Non-alcoholic Fatty Liver Disease, Nonalcoholic Fatty Liver Disease
Conditions
Keywords
17β-Hydroxysteroid Dehydrogenase type 13 Minimization for the treatment of NASH (HORIZON), GSK4532990, Non-alcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD)
Brief summary
The purpose of this study is to measure improvements in liver fibrosis and inflammation with GSK4532990 compared with placebo in participants with NASH and advanced fibrosis on biopsy (F3 or F4). The study duration will be up to 76 weeks including the screening period. The treatment duration will be up to 52 weeks.
Interventions
DRUGGSK4532990
GSK4532990 will be administered.
DRUGPlacebo
Placebo will be administered.
Sponsors
GlaxoSmithKline
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
* Body Mass Index (BMI) ≥25 kilogram per meter square (kg/m\^2) (all ethnic origins) except for Asian participants who qualify for the study with BMI ≥23 kg/m2 at Screening. * In the opinion of the investigator, there are features of metabolic syndrome and NAFLD is the most likely cause of liver disease. Metabolic syndrome may include type 2 diabetes mellitus (T2DM), obesity, dyslipidemia and hypertension. * A liver biopsy at baseline showing NAFLD Activity Score (NAS) \>=4 with at least 1 point each in steatosis, inflammation and ballooning and either Fibrosis 3 or Fibrosis 4 using NASH CRN Scoring System. * Able and willing to comply with all study assessments, including a liver biopsy at Week 52.
Exclusion criteria
* Current alcohol consumption ≥14 standard drinks (24 units, 196 g ethanol) per week for females or ≥21 standard drinks (37 units, 294g ethanol) per week for males. * Weight reduction surgery or procedures (including gastric banding and intragastric balloon insertion) within 2 years of Screening 1 and/or planned during the study. * History of cancer within previous 2 years from Screening 1, except basal or squamous cell carcinoma of the skin or in situ cervical carcinoma or any other type of cancer which has been treated medically or surgically with curative outcome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving ≥ 1 Stage Improvement in Histological Fibrosis with no Worsening of NASH - F3 Cohort | At Week 52 | Improvement in histological fibrosis is assessed with Clinical research network (CRN) Scoring. No worsening of NASH is defined as no increase in the NAFLD Activity Score (NAS) for steatosis, ballooning, or inflammation. |
| Percentage of Participants Achieving NASH Resolution with no Worsening of Fibrosis - F3 Cohort | At Week 52 | NASH resolution is defined as a ballooning score of 0 and an inflammation score of 0-1. No worsening of fibrosis is defined as no increase in CRN fibrosis score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving ≥ 1 Stage Improvement in Histological Fibrosis with no Worsening of NASH - Pooled Cohort (F3 participants and F4 participants) | At Week 52 | Improvement in histological fibrosis is assessed with Clinical research network (CRN) Scoring. No worsening of NASH is defined as no increase in the NAFLD Activity Score (NAS) for steatosis, ballooning, or inflammation. |
| Percentage of Participants Achieving NASH Resolution with no Worsening of Fibrosis - Pooled Cohort (F3 participants and F4 participants) | At Week 52 | NASH resolution is defined as a ballooning score of 0 and an inflammation score of 0-1. No worsening of fibrosis is defined as no increase in CRN fibrosis score. |
| Change from baseline in Pro-peptide of type III collagen (Pro-C3) - F3 Cohort | Baseline (Day 1) and at Week 24 and 52 | — |
| Change from baseline in liver fat using Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) - F3 Cohort | Baseline (Day 1) and at Week 24 and 52 | — |
| Change from baseline in Liver stiffness measurement (LSM) by Vibration-controlled transient elastography (VCTE) - F3 Cohort | Baseline (Day 1) and at Week 24 and 52 | — |
| Change from baseline in Enhanced Liver Fibrosis (ELF) Score - F3 Cohort | Baseline (Day 1) and at Week 24 and 52 | The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers, including tissue inhibitor of metalloproteinases-1 (TIMP-1), type III procollagen (PIIINP), and hyaluronic acid (HA). The ELF score is used as a prognostic marker for disease progression: ELF score \< 9.8 : Low risk of progression, ELF score 9.8 to \< 11.3 : Moderate risk of progression and ELF score \> = 11.3 : High risk of progression. |
| Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 24- F3 Cohort | At Week 24 | — |
| Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 52 - F3 Cohort | At Week 52 | — |
| Change from Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma-glutamyl transferase (GGT) (Units Per Liter) - F3 Cohort | Baseline (Day 1) and at Week 24 and 52 | — |
