage changes from 
baseline will be calculated by visit within each treatment group. 


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A listing of LFC data will be produced for the ITT set with site 065-S22. 
7.6.1.2 
Sensitivity Analysis for the Primary Analysis 
The imputation method described in the primary analysis will be repeated and each of 
the complete datasets after imputation will then be analyzed with non-parametric 
pairwise Wilcoxon tests stratified according to T2DM status and NASH CRN fibrosis scoring 
system. Hodges-Lehmann midpoint estimates along with their 95% confidence intervals 
will also be provided for the ITTS for each imputed data set and then combined using 
Rubin’s rule, see Appendix C for example SAS code. 
7.6.1.3 
Other Analyses for the Primary Endpoint  
The same statistical analyses described in Sections 7.6.1.1 and 7.6.1.2 will be repeated 
for the ITTS-w-065-S22.  
Additionally, analyses described in Sections 7.6.1.1 and 7.6.1.2 will be repeated without 
the multivariate imputation on missing Week 36 data for the ITTS and the PPS.  
7.6.1.4 
Subgroup Analysis 
Subgroup analyses will be performed for the primary endpoint for the following 
subgroups: 
• 
Baseline age group (<65 years, ≥ 65 years) ; 
• 
Baseline BMI (<median, ≥ median); 
• 
Sex (female and male); 
• 
Randomization strata of T2DM status (T2DM patients, non-T2DM patients); 
• 
Randomization strata of NASH CRN fibrosis scoring system (F1, F2/F3); 
• 
Baseline LFC (<median, ≥ median); 
• 
Site pooling. (Investigators specialty [Hepatology, Other]);  
For each subgroup, the LSM differences and the 90% CI will be presented. The subgroup 
by treatment interaction will be tested at the nominal alpha level of 0.1. The subgroup 
analysis will be performed on the ITTS.  
7.6.2 Secondary Endpoints 
7.6.2.1 
Absolute Change in LFC 
The absolute change in LFC (assessed by MRI-PDFF) from baseline to Week 36 (V8-EoT) 
will be analyzed in ANCOVA model adjusting for treatment, T2DM status (T2DM patients 
versus non-T2DM patients), and NASH CRN fibrosis scoring system (F1 versus F2/F3) 
and for baseline LFC as a continuous covariate. The method applied to missing data for 
the primary endpoint in Section 7.6.1.1 will also be utilized for this secondary endpoint. 
LSMs for treatment groups, standard error of the LSM, pairwise differences (PXL065 7.5 
mg QD, 15 mg QD and 22.5 mg QD versus placebo) in LSMs, p-values and 95% CIs will 


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be presented. In addition, descriptive statistics for LFC and change from baseline will be 
calculated by visit within each treatment group.  
The ANCOVA model validity will be checked using appropriate plots (studentized residuals 
vs predicted values, etc.). 
The analysis described in Section 7.6.1.2 and 7.6.1.3, except for the ITTS-w-065-S22 
will also be done for this secondary endpoint.  
7.6.2.2 
Analysis of Responders 
The 4 types of responders that will be analyzed are: 
• 
Absolute reduction in LFC ≥ 5% from baseline to Week 36 (V8-EoT)  
• 
Relative reduction in LFC ≥ 30% from baseline to Week 36 (V8-EoT)  
• 
Relative reduction in LFC ≥ 50% from baseline to Week 36 (V8-EoT)  
• 
LFC value at Week 36 (V8-EoT) that is normalized, i.e. ≤5%  
For each response, responder rate will be provided within each treatment group. The 
stratified Cochran-Mantel-Haenszel (CMH) will primarily be used to analyze the 
responders, stratifying for T2DM status (T2DM patients versus non-T2DM patients) and 
NASH CRN fibrosis scoring system (F1 versus F2/F3). Each PXL065 treatment group will 
be compared with placebo. The odds ratios (ORs), 95% CIs for the ORs, and p-values will 
be displayed for the ITTS. In addition, the number of responder’s and non-responders 
will be displayed for each treatment group, see  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix B: Sample SAS® code for analyses of efficacy endpoints for example SAS code.    


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The binary response will also be analyzed using a logistic regression model adjusting for 
treatment, stratification factors, i.e. T2DM status (T2DM patients versus non-T2DM 
patients) and NASH CRN fibrosis scoring system (F1 versus F2/F3), and for the baseline 
LFC as a continuous covariate. Pairwise differences for each PXL065 treatment group vs 
placebo will be estimated in the model as ORs along with their p-values and 95% CI. The 
binary response will also be analyzed using the approach proposed by Ge et al. (2011), 
see Appendix C: Ge et al. code.  
For each type of responder and analysis described above (CMH and logistic regression), 
two different methods of data handling will be applied: 
• 
Multiple imputation as per Section 7.6.1.1 
• 
No imputation and analysis set restriction (Restricting analysis to only include 
patients with Week 36 assessments) 
Analysis of responder defined as relative reduction in LFC ≥ 30% from baseline to Week 
36 (V8-EoT), will be repeated in the ITTS-w-065-S22, using multiple imputation as per 
Section 7.6.1.1. 
7.6.2.3 
Other Secondary Continuous Endpoints 
Efficacy will be further assessed based on the following secondary continuous endpoints: 
• 
Liver enzymes: ALT, AST, GGT, ALP 
• 
Measured glycemic parameters: FPG, HbA1c, serum insulin, C-peptide  
• 
Insulin resistance indexes: HOMA-IR, QUICKI, HOMA-β, Adipo-IR  
The change from baseline (Randomization Visit [V1]) to Week 36 (V8) will be analyzed 
using a Mixed Model for Repeated Measures (MMRM) for the secondary continuous 
parameters with fixed effects for treatment, stratification factors, i.e. T2DM status (T2DM 
patients versus non-T2DM patients) and NASH CRN fibrosis scoring system (F1 versus 
F2/F3), baseline endpoint specific parameter value, time-point, and treatment by 
time-point interaction. Covariance parameters will be estimated via the REML method. 
Compound symmetry will be used for the covariance structure. The Kenward and Roger’s 
method for evaluating the degrees of freedom will also be used. Example SAS code is 
shown in Appendix C. 
All patients in the ITTS with non-missing baseline data and at least one post-baseline 
data are included in the analysis mode, which uses values at all time points with data 
available. The MMRM analyses will use observed data only, no imputations of data will be 
performed.  
The LSMs for change from baseline at Week 36 and LSM differences for change from 
baseline between PXL065 treatment groups and placebo will be presented along with 
95% CIs and the comparison p-value. A two-sided nominal significance level of 0.05 will 
be used for treatment comparison. 
In addition, the results and changes from baseline at scheduled visits will be summarized 
by treatment group and visit using standard descriptive statistics for the ITTS. 
The same statistical analyses described above will be repeated for the ITTS-w-065-S22 
for the following secondary continuous endpoints: 
• 
Liver enzymes: ALT, AST 


