Study of PXL065 in Patients With Nonalcoholic Steatohepatitis (NASH)

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

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

Study Overview

• Status: Completed
• Conditions: NASH - Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: PXL065

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).

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Study site 11
    • Glendale, Arizona, United States, 85306
      • Study site 12
    • Tucson, Arizona, United States, 85712
      • Study site 13
    • Tucson, Arizona, United States, 85712
      • Study site 21
  • California
    • Chula Vista, California, United States, 91910
      • Study site 17
    • Fresno, California, United States, 93720
      • Study site 16
    • Huntington Park, California, United States, 90255
      • Study site 04
    • Los Angeles, California, United States, 90057
      • Study site 05
    • Orange, California, United States, 92866
      • Study site 22
    • Panorama City, California, United States, 90402
      • Study site 06
    • Santa Ana, California, United States, 92704
      • Study Site 07
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Study site 15
    • Fort Myers, Florida, United States, 33912
      • Study site 31
    • Port Orange, Florida, United States, 32127
      • Study Site 08
    • Sarasota, Florida, United States, 34240
      • Study site 01
  • Iowa
    • West Des Moines, Iowa, United States, 50265
      • Study site 28
  • Kansas
    • Kansas City, Kansas, United States, 61431
      • Study site 18
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Study site 24
    • Jackson, Mississippi, United States, 39216
      • Study site 10
  • New York
    • East Syracuse, New York, United States, 13057
      • Study site 27
  • North Carolina
    • Fayetteville, North Carolina, United States, 28304
      • Study site 14
  • South Carolina
    • Summerville, South Carolina, United States, 29485
      • Study site 29
  • Tennessee
    • Chattanooga, Tennessee, United States, 37411
      • Study site 25
    • Clarksville, Tennessee, United States, 37040
      • Study site 30
    • Germantown, Tennessee, United States, 38138
      • Study site 02
  • Texas
    • Austin, Texas, United States, 78746
      • Study site 19
    • Edinburg, Texas, United States, 78539
      • Study site 09
    • Edinburg, Texas, United States, 78539
      • Study site 23
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research (Study site 20)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; PXL065 Dose 1	Drug: PXL065; PXL065 oral tablet
Experimental: Group 2; PXL065 Dose 2	Drug: PXL065; PXL065 oral tablet
Experimental: Group 3; PXL065 Dose 3	Drug: PXL065; PXL065 oral tablet
Placebo Comparator: Group 4; Placebo oral tablet	Drug: Placebo oral tablet; Placebo oral tablet

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

Collaborators and Investigators

• Sponsor: Poxel SA

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): June 8, 2022
• Study Completion (Actual): June 20, 2022

Study Registration Dates

• First Submitted: March 23, 2020
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (Actual): March 25, 2020

Study Record Updates

• Last Update Posted (Actual): August 29, 2023
• Last Update Submitted That Met QC Criteria: August 4, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: PXL065-003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No