Clinical trial NCT03763877
Conditions: Nonalcoholic Fatty Liver
Sponsor: Poxel SA
Start date: 2019-03-29; Completion date: 2020-08-10
Enrollment: 121 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the efficacy and safety of 3 doses of PXL770 versus placebo after 12 weeks of treatment.

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

Arms: arm 1: PXL770 Dose 1 arm 2: PXL770 Dose 2 arm 3: PXL770 Dose 3 arm 4: Placebo oral capsule
Interventions: intervention 1: PXL770 intervention 2: Placebo Oral Capsule
Intervention descriptions: intervention 1: Oral capsule intervention 2: Oral capsule

Protocol documents:
Prot_000.pdf: 
PXL770 / Study No. PXL770-004 
Protocol Version 6.0 / 24th July 2020 
 
 
 
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CLINICAL TRIAL PROTOCOL  
 
 
 
Trial Protocol Number 
PXL770-004 
Study Full Title 
A randomized, double-blind, placebo-controlled, parallel 
group trial to assess the efficacy and safety of PXL770 
versus placebo after 12 weeks of treatment in patients with 
Nonalcoholic Fatty Liver Disease (NAFLD) with or 
without type 2 diabetes mellitus 
Study Short Title 
STAMP-NAFLD 
Program Acronym 
STAMP 
STudy of AMP kinase activator 
Phase 
Phase IIa 
Authors 
Carole Thang, PharmD 
Julie Dubourg, MD 
Pascale Fouqueray, MD, PhD 
IND Number / Serial Number 
140493 / 00013 
EudraCT Number 
N/A 
Coordinating investigator 
Prof. Kenneth Cusi, MD, PhD 
Staff, Malcom Randall VAMC 
Chief, Division of Endocrinology, Diabetes and Metabolism 
The University of Florida 
1600 SW Archer Rd; room H -2 
P.O. Box: 100226 
Gainesville, FL 32610-0226 
Direct phone: 352-273-7236 
Division phone: 352-273-8662 
Fax: 352-273-7441 
Sponsor 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon 
France 
Sponsor’s Legal Representative (EU) 
N/A 
Trial Protocol Version 
Version 6.0 / 24th July 2020 
Replaces Trial Protocol Version 
Version 5.0 / 20th November 2019 
Current Protocol Amendment 
No. 5 
Previous Protocol Amendments 
No. 4 
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Corporate confidential information 
NCT03763877 


PXL770 / Study No. PXL770-004 
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Signature Page 
 
Lead responsible for designing the clinical study: 
 
I approve the design of the study. 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Carole THANG, PharmD 
Associate Medical Director, Clinical Development 
POXEL S.A  
 
 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Jean-Marie GROUIN 
Statistics consultant for POXEL S.A 
 
 
 
Lead responsible for reviewing the clinical study protocol: 
 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Nadège DANEAU, MSc 
Clinical Project Manager 
POXEL S.A. 
 
 
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PXL770 / Study No. PXL770-004 
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Investigator Signature 
Study Title  
A randomized, double-blind, placebo-controlled, parallel 
group trial to assess the efficacy and safety of PXL770 versus 
placebo after 12 weeks of treatment in patients with 
Nonalcoholic Fatty Liver Disease (NAFLD) with or without 
type 2 diabetes mellitus 
Protocol Version / Date 
Version 6.0 / 24th July 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 Conference on 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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Summary of changes to version 5.0 
Underline indicates the addition and strikethrough indicates the deletion in this summary. 
Administrative changes: Minor changes involving grammar, wordsmithing, punctuation, and 
other editorial changes have been made throughout the document and are not detailed in this 
summary.  
Overall rationale for changes in the protocol: 
This study includes a main study and a sub-study. Up to 40 patients were expected to be 
included in this sub-study (i.e. up to 10 patients per treatment group). Due to unexpected 
recruitment difficulties, only 14 patients were randomized in the sub-study. In addition, the sub-
study site activities have been restricted due to the COVID-19 pandemic which made the sub-
study assessments even more complex if not impossible. The number of evaluable patients 
would have been very low and the decision was made by POXEL to discontinue the sub-study. 
Ongoing patients will continue the study visits and perform the assessments planned in the main 
study but will not performed the assessments planned in the sub-study at End-of-treatment Visit 
(V7). As a consequence, the sub-study objectives will be considered as exploratory. 
Other changes include the addition of key secondary endpoints and minor editorial and 
typographical updates. 
 
1. Synopsis (Planned Trial Period): update 
Study start: Q1 2019 
Study end: Q1Q3 2020 
 
1. Synopsis (Trial Objectives): edits 
Secondary Exploratory objectives for Sub-study only: 
• To assess the effect of PXL770 versus placebo in NAFLD patients on metabolic and non-
metabolic parameters at the daily dose of 250 md QD and BID and 500 mg QD after 12 
weeks of treatment: 
- 
Fructose stimulated hepatic De Novo Lipogenesis (DNL)  
- 
Glycemic parameters during a 3-hour oral glucose tolerance test (OGTT)  
 
The two tests being combined, OGTT will be a 3-hour glucose + fructose tolerance 
test (OGTT+F) 
• To assess PXL770 plasma concentrations before, during and after the 3-hour OGTT+F 
and fructose stimulated hepatic DNL assessment in NAFLD patients and correlation with 
pharmacodynamics and/or safety  
 
1. Synopsis (Diagnosis and main Inclusion and Exclusion Criteria): correction of typos  
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Inclusion criteria 
4. 
Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m² [min*1.73m²] at 
Screening Visit (V1) calculated by the Chronic Kidney Disease – Epidemiology 
collaboration (CKD-EPI) formulae 
Exclusion criteria 
7. 
Evidence of hepatic impairment at Screening Visit (V1) as defined by the combination 
of at least two of the following parameters: 
- 
Total bilirubin (TBL) ≥ 1.3 mg/dL 
- 
Serum albumin < 3.5 g/dL 
- 
International Normalized Ratio (INR) ≥ 1.2 
- 
Platelets < 150 000 G/L 
- 
Hemoglobin < 11 g/dL in females or < 12 g/dL in males 
- 
Presence of ascites 
 
1. Synopsis (Assessments for efficacy): edits 
Key secondary endpoints: 
• Absolute change in the percentage of liver fat mass (assessed by MRI-PDFF) from baseline 
(Randomization Visit (V3)) to Week 12 (V7) 
• Percentage of responders as defined by the percentage of patients who achieve a clinically 
meaningful reduction of at least 5 % (≥ 5%) in absolute liver fat mass (from baseline 
(Randomization Visit (V3)) as measured by MRI-PDFF at Week 12 (V7) 
• Percentage of responders as defined by the percentage of patients who achieve a relative 
reduction of at least 30% (≥ 30%) in liver fat mass (from baseline Randomization Visit 
(V3)) as measured by MRI-PDFF at Week 12 (V7)  
• Percentage of responders as defined by the percentage of patients who achieve a relative 
reduction of at least 50% (≥ 50%) in liver fat mass (from baseline Randomization Visit 
(V3)) as measured by MRI-PDFF at Week 12 (V7)  
• Percentage of responders as defined by the percentage of patients who achieve a liver 
fat mass value at Week 12 (V7) that is normalized, i.e. ≤ 5% 
[…] 
Secondary Exploratory endpoints for sub-study only: 
Change from baseline (Randomization Visit (V3)) in the following parameters at Week 12 (V7): 
• Fructose stimulated hepatic DNL as assessed during 6h by deuterated water incorporation 
in very low-density lipoprotein (VLDL)  
• Glucose, insulin, C-peptide, FFA, glycerol: fasting pre-dose and post dose as the area 
under the curve (AUC) during a 3-hour OGTT+F 
• Insulin sensitivity index calculated during the 3-hour OGTT+F (Matsuda) 
 
1. Synopsis (Statistical Methods): edits 
Analyses sets 
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• Screened Analysis Set: all patients who were screened for inclusion into the study  
• Run-in Safety Analysis Set (RISS): all patients having received at least one dose of 
the single-blind placebo run-in treatment. 
• Safety Set (SS): all randomized patients having received at least one dose of the IMP 
(either PXL770 or placebo) and considered as-treated. Primary set for safety analyses 
and tolerability will be analyzed on the Safety Set. 
• Randomized Set (RS): all patients randomized and considered as randomized 
regardless of the treatment actually received. 
• Intention-to-treat Set (ITTS): all patients having received at least one dose of the IMP 
(either PXL770 or placebo) and considered as randomized.   Primary set for efficacy 
analyses. 
• Per Protocol Set (PPS): ITT patients without any major violations. 
• Pharmacokinetic (PK) population: all patients from the SS who have been treated with 
PXL770 according to the protocol and have provided at least one pre-dose PK 
assessment during the study with sufficient plasma to derive the Cpre. 
Efficacy analyses 
Primary Endpoint:  
The primary endpoint, i.e. expressed as the relative change in the percentage of liver fat mass 
(assessed by MRI-PDFF) from baseline (Randomization Visit (V3)) to Week 12 (V7), will be 
analyzed in an analysis of covariance (ANCOVA) model adjusting for treatment (PXL770 doses 
of 250 mg QD, 250 mg BID and 500 mg QD and placebo) and for stratification factors, i.e. 
T2DM status (T2DM patients versus non-T2DM patients) and study site (main site 1 vs main 
site 2 vs main site 3 vs others) and baseline liver fat mass as a covariate. Least square means 
(LSMs) of the primary endpoint for treatment groups and pairwise differences in LSMs will be 
estimated along with their unadjusted p-values and 95% confidence intervals.  
Missing MRI-PDFF at Week 12 (V7) will be estimated using a multiple imputation method 
assuming missing at random (MAR) mechanism that will be detailed in the SAP. Missing 
baseline MRI-PDFF will not be estimated. 
[…] 
Key secondary Endpoints:  
• Absolute change in the percentage of liver fat mass from baseline (Randomization Visit 
(V3)) to Week 12 (V7): this will be analyzed in an analysis of covariance (ANCOVA) 
model adjusting for treatment, T2DM status (T2DM patients versus non-T2DM 
patients), site (main 1 vs main 2 vs main 3 vs others) and baseline liver fat mass. Least 
square means of the change in the percentage of liver fat mass for treatment groups 
(PXL770 doses of 250 mg QD, 250 mg BID and 500 mg QD and placebo) and pairwise 
differences in LSMs will be estimated along with their unadjusted p-values and 95% 
confidence intervals. 
• Responders (as defined in the Assessment for Efficacy Section): Response will be 
defined for a patient when the (absolute) reduction in liver fat mass (from baseline 
(Randomization Visit (V3)) to Week 12 (V7)) is higher than or equal to 5% (≥ 5 %). 
The response will be analyzed in a logistic regression model adjusting for treatment 
(PXL770 doses of 250 mg QD, 250 mg BID and 500 mg QD and placebo), T2DM status 
(T2DM patients versus non-T2DM patients), site (main 1 vs main 2 vs main 3 vs others) 
and baseline liver fat mass.  Pairwise differences in treatment groups will be estimated 
in this model as odds ratios along with their p-values and 95% confidence intervals. 
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Methods handling missing MRI-PDFF at Week 12 (V7) and therefore the responder 
status at Week 12 (V7) will be detailed in the SAP. 
Other secondary Endpoints (including the sub-study):  
The analysis of these secondary endpoints will be fully detailed in the SAP.   
 
3.3 Secondary Objectives for Sub-Study: edits 
3.3. Secondary Exploratory Objectives for Sub-Study 
• To assess the effect of PXL770 versus placebo in NAFLD patients on metabolic and non-
metabolic parameters at the daily dose of 250 md QD and BID and 500 mg QD after 12 
weeks of treatment: 
- 
Fructose stimulated hepatic DNL  
- 
Glycemic parameters during a 3-hour OGTT  
 
The two tests being combined, OGTT will be a 3-hour glucose + fructose tolerance 
test (OGTT+F) 
• To assess PXL770 plasma concentrations before, during and after the 3-hour OGTT+F 
and fructose stimulated hepatic DNL assessment in NAFLD patients and correlation with 
pharmacodynamics and/or safety  
 
5.1 Inclusion Criteria: correction of typos  
4. 
eGFR ≥ 60 mL/min/1.73m² [min*1.73m²] at Screening Visit (V1) calculated by the 
CKD-EPI formulae 
 
5.2 Exclusion Criteria: correction of typos 
7. 
Evidence of hepatic impairment at Screening Visit (V1) as defined by the combination of 
at least two of the following parameters: 
- 
TBL ≥ 1.3 mg/dL 
- 
Serum albumin < 3.5 g/dL 
- 
INR ≥ 1.2 
- 
Platelets < 150 000 G/L 
- 
Hemoglobin < 11 g/dL in females or < 12 g/dL in males 
- 
Presence of ascites 
 
 8.2.1 Liver fat mass assessed by MRI-PDFF – Central imaging core lab: edits 
[…] 
MRI-PDFF technique will be exclusively used for assessment of liver fat mass. 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. 
 
8.3.5.1 Standard Safety Laboratory Panel (Blood and Urine): edits 
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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 
Gamma-glutamyl transferase 
Total bilirubin 
Alkaline Phosphatase (ALP) 
Amylase 
Lipase 
TSH (at Screening Visit (V1) 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 Methods of Recording and Assessing Adverse Events: edits 
Each AE will be classified using the version of the Medical Dictionary for Regulatory Activities 
(MedDRA®) available at the start of the study. 
 
8.3.8.2 DILI: edits 
To detect and monitor a possible DILI, the following evaluations should be performed in the 
presence of significant elevations of liver indices. 
[…] 
• Close observation for suspected drug-induced liver injury 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 study drug has been discontinued and the patient is asymptomatic. 
- 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
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- 
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. 
- 
Obtaining additional tests to evaluate liver function, as appropriate (e.g. INR, direct 
bilirubin, lactate, liver ultrasound). 
- 
Considering gastroenterology or hepatology consultations. 
If a DILI is confirmed or suspected by the Investigator, or in case of liver function 
parameters (ALT, AST, ALT, TBL) above the threshold defined in this section, the 
Investigator will complete an Expedited Liver Assessment Report page form (ELAR) in 
the eCRF within 24 hours of knowledge of the case and submit it to Medpace Clinical 
Safety in the same timelines as a SAE (see Section 8.3.6.4 Procedure for Reporting 
Immediately Reportable Events (IREs= SAEs and Pregnancy)). If the DILI is 
confirmed, it should be reported in addition as an AE (see Section 8.3.6.2 Methods of 
Recording and Assessing Adverse Events). 
 
9.4.2 Safety analyses and Safety Set: addition 
The Run-in Safety Analysis Set (RISS) is defined as all patients having received at least one 
dose of the single-blind placebo run-in treatment.  The population will be used to assess 
exposure and compliance with the single-blind placebo run-in treatment only. 
The Safety Analysis Set (SS) comprises all randomized patients having received at least one 
dose of the study drug (either PXL770 or placebo) and considered as-treated. Safety and 
tolerability will be analyzed on the safety set. 
  
9.4.4 PK Population: edits 
The PK population corresponds to the Safety Set and includes all randomized patients who have 
been treated with PXL770 according to the protocol and have provided at least one pre-dose 
PK assessment during the study with sufficient plasma to derive the Cpre. 
 
9.5.1 Primary Endpoint: relative change in the percentage of liver fat mass: edits 
The primary analysis of efficacy will be performed on the ITTS. 
Primary analysis: 
The primary endpoint, i.e. expressed as the relative change in the percentage of liver fat mass 
(assessed by MRI-PDFF) from baseline (Randomization Visit (V3)) to Week 12 (V7), will be 
analyzed in an analysis of covariance (ANCOVA) model adjusting for treatment (PXL770 doses 
of 250 mg QD, 250 mg BID and 500 mg QD and placebo) and for stratification factors, i.e. 
T2DM status (T2DM patients versus non-T2DM patients) and study site (main site 1 vs main 
site 2 vs main site 3 vs other pooled sites) and baseline liver fat mass as a covariate.  
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Least square means (LSMs) of the primary endpoint for treatment groups and pairwise 
differences in LSMs will be estimated along with their unadjusted p-values and 95% confidence 
intervals.  
Missing MRI-PDFF at Week 12 (V7) will be estimated using a multiple imputation method 
(fully conditional specification method) assuming missing at random (MAR) mechanism 
which will be detailed in the SAP. Missing baseline MRI-PDFF will not be estimated. 
Validity of the ANCOVA model will be checked (studentized residuals will be plotted against 
predicted values, etc.).   
 
9.5.2.1 
Absolute Change in the percentage of liver fat mass: edits   
The (absolute) change in the percentage of liver fat mass (assessed by MRI-PDFF) from 
baseline (Randomization Visit (V3)) to Week 12 (V7) will be analyzed in an analysis of 
covariance (ANCOVA) model adjusting for treatment, T2DM status (T2DM patients versus 
non-T2DM patients), site (main 1 vs main 2 vs main 3 vs others) and baseline liver fat mass. 
Least square means of the change in the percentage of liver fat mass for treatment groups 
(PXL770 doses of 250 mg QD, 250 mg BID and 500 mg QD and placebo) and pairwise 
differences in LSMs will be estimated along with their unadjusted p-values and 95% confidence 
intervals.  
Missing MRI-PDFF at Week 12 (V7) will be estimated using a multiple imputation method 
(fully conditional specification method) assuming missing at random (MAR) mechanism 
which will be detailed in the SAP. Missing baseline MRI-PDFF will not be estimated. 
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: edits    
Four types of responders will be proposed and analyzed: 
- 
Response will be defined for a patient when the as an (absolute) reduction in liver fat 
mass (from baseline (Randomization Visit (V3)) to Week 12 (V7)) is higher than or 
equal to 5% (≥ 5 %). 
- 
Response defined as a relative reduction in liver fat mass (from baseline 
(Randomization Visit (V3)) to Week 12 (V7)) higher than or equal to 30% (≥ 30 %). 
- 
Response defined as a relative reduction in liver fat mass (from baseline 
(Randomization Visit (V3)) to Week 12 (V7)) higher than or equal to 50% (≥ 50 %). 
-  
Response defined as a liver fat mass value at Week 12 (V7)) that is normalized, i.e. 
lower than or equal to 5% (≤ 5 %). 
Percentages of response will be estimated within each treatment group. 
The response will be analyzed in a logistic regression model adjusting for treatment (PXL770 
doses of 250 mg QD, 250 mg BID and 500 mg QD and placebo), T2DM status (T2DM patients 
versus non-T2DM patients), site (main 1 vs main 2 vs main 3 vs others) and baseline liver fat 
mass.  Pairwise differences in treatment groups will be estimated in this model as odds ratios 
along with their p-values and 95% confidence intervals. 
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Methods handling missing MRI-PDFF at Week 12 (V7) and therefore missing responder 
status at Week 12 (V7) will be detailed in the SAP. 
 
9.5.3 Other Secondary Endpoints: endpoints for the sub-study moved to Section 9.5.4 
9.5.4 Exploratory Endpoints For (Sub-study only): 
• Fructose stimulated hepatic DNL as assessed during 6 hours by deuterated water 
incorporation in very low-density lipoprotein (VLDL) 
• Glucose, insulin, C-peptide, FFA, glycerol: pre-dose fasting and AUC during a 3-hour 
OGTT 
• Insulin sensitivity marker using a 3-hour OGTT (Matsuda) 
 
9.5.5.1 Adverse Events: edits 
AE will be coded using the most recent version available of the MedDRA® at the start of the 
study.  
 
11.1 Data collection and CRF management: edits 
The data in the eCRF should be consistent with the relevant source documents as verified by 
Medpace’s CRA during monitoring visits. The data will be processed, evaluated, and stored in 
anonymous pseudonymous form in accordance with the data-protection regulations. 
[…] 
• 
Blood samplings for DNL assessments will be sent to the University of Florida for 
analysis and results will be transferred electronically to Medpace Data Management 
Department. 
  
13 
Annex 1. Sponsor, Coordinating Investigators, Investigators and Study 
Administrative Structure: edits 
Changes in team members were reflected in this Section. 
 
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List of Abbreviations 
ACC 
Acetyl-CoA Carboxylase 
Adipo-IR 
Adipose tissue Insulin Resistance 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine amino Transferase 
ALP 
Alkaline Phosphatase 
AMPK 
5' adenosine monophosphate-activated protein kinase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate amino Transferase 
AUC 
Area under the concentration time curve 
AUCinf 
Area under the concentration time curve extrapolated to infinity 
βHCG 
Human Chorionic Gonadotropin 
BDRM 
Blinded Data Review Meeting 
Bid 
Twice a day (bis in die) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CABG 
Coronary Artery Bypass Graft 
CAP 
Controlled Attenuation Parameter 
CHF 
Congestive Heart Failure 
CKD-EPI 
Chronic Kidney Disease – Epidemiology Collaboration 
Cmax 
Maximum concentration 
Cpre 
Predose concentration 
CRA 
Clinical Research Associate 
CRC 
Clinical Research Coordinator 
DILI 
Drug-Induced Liver Injury 
DNL 
De Novo Lipogenesis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EDC 
Electronic Data Capture 
ELAR 
Expedited Liver Assessment Report 
EoS 
End-of-Study 
EoT 
End-of-Treatment 
ET 
Early Termination 
FA 
Fatty Acids 
FDA 
Food and Drug Administration 
FFA 
Free Fatty Acids 


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Fib-4 
Fibrosis 4 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP1-RA 
Glucagon-Like Peptide 1 – Receptor Agonist 
GMP 
Good Manufacturing Practice 
HbA1c 
Glycated hemoglobin 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HDL-c 
High Density Lipoprotein-cholesterol 
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 
HSL 
Hormone-Sensitive Lipase 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intention-To-Treat 
IWRS 
Interactive Web Response System 
LDL-c 
Low Density Lipoprotein-cholesterol 
LSM 
Least Square Mean 
MAD 
Multiple Ascending Dose 
MAR 
Missing at random 
MCP-1 
Monocyte Chemoattractant Protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeat Measurement 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NAFL 
Nonalcoholic Fatty Liver 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NASH 
Nonalcoholic steatohepatitis 
NFS 
NAFLD Fibrosis Score 
NOAEL 
No-observed-adverse-effect level 
NYHA 
New York Heart Association 


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OGTT+F 
Oral Glucose + Fructose Tolerance Test 
PDFF 
Proton Density Fat Fraction 
PGC-1α 
Peroxisome proliferator-activated receptor Gamma Coactivator 1-Alpha 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
QD 
Once a day (Quaque die) 
QUICKI 
Quantitative Insulin Sensitivity Check Index 
RNA 
Ribonucleic Acid 
RS 
Randomized Set 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SGLT2-I 
Sodium-Glucose-Co-Transportor-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 
TE 
Transient Elastography 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to reach the maximum concentration 
TMF 
Trial Master File 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States 
VLDL 
Very Low Density Lipoprotein 
WHO 
World Health Organization 
 
 
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Table of Contents 
SUMMARY OF CHANGES TO VERSION 5.0 
4 
1 
SYNOPSIS 
20 
2 
BACKGROUND INFORMATION 
36 
2.1 
Scientific Rationale 
36 
2.2 
PXL770 
37 
2.2.1 
Non-clinical Information 
37 
2.2.2 
Clinical Information 
38 
2.2.2.1 
PXL770-001: SAD phase I study 
38 
2.2.2.2 
PXL770-002: MAD phase I study 
39 
2.3 
Research Hypothesis 
40 
3 
STUDY OBJECTIVES 
41 
3.1 
Primary Objective 
41 
3.2 
Secondary Objectives 
41 
3.3 
Exploratory Objectives for Sub-Study 
41 
4 
STUDY DESIGN 
42 
4.1 
Study Design and Schedule 
42 
4.2 
Rationale for Study Design, Doses and Control Group 
42 
5 
STUDY POPULATION 
44 
5.1 
Inclusion Criteria 
44 
5.2 
Exclusion Criteria 
45 
5.3 
Restrictions during the Study 
47 
5.4 
Patients Incorrectly Enrolled in the Single-blind Placebo Run-in Period or 
Incorrectly Randomized 
47 
5.4.1 
Patients Incorrectly Enrolled in the Single-blind Placebo Run-in Period
  
47 
5.4.2 
Patients Incorrectly Randomized 
48 
5.5 
Criteria for Screen-failure 
48 
5.6 
Criteria for Withdrawal from the Study for Randomized Patients during the 
Double-blind Treatment Period 
49 
5.6.1 
Criteria for withdrawal from the study 
49 
5.6.2 
Procedure for withdrawal from the study 
49 
5.7 
Discontinuation of the Study 
50 
5.8 
Replacement Policy 
51 
6 
INVESTIGATIONAL MEDICINAL PRODUCT AND OTHER DRUGS USED IN THE TRIAL 
52 
6.1 
Description of Investigational Medicinal Product 
52 
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6.2 
Dosage and Administration 
52 
6.2.1 
Single-blind Placebo Run-in Period 
53 
6.2.2 
Double-blind Treatment Period 
53 
6.2.3 
Follow-up Period 
54 
6.3 
Treatment Assignment and Blinding 
54 
6.3.1 
Patient Numbering 
54 
6.3.2 
Treatment Assignment or Randomization 
54 
6.3.3 
Treatment Blinding 
55 
6.3.3.1 
Method of Blinding 
55 
6.3.3.2 
Emergency Unblinding 
56 
6.4 
Concomitant Medications and Therapies 
56 
6.5 
Non-permitted Medicines 
57 
6.6 
Packaging and Labeling 
58 
6.7 
Management of IMP 
58 
6.7.1 
Shipment of IMP 
58 
6.7.2 
Supply and Receipt of IMP 
58 
6.7.3 
Storage of IMP 
59 
6.7.4 
Dispensing, Accountability and Compliance of IMP 
59 
6.7.5 
Return and Destruction of IMP 
61 
6.8 
Overdose 
61 
6.8.1 
Preclinical and Clinical Status 
61 
6.8.2 
Overdose Definition 
61 
6.8.3 
Reporting 
62 
6.8.4 
Treatment 
62 
7 
STUDY PROCEDURES 
63 
7.1 
Screening Period, Screening Visit (V1): On-site Visit 
63 
7.2 
Single-blind Placebo Run-in Period, Run-in Visit (V2): On-site Visit 
64 
7.3 
Double-blind Treatment Period 
64 
7.3.1 
Randomization Visit (V3) (Day 0): On-site Visit 
64 
7.3.2 
Week 2 (V4): On-site Visit 
65 
7.3.3 
Week 4 (V5): On-site Visit 
66 
7.3.4 
Week 8 (V6): On-site Visit 
67 
7.3.5 
Week 12 – End-of-treatment Visit (V7): On-site Visit 
68 
7.4 
Follow-up Period, End-of-study Visit (V8): On-site Visit 
69 
7.5 
Withdrawal of Patients (Early termination Visit): On-site Visit 
69 
8 
STUDY ASSESSMENTS 
71 
8.1 
Blood Volume 
71 