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• 
Measured glycemic parameters: FPG, HbA1c  
A listing of secondary continuous efficacy endpoint data will be produced for the ITT set 
with site 065-S22.  
7.6.2.4 
Other Secondary Categorical Endpoint 
The other secondary categorical endpoint is responders with the following criteria: 
• 
Patients with normalization of liver enzymes in the subset of patients with 
increased baseline value  
Normalization of liver enzymes (ALT, AST, GGT or ALP) will be analyzed in the subset of 
patients with baseline greater than the upper reference range for the respective liver 
enzyme parameter. Patients will be classed as responders if the liver enzyme normalizes, 
i.e. decreases to < upper reference range at a post baseline visit. 
Responder rate will be provided within each treatment group. Patients who have no 
assessments at a particular visit will be defined as non-responders. The stratified CMH 
will primarily be used to analyze the responders, stratifying for T2DM status (T2DM 
patients versus non-T2DM patients) and NASH CRN fibrosis scoring system (F1 versus 
F2/F3). Each PXL065 treatment group will be compared with placebo. The OR, 95% CIs 
for the OR, and p-values will be displayed for the ITTS. In addition, the number of 
responders and non-responders will be displayed for each treatment group, see Appendix 
C for example SAS code.    
7.6.2.5 
Subgroup Analysis 
Analysis of responder defined as relative reduction in LFC ≥ 30% from baseline to Week 
36 (V8-EoT), will have a subgroup analysis performed using multiple imputation as per 
Section 7.6.1.1 for the following groups: 
• 
Randomization strata of T2DM status (T2DM patients, non-T2DM patients) 
• 
Randomization strata of NASH CRN fibrosis scoring system (F1, F2/F3) 
The MMRM analysis described in Section 7.6.2.3 will have subgroup analysis performed 
for the following parameters and subgroups in the ITT Set: 
• 
ALT (U/L) 
o 
Randomization strata of T2DM status (T2DM patients, non-T2DM patients) 
o 
Randomization strata of NASH CRN fibrosis scoring system (F1, F2/F3) 
• 
AST (U/L) 
o 
Randomization strata of T2DM status (T2DM patients, non-T2DM patients) 
o 
Randomization strata of NASH CRN fibrosis scoring system (F1, F2/F3) 
• 
FPG (mmol/L) 
o 
Randomization strata of T2DM status (T2DM patients, non-T2DM patients) 
• 
HbA1c (%) 
o 
Randomization strata of T2DM status (T2DM patients, non-T2DM patients) 
 


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7.6.3 Exploratory Endpoints 
The analyses described in Section 7.6.2.3 will be repeated for the ITTS for the following 
endpoints: 
• 
Adiponectin 
• 
Lipids (Percentage change): total cholesterol, LDL-c, HDL-c, triglycerides, FFA 
• 
Biomarker of inflammation: hsCRP 
For lipids (total cholesterol, LDL-C, HDL-C, triglycerides and FFA) summary statistics will 
be provided for both, absolute and percent change from baseline. 
Biomarkers of fibrosis (pro-C3, NFS, FIB-4 and ELF score) will be analyzed using a linear 
regression with the following covariates, treatment, T2DM status (T2DM patients versus 
non-T2DM patients) and NASH CRN fibrosis scoring system (F1 versus F2/F3), and for 
the baseline endpoint specific parameter value. LSMs for treatment groups, standard 
error of the LSM, pairwise differences (PXL065 7.5 mg QD, 15 mg QD and 22.5 mg QD 
versus placebo) in LSMs, p-values and 95% CIs will be presented. In addition, descriptive 
statistics for each parameter and change from baseline will be calculated by visit within 
each treatment group.  
The change from baseline in NAS, in each component of NAS (steatosis, ballooning and 
inflammation), total NAS score and in NASH CRN fibrosis score will be analyzed using a 
non-parametric ANCOVA method of Koch, Tangen, Jung, and Amara (Koch et al), with 
fixed effects for treatment, stratification factors, i.e. T2DM status (T2DM patients versus 
non-T2DM patients) and NASH CRN fibrosis scoring system (F1 versus F2/F3), baseline 
endpoint specific parameter value. This analysis will be performed using the SAS macro 
for non-parametric randomization-based ANCOVA ‘NParCov4’. An example of the SAS 
code is given below: 
%NParCov4(OUTCOMES=chg, COVARS=diab fibrosis base, 
HYPOTH=ALT, TRTGRPS=trtpn, TRANSFORM=NONE, 
DSNIN=<dataset>, DSNOUT=<outd 
at _outdat_deptest outdat_ci>); 
 
where 
 
chg 
  
= change from baseline analysis value  
trtpn   
= treatment (numeric value for planned treatment) 
diab 
 
= type 2 diabetes category (yes, no) 
gender 
= gender category (male, female) 
fibrosis  
= fibrosis stage (F1, F2/F3) 
Base  
= Baseline for the parameter (categorical) 
 
Note: The variance under the null (HYPOTH=NULL) will be the structure for producing 
p-values, while the variance under the alternative (HYPOTH=ALT) will be used for 
computing confidence intervals. 
 
