Study of PXL065 in Patients With Nonalcoholic Steatohepatitis (NASH)

Phase 2

Completed

Conditions: NASH - Nonalcoholic Steatohepatitis

Interventions: Drug: PXL065
Drug: Placebo oral tablet

Registration Number: NCT04321343

Lead Sponsor: Poxel SA

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 117

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1	PXL065	PXL065 Dose 1
Group 2	PXL065	PXL065 Dose 2
Group 3	PXL065	PXL065 Dose 3
Group 4	Placebo oral tablet	Placebo oral tablet

Primary Outcome Measures

Name	Time	Method
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])	Baseline and Week 36	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.
Relative Change From Baseline to Week 36 in the Percentage of LFC (Assessed by MRI-PDFF) (Wilcoxon Test Sensitivity Analysis)	Baseline and Week 36	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Responders (Relative Reduction of at Least 30% in LFC) at Week 36	Baseline and 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
Change From Baseline to Week 36 in Alanine Amino Transferase (ALT)	Baseline to Week 36	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.
Percentage of Responders (Normalization of ALT)	Baseline to Week 36	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.
Percentage of Responders (Normalization of AST)	Baseline to Week 36	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.
Change From Baseline to Week 36 in Gamma Glutamyltransferase (GGT)	Baseline to Week 36	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.
Absolute Change From Baseline to Week 36 in the Percentage of LFC (Assessed by MRI-PDFF)	Baseline and Week 36	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.
Change From Baseline to Week 36 in Aspartate Amino Transferase (AST)	Baseline to Week 36	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.
Change From Baseline to Week 36 in Alkaline Phosphatase (ALP)	Baseline to Week 36	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.
Change From Baseline to Week 36 in Pro-C3	Baseline and Week 36	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.
Change From Baseline to Week 36 in Enhanced Liver Fibrosis (ELF) Score	Baseline and Week 36	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.
Change From Baseline to Week 36 in Fibrosis-4 (Fib-4) Score	Baseline and Week 36	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.
Change From Baseline to Week 36 in NAFLD Fibrosis Score	Baseline and Week 36	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)
Change From Baseline to Week 36 in Serum Insulin	Baseline to Week 36	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.
Change From Baseline to Week 36 in Serum C-peptide	Baseline to Week 36	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.
Improvement in NAS of at Least 2 Points With no Worsening in NASH CRN Fibrosis Score From Baseline to Week 36	Baseline and 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.
NASH Resolution With no Worsening in NASH CRN Fibrosis Score at Week 36	Baseline and 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.
Change From Baseline to Week 36 in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)	Baseline to Week 36	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.
Change From Baseline to Week 36 in Adipo-IR	Baseline to Week 36	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.
Change From Baseline to Week 36 in Adiponectin	Baseline to Week 36	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.
Improvement of at Least 1 Point in NASH CRN Fibrosis Score From Baseline to Week 36	Baseline and Week 36	Improvement in fibrosis is defined as a decrease of at least one stage in NASH CRN fibrosis score.
Change From Baseline to Week 36 in Glycated Hemoglobin (HbA1c)	Baseline to Week 36	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.
Change From Baseline to Week 36 in Quantitative Insulin Sensitivity Check Index (QUICKI)	Baseline to Week 36	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.
Change From Baseline to Week 36 in Weight	Baseline to Week 36	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.
NASH Resolution With Improvement of at Least 1 Point in NASH CRN Fibrosis Score at Week 36	Baseline and 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.
Change From Baseline to Week 36 in Fasting Plasma Glucose (FPG)	Baseline to Week 36	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.

Trial Locations

Locations (29): Study site 30
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Clarksville, Tennessee, United States
Study site 04
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Huntington Park, California, United States
Study site 09
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Edinburg, Texas, United States
Study site 24
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Flowood, Mississippi, United States
Study site 13
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Tucson, Arizona, United States
Study site 19
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Austin, Texas, United States
Study site 14
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Fayetteville, North Carolina, United States
Study Site 02
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Germantown, Tennessee, United States
Study site 28
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West Des Moines, Iowa, United States
Study site 05
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Los Angeles, California, United States
Study site 15
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Boca Raton, Florida, United States
Study site 31
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Fort Myers, Florida, United States
Study site 01
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Sarasota, Florida, United States
Study site 10
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Jackson, Mississippi, United States
Study site 27
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East Syracuse, New York, United States
Study site 25
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Chattanooga, Tennessee, United States
Pinnacle Clinical Research (Study site 20)
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San Antonio, Texas, United States
Study site 17
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Chula Vista, California, United States
Study site 11
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Chandler, Arizona, United States
Study site 12
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Glendale, Arizona, United States
Study site 21
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Tucson, Arizona, United States
Study site 16
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Fresno, California, United States
Study site 06
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Panorama City, California, United States
Study site 22
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Orange, California, United States
Study site 07
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Santa Ana, California, United States
Study site 18
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Kansas City, Kansas, United States
Study site 08
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Port Orange, Florida, United States
Study site 29
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Summerville, South Carolina, United States
Study site 23
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Edinburg, Texas, United States