Nonalcoholic Fatty Liver
Conditions
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).
Interventions
DRUGPXL770
Oral capsule
DRUGPlacebo Oral Capsule
Oral capsule
Sponsors
Poxel SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients have given written informed consent * Body mass index (BMI) ≥ 25 to ≤ 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) ≥ 60 mL/\[min\*1.73m²\] * Alanine amino transferase (ALT) \> 20 IU/L in females and \> 30 IU/L in males * Hepatic steatosis (MRI-PDFF ≥ 10%) * 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 with 24 weeks prior to screening * Uncontrolled high blood pressure * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change in the Percentage of Liver Fat Mass (Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction [MRI-PDFF]) From Baseline to Week 12/End of Treatment (EOT) | Baseline to Week 12 | MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 region of interest (ROI) was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint. |
| Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Per Protocol Sensitivity Analysis) | Baseline to Week 12 | MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint. |
| Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Unstratified Wilcoxon Sensitivity Analysis) | Baseline to Week 12 | MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint. |
| Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Subgroup Analysis - Type 2 Diabetes Mellitus [T2DM]) | Baseline to Week 12 | MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week12/End of Treatment | Baseline to Week 12 | 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 in Glycated Hemoglobin (HbA1c) From Baseline to Week12/End of Treatment | Baseline to Week 12 | 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 in Total Cholesterol From Baseline to Week12/End of Treatment | Baseline to Week 12 | 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 in High Density Lipoprotein-Cholesterol (HDL-C) From Baseline to Week12/End of Treatment | Baseline to Week 12 | 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 in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment | Baseline to Week 12 | MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint. |
| Change in Triglycerides From Baseline to Week12/End of Treatment | Baseline to Week 12 | 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 in Fibrosis-4 (Fib-4) Score From Baseline to Week 12/End of Treatment | Baseline to Week 12 | 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 in Body Weight From Baseline to Week 12/End of Treatment | Baseline to Week 12 | 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. |
| Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline to Week12/End of Treatment | Baseline to Week 12 | 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 (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Baseline to Week 12 | Responders were defined as patients who achieved a clinically meaningful relative reduction of at least 30% in liver fat mass From baseline to Week 12/EOT as assessed by MRI-PDFF |
| Change in Alanine Amino Transferase (ALT) From Baseline to Week 12/End of Treatment | Baseline to Week 12 | 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 in Aspartate Amino Transferase (AST) From Baseline to Week 12/End of Treatment | Baseline to Week 12 | 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. |
Countries
United States
Participant flow
Recruitment details
Patients were screened for the study at 15 sites in the United States between 29Mar19 and 13Mar20.
Pre-assignment details
Following a Screening period of maximum 2 weeks, eligible participants entered in a single-blind placebo Run-in period of 4 weeks. This Run-in period was set to reduce any bias regarding placebo effect, to assess patient compliance, and to minimize the possible confounding influence of dietary and activity changes. Only participants who have met all the applicable Inclusion criteria and none of the Exclusion criteria at the end the Run-in period were to be randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two capsules were taken BID at least 15 minutes before a meal for 12 weeks | 31 |
| PXL770 250 mg QD Two capsules were taken BID at least 15 minutes before a meal for 12 weeks | 30 |
| PXL770 250 mg BID Two capsules were taken BID at least 15 minutes before a meal for 12 weeks | 30 |
| PXL770 500 mg QD Two capsules were taken BID at least 15 minutes before a meal for 12 weeks | 29 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 3 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 3 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | PXL770 500 mg QD | PXL770 250 mg BID | PXL770 250 mg QD |
|---|---|---|---|---|---|
