IRB Study Number 25-342
Status Recruiting
Location Cleveland Clinic Weston Hospital
Institute Digestive Disease & Surgery Institute
Description
This study is for adults with compensated cirrhosis (scarring of the liver) caused by nonalcoholic / metabolic steatohepatitis (NASH/MASH) who are still stable (no past ascites, encephalopathy, or variceal bleeding).
The study is testing an investigational medication called efruxifermin (EFX), given as a weekly injection under the skin, compared with a placebo (a look-alike injection with no active drug). The main goals are to see whether EFX can:
Delay or prevent serious liver-related events (such as decompensation, need for liver transplant, or death), and
Improve liver scarring (fibrosis) without making NASH/MASH worse on liver biopsy.
Participants will:
Be randomly assigned 1:1 to receive either EFX 50 mg or placebo once weekly,
Continue standard care for cirrhosis and metabolic risk factors,
Have regular clinic visits, blood tests, heart tests, liver imaging, and non-invasive fibrosis assessments, and
In some cases, have liver biopsies during the study (for example, at baseline and around Week 96) to check for changes in scarring and inflammation.
Treatment can continue for several years, with close safety monitoring throughout.
Inclusion Criteria
Age 18–80 years, male or female (not pregnant or breastfeeding).
Compensated cirrhosis due to NASH/MASH, documented by either:
Liver biopsy showing fibrosis stage 4 with NASH/MASH features, or
Non-invasive evidence of cirrhosis such as FibroScan liver stiffness ≥ 20 kPa or ELF score ≥ 10.5, plus evidence of fatty liver (steatosis) by biopsy, MRI-PDFF, or FibroScan CAP.
Underlying metabolic risk, defined as either:
Known type 2 diabetes, or
At least 2 out of 4 features of metabolic syndrome (obesity, abnormal lipids, high blood pressure, elevated fasting glucose).
Body mass index (BMI) ≥ 25 kg/m².
Blood tests showing compensated liver function and adequate organ function, including:
Albumin ≥ 3.5 g/dL,
Platelets ≥ 75,000/µL,
Total bilirubin < 1.3 mg/dL (with specific allowances for benign conditions such as Gilbert’s syndrome or hemolysis),
ALT and AST ≤ 5 × upper limit of normal, ALP < 1.5 × upper limit of normal,
eGFR ≥ 15 mL/min/1.73 m² (or ≥ 30 mL/min/1.73 m² in some regions, per protocol),
Triglycerides ≤ 500 mg/dL,
HbA1c ≤ 9.5%,
25-OH vitamin D ≥ 13 ng/mL (supplementation allowed if initially low).
On stable doses of allowed background medications (for diabetes, lipids, blood pressure, etc.) as defined in the protocol.
Able and willing to:
Sign informed consent,
Follow study procedures and visit schedule (including liver biopsy and endoscopy if assigned), and
Use protocol-approved contraception if of child-bearing potential and have negative pregnancy tests at screening and baseline.
Exclusion Criteria
Recent major weight loss: more than 10% of body weight in the 90 days before screening or randomization.
Type 1 diabetes or unstable type 2 diabetes, including:
Large recent insulin dose changes (more than 35% within 30 days),
Recent diabetic ketoacidosis or hyperosmolar state,
Severe or unawareness hypoglycemia within 90 days.
Osteoporosis or DXA T-score ≤ –2.5 at the femoral neck or lumbar spine.
Poorly controlled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite treatment).
Varices or decompensation:
Cohort 1: presence of esophageal or gastric varices on screening endoscopy,
Cohort 2: high-risk varices,
Any prior decompensated liver disease (ascites, variceal bleeding, or hepatic encephalopathy).
MELD-3 score > 12 or Child-Pugh class B or C (score > 6), unless elevations are clearly due to benign causes such as Gilbert’s syndrome, hemolysis, or therapeutic anticoagulation.
History of significant pancreatic disease (acute or chronic pancreatitis, hereditary pancreatitis, or pancreatic cancer).
Chronic viral hepatitis or other significant liver disease, including:
Chronic hepatitis B (HBsAg positive),
Chronic hepatitis C with active viremia or sustained virologic response less than 2 years,
Alcohol-related liver disease, autoimmune liver diseases (PBC, PSC, autoimmune hepatitis), Wilson disease, clinically significant iron overload, severe alpha-1 antitrypsin deficiency, or other competing liver etiologies.
Prior liver transplant or history of hepatocellular carcinoma.
Current Cushing’s syndrome.
Significant alcohol use (more than 1 drink per day for women or more than 2 drinks per day for men for more than 3 consecutive months within 1 year).
HIV infection.
Significant, unstable cardiovascular disease (for example, myocardial infarction, PCI/CABG, or stroke within 90 days; serious arrhythmia; markedly prolonged QTcF; poorly controlled heart failure).
Life expectancy less than 2 years from any condition.
Bariatric surgery (or its failure) within the last 2 years, or planned bariatric surgery during the study.
Use of other investigational drugs within 30 days or 5 half-lives (whichever is longer), prior exposure to efruxifermin, or use of prohibited concomitant medications as defined in the protocol.
Positive urine drug screen for amphetamines, cocaine, or non-prescribed opiates, unless explained by stable prescription therapy; recent or unstable substance abuse.
(For biopsy cohort) Unable to safely undergo liver biopsy.
Any major uncontrolled systemic illness (such as severe lung disease, heart failure, renal failure, active malignancy, serious psychiatric illness, etc.) that in the investigator’s opinion makes study participation unsafe or follow-up unreliable.
Pregnant, planning pregnancy, or breastfeeding; unwilling to use required contraception.
Known allergy or hypersensitivity to efruxifermin or any component of the formulation.
