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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05832229
Other study ID # Pro00070580
Secondary ID U24DK130164
Status Recruiting
Phase Phase 2
First received
Last updated
Start date October 11, 2023
Est. completion date November 1, 2026

Study information

Verified date October 2023
Source National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact Crystal Santillanes
Phone 312-503-5536
Email lcn@northwestern.edu
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This is a double-blind, phase 2 study to evaluate safety and efficacy of rosuvastatin in comparison to placebo after 2 years in patients with compensated cirrhosis.


Description:

This study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial, of 20mg (or 10mg for participants of East Asian ancestry) of rosuvastatin by mouth, once daily. Participants will be randomized (1:1) to either once daily placebo or once daily rosuvastatin. Patients meeting all eligibility criteria will be assigned to a randomization arm prior to initiation of a 4-week lead-in phase of the study. All participants will undergo a 4-week, open-label active run-in phase to evaluate initial safety and adherence to rosuvastatin. During this active run-phase, all participants will receive target dose rosuvastatin-- 20 mg daily (10 mg daily for participants of East-Asian ancestry). After the active run-in phase, all participants will continue with their pre-assigned randomization (1:1) treatment of rosuvastatin 20 mg daily (10 mg daily for participants of East-Asian ancestry) or matching placebo. The total duration of the study will be 96 weeks in the assigned treatment arm plus the 4-week lead-in period. The primary outcome will be the mean change in liver stiffness from the baseline measurement to the end of study liver stiffness, as measured by ultrasound-based vibration-controlled transient elastography (VCTE). There are 10 participating clinical centers, and we anticipate a total of 256 patients will be recruited for the initial lead-in as we estimate 20% of participants may dropout after the lead-in (256 x 0.8 = 204 for randomization into the study drug treatment phase).