| Age, Continuous | 51.5 years STANDARD_DEVIATION 12.17 | 52.5 years STANDARD_DEVIATION 12.49 | 55.7 years STANDARD_DEVIATION 12.63 | 50.6 years STANDARD_DEVIATION 12.26 | 52.5 years STANDARD_DEVIATION 12.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 42 Participants | 7 Participants | 13 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 78 Participants | 22 Participants | 17 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 10 Participants | 4 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 103 Participants | 24 Participants | 25 Participants | 27 Participants |
| Sex: Female, Male Female | 16 Participants | 78 Participants | 22 Participants | 23 Participants | 17 Participants |
| Sex: Female, Male Male | 15 Participants | 42 Participants | 7 Participants | 7 Participants | 13 Participants |
| T2DM status (stratification group) Non-T2DM | 17 Participants | 67 Participants | 17 Participants | 16 Participants | 17 Participants |
| T2DM status (stratification group) T2DM | 14 Participants | 53 Participants | 12 Participants | 14 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 30 | 0 / 30 | 0 / 29 |
| other Total, other adverse events | 8 / 31 | 13 / 30 | 14 / 30 | 13 / 29 |
| serious Total, serious adverse events | 0 / 31 | 0 / 30 | 2 / 30 | 1 / 29 |
Outcome results
Primary
Relative Change in the Percentage of Liver Fat Mass (Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction [MRI-PDFF]) From Baseline to Week 12/End of Treatment (EOT)
MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 region of interest (ROI) was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint.
Time frame: Baseline to Week 12
Population: Intent-to-treat set (ITTS), defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Relative Change in the Percentage of Liver Fat Mass (Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction [MRI-PDFF]) From Baseline to Week 12/End of Treatment (EOT) | -1.14 percentage | Standard Error 6.344 |
| PXL770 250 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction [MRI-PDFF]) From Baseline to Week 12/End of Treatment (EOT) | -1.03 percentage | Standard Error 6.764 |
| PXL770 250 mg BID | Relative Change in the Percentage of Liver Fat Mass (Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction [MRI-PDFF]) From Baseline to Week 12/End of Treatment (EOT) | -14.28 percentage | Standard Error 6.697 |
| PXL770 500 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction [MRI-PDFF]) From Baseline to Week 12/End of Treatment (EOT) | -14.68 percentage | Standard Error 6.452 |
p-value: 0.988395% CI: [-15.42, 15.66]ANCOVA
p-value: 0.084295% CI: [-28.06, 1.78]ANCOVA
p-value: 0.076395% CI: [-28.51, 1.43]ANCOVA
Primary
Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Per Protocol Sensitivity Analysis)
MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint.
Time frame: Baseline to Week 12
Population: Per Protocol Set (PPS), defined as all patients in the ITTS 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Per Protocol Sensitivity Analysis) | -0.69 percentage | Standard Error 5.818 |
| PXL770 250 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Per Protocol Sensitivity Analysis) | -2.27 percentage | Standard Error 6.036 |
| PXL770 250 mg BID | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Per Protocol Sensitivity Analysis) | -13.94 percentage | Standard Error 6.232 |
| PXL770 500 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Per Protocol Sensitivity Analysis) | -18.00 percentage | Standard Error 6.012 |
p-value: 0.828395% CI: [-16.01, 12.85]ANCOVA
p-value: 0.069895% CI: [-27.6, 1.1]ANCOVA
p-value: 0.018495% CI: [-31.63, -2.99]ANCOVA
Primary
Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Subgroup Analysis - Type 2 Diabetes Mellitus [T2DM])
MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint.
Time frame: Baseline to Week 12
Population: ITTS T2DM subgroup, defined as all as-randomized T2DM patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Subgroup Analysis - Type 2 Diabetes Mellitus [T2DM]) | -6.11 percentage | Standard Deviation 9.745 |
| PXL770 250 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Subgroup Analysis - Type 2 Diabetes Mellitus [T2DM]) | 1.15 percentage | Standard Deviation 9.266 |
| PXL770 250 mg BID | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Subgroup Analysis - Type 2 Diabetes Mellitus [T2DM]) | -16.71 percentage | Standard Deviation 8.997 |
| PXL770 500 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Subgroup Analysis - Type 2 Diabetes Mellitus [T2DM]) | -27.24 percentage | Standard Deviation 9.572 |
p-value: 0.573395% CI: [-18, 32.51]ANCOVA
p-value: 0.386195% CI: [-34.6, 13.38]ANCOVA
p-value: 0.101995% CI: [-46.46, 4.19]ANCOVA
Primary
Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Unstratified Wilcoxon Sensitivity Analysis)
MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint.