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8.2 
Efficacy Assessment 
71 
8.2.1 
Liver fat mass assessed by MRI-PDFF – Central imaging core lab 
71 
8.2.2 
Other Efficacy Parameters 
72 
8.3 
Safety 
73 
8.3.1 
Physical Examination 
73 
8.3.2 
Vital Signs 
74 
8.3.3 
Patient Diary 
74 
8.3.4 
Supine 12-Lead ECG 
75 
8.3.5 
Laboratory Assessments 
75 
8.3.5.1 
Standard Safety Laboratory Panel (Blood and Urine) 
76 
8.3.5.2 
Viral Infection Screen Panel 
76 
8.3.5.3 
eGFR 
76 
8.3.5.4 
Serum and urine Pregnancy Test 
77 
8.3.6 
Adverse Events 
77 
8.3.6.1 
Adverse Event Definitions 
77 
8.3.6.2 
Methods of Recording and Assessing Adverse Events 
79 
8.3.6.3 
Definition of the Adverse Event Reporting Period 
80 
8.3.6.4 
Procedure for Reporting Immediately Reportable Events (IREs= 
SAEs and Pregnancy) 
81 
8.3.6.5 
Monitoring of Patients with Adverse Event 
82 
8.3.7 
Pregnancy and In Utero Drug Exposure 
82 
8.3.8 
Special Precautions 
83 
8.3.8.1 
Hypoglycemia 
83 
8.3.8.2 
DILI 
84 
8.4 
Pharmacokinetics 
86 
8.5 
Biobanking Samples for Post-hoc Assessments 
86 
8.6 
Pharmacogenetics 
86 
8.7 
Acceptable deviation times 
86 
9 
STATISTICAL METHODS 
88 
9.1 
General considerations 
88 
9.2 
Sample Size Determination 
88 
9.3 
Randomization 
89 
9.4 
Analysis Sets 
89 
9.4.1 
Screened Analyses Set 
89 
9.4.2 
Safety analyses and Safety Set 
89 
9.4.3 
Efficacy Analyses 
90 
9.4.3.1 
Randomized Set (RS): 
90 
9.4.3.2 
Intention-to-treat Set 
90 


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9.4.3.3 
Per Protocol Set (PPS) 
90 
9.4.4 
PK Population 
90 
9.5 
Efficacy analysis 
90 
9.5.1 
Primary Endpoint: relative change in the percentage of liver fat mass 
90 
9.5.2 
Key Secondary Endpoints 
91 
9.5.2.1 
Absolute Change in the percentage of liver fat mass 
91 
9.5.2.2 
Analysis of responders 
92 
9.5.3 
Other Secondary Endpoints 
92 
9.5.4 
Exploratory Endpoints ( Sub-study only) 
92 
9.5.5 
Safety Analysis 
93 
9.5.5.1 
Adverse Events 
93 
9.5.5.2 
Concomitant Medications 
93 
9.5.5.3 
Vital Signs, ECG, Body Weight, Waist Circumference, waist to 
hip ratio, BMI and Physical Examination 
93 
9.5.5.4 
Clinical Laboratory Data 
93 
9.5.5.5 
Withdrawals of study 
94 
9.5.6 
Analysis of Further Endpoints 
94 
9.6 
Interim Analysis 
94 
10 ETHICAL AND REGULATORY ASPECTS 
95 
10.1 Ethics and Good Clinical Practice 
95 
10.2 Patient Information and Informed Consent 
95 
10.3 Patient Identification and Privacy 
96 
10.4 Emergency Medical Support and Patient Emergency Card 
96 
10.5 Patient Insurance and Compensation to Patients 
97 
10.6 Institutional Review Board/Ethics committee 
97 
10.7 Regulatory Authorities 
98 
11 STUDY MANAGEMENT 
99 
11.1 Data collection and CRF management 
99 
11.2 Handling of Protocol Deviations 
100 
11.3 Source Data and Patient Files 
100 
11.4 Investigator Site File and Archiving 
101 
11.5 Monitoring, Quality Assurance and Inspection by Authorities 
101 
11.6 Changes to the Protocol 
102 
11.7 Clinical Study Report and Publication Policy 
102 
11.7.1 Clinical Study Report 
102 
11.7.2 Publication 
102 
11.7.3 Disclosure and Confidentiality 
103 
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12 REFERENCES 
104 
13 ANNEX 1. SPONSOR, COORDINATING INVESTIGATORS, INVESTIGATORS AND STUDY 
ADMINISTRATIVE STRUCTURE 
106 
 
 
Index of Tables 
Table 1. Visit Schedule Chart 
32 
Table 2. Treatments to be administered in the 4 treatment groups 
53 
Table 3. Acceptable deviation times 
87 
 
Index of Figures 
Figure 1. Diagram of Study Design 
31 
Figure 2. Diagram of sub-study assessments 
35 
 
 
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1 Synopsis 
Protocol Number 
PXL770-004 
Study Full Title 
A randomized, double-blind, placebo-controlled, parallel group 
trial to assess the efficacy and safety of PXL770 versus placebo 
after 12 weeks of treatment in patients with Nonalcoholic Fatty 
Liver Disease (NAFLD) with or without type 2 diabetes mellitus 
Study Short Title 
STAMP-NAFLD 
Program Acronym 
STAMP 
STudy of AMP kinase activator 
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 enrollment-last patient out) 
Study start: Q1 2019 
Study end: Q3 2020 
Trial Objectives 
Primary objective 
• To assess the effect of PXL770 versus placebo on hepatic 
steatosis in NAFLD patients at the daily dose of 250 mg 
once a day (QD) and twice a day (BID) and 500 mg QD 
after 12 weeks of treatment 
Secondary objectives 
• To assess the safety and tolerability of PXL770 versus 
placebo in NAFLD patients at the daily dose of 250 mg QD 
and BID and 500 mg QD after 12 weeks of treatment 
• To assess the effect of PXL770 versus placebo in NAFLD 
patients on metabolic and non-metabolic parameters at the 
daily dose of 250 mg QD and BID and 500 mg QD after 12 
weeks of treatment: 
- 
Liver enzymes 
- 
Lipid parameters 
- 
Glycemic parameters in fasting conditions 
- 
Biomarkers of inflammation 
- 
Biomarkers of fibrosis 
- 
Anthropomorphic parameters 
• To compare the 2 dose regimens of PXL770 (BID versus 
QD) on efficacy and safety parameters in NAFLD patients 
• To describe PXL770 pre-dose plasma concentrations 
during the course of the treatment and pre- and post-dose 
plasma concentrations after 12 weeks of treatment in 
NAFLD patients 
 
 


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Exploratory objectives for Sub-study only: 
• To assess the effect of PXL770 versus placebo in NAFLD 
patients on metabolic and non-metabolic parameters at the 
daily dose of 250 md QD and BID and 500 mg QD after 12 
weeks of treatment: 
- 
Fructose stimulated hepatic De Novo Lipogenesis 
(DNL)  
- 
Glycemic parameters during a 3-hour oral glucose 
tolerance test (OGTT)  
 
The two tests being combined, OGTT will be a 3-hour 
glucose + fructose tolerance test (OGTT+F) 
• 
To assess PXL770 plasma concentrations before, during 
and after the 3-hour OGTT+F and fructose stimulated 
hepatic DNL assessment in NAFLD patients and 
correlation with pharmacodynamics and/or safety 
Trial Design and Plan 
(Design description in Figure 1 
and schedule of visits in Table 1) 
Phase IIa, multi-center, double-blind, placebo-controlled, 
randomized study with 4 parallel groups in NAFLD patients. 
There will be a total of 4 study periods, as follows: 
• Screening period: maximum of 2 weeks 
• Single-blind placebo Run-in period: 4 weeks  
• Double-blind treatment period: 12 weeks  
• Follow-up period: 1 week  
Patients will be randomized in a 1:1:1:1 ratio to receive either: 
• PXL770 250 mg QD 
• PXL770 250 mg BID 
• PXL770 500 mg QD 
• Placebo 
Randomization will be stratified according to type 2 diabetes 
mellitus (T2DM) status (T2DM patients versus non-T2DM 
patients) and study site (main study site 1 vs main study site 2 vs 
main study site 3 vs other study sites).  
A sub-study will be performed in up to 3 study sites. This sub-
study will include: 
- 
A fructose stimulated hepatic DNL assessment  
- 
A 3-hour OGTT+F 
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. Among the 120 randomized patients, up 
to 40 patients will be included in the sub-study (i.e. up to 10 
patients per treatment group). 
 
 
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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) ≥ 25 to ≤ 50 kg/m²at Screening 
Visit (V1) and Randomization Visit (V3) 
4. Estimated glomerular filtration rate (eGFR) ≥ 60 
mL/min/1.73m² at Screening Visit (V1) calculated by the 
Chronic Kidney Disease – Epidemiology collaboration 
(CKD-EPI) formulae 
5. For patients with T2DM: 
- 
Either naïve of treatment with no glucose lowering 
drug for the last 12 weeks prior to Screening Visit (V1) 
or under stable oral glucose lowering drug (mono- or 
bi-therapy) for the last 12 weeks prior to Screening 
Visit 
(V1) 
(See 
non-permitted 
concomitant 
medications in exclusion criteria #25) 
- 
Glycated hemoglobin (HbA1c) ≤ 9.0% at Screening 
Visit (V1) 
6. Not applicable – intentionally left blank for data 
management purposes (consistency in eCRF capture of 
eligibility criteria historically) 
7. Hepatic steatosis: 
- 
Evidenced by transient elastography (TE) with 
controlled attenuation parameter (CAP) ≥ 300 dB/m or 
by ultrasound or magnetic resonance imaging (MRI), 
performed within the last 12 weeks prior to Screening 
Visit (V1). If none of these assessments are available 
prior to Screening Visit (V1), TE with CAP ≥ 300 
dB/m should be evidenced at Run-in Visit (V2) 
- 
Confirmed by MRI performed within 8 ± 4 days prior 
to Randomization Visit (V3) with a proton density fat 
fraction (PDFF) value ≥ 10% 
8. Women of child-bearing potential (e.g. not surgically 
sterile or not postmenopausal) must have a negative serum 
pregnancy test at Screening Visit (V1) and a negative urine 
pregnancy test at Randomization Visit (V3) 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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9. Male patients must have agreed on an effective 
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 both POXEL and Medpace staff and/or staff at 
the study site) 
2. Participation in another clinical study with intake of an 
investigational product during the last 12 weeks prior to 
Screening Visit (V1)  
3. Previous participation in any clinical study with PXL770 
intake  
Target disease exclusions 
4. Evidence of another form of 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) 
5. Evidence of liver cirrhosis on laboratory assessment or 
Transient Elastography ≥ 14 kPa at Run-in Visit (V2) 
6. Aspartate amino transferase (AST) or alanine amino 
transferase (ALT) > 200 IU/L at Screening Visit (V1) 
7. Evidence of hepatic impairment at Screening Visit (V1) as 
defined by the combination of at least two of the following 
parameters: 
- 
Total bilirubin (TBL) ≥ 1.3 mg/dL 
- 
Serum albumin < 3.5 g/dL 
- 
International Normalized Ratio (INR) ≥ 1.2 
- 
Platelets < 150 G/L 
- 
Hemoglobin < 11 g/dL in females or < 12 g/dL in males 
- 
Presence of ascites 
8. Bariatric surgery of any kind at any time prior to 
Randomization Visit (V3) or change in body weight greater 
than 5% within the last 12 weeks prior to the Screening 
Visit (V1) or between Screening Visit (V1) and 
Randomization Visit (V3) 
9. Positive serologic evidence of current infectious liver 
disease including hepatitis B surface antigen (HBsAg), 
and/or anti-hepatitis C virus (HCV) antibody with detected 
circulating ribonucleic acid (RNA) at the Screening Visit 
(V1).  
10. History of excessive alcohol intake defined by equal or 
greater than 21 units of alcohol/ week in males and equal 
or greater than 14 units of alcohol/ week in females for 2 


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years prior to the Screening Visit (V1), where a unit of 
alcohol is equal to 10 g pure alcohol.  
Medical History and Concurrent Disease Exclusions 
Cardiovascular diseases 
11. Any of the following disease within 24 weeks prior to 
Screening Visit (V1) or between Screening Visit (V1) and 
Randomization Visit (V3): 
- 
Myocardial infarction 
- 
Cardiac revascularization surgery (coronary artery 
bypass 
graft/percutaneous 
transluminal coronary 
angioplasty (CABG/PTCA)) 
- 
Unstable angina 
- 
Unstable congestive heart failure (CHF) 
- 
New York Heart Association (NYHA) Class III or IV  
- 
Transient ischemic attack, stroke or cerebrovascular 
disease 
12. Unstable or undiagnosed arrhythmias, long QT syndrome, 
short QT syndrome, history of drug-induced Torsade de 
Pointe 
13. Uncontrolled high blood pressure (BP): diastolic BP ≥ 
100 mmHg or systolic BP ≥ 160 mmHg with or without 
antihypertensive treatment at Screening Visit (V1) 
Hematological and oncological diseases 
14. Malignancy within 5 years prior to Screening Visit (V1) 
(with the exception of treated basal cell carcinoma or 
treated squamous cell carcinoma of the skin)  
15. History of haemoglobinopathies (e.g., sickle cell anemia or 
thalassemia, sideroblastic anemia) 
16. Patient who donated blood products to a blood bank or who 
received blood transfusion within 12 weeks prior to 
Screening Visit (V1) or between Screening Visit (V1) and 
Randomization Visit (V3) 
Endocrinological disease 
17. Diabetes other than T2DM 
18. Uncontrolled 
hypothyroidism 
(thyroid 
stimulating 
hormone (TSH) > 2 x the upper limit of normal (ULN) at 
Screening Visit (V1)) 
Other exclusion conditions 
19. Immunocompromised patients such as patients that 
underwent organ transplantation or were diagnosed with 
human immunodeficiency virus (HIV) 
20. Any other known serious disease (such as major infection, 
clinically significant gastrointestinal disorder, major 
autoimmune disease…) or other disease which in the 


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Investigator’s opinion would exclude the patient from the 
study 
21. Any current drug addiction  
22. 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  
23. Anorexia or bulimia 
24. Known hypersensitivity to any of the constituents or 
excipients of the investigational medicinal product (IMP), 
or history of relevant drug and/or food allergies (e.g. 
anaphylactic, anaphylactoid reactions) 
25. Use of non-permitted concomitant medication within 
24 weeks prior to Screening Visit (V1) and at any time 
between the Screening Visit (V1) and the Randomization 
Visit (V3): 
- 
Pioglitazone, 
insulin, 
Glucagon-Like 
Peptide-1 
Receptor Agonist (GLP1-RA), Sodium-Glucose-Co-
Transportor-2 inhibitor (SGLT2-I), anticoagulants, 
amiodarone, bile salt chelators, methotrexate, equal or 
more than 400 U of vitamin E per day, corticosteroids 
with a systemic effect, or any other medications known 
to affect liver function / steatosis at the Investigator’s 
discretion, 
strong 
inhibitors 
of 
CYP2C8 
(i.e. 
gemfibrozil and clopidogrel) and CYP2C9 (i.e. 
tazizulam, miconazole and sulfaphenazole), rifampin 
(moderate inducer of both CYP2C8 and CYP2C9), any 
herbal drug or Chinese traditional medicines  
26. 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 
27. Pregnancy or lactation 
Investigational Medicinal 
Product(s) (IMP): dose/ dosing 
schedule/ mode of administration 
PXL770 capsules (capsules of 250 mg each) orally 
Placebo capsules orally 
Treatments to be administered in the 4 treatment groups: 
• PXL770 250 mg QD (morning) + placebo BID 
(morning and evening) 
• PXL770 250 mg BID + placebo BID 
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• PXL770 500 mg QD (morning) + placebo QD 
(evening) 
• Placebo BID 
Planned Study Duration per 
Patient 
Study duration per patient (from Screening Visit (V1) up to End-
of-study Visit (V8)) 
• Minimum: 17 weeks 
• Maximum: 19 weeks 
Assessments for Efficacy 
Primary endpoint 
Relative change in the percentage of liver fat mass (assessed by 
MRI-PDFF) from baseline (Randomization Visit (V3)) to Week 
12 (V7) 
Key secondary endpoints 
• Absolute change in the percentage of liver fat mass 
(assessed by MRI-PDFF) from baseline (Randomization 
Visit (V3)) to Week 12 (V7) 
• Percentage of responders as defined by the percentage of 
patients who achieve a clinically meaningful reduction of at 
least 5 % (≥ 5%) in absolute liver fat mass (from baseline 
(Randomization Visit (V3)) as measured by MRI-PDFF at 
Week 12 (V7) 
• Percentage of responders as defined by the percentage of 
patients who achieve a relative reduction of at least 30% (≥ 
30%) in liver fat mass (from baseline Randomization Visit 
(V3)) as measured by MRI-PDFF at Week 12 (V7)  
• Percentage of responders as defined by the percentage of 
patients who achieve a relative reduction of at least 50% (≥ 
50%) in liver fat mass (from baseline Randomization Visit 
(V3)) as measured by MRI-PDFF at Week 12 (V7)  
• Percentage of responders as defined by the percentage of 
patients who achieve a liver fat mass value at Week 12 (V7) 
that is normalized, i.e. ≤ 5% 
Secondary endpoints 
Change from baseline (Randomization Visit (V3)) in the 
following parameters at Week 12 (V7): 
• Liver enzymes: ALT and AST  
• Measured metabolic parameters: Fasting plasma glucose 
(FPG), HbA1c, serum insulin, C-peptide, total cholesterol, 
high density lipoprotein-cholesterol (HDL-c), low-density 
lipoprotein-cholesterol (LDL-c), triglycerides, Apo A1, 
Apo B, free fatty acids (FFA), glycerol and adiponectin 
• Calculated metabolic parameters: Homeostasis model 
assessment of insulin resistance (HOMA-IR), Quantitative 
insulin sensitivity check index (QUICKI), Homeostasis 


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model assessment of β-cell function (HOMA-β) and 
Adipose tissue insulin resistance (Adipo-IR) 
• High-sensitivity C-reactive protein (hsCRP) and other 
markers of inflammation: fibrinogen and monocyte 
chemoattractant protein-1 (MCP-1)  
• Markers of fibrosis: NAFLD Fibrosis score (NFS) and 
Fibrosis 4 (Fib-4) score 
• Body weight, waist circumference and waist-to-hip ratio 
Exploratory endpoints for sub-study only: 
Change from baseline (Randomization Visit (V3)) in the 
following parameters at Week 12 (V7): 
• Fructose stimulated hepatic DNL as assessed during 6h by 
deuterated water incorporation in very low-density 
lipoprotein (VLDL)  
• Glucose, insulin, C-peptide, FFA, glycerol: fasting pre-dose 
and post dose as the area under the curve (AUC) during a 
3-hour OGTT+F 
• Insulin sensitivity index calculated during the 3-hour 
OGTT+F (Matsuda) 
Assessments for Safety 
Safety and tolerability will be assessed on the following 
parameters: 
• Adverse events (AE) 
• Physical examination 
• Weight, waist and hip circumferences and BMI 
• Vital signs (systolic BP, diastolic BP, heart rate (HR))  
• 12-lead electrocardiogram (ECG) 
• Biological 
parameters: 
biochemistry, 
hematology, 
coagulation 
• eGFR (CKD-EPI formula) 
• Urinalysis 
Pharmacokinetics (PK) 
A pre-dose sample will be drawn before the morning dose at V4, 
V5, V6 and V7, for the determination of PXL770 plasma 
concentrations.  
For patients not included in the sub-study: 
At V7, a post-dose sample will be drawn at 2h post-dose for the 
determination of PXL770 plasma concentrations. A last sample 
will be drawn at the End-of-study Visit (V8). 
For patients included in the sub-study only: 
At V7, post-dose samples will be drawn before, during and after 
the 3h-OGTT+F and fructose stimulated hepatic DNL for the 
determination of PXL770 plasma concentrations: 
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At 2h (prior to glucose + fructose load), 2.5h, 3h, 4h, 5h and 8h 
post-dose (at time of 3h-OGTT+F and/or fructose stimulated 
hepatic DNL samples)  
A last sample will be drawn at the End-of-study Visit (V8). 
Other Assessment 
Blood sample will be drawn in all patients for extra-samples at 
V3 and V7 to allow post-hoc testing of any additional safety and 
efficacy parameters or any potential biomarkers related to liver, 
cardiovascular diseases or metabolic diseases in relation with the 
drug target.  
In addition, blood sample will be drawn at V3 and V7 to allow 
post-hoc genetic and pharmacogenetic research on the 
DNA/RNA samples from patients who sign an optional, 
additional informed consent.  
The frozen samples will be 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 endpoint, i.e. 
the relative percent change in liver fat mass (assessed by MRI-
PDFF) from baseline (Randomization Visit (V3) to Week 12 
(V7). 
Assuming an expected difference of 30% between at least one 
dose of  PXL770 and placebo, a common standard deviation of 
30% (estimated from previous published data [1]), a two-sided 
significance level of 0.05, 24 patients per treatment group are 
required to achieve a power of 90%. Given the early stage of 
development (i.e. a Phase II trial for internal decision), no 
adjustment for comparison multiplicity will be considered. 
The sample size is expanded to 30 patients per group to account 
for an expected 20% drop-out rate, which amounts to a total 
required number of 120 patients to be randomized. 
Statistical methods 
Full details of analyses will be provided in the Statistical 
Analysis Plan (SAP), which will be finalized prior to the 
unblinding and locking of the database. 
Analyses sets 
• Screened Analysis Set: all patients who were screened 
for inclusion into the study  
• Run-in Safety Analysis Set (RISS): all patients having 
received at least one dose of the single-blind placebo run-
in treatment. 
• Safety Set (SS): all randomized patients having received 
at least one dose of the IMP (either PXL770 or placebo) 
and considered as-treated. Primary set for safety analyses 
and tolerability will be analyzed on the Safety Set. 
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• Randomized Set (RS): all patients randomized and 
considered as randomized regardless of the treatment 
actually received. 
• Intention-to-treat Set (ITTS): all patients having received 
at least one dose of the IMP (either PXL770 or placebo) 
and considered as randomized.   Primary set for efficacy 
analyses. 
• Per Protocol Set (PPS): ITT patients without any major 
violations. 
• Pharmacokinetic (PK) population: all patients from the 
SS who have been treated with PXL770 according to the 
protocol and have provided at least one pre-dose PK 
assessment during the study. 
Efficacy analyses 
Primary Endpoint:  
The primary endpoint, i.e. expressed as the relative change in 
the percentage of liver fat mass (assessed by MRI-PDFF) from 
baseline (Randomization Visit (V3)) to Week 12 (V7), will be 
analyzed in an analysis of covariance (ANCOVA) model 
adjusting for treatment (PXL770 doses of 250 mg QD, 250 mg 
BID and 500 mg QD and placebo) and for stratification factors, 
i.e. T2DM status (T2DM patients versus non-T2DM patients) 
and study site (main site 1 vs main site 2 vs main site 3 vs 
others) and baseline liver fat mass as a covariate. Least square 
means (LSMs) of the primary endpoint for treatment groups 
and pairwise differences in LSMs will be estimated along with 
their p-values and 95% confidence intervals.  
Missing MRI-PDFF at Week 12 (V7) will be estimated using a 
multiple imputation method assuming missing at random 
(MAR) mechanism that will be detailed in the SAP. Missing 
baseline MRI-PDFF will not be estimated 
Sensitivity analyses will be performed based on a rank analysis.  
Subgroup analyses will be performed: 
- within each T2DM status (T2DM patients versus non-T2DM 
patients). The treatment by T2DM status interaction will be 
tested.  
- within each site (main site 1 vs main site 2 vs main site 3 vs 
other pooled sites). The treatment by site (main 1 vs main 2 vs 
main 3 vs others) interaction will be tested.  
Key secondary Endpoints:  
• Absolute change in the percentage of liver fat mass from 
baseline (Randomization Visit (V3)) to Week 12 (V7): 
this will be analyzed in an analysis of covariance 
(ANCOVA) model adjusting for treatment, T2DM status 
(T2DM patients versus non-T2DM patients), site (main 
1 vs main 2 vs main 3 vs others) and baseline liver fat 
mass. Least square means of the change in the percentage 
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of liver fat mass for treatment groups (PXL770 doses of 
250 mg QD, 250 mg BID and 500 mg QD and placebo) 
and pairwise differences in LSMs will be estimated 
along with their p-values and 95% confidence intervals. 
• Responders (as defined in the Assessment for Efficacy 
Section) will be analyzed in a logistic regression model 
adjusting for treatment (PXL770 doses of 250 mg QD, 
250 mg BID and 500 mg QD and placebo), T2DM status 
(T2DM patients versus non-T2DM patients), site (main 
1 vs main 2 vs main 3 vs others) and baseline liver fat 
mass.  Pairwise differences in treatment groups will be 
estimated in this model as odds ratios along with their p-
values and 95% confidence intervals.  
Methods handling missing MRI-PDFF at Week 12 (V7) 
and therefore the responder status at Week 12 (V7) will 
be detailed in the SAP. 
Other secondary Endpoints:  
The analysis of these secondary endpoints will be fully detailed 
in the SAP.   
Safety Endpoints:  
Safety endpoints will be analyzed with usual descriptive 
methods. 
PK Endpoints:  
Pharmacokinetic data (PXL770 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. 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
ET 
Screening 
Run-in 
Randomization 
Week 2 
Week 4 
Week 8 
Week 12 EoT 
Week 13 EoS 
- 
Timeframe 
-6 weeks max + 
2 days 
-4 weeks 
Day 0 
Day 14 
Day 28 
Day 56 
Day 84 
Day 91 
- 
Time windows 
- 
Within 2W after 
V1 
4W after V2 
± 2 days 
2W after V3 
± 2 days 
4W after V3 
± 2 days 
8W after V3 
± 3 days1 
12W after V3 
± 4 days1 
1W after V7 
± 2 days 
Within 11 days 
after IMP 
discontinuation 
Informed consent 
X 
 
 
 
 
 
 
 
 
IWRS log-on 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior medications 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete phys ex.2,3 
X 
 
