A Pivotal Clinical Study to Investigate Efimosfermin Alfa in Participants With Biopsy-confirmed F2- or F3-stage MASH

NCT07221227
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Phase
Phase 3
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Recruitment status
Recruiting
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Participants
1,200
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Lead sponsor
GlaxoSmithKline
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Start date
2025-10-24
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Number of sites
91
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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.
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Acronym
ZENITH-1
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Short title
A Pivotal Clinical Study to Investigate Efimosfermin Alfa in Participants With Biopsy-confirmed F2- or F3-stage MASH
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Official title
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study to Investigate the Safety and Efficacy of Efimosfermin Alfa in Participants With Biopsy-Confirmed F2- or F3-Stage Metabolic Dysfunction-Associated Steatohepatitis (MASH) (ZENITH-1)
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Control arm
Placebo
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Registry reports results
No
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Listing at source
Listed
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Recruitment status
Recruiting
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Phase
Phase 3
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Study type
Interventional
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Completion date
2031-12-12
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First posted
2025-10-27
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Registry last updated
2026-07-27
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Primary completion date
2028-03-29
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Start date
2025-10-24
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Participants
1,200
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Participant count basis
Estimated
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Planned participants
1,200
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Protocol amendments
1
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Number of sites
91
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Data monitoring committee
Yes
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Registry sponsor category
Industry
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Lead sponsor
GlaxoSmithKline
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Source registry
ClinicalTrials.gov
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Registry ID
NCT07221227
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ClinicalTrials.gov ID
NCT07221227
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Registry record
Open registry record
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Allocation
Randomised
Model
Parallel groups
Purpose
Treatment
Masking
Double masking
Masking description
This is a double blind study.
Masked roles
Participants, Investigators
Sources for study design
clinicaltrials.gov

  1. Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of steatohepatitis at Week 52

    Timeframe: 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.

  2. Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN fibrosis score at Week 52

    Timeframe: 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.

  3. Time from randomization to an adjudicated composite liver-related clinical outcome

    Timeframe: From Randomization (Day 1) to 48 months

    Liver-related outcome will comprised of all-cause mortality; transplantation; occurrence of significant hepatic events.

  1. Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity

    Timeframe: At Week 52 and at Month 48

  2. Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity

    Timeframe: At Week 52 and at Month 48

  3. Number of participants with Grade 3 and Grade 4 laboratory abnormalities

    Timeframe: At Week 52 and at Month 48

  4. Proportion of participants experiencing resolution of steatohepatitis on overall histopathological reading and improvement in liver fibrosis of >=1 stage at Week 52

    Timeframe: 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

  5. Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of Steatohepatitis at Month 48

    Timeframe: 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.

  6. Proportion of participants experiencing improvement in fibrosis by >=2 stage and no worsening of Steatohepatitis at Week 52 and Month 48

    Timeframe: 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

  7. Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN score at Month 48

    Timeframe: 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.

  8. Absolute change from Baseline in vibration-controlled transient elastography-liver stiffness measurement (VCTE-LSM)

    Timeframe: Baseline (Day 1), Week 52 and Month 48

  9. Percent change from Baseline in VCTE-LSM

    Timeframe: Baseline (Day 1), Week 52 and Month 48

  10. Absolute change from Baseline in controlled attenuation parameter (CAP) scores

    Timeframe: 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.

  11. Percent change from Baseline in CAP scores

    Timeframe: 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.

  12. Proportion of participants achieving Change from Baseline in VCTE-LSM >=30 percent (%) at Week 52 and Month 48

    Timeframe: 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).

  13. Absolute change from Baseline in magnetic resonance elastography (MRE) scores

    Timeframe: 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.

  14. Percent change from Baseline in MRE Score

    Timeframe: 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.

  15. Absolute change from Baseline in Enhanced Liver Fibrosis (ELF) Score

    Timeframe: 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.

  16. Percent change from Baseline in ELF Score

    Timeframe: 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.

  17. Proportion of participants experiencing improvement in ELF score of >=0.5

    Timeframe: 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.

  18. Absolute change from Baseline in hepatic fat fraction (HFF) by MRI-derived proton density fat fraction (PDFF)

    Timeframe: 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.

  19. Percent change from Baseline in HFF by MRI-PDFF

    Timeframe: 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.

  20. Absolute change from Baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (International units per liter)

    Timeframe: Baseline (Day 1), Week 52 and Month 48

  21. Percent change from Baseline in ALT and AST (International units per liter)

    Timeframe: Baseline (Day 1), Week 52 and Month 48

  22. Absolute change from Baseline in ALT and AST ratio (ALT/AST)

    Timeframe: Baseline (Day 1), Week 52 and Month 48

    ALT/AST ratio is calculated as ALT/AST ratio equal to ALT divided by AST.

  23. Percent change from Baseline in ALT and AST ratio (ALT/AST)

    Timeframe: Baseline (Day 1), Week 52 and Month 48

    ALT/AST ratio is calculated as ALT/AST ratio equal to ALT divided by AST.

  24. Proportion of participants experiencing ALT and HFF normalization at Week 52 and Month 48

    Timeframe: At Week 52 and Month 48

  25. Proportion of participants experiencing HFF <=5% at Week 52 and Month 48

    Timeframe: 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.

And 7 more, listed on the interactive page.

Sources for outcomes
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Sex
All
Age groups
Adults, Older adults
Minimum age
18 Years
Maximum age
75 Years
Healthy volunteers
No

  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

  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

Sources for eligibility
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  • GSK Investigational SiteChandler, United StatesRecruiting
  • GSK Investigational SiteTucson, United StatesRecruiting
  • GSK Investigational SiteLittle Rock, United StatesRecruiting
  • GSK Investigational SiteArcadia, United StatesRecruiting
  • GSK Investigational SiteCovina, United StatesRecruiting
  • GSK Investigational SiteFolsom, United StatesRecruiting
  • GSK Investigational SiteLos Angeles, United StatesRecruiting
  • GSK Investigational SiteMontclair, United StatesRecruiting
  • GSK Investigational SiteRiverdale, United StatesRecruiting
  • GSK Investigational SiteSan Diego, United StatesRecruiting
  • GSK Investigational SiteSanta Maria, United StatesRecruiting
  • GSK Investigational SiteVan Nuys, United StatesRecruiting
  • GSK Investigational SiteColorado Springs, United StatesRecruiting
  • GSK Investigational SiteBoynton Beach, United StatesRecruiting
  • GSK Investigational SiteCape Coral, United StatesRecruiting
  • GSK Investigational SiteClermont, United StatesRecruiting
  • GSK Investigational SiteFort Myers, United StatesRecruiting
  • GSK Investigational SiteHialeah, United StatesRecruiting
  • GSK Investigational SiteHialeah, United StatesRecruiting
  • GSK Investigational SiteHomestead, United StatesRecruiting
  • GSK Investigational SiteInverness, United StatesRecruiting
  • GSK Investigational SiteJacksonville, United StatesRecruiting
  • GSK Investigational SiteKissimmee, United StatesRecruiting
  • GSK Investigational SiteLakeland, United StatesRecruiting
  • GSK Investigational SiteMaitland, United StatesRecruiting

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Sources for sites
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  • 2025
  • 2025-523675-39
Sources for references
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Related records

Drugs (1)

Lead sponsors (1)

Conditions (1)