Non-alcoholic Fatty Liver Disease
Conditions
Keywords
Efimosfermin Alfa, Metabolic Dysfunction-Associated Steatohepatitis, Non-alcoholic Fatty Liver Disease, ZENITH-1
Brief summary
The purpose of this study is to assess the safety and efficacy of efimosfermin alfa in the resolution of steatohepatitis and improvement of liver-related clinical outcome compared to placebo in individuals with MASH and biopsy-confirmed F2- or F3-stage fibrosis.
Interventions
Efimosfermin alfa will be administered
DRUGPlacebo
Placebo will be administered
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
This is a double blind study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Able and willing to understand and sign a written informed consent form that must be obtained prior to the initiation of study procedures 2. Age \>=18 and \<=75 years at enrollment 3. History or presence of 2 or more of the 5 components of metabolic syndrome per American Heart Association definition 4. Liver biopsy confirmation of MASH consistent with stage F2 or F3 fibrosis and a NAS score \>=4 confirmed by a central pathologist
Exclusion criteria
1. Contraindication or ineligibility for percutaneous liver biopsy 2. ALT or AST \>=5 x upper limit of normal (ULN) 3. Total bilirubin \>=1.3 milligram per deciliter (mg/dL). Individuals with documented Gilbert's syndrome may be enrolled if they experienced an isolated increase in total bilirubin of \>=1.3 mg/dL and direct bilirubin is \<=20% of total bilirubin; otherwise, the individual will be excluded. 4. Serum albumin \<=3.5 grams per deciliter (g/dL) 5. International normalized ratio (INR) \>=1.3 not due to therapeutic anticoagulation. Individuals receiving chronic anticoagulant treatment with higher INR values may be enrolled at the discretion of the Investigator and Study Medical Monitor. 6. Alkaline phosphatase (ALP) \>=2\*ULN 7. Platelet (PLT) count \<140,000 per (/) cubic millimeter (mm\^3); individuals with a PLT count between 110,000/mm\^3 and 140,000/mm\^3 may be enrolled after discussion with the Study Medical Monitor. 8. Serum creatinine \>=1.5 mg/dL or creatinine clearance \<=60 milliliter (mL)/minute (min)/1.73 square meter by Chronic Kidney Disease Epidemiology Collaboration equation 9. Alpha-fetoprotein \>=20 nanogram per milliliter (ng/mL) 10. Glycated hemoglobin \>=9.0% 11. Model for End-Stage Liver Disease score \>=12 unless the score is elevated in the absence of liver dysfunction (e.g., Gilbert's syndrome) 12. Phosphatidyl ethanol (PEth) \>=80 ng/mL at Screening 13. Evidence of infection with any of the following: 1. Human immunodeficiency virus; 2. Hepatitis B virus (detectable HBsAg at Screening); 3. Hepatitis C virus (HCV); 14. Chronic liver disease from any other cause including, but not limited to, alcoholic liver disease; evidence of portal hypertension; viral hepatitis or any history or evidence of cirrhosis on screening liver biopsy; or decompensated liver disease such as clinical ascites, bleeding gastroesophageal varices, hepatorenal syndrome, or hepatic encephalopathy prior to Screening or Day 1. 15. Current or history of excessive alcohol intake for \>=3 months within the 12-month period prior to Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of steatohepatitis at Week 52 | At Week 52 | Proportion of participants experiencing improvement in fibrosis of greater than or equal to (\>=) 1 stage by MASH clinical research network (CRN) fibrosis scores and no worsening of steatohepatitis (defined as no increase in nonalcoholic fatty liver disease activity score \[NAS\] for ballooning, inflammation, or steatosis) at 52 weeks will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity. |
| Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN fibrosis score at Week 52 | At Week 52 | Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. NAS score ranges from 0 to 8, higher score indicates worse disease activity. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. |
| Time from randomization to an adjudicated composite liver-related clinical outcome | From Randomization (Day 1) to 48 months | Liver-related outcome will comprised of all-cause mortality; transplantation; occurrence of significant hepatic events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity | At Week 52 and at Month 48 | — |
| Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity | At Week 52 and at Month 48 | — |
