Study of PXL065 in Patients With Nonalcoholic Steatohepatitis (NASH)

Study Overview
=================
Brief Summary
-----------------
This study will assess the effect of 3 doses of PXL065 versus placebo on liver fat content in NASH patients after 36 weeks of treatment

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

Official Title
-----------------
A 36-week, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Assess the Efficacy and Safety of PXL065 Versus Placebo in Noncirrhotic Biopsy-proven NonAlcoholic SteatoHepatitis (NASH) Patients

Conditions
-----------------
NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
-----------------
* Drug: PXL065
* Drug: Placebo oral tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients have given written informed consent Body mass index (BMI) ≤ 50 kg/m² For patients with type 2 diabetes mellitus: either naive of glucose lowering drug or under stable oral glucose lowering drug Estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m² Liver fat content ≥ 8% on MRI-PDFF Qualifying liver biopsy (NAS) ≥ 4 and fibrosis score F1, F2 or F3 Effective contraception for women of child bearing potential Exclusion Criteria: Evidence of another form of liver disease Evidence of liver cirrhosis Evidence of hepatic impairment Positive serologic evidence of current infectious liver disease History of excessive alcohol intake Acute cardiovascular disease within 6 months prior to Randomization Any disease which in the Investigator's opinion which in the Investigator's opinion would exclude the patient from the study Use of non-permitted concomitant medication Pregnancy or lactation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>PXL065 Dose 1 | Drug: PXL065<br>* PXL065 oral tablet<br>|
| Experimental: Group 2<br>PXL065 Dose 2 | Drug: PXL065<br>* PXL065 oral tablet<br>|
| Experimental: Group 3<br>PXL065 Dose 3 | Drug: PXL065<br>* PXL065 oral tablet<br>|
| Placebo Comparator: Group 4<br>Placebo oral tablet | Drug: Placebo oral tablet<br>* Placebo oral tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline to Week 36 in the Percentage of Liver Fat Content (LFC) (Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction [MRI-PDFF]) | MRI-PDFF was performed using a standardized imaging protocol, and a central reader analyzed the results. The central reader for this study trained the local imaging centers and provided the imaging manual. Relative change from baseline to Week 36 was calculated as follows: (LFC at Week 36 - LFC at baseline) / LFC at baseline x 100. The primary analysis was performed for the Intent-to-treat Set (ITTS) using an analysis of covariance (ANCOVA) model adjusting for treatment, for stratification factors, and for the baseline LFC as a continuous covariate. LFC missing values at Week 36 were imputed using a multivariate imputation approach by fully conditional specification regression method assuming Missing At Random Mechanism. | Baseline and Week 36 | 
| Relative Change From Baseline to Week 36 in the Percentage of LFC (Assessed by MRI-PDFF) (Wilcoxon Test Sensitivity Analysis) | MRI-PDFF was performed using a standardized imaging protocol, and a central reader analyzed the results. The central reader for this study trained the local imaging centers and provided the imaging manual. The sensitivity analysis was performed for the Intent-to-treat Set (ITTS) using a non parametric pairwise Wilcoxon test stratified according to T2DM status and NASH CRN fibrosis scoring system. LFC missing values at Week 36 were imputed using a multivariate imputation approach by fully conditional specification regression method assuming Missing At Random Mechanism. | Baseline and Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline to Week 36 in the Percentage of LFC (Assessed by MRI-PDFF) | MRI-PDFF was performed using a standardized imaging protocol, and a central reader analyzed the results. The central reader for this study trained the local imaging centers and provided the imaging manual. Absolute change from baseline to Week 36 was calculated as follows: LFC at Week 36 - LFC at baseline. The analysis of the absolute change in LFC was performed for the Intent-to-treat Set (ITTS) using an ANCOVA model adjusting for treatment, for stratification factors, and for the baseline LFC as a continuous covariate. LFC missing values at Week 36 were imputed using a multivariate imputation approach by fully conditional specification regression method assuming Missing At Random Mechanism. | Baseline and Week 36 | 
| Percentage of Responders (Relative Reduction of at Least 30% in LFC) at Week 36 | Responders were defined as patients who achieved a clinically meaningful relative reduction of at least 30% in LFC from baseline to Week 36 as assessed by MRI-PDFF | Baseline and Week 36 | 