Recruitment information / eligibility

Status Recruiting
Enrollment 256
Est. completion date November 1, 2026
Est. primary completion date November 1, 2026
Accepts healthy volunteers No
Gender All
Age group 18 Years to 75 Years
Eligibility Inclusion Criteria: 1. Age 18-75 years 2. Cirrhosis due to nonalcoholic steatohepatitis, alcohol-associated liver disease, or chronic viral hepatitis (treated hepatitis B virus or hepatitis C virus), or cryptogenic cirrhosis 3. Clinical diagnosis of cirrhosis as defined investigator confirmation and the following: 1. At least one liver biopsy within 5 years prior to consent showing either: Metavir stage 4 fibrosis; Ishak Stage 5-6 fibrosis, OR 2. At least 2 of the following: i. Evidence on imaging: Nodular liver with either splenomegaly or recanalized umbilical vein within the past 48 weeks ii. Liver stiffness: vibration-controlled transient elastography within 48 weeks prior to consent or during Screening =12.5 kilopascal or magnetic resonance elastography within 48 weeks prior to consent or during Screening =5 kilopascal iii. Evidence of varices demonstrated on imaging or endoscopy within 3 years prior to consent or during Screening iv. Either: Fibrosis-4>2.67 or platelets <150/mL within 6 months prior to consent or during Screening 4. Two measures of vibration-controlled transient elastography: one at screening and one at the randomization study visit, meeting the following criteria: 1. The first measure must be = 12.5 kilopascal. 2. The two measures must be at least 1 day apart and no more than 60 days apart from one another. 3. The mean of two measurements must be = 12.5 kilopascal. 5. Compensated defined by: 1. Absence of ascites/hydrothorax, hepatic encephalopathy or variceal bleeding currently or in the last 48 weeks, as determined clinically by investigator. 2. If prior history of decompensation, must be without current symptoms of decompensation and no longer requiring treatment of complications for the last 48 weeks, including the use of diuretics for the treatment of ascites, and/or rifaximin or lactulose for the treatment of hepatic encephalopathy. Use of non-selective beta blockers will be allowed. 3. Child-Pugh score <8 6. Provision of written informed consent. Exclusion Criteria: 1. Currently on a statin or any statin exposure within 48 weeks prior to consent. 2. Known indication for statin therapy, defined as: 1. Prior peripheral vascular, cardiovascular or cerebrovascular event for which statins are indicated for secondary prevention, OR 2. Documented familial hypercholesterolemia, heterozygous familial hypercholesterolemia, OR 3. Fasting LDL-C = 190 mg/dL 4. Myocardial infarction, Unstable angina, transient ischemic events, or stroke within 24 weeks of screening. 3. Alcohol Use Disorder Identification Test (AUDIT) score of =8. 4. Patients with limitations in attending study visits. 5. Prisoners. 6. Known prior or current hepatocellular carcinoma (HCC) or cholangiocarcinoma. 7. Known transjugular intrahepatic portosystemic shunt (TIPS), balloon retrograde transvenous obliteration (BRTO) or porto-systemic shunt surgery regardless of time of occurrence. 8. Current (in past 24 weeks prior to consenting) use of medications known to cause hepatic fibrogenesis or confound endpoint assessment, defined as: 1. amiodarone 2. methotrexate 3. warfarin 9. Current (in past 24 weeks prior to consenting) use of medications which may increase risk for rosuvastatin-related myositis or drug-induced liver injury, defined as: a. fenofibrate b. erythromycin c. gemfibrozil d. niacin (500 mg or more) e. HIV protease inhibitors (darunivar, indinavir, nelfinavir, amprenavir) in patients of East Asian descent f. colchicine g. cyclosporin 10. Presence of portal or hepatic vein thrombosis 11. Receiving an elemental diet or parenteral nutrition 12. Chronic pancreatitis or pancreatic insufficiency 13. Etiology of cirrhosis other than alcohol-associated liver disease, NAFLD, viral hepatitis or cryptogenic (including immune-mediated such as autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cholangitis, cardiac cirrhosis or Fontan-associated liver disease, alpha-1-anti-trypsin, Wilson's disease, etc) 14. Conditions which may confound study outcome: a. Unstable or active inflammatory bowel disease b. Active infection c. Any malignant disease (other than squamous or basal cell carcinoma of the skin) within previous 5 years d. Prior solid organ or hematopoietic cell transplant e. Bariatric surgery in the last 24 weeks prior to consent or planned bariatric surgery within the next 96 weeks f. Current liver-unrelated end-stage organ failures such as end-stage renal disease on dialysis, stage 3-4 congestive heart failure (CHF), current chronic obstructive pulmonary disease (COPD) on home oxygen. 15. Known current medical or psychiatric conditions which, in the opinion of the investigator, would make the participant unsuitable for the study for safety reasons or interfere with or prevent adherence to the protocol. 16. The following laboratory abnormalities within 90 days of screening: 1. Absolute neutrophil count <1.0 x 109 / L 2. Hemoglobin <10 g/dL 3. Albumin <3.0 g/dL 4. Prolonged international normalized ratio (INR) >1.5 5. Total bilirubin = 2.0 mg/dl (unless due to Gilbert's syndrome or hemolysis as denoted by normal direct bilirubin fraction) 6. Uncontrolled diabetes (HbA1c = 9.0%) within past 24 weeks 17. Kidney function abnormalities including: a. Dialysis b. Baseline epidermal growth factor receptor < 30 cc/min with chronic kidney disease-Epi equation c. Known nephrotic proteinuria, defined as 3g or greater of protein in 24-hour urine collection 18. Recent (within 48 weeks) or present hepatic decompensation with ascites/hydrothorax, hepatic encephalopathy or variceal bleeding 19. Untreated chronic hepatitis B or C infection 1. Hepatitis C virus eligible for enrollment if hepatitis C virus RNA negative and after sustained virologic response at 24 weeks 2. Hepatitis B virus eligible if Hepatitis B virus DNA <100 IU/mL and on treatment 20. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) = 200 U/L within the past 24 weeks 21. Documented history of intolerance to statins 22. Serious co-morbid medical disease which in the investigator's opinion renders a life-expectancy less than 96 weeks 23. Active illicit substance abuse, including inhaled or injected drugs, in the 48 weeks prior to screening 24. Pregnancy, planned pregnancy or breast-feeding 25. Current participation in active medication treatment trials (within 24 weeks prior to randomization) or planned participation in active medication treatment trials simultaneous to participation in present trial. 26. Significant existing muscle pain or tenderness as determined by a site physician. 27. Failure or inability to provide informed consent.