Total NAS score is the sum of three scores: 
• 
Steatosis (0-3) 
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• 
Ballooning (0-2) 
• 
Inflammation (0-3) 
 
The statistical model will be used to calculate the treatment difference (PXL065 - 
placebo), 95% CI and p-value at Week 36  
 
The number of percentage of patients in each category below from baseline to Week 36 
will also be presented by treatment group on the ITTS: 
• 
Improvement in each component of NAS (steatosis, lobular inflammation and 
hepatocellular ballooning) by ≥ 1 point without worsening of fibrosis  
• 
Improvement in NAS ≥ 2 points without worsening of fibrosis  
• 
Improvement in NASH CRN fibrosis score by ≥ 1 point  
• 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis)  
• 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) with improvement in NASH CRN fibrosis score by ≥ 1 point  
• 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) with no worsening in NASH CRN fibrosis score  
• 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) and improvement in NAS ≥ 2 points with no worsening in NASH 
CRN fibrosis score  
For each response, responder rate will be provided within each treatment group for 
patients with Week 36 assessments. The stratified Cochran-Mantel-Haenszel (CMH) will 
primarily be used to analyze the responders, stratifying for T2DM status (T2DM patients 
versus non-T2DM patients) and NASH CRN fibrosis scoring system (F1 versus F2/F3). 
Each PXL065 treatment group will be compared with placebo. The odds ratios (ORs), 95% 
CIs for the ORs, and p-values will be displayed for the ITTS. In addition, the number of 
responder’s and non-responders will be displayed for each treatment group, see for 
example SAS code.    
A listing of these endpoints will also be produced for the ITTS-w-065-S22. 
In addition, the following categories will be summarized for responders/non-responders 
by treatment group in the ITTS in the subpopulation of responders for LFC (defined as 
patients with a Relative Reduction in LFC (%) ≥ 30% at Week 36): 
• 
NASH resolution (NAS score of 0-1 for inflammation, 0 for ballooning, and any 
value for steatosis) with No Worsening in NASH CRN Fibrosis Score from Baseline 
to Week 36  
• 
Improvement in NASH CRN Fibrosis Score of At Least One Point from Baseline to 
Week 36  


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7.7 Safety 
7.7.1 Extent of Exposure 
Duration of exposure will be listed for the Safety set with site 065-S22 and summarized 
using descriptive statistics for each treatment group for the Safety set, based on dosing 
records of the IMP medication on the eCRF. Duration of exposure will be calculated as 
follows: 
Date of Last Study Drug Administration – Date of First Study Drug Administration + 1. 
 
7.7.2 Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary [Version 23.0] 
and classified as either pre-treatment AEs, treatment-emergent AEs (TEAEs) or post-
treatment AEs as follows: 
• 
Pre-treatment AEs are events that start after the patient is included into the 
study (Date of ICF signature) and prior to the date of first dose of IMP 
• 
TEAEs are events with start date and time on or after the date and time of first 
dose of IMP and up to 7 days post-IMP discontinuation, or events with start date 
and time prior to the date and time of first dose of IMP whose severity or 
relationship to IMP worsens on or after the date and time of first dose of IMP up 
to 7 days post-IMP discontinuation. TEAEs also include AEs that are considered 
by the Investigator as related to IMP treatment, or with unknown/missing 
relationship to IMP treatment that start 8 days post IMP discontinuation.  
• 
Post-treatment AEs are AEs that start 8 days after IMP discontinuation, with the 
exclusion of those AEs that are considered by the Investigator as related to IMP 
treatment. 
Summary tables of pre-treatment AEs, TEAEs and post-treatment AEs by treatment 
group will be produced for the Safety set. No statistical comparisons of AEs between 
treatment groups will be performed. 
All pre-treatment AEs, TEAEs, and post-treatment AEs will be listed by treatment group 
for the Safety set with site 065-S22. Details of SAEs, AEs leading to permanent 
discontinuation of IMP, AEs resulting in death, and adverse events of special interest 
(AESI) will be listed separately. 
Assessment of AE severity will be based on the Common Terminology Criteria for AEs 
(CTCAE, version 5). 
The relationship between a TEAE and IMP treatment is assessed as unrelated or related. 
A treatment-related TEAE is a TEAE considered by the Investigator as related to IMP 
treatment. 
Overview tables will summarize the number and percentage of patients with at least one 
of the following AEs, where patients with more than one AE in a particular category are 
counted only once in that category: 
• any pre-treatment AEs, TEAEs, post-treatment AEs 