| Number of participants with Grade 3 and Grade 4 laboratory abnormalities | At Week 52 and at Month 48 | — |
| Proportion of participants experiencing resolution of steatohepatitis on overall histopathological reading and improvement in liver fibrosis of >=1 stage at Week 52 | At Week 52 | Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis on overall histopathological reading on liver biopsies. Proportion of participants experiencing improvement in fibrosis of \>=1 stage by MASH CRN fibrosis scores and resolution of steatohepatitis on overall histopathological reading at 52 weeks will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity |
| Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of Steatohepatitis at Month 48 | At Month 48 | Proportion of participants experiencing improvement in fibrosis of \>=1 stage by MASH CRN fibrosis scores and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Month 48 will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity. |
| Proportion of participants experiencing improvement in fibrosis by >=2 stage and no worsening of Steatohepatitis at Week 52 and Month 48 | At Week 52 and Month 48 | Proportion of participants experiencing improvement in fibrosis of \>=2 stage by MASH CRN fibrosis scores and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at at Week 52 and Month 48 will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity |
| Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN score at Month 48 | At Month 48 | Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. NAS score ranges from 0 to 8, higher score indicates worse disease activity. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. |
| Absolute change from Baseline in vibration-controlled transient elastography-liver stiffness measurement (VCTE-LSM) | Baseline (Day 1), Week 52 and Month 48 | — |
| Percent change from Baseline in VCTE-LSM | Baseline (Day 1), Week 52 and Month 48 | — |
| Absolute change from Baseline in controlled attenuation parameter (CAP) scores | Baseline (Day 1), Week 52 and Month 48 | The CAP score is measured by FibroScan, will be used to quantify and detect liver fat. CAP less than (\<) 238 decibel-milliwatts (dB/m) indicated no hepatic steatosis, 238 less than or equal to (\<=) CAP \<=259 dB/m denoted mild steatosis, 260 \<=CAP \<=291 dB/m indicated moderate steatosis, and CAP greater than (\>) 291 dB/m denoted severe steatosis. |
| Percent change from Baseline in CAP scores | Baseline (Day 1), Week 52 and Month 48 | The CAP score is measured by FibroScan, will be used to quantify and detect liver fat. CAP \<238 dB/m indicated no hepatic steatosis, 238 \<=CAP \<=259 dB/m denoted mild steatosis, 260 \<=CAP \<=291 dB/m indicated moderate steatosis, and CAP \>291 dB/m denoted severe steatosis. |
| Proportion of participants achieving Change from Baseline in VCTE-LSM >=30 percent (%) at Week 52 and Month 48 | Baseline (Day 1), Week 52 and Month 48 | VCTE-LSM is a non-invasive test that uses vibration-controlled transient elastography to measure the stiffness of the liver in kilopascal (kPa). |
| Absolute change from Baseline in magnetic resonance elastography (MRE) scores | Baseline (Day 1), Week 52 and Month 48 | MRE is a non-invasive imaging technique that combine magnetic resonance imaging (MRI) scanning with low-frequency mechanical vibrations to measure the stiffness of liver. MRE scores \<2.5 is normal, 2.5 - 3.0 Normal or inflammation, 3.0 - 3.5 Stage 1-2 fibrosis, 3.5 - 4.0 Stage 2-3 fibrosis, 4.0 - 5.0 Stage 3-4 fibrosis and \> 5.0 Stage 4 fibrosis. |
| Percent change from Baseline in MRE Score | Baseline (Day 1), Week 52 and Month 48 | MRE is a non-invasive imaging technique that combine MRI scanning with low-frequency mechanical vibrations to measure the stiffness of liver. MRE scores \<2.5 is normal, 2.5 - 3.0 Normal or inflammation, 3.0 - 3.5 Stage 1-2 fibrosis, 3.5 - 4.0 Stage 2-3 fibrosis, 4.0 - 5.0 Stage 3-4 fibrosis and \> 5.0 Stage 4 fibrosis. |
| Absolute change from Baseline in Enhanced Liver Fibrosis (ELF) Score | Baseline (Day 1), Week 52 and Month 48 | The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers. 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. |
| Percent change from Baseline in ELF Score | Baseline (Day 1), Week 52 and Month 48 | The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers. 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. |