X 
 
 
 
X 
X 
X 
Limited phys ex.4 
 
X 
 
X 
X 
X 
 
 
 
Vital signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG14 
X 
 
X 
X 
X 
X 
X15 
X 
X 
hsCRP 
X 
 
X 
X 
X 
X 
X 
X 
X 
FPG 
X 
 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
X 
 
 
 
X 
 
X 
Safety lab8 
X 
 
X 
X 
X 
X 
X 
X 
X 
eGFR 
X 
 
X 
 
 
 
X 
 
X 
Pregnancy test12 
X 
 
X 
X 
X 
X 
X 
X 
X 
Viral screen lab11 
X 
 
 
 
 
 
 
 
 
Measured metabolic param6 
 
 
X 
 
X 
X 
X 
 
X 
Calculated metabolic param7 
 
 
X 
 
X 
 
X 
 
X 
Inflammatory biomarkers9 
 
 
X 
 
 
 
X 
 
X 
Fibrosis biomarkers10 
 
 
X 
 
 
 
X 
 
X 
Biobanking sampling 
 
 
X 
 
 
 
X 
 
 
Pharmacogenetic sampling17 
 
 
X 
 
 
 
X 
 
 
PK sampling16 
 
 
 
X 
X 
X 
X 
X 
 
Transient Elastography13 
 
X 
 
 
 
 
 
 
 
MRI-PDFF 
 
 
X* 
 
 
 
X** 
 
 
IMP compliance 
 
 
X 
X 
X 
X 
X 
 
X 
IMP dispensing 
 
X 
X 
 
X 
X 
 
 
 
Patient Emerg. Card dispensing 
X 
 
 
 
 
 
 
 
 
Diary dispensing  
 
X 
X 
 
X 
X 
 
 
 
Diary review 
 
 
X 
X 
X 
X 
X 
 
X 
SMBG dispensing18 
 
X 
 
 
 
 
 
 
 
SMBG measurements review19 
 
 
X 
X 
X 
X 
X 
X 
X 


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V1 
V2 
V3 
V4 
V5 
 
V6 
 
V7 
V8 
ET 
Screening 
Run-in 
Randomization 
Week 2 
Week 4 
 
Week 8 
 
Week 12 EoT 
Week 13 EoS 
- 
Timeframe 
-6 weeks max + 
2 days 
-4 weeks 
Day 0 
Day 14 
Day 28 
 
Day 56 
 
Day 84 
Day 91 
- 
Time windows 
- 
Within 2W after 
V1 
4W after V2 
± 2 days 
2W after V3 
± 2 days 
4W after V3 
± 2 days 
 
8W after V3 
± 3 days1 
 
12W after V3 
± 4 days1 
1W after V7 
± 2 days 
Within 11 days 
after IMP 
discontinuation 
SUB-STUDY ONLY 
OGTT+F 
 
 
X 
 
 
 
 
 
X 
 
 
DNL assessment 
 
 
X 
 
 
 
 
 
X 
 
 
X*: MRI-PDFF must be performed within 8 ± 4 days prior to Randomization Visit (V3); X** MRI must be performed before or on the day of Week 12 (V7), i.e. 84 days (- 4 days) after Randomization Visit 
(V3). 
DNL: de novo lipogenesis; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; EoS: End of Study; EoT: End of Treatment; ET: Early Termination; Emerg: 
Emergency; FPG: Fasting Plasma Glucose; HbA1c: glycated hemoglobin; hsCRP: High-sensitivity C-Reactive Protein; IMP: Investigational medicinal product; IWRS: 
Interactive Web Response System; lab: laboratory; MRI-PDFF: Magnetic Resonance Imaging - Proton Density Fat Fraction;  OGTT+F: oral glucose + fructose tolerance 
test; param.: parameters; phys ex.: physical examination; PK: pharmacokinetics; SMBG: self-monitoring blood glucose; V: visit; W: week(s) 
 
1:  the interval between two on-site visits must not exceed 32 days 
2:  includes head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems 
3:  includes height, weight, body mass index (BMI), waist and hip circumferences for Screening Visit (V1) and weight, BMI, waist and hip circumferences for other visits 
4:  includes general appearance, the cardiovascular system as well as reported symptoms by the patient to the Investigator; includes weight, waist and hip circumferences 
5:  includes one measurement of heart rate and three measurements of blood pressure in supine position 
6:  includes serum insulin, C-peptide, total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, Apo A1, Apo B, 
free fatty acids (FFA), glycerol and adiponectin  
7:  includes Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), Quantitative Insulin Check Index (QUICKI), Homeostasis Model Assessment of β-cell function 
(HOMA-β) and Adipose tissue Insulin Resistance (Adipo-IR). 
 
For the determination of these parameters, two blood samples should be collected at a 10-min interval. 
8:  includes biochemistry, hematology, coagulation and urinalysis 
9:  includes fibrinogen and Monocyte Chemoattractant Protein-1 (MCP-1)  
10:  includes Non-Alcohol Fatty Liver Disease (NAFLD) Fibrosis score (NFS) and Fibrosis-4 (Fib-4) score 
11:  includes Hepatitis B surface 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 
12:  for female patients of child-bearing potential only, serum pregnancy test (Human Chorionic Gonadotropin (β-HCG)) at Screening Visit (V1), End-of-study Visit (V8) and 
Early termination Visit (ET) and urine pregnancy test at all other visits where a pregnancy test is planned 
13:  if required as per inclusion criterion #7, transient elastography should include Controlled Attenuation Parameter (CAP) assessment  
14:  includes single ECG at Screening Visit (V1) and triplicate ECGs at the other visits 
15:  ECG should be performed at pre-dose and 2h post-dose (i.e. before the PK sampling and the glucose and fructose load (if applicable))  
16:  blood sampling should be performed at the following timepoints: 
 
For all randomized patients: 
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- 
At V4, V5 and V6: pre-dose 
- 
At V7: pre-dose and at 2 hours post-dose (i.e. after the ECG but before the glucose and fructose load (if applicable)) 
- 
At V8 
 
For patients enrolled in the sub-study only: 
- 
At V7: 2.5h, 3h, 4h, 5h and 8h post-dose 
17: Optional collection of DNA/RNA sample 
18: SMBG dispensed to T2DM patients only. SMBG to be brought back to the study site at each visit for measurement review. SMBG will be kept by the patient after the end 
of his/her study participation.  
19: For T2DM patients only. 
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Figure 2. Diagram of sub-study assessments  
a) Baseline assessments (Randomization Visit (V3)) 
 
 
b) End of treatment assessments (End-of-treatment Visit (V7)) 
 
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2 Background Information 
2.1 Scientific Rationale 
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease associated with fat 
accumulation in the liver exceeding 5% in people with no or little alcohol consumption [2]. The 
development of non-alcoholic steatohepatitis (NASH) is the result of both environmental 
(sedentary lifestyle and excessive calorie intake) and individual predispositions, which lead to 
adipose tissue expansion, insulin resistance, liver fat accumulation (steatosis or non-alcoholic fatty 
liver - NAFL) with potentially development of inflammation and fibrosis (NASH). The ultimate 
stage of cirrhosis contributes to hepatic impairment and development of hepato-carcinoma. 
NAFLD has shown a rapid increase in prevalence worldwide (25% in the global population) and 
is particularly important in subjects with obesity, metabolic syndrome and T2DM reaching 70% to 
90% in these high-risk populations [3]. It is estimated that around 1.8 billion individuals have 
NAFLD worldwide [4].  Up to now, the best therapeutic approach for NAFLD consists in diet and 
exercise. This approach has proven an efficacy evidenced by improvement of liver biopsy [5]. 
However, these important lifestyle modifications are difficult to achieve and to sustain for the wide 
majority of the population [6]. Although the initial description was published in 1980 [7], its full 
spectrum and impact as a major chronic liver disease have only been recognized for the past 2 
decades [8]. To date, no pharmacological agent has proven a clinically meaningful benefit/risk 
profile as potential drug for NAFLD, and, to date, no drug has been recognized as standard 
pharmacotherapy and approved in this indication. Hence, there is an unmet medical need for 
pharmacological agents for management of NAFLD patients. 
The pathogenesis of NALFD is primarily driven by the progressive expansion of the adipose tissue 
secondary to poor lifestyle, triggering a low-grade inflammation state responsible for insulin 
resistance. Insulin resistance enhances fatty acids (FAs) release from the adipose tissue (lipolysis) 
towards the liver, FAs synthesis from carbohydrate in the liver (DNL), both promoting unexpected 
FAs accumulation in the liver (steatosis). Steatosis can stay uncomplicated for decades, but in a 
subset of subjects, inflammatory processes will develop leading to hepatocellular injuries and 
promoting fibrosis (steatohepatitis).  
5' adenosine monophosphate-activated protein kinase (AMPK) is an energy sensor that regulates 
cellular metabolism in multiple peripheral tissues (liver, adipose tissue, muscle, pancreatic  
cells…). When activated under low energy condition, AMPK stimulates catabolic pathways to 
produce energy (glucose uptake and lipid oxidation) while turning off energy consuming processes 
(gluconeogenesis and FA synthesis), in order to restore energy balance. In addition or in parallel 
to its metabolic effect, AMPK activation has been shown to have anti-inflammatory effects, 
improving the cellular functional environment. It is already well-established that AMPK activation 
by pharmacological compounds (metformin, thiazolidinediones), adipokines (leptin, adiponectin) 


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or physical activity causes many beneficial metabolic changes in subjects with metabolic syndrome. 
New drugs that directly activate AMPK are expected to improve both glucose and lipid homeostasis 
and may bring a substantial improvement in the treatment of NAFLD.  
PXL770 is a new chemical entity from a new class of drug. It is a direct AMPK activator and is 
currently under development in the treatment of NAFLD.  
2.2 PXL770 
2.2.1 Non-clinical Information 
PXL770 activates AMPK isoforms both allosterically and by protecting the enzyme from its 
dephosphorylation.  PXL770 binding involves 1 and 2 subunits.  PXL770 activates most of all 
12 AMPK complexes with a higher potency for 1 isoforms.  It triggers downstream AMPK 
signaling, including acetyl-CoA carboxylase (ACC) inhibition and peroxisome proliferator-
activated receptor gamma coactivator 1-alpha (PGC-1α) activation in the liver, as well as hormone-
sensitive lipase (HSL) inhibition in adipose tissue. PXL770 was shown in vitro to induce inhibition 
in hepatic gluconeogenesis, to increase muscle glucose uptake, and to decrease hepatic lipogenesis 
both in mouse and human hepatocytes. 
In various in vivo rodent models of diabetes, PXL770 (25, 50, 75, 100 and 150 mg/kg BID orally) 
was shown to significantly decrease HbA1c and basal glycemia, to improve oral glucose tolerance 
with a concomitant decrease in insulin secretion suggesting a potential insulin sensitizing effect, 
and to delay the onset of diabetes.  A significant benefit in lipid profile was also observed with a 
significant decrease in plasma triglycerides and FFA.  PXL770 was shown also to improve liver 
steatosis.  
In a mouse model of NASH, PXL770 treatment increased AMPK phosphorylation, reduced liver 
weight, reduced liver triglyceride levels, reduced liver inflammation, and reduced markers of liver 
damage (including ALT and AST).  PXL770 also improved the overall NAFLD Activity Score, 
which is the sum of an individual’s scores for steatosis, inflammation, and ballooning. 
A decrease in body weight during first days of treatment was only observed in some obese mouse 
models associated with a decrease in food intake.  During these first days of treatment 
gastrointestinal (GI) events (diarrhea) were also observed in some specific obese mouse models.  
PXL770 administration with progressive dose escalation prevented the GI adverse reaction while 
still inducing a sustained decrease in food intake and in body weight. PXL770 administered orally 
was tested up to 1000 mg/kg/day in the rat and was well-tolerated in the 4-week study while in the 
13-week toxicity study, one satellite female rat in the 1000 mg/kg/day group died prematurely 
following clinical signs (hypothermia and decreased activity). At the doses of 400 and 1000 mg/kg, 
some gastrointestinal symptoms were observed, mainly diarrhea, hypersalivation and abdominal 
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distension, with a dose-dependent increase in the incidence and severity of the symptoms. The no-
observed-adverse-effect-level (NOAEL) was considered to be 400 mg/kg/day in rat. In dog 
PXL770 was tested up to 300 mg/kg/day. In the 13-week toxicity study, instances of severe liquid 
feces occurred that were considered adverse at doses of 300 mg/kg/day, but were completely and 
rapidly reversible. No treatment-related changes in cardiac function were observed during the 
13-week dosing period, as shown by telemetry and absence of glycogen accumulation in the heart. 
The NOAEL was considered to be 150 mg/kg/day in dog. 
PXL770 did not show any evidence of genotoxicity and no specific findings were reported during 
the safety pharmacology studies.  
2.2.2 Clinical Information 
The development of PXL770 started in Europe, and the following studies were conducted: 
• A first-in-human, single ascending dose (SAD), phase I study (PXL770-001) to evaluate 
the safety, tolerability and pharmacokinetic profile of single doses of PXL770 ranging from 
30 mg up to 500 mg and to assess the food effect in Caucasian healthy male subjects. 
• A multiple ascending dose (MAD), phase I study (PXL770-002) to evaluate the safety, 
tolerability and pharmacokinetic profile of multiple doses of PXL770 ranging from 60 mg 
up to 500 mg for 10 days and to assess the drug-drug interaction with rosuvastatin in 
Caucasian healthy male subjects. 
2.2.2.1 PXL770-001: SAD phase I study 
In this study, the safety and tolerability profile of PXL770 doses up to 500 mg were very good. The 
only treatment-emergent adverse event (TEAE) considered possibly related to PXL770 was mild 
dizziness and occurred in the 250 mg treatment group.  
After a single oral dose of 30 mg to 500 mg, PXL770 is rapidly absorbed and distributed, and is 
eliminated according to a multi-exponential decay with a first elimination phase from 8h to 24h 
and a terminal elimination phase after 24h with an estimated terminal half-life ranging from 19h to 
30h (enterohepatic cycle).  PXL770 is metabolized by the liver and is not eliminated in urine. The 
median time to reach the maximum concentration (Tmax) is 1.5-2.5 hours across all doses.  Plasma 
exposures increase approximately linearly and dose proportionally.  PXL770 maximum 
concentration (Cmax) and exposure decrease in presence of food by around 60%.    Dose escalation 
was stopped after a single dose of 500 mg as the corresponding PXL770 AUCinf exceeded the 
defined AUC PK cap (corresponding to plasma exposure observed in dog after 4 weeks of repeated 
administration at the NOAEL dose (100 mg/kg/day)) by around 11%. The maximum tolerated dose 
(MTD) was not reached. A food effect was also investigated at the dose of 250 mg. There was a 
decrease in the Cmax (57% of fasting state) and in the exposure AUC0-24h (67% of the fasting state) 
of PXL770 observed after a high fat breakfast compared to the values observed in fasting condition. 
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2.2.2.2 PXL770-002: MAD phase I study 
In this study, the safety and tolerability profile of PXL770 doses up to 500 mg were good.  There 
were no Serious Adverse Events (SAEs), nor premature discontinuation. Related TEAE were 
reported in 17% of subjects receiving the placebo and in 36% of the subjects receiving PXL770 
without clear dose dependency. All AEs were of mild or moderate intensity.  They were mainly 
from the gastrointestinal system (transient abdominal pain or discomfort) or from the central 
nervous system (headache). All TEAEs were resolved at the end of the study. During the drug-drug 
interaction assessment with rosuvastatin, only one TEAE (headache) was considered as related in 
the rosuvastatin alone group. 
PXL770 was rapidly absorbed and distributed. The elimination was multi-phasic with a slow 
terminal phase. The median Tmax was 1.5-3 hours across all doses.  Plasma exposures (Cmax and 
AUCinf) were approximately linear and dose proportional up to 375 mg and tended to saturate 
between 375 mg and 500 mg. Steady-state was reached after 6 days of treatment. The highest mean 
PXL770 Cmax and AUCinf were observed at the 375 mg dose and represented approximately 40% 
and 67% of their respective tox-covers. There was no relevant accumulation for Cmax but a slight 
accumulation for exposure was observed (slightly exceeded one (up to 1.88 after QD regimen (60 
mg) and 1.96 at a BID regimen) after 10 days of treatment. The PK was shown to be time invariant. 
Inter-interindividual variability of the PK parameters was overall moderate. Urinary excretion of 
PXL770 after repeated oral administration was almost null. There was no clinically relevant drug-
drug interaction between PXL770 and rosuvastatin. 
A concentration-response model between QTcF and PXL770 concentrations was developed to 
describe the relationship between changes from baseline in QTcF (∆QTcF) and PXL770 plasma 
concentrations. 
Predicted ∆∆QTcF calculated for each dose level were always negative due to a shift in intercept 
for PXL770 treated subject compared to placebo. Indeed, the subjects receiving PXL770 had a 
difference of -3.2 msec in intercept compared to placebo subjects. However, this difference was 
not significant (p=0.4928) and did not suggest any model misspecification. The 90% CI upper were 
all below the regulatory threshold of 10 msec allowing to conclude that PXL770 is unlikely to 
induce QT/QTc prolongation. 
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of PXL770, please refer to the latest version of the Investigator's Brochure (IB) for 
PXL770. 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, Investigators and Study Administrative Structure. 
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2.3 Research Hypothesis  
After 12 weeks of double-blind treatment, we aim to show superiority in liver fat mass reduction, 
assessed by MRI-PDFF, achieved with PXL770 compared to placebo in NAFLD patients. 


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3 Study Objectives 
3.1 Primary Objective 
To assess the effect of PXL770 versus placebo on hepatic steatosis in NAFLD patients at the daily 
dose of 250 mg QD and BID and 500 mg QD after 12 weeks of treatment 
3.2 Secondary Objectives 
• 
To assess the safety and tolerability of PXL770 versus placebo in NAFLD patients at the daily 
dose of 250 mg QD and BID and 500 mg QD after 12 weeks of treatment 
• To assess the effect of PXL770 versus placebo in NAFLD patients on metabolic and non-
metabolic parameters at the daily dose of 250 mg QD and BID and 500 mg QD after 12 weeks 
of treatment: 
- 
Liver enzymes 
- 
Lipid parameters 
- 
Glycemic parameters in fasting conditions 
- 
Biomarkers of inflammation 
- 
Biomarkers of fibrosis 
- 
Anthropomorphic parameters 
• To compare the 2 doses regimens of PXL770 (BID versus QD) on efficacy and safety 
parameters in NAFLD patients 
• To describe PXL770 pre-dose plasma concentrations during the course of the treatment and 
pre- and post-dose plasma concentrations after 12 weeks of treatment in NAFLD patients.  
3.3 Exploratory Objectives for Sub-Study 
• To assess the effect of PXL770 versus placebo in NAFLD patients on metabolic and non-
metabolic parameters at the daily dose of 250 mg QD and BID and 500 mg QD after 12 weeks 
of treatment: 
- 
Fructose stimulated hepatic DNL 
- 
Glycemic parameters during a 3-hour OGTT 
The two tests being combined, OGTT will be a 3-hour glucose + fructose tolerance 
test (OGTT+F). 
• To assess PXL770 plasma concentrations before, during and after a 3-hour OGTT+F and 
fructose stimulated hepatic DNL assessment in NAFLD patients and correlation with 
pharmacodynamics and/or safety 
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4 Study Design 
4.1 Study Design and Schedule 
This study is a phase IIa, multi-center, double-blind, placebo-controlled, randomized study with 4 
parallel groups in NAFLD patients. 
There will be a total of 4 study periods, as follows: 
• Screening period: maximum of 2 weeks 
• Single-blind placebo Run-in period: 4 weeks  
• Double-blind treatment period: 12 weeks  
• Follow-up period: 1 week  
Patients will be randomized in a 1:1:1:1 ratio to receive either: 
• PXL770 250 mg QD 
• PXL700 250 mg BID 
• PXL770 500 mg QD 
• Placebo 
Randomization will be stratified according to T2DM status (T2DM patients versus non-T2DM 
patients) and study site (main study site 1 vs main study site 2 vs main study site 3 vs other study 
sites).  
The study site stratification “Main study site # (1 to 3)” refers to sites of the sub-study only. 
A sub-study will be performed in up to 3 study sites. This sub-study will include: 
- 
A fructose stimulated hepatic DNL assessment 
- 
A 3-hour OGTT+F 
The diagram of the study design is shown in Figure 1 and the visit schedule is tabulated in Table 
1 and in Figure 2.  
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 17 and 19 weeks.  
The End-of-study 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 IIa, multi-center, double-blind, placebo-controlled, randomized, parallel-
group study in NAFLD patients to assess the efficacy, safety and tolerability of PXL770 
administered as monotherapy, following International Conference on Harmonization (ICH) E6 
Good Clinical Practice (GCP).  
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The Single-blind placebo Run-in period is set to reduce any bias regarding placebo effect, to assess 
patient compliance and to minimize the possible confounding influence of dietary and activity 
changes. The 12-week Double-blind treatment duration period is selected based on the 
pharmacological data observed in the rodent NASH model. This duration is supported by the 13-
week toxicological studies in rats and dogs.  The Follow-up period is set to examine the reversibility 
of potential AE after taking the last dose of IMP. 
The dose selection was based on the estimated dose range of efficacy established during the 
pharmacological program and the PK, safety and tolerability observed in healthy subjects during 
the SAD/MAD phase I studies. The study has been designed to investigate the effects of two daily 
doses (250 mg or 500 mg) and two regimens (QD or BID).  As a matter of fact, the Cmax and AUCinf 
were approximately linear and dose proportional from 60 mg up to 375 mg but they both tended to 
saturate between 375 mg and 500 mg (highest dose tested in the MAD phase I study but not the 
MTD). As mentioned previously, the food affects both the Cmax and the exposure of the drug (57% 
and 67% of the fasting values, respectively). The active dose range is expected to be 165 mg to 350 
mg QD based on the effects observed during the pharmacological studies in several animal models 
of NASH and T2DM. Considering the good tolerability of the drug in phase I and the food effect, 
the doses of 500 mg and 250 mg have been selected for evaluation in this proof of concept study, 
250 mg being in the lower part of the expected active dose  range  and 500 mg QD at the higher 
end of the active dose range. The once daily regimen is expected to be the appropriate regimen 
based on the relatively long half-life of the compound. However, it is not fully determined whether 
the effects of PXL770 are mainly driven by the Cmax or by the exposure as the half-life is shorter 
in the rodents and most of the studies have been conducted with a twice daily regimen. So, it 
appeared also critical to investigate the activity of the top dose (500 mg per day) administered as a 
twice daily regimen.   
A sub-study will be performed in up to 3 study sites. This will be a mechanistic study performed 
in T2DM or non T2DM population. It is expected to include up to 10 patients per treatment group 
for a total of up to 40 patients. 
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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. Re-screening will not be allowed. 
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. BMI ≥ 25 to ≤ 50 kg/m²at Screening Visit (V1) and Randomization Visit (V3) 
4. eGFR ≥ 60 mL/min/1.73m² at Screening Visit (V1) calculated by the CKD-EPI formulae 
5. For patients with T2DM: 
- 
Either naïve of treatment with no glucose lowering drug for the last 12 weeks prior to 
Screening Visit (V1) or under stable oral glucose lowering drug (mono- or bi-therapy) for 
the last 12 weeks prior to Screening Visit (V1) (See non-permitted concomitant 
medications in exclusion criteria #25) 
- 
HbA1c ≤ 9.0% at Screening Visit (V1) 
6. Not applicable – intentionally left blank for data management purposes (consistency in eCRF 
capture of eligibility criteria historically) 
7. Hepatic steatosis: 
- 
Evidenced by TE with CAP ≥ 300 dB/m or by ultrasound or MRI, performed within the 
last 12 weeks prior to Screening Visit (V1). If none of these assessments are available 
prior to Screening Visit (V1), TE with CAP ≥ 300 dB/m should be evidenced at Run-in 
Visit (V2) 
- 
Confirmed by MRI performed within 8 ± 4 days prior to Randomization Visit (V3) with 
a PDFF value ≥ 10% 
8. Women of child-bearing potential (e.g. not surgically sterile or not postmenopausal) must 
have a negative serum pregnancy test at Screening Visit (V1) and a negative urine pregnancy 
test at Randomization Visit (V3) 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  
9. Male patients must have agreed on an effective contraception with their female partner 
 
Patients who were screened failed due to ALT values as per protocol versions prior to version 5.0 
can be rescreened one time for this study. 


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5.2 Exclusion Criteria 
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 both POXEL and 
Medpace staff and/or staff at the study site) 
2. Participation in another clinical study with intake of an investigational product during the last 
12 weeks prior to Screening Visit (V1)  
3. Previous participation in any clinical study with PXL770 intake 
Target disease exclusions 
4. Evidence of another form of 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 DILI 
5. Evidence of liver cirrhosis on laboratory assessment or TE ≥ 14 kPa at Run-in Visit (V2) 
6. AST or ALT > 200 IU/L at Screening Visit (V1) 
7. Evidence of hepatic impairment at Screening Visit (V1) as defined by the combination of at 
least two of the following parameters: 
- 
TBL ≥ 1.3 mg/dL 
- 
Serum albumin < 3.5 g/dL 
- 
INR ≥ 1.2 
- 
Platelets < 150 G/L 
- 
Hemoglobin < 11 g/dL in females or < 12 g/dL in males 
- 
Presence of ascites 
8. Bariatric surgery of any kind at any time prior to Randomization Visit (V3) or change in body 
weight greater than 5% within the last 12 weeks prior to the Screening Visit (V1) or between 
Screening Visit (V1) and Randomization Visit (V3) 
9. Positive serologic evidence of current infectious liver disease including HBsAg, and/or anti-
HCV antibody with detected RNA at the Screening Visit (V1).  
10. History of excessive alcohol intake defined by equal or greater than 21 units of alcohol/ week 
in males and equal or greater than 14 units of alcohol/ week in females for 2 years prior to the 
Screening Visit (V1), where a unit of alcohol is equal to 10 g pure alcohol.  
 