Time frame: Baseline to Week 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Unstratified Wilcoxon Sensitivity Analysis) | 0.49 percentage |
| PXL770 250 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Unstratified Wilcoxon Sensitivity Analysis) | 1.44 percentage |
| PXL770 250 mg BID | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Unstratified Wilcoxon Sensitivity Analysis) | -8.32 percentage |
| PXL770 500 mg QD | Relative Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment (Unstratified Wilcoxon Sensitivity Analysis) | -15.29 percentage |
p-value: 0.553795% CI: [-15.64, 8.65]Wilcoxon (Mann-Whitney)
p-value: 0.100595% CI: [-26.19, 1.88]Wilcoxon (Mann-Whitney)
p-value: 0.038795% CI: [-31.95, -1.58]Wilcoxon (Mann-Whitney)
Secondary
Absolute Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment
MRI acquisitions were performed at pre-qualified local MRI facilities using qualified and standardized instruments at high field strength (3 T or 1.5T) without oral or intravenous contrast. All acquisitions images were transferred to a central reader vendor for central calculation and measurement of MRI-PDFF using the method of Zhong et al. to estimate water and fat components. A 3 cm2 ROI was placed in each Couinaud segment. Central reading was masked to treatment group, clinical data, study site of origin and timepoint.
Time frame: Baseline to Week 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment | 0.023 percentage | Standard Error 1.1117 |
| PXL770 250 mg QD | Absolute Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment | -0.218 percentage | Standard Error 1.1801 |
| PXL770 250 mg BID | Absolute Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment | -2.548 percentage | Standard Error 1.1988 |
| PXL770 500 mg QD | Absolute Change in the Percentage of Liver Fat Mass (Assessed by MRI-PDFF) From Baseline to Week 12/End of Treatment | -2.391 percentage | Standard Error 1.1399 |
p-value: 0.861795% CI: [-2.961, 2.478]ANCOVA
p-value: 0.060995% CI: [-5.26, 0.117]ANCOVA
p-value: 0.076695% CI: [-5.087, 0.258]ANCOVA
Secondary
Change in Alanine Amino Transferase (ALT) From Baseline to Week 12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Alanine Amino Transferase (ALT) From Baseline to Week 12/End of Treatment | 1.0 U/L | Standard Error 2.88 |
| PXL770 250 mg QD | Change in Alanine Amino Transferase (ALT) From Baseline to Week 12/End of Treatment | 0.0 U/L | Standard Error 2.95 |
| PXL770 250 mg BID | Change in Alanine Amino Transferase (ALT) From Baseline to Week 12/End of Treatment | 0.3 U/L | Standard Error 3.1 |
| PXL770 500 mg QD | Change in Alanine Amino Transferase (ALT) From Baseline to Week 12/End of Treatment | -6.3 U/L | Standard Error 3.04 |
p-value: 0.801395% CI: [-8.3, 6.4]Mixed Models Analysis
p-value: 0.869495% CI: [-8.2, 7]Mixed Models Analysis
p-value: 0.058195% CI: [-14.9, 0.3]Mixed Models Analysis
Secondary
Change in Aspartate Amino Transferase (AST) From Baseline to Week 12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Aspartate Amino Transferase (AST) From Baseline to Week 12/End of Treatment | -2.8 U/L | Standard Error 1.95 |
| PXL770 250 mg QD | Change in Aspartate Amino Transferase (AST) From Baseline to Week 12/End of Treatment | -1.7 U/L | Standard Error 1.99 |
| PXL770 250 mg BID | Change in Aspartate Amino Transferase (AST) From Baseline to Week 12/End of Treatment | -2.2 U/L | Standard Error 2.08 |