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• any pre-treatment AEs, TEAEs, post-treatment AEs by severity (Grade 1, Grade 2, 
Grade 3, Grade 4, Grade 5) 
• treatment-related TEAEs 
• treatment-related TEAEs by maximum severity (Grade 1, Grade 2, Grade 3, Grade 
4, Grade 5) 
• TEAEs leading to IMP treatment discontinuation 
• SAEs 
• treatment-related treatment-emergent serious AEs (TESAEs) by maximum 
severity (Grade 1, Grade 2, Grade 3, Grade 4, Grade 5) 
• SAEs leading to death 
• TESAEs leading to IMP treatment discontinuation 
• TEAEs related to study procedures 
• Treatment-emergent AESI’s (Heart failure, Pitting edema, Bladder cancer, Bone 
fracture, Drug-induced liver injury – DILI)  
The overview table will also summarize the number of events for the same categories in 
the Safety set. 
Overview table for TEAEs will be repeated in the Safety set with site 065-S22. 
The number and percentage of patients reporting each pre-treatment AEs, TEAE, 
post-treatment AEs will be summarized by SOC and PT. Tables will be sorted by 
descending overall frequency of SOC. PTs will be sorted by descending overall total. The 
following summaries will be produced: 
• Pre-treatment AEs, TEAEs, post-treatment AEs by SOC and PT 
• TEAEs related to IMP treatment, by SOC and PT 
• TEAEs causing discontinuation from IMP treatment, by SOC and PT 
• TEAEs related to IMP treatment and causing discontinuation from IMP treatment, 
by SOC and PT 
• TEAEs, by severity, SOC and PT 
• Pre-treatment SAEs, TESAEs, post-treatment SAEs, by SOC and PT 
• TESAEs related to IMP treatment, by SOC and PT 
• Pre-treatment AEs, TEAEs, post-treatment AEs leading to death, by SOC and PT 
• Pre-treatment AEs, TEAEs, post-treatment AESIs by SOC and PT 
In the above summaries, patients with more than one AE within a particular SOC are 
counted only once for that SOC. Similarly, patients with more than one AE within a 
particular PT are counted only once for that PT. For summaries by maximum severity, 
patients with multiple AEs within a particular SOC or PT will be counted under the 
category of their most severe AE within that SOC or PT.  
Additionally, the number and percent of each AE will be summarized for each treatment 
group, by descending overall frequency of SOC and PT (sorted by descending overall 
total), displaying the number of observed events for each PT. 


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TEAEs that are described as cardiovascular will also be summarized for each treatment 
group, by descending overall frequency of SOC and PT (sorted by descending overall 
total) displaying number of observed events for the Safety set. 
Summary tables, will be repeated in the Safety set with site 065-S22 for: 
• TEAEs by SOC and PT 
• TEAEs related to IMP treatment, by SOC and PT 
• TESAEs by SOC and PT 
 
7.7.2.1 
Hypoglycemia 
T2DM Patients are requested to immediately perform a finger stick glucose measurement 
with the self-monitoring blood glucose (SMBG) device provided for this study (unless CGM 
is used) if any symptoms occur that may be related to hypoglycemia and to avoid any 
delay in treating these symptoms. After the recovery of the symptoms, patients may 
report all the symptoms, date and time, dietary intake states, time of the recovery in the 
patient diary as well as blood glucose values if available. 
Only symptoms and/or plasma glucose concentration values deemed by the Investigator 
to meet the definition of hypoglycemia should be reported on the AE section of the eCRF. 
Hypoglycemia will be reported as recommended by the FDA guidance [2]: 
• Probable symptomatic hypoglycemia: Hypoglycemia evidenced only by symptoms 
without blood glucose measurement 
• Asymptomatic Hypoglycemia: Hypoglycemia evidenced only by plasma glucose 
concentration of less than 70 mg/dL (3.9 mmol/L) and not accompanied by typical 
symptoms of hypoglycemia  
• Documented Symptomatic Hypoglycemia: Hypoglycemia evidenced both by typical 
symptoms and plasma glucose concentration of less than 70 mg/dL (3.9 mmol/L) 
• Severe Hypoglycemia: Hypoglycemia requiring assistance of another person to 
administer carbohydrate or glucagon or other procedure 
In case of AE of hypoglycemia, the Investigator should query the patient to understand 
the clinical context that may have explained a low glucose value (exercise, missing meal, 
timing of drug intake and SMBG). All these data should be reviewed by Labcorp Medical 
Monitor. 
Summary tables of probable symptomatic hypoglycemia, asymptomatic hypoglycemia, 
documented symptomatic hypoglycemia and severe hypoglycemia by treatment group 
will be produced for the Safety set. 
Hypoglycemic events will be hardcoded with SOC “Metabolism and nutrition disorders” 
and PT “Hypoglycaemia”.   
Hypoglycemia events will be listed for the Safety set with site 065-S22. 
 
7.7.3 Laboratory Evaluations 
All laboratory data will be reported in International System of Units (SI). 


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Laboratory data will be summarized using standard descriptive statistics for each 
treatment group, by scheduled visit for the Safety population. 
7.7.3.1 
Standard Safety Laboratory Panel 
Data for the following hematology, biochemistry, urinalysis and coagulation received from 
central laboratory will be listed for the Safety set with site 065-S22 and summarized by 
treatment group and visit for the Safety set. Local laboratory results will be listed only.   
Hematology 
Biochemistry 
Urinalysis 
Erythrocytes 
Hemoglobin 
Hematocrit 
Red Blood Cell Morphology 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Leucocytes 
Differential blood count 
(lymphocytes, monocytes, 
eosinophils, basophils, 
neutrophils/ absolute values 
and percentages should be 
given) 
Thrombocytes 
Blood Urea Nitrogen 
Creatinine 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
Inorganic phosphate 
Total protein 
Albumin 
Uric acid 
Creatine phosphokinase 
AST 
ALT 
GGT 
Total bilirubin 
ALP 
hsCRP 
TSH (during Screening Period 
only) 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Nitrites 
Urobilinogen 
Blood 
Leucocytes 
If the dipstick result is 
abnormal: microscopic 
examination of the 
sediment for blood cells, 
cylinders, etc. 
 