Medical History and Concurrent Disease Exclusions 
Cardiovascular diseases 
11. Any of the following disease within 24 weeks prior to Screening Visit (V1) or between 
Screening Visit (V1) and Randomization Visit (V3): 
- 
Myocardial infarction 
- 
Cardiac revascularization surgery (CABG/PTCA) 
- 
Unstable angina 


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- 
Unstable CHF 
- 
NYHA Class III or IV  
- 
Transient ischemic attack, stroke or cerebrovascular disease 
12. Unstable or undiagnosed arrhythmias, long QT syndrome, short QT syndrome, history of 
drug-induced Torsade de Pointe 
13. Uncontrolled high BP: diastolic BP ≥ 100 mmHg or systolic BP ≥ 160 mmHg with or without 
antihypertensive treatment at Screening Visit (V1)  
Hematological and oncological diseases 
14. Malignancy within 5 years prior to Screening Visit (V1) (with the exception of treated basal 
cell carcinoma or treated squamous cell carcinoma of the skin)  
15. History of haemoglobinopathies (e.g., sickle cell anemia or thalassemia, sideroblastic anemia) 
16. Patient who donated blood products to a blood bank or who received blood transfusion within 
12 weeks prior to Screening Visit (V1) or between Screening Visit (V1) and Randomization 
Visit (V3) 
Endocrinological disease 
17. Diabetes other than T2DM 
18. Uncontrolled hypothyroidism (TSH > 2 x ULN at Screening Visit (V1)) 
Other exclusion conditions 
19. Immunocompromised patients such as patients that underwent organ transplantation or were 
diagnosed with HIV 
20. 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 
21. Any current drug addiction  
22. 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  
23. Anorexia or bulimia 
24. Known hypersensitivity to any of the constituents or excipients of the IMP, or history of 
relevant drug and/or food allergies (e.g. anaphylactic, anaphylactoid reactions) 
25. Use of non-permitted concomitant medication within 24 weeks prior to Screening Visit (V1) 
and at any time between the Screening Visit (V1) and the Randomization Visit (V3): 
- 
Pioglitazone, insulin, GLP1-RA, SGLT2-I, anticoagulants, amiodarone, bile salt 
chelators, methotrexate, equal or more than 400 U of vitamin E per day, corticosteroids 
with systemic effect, or any other medications known to affect liver function / steatosis at 
the Investigator’s discretion, strong inhibitors of CYP2C8 (i.e. gemfibrozil and 
clopidogrel) and CYP2C9 (i.e. tazizulam, miconazole and sulfaphenazole), rifampin 
(moderate inducer of both CYP2C8 and CYP2C9), any herbal drug or Chinese traditional 
medicines 
26. Contraindications to MRI 
 
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- 
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 
27. Pregnancy or lactation 
5.3 Restrictions during the Study 
Patients must make every attempt to maintain the same diet/exercise treatment through the study. 
Patients must be in a fasting condition at least 10 hours (during which only water is permitted) 
prior to all on-site study visits except at V2. 
Patients included in the sub-study will be admitted to the site at around 5:00 pm the day prior to 
Randomization Visit (V3) and End-of-treatment Visit (V7). A dinner will be served at around 5:00 
pm to 6:00 pm. Patients should drink 3 doses of deuterated water 70% as described in Figure 2. 
Deuterated water 0.5% will be provided ad libitum to patients. This will be the only beverage 
allowed during DNL and OGTT+F procedures. 
To respect Inclusion criteria #8, 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 
birth control method. 
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. 
5.4 Patients Incorrectly Enrolled in the Single-blind Placebo Run-in Period or 
Incorrectly Randomized 
Patients who fail to meet the Inclusion/Exclusion criteria must not, under any circumstances, enter 
the Single-blind placebo Run-in period, or enter the Double-blind treatment period.  
5.4.1 Patients Incorrectly Enrolled in the Single-blind Placebo Run-in Period 
If a patient who does not meet the Inclusion/Exclusion criteria mistakenly enters the study and 
performs the Single-blind placebo Run-in period, the POXEL Medical Representative and the 
Medpace Medical Monitor should be immediately informed. This patient will be immediately 
withdrawn from the study and will be considered as screen failure.  
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5.4.2 Patients Incorrectly Randomized 
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 
Medpace 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. 
5.5 Criteria for Screen-failure 
Patients who are withdrawn from the study between the Screening Visit (V1) and the 
Randomization Visit (V3) will be considered as screen failure. 
Patients must be screen-failed in the event of any of the following: 
1. Target hepatic steatosis not met (as defined in Section 5.1 Inclusion Criteria, Inclusion 
Criteria #7) 
2. Target eGFR not met (as defined in Section 5.1 Inclusion Criteria, Inclusion Criteria #4) 
3. Other Inclusion criteria not met (as defined in Section 5.1 Inclusion Criteria) 
4. Occurrence of an Exclusion criteria (as defined in Section 5.2 Exclusion 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 
Investigator or POXEL Medical Representative/designee 
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. Withdrawal of patient informed consent  
10. Lost to follow-up  
The reason for screen failure must be documented in source documents and reported in the 
electronic Case Report Form (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. 
Patients should return at study site to bring back the remaining IMP Run-in kits, the patient diary 
dispensed and the SMBG device, if applicable. The Investigator will perform the IMP 
accountability; verify the patient diary, AE and concomitant medications and SMBG measurements 
if applicable. The SMBG device will be kept by the patient after the end of his/her study 
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Patients will then be referred to their physician for the pursuit of routine medical care. 
5.6 Criteria for Withdrawal from the Study for Randomized Patients during 
the Double-blind Treatment Period 
5.6.1 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, if 
discontinuation of the IMP is considered necessary by the Investigator or POXEL Medical 
Representative  
2. Occurrence of DILI (as defined in Section 8.3.8.2 DILI) 
3. Occurrence of pregnancy 
4. Important protocol deviation if discontinuation of IMP is considered necessary by the 
Investigator or POXEL Medical Representative/designee 
5. 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 
6. Requirement of an emergency unblinding (as described in Section 6.3.3.2 Emergency 
Unblinding  
7. Withdrawal of patient informed consent  
8. Lost to follow-up  
9. Sponsor decision (as defined in Section 5.7 Discontinuation of the Study) 
In case of temporary discontinuation of the IMP, the decision to resume the IMP should be taken 
in agreement by the Investigator, POXEL Medical Representative and Medpace Medical Monitor. 
5.6.2 Procedure for withdrawal from the study 
In the case of discontinuation of IMP for any reason listed in Section 5.6.1 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 11 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 
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applicable. The SMBG device will be kept by the patient after the end of his/her study participation 
if applicable. Investigator will complete the eCRF (Early Termination Visit section).  
The reason and date for withdrawal from the study must be documented in source documents, in 
the eCRF and reported 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 satisfactory health has returned. The Investigator must make 
every effort to collect the information related to the outcome of the event. This information is 
recorded in the part of eCRF dedicated to AEs. If the Investigator cannot organize a follow-up visit 
to collect this information, he/she must try to call the patient and/or his/her treating physician. If 
the IMP is discontinued as a result of a SAE, the procedure described in Section 8.3.6.4 Procedure 
for Reporting Immediately Reportable Events (IREs= SAEs and Pregnancy) 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 and reported in the 
eCRF.  
Irrespective of the withdrawal reasons, any withdrawal is to be notified immediately to the 
Medpace Medical Monitor and Poxel Medical Representative. 
5.7 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: 
▪ Occurrence of significant previously unknown adverse reactions or unexpectedly 
high intensity 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  
Competent Authorities and institutional review boards/ethics committees (IRBs/ECs) will be 
informed about the discontinuation of the study in accordance with applicable regulations. 


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The study may be terminated or suspended upon request of Competent Authorities. 
5.8 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” [9]. 
In this study, the terminology IMP refers both to PXL770 or placebo. 
The IMP administered are hard gelatin capsules (Swedish orange size 00). The capsules are 
packaged in blisters.   A description of the two types of capsules, PXL770 and placebo, is given in 
the IB [10]. 
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 
PXL770 capsules will contain 250 mg of PXL770 plus the excipients. The active pharmaceutical 
ingredient is the monohydrate potassium salt of PXL770. Placebo capsules will contain excipients 
alone, as described in the IB [10]. Both capsules have the same shape, size and appearance 
(including the same color, smell and taste).  
6.2 Dosage and Administration 
PXL770 and/or placebo capsules will be taken BID with a glass of water. An optimal interval 
between the two IMP intakes would be 12 ± 2 hours. The interval of IMP intakes must not be less 
than 6 hours.  
To harmonize IMP intake, it is recommended to take IMP at least 15 min before a meal in the 
morning time and in the evening time.  
No IMP should be taken in the morning at home before each on-site visit. IMP will be taken at 
study site after all visit assessments are performed as specified in Table 1. 
Patients will be provided with the patient diary (paper format) as specified in Table 1. IMP intake 
(date and time) will be documented by the patients in the patient diary.  
The patient diary is to be returned at each visit together with the IMP kit(s) (used and unused).  
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6.2.1 Single-blind Placebo Run-in Period 
At Run-in Visit (V2), patients will start an oral dose of 2 capsules of placebo BID (4 capsules per 
day). The Single-blind placebo Run-in period will last for 4 weeks from Run-In Visit (V2) to 
Randomization Visit (V3). 
First dose intake of IMP will be taken by the patient in the evening time on the day of Run-in Visit 
(V2). Last IMP intake will be at study site on the day of Randomization Visit (V3) (morning time; 
after completion of all pre-dose assessments). 
6.2.2 Double-blind Treatment Period 
The Double-blind treatment period starts on the day of the Randomization Visit (V3) (evening 
time), following randomization to one of the 4 double-blind treatment groups in this study. On the 
day of Randomization Visit (V3), the first dose of Double-blind treatment period IMP will be taken 
by the patient in the evening. 
To ensure a double-blind design, regardless of the treatment group, all patients will take an oral 
dose of 2 capsules BID of either placebo and/or PXL770 250 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 Capsules (Total = 4 Capsules/Day) 
PXL770 250 mg QD (250 mg/day) 
- 1 capsule of PXL770 250 mg + 1 capsule of placebo 
in the morning 
- 2 capsules of placebo in the evening 
PXL770 250 mg BID (500 mg/day) 
- 1 capsule of PXL770 250 mg + 1 capsule of placebo 
in the morning 
- 1 capsule of PXL770 250 mg + 1 capsule of placebo 
in the evening 
PXL770 500 mg QD (500 mg/day) 
- 2 capsules of PXL770 250 mg in the morning 
- 2 capsules of placebo in the evening 
Placebo 
- 2 capsules of placebo in the morning 
- 2 capsules of placebo in the evening 
The Double-blind treatment period will last for 12 weeks after Randomization Visit (V3). 
The last dose of each IMP kit should be taken by the patient at site in the morning of the visit after 
completion of all pre-dose assessments. Then, the first dose from the new IMP kits dispensed 
during the visit should be taken in the evening time on the day of the visit. 


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Last IMP intake will be at study site on the day of End-of-treatment Visit (V7) (morning time; after 
completion of all pre-dose assessments). 
6.2.3 Follow-up Period 
The Follow-up period starts at the end of the 12-week Double-blind treatment period. At the End-
of-treatment Visit (V7), patients will not receive an IMP kit and consequently they will not take 
IMP during the follow-up period.  
The Follow-up period will last for 1 week. 
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 (V1 to V8) by a patient number assigned at 
Screening Visit (V1). 
The patient number consists of a unique 5-digit number using the schema XX-YYY. The first 2 
digits (XX) indicate the pre-defined study site number. The last 3 digits (YYY) identify the patient 
within the study site. The first patient entered in a study site will be assigned the number 001, the 
second will be assigned the number 002, and so on. For example, patient 04-001 will be the first 
patient screened at study site 04. So that each patient is numbered uniquely across all clinical 
databases (IWRS, eCRF…). 
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. Once assigned, the patient number must not be reused for any other patient and the patient 
number for this patient must not be changed. 
6.3.2 Treatment Assignment or Randomization 
Single-blind placebo Run-in period 
At Run-in Visit (V2), once eligibility criteria have been checked by the Investigator, the 
Investigator (or designee) will log on to the IWRS to confirm the patient eligibility and enter the 
patient into the Single-blind placebo Run-in period for 4 weeks.  
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At Randomization Visit (V3), after re-confirming the eligibility criteria, the Investigator (or 
designee) will log on to the IWRS to re-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 PXL770 250 
mg QD, 250 mg BID, 500 mg QD or placebo for 12 weeks.  
Randomization will be stratified according to T2DM status (T2DM patients versus non-T2DM 
patients) at Randomization Visit (V3) and according to study sites (main study site 1 vs main study 
site 2 vs main study site 3 versus other study sites).  
Patients will be assigned a unique randomization number at the Randomization Visit (V3) by 
IWRS. This randomization number identifies which record in the randomization list and therefore 
which treatment will be allocated to the patient.  
The randomization list will be generated and kept by the Medpace statistical department by a 
statistician independent of the project team. A copy will be provided to Creapharm in charge of 
medication packaging and logistics, and to the bioanalytical laboratory in charge of the PK 
assessments on samples from patients receiving PXL770. 
During the Double-blind treatment period, at each on-site visit (except at Week 2 (V4)) 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 a placebo capsule that has the same 
shape, size and appearance (including the same color, smell and taste) as the PXL770 capsules. 
Whatever the dose group they will be assigned to, patients will receive the same number of capsules 
(PXL770 and/or placebo) in order to keep the blind, both during the Single-blind placebo Run-in 
period and the Double-blind treatment period. 
PXL770 and placebo capsules 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.  
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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 Medpace before code breaking. Once the code is 
broken for a patient, this patient must discontinue IMP, perform Early termination Visit and 
withdraw from the study. 
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 Medpace Medical Monitor and the Poxel Medical Representative 
within 24 hours in writing. 
POXEL and / or its designee(s) will also receive an authorization to access IWRS’s 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 8.3.6.4 Procedure for Reporting Immediately Reportable Events (IREs= SAEs and 
Pregnancy)). 
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 to the End-of-study Visit (V8). Patients must not take any unlicensed medication, 
i.e. other investigational drugs except PXL770 or placebo, during their participation in the study.  
Medications taken within 28 days prior to ICF signature and stopped before or on ICF signature 
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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 
(V8)) will be considered as new medication. 
Any concomitant 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. 
6.5 Non-permitted Medicines 
Patients must not take any of the following licensed medication within the 24 weeks prior to the 
Screening Visit (V1): 
• Pioglitazone 
• Insulin 
• GLP1-RA 
• SGLT2-I 
• Anticoagulant agents 
• Amiodarone 
• Bile salt chelators 
• Methotrexate 
• Equal or more than 400 U of vitamin E per day 
• Corticosteroids with significant systemic effect (e.g. oral or intravenous administrations) 
• Any other medications known to affect liver function / steatosis at the Investigator’s 
discretion 
• Strong inhibitors of CYP2C8 (i.e. gemfibrozil and clopidogrel) and CYP2C9 (i.e. tazizulam, 
miconazole and sulfaphenazole) 
• Rifampin (moderate inducer of both CYP2C8 and CYP2C9) 
• Any herbal drug or Chinese traditional medicines 
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 Medpace Medical Monitor will decide whether the patient can continue the IMP. 
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6.6 Packaging and Labeling 
PXL770 and placebo capsules will be packaged in appropriate blister and will be labeled in English 
with respect to the regulatory requirements in the US. 
Blister: A blister contains 32 capsules corresponding to 8 days of BID treatment. The morning and 
evening doses will be clearly identified. The patient must strictly follow these indications. 
IMP kit: An IMP kit contains 4 blisters (128 capsules – 32 days). 
• During the Single-blind placebo Run-in period, 1 IMP kit containing 4 blisters (total of 
4 blisters – 128 capsules – 32 days) will be dispensed at Run-in Visit (V2). 
• During the Double-blind treatment period, 1 IMP kit containing 4 blisters (total of 4 blisters 
– 128 capsules – 32 days) will be dispensed at each dispensing visit.  
IMP kit numbering 
The IMP kit number will identify medication packs.  
Packaging and labeling will be in accordance with applicable US regulatory requirements. 
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 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 and 
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 Master Accountability log throughout the whole duration of the study. 
IMP resupply will be managed automatically through IWRS.  


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6.7.3 Storage of IMP 
The Investigator (or designee) will ensure that all IMPs are stored under recommended storage 
conditions and in accordance with applicable US regulatory requirements. IMP must be carefully 
and safely stored at the study site, and 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) and before 
the first dispensation of the day, at least on every working day (i.e. manually or by using alarm 
system to alert of any excursions) 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, the Investigator is 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. 
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 on-site visit. The IMP expiry date might be extended after the drug 
stability has been re-analyzed. In such case, IMP should then be re-labeled before dispensation. 
The re-labeling of the medication will be performed by an authorized person at the US depot, 
following appropriate instructions and documented. 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 
Medpace. 
IMP accountability 
The Investigator (or designee) must maintain an accurate record as follows: 
• Master Accountability 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. 
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• Subject Accountability log recording IMP dispensing and IMP return by patient detailed in 
terms of number of capsules.    
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) from Run-in Visit (V2) to 
Randomization Visit (V3) for the Single-blind Run-in period and from Randomization Visit (V3) 
to End-of-treatment Visit (V7) (from Day 0 to Week 12) for the Double-blind treatment period 
based on the patient diary and IMP kits returned by the patient.  
The Investigator (or designee) must document the IMP compliance in source document and in the 
eCRF. 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 capsules taken×100 
Theoretical number of capsules to be taken during the period (based on on-site visit days)*  
* In case of IMP temporary interruption requested by the Investigator (e.g. due to AE), the duration 
of the temporary interruption should be deducted from the theoretical number of capsules to be 
taken during the period. 
The acceptable 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 
during Double-blind treatment period) and the Investigator must remind the patient to follow the 
IMP instructions.  


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6.7.5 Return and Destruction of IMP 
The Investigator (or designee) will reconcile capsules returned by the patients with the Subject 
Accountability Logs. 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 database 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 
The packaging has been designed to prevent any overdose with a clear indication on the blisters of 
the morning and evening 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, 4 extra daily doses are provided between 2 on-site visits (4 weeks). 
For Week 2 (V4, 2 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 (V3) until Week 4 (V5, 4 weeks after randomization). 
6.8.1 Preclinical and Clinical Status 
Clinical data available so far with PXL770 showed a good safety and tolerability profile in healthy 
Caucasian male subjects after single administration of PXL770 up to 500 mg and multiple 
administrations (10 days) up to 500 mg QD. The dose of 500 mg QD is the maximal dose tested in 
humans. 
6.8.2 Overdose Definition 
Based on available data, an overdose is considered as any dose greater than the highest daily dose 
administered as single or repeated doses in the phase I study (i.e. 500 mg per intake and per day). 
Plasma exposures (Cmax and AUCinf) were approximately linear and dose proportional up to 375 
mg and tended to saturate between 375 mg and 500 mg. Steady-state was reached after 6 days of 
treatment. The median Tmax is 1.5-2.5 hours across all doses.  Plasma exposures increase 
approximately linearly and dose proportionally.  PXL770 Cmax and exposure decrease in presence 
of food by around 60%.     
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However, this study will be blinded during the Double-blind treatment period. As 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 capsules administered over a defined period of time. 
Based on data obtained during the single and repeated dose administration up to 500 mg in healthy 
subjects, overdose is defined by the intake of 3 capsules or more per intake and/or more than 4 
capsules per day (if morning and evening indications are followed) and/or 3 capsules or more per 
day if at least 3 capsules come from the morning part of the blister).  
Error in dosing schedule may happen as for instance misdosing (i.e. 4 capsules QD in place of 2 
capsules BID). In such cases, dosing error will be recorded in the patient file by the Investigator 
and reported as a protocol deviation by the CRA. Patient will be retrained by the Investigator and 
it will be documented in source documents.  
In any case, these overdoses based on number of capsules will need to be confirmed at the end of 
the study, once unblinding and identification of the treatment group will allow real dose calculation. 
Only doses exceeding 500 mg per day will be considered as overdose. 
Conclusion on overdose will be included in the final study report. 
6.8.3 Reporting 
Any suspicion of overdose, when occurring in the Double-blind treatment period, whether or not 
associated with an AE (serious or non-serious) must be reported to POXEL/Medpace in an 
expedited manner. 
 
6.8.4 Treatment 
No specific antidote is currently available for PXL770 and only symptomatic therapy is possible. 
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7 Study Procedures 
At each visit, it will be recommended to perform the assessments in the following order: ECGs, 
vital signs and blood samplings. Blood sampling for PK analysis should be collected nearest to the 
scheduled time point. 
7.1 Screening Period, Screening Visit (V1): On-site Visit 
Eligible patients (see definition in section 5.1 Inclusion Criteria) will be informed about the study 
in detail and sign the ICF prior to any study-related procedure. Re-screening will not be allowed. 
The Screening period starts from the date of ICF signature. 
On the basis of the findings from the assessments made at this visit, the Investigator will decide 
whether the patient is to be included in the study.  
The following procedures will be completed: 
• Obtain written ICF 
• Register the patient in the IWRS to retrieve his/her patient study number  
• Review Inclusion and Exclusion criteria  
• Obtain demography (year of birth, age, gender, ethnic origin, race, child-bearing potential if 
woman) 
• 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 this visit 
• Conduct complete physical examination including height, weight, BMI, waist and hip 
circumferences  
• Record supine vital signs (BP and HR)  
• 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: 
- 
hsCRP 
- 
FPG and HbA1c 
- 
Standard safety laboratory panel (blood and urine)  
- 
eGFR using the CKD-EPI formula 


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- 
Serum pregnancy test (if applicable) 
- 
Viral infection screen panel 
• Dispense patient emergency card 
In case the patient is not fasting in the morning of the Screening Visit (V1), the visit should proceed 
according to the protocol description, with the exception of the laboratory sampling which can be 
postponed up to 3 days later. The reason for this should be carefully mentioned in the patient file. 
7.2 Single-blind Placebo Run-in Period, Run-in Visit (V2): On-site Visit 
Run-in Visit (V2) will take place within maximum 2 weeks after the Screening Visit (V1). 
The following procedures will be completed:  
• Log on to IWRS to confirm patient eligibility and retrieve IMP kit number assigned by the 
system  
• Review Inclusion and Exclusion criteria 
• Collect AE 
• Collect concomitant medication 
• Conduct limited physical examination including weight, BMI, waist and hip circumferences  
• Record supine vital signs (BP and HR) 
• Perform Transient elastography. If required as per inclusion criterion #7, this TE should 
include CAP measurement  
• Dispense placebo capsules for 4 weeks and patient diary 
• Dispense self-monitoring blood glucose (SMBG) device only for T2DM patients 
During the Single-blind placebo Run-in period starting from V2 to V3, the patient must 
undergo an MRI with PDFF evaluation within 8 ± 4 days prior to Randomization Visit (V3). 
7.3 Double-blind Treatment Period 
7.3.1 Randomization Visit (V3) (Day 0): On-site Visit 
Randomization Visit (V3) will take place 4 weeks (± 2 days) after the Run-in Visit (V2). 
The following procedures will be completed:  
• Log on to IWRS to confirm patient eligibility and retrieve IMP kit number assigned by the 
system 
• Review Inclusion and Exclusion criteria including review of MRI-PDFF performed within 
8 ± 4 days prior to this visit 


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• Collect AE 
• Collect concomitant medication 
• Conduct complete physical examination including weight, BMI, waist and hip 
circumferences  
• Record supine vital signs (BP and HR)  
• Perform standard supine triplicate 12-lead ECGs  
• Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
hsCRP 
- 
FPG and HbA1c 
- 
Standard safety laboratory panel (blood and urine) 
- 
eGFR using the CKD-EPI formula 
- 
Urine pregnancy test (if applicable) 
- 
Measured metabolic parameters 
- 
Calculated metabolic parameters 
- 
Inflammatory biomarkers 
- 
Fibrosis biomarkers 
- 
Biobanking sampling  
- 
Blood sampling for DNA/RNA (only for patients who have signed the additional, 
specific consent form) 
• Review the patient diary dispensed at Run-In Visit (V2)  
• For T2DM patients, review SMBG measurements performed according to the Investigator 
(or designee) recommendations. 
• Record IMP compliance for the period Run-In Visit (V2) to Randomization Visit (V3) 
• Dispense placebo and/or PXL770 capsules for 4 weeks and patient diary 
The following procedures will be completed only in the sub-study as detailed in Figure 2:  
• Perform 3-hour OGTT+F; A SMBG measurement should be performed prior to the beginning 
of the procedure in order to ensure that the glycemic status of the patient allows the procedure. 
• Assess fructose stimulated hepatic DNL for 6 hours 
7.3.2 Week 2 (V4): On-site Visit 
Week 2 (V4) will take place 2 weeks (± 2 days) after Randomization Visit (V3).  
The following procedures will be completed:  
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• Log on to IWRS to register patient visit date 
• Collect AE 
• Collect concomitant medication 
• Conduct limited physical examination including weight, BMI, waist and hip circumferences  
• Record supine vital signs (BP and HR)  
• Perform standard supine triplicate 12-lead ECGs  
• Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
hsCRP 
- 
FPG 
- 
Standard safety laboratory panel (blood and urine) 
- 
Urine pregnancy test (if applicable)  
- 
PK sampling 
• Review the patient diary dispensed at Randomization Visit (V3) 
• For T2DM patients, review SMBG measurements performed according to the Investigator 
(or designee) recommendations. 
• Record IMP compliance for the period Randomization Visit (V3) to Week 2 (V4) 
7.3.3 Week 4 (V5): On-site Visit 
Week 4 (V5) will take place 4 weeks (± 2 days) after Randomization Visit (V3).  
The following procedures will be completed:  
• Log on to IWRS to retrieve IMP kit number assigned by the system 
• Collect AE 
• Collect concomitant medication 
• Conduct limited physical examination including weight, BMI, waist and hip circumferences  
• Record supine vital signs (BP and HR)  
• Perform standard supine triplicate 12-lead ECGs 
• Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following:  
- 
hsCRP 
- 
FPG 
- 
Standard safety laboratory panel (blood and urine)  


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- 
Urine pregnancy test (if applicable) 
- 
Measured metabolic parameters 
- 
Calculated metabolic parameters 
- 
PK sampling 
• Review the patient diary dispensed at Randomization Visit (V3) 
• For T2DM patients, review SMBG measurements performed according to the Investigator 
(or designee) recommendations. 
• Record IMP compliance for the period Week 2 (V4) to Week 4 (V5) 
- 
Dispense placebo and/or PXL770 capsules for 4 weeks and patient diary 
7.3.4 Week 8 (V6): On-site Visit 
Week 8 (V6) will take place 8 weeks (± 3 days) after Randomization Visit (V3). The interval 
between V5 and V6 must not exceed 32 days. 
The following procedures will be completed:  
• Log on to IWRS to retrieve IMP kit number assigned by the system  
• Collect AE 
• Collect concomitant medication 
• Conduct limited physical examination including weight, BMI, waist and hip circumferences  
• Record supine vital signs (BP and HR)  
• Perform standard supine triplicate 12-lead ECGs  
• Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
hsCRP 
- 
FPG 
- 
Standard safety laboratory panel (blood and urine)  
- 
Urine pregnancy test (if applicable) 
- 
Measured metabolic parameters 
- 
PK sampling 
• Review the patient diary dispensed at Week 4 (V5) 
• For T2DM patients, review SMBG measurements performed according to the Investigator 
(or designee) recommendations. 
• Record IMP compliance for the period Week 4 (V5) to Week 8 (V6) 
• Dispense placebo and/or PXL770 capsules for 4 weeks and patient diary 