| PXL770 500 mg QD | Change in Aspartate Amino Transferase (AST) From Baseline to Week 12/End of Treatment | -7.0 U/L | Standard Error 2.04 |
p-value: 0.668195% CI: [-3.8, 5.9]Mixed Models Analysis
p-value: 0.822495% CI: [-4.4, 5.5]Mixed Models Analysis
p-value: 0.092495% CI: [-9.2, 0.7]Mixed Models Analysis
Secondary
Change in Body Weight From Baseline to Week 12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Body Weight From Baseline to Week 12/End of Treatment | 0.96 kg | Standard Error 0.476 |
| PXL770 250 mg QD | Change in Body Weight From Baseline to Week 12/End of Treatment | 0.92 kg | Standard Error 0.486 |
| PXL770 250 mg BID | Change in Body Weight From Baseline to Week 12/End of Treatment | 0.20 kg | Standard Error 0.508 |
| PXL770 500 mg QD | Change in Body Weight From Baseline to Week 12/End of Treatment | 0.08 kg | Standard Error 0.505 |
p-value: 0.955295% CI: [-1.34, 1.27]Mixed Models Analysis
p-value: 0.263395% CI: [-2.1, 0.58]Mixed Models Analysis
p-value: 0.196295% CI: [-2.21, 0.46]Mixed Models Analysis
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fasting Plasma Glucose (FPG) From Baseline to Week12/End of Treatment | 0.36 mmol/L | Standard Error 0.199 |
| PXL770 250 mg QD | Change in Fasting Plasma Glucose (FPG) From Baseline to Week12/End of Treatment | 0.19 mmol/L | Standard Error 0.205 |
| PXL770 250 mg BID | Change in Fasting Plasma Glucose (FPG) From Baseline to Week12/End of Treatment | -0.17 mmol/L | Standard Error 0.211 |
| PXL770 500 mg QD | Change in Fasting Plasma Glucose (FPG) From Baseline to Week12/End of Treatment | -0.16 mmol/L | Standard Error 0.209 |
p-value: 0.514895% CI: [-0.68, 0.34]Mixed Models Analysis
p-value: 0.043495% CI: [-1.05, -0.02]Mixed Models Analysis
p-value: 0.049495% CI: [-1.04, 0]Mixed Models Analysis
Secondary
Change in Fibrosis-4 (Fib-4) Score From Baseline to Week 12/End of 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 to Week 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fibrosis-4 (Fib-4) Score From Baseline to Week 12/End of Treatment | -0.11 Fib-4 score | Standard Error 0.06 |
| PXL770 250 mg QD | Change in Fibrosis-4 (Fib-4) Score From Baseline to Week 12/End of Treatment | -0.07 Fib-4 score | Standard Error 0.062 |
| PXL770 250 mg BID | Change in Fibrosis-4 (Fib-4) Score From Baseline to Week 12/End of Treatment | -0.09 Fib-4 score | Standard Error 0.064 |
| PXL770 500 mg QD | Change in Fibrosis-4 (Fib-4) Score From Baseline to Week 12/End of Treatment | -0.15 Fib-4 score | Standard Error 0.063 |
p-value: 0.569595% CI: [-0.19, 0.11]ANCOVA
p-value: 0.573795% CI: [-0.11, 0.19]ANCOVA
p-value: 0.756395% CI: [-0.12, 0.17]ANCOVA
Secondary
Change in Glycated Hemoglobin (HbA1c) From Baseline to Week12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Glycated Hemoglobin (HbA1c) From Baseline to Week12/End of Treatment | 0.05 percent | Standard Error 0.092 |
| PXL770 250 mg QD | Change in Glycated Hemoglobin (HbA1c) From Baseline to Week12/End of Treatment | -0.08 percent | Standard Error 0.095 |
| PXL770 250 mg BID | Change in Glycated Hemoglobin (HbA1c) From Baseline to Week12/End of Treatment | -0.18 percent | Standard Error 0.101 |
| PXL770 500 mg QD | Change in Glycated Hemoglobin (HbA1c) From Baseline to Week12/End of Treatment | -0.24 percent | Standard Error 0.096 |
p-value: 0.244995% CI: [-0.35, 0.09]ANCOVA
p-value: 0.050295% CI: [-0.46, 0]ANCOVA
p-value: 0.012395% CI: [-0.51, -0.06]ANCOVA