Coagulation 
Activated Partial Thromboplastin Time (aPTT) 
Prothrombin Time 
International Normalized Ratio (INR) 
 
Values outside the normal range will be categorized as H (above the normal range) or L 
(below the normal range) based on the central laboratory’s normal reference range. 
Laboratory data will be summarized by visit using standard descriptive statistics. Changes 
from baseline will also be summarized. 
The following elevations will be assessed: 
Predefined Limits of Change (PDLC) 
ALT (SGPT) (U/L) 
Value >3xULN 
ALT (SGPT) (U/L) 
Value >5xULN 
ALT (SGPT) (U/L) 
Value >8xULN 
AST (SGOT) (U/L) 
Value >3xULN 
AST (SGOT) (U/L) 
Value >5xULN 
AST (SGOT) (U/L) 
Value >8xULN 
Total Bilirubin (µmol/L) 
Value >2xULN 


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Predefined Limits of Change (PDLC) 
ALP (U/L) 
Value >2xULN 
A listing of patients with elevated PDLC criteria will be produced for Safety set with site 
065-S22. 
7.7.3.2 
eGFR 
Data for eGFR received from central laboratory will be listed and summarized by 
treatment group and visit. Local laboratory results will be listed only.   
eGFR will be calculated using the chronic kidney disease – epidemiology collaboration 
(CKD-EPI) formula, as follows [14]: 
  
141 x min(Scr/κ,1)α x max(Scr/κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 
 [if black] 
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.  
CKD stages are defined as: 
• 
CKD stage 1 (eGFR ≥90 mL/min/1.73m2) 
• 
CKD stage 2 (eGFR ≥60 to <90 mL/min/1.73m2) 
• 
CKD stage 3a (eGFR ≥45 to <60 mL/min/1.73m2) 
• 
CKD stage 3b (eGFR ≥30 to <45 mL/min/1.73m2) 
• 
CKD stage 4 (eGFR ≥15 to <30 mL/min/1.73m2) 
• 
CKD stage 5 (eGFR <15 mL/min/1.73m2) 
Shift tables from baseline will be presented at each post-baseline visit showing the 
number of patients per treatment group with each populated CKD stage for the Safety 
set. 
eGFR data will be summarized by treatment group and visit using standard descriptive 
statistics, changes from baseline will also be summarized. Summary tables will be 
produced for the Safety set. 
A listing of eGFR data will be produced for the Safety set with site 065-S22. 
7.7.3.3 
Viral Infection Screen Panel 
Data for viral infection screen panel received from central and local laboratory will be 
listed by treatment group and visit for Safety set with site 065-S22. 
Hepatitis screening 
 
HIV screening 
Hepatitis B antigen (HBsAg) 
Hepatitis C virus antibody (anti-HCV), in case of 
positive result, reflex test of HCV circulating 
Ribonucleic acid (RNA) 
 
Anti-human 
immunodeficiency virus 
(HIV) 1 and 2 
 


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7.7.3.4 
Serum and Urine Pregnancy Test 
For female patients of child-bearing potential only, a serum B Human Chorionic 
Gonadotropin (β-HCG) test or a urine pregnancy test will be performed. 
Additional serum pregnancy testing should be performed during the study whenever a 
menstrual cycle is missed or when pregnancy is otherwise suspected.  
Serum and Urine pregnancy test results will be summarized for the Safety set. 
Serum and Urine pregnancy test results, and immediate pregnancy reporting will be listed 
for the Safety set with site 065-S22. 
 
7.7.4 Bone Mineral Density 
For postmenopausal women only, a standard dual-energy X-ray absorptiometry (DXA) 
testing will be performed during the study.  
If possible, all DXA testing for a given patient (historical testing or testing performed 
during study) should be performed at the same facility and using the same procedure. 
Bone mineral density will be summarized by visit using standard descriptive statistics for 
each treatment group, changes from baseline will also be summarized. Summary tables 
will be produced for the Safety set. 
Bone mineral density test results will also be listed for the Safety set with site 065-S22. 
 
7.7.5 Vital Signs and Body Measurements 
The following vital sign and body measurements will be taken during the study: 
• 
height (cm) 
• 
weight (kg) 
• 
waist circumference (cm) 
• 
hip circumference (cm) 
• 
Waist-to-hip ratio [Derived as waist circumference (cm)/hip circumference (cm)] 
• 
heart rate (bpm) 
• 
SBP (mmHg) with 3 readings 
• 
DBP (mmHg) with 3 readings 
The following vital sign results are derived on the eCRF: 
• 
calculated BMI (kg/m2) 
• 
mean SBP (mmHg) 
• 
mean DBP (mmHg) 
Vital signs data and changes from baseline in vital signs will be summarized visit by using 
standard descriptive statistics for each treatment group the Safety set. For summaries, 
the average of the 3 blood pressure readings will be used.  
Summary table on weight will be repeated in the Safety set with site 065-S22. 


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The MMRM analysis described in Section 7.6.2.3 will be repeated for the Safety set, Safety 
set with site 065-S22 and ITTS for weight (kg). 
A listing of vital signs data will be produced for the Safety set with site 065-S22.  
7.7.6 Electrocardiograms 
The following quantitative ECG measurements will be taken during the study: 
• 
heart rate (bpm); 
• 
PR interval (msec); 
• 
QRS interval (msec); 
• 
QT interval (msec); 
• 
Fridericia corrected QT (QTcF) interval (msec); 
An overall Investigator assessment of ECG will be provided (categories “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”). Any new 
clinically significant findings or worsening of abnormalities previously recorded as Medical 
History on the ECG will be reported as AEs, and followed up and/or treated locally until 
the AE has resolved or the condition has stabilized.  
The ECG measurements and changes from baseline in ECG will be listed for the Safety 
set with site 065-S22 and summarized by treatment group and visit using standard 
descriptive statistics for the Safety set. 
The Investigator assessment will be listed for the Safety set with site 065-S22 and the 
number and percentage of subjects within each assessment category will be tabulated 
for each treatment group by visit for the Safety set.  
Summary tables will be produced for the Safety set. 
A listing of ECG measurements and findings will be produced for the Safety set with site 
065-S22. 
7.7.7 Physical Examination 
Any new clinically significant abnormal findings or worsening of conditions previously 
recorded as medical history should be documented in the source documents and reported 
in the eCRF as AE.  
Physical examination date will be listed for the Safety set with site 065-S22. 
7.7.8 Pitting Edema  
Shift tables from baseline will be presented at each post-baseline visit showing the 
number of patients per treatment group with each populated grade for the Safety set. 
A listing will also be provided for the Safety set with site 065-S22.  
7.7.9 Other Safety Variables 
Blood (total, plasma and serum) samples for supplementary tests will be collected at 
particular visits to enable post-hoc testing of any additional efficacy and safety 
parameters or any potential biomarkers related to liver, cardiovascular diseases or 
metabolic diseases in relation with the drug target. The samples will be stored until 