Study Design


Intervention

Drug:
Rosuvastatin
Patients meeting all eligibility criteria will be assigned to a randomization arm prior to initiation of a 4-week lead-in phase of the study. All participants will undergo a 4-week, open-label active run-in phase to evaluate initial safety and adherence to rosuvastatin. During this active run-phase, all participants will receive target dose rosuvastatin-- 20 mg daily (10 mg daily for participants of East-Asian ancestry). After the active run-in phase, all participants will continue with their pre-assigned randomization (1:1) treatment of rosuvastatin 20 mg daily (10 mg daily for participants of East-Asian ancestry) or matching placebo.

Locations

Country Name City State
United States University of Michigan Ann Arbor Michigan
United States Cleveland Clinic Cleveland Ohio
United States Duke Liver Center Durham North Carolina
United States University of California San Diego NAFLD Research Center La Jolla California
United States Keck Medical Center of USC Los Angeles California
United States LAC + USC Medical Center Los Angeles California
United States University of Miami Health System Miami Florida
United States Columbia University Iriving School of Medicine New York New York
United States New York Presbyterian/Weill Cornell New York New York
United States Virginia Commonwealth University Richmond Virginia
United States Mayo Clinic Rochester Minnesota
United States UCSF Medical Center San Francisco California
United States UCSF/Zuckerberg San Francisco General Hospital and Trauma Center San Francisco California

Sponsors (15)

Lead Sponsor Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Columbia University, Duke University, LAC+USC Medical Center, Mayo Clinic, National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), The Cleveland Clinic, University of California, San Diego, University of California, San Francisco, University of Miami, University of Michigan, University of Southern California, Virginia Commonwealth University, Weill Medical College of Cornell University

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Mean change in liver stiffness Mean change in liver stiffness as measured in kilopascal with Vibration-Controlled Transient Elastography between study entry and week 96. Range: 2 to 75 kilopascal. Higher stiffness indicates increased disease progression 96 weeks
Secondary Time to disease progression Time to disease progression defined as time to development of decompensation event (ascites, hepatic encephalopathy, variceal bleed) or hepatocellular carcinoma. Analyzed as time-to-event; binary if low counts. 96 weeks
Secondary All-cause mortality All-cause mortality: time-to-event, binary if low counts 96 weeks
Secondary Time to development of ascites Ascites: time-to-event, binary if low counts 96 weeks
Secondary Time to development of overt hepatic encephalopathy Time to development of overt hepatic encephalopathy: time-to-event, binary if low counts 96 weeks
Secondary Time to development of variceal bleed Variceal bleed: time-to-event, binary if low counts 96 weeks
Secondary Time to development of hepatocellular carcinoma Hepatocellular carcinoma: time-to-event, binary if low counts 96 weeks
Secondary Change in Child-Turcotte-Pugh score Ordinal score from 5 to 15; higher score indicates further disease progression 96 weeks
Secondary Change in Model for End Stage Liver Disease - Sodium (MELD-Na) Unitless; Range: 6-40; higher score indicates further disease progression 96 weeks
Secondary Change in spleen stiffness as measured by Vibration-Controlled Transient Elastography (VCTE) Units: kilopascal; Range: 5 to 100 kilopascal; higher stiffness indicates increased disease progression 96 weeks
Secondary Change in liver stiffness via Magnetic Resonance Elastography Units: kilopascal; Range: 0 to 20; higher stiffness indicates increased disease progression 96 weeks
Secondary Change in Enhanced Liver Fibrosis test Unitless; Range: 5 to 11; Higher score is worse 96 weeks
Secondary Change in Fibrosis-4 Unitless; Range: 0 to 10; higher score indicates more stiffness 96 weeks
Secondary Time to new onset diabetes New onset diabetes: time-to-event, binary if low counts 96 weeks
Secondary Time to cardiovascular events Cardiovascular events: time-to-event, binary if low counts 96 weeks
Secondary Change in patient-reported quality of life scores Patient Reported Outcomes Measurement Information System (29-item version) Global Health T-Score: Population centered at 50 points, standard deviation of 10 (higher score signifies "better" health) 96 weeks
Secondary Rate of adverse events Count 96 weeks
Secondary Rate of serious adverse events Count 96 weeks
Secondary Rate of adverse events of special interest Rate of adverse events of special interest (myopathy, drug-induced liver injury, cardiovascular events, cancer other than hepatocellular carcinoma, new onset diabetes as separate outcomes): Count 96 weeks
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