Secondary
Change in High Density Lipoprotein-Cholesterol (HDL-C) From Baseline to Week12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in High Density Lipoprotein-Cholesterol (HDL-C) From Baseline to Week12/End of Treatment | -0.007 mmol/L | Standard Error 0.0357 |
| PXL770 250 mg QD | Change in High Density Lipoprotein-Cholesterol (HDL-C) From Baseline to Week12/End of Treatment | -0.025 mmol/L | Standard Error 0.0371 |
| PXL770 250 mg BID | Change in High Density Lipoprotein-Cholesterol (HDL-C) From Baseline to Week12/End of Treatment | -0.085 mmol/L | Standard Error 0.0381 |
| PXL770 500 mg QD | Change in High Density Lipoprotein-Cholesterol (HDL-C) From Baseline to Week12/End of Treatment | 0.002 mmol/L | Standard Error 0.0375 |
p-value: 0.695195% CI: [-0.111, 0.075]Mixed Models Analysis
p-value: 0.10395% CI: [-0.171, 0.016]Mixed Models Analysis
p-value: 0.858395% CI: [-0.085, 0.102]Mixed Models Analysis
Secondary
Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline to Week12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline to Week12/End of Treatment | 0.011 mmol/L | Standard Error 0.1401 |
| PXL770 250 mg QD | Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline to Week12/End of Treatment | -0.094 mmol/L | Standard Error 0.1391 |
| PXL770 250 mg BID | Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline to Week12/End of Treatment | 0.155 mmol/L | Standard Error 0.1427 |
| PXL770 500 mg QD | Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline to Week12/End of Treatment | 0.092 mmol/L | Standard Error 0.1456 |
p-value: 0.557695% CI: [-0.457, 0.248]Mixed Models Analysis
p-value: 0.426195% CI: [-0.213, 0.501]Mixed Models Analysis
p-value: 0.657195% CI: [-0.281, 0.443]Mixed Models Analysis
Secondary
Change in Total Cholesterol From Baseline to Week12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Total Cholesterol From Baseline to Week12/End of Treatment | 0.107 mmol/L | Standard Error 0.165 |
| PXL770 250 mg QD | Change in Total Cholesterol From Baseline to Week12/End of Treatment | -0.144 mmol/L | Standard Error 0.1714 |
| PXL770 250 mg BID | Change in Total Cholesterol From Baseline to Week12/End of Treatment | 0.058 mmol/L | Standard Error 0.1761 |
| PXL770 500 mg QD | Change in Total Cholesterol From Baseline to Week12/End of Treatment | 0.081 mmol/L | Standard Error 0.1764 |
p-value: 0.25195% CI: [-0.682, 0.18]Mixed Models Analysis
p-value: 0.824695% CI: [-0.486, 0.388]Mixed Models Analysis
p-value: 0.906795% CI: [-0.466, 0.414]Mixed Models Analysis
Secondary
Change in Triglycerides From Baseline to Week12/End of 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 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Triglycerides From Baseline to Week12/End of Treatment | 0.156 mmol/L | Standard Error 0.2177 |
| PXL770 250 mg QD | Change in Triglycerides From Baseline to Week12/End of Treatment | -0.006 mmol/L | Standard Error 0.2278 |
| PXL770 250 mg BID | Change in Triglycerides From Baseline to Week12/End of Treatment | 0.017 mmol/L | Standard Error 0.233 |
| PXL770 500 mg QD | Change in Triglycerides From Baseline to Week12/End of Treatment | -0.045 mmol/L | Standard Error 0.2291 |
p-value: 0.573295% CI: [-0.727, 0.405]Mixed Models Analysis
p-value: 0.631295% CI: [-0.712, 0.434]Mixed Models Analysis
p-value: 0.485795% CI: [-0.769, 0.368]Mixed Models Analysis
Secondary
Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment
Responders were defined as patients who achieved a clinically meaningful relative reduction of at least 30% in liver fat mass From baseline to Week 12/EOT as assessed by MRI-PDFF
Time frame: Baseline to Week 12
Population: ITTS, defined as all as-randomized patients who received at least one dose of study treatment.~For patients with missing Week 12/End of Treatment, multiple imputation by fully conditional specification methods was used for analysis, although the n counts and percentages reflect only the observed data.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction ≥30% | 2 Participants |
| Placebo | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction <30% | 25 Participants |
| PXL770 250 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction <30% | 22 Participants |
| PXL770 250 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction ≥30% | 4 Participants |
| PXL770 250 mg BID | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction ≥30% | 4 Participants |
| PXL770 250 mg BID | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction <30% | 19 Participants |
| PXL770 500 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction ≥30% | 8 Participants |
| PXL770 500 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment | Relative reduction <30% | 16 Participants |
p-value: 0.559295% CI: [0.27, 11.267]Regression, Logistic
p-value: 0.374795% CI: [0.368, 14.208]Regression, Logistic
p-value: 0.050195% CI: [1, 32.149]Regression, Logistic
Post Hoc
Change in ALT From Baseline to Week 12/End of Treatment (T2DM Subgroup)
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 12
Population: ITTS T2DM subgroup, defined as all as-randomized T2DM patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in ALT From Baseline to Week 12/End of Treatment (T2DM Subgroup) | 2.1 U/L | Standard Error 4.36 |
| PXL770 250 mg QD | Change in ALT From Baseline to Week 12/End of Treatment (T2DM Subgroup) | -2.2 U/L | Standard Error 4.2 |
| PXL770 250 mg BID | Change in ALT From Baseline to Week 12/End of Treatment (T2DM Subgroup) | -3.8 U/L | Standard Error 4.19 |
| PXL770 500 mg QD | Change in ALT From Baseline to Week 12/End of Treatment (T2DM Subgroup) | -12.8 U/L | Standard Error 4.59 |
p-value: 0.462695% CI: [-16.1, 7.5]Mixed Models Analysis
p-value: 0.31695% CI: [-17.9, 5.9]Mixed Models Analysis
p-value: 0.020495% CI: [-27.4, -2.4]Mixed Models Analysis
Post Hoc
Change in AST From Baseline to Week 12/End of Treatment (T2DM Subgroup)
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 12
Population: ITTS T2DM subgroup, defined as all as-randomized T2DM patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in AST From Baseline to Week 12/End of Treatment (T2DM Subgroup) | -0.8 U/L | Standard Deviation 2.92 |
| PXL770 250 mg QD | Change in AST From Baseline to Week 12/End of Treatment (T2DM Subgroup) | -3.7 U/L | Standard Deviation 2.87 |
| PXL770 250 mg BID | Change in AST From Baseline to Week 12/End of Treatment (T2DM Subgroup) | -0.9 U/L | Standard Deviation 2.82 |
| PXL770 500 mg QD | Change in AST From Baseline to Week 12/End of Treatment (T2DM Subgroup) | -10.7 U/L | Standard Deviation 3.09 |
p-value: 0.460195% CI: [-10.8, 5]Mixed Models Analysis
p-value: 0.978295% CI: [-8.1, 7.9]Mixed Models Analysis
p-value: 0.020595% CI: [-18.3, -1.6]Mixed Models Analysis
Post Hoc
Change in FPG From Baseline to Week12/End of Treatment (T2DM Subgroup)