| Proportion of participants experiencing improvement in ELF score of >=0.5 | At Week 52 and Month 48 | The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers. 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. |
| Absolute change from Baseline in hepatic fat fraction (HFF) by MRI-derived proton density fat fraction (PDFF) | Baseline (Day 1), Week 52 and Month 48 | HFF is the percentage of fat in the liver measured by MRI proton density fat fraction technique, which ranges from 0-75%. Greater than 5% is considered extra fat in the liver. |
| Percent change from Baseline in HFF by MRI-PDFF | Baseline (Day 1), Week 52 and Month 48 | HFF is the percentage of fat in the liver measured by MRI proton density fat fraction technique, which ranges from 0-75%. Greater than 5% is considered extra fat in the liver. |
| Absolute change from Baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (International units per liter) | Baseline (Day 1), Week 52 and Month 48 | — |
| Percent change from Baseline in ALT and AST (International units per liter) | Baseline (Day 1), Week 52 and Month 48 | — |
| Absolute change from Baseline in ALT and AST ratio (ALT/AST) | Baseline (Day 1), Week 52 and Month 48 | ALT/AST ratio is calculated as ALT/AST ratio equal to ALT divided by AST. |
| Percent change from Baseline in ALT and AST ratio (ALT/AST) | Baseline (Day 1), Week 52 and Month 48 | ALT/AST ratio is calculated as ALT/AST ratio equal to ALT divided by AST. |
| Proportion of participants experiencing ALT and HFF normalization at Week 52 and Month 48 | At Week 52 and Month 48 | — |
| Proportion of participants experiencing HFF <=5% at Week 52 and Month 48 | At Week 52 and Month 48 | HFF is the percentage of fat in the liver measured by MRI proton density fat fraction technique, which ranges from 0-75%. Less than or equal to 5% is considered normal (no significant fatty infiltration (steatosis) in the liver. |
| Change from Baseline in glycated hemoglobin (HbA1c) (Percentage of HbA1c) in participants with Type 2 Diabetes Mellitus (T2DM) | Baseline (Day 1), Week 52 and Month 48 | — |
| Change from Baseline in body weight (kilograms) | Baseline (Day 1), Week 52 and Month 48 | — |
| Change from Baseline in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)- cholesterol, and triglycerides (Millimoles per liter) | Baseline (Day 1), Week 52 and Month 48 | — |
| Proportion of participants with antidrug and antiFGF21 antibody (ADA) | At Week 52 and Month 48 | — |
| Change from Baseline in Chronic Liver Disease Questionnaire-Nonalcoholic Steatohepatitis (CLDQ-NASH) in domain and total score | Baseline (Day 1), Week 52 and Month 48 | CLDQ-NASH is a NASH-specific health-related quality of life (HRQoL) Patient-Reported Outcomes (PRO) designed to assess 6 health domains over 36 items: abdominal symptoms (3 items), activity/energy (5 items), emotional health (9 items), fatigue (6 items), systemic symptoms (6 items) and worry (7 items). The domain scores range from 1 to 7, higher scores indicating better HRQoL. A score of 1 meaning the symptom being assessed is "present always" while a score of 7 means the symptom is "never present". The total score can range from 36 to 252, a higher score corresponds to a better quality of life while a lower score corresponds to a worse quality of life. |
| Change from Baseline in Short Form-36 (SF-36) component and domain scores at Week 52 and Month 48 | Baseline (Day 1), Week 52 and Month 48 | SF-36 is a generic HRQoL PRO designed to assess 8 health domains over 36 items: physical functioning (10 items), bodily pain (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), general health (5 items), mental health (5 items), social functioning (2 items), and vitality (4 items). Each domain is scored from 0 (poorer health) to 100 (better health). SF-36 is scored into 8 domains and 2 component scores: physical component summary (PCS) and mental component summary (MCS). The domain and component scores range from 0 to 100, with higher scores indicating better HRQoL. |
| Serum drug Concentration of efimosfermin alfa | Up to Month 48 | — |
Countries
Australia, Canada, Hong Kong, Japan, New Zealand, Puerto Rico, Saudi Arabia, Taiwan, United States
Contacts
CONTACTUS GSK Clinical Trials Call Center
CONTACTEU GSK Clinical Trials Call Center
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Outcome results
None listed