Liver Cirrhosis Network Rosuvastatin Efficacy and Safety for Cirrhosis in the United States

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Liver Cirrhosis Network (LCN) Rosuvastatin Efficacy and Safety for Cirrhosis in the United States (RESCU): A Double-Blind Randomized, Placebo-Controlled Phase 2 Study

Conditions
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Cirrhosis, Cirrhosis, Liver, Cirrhosis Early, Cirrhosis Due to Hepatitis B, Cirrhosis Advanced, Cirrhosis Infectious, Cirrhosis Alcoholic, Cirrhosis, Biliary, Cirrhosis Cryptogenic, Cirrhosis Due to Hepatitis C, Cirrhosis Due to Primary Sclerosing Cholangitis

Intervention / Treatment
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* Drug: Rosuvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years Cirrhosis due to nonalcoholic steatohepatitis, alcohol-associated liver disease, or chronic viral hepatitis (treated hepatitis B virus or hepatitis C virus), or cryptogenic cirrhosis Clinical diagnosis of cirrhosis as defined investigator confirmation and the following: At least one liver biopsy within 5 years prior to consent showing either: Metavir stage 4 fibrosis; Ishak Stage 5-6 fibrosis, OR 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 Two measures of vibration-controlled transient elastography: one at screening and one at the randomization study visit, meeting the following criteria: The first measure must be ≥ 12.5 kilopascal. The two measures must be at least 1 day apart and no more than 60 days apart from one another. The mean of two measurements must be ≥ 12.5 kilopascal. Compensated defined by: Absence of ascites/hydrothorax, hepatic encephalopathy or variceal bleeding currently or in the last 48 weeks, as determined clinically by investigator. 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. Child-Pugh score <8 Provision of written informed consent. Exclusion Criteria: Currently on a statin or any statin exposure within 48 weeks prior to consent. Known indication for statin therapy, defined as: Prior peripheral vascular, cardiovascular or cerebrovascular event for which statins are indicated for secondary prevention, OR Documented familial hypercholesterolemia, heterozygous familial hypercholesterolemia, OR 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: amiodarone methotrexate 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: Absolute neutrophil count <1.0 x 109 / L Hemoglobin <10 g/dL Albumin <3.0 g/dL Prolonged international normalized ratio (INR) >1.5 Total bilirubin ≥ 2.0 mg/dl (unless due to Gilbert's syndrome or hemolysis as denoted by normal direct bilirubin fraction) 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 Hepatitis C virus eligible for enrollment if hepatitis C virus RNA negative and after sustained virologic response at 24 weeks 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>Open-label lead-in period of 4 weeks on 20 mg (10 mg for participants of East ancestry) rosuvastatin by mouth once daily, followed by a period of 96 weeks rosuvastatin 20 mg daily (10 mg daily for participants of East-Asian ancestry). | Drug: Rosuvastatin<br>* 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.<br>* Other names: Rosuvastatin 10 mg;|
| Placebo Comparator: Placebo<br>Open-label lead-in period of 4 weeks on 20 mg (10 mg for participants of East ancestry) rosuvastatin by mouth once daily, followed by a period of 96 weeks placebo. | Drug: Rosuvastatin<br>* 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.<br>* Other names: Rosuvastatin 10 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| All-cause mortality | All-cause mortality: time-to-event, binary if low counts | 96 weeks | 
| Time to development of ascites | Ascites: time-to-event, binary if low counts | 96 weeks | 
| Time to development of overt hepatic encephalopathy | Time to development of overt hepatic encephalopathy: time-to-event, binary if low counts | 96 weeks | 
| Time to development of variceal bleed | Variceal bleed: time-to-event, binary if low counts | 96 weeks | 
| Time to development of hepatocellular carcinoma | Hepatocellular carcinoma: time-to-event, binary if low counts | 96 weeks | 
| Change in Child-Turcotte-Pugh score | Ordinal score from 5 to 15; higher score indicates further disease progression | 96 weeks | 
| Change in Model for End Stage Liver Disease - Sodium (MELD-Na) | Unitless; Range: 6-40; higher score indicates further disease progression | 96 weeks | 
| 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 | 
| Change in liver stiffness via Magnetic Resonance Elastography | Units: kilopascal; Range: 0 to 20; higher stiffness indicates increased disease progression | 96 weeks | 
| Change in Enhanced Liver Fibrosis test | Unitless; Range: 5 to 11; Higher score is worse | 96 weeks | 
| Change in Fibrosis-4 | Unitless; Range: 0 to 10; higher score indicates more stiffness | 96 weeks | 
| Time to new onset diabetes | New onset diabetes: time-to-event, binary if low counts | 96 weeks | 
| Time to cardiovascular events | Cardiovascular events: time-to-event, binary if low counts | 96 weeks | 
| 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 | 
| Rate of adverse events | Count | 96 weeks | 
| Rate of serious adverse events | Count | 96 weeks | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cirrhosis, Liver, Nonalcoholic Fatty Liver Disease, NASH, Nonalcoholic steatohepatitis