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 12
Population: ITTS T2DM subgroup, defined as all as-randomized T2DM patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in FPG From Baseline to Week12/End of Treatment (T2DM Subgroup) | 0.54 mmol/L | Standard Error 0.399 |
| PXL770 250 mg QD | Change in FPG From Baseline to Week12/End of Treatment (T2DM Subgroup) | 0.51 mmol/L | Standard Error 0.404 |
| PXL770 250 mg BID | Change in FPG From Baseline to Week12/End of Treatment (T2DM Subgroup) | -0.29 mmol/L | Standard Error 0.384 |
| PXL770 500 mg QD | Change in FPG From Baseline to Week12/End of Treatment (T2DM Subgroup) | -0.65 mmol/L | Standard Error 0.427 |
p-value: 0.952995% CI: [-1.12, 1.05]Mixed Models Analysis
p-value: 0.128595% CI: [-1.9, 0.25]Mixed Models Analysis
p-value: 0.041795% CI: [-2.32, -0.05]Mixed Models Analysis
Post Hoc
Change in HbA1c From Baseline to Week12/End of Treatment (T2DM Subgroup)
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 12
Population: ITTS T2DM subgroup, defined as all as-randomized T2DM patients who received at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in HbA1c From Baseline to Week12/End of Treatment (T2DM Subgroup) | 0.20 percent | Standard Error 0.175 |
| PXL770 250 mg QD | Change in HbA1c From Baseline to Week12/End of Treatment (T2DM Subgroup) | -0.04 percent | Standard Error 0.176 |
| PXL770 250 mg BID | Change in HbA1c From Baseline to Week12/End of Treatment (T2DM Subgroup) | -0.23 percent | Standard Error 0.175 |
| PXL770 500 mg QD | Change in HbA1c From Baseline to Week12/End of Treatment (T2DM Subgroup) | -0.44 percent | Standard Error 0.188 |
p-value: 0.314195% CI: [-0.69, 0.23]ANCOVA
p-value: 0.065695% CI: [-0.88, 0.03]ANCOVA
p-value: 0.010195% CI: [-1.12, -0.16]ANCOVA
Post Hoc
Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup)
Responders were defined as patients who achieved a clinically meaningful relative reduction of at least 30% in liver fat mass From baseline to Week 12/EOT as assessed by MRI-PDFF
Time frame: Baseline to Week 12
Population: ITTS T2DM subgroup, defined as all as-randomized T2DM patients who received at least one dose of study treatment.~For patients with missing Week 12/End of Treatment, multiple imputation by fully conditional specification methods was used for analysis, although the n counts and percentages reflect only the observed data.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction ≥30% | 1 Participants |
| Placebo | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction <30% | 10 Participants |
| PXL770 250 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction <30% | 10 Participants |
| PXL770 250 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction ≥30% | 2 Participants |
| PXL770 250 mg BID | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction ≥30% | 3 Participants |
| PXL770 250 mg BID | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction <30% | 9 Participants |
| PXL770 500 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction ≥30% | 7 Participants |
| PXL770 500 mg QD | Percentage of Responders (Relative Reduction of at Least 30% in Liver Fat Mass) at Week 12/End of Treatment (T2DM Subgroup) | Relative reduction <30% | 3 Participants |
p-value: 0.824595% CI: [0.094, 19.554]Regression, Logistic
p-value: 0.41495% CI: [0.238, 32.752]Regression, Logistic
p-value: 0.034195% CI: [1.226, 180.452]Regression, Logistic