Study of PXL065 in Patients With Nonalcoholic Steatohepatitis (NASH)

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.

Time frame: Baseline and Week 36

Population: Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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)

Time frame: Baseline and Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: Safety Set, defined as all as-treated patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: Patients With Week 36 Assessment from the Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

Improvement in fibrosis is defined as a decrease of at least one stage in NASH CRN fibrosis score.

Time frame: Baseline and Week 36

Population: Patients With Week 36 Assessment from the Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: Patients With Week 36 Assessment from the Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: Patients With Week 36 Assessment from the Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: Subset of patients with increased baseline value from the ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: Subset of patients with increased baseline value from the ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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

Time frame: Baseline and Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.~For patients with missing Week 36/Early termination, multiple imputation by fully conditional specification methods was used for analysis, although the n counts and percentages reflect only the observed data.

PIIINP is the amino-terminal propeptide of type III procollagen. 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.

Time frame: Baseline and Week 36

Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline to Week 36

Population: Safety Set, defined as all as-treated patients who received at least one dose of study treatment, Excluding Week 36 for one patient (erroneous data), and Excluding Patients With Weight Loss \> 10kg from Baseline to Week 36.

Improvement in fibrosis is defined as a decrease of at least one stage in NASH CRN fibrosis score. No worsening of NASH is defined as no increase in steatosis, inflammation or ballooning

Time frame: Baseline and Week 36

Population: Patients With Week 36 Assessment from the Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.

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.

Time frame: Baseline and Week 36

Population: Patients With Week 36 Assessment from the Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.