| Change From Baseline to Week 36 in Alanine Amino Transferase (ALT) | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Percentage of Responders (Normalization of ALT) | Normalization of ALT was analyzed in the subset of patients with baseline greater than the upper reference range. Patients were classed as responders if ALT normalized, i.e. decreased to < upper reference range at a post baseline visit. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Aspartate Amino Transferase (AST) | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Percentage of Responders (Normalization of AST) | Normalization of AST was analyzed in the subset of patients with baseline greater than the upper reference range. Patients were classed as responders if AST normalized, i.e. decreased to < upper reference range at a post baseline visit. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Gamma Glutamyltransferase (GGT) | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Alkaline Phosphatase (ALP) | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Pro-C3 | Pro-C3 is the released N-terminal pro-peptide of type III collagen. It is a fibrosis marker. Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline and Week 36 | 
| Change From Baseline to Week 36 in Enhanced Liver Fibrosis (ELF) Score | ELF score is an extracellular matrix marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) showing good correlations with fibrosis stages in chronic liver disease.The set cutoffs for this scoring are: ELF < 7.7: no to mild fibrosis; ELF between 7.7 - 9.8: moderate fibrosis; ELF between 9.8 - 11.3: severe fibrosis; and ELF > or = 11.3: cirrhosis. Blood samples used for TIMP-1, PIIINP and HA were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline and Week 36 | 
| Change From Baseline to Week 36 in Fibrosis-4 (Fib-4) Score | Fib-4 score is a non invasive method based on clinical determinations that indicates the level of fibrosis/ scarring of the liver. The set cutoffs for this scoring are: Fib-4 < 1.45: absence of cirrhosis; Fib-4 between 1.45 - 3.25: inconclusive and Fib-4 > 3.25: cirrhosis. Fib-4 score was calculated as (Age [years] × AST [U/L]) / (platelet [10^9/L] × √[ALT [U/L]]). Blood samples used for AST, ALT and platelet counts were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline and Week 36 | 
| Change From Baseline to Week 36 in NAFLD Fibrosis Score | The NFS is based on a combination of clinical and laboratory measurements (i.e. age, glycemia, BMI, platelet, albumin and AST/ALT ratio). The set cutoffs for this scoring are: < -1.455 for exclusion of advance fibrosis, > -1.455 to < or = 0.675 for indetermined, and > 0.675 for presence of advance fibrosis. NFS was calculated as: 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 (10^9/L) - 0.66 x albumin (g/dL) | Baseline and Week 36 | 
| Improvement of at Least 1 Point in NASH CRN Fibrosis Score From Baseline to Week 36 | Improvement in fibrosis is defined as a decrease of at least one stage in NASH CRN fibrosis score. | Baseline and Week 36 | 
| Improvement in NAS of at Least 2 Points With no Worsening in NASH CRN Fibrosis Score From Baseline to Week 36 | NAS is the NAFLD activity score, calculated as the sum of steatosis, lobular inflammation and ballooning scores. Improvement in NAS is defined as a decrease of at least 2 points. No worsening in NASH CRN fibrosis score means that the score remained stable or decreased. | Baseline and Week 36 | 
| NASH Resolution With no Worsening in NASH CRN Fibrosis Score at Week 36 | NASH resolution is defined as a NAS score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis. No worsening in NASH CRN fibrosis score means that the score remained stable or decreased. | Baseline and Week 36 | 
| NASH Resolution With Improvement of at Least 1 Point in NASH CRN Fibrosis Score at Week 36 | NASH resolution is defined as a NAS score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis. Improvement in fibrosis is defined as a decrease of at least one stage in NASH CRN fibrosis score. | Baseline and Week 36 | 
| Change From Baseline to Week 36 in Glycated Hemoglobin (HbA1c) | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Fasting Plasma Glucose (FPG) | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Serum Insulin | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Serum C-peptide | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | HOMA-IR was calculated as: Serum C-peptide (ng/mL) × FPG (mg/dL) / 405 Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. HOMA-IR is an indicator of insulin resistance. The higher the value, the greater the insulin resistance. There is no minimum or maximum index score. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Quantitative Insulin Sensitivity Check Index (QUICKI) | The QUICKI was calculated as: 1 / (log (FPG [mg/dL]) + log (C-peptide [ng/mL])). Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. QUICKI is an indicator of insulin resistance. Lower numbers reflect greater insulin resistance. There is no minimum or maximum index score. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Adipo-IR | The Adipo-IR was calculated as: Fasting serum Free Fatty Acids (mmol/L) x Fasting serum insulin (μIU/mL) Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. The Adipo-IR is a marker of adipose tissue insulin resistance. Higher the value, the greater the insulin resistance. There is no minimum or maximum index score. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Adiponectin | Blood samples were collected, handled and stored according to the instructions described in the laboratory manual and all measurements were performed at a central laboratory. | Baseline to Week 36 | 
| Change From Baseline to Week 36 in Weight | Body weight was measured using a scale with appropriate resolution, placed on a stable, flat surface. Shoes, bulky layers of clothing, and jackets had to be removed so that only light clothing remained. | Baseline to Week 36 |