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7.3.5 Week 12 – End-of-treatment Visit (V7): On-site Visit 
End-of-treatment Visit (V7) will take place 12 weeks (± 4 days) after Randomization Visit (V3). 
The interval between V6 and V7 must not exceed 32 days. 
The following procedures will be completed:  
• Log on to IWRS to register patient visit date  
• Collect AE 
• Collect concomitant medication 
• Conduct complete physical examination including weight, BMI, waist and hip 
circumferences  
• Record supine vital signs (BP and HR)  
• Perform standard supine triplicate 12-lead ECGs (pre-dose and 2h post-dose (i.e. before the 
PK sampling and the glucose and fructose load (if applicable)) 
• Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
hsCRP 
- 
FPG and HbA1c 
- 
Standard safety laboratory panel (blood and urine)  
- 
Urine pregnancy test (if applicable) 
- 
eGFR using the CKD-EPI formula 
- 
Measured metabolic parameters 
- 
Calculated metabolic parameters 
- 
Inflammatory biomarkers 
- 
Fibrosis biomarkers 
- 
Biobanking sampling (including optional collection of blood sample for 
DNA/RNA (only for patients who have signed the additional, specific consent 
form) 
• Perform PK samplings at pre-dose and 2h post-dose (i.e. after the 12-lead ECGs and before 
the glucose and fructose load (if applicable)) 
• Perform MRI with PDFF evaluation before or on the day of Week 12 (V7), i.e. 84 days (- 4 
days) after Randomization Visit (V3) 
• Review the patient diary dispensed at Week 8 (V6)  
• For T2DM patients, review SMBG measurements performed according to the Investigator 
(or designee) recommendations. 
• Record IMP compliance for the period Week 8 (V6) to End-of-treatment Visit (V7) 
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The following procedures will be completed only in the sub-study as detailed in Figure 2:  
• Perform 3-hour OGTT+F; A SMBG measurement should be performed prior to the beginning 
of the procedure in order to ensure that the glycemic status of the patient allows the procedure. 
• Assess fructose stimulated hepatic DNL for 6 hours 
• Collect PK plasma samples 
7.4 Follow-up Period, End-of-study Visit (V8): On-site Visit 
End-of-study Visit (V8) will take place 1 week (± 2 days) after End-of-treatment Visit (V7). 
The following procedures will be completed:  
• Log on to IWRS to register patient visit date  
• Collect AE 
• Collect concomitant medication 
• Conduct complete physical examination including weight, BMI, waist and hip 
circumferences  
• Record supine vital signs (BP and HR)  
• Perform standard supine triplicate 12-lead ECGs  
• Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
hsCRP 
- 
FPG 
- 
Standard safety laboratory panel (blood and urine)  
- 
Serum pregnancy test (if applicable)  
- 
PK sampling 
• For T2DM patients, review SMBG measurements performed according to the Investigator 
(or designee) recommendations 
• Refer patient to his/her previous physician for the pursuit of his/her routine medical care 
7.5 Withdrawal of Patients (Early termination Visit): On-site Visit 
The following procedures will be completed during an on-site visit within 11 days after the IMP 
discontinuation: 
• Log on to IWRS to register patient withdrawal date  
• Collect AE 
• Collect concomitant medication 
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• Conduct complete physical examination including weight, BMI, waist and hip 
circumferences  
• Record supine vital signs (BP and HR) 
• Perform standard supine triplicate 12-lead ECGs 
• Following at least a 10-hour fast (food and drink, except water), collect blood and urine 
specimens for the following: 
- 
hsCRP 
- 
FPG and HbA1c 
- 
Standard safety laboratory panel (blood and urine)  
- 
eGFR using the CKD-EPI formula  
- 
Serum pregnancy test (if applicable) 
- 
Measured metabolic parameters 
- 
Calculated metabolic parameters 
- 
Inflammatory biomarkers 
- 
Fibrosis biomarkers 
• Review the patient diary dispensed at the previous visit 
• For T2DM patients, review SMBG measurements performed according to the Investigator 
(or designee) recommendations. 
• Record IMP compliance for previous period 
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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 assessed by MRI-PDFF – Central imaging core lab 
The primary evaluation of efficacy will be based on MRI-PDFF. This primary endpoint will be the 
relative change in the percentage of liver fat mass (assessed by MRI-PDFF) from baseline 
(Randomization Visit (V3)) to Week 12 (End-of-treatment Visit, V7).  
As key secondary efficacy endpoints, the (absolute) change in the percentage of liver fat mass 
(assessed by MRI-PDFF) from baseline (Randomization Visit (V3)) to Week 12 (V7) and the 
percentage of responders defined by the percentage of patients who achieve a clinically meaningful 
reduction of at least 5 % (≥ 5%) in absolute liver fat mass as measured by MRI-PDFF at Week 12 
(V7) will be also compared between placebo and PXL770 groups. 
Local MRI facilities in each study site will complete a qualification and quality assurance process 
prior to perform MRI acquisitions. MRI scans will be then performed on qualified and standardized 
devices at high field strength (either 3 or 1.5 Tesla) without enhanced contrast agents. MRI-PDFF 
acquisition protocols will include the acquisition guidelines for multi-echo PDFF sequence for 
most common manufacturers (GE, Siemens, Philips) and field strength (1.5T and 3.0T). All 
acquisitions images will be transferred to the Medpace Core Laboratories for central calculation 
and measurement of MRI-PDFF using a validated and established technique. The imaging 
submission manual will provide sites with information on data submission to Medpace Core 
Laboratories. Central readings will be performed by masking study sites, timepoints, clinical data 
and treatment groups information.  
Fat mass results of MRI-PDFF at Randomization Visit (V3) and Week 12 (End-of-treatment Visit, 
V7) will be blinded for Investigators and POXEL until database hard lock.  
 
 


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MRI-PDFF technique will be exclusively used for assessment of liver fat mass. 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. 
Please refer to central imaging core lab manual for further details. 
8.2.2 Other Efficacy Parameters 
The following parameters will be also determined at various timepoints to further assess efficacy:  
• Liver enzymes: ALT and AST 
• Measured metabolic parameters: FPG, HbA1c, serum insulin, C-peptide, total cholesterol, 
HDL-c, LDL-c, triglycerides, Apo A1, Apo B, FFA, glycerol and adiponectin  
• Calculated metabolic parameters: HOMA-IR, QUICKI, HOMA-β, Adipo-IR 
The homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin 
sensitivity check index (QUICKI) and the homeostasis model assessment of β-cell function 
(HOMA-ß) will be calculated using the fasting insulin and FPG values at visits specified in 
Table 1. The adipo-IR will be calculated using fasting insulin and fasting FFA.  
- The HOMA-IR is calculated as [11]:  
Fasting insulin (µIU/mL) × FPG (mg/dL) / 405 
- The QUICKI is calculated as [12]:  
1 / (log (FPG (mg/dL)) ＋ log (Fasting insulin (µIU/mL))) 
- The HOMA-ß is calculated as [11]:  
(Fasting insulin (µIU/mL) × 360) / (FPG (mg/dL) – 63) 
- The Adipo-IR is calculated as [13]: 
Fasting FFA (mmol/L) x Fasting insulin (µIU/mL) 
To minimize the variability in insulin concentration, two blood samples should be collected at 
a 10-min interval at each timepoint these metabolic parameters are calculated. In the above 
formulas, the mean of the two insulin results will be used. 
• hsCRP and other biomarkers of inflammation: fibrinogen and MCP-1 
• Fibrosis biomarkers: NAFLD Fibrosis score (NFS) and Fib-4 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) [14].  
- NFS is calculated as [14]:  
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) 


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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 [15, 16].  
- Fib-4 score is calculated as [15]:  
(Age (years) x AST (U/L))/ (platelet (109/L) x √(ALT (UI/L))) 
• Body weight, waist circumference and waist-to-hip ratio 
For Sub-study only: 
Fructose stimulated hepatic DNL assessment and OGTT+F will be performed at baseline 
(Randomization Visit (V3)) and at Week 12 (End-of-treatment Visit, V7). The following 
parameters will be determined: 
• Fructose stimulated hepatic DNL as assessed by deuterated water incorporation in very low-
density lipoprotein (VLDL) 
• Glucose, insulin, C-peptide, FFA, glycerol: pre-dose fasting and AUC during a 3-hour 
OGTT+F; A SMBG measurement should be performed prior to the beginning of the 
procedure in order to ensure that the glycemic status of the patient allows the procedure. 
• Insulin sensitivity index using the 3-hour OGTT+F (Matsuda index [17]) 
Patients included in the sub-study will be admitted to the site at around 5:00 pm the day prior 
to Randomization Visit (V3) and the day prior to Week 12 (End-of-treatment Visit, V7). A 
blood sample will be collected to evaluate the natural abundance of the palmitate enrichment 
and the IMP will be administered before dinner which will be served at around 5:00 pm to 
6:00 pm. Patients should drink 3 doses of deuterated water 70% at around 7:00 pm, 10:00 pm 
and 03:00 am as described in Figure 2. Deuterated water 0.5% will be provided ad libitum to 
patients. This will be the only beverage allowed during DNL and OGTT+F procedures. After 
an overnight fast and after completion of pre-dose assessments as per protocol, patients will 
take their IMP at study site: last intake of single blind placebo IMP at Randomization Visit 
(V3) and last intake of Double-blind IMP at End-of-treatment Visit (V7). 
Two (2) hours after the intake of the last single blind placebo IMP (for Randomization Visit 
(V3)) or after the last intake of Double-blind IMP (for End-of-treatment Visit (V7)), two blood 
samples will be collected at a 10-min interval for evaluation of FPG, insulin, C-peptide, FFA, 
glycerol and fructose stimulated hepatic DNL. Then, patients will drink a solution containing 
75 grams of glucose and 25 grams of fructose in 5 minutes. The beginning of the drinking will 
correspond to the time 0 for the subsequent blood collections. Blood will be drawn at regular 
time-points up to 6 hours post glucose + fructose load as detailed in Figure 2. 
8.3 Safety 
8.3.1 Physical Examination 
Physical examination must be conducted by the Investigator.  
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A complete physical examination will include head, ears, eyes, nose, mouth, skin, heart 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.  
Physical examinations (complete and limited) will also include height, weight, BMI, waist and hip 
circumferences for Screening Visit (V1) and weight, BMI, waist and hip circumferences for other 
visits as planned in Table 1. 
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. 
For weight measurement, a scale with appropriate resolution will be used and should be placed on 
a stable, flat surface. Patients should remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains.  
8.3.2 Vital Signs 
One HR measurement will be taken after the patient has been rest in supine 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 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.  
8.3.3 Patient Diary 
Patient diary will be dispensed according to Table 1.  
Patients will be asked to report their IMP intakes (date + dose + time) and meal taken after IMP 
intakes (date + 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 and will 
report in eCRF the appropriate data. To confirm the review, the Investigator will have to sign and 
date the previous patient diary and it will be kept in the patient file.   


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8.3.4 Supine 12-Lead 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 at Screening Visit (V1) and 
in triplicate, at least 1 minute apart at all other visits. 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.  
All 12-lead ECGs will be sent to Banook for a centralized interpretation a posteriori by 
cardiologists. 
8.3.5 Laboratory Assessments 
All laboratory measurements will be performed at 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 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. 
The following panel will be evaluated. 
 


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8.3.5.1 Standard Safety Laboratory Panel (Blood and Urine) 
Hematology 
Biochemistry 
Urinalysis 
Erythrocytes 
Hemoglobin 
Hematocrit 
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 
Gamma-glutamyl transferase 
Total bilirubin 
Alkaline Phosphatase (ALP) 
Amylase 
Lipase 
TSH (at Screening Visit (V1) 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 
8.3.5.2 Viral Infection Screen Panel 
Hepatitis screening 
HIV screening 
HBsAg 
Hepatitis C virus antibody (anti-HCV), in case of 
positive result, reflex test of HCV circulating RNA 
Anti-HIV 1 and 2 
8.3.5.3 eGFR  
eGFR will be calculated using the CKD-EPI formula, as follows [18]:  
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 


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-0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ 
or 1. 
8.3.5.4 Serum and urine Pregnancy Test 
For female patients of child-bearing potential only, a serum or urine β-HCG test will be performed 
at the visits shown in the Visit Schedule Chart in Table 1. 
8.3.6 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.  
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. 
8.3.6.1 Adverse Event Definitions 
8.3.6.1.1 Adverse Event 
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 (V8) performed one week after the End-of-treatment 
Visit (V7). 
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. 
The Investigator is required to grade the severity/intensity of each AE. 
8.3.6.1.2 Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered ADR. 


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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.  
8.3.6.1.3 Serious Adverse Event (SAE) 
A SAE is an AE occurring during any study phase (i.e., Screening, Run-in, 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 
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 


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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 at the informed consent visit 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.  
8.3.6.2 Methods of Recording and Assessing Adverse Events 
All AEs will be collected from the time of ICF signature to the End-of-study Visit (V8). All AEs 
will be followed until the event has resolved or the condition has stabilized or until the database 
hard lock if not resolved or stabilized before. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined above) 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 grade as assessed by the Investigator according to the following definitions: 
- 
Mild (awareness of event but easily tolerated) 
- 
Moderate (discomfort enough to cause interference with usual activity) 
- 
Severe (inability to carry out usual activity) 
• 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: 
• 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, according to Section 8.3.6.1, Adverse Event Definitions 
• The date of onset 
• The outcome according to criteria already mentioned 
• Causality assessed by the Investigator according to the criteria already mentioned 
• Date and time of last IMP intake prior to SAE 
If a patient experienced several times the same AE along 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 Medical Dictionary for Regulatory Activities (MedDRA®). 
8.3.6.3 Definition of the Adverse Event Reporting Period 
The AE reporting period for safety surveillance begins when the patient is included into the study 
(date of first ICF signature) and continues through the end of the study’s post-treatment Follow-up 
period, defined as the End-of-study Visit (V8). In case any AE occurs, the Investigator will follow 


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up the patient until the event has resolved or the condition has stabilized. All SAEs that the 
Investigator considers related to IMP occurring after the post-treatment Follow-up period must be 
reported to POXEL. 
AE will be recorded on an ongoing basis from date of ICF signature up to the End-of-study Visit 
(V8). 
Only events that occur after the first dose intake of IMP of the Double-blind treatment period (V3) 
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 TEAEs.  
8.3.6.4 Procedure for Reporting Immediately Reportable Events (IREs= SAEs and 
Pregnancy) 
The Investigator must report immediately (within 24 hours of the Investigator’s awareness) to 
Medpace all SAEs/Pregnancy occurring from the date of ICF signature to the End-of-study Visit 
(V8) or to the last study visit performed in case of premature discontinuation.  
An AE eCRF page must be completed with as much available information within 24 hours of 
knowledge of the SAEs. 
For pregnancy the study site will be required to complete the appropriate eCRF page within 
24 hours of knowledge of the event and also complete the Manual Exposure in Utero Form once 
received from Medpace.  
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 Exposure in Utero Form 
• Email (preferred) or Fax the form to Medpace Clinical Safety 
When the EDC system becomes available, the EDC system should be updated with all previously 
reported information. 
 
Safety Contact Information: 
Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, dial “3” or +1-513-5799-9911, dial “3” 
 
 
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Facsimile: +1-866-336-5320 or +1-513-570-5196 
Email: medpace-safetynotification@medpace.com 
8.3.6.4.1 Safety Reporting to Regulatory Authorities, Investigators and Independent 
Ethics Committees/Institutional Review Boards 
SUSARs and other safety information requiring expedited reporting will be reported to 
Investigators, Ethics Committees and/or Competent Authorities in agreement with applicable 
guidelines and US regulations. 
In accordance with ICH GCP guidelines, POXEL 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 AE that are both serious and unexpected and 
are considered to be related to the administered product (“suspected unexpected serious adverse 
reactions” or 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. 
8.3.6.5 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 outcome is known, 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. 
8.3.7 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 (V8) must be reported. Upon immediate notification, the Investigator (or designee) will 
complete the Pregnancy eCRF page. Medpace Clinical Safety will send the Exposure In Utero form 
to the study site for completion within 24 hours. POXEL must be notified by Medpace Clinical 
Safety within 24 hours of being notified. 
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 
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4. Death of newborn 
5. Congenital anomaly 
6. Delivery within appropriate pregnancy terms, but congenital abnormalities in the newborn  
should be reported first to Medpace Clinical Safety with 24 hours of the Investigator’s awareness. 
The Exposure In Utero form should be used for the reporting of the outcome. 
The Medpace Clinical Safety will forward pregnancy reports to POXEL the next business day. If 
the pregnancy outcome occurs following the end of the study; the Investigator will report the 
pregnancy outcome directly to POXEL. 
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. The Exposure In Utero form can be used to report the pregnancy information for the 
partner of a male patient. 
8.3.8 Special Precautions  
8.3.8.1 Hypoglycemia 
PXL770 is an insulin sensitizer and preclinical data in diabetic models, showed an improvement in 
insulin sensitivity. Based on this mechanism of action, hypoglycemia is not expected. However, as 
this study allows the inclusion of T2DM patients with mono- or bi-therapy, the improvement of 
glycemic control could lead to hypoglycemia induced by the background oral hypoglycemic 
agent(s). 
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 are requested to immediately perform a finger stick glucose measurement with the SMBG 
device provided for this study if any symptoms occur that may be related to hypoglycemia but 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 [19]: 
- 
Hypoglycemia evidenced only by symptoms without blood glucose measurement will be 
reported as probable symptomatic hypoglycemia. 
 
 
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- 
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. 
Therefore, there might be values coming from the SMBG device 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…). 
8.3.8.2 DILI 
To detect and monitor a possible DILI, the following evaluations should be performed in the 
presence of significant elevations of liver indices.  
• For patients with normal liver transaminases and total bilirubin at baseline 
(Randomization Visit (V3)):  
If patients with normal baseline (Randomization Visit (V3)) liver indices develop new elevations 
of AST or ALT or ALP >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. 
- 
ALT or AST >3  ULN and (TBL >2  ULN or INR >1.5) 
- 
ALT or AST >3  ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 


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• For patients with elevations in liver transaminases or total bilirubin at baseline 
(Randomization Visit (V3)):  
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. 
- 
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 drug-induced liver injury 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 study drug 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. 
- 
Obtaining additional tests to evaluate liver function, as appropriate (e.g. INR, direct 
bilirubin, lactate, liver ultrasound). 
- 
Considering gastroenterology or hepatology consultations. 
If a DILI is confirmed or suspected by the Investigator, or in case of liver function parameters 
(ALT, AST, ALT, TBL) above the threshold defined in this section, the Investigator will complete 


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an Expedited Liver Assessment Report page (ELAR) in the eCRF within 24 hours of knowledge 
of the case. If the DILI is confirmed, it should be reported in addition as an AE (see Section 8.3.6.2 
Methods of Recording and Assessing Adverse Events). 
8.4 Pharmacokinetics 
During this study, pre-dose and post-dose plasma concentration of PXL770 will be assessed as 
indicated in Table 1. 
The assays of PXL770 will only be carried out in patients who have received the active drug. 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 PXL770, blood samples will be taken by 
an indwelling catheter or direct venipuncture, as appropriate.  
Please refer to the lab manual for further explanations. 
8.5 Biobanking Samples for Post-hoc Assessments 
Blood 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 frozen and stored until further use. All the biobanking samples will be destroyed within 
2 years after the final study report is issued. 
Please refer to the lab manual for further explanations. 
8.6 Pharmacogenetics 
Blood samples for genotyping purposes will be collected at visits shown in Table 1 to enable post-
hoc genetic and pharmacogenetic research on the DNA/RNA samples from patients who sign an 
optional, additional informed consent. The samples will be frozen and stored until further use. All 
samples will be destroyed within 2 years after the final study report is issued. 
Please refer to the lab manual for further explanations. 
8.7 Acceptable deviation times 
The following will not be regarded as protocol deviations: 


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Table 3. Acceptable deviation times 
Procedure 
Timepoint 
Acceptable deviation 
Blood sampling for OGTT 
and/or DNL 
Day before the Visit (before 
dinner) 
Up to 45 min before dinner (and 
should be before IMP intake) 
10 min pre-load 
±2 min of the scheduled time 
Pre-load 
Up to 2 min before fructose + 
glucose load 
Up to and including 3h post-load 
±2 min of the scheduled time 
After 3h to 6h post-load 
±5 min of the scheduled time 
Blood sampling for PK 
Predose 
Up to 30 min before IMP intake 
Up to and including 3h post-dose ±2 min of the scheduled time 
After 3h to 8h post-dose 
±5 min of the scheduled time 
Blood sampling for insulin Second sample performed 10 min 
after the first sample 
±2 min of the scheduled time 
ECG 
Predose 
Up to 180 min before IMP intake 
2h post-dose 
±10 min of the scheduled time 
All other procedures 
Predose 
Up to 180 min before IMP intake 
 
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9 Statistical methods 
Statistical analysis will be performed by Medpace 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 Statistical Analysis Plan (SAP), which will 
be finalized prior to the unblinding and locking of the database. 
9.1 General considerations 
In general, summary tabulations will be presented by treatment arm and will display the number of 
observations, mean, standard deviation, median, 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 II trial for internal decision), no adjustment for 
multiplicity will be considered. Hence, pairwise comparisons between PXL770 doses (250 mg QD, 
250 mg BID and 500 mg QD) vs placebo and pairwise comparisons between active doses will be 
tested at the two-sided nominal level of significance of 0.05. 
The primary endpoint will be the relative change in the percentage of liver fat mass (assessed by 
MRI-PDFF) from baseline (Randomization Visit (V3)) to Week 12 (V7). 
The primary set for efficacy analysis will be the Intention-to-treat Set. 
No interim analysis is planned for this study. 
Few missing data are expected and, unless stated otherwise, they will be not replaced. 
9.2 Sample Size Determination 
Sample size determination is based on the primary endpoint, i.e. the relative change in the 
percentage of liver fat mass (assessed by MRI-PDFF) from baseline (Randomization Visit (V3)) 
to Week 12 (V7) and the following assumptions: 
• Superiority design of PXL770 compared to placebo 
• 2-sided alpha (Type 1) error = 0.05 
• Beta (Type 2) error = 0.10 (Power = 90%) 
• Expected difference (percentage change in liver fat mass):  30% 
 


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• Relative change in percentage liver fat mass: standard deviation (SD) = 30%, estimated from 
previous published data [1] 
• No adjustment for multiple comparisons between PXL770 doses and placebo 
With these assumptions, the sample size is 24 evaluable patients in each group to achieve a 90% 
power for each pairwise comparison. 
Assuming a dropout rate of approximately 20%, 30 patients are to be randomized per treatment 
group (120 patients in total). 
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: Placebo 
• Group 2: PLX770 250 mg QD 
• Group 3: PXL770 250 mg BID 
• Group 4: PXL770 500 mg QD  
Randomization will be stratified according to T2DM status (T2DM patients versus non-T2DM 
patients) and study site (main study site 1 vs main study site 2 vs main study site 3 vs other study 
sites).  
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 Analyses Set 
The Screened Analysis Set is defined as all patients who were screened for inclusion into the study. 
9.4.2 Safety analyses and Safety Set 
The Run-in Safety Analysis Set (RISS) is defined as all patients having received at least one dose 
of the single-blind placebo run-in treatment.  The population will be used to assess exposure and 
compliance with the single-blind placebo run-in treatment only. 
The Safety Analysis Set (SS) comprises all randomized patients having received at least one dose 
of the study drug (either PXL770 or placebo) and considered as-treated. Safety and tolerability will 
be analyzed on the safety set.  
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9.4.3 Efficacy Analyses  
All primary and secondary efficacy endpoints will be analyzed using the intention-to-treat set 
(ITTS). The per protocol (PP) set 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 
The ITTS consists of all as-randomized patients having received at least one dose of the IMP (either 
PXL770 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 major violations of study procedures. Major 
protocol violations will be identified prior to breaking the blind. Protocol deviations will be 
reviewed and classified as minor or major during a data review meeting that will be held before 
database lock and breaking the blind.   
9.4.4 PK Population 
The PK population corresponds to the Safety Set and includes all randomized patients who have 
been treated with PXL770 according to the protocol and have provided at least one pre-dose PK 
assessment during the study. 
9.5 Efficacy analysis 
9.5.1 Primary Endpoint: relative change in the percentage of liver fat mass 
The primary analysis of efficacy will be performed on the ITTS. 
Primary analysis: 
The primary endpoint, i.e. expressed as the relative change in the percentage of liver fat mass 
(assessed by MRI-PDFF) from baseline (Randomization Visit (V3)) to Week 12 (V7), will be 
analyzed in an analysis of covariance (ANCOVA) model adjusting for treatment (PXL770 doses 
of 250 mg QD, 250 mg BID and 500 mg QD and placebo) and for stratification factors, i.e. T2DM 