| Change from baseline in Pro-peptide of type III collagen (Pro-C3) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and at Week 24 and 52 | — |
| Change from baseline in liver fat using Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and at Week 24 and 52 | — |
| Change from baseline in Liver stiffness measurement (LSM) by Vibration-controlled transient elastography (VCTE) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and at Week 24 and 52 | — |
| Change from baseline in Enhanced Liver Fibrosis (ELF) Score - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and at Week 24 and 52 | The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers, including tissue inhibitor of metalloproteinases-1 (TIMP-1), type III procollagen (PIIINP), and hyaluronic acid (HA). The ELF score is used as a prognostic marker for disease progression: ELF score \< 9.8 : Low risk of progression, ELF score 9.8 to \< 11.3 : Moderate risk of progression and ELF score \> = 11.3 : High risk of progression. |
| Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 24 - Pooled Cohort (F3 participants and F4 participants) | At Week 24 | — |
| Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 52 - Pooled Cohort (F3 participants and F4 participants) | At Week 52 | — |
| Change from Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma-glutamyl transferase (GGT) (Units Per Liter) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and at Week 24 and 52 | — |
| Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) - F3 Cohort | Up to Week 66 | — |
| Change from Baseline in Vital Signs - Blood Pressure (millimeters of Mercury) - F3 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Temperature (Celsius) - F3 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Heart Rate (Beats per minute) - F3 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Respiratory Rate (Breaths per minute) - F3 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change From Baseline in Clinical Chemistry Parameter: total bilirubin, direct Bilirubin and creatinine (Micromoles per Liter) - F3 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) - F4 Cohort | Up to Week 66 | — |
| Change from Baseline in Vital Signs - Blood Pressure (millimeters of Mercury) - F4 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Temperature (Celsius) - F4 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Heart Rate (Beats per minute) - F4 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Respiratory Rate (Breaths per minute) - F4 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Change From Baseline in Clinical Chemistry Parameter: total bilirubin, direct Bilirubin and creatinine (Micromoles per Liter) - F4 Cohort | Baseline (Day 1) and up to Week 52 | — |
| Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) - Pooled Cohort (F3 participants and F4 participants) | Up to Week 66 | — |
| Change from Baseline in Vital Signs - Blood Pressure (millimeters of Mercury) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Temperature (Celsius) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Heart Rate (Beats per minute) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and up to Week 52 | — |
| Change from Baseline in Vital Signs - Respiratory Rate (Breaths per minute) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and up to Week 52 | — |
| Change From Baseline in Clinical Chemistry Parameter: total bilirubin, direct Bilirubin and creatinine (Micromoles per Liter) - Pooled Cohort (F3 participants and F4 participants) | Baseline (Day 1) and up to Week 52 | — |
| Area under the concentration-time curve from time zero (pre-dose) to the last quantifiable concentration (AUC0-t) of GSK4532990 - F3 Cohort | Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose | — |
| Maximum observed concentration (Cmax) of GSK4532990- F3 Cohort | Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose | — |
| Percentage of Participants with Anti-drug Antibodies (ADA) to GSK4532990- F3 Cohort | Up to Week 52 | — |
| Area under the concentration-time curve from time zero (pre-dose) to the last quantifiable concentration (AUC0-t) of GSK4532990 - F4 Cohort | Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose | — |
| Maximum observed concentration (Cmax) of GSK4532990- F4 Cohort | Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose | — |
| Percentage of Participants with Anti-drug Antibodies (ADA) to GSK4532990- F4 Cohort | Up to Week 52 | — |
Countries
Argentina, Australia, Belgium, Canada, France, Greece, India, Italy, Japan, Mexico, Panama, Puerto Rico, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Outcome results
None listed