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further use. All the biobanking samples will be destroyed within 2 years after the final 
study report is issued. 
 
7.8 Interim Analysis 
Not applicable 
8. Changes in Planned Analysis 
• 
Changes from SAP v2.0 (12May2022) to SAP Final v3.0 (12Aug2022): 
o Treatment exposure end date coded as 23rd December 2021 per NTF for 
patients that did not complete the study at site 065-S22 
o PPS description updated following the BDRM 
o Removal of analyses utilizing multiple imputation on the PPS 
o Multiple imputation method updated to consider a minimum and 
maximum value 
o CMH and logistic regression analysis removed for “Patients without any 
MRI assessments on treatment being classified as non-responders” 
o Analysis on biopsy exploratory endpoints updated to consider only 
patients with Week 36 assessments 
o EoS Visit end date removed for derivation of new medications  
• 
Changes from SAP v1.0 (03Dec2020) to SAP Final v2.0 (17May2022): 
o Updates per issue with site 065-S22 
 
Section 1 updated to mention note to file for the handling of site 
065-S22 
 
Analysis populations section includes description of the issue with 
site 065-S22 and the handling of the analysis sets 
 
Section 7 updated to specify which analyses are done with and 
without site 065-S22 
 
Updates to disposition table 
 
Additional MMRM analysis for weight (kg) 
 
Section 7.6.2.5 added for new subgroup analyses on secondary 
endpoints 
o Updates per dry run 1 
 
Rescreened patients excluded from screened set 
 
Demographics - BMI and Weight at baseline rather than 
randomization 
 
Updates to TEAE overall table 
 
Inclusion of urine pregnancy summary and listing 
 
Inclusion of immediate pregnancy reporting listing  
o Updates per protocol amendment 5  
 
Additional section for handling of rescreened patients 
 
Removal of albuminuria/creatininuria ratio 
 
Updates to prohibited medication 
o Imputation rules added for type 2 diabetes diagnosis  
o PK analysis is now being reported separately  


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o References to Covance updated to Labcorp/Labcorp Drug Development 
• 
Approval of SAP version 1.0 dated 03Dec2020 
9. Data Issues 
Issues concerning site 065-S22 have been documented in Section 5 and in a note to 
file. 
 


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10. References 
1 
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
http://www.emea.eu.int/pdfs/human/ich/036396en.pdf 
2 
CPMP. Points to Consider on Missing Data. EMEA: London, 2001. Available at 
http://www.emea.eu.int/pdfs/human/ewp/177699EN.pdf 
3 
Phillips A and Haudiquet V. ICH E9 guideline “Statistical principles for clinical 
trials”: a case study. Statistics in Medicine 2003; 22:1-11 
4 
Brown D J. ICH E9 guideline “Statistical principles for clinical trials”: a case 
study. Response to A. Phillips and V. Haudiquet. Statistics in Medicine 2003; 
22:13-17 
5 
Phillips A, Ebbutt A, France L, Morgan D, Ireson M, Struthers L and Heimann 
G. Issues in applying recent CPMP “Points to Consider” and FDA guidance 
documents with biostatistical implications. Pharmaceutical Statistics 2003; 
2:241-251 
6 
Senn S. Statistical Issues in Drug Development. John Wiley & sons 
(Chichester), 1997. 
7 
Chow S-C and Liu J-P. Design and Analysis of Clinical Trials: Concepts and 
Methodologies. John Wiley & sons (New York), 1998. 
8 
Brown H and Prescott R. Applied Mixed Models in Medicine. John Wiley & sons 
(Chichester), 1999. 
9 
Fairclough D L. Design and Analysis of Quality of Life Studies in Clinical Trials. 
Chapman & Hall/CRC, 2002. 
10 
Green S, Benedetti J and Crowley J. Clinical Trials in Oncology (2nd edition). 
Chapman & Hall/CRC, 2002. 
11 
McEntegart D. Forced randomization when using interactive voice response 
systems. Applied Clinical Trials October 2003; 50-58. 
12 
CPMP. Points to Consider on Adjustment for Baseline Covaraites. EMEA: 
London, 2003 
13 
ICH. ICH E3 Guideline: Structure and Content of Clinical Study Reports 
Questions & Answers, 2012. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Eff
icacy/E3/E3_QAs_R1_Step4.pdf 
14 
Levey, A.S., et al., A new equation to estimate glomerular filtration rate. 
Ann Intern Med, 2009. 150(9): p. 604-12. 
15 Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). 
Covariate-adjusted difference in proportions from clinical trials using 
logistic regression and weighted risk differences. Drug Information 
Journal, 45(4), 481-493. 
16 
KDIGO. Kidney Disease: Improving Global Outcomes (KDIGO) clinical 
practice guideline for acute kidney injury. Kidney International Supplement. 
2012; 2: 19-36. Available at https://kdigo.org/wp-
content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf 


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17 Stokes, Maura E., Charles S. Davis, and Gary G. Koch. Categorical data 
analysis using SAS. SAS institute, 2012 
18 Dmitrienko A and Koch G. Analysis of Clinical Trials using SAS A 
Practical Guide 2nd ed., SAS Institute July 2017 
19 Koch GG, Tangen CM, Jung JW, Amara IA (1998). \Issues for 
Covariance Analysis of 
20 Dichotomous and Ordered Categorical Data from Randomzied Clinical 
Trials and Non-Parametric Strategies for Addressing Them." Statistics in 
Medicine, 17, 1863-92. 
 