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status (T2DM patients versus non-T2DM patients) and study site (main site 1 vs main site 2 vs 
main site 3 vs other pooled sites) and baseline liver fat mass as a covariate.  
Least square means (LSMs) of the primary endpoint for treatment groups and pairwise differences 
in LSMs will be estimated along with their p-values and 95% confidence intervals.  
Missing MRI-PDFF at Week 12 (V7) will be estimated using a multiple imputation method (fully 
conditional specification method) assuming missing at random (MAR) mechanism which will be 
detailed in the SAP. Missing baseline MRI-PDFF will not be estimated. 
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 Site 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. 
Subgroup analyses: 
Subgroup analyses will be performed: 
• within each T2DM status (T2DM patients versus non-T2DM patients). The treatment by 
T2DM status interaction will be tested.  
• within each site (main site 1 vs main site 2 vs main site 3 vs other pooled sites). The treatment 
by site (main 1 vs main 2 vs main 3 vs others) interaction will be tested. 
9.5.2 Key Secondary Endpoints 
9.5.2.1 Absolute Change in the percentage of liver fat mass   
The (absolute) change in the percentage of liver fat mass (assessed by MRI-PDFF) from baseline 
(Randomization Visit (V3)) to Week 12 (V7) will be analyzed in an analysis of covariance 
(ANCOVA) model adjusting for treatment, T2DM status (T2DM patients versus non-T2DM 
patients), site (main 1 vs main 2 vs main 3 vs others) and baseline liver fat mass. Least square 
means of the change in the percentage of liver fat mass for treatment groups (PXL770 doses of 250 
mg QD, 250 mg BID and 500 mg QD and placebo) and pairwise differences in LSMs will be 
estimated along with their p-values and 95% confidence intervals.  
Missing MRI-PDFF at Week 12 (V7) will be estimated using a multiple imputation method (fully 
conditional specification method) assuming missing at random (MAR) mechanism which will be 
detailed in the SAP. Missing baseline MRI-PDFF will not be estimated. 
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.  
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9.5.2.2 Analysis of responders    
Four types of responders will be proposed and analyzed: 
- 
Response defined as an absolute reduction in liver fat mass (from baseline 
(Randomization Visit (V3)) to Week 12 (V7)) higher than or equal to 5% (≥ 5 %). 
- 
Response defined as a relative reduction in liver fat mass (from baseline (Randomization 
Visit (V3)) to Week 12 (V7)) higher than or equal to 30% (≥ 30 %). 
- 
Response defined as a relative reduction in liver fat mass (from baseline (Randomization 
Visit (V3)) to Week 12 (V7)) higher than or equal to 50% (≥ 50 %). 
- 
Response defined as a liver fat mass value at Week 12 (V7)) that is normalized, i.e. lower 
than or equal to 5% (≤ 5 %). 
Percentages of response will be estimated within each treatment group. 
The response will be analyzed in a logistic regression model adjusting for treatment (PXL770 doses 
of 250 mg QD, 250 mg BID and 500 mg QD and placebo), T2DM status (T2DM patients versus 
non-T2DM patients), site (main 1 vs main 2 vs main 3 vs others) and baseline liver fat mass.  
Pairwise differences in treatment groups will be estimated in this model as odds ratios along with 
their p-values and 95% confidence intervals. 
Methods handling missing MRI-PDFF at Week 12 (V7) and therefore missing responder status at 
Week 12 (V7) will be detailed in the SAP. 
9.5.3 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 and AST 
• Measured metabolic parameters: FPG, HbA1c, insulin, C-peptide, Total cholesterol, HDL-c, 
LDL-c, triglycerides, Apo A1, Apo B, FFA, glycerol and adiponectin  
• Calculated metabolic parameters: HOMA-IR, QUICKI, HOMA-β and Adipo-IR 
• hsCRP and other markers of inflammation: fibrinogen and MCP-1  
• Fibrosis markers: NFS and Fib-4 score 
• Body weight, waist circumference and waist-to-hip ratio 
9.5.4 Exploratory Endpoints ( Sub-study only) 
• Fructose stimulated hepatic DNL as assessed during 6 hours by deuterated water incorporation 
in very low-density lipoprotein (VLDL) 
• Glucose, insulin, C-peptide, FFA, glycerol: pre-dose fasting and AUC during a 3-hour OGTT 
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• Insulin sensitivity marker using a 3-hour OGTT (Matsuda) 
The timepoints for collection of each of these are given in detail in Section 7 Study Procedures 
and in Table 1. 
9.5.5 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: 
9.5.5.1 Adverse Events 
AE will be coded using MedDRA®. The frequency and incidence of TEAE will be presented by 
System Organ Class (SOC) and preferred term for PXL770 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 AE 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 SAE and AE leading to permanent discontinuation of IMP or to death will be 
listed separately.  
9.5.5.2 Concomitant Medications 
Previous, concomitant and new medications will be coded using the World Health Organization 
(WHO) Dictionary.  
Previous, concomitant and new medication will be tabulated and summarized by treatment groups. 
9.5.5.3 Vital Signs, ECG, Body Weight, Waist Circumference, waist to hip ratio, BMI and 
Physical Examination 
Vital signs, ECG parameters, body weight, waist circumference, waist to hip ratio and BMI will be 
summarized descriptively by treatment and timepoint. Similarly, changes from baseline 
(Randomization Visit (V3)) will be summarized. 
Physical examination results will be listed by patients and body system. 
9.5.5.4 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 
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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. 
9.5.5.5 Withdrawals of study 
Patients who withdraw from the study will be summarized by treatment group according to their 
reason of withdrawal. 
9.5.6 Analysis of Further Endpoints 
Pharmacokinetic parameters assessment will include pre- and post-dose concentrations of PXL770 
in blood at visits and timepoints specified in Table 1. 
Pharmacokinetic data (PXL770 concentrations) will be analyzed using PopPK model. The 
evaluated PK parameters will be listed and summarized by treatment groups, by visits and by 
timepoints. 
Post-hoc testing of any additional safety parameters or any potential biomarkers related to liver, 
cardiovascular diseases or metabolic diseases in relation with the drug target evaluation will be 
assessed using the Safety Set. 
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. A copy of the Declaration of Helsinki will be provided to each study site. 
All studies 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 experience 
and training must be documented on the Curriculum Vitae. 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 Medpace 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 Investigator 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 retrieved 
at any time for monitoring, auditing and inspection purposes. A copy of the signed and dated ICF 
 


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should be provided to patients prior to participation. The whole consenting process must be clearly 
documented in the patient file. 
The 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 
at Screening Visit (V1). 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 (including genetic tests) will be stored under this number. 
Only the Investigator will be able to link the patient’s study data to the patient via an identification 
list kept at the study site. 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 at Screening Visit 
(V1). 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; this may include the possibility of emergency unblinding if needed, in case of blinded 
studies. 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) 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 Medpace. 
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 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 
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11 Study Management 
11.1 Data collection and CRF management 
In this study, an eCRF will be used. CRF data will be captured via EDC using ClinTrak EDC, 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 8.3.3 Patient 
Diary. 
The data in the eCRF should be consistent with the relevant source documents as verified by 
Medpace’s CRA during monitoring visits. The data will be processed, evaluated, and stored in 
pseudonymous 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 
Medpace. 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 Medpace Data Management Department.  
• ECGs performed during the study will be sent to a centralized ECG core laboratory. Results 
will be electronically transferred to the Medpace Data Management Department. 
• Laboratory blood and urine samplings will be sent to Medpace centralized laboratory and 
results will be transferred electronically to Medpace Data Management Department. 
• Blood samplings for DNL assessments will be sent to the University of Florida for analysis. 
 
 
 
 
 
 
 
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• PK samplings will be sent to Charles River Saint-Nazaire for analysis and results will be 
transferred electronically to Medpace Data Management Department. 
Reconciliation of all centralized data will be done by Medpace before database lock and final data 
transfer received. 
During the study, SAE data (reported on the AE form in eCRFs) will be integrated into the Medpace 
centralized pharmacovigilance database upon receipt of these forms and after a duplicate check. 
Each case will be assigned a case identification number. Each case will be assessed by POXEL 
before being reported to the relevant authorities as necessary. 
The information from the pharmacovigilance database cases will be reconciled with that in the 
clinical database. 
All these data will be integrated into a validated database. Medpace will be responsible for data 
processing, in accordance with Medpace’s data management procedures. 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. 
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. 
It must be possible to identify each patient by using this patient file. 
 
 
 
 
 
 


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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.  
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 ICF. 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 
• Investigator Site File (ISF) (e.g. Protocol & Amendments and Regulatory sections, 
delegation list and training records) 
• that IMP handling is compliant with the protocol requirements 
• 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 


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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 
Medpace under the direction of POXEL.  
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 entirely 
and not as individual study site data, except for ancillary studies.  
 


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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. 
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. 
2. 
van der Poorten, D., et al., Visceral fat: a key mediator of steatohepatitis in metabolic liver 
disease. Hepatology, 2008. 48(2): p. 449-57. 
3. 
Younossi, Z., et al., Global burden of NAFLD and NASH: trends, predictions, risk factors 
and prevention. Nat Rev Gastroenterol Hepatol, 2018. 15(1): p. 11-20. 
4. 
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. 
5. 
Vilar-Gomez, E., et al., Weight Loss Through Lifestyle Modification Significantly Reduces 
Features of Nonalcoholic Steatohepatitis. Gastroenterology, 2015. 149(2): p. 367-78.e5; 
quiz e14-5. 
6. 
Stewart, K.E., et al., Readiness for behaviour change in non-alcoholic fatty liver disease: 
implications for multidisciplinary care models. Liver Int, 2015. 35(3): p. 936-43. 
7. 
Ludwig, J., et al., Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto 
unnamed disease. Mayo Clin Proc, 1980. 55(7): p. 434-8. 
8. 
Caldwell, S.H. and D.M. Crespo, The spectrum expanded: cryptogenic cirrhosis and the 
natural history of non-alcoholic fatty liver disease. J Hepatol, 2004. 40(4): p. 578-84. 
9. 
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). 
10. 
POXEL Investigator's Brochure Version 4.0 / 12 Nov 2018. 
11. 
Matthews, D.R., et al., Homeostasis model assessment: insulin resistance and beta-cell 
function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 
1985. 28(7): p. 412-9. 
12. 
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. 
13. 
Lomonaco, R. and al., Effect of Adipose Tissue Insulin Resistance on Metabolic Parameters 
and Liver Histology in Obese Patients With Nonalcoholic Fatty Liver Disease. Hepatology, 
2012. 55: p. 1389–1397 
14. 
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. 


PXL770 / Study No. PXL770-004 
Protocol Version 6.0 / 24th July 2020 
 
CONFIDENTIAL 
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15. 
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. 
16. 
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. 
17. 
Matsuda, M. and R.A. DeFronzo, Insulin sensitivity indices obtained from oral glucose 
tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care, 1999. 
22(9): p. 1462-70.  
18. 
Levey, A.S., et al., A new equation to estimate glomerular filtration rate. Ann Intern Med, 
2009. 150(9): p. 604-12. 
19. 
Guidance for Industry. Diabetes mellitus: developing drugs and therapeutic biologics for 
treatment and prevention. FDA, Clinical/Medical. 
 


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13 Annex 1. Sponsor, Coordinating Investigators, 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 
 
Medical Director, Clinical Development 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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Clinical Project Manager at POXEL  
Nadège Daneau, MSc 
POXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 7 63 63 66 20 
Fax: +33 4 37 70 88 15 
E-mail: nadege.daneau@poxelpharma.com 
 
Senior Clinical Project Manager at POXEL  
Béatrice Jacolin-Maffei, MSc 
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  
Katell AloryPOXEL S.A. 
259-261, avenue Jean Jaurès 
69007 Lyon, France 
Mobile: +33 7 64 37 70 38 
Fax: +33 4 37 70 88 15 
E-mail: katell.alory@poxelpharma.com 
 
CRO information and vendors: 
 
Clinical Trial Manager, Clinical Trial Management at Medpace 
Mary Beth RothMedpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Mobile: +1 513 873 0205 
E-mail: m.roth@medpace.com 
 
 
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Medical Director, Medical Affairs at Medpace 
Hervé Momméja-Marin, MD 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Mobile: +1 513 497 9810 
E-mail: h.mommeja-marin@medpace.com 
 
Safety Manager, Clinical Safety at Medpace 
Kanan Bhavsar 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Phone: +1 513 579 9911 x16062 
E-mail: k.bhavsar@medpace.com 
 
Medpace Reference Laboratories (MRL) Project Manager 
David Burriss 
Medpace Reference Laboratories 
5365 Medpace Way 
Cincinnati, Ohio 45227 
Mobile: +1 513 679 0652 
E-mail: d.burriss@medpacelab.com 
 
Medpace Imaging Core Laboratories (MICL) Project Manager 
Medpace Core Laboratories 
5365 Medpace Way 
Cincinnati, Ohio 45227 
 
IVRS Project Manager, Randomization & Study Product Management at Medpace 
Steve Strassell 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Mobile: +1 513 206 4920 
E-mail: s.strassell@medpace.com 
 
 
 
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Data Manager, Data Management at Medpace 
Daniel Murphy 
Medpace 
Wallace House 
17-21 Maxwell Place 
Stirling, Scotland FK8 1JU, United Kingdom 
Phone: +44 1786 460 400 x24435 
E-mail: d.murphy1@medpace.com 
 
Biostatistician, Biostatistics at Medpace 
Miriam ZangmeisterMedpace 
5375 Medpace Way 
Cincinnati, Ohio 45227Phone: +1.513.978.2511 
E-mail: m.zangmeister@medpace.com 
 
IMP kit packaging and supply chain management 
Creapharm 
Z.A. Air-Space - Av. de Magudas - CS2007 
33187 - Le Haillan Cedex, France 
 
Central ECG core laboratory 
Banook Group 
84 avenue du XXème Corps 
54000 Nancy, France 
 
Bioanalytical laboratory for assay of plasma concentrations of PXL770 
Charles River Saint- Nazaire1, rue Graham Bell 
ZI de Brais, BP 40309 
44605 Saint Nazaire, France 
 
Bioanalytical laboratory for DNL assessments 
The University of Florida 
1600 SW Archer Rd 
Suite R4-135 
Gainesville, FL 32610, United States 
 
 
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Study Sites and Coordinating / Principal Investigators 
List of Study Sites and Coordinating / Principal Investigators will be attached separately. 
 
 
Corporate confidential information 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A randomized, double-blind, placebo-controlled, parallel 
group trial to assess the efficacy and safety of PXL770 
versus placebo after 12 weeks treatment in patients with 
Nonalcoholic Fatty Liver Disease (NAFLD) with or without 
type 2 diabetes mellitus 
 
Protocol Number: 
PXL770-004 
Protocol Version/Date: 
Current: Version 6.0 / 24th July 2020 
including memo to address COVID-19 elements 
 
Investigational Product: PXL770 
 
 
Sponsor: 
POXEL S.A. 
Immeuble Le Sunway 
259-261 Avenue Jean Jaures 
69007 Lyon 
France 
 
 
SAP Version/Date: 
Version 3.0 / 15-SEP-2020 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
 
NCT03763877 


POXEL S.A. 
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Statistical Analysis Plan 
PXL770-004 
 
Version 3.0 / 15-SEP-2020 
Page 2 of 33 
 
SIGNATURE PAGE 
Protocol Title: 
A randomized, double-blind, placebo-controlled, parallel 
group trial to assess the efficacy and safety of PXL770 versus 
placebo after 12 weeks treatment in patients with 
Nonalcoholic Fatty Liver Disease (NAFLD) with or without 
type 2 diabetes mellitus 
 
Protocol Number: 
PXL770-004 
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
  
Signature 
 Date 
 
  
 
  
Miriam Zangmeister 
Senior Statistical Scientist 
Medpace, Inc. 
  
 
  
 
  
Herve Mommeja-Marin 
Medical Monitor 
Medpace, Inc. 
  
 
  
 
  
Carole Thang, PharmD 
Associate Medical Director, Clinical Development 
POXEL S.A. 
  
 
  
 
  
Jean-Marie Grouin 
Statistics consultant for POXEL S.A 
 
  
 
 
Corporate confidential information 


POXEL S.A. 
CONFIDENTIAL 
Statistical Analysis Plan 
PXL770-004 
 
Version 3.0 / 15-SEP-2020 
Page 3 of 33 
 
VERSION HISTORY 
 
Version 
Version Date 
Description 
0.1 
June 2019 
First Draft 
0.2 
August 2019 
Updates following Poxel Review 
0.3 
December 2019 
Updates following Poxel Review of v0.2 
0.4 
March 2020 
Updates following Poxel Review of v0.3 
1.0 
23-Apr-2020 
Final approved version. 
1.1 
27-Jul-2020 
• Remove substudy analyses (downgraded to 
exploratory in Protocol V6.0). 
• Modifications due to COVID-19 pandemic 
circumstances, such as inclusion of extension visits. 
• Dropping Modified ITT Set and including multiple 
imputation for the primary analysis. 
• Up-versioning of the MedDRA dictionary. 
1.2 
30-Jul-2020 
• Additional MRI-PDFF responder endpoints are added 
(included in Protocol V6.0). 
• Other minor clarifications based on programming and 
Sponsor comments. 
1.3 
03-Aug-2020 
• Clarity added in the AE section for how DILI events will 
be handled. 
1.4 
04-Aug-2020 
• Regarding study site stratification, 2 groups will be 
used for analysis instead of 4. 
• Additional restriction added for Week 12/EoT MRI to 
be used for analysis. 
2.0 
05-Aug-2020 
Final approved version. 
2.1 
04-Sep-2020 
After soft lock delivery but prior to final database lock: 
• Add sensitivity analysis of the primary endpoint which 
removes the site stratification from the model because 
the number of patients in the sub-study is very low and 
they are mainly diabetic patients. 
• Include wording regarding “Firth” option for responder 
analysis (already implemented for soft lock delivery). 
2.2 
09-Sep-2020 
Updates per soft lock TFL comments: 
• Include clarification on how Visit 7 is treated for 
analysis visits for subjects with extended treatment. 
2.3 
10-Sep-2020 
Updates per Blinded Data Review Meeting: 
• Clarification of the sensitivity population “ITTS 
excluding subjects whose study treatment period was 
extended due to COVID-19 pandemic circumstances”. 
• Various clarifications for the Per Protocol Set. 
2.4 
14-Sep-2020 
Updates per Sponsor commens: 
• Use Wk12/EoT instead of Wk12 in other efficacy 
analysis. 
• Other minor clarifications and fixes. 
3.0 
15-Sep-2020 
Final approved version. 
 
 
Corporate confidential information 


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Statistical Analysis Plan 
PXL770-004 
 
Version 3.0 / 15-SEP-2020 
Page 4 of 33 
 
TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 8 
2 
Study Overview ................................................................................................................... 8 
2.1 
Study Objectives and Endpoints .................................................................................. 8 
2.2 
Study Design ..............................................................................................................10 
2.2.1 
Overview ..............................................................................................................10 
2.2.2 
Sample Size Determination ..................................................................................16 
3 
Statistical Methodology ......................................................................................................16 
3.1 
General Considerations ..............................................................................................16 
3.1.1 
Analysis Day ........................................................................................................16 
3.1.2 
Definition of Baseline ...........................................................................................16 
3.1.3 
Analysis Visits ......................................................................................................16 
3.1.4 
Change and Relative Change from Baseline .......................................................18 
3.1.5 
Summary Statistics ..............................................................................................18 
3.1.6 
Hypothesis Testing ..............................................................................................18 
3.1.7 
Handling of Dropouts and Missing Data ...............................................................18 
3.2 
Analysis Populations ...................................................................................................18 
3.2.1 
Screened Analysis Set .........................................................................................18 
3.2.2 
Run-in Safety Analysis Set (RISS) .......................................................................18 
3.2.3 
Safety Analysis Set (SS) ......................................................................................19 
3.2.4 
Randomized Set (RS) ..........................................................................................19 
3.2.5 
Intent-To-Treat Set (ITTS)....................................................................................19 
3.2.6 
Per Protocol Set (PPS) ........................................................................................19 
3.2.7 
Pharmacokinetic (PK) Population .........................................................................20 
3.3 
Patient Data and Study Conduct .................................................................................20 
3.3.1 
Patient Disposition ...............................................................................................20 
3.3.2 
Protocol Deviations ..............................................................................................21 
3.3.3 
Analysis Populations ............................................................................................21 
3.3.4 
Demographic and Baseline Characteristics ..........................................................21 
3.3.5 
Medical History ....................................................................................................21 
3.3.6 
Concomitant Medications .....................................................................................22 
3.3.7 
Study Treatment Exposure and Compliance ........................................................22 
3.4 
Efficacy Assessment ...................................................................................................24 
3.4.1 
Analyses of Liver Fat Mass Assessed by MRI-PDFF ...........................................24 
3.4.2 
Analyses of Other Efficacy Endpoints ..................................................................27 
3.5 
Pharmacokinetic Assessment .....................................................................................28 
3.6 
Safety Assessment .....................................................................................................28 
3.6.1 
Adverse Events (AEs) ..........................................................................................28 
3.6.2 
Clinical Laboratory Tests .....................................................................................30 
3.6.3 
Vital Signs ............................................................................................................30 


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3.6.4 
Electrocardiograms ..............................................................................................30 
3.6.5 
Physical Examinations .........................................................................................31 
4 
Analysis Timing ..................................................................................................................31 
4.1 
Dry Runs/Blinded Data Reviews .................................................................................31 
4.2 
Blinded Data Review Meeting (BDRM) .......................................................................31 
4.3 
Pre-Final Analysis .......................................................................................................31 
4.4 
Final Analysis ..............................................................................................................31 
5 
Changes from Protocol-Specified Statistical Analyses .......................................................31 
6 
Programming Specifications ..............................................................................................32 
Appendix A:  References ..........................................................................................................33 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADaM 
Analysis Data Model 
Adipo-IR 
Adipose tissue Insulin Resistance 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the concentration time curve 
BDRM 
Blinded Data Review Meeting 
BID 
Twice a day (bis in die) 
BMI 
Body Mass Index 
CAP 
Controlled Attenuation Parameter 
CDISC 
Clinical Data Interchange Standards 
Consortium 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease – Epidemiology 
Collaboration 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DNL 
De Novo Lipogenesis 
DILI 
Drug Induced Liver Injury 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FFA 
Free Fatty Acids 
Fib-4 
Fibrosis 4 
FPG 
Fasting Plasma Glucose 
HbA1c 
Glycated hemoglobin 
HDL-c 
High Density Lipoprotein-cholesterol 
HOMA-β 
Homeostasis Model Assessment of β-cell 
function 
HOMA-IR 
Homeostasis Model Assessment of Insulin 
Resistance 
HR 
Heart Rate 
hsCRP 
High-sensitivity C-Reactive Protein 
ICF 
Informed Consent Form 
INR 
International Normalized Ratio 
IQR 
Inter-quartile range 
ITTS 
Intent-to-treat Set 
LDL-c 
Low Density Lipoprotein-cholesterol 
LSM 
Least Square Mean 
MAR 
Missing at Random 
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Statistical Analysis Plan 
PXL770-004 
 
Version 3.0 / 15-SEP-2020 
Page 7 of 33 
 
Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP-1 
Monocyte Chemoattractant Protein-1 
MMRM 
Mixed-Model Repeated Measures 
MRI 
Magnetic Resonance Imaging 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NFS 
NAFLD Fibrosis Score 
OGTT 
Oral Glucose Tolerance Test 
OGTT+F 
Oral Glucose + Fructose Tolerance Test 
PDFF 
Proton Density Fat Fraction 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PT 
Prothrombin Time 
QD 
Once a day (Quaque die) 
QUICKI 
Quantitative Insulin Sensitivity Check Index 
RS 
Randomized Set 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SEM 
Standard error of the mean 
SS 
Safety Analysis Set 
T2DM 
Type 2 Diabetes Mellitus 
TE 
Transient Elastography 
TEAE 
Treatment-emergent adverse event 
TFL 
Tables, Listings and Figures 
VLDL 
Very Low Density Lipoprotein 
WHO 
World Health Organization 
 
 
 
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Statistical Analysis Plan 
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Version 3.0 / 15-SEP-2020 
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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number 
PXL770-004.  The SAP will be finalized prior to database lock.  Any deviations from the SAP after 
database lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives and Endpoints 
 
Primary 
Objective 
Endpoint 
To assess the effect of PXL770 versus 
placebo on hepatic steatosis in nonalcoholic 
fatty liver disease (NAFLD) patients at the 
daily dose of 250 mg once daily (QD) and 
twice daily (BID) and 500 mg QD after 12 
weeks of treatment. 
Primary Endpoint 
• 
Relative change (%) from baseline to 
Week 12/End of Treatment in the 
percentage of liver fat mass (assessed by 
Magnetic Resonance Imaging – Protein 
Density Fat Fraction [MRI-PDFF]). 
Key Secondary Endpoints 
• 
Change from baseline to Week 12/End of 
Treatment in the percentage of liver fat 
mass (assessed by MRI-PDFF). 
• 
Response defined as: 
• an absolute reduction in liver fat mass 
(assessed by MRI-PDFF) of at least 
5%. 
• a relative reduction in liver fat mass 
(assessed by MRI-PDFF) of at least 
30%. 
• a relative reduction in liver fat mass 
(assessed by MRI-PDFF) of at least 
50%.  
• a liver fat mass value at Week 12/End 
of Treatment that is normalized, i.e. 
≤ 5 %. 
Secondary 
Objective 
Endpoint 
To assess the safety and tolerability of 
PXL770 versus placebo in NAFLD patients at 
the daily dose of 250 mg QD and BID and 
500 mg QD after 12 weeks of treatment. 
• 
Adverse events (AEs) 
• 
Physical examination 
• 
Vital signs: systolic blood pressure (SBP), 
diastolic blood pressure (DBP) and heart 
rate (HR) 
• 
12-lead electrocardiogram (ECG) 
• 
Biological parameters: biochemistry, 
hematology, coagulation and urinalysis 
• 
Estimated glomerular filtration rate 
(eGFR) using the Chronic Kidney Disease 


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– Epidemiology Collaboration (CKD-EPI) 
formula 
To assess the effect of PXL770 versus 
placebo in NAFLD patients on metabolic and 
non-metabolic parameters at the daily dose 
of 250 mg QD and BID and 500 mg QD after 
12 weeks of treatment: 
Change and relative change (%) from 
baseline to each timepoint throughout the 
study in: 
• 
Liver enzymesA 
• 
Alanine amino Transferase (ALT) 
• 
Aspartate amino Transferase (AST) 
• 
Lipid parameters 
• 
Total cholesterol 
• 
High density lipoprotein-cholesterol 
(HDL-c)  
• 
Low density lipoprotein-cholesterol 
(LDL-c)  
• 
Triglycerides 
• 
Apo A1 
• 
Apo B 
• 
Free fatty acids (FFA) 
• 
Glycerol 
• 
Adiponectin 
• 
Glycemic parameters in fasting 
conditions 
Measured metabolic parameters: 
• 
Fasting plasma glucose (FPG) 
• 
Glycated hemoglobin (HbA1c) 
• 
Serum insulin 
• 
C-peptide 
 
Calculated metabolic parameters:  
1. Homeostasis Model Assessment of 
Insulin Resistance (HOMA-IR) 
2. Quantitative Insulin Sensitivity Check 
Index (QUICKI) 
3. Homeostasis Model Assessment of β-cell 
function (HOMA-β) 
4. Adipose tissue Insulin Resistance 
(Adipo-IR) 
• 
Biomarkers of inflammation 
 
 
• 
High-sensitivity C-Reactive Protein 
(hsCRP) 
• 
Fibrinogen  
• 
Monocyte chemoattractant protein-1 
(MCP-1) 
• 
Biomarkers of fibrosis 
• 
NAFLD Fibrosis score (NFS)  
• 
Fibrosis-4 (Fib-4) score 
• 
Anthropomorphic parameters1 
• 
Body weight 
• 
Waist circumference  
• 
Waist-to-hip ratio 
To compare the 2 dose regimens of PXL770 
(BID versus QD) on efficacy and safety 
parameters in NAFLD patients. 
Efficacy and safety parameters as described 
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To describe PXL770 pre-dose plasma 
concentrations during the course of the 
treatment and pre- and post-dose plasma 
concentrations after 12 weeks of treatment in 
NAFLD patients. 
PXL770 plasma concentration at each 
applicable timepoints 
Exploratory – Sub-study 
Objective  
Endpoint 
To assess the effect of PXL770 versus 
placebo in NAFLD patients on metabolic and 
non-metabolic parameters at the daily dose 
of 250 mg QD and BID and 500 mg QD after 
12 weeks of treatment: 
• 
Fructose stimulated hepatic de novo 
lipogenesis (DNL) 
 
• 
Glycemic parameters during a 3-hour 
Oral Glucose Tolerance Test (OGTT) 
 
 
 
 
 
 
The two tests being combined, OGTT will be 
a 3-hour glucose + fructose tolerance test 
(OGTT+F). 
Change from baseline to Week 12 in the 
following parameters: 
 
 
 
• 
Deuterated water incorporation in very 
low-density lipoprotein (VLDL) during a 6-
hour OGTT+F 
• 
Pre-dose fasting and post-dose as the 
area under the concentration time curve 
(AUC) during a 3-hour OGTT+F for: 
o Glucose 
o Insulin 
o C-peptide 
o FFA 
o Glycerol 
• 
Insulin sensitivity index using the 3-hour 
OGTT+F (Matsuda index2) 
To assess PXL770 plasma concentrations 
before, during and after a 3-hour OGTT+F 
and fructose stimulated hepatic DNL 
assessment in NAFLD patients and 
correlation with pharmacodynamics and/or 
safety. 
PXL770 plasma concentration at each 
applicable timepoints 
A The liver enzymes and anthropometric endpoints can be considered both efficacy and safety 
endpoints; details of these endpoints and their analysis will be discussed in the Efficacy 
Assessment section below. 
2.2 Study Design 
2.2.1 Overview 
This study is a phase IIa, multi-center, double-blind, placebo-controlled, randomized study with 4 
parallel groups in NAFLD patients. 
There will be a total of 4 study periods, as follows: 
• 
Screening period:  
 
 
maximum of 2 weeks 
• 
Single-blind placebo Run-in period:  4 weeks 
• 
Double-blind treatment period:  
12 weeks 
• 
Follow-up period:  
 
 
1 week 
Patients will be randomized in a 1:1:1:1 ratio to receive either: 
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• 
PXL770 250 mg QD 
• 
PXL770 250 mg BID 
• 
PXL770 500 mg QD 
• 
Placebo 
Randomization will be stratified according to type 2 diabetes mellitus (T2DM) status (T2DM 
patients vs non-T2DM patients) and study site (main site 1 vs main site 2 vs main site 3 vs other 
pooled sites). For all analyses using study site stratification group, the main study sites will be 
pooled together (i.e. we will have sub-study sites group vs. other pooled sites group) due to the 
few number of subjects randomized in the individual main study sites. 
Patients will be assigned a unique randomization number at the Randomization Visit by Interactive 
Web Response System (IWRS).  This randomization number identifies which record in the 
randomization list and therefore which treatment should be allocated to the patient. 
The randomization list will be generated by a Medpace independent statistician. 
During the Single-blind placebo Run-in period, patients will take an oral dose of 2 capsules of 
placebo BID (4 capsules per day).  The Single-blind placebo Run-in period will last for 4 weeks. 
During the Double-blind treatment period, patients will take a total of 4 capsules per day (2 in the 
morning and 2 in the evening).  The Double-blind treatment period will last for 12 weeks. 
A sub-study will be performed in up to 3 study sites.  This sub-study will include: 
• 
A 6-hour fructose stimulated hepatic DNL assessment 
• 
A 3-hour OGTT+F 
The diagram of the study design is shown in Figure 1 and sub-study assessments in Figure 2.  
Details of the Visit Schedule are included 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 17 and 19 weeks. 
The End-of-study is defined as the date of last visit of last patient participating in the study. 
Alternative processes to mitigate the impact of COVID-19 pandemic on the conduct of this clinical 
trial and to eliminate apparent immediate additional risks to subjects may be implemented. Most 
notably for analysis, the double-blind treatment duration could be extended to a maximum 
duration of 20 weeks in total (i.e. 8 extra weeks) if Visit 7 (including MRI) could not be performed 
after 12 weeks of treatment. This prolongation should be as short as possible. An additional on-
site visit or if not possible, phone contact or virtual visit including laboratory assessments (at 
central laboratory or if not possible at local laboratory) should be performed after 4 weeks (+/- 4 
days) of treatment prolongation (i.e. Week 16). In case of temporary treatment interruption (≤ 3 
weeks) due to IMP dispensation issues, the IMP must have been resumed for at least 2 weeks 
prior to performing the End of treatment MRI-PDFF. 
 
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Figure 1. Diagram of Study Design 
 
 
 
 


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Figure 2. Diagram of sub-study assessments 
a) Baseline assessments (Randomization Visit (V3)) 
 
b) End of treatment assessments (End-of-treatment Visit (V7)) 
 
 
 
 
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Table 1. Visit Schedule 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
ET 
Screening 
Run-in 
Randomization 
Week 2 
Week 4 
Week 8 
Week 12 EoT 
Week 13 EoS 
- 
Timeframe 
-6 weeks max + 2 
days 
-4 weeks 
Day 0 
Day 14 
Day 28 
Day 56 
Day 84 
Day 91 
- 
Time windows 
 
- 
Within 2W after 
V1 
4W after V2 
± 2 days 
2W after V3 
± 2 days 
4W after V3 
± 2 days 
8W after V3 
± 3 days1 
12W after V3 
± 4 days1 
1W after V7  
± 2 days 
Within 11 days 
after IMP 
discontinuation 
Informed Consent 
X 
 
 
 
 
 
 
 
 
IWRS log-on 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior medications 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete phys ex.2,3 
X 
 
X 
 
 
 
X 
X 
X 
Limited phys ex.4 
 
X 
 
X 
X 
X 
 
 
 
Vital signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG14 
X 
 
X 
X 
X 
X 
X15 
X 
X 
hsCRP 
X 
 
X 
X 
X 
X 
X 
X 
X 
FPG 
X 
 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
X 
 
 
 
X 
 
X 
Safety lab8 
X 
 
X 
X 
X 
X 
X 
X 
X 
eGFR 
X 
 
X 
 
 
 
X 
 
X 
Pregnancy test12 
X 
 
X 
X 
X 
X 
X 
X 
X 
Viral screen lab11 
X 
 
 
 
 
 
 
 
 
Measured metabolic param6 
 
 
X 
 
X 
X 
X 
 
X 
Calculated metabolic param7 
 
 
X 
 
X 
 
X 
 
X 
Inflammatory biomarkers9  
 
 
X 
 
 
 
X 
 
X 
Fibrosis biomarkers10 
 
 
X 
 
 
 
X 
 
X 
Biobanking sampling 
 
 
X 
 
 
 
X 
 
 
Pharmacogenetic sampling17 
 
 
X 
 
 
 
X 
 
 
PK sampling16 
 
 
 
X 
X 
X 
X 
X 
 
Transient Elastography13 
 
X 
 
 
 
 
 
 
 
MRI-PDFF 
 
 
X* 
 
 
 
X** 
 
 
IMP compliance 
 
 
X 
X 
X 
X 
X 
 
X 
IMP dispensing 
 
X 
X 
 
X 
X 
 
 
 
Patient Emerg. Card dispensing 
X 
 
 
 
 
 
 
 
 
Diary dispensing 
 
X 
X 
 
X 
X 
 
 
 
Diary review 
 
 
X 
X 
X 
X 
X 
 
X 
SMBG dispensing18 
 
X 
 
 
 
 
 
 
 
SMBG measurements review19 
 
 
X 
X 
X 
X 
X 
X 
X 
SUB-STUDY ONLY 
OGTT+F 
 
 
X 
 
 
 
X 
 
 
DNL assessment 
 
 
X 
 
 
 
X 
 
 
X*: MRI-PDFF must be performed within 8 ± 4 days prior to Randomization Visit (V3); X**: MRI must be performed before or on the day of Week 12 (V7), i.e. 84 days (- 4 days) after Randomization Visit (V3). 
DNL: de novo lipogenesis; ECG: electrocardiogram: eGFR: estimate glomerular filtration rate; EoS: End of Study; EoT: End of Treatment; ET: Early Termination; Emerg: Emergency; FPG: Fasting Plasma 
Glucose; HbA1c: glycated hemoglobin; hsCRP: High-sensitivity C-Reactive Protein; IMP: Investigational medicinal product; IWRS: Interactive Web Response System; lab: laboratory; MRI-PDFF: Magnetic 
Resonance Imaging – Proton Density Fat Fraction; OGTT+F: oral glucose + fructose tolerance test; param.: parameters; phys ex.: physical examination; PK: pharmacokinetics; SMBG: self-monitoring blood 
glucose; V: visit; W: week(s) 
 
1 : the interval between two on-site visits must not exceed 32 days. 
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2 : includes head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. 
3 : includes height, weight, body mass index (BMI), waist and hip circumferences for Screening Visit (V1) and weight, BMI, waist and hip circumferences for other visits. 
4 : includes general appearance, the cardiovascular system as well as reported symptoms by the patient to the Investigatory; includes weight, waist and hip circumferences. 
5 : includes one measurement of heart rate and three measurements of blood pressure in supine position. 
6 : includes serum insulin, C-peptide, total cholesterol. Low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol; triglycerides, Apo A1, Apo B, free fatty acids (FFA), glycerol and  
    adiponectin. 
7 : includes Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), Quantitative Insulin Check Index (QUICKI), Homeostasis Model Assessment of β-cell function (HOMA-β) and Adipose tissue  
    Insulin Resistance (Adipo-IR). 
8 : includes biochemistry, hematology, coagulation and urinalysis. 
9 : includes fibrinogen and Monocyte Chemoattractant Protein-1 (MCP-1). 
10: includes Non-Alcohol Fatty Liver Disease (NAFLD) Fibrosis score (NFS) and Fibrosis-4 (Fib-4) score. 
11: includes Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibody (anti-HCV), in case of positive results, reflex test of HCV circulating ribonucleic acid (RNA), anti-human immunodeficiency virus (HIV)  
      1 and 2. 
12: for female patients of child-bearing potential only, serum pregnancy test (Human Chorionic Gonadotropin (β-HCG)) at Screening Visit (V1), End-of-study Visit (V8) and Early termination Visit (ET) and urine  
      pregnancy test at all other visits where a pregnancy test is planned. 
13: if required as per inclusion criterion #7, transient elastography should include Controlled Attenuation Parameter (CAP) assessment. 
14: includes single ECG at Screening Visit (V1) and triplicate ECGs at the other visits. 
15: ECG should be performed at pre-dose and 2h post-dose (i.e. before the PK sampling and the glucose and fructose load (if applicable)). 
16: blood sampling should be performed at the following timepoints: 
      For all randomized patients: 
      - At V4, V5 and V6: pre-dose 
      - At V7: pre-dose and at 2 hours post-dose (i.e. after the ECG but before the glucose and fructose load (if applicable)) 
      - At V8. 
      For patients enrolled in the sub-study only: 
      - At V7: 2.5h, 3h, 4h, 5h and 8h post-dose. 
17: Optional collection of DNA/RNA sample. 
18: SMBG dispensed to T2DM patients only.  SMBG to be brought back to the study site at each visit for measurement review.  SMBG will be kept by the patient after the end of his/her study participation. 
19: For T2DM patients only. 
 
 
 
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2.2.2 Sample Size Determination 
Sample size determination is based on the primary endpoint, i.e. the relative change in the 
percentage of liver fat mass (assessed by MRI-PDFF) from baseline to Week 12/End of 
Treatment.  The primary objective is to show the superiority of at least one PXL770 dose over 
placebo with regard the primary endpoint and the following assumptions: 
• 
Superiority design of PXL770 compared to placebo 
• 
2-sided alpha = 0.05 
• 
Power of 90% 
• 
Expected difference of 30% between at least one PXL770 dose and placebo 
• 
Relative change in percentage liver fat mass: standard deviation (SD) = 30%, estimated 
from previous published data1 
• 
No adjustment for multiple comparisons between PXL770 doses and placebo was 
considered 
With these assumptions, the sample size is 24 evaluable patients in each group to achieve a 90% 
power for each pairwise comparison. 
Assuming a dropout rate of approximately 20%, 120 patients in total (30 patients per arm) are to 
be randomized in the study. 
In the event that the drop-out rate exceeds 20% and the initial planned number of 120 randomized 
patients does not allow to obtain at least 96 evaluable patients, up to 20 additional patients could 
be randomized. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of double-blind study treatment.  The 
day of the first dose of study treatment will be Day 1, and the day immediately before Day 1 will 
be Day -1.  There will be no Day 0. 
Analysis Day will be calculated as: 
Date of assessment – date of first dose of study treatment 
+ 1 (if date of assessment ≥ date if first dose of study treatment) 
3.1.2 Definition of Baseline  
Baseline for all efficacy and safety variables will be defined as the value obtained at the 
Randomization Visit (Day 1) prior to the first dose of double-blind study treatment. If the 
measurement at this visit is missing, the last measurement prior to the first dose of double-blind 
study treatment will be used as baseline. 
3.1.3 Analysis Visits 
For the primary endpoint, liver fat mass (assessed by MRI-PDFF), analysis visits will be assigned 
according to the labelled visit: Baseline or Week 12/End of Treatment. Even if MRI-PDFF is 
assessed after treatment extension, it will be included for analysis. However, note that the Week 


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12/End of Treatment assessment must meet each of the following criteria in order to be included 
for analysis:  
• 
Must be performed within 14 days (inclusive) of the last dose of study treatment. It may 
be performed more than 14 days prior to last dose of study treatment, but cannot be 
performed more than 14 days after last dose of study treatment in order to be included for 
analysis. 
• 
The MRI analysis day must be between 8 and 20 weeks (57 and 141 days), inclusive. 
Other efficacy assessment and safety assessment analysis visits will be assigned according to 
the labelled visit as well. In addition to maximize the data available for assessments with regular 
scheduled visits, where possible, results from early termination (ET) and unscheduled visits will 
be allocated to a post-baseline scheduled visit according to the following rules and visit windows 
described in the table below (defined as the halfway point between the target visit days). 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.  
Note that Visit 7 for subjects that extended treatment due to COVID-19 will be handled similar to 
unscheduled/ET visits. It will not be set to Week 12 by default. It will be checked for an analysis 
visit window according to the table below. For example, Visit 7 may be treated as Week 20 for 
these subjects. 
If there is more than one assessment within a visit window, then the analysis visit will be assigned 
by the following priorities: 
1. Use the assessment from the visit with the matching visit label. 
2. Use the visit closest to the target visit day; in the case of ties, use the earlier visit. 
Further details of analysis visit assignment will be provided in the Analysis Data Model (ADaM) 
Specifications. 
Analysis  
Visit 
Target  
Analysis 
Day 
Visit Windows (Analysis Days) 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Baselinea 
1 
1 
1 
1 
1 
 
Week 2 
15 
2 – 22 
 
 
 
1 – 22 
Week 4 
29 
23 – 43 
2 – 43 
2 - 43 
 
23 – 43 
Week 8 
57 
44 – 71 
44 - 71 
 
 
44 – 71 
Week 12 
85 
72 – 99 
72 - 99 
44 - 99 
58 - 99 
72 – 89 
Week 16 
113 
100 – 127 
100 – 127 
100 – 127 
100 – 127 
 
Week 20 
141 
128+ 
128+ 
128+ 
128+ 
 
Week 12/End 
of Treatment 
The last post-dose observation within 7 days (inclusive) of last dose of 
double-blind study treatment will be used. This will be an added visit in 
the analysis database (i.e. a Week 12 or Week 20 result may be used). 
 
End of Study 
The last observation after last dose of double-blind study treatment will 
be used. 
 
Week 13  
92 
 
 
 
 
90+ 
a Baseline is defined as assumed to occur on Day 1 but will be defined as detailed in section 3.1.2. 
 


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All efficacy assessments (excluding the End of Study analysis visit) must be within 7 days (inclusive) of 
last dose of double-blind study treatment to be used for analysis. There is no upper limit for what may 
be used for the End of Study analysis visit. 
 
Group 1 refers to liver enzymes, FPG, hsCRP, anthropometric parameters, physical examination, vital 
signs, 12-lead ECG and biological parameters (biochemistry, hematology, coagulation and urinalysis). 
Group 2 refers to lipids and the measured metabolic parameters (serum insulin and C-peptide). 
Group 3 refers to the calculated metabolic parameters. 
Group 4 refers to the biomarkers of inflammation and fibrosis, HbA1c and eGFR. 
Group 5 refers to PK sampling 
3.1.4 Change and Relative Change from Baseline 
Change from baseline will be derived for each analysis visit as visit value minus baseline. 
Relative change from baseline will be derived for each analysis visit as 100 * [(visit value minus 
baseline)/baseline]. 
3.1.5 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of patients.  The 
denominator used for the percentage calculation will be clearly defined.  Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, standard deviation, standard error of the mean (SEM), median, Q1 and Q3, minimum, and 
maximum. 
3.1.6 Hypothesis Testing 
Unless stated otherwise, tests will be performed at the nominal alpha two-sided level of 0.05.  
95% two-sided confidence intervals will also be reported. 
Given the early stage of development (i.e. a Phase II trial), no adjustment for multiplicity will be 
considered.  Hence, pairwise comparisons between PXL700 doses (250 mg QD, 250 mg BID and 
500 mg QD) vs placebo and pairwise comparisons between active doses will be tested at the two-
sided nominal level of significance of 0.05. 
3.1.7 Handling of Dropouts and Missing Data 
Few missing data are expected and, unless stated otherwise, they will not be replaced. 
3.2 Analysis Populations 
3.2.1 Screened Analysis Set 
The Screened Analysis Set is defined as all patients who were screened for inclusion into the 
study. 
3.2.2 Run-in Safety Analysis Set (RISS) 
The Run-in Safety Analysis Set (RISS) is defined as all patients having received at least one dose 
of the single-blind placebo run-in treatment.  The population will be used to assess exposure and 
compliance with the single-blind placebo run-in treatment only. 


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3.2.3 Safety Analysis Set (SS) 
The Safety Analysis Set (SS) is defined as all randomized patients having received at least one 
dose of the double-blind study treatment (either PXL770 or placebo) and considered as-treated.  
All safety and tolerability data will be analyzed on the Safety Analysis Set. 
3.2.4 Randomized Set (RS) 
The Randomized Set (RS) is defined as all as-randomized patients.  Patients will be assigned to 
the treatment group as randomized for the Randomized Set. 
3.2.5 Intent-To-Treat Set (ITTS) 
The Intent-To-Treat Set (ITTS) is defined as all randomized patients having received at least one 
dose of the double-blind study treatment (either PXL770 or placebo).  Patients will be assigned 
to the treatment group as-randomized for the ITT Set.  The ITTS will be considered as the primary 
set for efficacy analysis. 
Additionally, some summaries and analyses may be performed on the ITTS excluding subjects 
whose study treatment period was extended due to COVID-19 pandemic circumstances. The 
subjects excluded will be defined as those that have checked “study treatment period was 
extended due to COVID-19 pandemic circumstances” on the eCRF and their overall double-blind 
study treatment duration is >98 days. 
3.2.6 Per Protocol Set (PPS)  
The Per Protocol Set (PPS) is defined as all patients in the ITT who complete the double-blind 
treatment period and have an overall treatment duration ≥8 weeks (≥56 days) without any CSR 
reportable protocol deviations (PD) that is deemed to affect the primary efficacy endpoint of MRI-
PDFF.   
CSR reportable PDs likely to affect the primary efficacy endpoint include the following categories 
(see Protocol Deviation Plan for further details): 
• 
A patient who did not meet entry criteria; 
• 
A patient who developed withdrawal criteria but were not withdrawn; 
• 
A patient who received the wrong treatment or incorrect dose; 
• 
A patient who was non-compliant with double-blind study treatment (overall <80% or > 
120% compliant, or <70% compliant in the last visit interval prior to End of Treatment MRI 
assessment); 
• 
A patient who received prohibited concomitant medications that affect the primary efficacy 
assessment (MRI-PDFF); 
• 
A patient who missed the primary efficacy assessment (MRI-PDFF) at baseline or Week 
12/End of Treatment. Subjects with extended treatment may be included in the PPS. The 
MRI must be performed within 14 days (inclusive) of the last dose of study treatment in 
order to be included. 
During the Blind Data Review Meeting (BDRM), all patients with a CSR reportable protocol 
deviation will be reviewed and assessed for inclusion into the PP Analysis Set; this review will be 
carried out by the Sponsor and Medical Monitor and agreed upon prior to database lock. 


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3.2.7 Pharmacokinetic (PK) Population 
The Pharmacokinetic (PK) population is defined as those patients from the Safety Analysis Set 
who have been treated with PXL770 according to the protocol and have provided at least one 
pre-dose PK assessment during the study. 
3.3 Patient Data and Study Conduct 
3.3.1 Patient Disposition 
A patient who fails during the screening period (between V1 and V2) is deemed to be a screen 
failure.  A patient who fails during the Run-in period (between the Run-in (V2) and run-in kit 
dispensed, and Randomization (V3) Visits), prior to randomization is deemed to be a run-in failure. 
Note that subjects may rescreen. Subjects that screen fail twice will only be counted once 
according to their 2nd reason for screen failure for summary, but all reasons will be listed. If a 
subject rescreens and successfully enters the Run-in period, they will not be counted as a screen 
failure for summary, although their reason for initial screen failure will be listed. 
The reason given for each screen failure and each run-in failure will be summarized and listed 
separately.  The listings for screen failures and run-in failures will include date of screening, date 
of screen/run-in failure and the primary reason for screen/run-in failure. 
A patient disposition summary for Screening and Run-in will be provided for the Screened 
Analysis Set and will include the following categories: 
• 
Patients who were screened for inclusion into the study 
• 
Patients who failed screening (and reasons for screen failure) 
• 
Patients who entered the run-in period 
• 
Patients who failed during run-in (and reasons for run-in failure) 
• 
Patients who were randomized 
A patient disposition summary for the Treatment Period will be provided for the Randomized Set 
and repeated for the PPS and will include the following categories: 
• 
Patients who were randomized 
• 
Patients who received at least one dose of double-blind study treatment 
• 
Patients who completed the double-blind period (i.e. Visit 7) 
• 
Patients who withdrew from the double-blind period (and reasons for withdrawal) 
• 
Patients who completed the follow-up period (i.e. completed the study overall) 
• 
Patients who withdrew from the follow-up period (and reasons for withdrawal) 
• 
Patients who had study treatment temporarily interrupted due to COVID-19 pandemic 
circumstances 
• 
Patients who stopped study treatment due to COVID-19 pandemic circumstances 
• 
Patients whose study treatment period was extended due to COVID-19 pandemic 
circumstances 
• 
Patients whose primary reason for withdrawal was due to COVID-19 
Disposition events during the screening or run-in periods will be summarized overall.  Disposition 
events from the Randomization Visit (V3) onwards will be summarized by treatment group and 
overall. 