 
 


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11. Appendix A: Visit Schedule Chart 
 
 


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AASLD: American Association for the Study of Liver Diseases; AE: adverse event; DXA: dual-energy X-ray absorptiometry; 
ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; EoS: End-of-Study Visit; EoT: End-of-Treatment Visit; 
ET: Early Termination Visit; FPG: Fasting Plasma Glucose; HbA1c: glycated hemoglobin; hsCRP: High-sensitivity C-Reactive 
Protein; ICF: informed consent form; IMP: Investigational medicinal product; IWRS: Interactive Web Response System; 
lab: laboratory; MRI-PDFF: Magnetic Resonance Imaging - Proton Density Fat Fraction; param.: parameters; phys ex.: 
physical examination; PK: pharmacokinetics; SMBG: self-monitoring blood glucose;T2DM: Type 2 Diabetes mellitus V: visit; 
W: week(s) 
1: The interval between 2 on-site visits must not exceed 48 days. 
2: SMBG device dispensed to T2DM patients only. SMBG devices to be brought back to the study site at each visit for measurement 
review. SMBG device will be kept by the patient after the end of his/her study participation. Continuous Glucose Monitoring (CGM) 
is accepted and no SMBG device needs to be dispensed in this case. 
3: Investigators will explain AASLD guidance regarding diet and exercise at Randomization Visit (V1). Investigators will collect the 
compliance to this guidance at each subsequent visit. 
4: The complete physical examination will include head, ears, eyes, nose, mouth, skin, cardiovascular and lung examinations, 
lymph nodes, gastrointestinal, musculoskeletal and neurological systems. The limited physical examination will be focused on 
general appearance, the cardiovascular system as well as towards patient reported symptoms. 
5: Vital signs and labs body measurements include: heart rate and 3 blood pressure measurements in supine or sitting position, 
and, height (during Screening Period only), body weight, BMI, waist and hip circumferences. 
6: Postmenopausal women must have BMD T-score results assessed by standard DXA testing within 6 months prior to 
Randomization Visit (V1). If there is no available BMD T-score within this period, a DXA testing must be performed during the 
Screening Period only after receiving confirmation of eligibility on history, clinical examination and labs. DXA testing must also be 
performed before (within 8 days) or on the day of Week 36 (V8-EoT). 
7: MRI-PDFF must be performed only after receiving confirmation of eligibility on history, clinical examination and labs during 
Screening Period. MRI-PDFF must also be performed before (within 8 days) or on the day of Week 36 (V8-EoT). MRI-PDFF must 
also be performed at Early termination Visit (ET) only for patients who withdraw from the study at or after Week 12 (V4) and 
only when the IMP was discontinued less than 14 days before the ET Visit. 
8: Eligibility is to be confirmed based on all assessments before performing liver biopsy and/or sending material to histopathology 
laboratory. A qualifying liver biopsy is required within 6 months prior to the Randomization Visit (V1). If no appropriate historical 
liver biopsy material is available, a liver biopsy must be performed during Screening Period. A second liver biopsy must be 
performed before (within 8 days) or on the day of Week 36 (V8-EoT). 
9: The viral infection screen panel includes hepatitis screening (hepatitis B surface antigen (HBsAg), hepatitis C virus antibody 
(anti-HCV) and in case of positive result, reflex test of HCV circulating ribonucleic acid (RNA), anti-human immunodeficiency virus 
(HIV) 1 and 2) 
10: The standard safety laboratory panel (blood and urine) includes hematology, biochemistry, coagulation and urinalysis 


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11: For female patients of child-bearing potential only. Serum pregnancy test (Human Chorionic Gonadotropin (β-HCG)) during 
Screening Period, End-of-study Visit (V9) and Early Termination Visit (ET) and urine pregnancy test at Randomization Visit (V1) 
and Week 18 (V5). 
12: Measured metabolic parameters include serum insulin, C-peptide, adiponectin, total cholesterol, low-density lipoprotein 
cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglycerides, free fatty acids (FFA) 
13: Insulin resistance indexes include Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), Quantitative Insulin 
Sensitivity Check Index (QUICKI), Homeostasis Model Assessment of β-cell function (HOMA-β) and Adipose Tissue Insulin 
Resistance (Adipo-IR) 
14: Fibrosis biomarkers include: N-terminal type III collagen propeptide (pro-C3), Nonalcoholic Fatty Liver Disease (NALFD) 
Fibrosis Score (NFS), Fibrosis 4 (FIB-4) score and Enhanced Liver Fibrosis (ELF) score 
15: One pre-dose blood sample will be drawn just before the IMP daily intake at, Week 12, Week 24 and Week 36 (visits V3, V4, 
V6 and V8-EoT) and one sample between 1h and 4h post-dose at Week 36 (last IMP intake, V8- EoT). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. Appendix B: Sample SAS® code for analyses of efficacy endpoints 
 
/* Multivariate imputation by FCS regression */ 
proc mi data=adeff seed=75319 nimpute=1000 out=outex min = 0 max = 50 round = 0.1; 
   class trtpn strata1 strata2; 
   fcs nbiter=100; 
   reg (vis9 = vis0 trtpn strata1 strata2); 
   var vis9 vis0 trtpn strata1 strata2 ; 
run; 
 