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A disposition listing containing the randomization details (randomized treatment group and date 
of randomization), dates of first and last dose of study treatment and completion status (with date 
and reasons for withdrawal for patients who withdrew) will be provided for all patients in the 
Randomized Set. 
3.3.2 Protocol Deviations 
Counts and percentages of patients with CSR reportable protocol deviations by deviation category 
will be summarized by treatment group and overall for the Randomized Set.  A separate summary 
table will also be produced for the CSR reportable protocol deviations that led to exclusion from 
the Per Protocol Set. A separate summary table will also be produced for all protocol deviations, 
CSR reportable or not, that were due to COVID-19 pandemic circumstances. 
A listing of CSR reportable deviations will also be produced for the Randomized Set. 
Inclusion/Exclusion criteria deviations will also be listed for the Randomized Set; an additional 
listing for the Non-randomized patients will also be presented. 
3.3.3 Analysis Populations 
Counts and percentages of patients in each analysis population will be summarized by treatment 
group and overall.  Only counts will be displayed for the Screened Analysis Set, the Run-in Safety 
Analysis Set and the Randomized Set.  The denominator for the other Analysis Sets will be based 
on the Randomized Set.   
A listing of analysis set inclusion will also be provided. 
3.3.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics or counts 
and percentages of patients as appropriate by treatment group and overall for the ITT Set. 
Demographic characteristics include age, gender, childbearing potential, if female, ethnicity and 
race. 
Baseline characteristics include: 
• 
Stratification variables – T2DM status and study site 
• 
Diabetes disease history –history of disease, duration of disease, currently treated 
• 
Hepatic Steatosis Disease history – duration of disease   
• 
Cardiovascular disease (hypertension and dyslipidemia) history – history of disease, 
duration of disease, currently treated  
• 
Liver fat mass (%) as assessed from MRI-PDFF  
• 
Anthropometric parameters –weight and Body Mass Index (BMI) 
• 
Alcohol, tobacco and drug use 
• 
Liver enzymes – ALT, AST 
• 
Glycemic parameters - HbA1c, FPG 
3.3.5 Medical History 
Separate listings for Hepatic Steatosis, Diabetes, Cardiovascular Disease (Hypertension and 
Dyslipidemia) and Other Medical History will be provided for the Randomized Set.  
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Other Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.0 COVID-19 update.  The number and percentage of patients with medical 
history will be summarized by preferred term within system organ class and treatment group for 
the Randomized Set and presented by descending overall frequency of SOC, and within SOC by 
descending incidence of PT. 
3.3.6 Concomitant Medications 
Concomitant medications will be coded using the WHODrug Dictionary version Sep2018G B3.  
For summary purposes, medications will be considered prior medications if they were taken within 
28 days prior to ICF signature and stopped before or on ICF signature date.  Medications that are 
ongoing before and continue after the ICF signature will be considered as concomitant 
medications.  Medications that were prescribed during the study (from the ICF signature to End-
of study Visits) will be considered as new medications. If a subject rescreens, the later ICF 
signature date will be used as reference. If a subject rescreens, the medications initially reported 
for the subject in their first screening will not be reported for summary purposes; only the 
medications from their rescreening will be used for summary. 
If a medication has incomplete start or stop dates, dates will be imputed to determine whether a 
medication should be considered prior, concomitant or new.  If a medication start date is 
incomplete, the first day of the month will be imputed for missing day and January will be imputed 
for missing month.  If a medication stop date is incomplete, the last day of the month will be 
imputed for missing day and December will be imputed for missing month.  Incomplete start and 
stop dates will be listed as collected without imputation. 
The number and percentage of patients taking prior, concomitant and new medications by 
preferred term within Anatomical Therapeutic Chemical (ATC) Classification Systems levels 1, 3 
and 4 will be summarized by double-blind treatment group and in total based on the Safety 
Analysis Set.   
3.3.7 Study Treatment Exposure and Compliance 
3.3.7.1 
Single-Blind Placebo Run-In 
The number of days of exposure to the single-blind placebo run-in treatment will be listed and 
summarized for the Run-In Safety Analysis Set.  Exposure, in days, will be calculated as the 
difference in dates between the first and last dose of single-blind placebo run-in treatment plus 1. 
If these dates are partial or missing, they will be imputed for the purpose of calculating exposure. 
Details of the imputation will be described in the programming specifications. 
Percent compliance will be calculated as: 
Number of single blind placebo run in capsules taken x 100
Theoretical number of single blind placebo run in capsules to be taken during the run in treatment period  
 
The number of single-blind placebo run-in capsules taken will be derived by adding the number 
of actual morning and evening capsules taken as recorded on the electronic Case Report Form 
(eCRF).  If this is not recorded, then the estimated number of capsules taken, as recorded on the 
eCRF, will be used. 
The theoretical number of single-blind placebo run-in capsules to be taken will be derived as the 
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it will be imputed using the screen failure date for the purpose of calculating the theoretical number 
of capsules. 
Percent compliance with the single-blind run-in study treatment will be summarized overall for the 
Run-In Safety Population using descriptive statistics.   
3.3.7.2 
Double-Blind Study Treatment 
Days of overall exposure to double-blind study treatment will be summarized by treatment group 
for the Safety Analysis Set using descriptive statistics. Exposure, in days, will be calculated as: 
date of last dose of double-blind study treatment – date of first dose + 1 
If these dates are partial or missing, they will be imputed for the purpose of calculating exposure. 
Details of the imputation will be described in the programming specifications.  
Note that the exposure calculation is intended to describe the length of time a patient was exposed 
to double-blind study treatment and therefore does not take double-blind study treatment 
interruptions into account.   
In addition, a contingency table will be provided to display the number and percentage of patients 
with exposure in the following categories: 
• 
≤4 weeks (≤30 days) 
• 
>4 to ≤8 weeks (31 - 59 days) 
• 
>8 to ≤12 weeks (60 days – 88 days) 
• 
>12 to ≤16 weeks (89 – 116 days) 
• 
>16 weeks (>116 days) 
In addition, exposure will be calculated per visit interval using the same intervals as the 
compliance calculations. If mid-study administration dates are partial or missing, they will be 
imputed using the visit dates for the purpose of calculating exposure. 
Percent compliance will be calculated as: 
Number of capsules taken x 100
Theoretical number of capsules to be taken during the period (based off on −site visit days) 
 
The number of capsules taken will derived by adding the number of actual morning and evening 
capsules taken as recorded on the electronic Case Report Form (eCRF).  If this is not recorded, 
then the estimated number of capsules taken, as recorded on the eCRF, will be used only if it is 
the last study drug return. 
The theoretical number of capsules to be taken will be derived from the date of first dispensation 
visit to the date of last return visit of the double-blind study treatment, assuming 4 capsules are 
taken per day.  In other words, on-site visit dates are used in the calculation by visit interval and 
overall. These visit intervals will be based on actual data reported, not the planned visit schedule. 
In other words, a wider interval may be used if study drug was not returned at an intermediate 
visit. Or unscheduled visits may be used, if reported. If a subject early withdrawals, the last study 
drug return visit date will be used. Days of exposure by visit will use the same visit intervals as 
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Percent compliance with the study treatment will be summarized by treatment group for the Safety 
Population using descriptive statistics.  Additionally, the number and percentage of patients within 
each treatment group with overall compliance in the following categories will be provided: 
• 
<80% 
• 
80-120% 
• 
>120% 
3.4 Efficacy Assessment 
In general, efficacy data will be summarized by treatment group.  All efficacy data will be listed 
for the Randomized Set. 
3.4.1 Analyses of Liver Fat Mass Assessed by MRI-PDFF 
Summary statistics for liver fat mass at baseline, Week 12/End of Treatment and the change and 
relative change from baseline will be provided for the ITT and PP Analysis Sets. 
3.4.1.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the relative change in the percentage of liver fat mass (assessed 
by MRI-PDFF) from baseline to Week 12/End of Treatment.   
The primary analysis of the primary endpoint will be performed on the ITT set using an analysis 
of covariance (ANCOVA) model with treatment (PXL770 doses of 250 mg QD, 250 mg BID, 500 
mg QD and placebo) and stratification factors – T2DM status (T2DM patients vs non-T2DM 
patients) and study site (sub-study sites vs. other pooled sites) as factors and baseline liver fat 
mass as a covariate.  The least square means (LSMs) for liver fat mass within the treatment 
groups and pairwise differences in LSMs will be estimated along with their 95% confidence 
intervals (CIs) and p-values. Sample SAS code: 
/**************************************************************** 
TRTPN: 0=Placebo, 1=PXL770 250 mg QD, 2=PXL770 250 mg BID,  
       3=PXL770 500 mg QD 
T2DM: T2DM status stratification factor  
      (T2DM patients vs non-T2DM patients) 
SITEGR: Study site stratification factor (sub-study sites vs. other  
        pooled sites)  
PCHG: Relative change from baseline to Week 12/End of Treatment  
      in liver fat mass 
BASE: Baseline liver fat mass 
****************************************************************/ 
proc glm; 
    class TRTPN T2DM SITEGR; 
    model PCHG = T2DM SITEGR TRTPN BASE / p; 
    lsmeans TRTPN / stderr pdiff cl; 
    estimate "PXL770 250 mg QD : Placebo"  TRTPN -1 1 0 0; 
    estimate "PXL770 250 mg BID : Placebo" TRTPN -1 0 1 0; 
    estimate "PXL770 500 mg QD : Placebo"  TRTPN -1 0 0 1; 
    run; 
The ANCOVA model validity will be checked using appropriate plots (studentized residuals vs 
predicted values, etc.).  
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Missing MRI-PDFF at Week 12/End of Treatment will be estimated using a multiple imputation 
method (fully conditional specification method as well) assuming missing at random (MAR) 
mechanism. Missing baseline MRI-PDFF will not be estimated. 
The multiple imputation procedure and the analysis will be conducted in three separate steps: 1) 
Multiple Imputation 2) ANCOVA Model based analysis by Imputed data set 3) combination of 
results using Rubin’s rule. PROC MIANALYZE  
1. Multiple imputation (using SAS PROC MI): since there is only one post randomization visit 
(Week 12/End of Treatment) for MRI assessment, the missing pattern is monotone. The 
imputation model will include treatment, stratification factors (T2DM status and study site [sub-
study sites vs. other pooled sites]), and baseline liver fat mass and the fully conditional 
specification (FCS) method as well will be used. Missing data will be imputed 100 times to 
generate 100 imputed data sets. The seed will be 7704. Sample SAS code is below. 
/**************************************************************** 
TRTPN: 0=Placebo, 1=PXL770 250 mg QD, 2=PXL770 250 mg BID,  
       3=PXL770 500 mg QD 
T2DM: T2DM status stratification factor  
      (T2DM patients vs non-T2DM patients) 
SITEGR: Study site stratification factor (sub-study sites vs. other  
        pooled sites)  
Baseline: Baseline liver fat mass 
Week_12: Week 12/End of Treatment liver fat mass 
****************************************************************/ 
proc mi nimpute=100 seed=7704  
    minimum=(. . . 10 0) maximum=(. . . 100 100); 
    class TRTPN T2DM SITEGR; 
    var TRTPN T2DM SITEGR Baseline Week_12; 
    FCS reg(Week_12 = TRTPN T2DM SITEGR Baseline); 
    run; 
2. Analysis of imputed data sets: imputed data sets will then be analyzed separately using the 
same model for the primary endpoint analysis (ANCOVA model).  
3. Combination of estimates across imputed datasets (using SAS PROC MIANALYZE):  this will 
be performed using Rubin’s rule and the overall treatment estimates vs placebo along with 
their 95% CI and p value will be provided.  
3.4.1.2 
Sensitivity Analyses for Primary Efficacy Endpoint 
The same ANCOVA model with multiple imputation will be conducted on the ITTS excluding 
subjects whose study treatment period was extended due to COVID-19 pandemic circumstances. 
The same ANCOVA analysis will be repeated on the PPS (of note, as patients with missing MRI 
assessments will be excluded from the PPS, no multiple imputation is necessary). A sensitivity 
analysis will be performed on the ITT whereby patients with missing Week 12/End of Treatment 
liver fat mass will have their Week 12/End of Treatment value imputed using the Baseline Carried 
Forward Method (i.e. assuming no change).  A similar ANCOVA model to that described for the 
primary analysis will be used. 
A similar ANCOVA model with multiple imputation will be conducted on the ITTS, but removing 
the study site stratification factor from the model. 
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An unstratified Wilcoxon based sensitivity analysis will also be performed and the Hodges-
Lehmann estimate along its their 95% confidence intervals will also be provided.  These analyses 
will be performed on the ITT and PP Sets without replacement of missing data.  
3.4.1.3 
Subgroup Analyses for Primary Efficacy Endpoint 
The primary analysis for the relative change in liver fat mass will be performed for the ITT Analysis 
Set for the following subgroups: 
• 
Within each T2DM status (T2DM patients vs non-T2DM patients).  
• 
Within each site (sub-study sites vs other pooled sites). 
A forest plot will be provided displaying the 3 estimates (PXL770 groups) vs placebo with their 
95% CI by factor level (i.e. by TD2M status or by site) along with the factor by treatment interaction 
test p-value for each factor. 
3.4.1.3.1 Key Secondary Efficacy Analysis: Absolute Change in Liver Fat Mass Assessed by MRI-PDFF 
The change from baseline to Week 12/End of Treatment in liver fat mass will be analyzed with 
the same approach proposed for the analysis of the primary endpoint (including sensitivity 
analyses). 
3.4.1.3.2 Key Secondary Efficacy Analysis: Analysis of Responders 
Four types of responders will be proposed and analyzed: 
- 
Response defined as an absolute reduction in liver fat mass (from baseline 
(Randomization Visit [V3]) to Week 12 [V7]/End of Treatment) higher than or equal to 5% 
(≥ 5 %). 
- 
Response defined as a relative reduction in liver fat mass (from baseline [Randomization 
Visit {V3}] to Week 12 [V7]/End of Treatment) higher than or equal to 30% (≥ 30 %). 
- 
Response defined as a relative reduction in liver fat mass (from baseline [Randomization 
Visit {V3}] to Week 12 [V7]/End of Treatment) higher than or equal to 50% (≥ 50 %). 
- 
Response defined as a liver fat mass value at Week 12 (V7)/End of Treatment that is 
normalized, i.e. lower than or equal to 5% (≤ 5 %). 
The number and percentage of responders will be summarized by treatment group.   
The response will be analyzed in a logistic regression model adjusting for treatment, stratification 
factors (T2DM status and study site [sub-study sites vs. other pooled sites]) and baseline liver fat 
mass using the ITT Analysis Set. Pairwise differences in treatment groups will be estimated in 
this model as odds ratios along with their 95% CIs and p-values. A multiple imputation procedure 
similar to that proposed for the analysis of the primary endpoint will be proposed to impute missing 
MRI-PDFF at Week 12/End of Treatment. Imputed values will be used to classify patients as 
responders or not.  Of note, Missing baseline MRI-PDFF will be not replaced and patients without 
baseline MRI-PDFF will be not taken into account in the analysis. 
A sensitivity analysis will be proposed considering patients with missing MRI-PDFF either at 
baseline or at Week 12/End of Treatment as non responders.  
If needed, Firth’s penalized likelihood approach will be used to address the quasi-complete 
separation in the logistic regression analysis. 
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3.4.2 Analyses of Other Efficacy Endpoints 
All other secondary efficacy endpoints will be summarized and analyzed based on the ITT 
Analysis Set.  Descriptive statistics of the baseline change from baseline and/or relative change 
from baseline to each post-baseline visit will be presented by treatment group for each secondary 
efficacy parameter. 
3.4.2.1 
Liver enzymes  
The change (and relative change) from baseline in ALT and AST at Weeks 2, 4, 8 and 12/End of 
Treatment will be analyzed using a Mixed Model for Repeated Measures (MMRM) assuming MAR 
mechanism.  Hence, no imputation of missing data will be performed. The factors in the model 
will be treatment group, stratification factors (T2DM status and study site (sub-study sites vs. other 
pooled sites), baseline value, visit, treatment by visit and baseline by visit interactions.  An 
unstructured covariance matrix will be used (TYPE=UN).  The LSMs for change from baseline at 
each post-baseline visit will be estimated and compared between treatment groups. Sample SAS 
code is below. 
/**************************************************************************** 
 
USUBJID = Unique subject identifier 
 
T2DM = T2DM status (T2DM patients vs non-T2DM patients) 
SITEGR: Study site stratification factor (sub-study sites vs. other  
        pooled sites)  
 
CHG = observed change from baseline 
 
BASE = baseline value 
 
TRTPN = treatment identifier, e.g. 0 (Placebo), 1 (PXL770 250 mg QD),  
              2 (PXL770 250 mg BID), 3 (PXL770 500 mg QD) 
 
AVISITN = analysis visit (weeks 2, 4, 8, and 12/End of Treatment) 
****************************************************************************/ 
proc mixed;  
    class USUBJID T2DM SITEGR TRTPN AVISITN; 
    model CHG = T2DM SITEGR TRTPN BASE AVISITN TRTPN*AVISITN BASE*AVISITN /  
          ddfm=KR; 
    Repeated AVISITN / TYPE=UN sub=USUBJID; 
    lsmeans AVISITN*TRTPN / cl pdiff slice=AVISITN;   
    run;   
3.4.2.2 
Measured Metabolic Parameters 
3.4.2.2.1 Lipid Parameters 
The change (and relative change) from baseline in Total Cholesterol, HDL-c, LDL-C, 
Triglycerides, Apo A1, Apo B, FFA, Glycerol and Adiponectin at Weeks 4, 8 and 12/End of 
Treatment will be analyzed using the same MMRM model for the analysis of liver enzymes.   
3.4.2.2.2 Other measured metabolic parameters 
The change from baseline in FPG at Weeks 2, 4, 8 and 12/End of Treatment will be analyzed 
using the same MMRM model for the analysis of liver enzymes.  
The change from baseline in HbA1c at Week 12/End of Treatment will be analyzed using an 
ANCOVA model.  No imputation will be performed.  The factors in the model will be treatment 
group, stratification factors (T2DM status and study site [sub-study sites vs. other pooled sites] 
and the baseline HbA1c value. 
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The change from baseline in serum insulin and C-peptide, at Weeks 4, 8 and 12/End of Treatment 
will be analyzed using the same MMRM model for the analysis of liver enzymes. 
3.4.2.3 
Calculated Metabolic Parameters 
The change from baseline in HOMA-IR, QUICKI, HOMA-β and Adipo-IR assessed at Weeks 4 
and 12/End of Treatment will be analyzed using a MMRM model similar to the analysis of liver 
enzymes.  
3.4.2.4 
hsCRP 
The change from baseline in hsCRP at Weeks 2, 4, 8 and 12/End of Treatment will be analyzed 
the same MMRM model for the analysis of liver enzymes.  
3.4.2.5 
Other Inflammatory Biomarkers 
The change from baseline in fibrinogen and MCP-1 at Week 12/End of Treatment will be analyzed 
using the ANCOVA model for the analysis of the change in HbA1c.    
3.4.2.6 
Fibrosis Biomarkers 
The change from baseline in NFS and Fib-4 score at Week 12/End of Treatment will be analyzed 
using the ANCOVA model for the analysis of the change in HbA1c.  
3.4.2.7 
Body weight, waist circumference and waist-to-hip ratio 
The change (and relative change) from baseline in body weight, waist circumference and waist-
to-hip ratio at Weeks 2, 4, 8 and 12/End of Treatment will be analyzed using the same MMRM 
model for the analysis of liver enzymes. 
3.5 Pharmacokinetic Assessment 
For all patients in the Randomized Set, pre-dose pharmacokinetic (PK) samples will be taken at 
Weeks 2, 4, 8 and 12.  A post-dose PK sample will be taken at Week 12 2 hours after the last 
intake of study treatment.  A PK sample will also be taken at Week 13. 
For patients enrolled into the sub-study, additional post-dose PK samples will be taken at Week 
12 at 2.5h, 3h, 4h, 5h and 8h after the last intake of study treatment. 
Plasma concentrations of PXL770 will be summarized by visit and time point for the PK 
Population; results will be displayed by treatment group.  In addition to the standard summary 
statistics, geometric mean and CV will also be presented for the plasma concentrations. 
3.6 Safety Assessment 
The safety data for this study include Adverse Events (AEs), vital signs, ECGs, physical 
examinations and safety laboratory assessments.  The safety data will be summarized based on 
the Safety Analysis Set and presented by treatment group.  Missing values will not be imputed.   
3.6.1 Adverse Events (AEs) 
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 the 
medicinal product, whether or not considered related to the medicinal product. 
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For analysis, a treatment emergent AE (TEAE) is defined as any AE that occurred for the first 
time after the first dose of double-blind study treatment or existed prior to the first dose and 
worsened after the first dose.  AE worsening applies to severity, or relationship to study treatment.  
If part of the date/time for the onset/end of an AE is missing, but the existing parts allow 
determination of timing of AE onset relative to the first dose of double-blind study treatment, then 
the AE will be classified as treatment-emergent or not per review of the existing parts of the 
date/time.  If timing of the AE onset/end relative to the first dose of double-blind study treatment 
is missing, then the AE will be assumed to be treatment-emergent. 
A summary overview of all AEs will be provided, which presents the number and percentage of 
patients in each treatment group from the Safety Analysis Set, including number of events, 
satisfying each of the following categories: 
• 
Any Adverse Event 
• 
Any non-TEAE 
• 
Any TEAE 
• 
Maximum severity of TEAEs 
• 
Study-medication related TEAEs 
• 
Maximum severity of study-medication related TEAEs 
• 
TEAEs of special interest – Drug Induced Liver Injury (DILI), sourced from the End of 
Study eCRF reason for withdrawal 
• 
All serious AEs (SAEs) 
• 
All serious TEAEs (TESAEs) 
• 
All study treatment-related TESAEs 
• 
TEAEs leading to death 
• 
TEAEs leading to temporary interruption 
• 
TEAEs leading to study treatment discontinuation 
Adverse events will be coded using MedDRA v23.0 COVID-19 update.  The number and 
percentage of patients with AEs, including the number of AEs, will be summarized by their 
MedDRA preferred term within system organ class and treatment group.  For patient count 
summaries, multiple AE events with the same MedDRA coded terms (preferred term and system 
organ class) from the same patients will only be counted once.  Similar summaries will be 
presented for each of the categories above. 
The number and percentage of patients with TEAEs will be summarized by reported maximum 
severity within each MedDRA preferred term within system organ class and by treatment group.  
Similar summaries will be provided for study-medication related TEAEs. 
Detailed listings will be provided for all AEs; separate listings will be provided for non-TEAEs and 
TEAEs.  Separate listings will also be provided for AEs of Special Interest, SAEs, AEs leading to 
study treatment discontinuation and AEs leading to death. 
Note that if there is an occurrence of suspected DILI, sites are instructed to enter the AE (e.g. 
elevated ALT) and also fill out the DILI eCRF. Only if it is a confirmed DILI event will the reason 
for withdrawal be “occurrence of DILI”. In order to avoid the appearance of duplicate AEs, the 
information from the DILI eCRF will not be included in the TFLs. 


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3.6.2 Clinical Laboratory Tests 
Biochemistry, hematology, coagulation and urinalysis will be collected at the Screening, 
Randomization, Weeks 2, 4, 8, 12 and 13 and at the Early Termination Visits. 
Biochemistry parameters include: Albumin, Alkaline phosphatase (ALP), Amylase, Bicarbonate, 
Blood Urea Nitrogen, Calcium, Chloride, Creatine phosphokinase, Creatinine, eGFR (using CKD-
EPI formula), Gamma-glutamyl transferase, Inorganic phosphate, Lipase, Potassium, Sodium, 
Total bilirubin, Total protein and Uric acid. 
Hematology parameters include: Differential blood count (lymphocytes, monocytes, eosinophils, 
basophils, neutrophils – absolute values and percentages), Erythrocytes, Hemoglobin, 
Hematocrit, Leucocytes, Mean corpuscular volume, Mean corpuscular hemoglobin, Mean 
corpuscular hemoglobin concentration, Red Blood Cell Morphology, and Thrombocytes. 
Coagulation parameters include: activated Partial Thromboplastin Time (aPTT), International 
Normalized Ratio (INR) and Prothrombin Time (PT). 
Urinalysis parameters include: Blood, Glucose, Ketones, Leucocytes, Nitrites, pH, Protein, 
Specific gravity and Urobilinogen. 
Descriptive statistics of each safety laboratory parameter will be presented for baseline values 
and for values and the change from baseline at each post-baseline visit.   
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 for Alkaline Phosphatase, Creatine Phosphokinase, eGFR (using CKD-EPI formula), 
Gamma-Glutamyl Transferase (GGT) and Total Bilirubin.  The shift tables will show the shift from 
baseline to the last on-treatment value and will present the number of patients per treatment group 
with N, H or L. 
3.6.3 Vital Signs 
Vital signs will be measured at the Screening, Run-in, Randomization, Weeks 2, 4, 8, 12 and 13 
and at the Early Termination Visits. Vital signs parameters include systolic and diastolic blood 
pressure and heart rate.  At each visit, three measurements for blood pressure will be taken, the 
average of the three measurements will be used in the analysis. 
Descriptive statistics of each vital signs parameter will be presented for baseline values and for 
values and the change from baseline at each post-baseline visit.  These will be presented by 
treatment group for each parameter using the Safety Analysis Set. 
3.6.4 Electrocardiograms 
ECGs will be performed at the Screening, Randomization, Weeks 2, 4, 8, 12, 13 and at the Early 
Termination Visits.  A single ECG will be performed at the Screening Visit, and in triplicate at all 
other visits.  The average of the triplicate measurements will be used in the analysis. 
Descriptive statistics of each ECG parameter will be presented for baseline values and for values 
and the change from baseline at each post-baseline visit.  Overall interpretation will also be 
summarized at each post-baseline visit.  These will be presented by treatment group for each 
parameter using the Safety Analysis Set. 


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3.6.5 Physical Examinations 
A complete physical examination will be carried out at the Screening, Randomization, Weeks 12 
and 13 and at the Early Termination Visits.  A limited physical examination will be carried out at 
the other study visits (i.e. Run-in, Weeks 2, 4 and 8). 
A complete listing of the physical examination results will be provided. 
4 ANALYSIS TIMING 
4.1 Dry Runs/Blinded Data Reviews 
Two dry run of all analysis tables, figures and listings (TFLs) will be provided: 
• 
The first will occur approximately 3 months prior to database lock with the main aim for the 
Sponsor to review TFL layout, etc. 
• 
The second will occur after soft lock, approximately 2 weeks prior to database lock for blinded 
data review. 
Draft TFLs will include text in the titles or on the cover page of the compiled document to indicate 
that they are draft and use dummy treatment assignments (e.g., Table 14.1.1.1 - DRAFT/DUMMY 
TREATMENT ASSIGNMENTS APPLIED).   
4.2 Blinded Data Review Meeting (BDRM) 
Prior to database lock, a BDRM will be scheduled during which the blinded data will be reviewed, 
and decisions will be made as to whether patients will be included or excluded from the Per 
Protocol Analysis Set. 
4.3 Pre-Final Analysis 
After the database is locked and exclusions from analysis populations have been finalized, the 
randomized treatment assignments will be unblinded and the pre-final analysis will be generated.  
Topline TFLs will be provided approximately 1 week after database lock and unblinding and pre-
final TFLs will be provided approximately 3 weeks after database lock and unblinding.   
4.4 Final Analysis 
After all comments on the pre-final analysis have been resolved and the study database is 
declared final, the final analysis will be generated.  Final TFLs will be provided approximately 1 
week after the study database is declared final.  If there were no changes to the pre-final analysis 
or the study database, the pre-final TFLs may be considered final.  In addition to TFLs, Study 
Data Tabulation Model (SDTM) data and ADaM data along with associated files will be provided.  
Associated files may include:  annotated case report forms (CRFs), SDTM specifications, SDTM 
programs, ADaM specifications, ADaM programs, TFL programs, and Clinical Data Interchange 
Standards Consortium (CDISC) Define packages for both SDTM and ADaM data.   
5 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
For calculation of study drug compliance, the Protocol states “In case of IMP temporary 
interruption requested by the Investigator (e.g. due to AE), the duration of the temporary 
interruption should be deducted from the theoretical number of capsules to be taken during the 


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period.” This rule will not be applied; compliance will be calculated without regard to temporary 
interruptions requested by the Investigator. Temporary interruptions (documented for SAEs and 
in the free text fields of the study drug return pages) will only be considered for the review of the 
protocol deviations reported in case of compliance below 80%. 
6 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS version 9.4 or higher.  All available data will be presented 
in patient data listings which will be sorted by patients and visit date as applicable.  Detailed 
Programming Specifications will be provided in a separate document. 
 
 


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APPENDIX A:  REFERENCES 
1. Harrison, S.A., et al., NGM282 for treatment of non-alcoholic steatohepatitis: a multicenter, 
randomized, double-blind, placebo-controlled, phase 2 trial.  Lancet, 2018. 391(10126): P. 
1174-1185. 
2. Matsuda, M. and R.A. DeFronzo, Insulin sensitivity indices obtained from oral glucose 
tolerance testing: comparison with the euglycemic insulin clamp.  Diabetes Care, 1999.  
22(9): p. 1462-70.