/* ANCOVA model */ 
PROC MIXED DATA= adeff; 
class trtp; 
MODEL pchg = trtp base strata1 strata2 ; 
LSMEANS trtp/ PDIFF CL; 
RUN; 
 
/* Combining results using Rubin’s rule */ 
PROC MIANALYZE DATA = lsmestimates; 
BY label; 
MODELEFFECTS estimate; 
STDERR stderr; 
ODS OUTPUT PARAMETERESTIMATES = dataout; 
RUN; 
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/* Wilcoxon test with Hodges-Lehmann estimate and CI */ 
proc npar1way hl alpha=.05 data=adeff; 
   class strata1 strata2; 
   var pchg; 
   exact hl; 
   ods select WilcoxonScores HodgesLehmann; 
run; 
 
/* Cochran-Mantel-Haenszel */ 
proc freq data=adeff; 
   tables strata1*strata2*Treatment*Response /cmh out = fadeff; 
   weight wgt/zeroes;  
   ods output CommonRelRisks = CommonRelRisks cmh = cmh; 
run; 
 
/* Example SAS code for MMRM */ 
 
PROC MIXED DATA=ADLB; 
CLASS treatment week strata1 strata2 usubjid; 
MODEL chg = treatment week treatment*week strata1 strata2 baseline_aval / DDFM=KR; 
REPEATED week / SUBJECT = usubjid TYPE = CS; 
LSMEANS treatment*week / PDIFF CL; 
RUN; 
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13. Appendix C: Ge et al. code 
%macro LR ( 
data=, /* input data set */ 
var1=, /* continuous covariates in the logistic regression */ 
var2=, /* categorical covariates in the logistic regression */ 
p1=, /* number of continuous covariates in the logistic regression */ 
p2=, /* number of categorical covariates in the logistic regression */ 
resp=, /* binary response variable in the logistic regression */ 
ntrt= ); /* position of the treatment variable in the categorical covariates */ 
 
/* delete the observations with missing values in either numeric or categorical covariates */ 
data newdata; 
set &data; 
if cmiss(of &var1 &var2)>0 then delete; 
run; 
 
/* extract the design matrix and variance-covariance matrix of the regression and store them in 
data1 and parms respectively */ 
 
/* cases when there is no continuous covariates */ 
%if &p1=0 %then 
%do; 
proc transreg data=newdata dummy noprint; 
model identity(&resp) = class(&var2/zero=first); 
output out = data1(drop=_: &var2 &resp) replace; 
run; 
proc logistic data=newdata desc covout outest=parms(drop=_:) 
noprint; 
class &var2 / param=ref ref=first; 
model &resp = &var2; 
run; 
%end; 
 
/* cases when both categorical and continuous covariates exist */ 
%else 
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%do; 
proc transreg data=newdata dummy noprint; 
model identity(&resp) = class(&var2/zero=first) identity(&var1); 
output out = data1(drop=_: &var2 &resp) replace; 
run; 
 
proc logistic data=newdata desc covout outest=parms(drop=_:) 
noprint; 
class &var2 / param=ref ref=first; 
model &resp = &var2 &var1; 
run; 
%end; 
 
/* estimate the proportion difference and standard error to construct the 95% confidence 
interval */ 
proc iml; 
use parms; 
read all into params; 
close parms; 
use data1; 
read all into xmat; 
close data1; 
p = nrow(params)-2; 
cov = params[2:(p+2),]; 
psize = nrow(xmat); 
ntrt = &ntrt+1; 
xt = xmat; 
xt[,ntrt] = J(psize,1,1); 
axT = xt*params[1,]`; 
xc = xmat; 
xc[,ntrt] = J(psize,1,0); 
axC = xc*params[1,]`; 
pderT = J(psize,1,0); 
pderC = J(psize,1,0); 
pderivT = J(psize,(p+1),0); 
pderivC = J(psize,(p+1),0); 
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gt = J(1,(p+1),0); 
gc = J(1,(p+1),0); 
do k=1 to psize; 
pderT[k] = exp(axT[k])/(1+exp(axT[k])); 
pderC[k] = exp(axC[k])/(1+exp(axC[k])); 
pderivT[k,] = pderT[k]*(1-pderT[k])*xt[k,]; 
pderivC[k,] = pderC[k]*(1-pderC[k])*xc[k,]; 
end; 
difb=sum(pderT-pderC)/psize; 
pT=sum(pderT)/psize; 
pC=sum(pderC)/psize; 
do k=1 to (p+1); 
gt[k] = sum(pderivT[,k])/psize; 
gc[k] = sum(pderivC[,k])/psize; 
end; 
se=sqrt(gt*cov*gt`+ gc*cov*gc`-2*gt*cov*gc`); 
upperb=difb+1.96*se; 
lowerb=difb-1.96*se; 
store difb se pT pC lowerb upperb; 
quit; 
%mend; 
 
/* print out the LR estimation results */ 
%macro printLR (data=, var1=, var2= ); 
title ‘Study:’ “&data”; 
proc iml; 
load difb se pT pC lowerb upperb; 
print , ‘LR estimation of study’ “&data”,; 
print , ‘*********************************************************’,; 
print , ‘Covariates:’ “&var1” “&var2” ,; 
print , ‘PropDiff=’ difb ,; 
print , ‘PropT=’ pT ,; 
print , ‘PropC=’ pC ,; 
print , ‘SE=’ se ,; 
print , ‘95% Confidence Interval = [‘ lowerb ‘,’ upperb ‘]’,; 
print , ‘*********************************************************’,; 
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quit; 
%mend; 
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