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

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT05832229

Collaborator

The Cleveland Clinic (Other), Columbia University (Other), Weill Medical College of Cornell University (Other), Duke University (Other), Mayo Clinic (Other), University of Miami (Other), University of Michigan (Other), University of California, San Diego (Other), University of California, San Francisco (Other), LAC+USC Medical Center (Other), Virginia Commonwealth University (Other), National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH), National Cancer Institute (NCI) (NIH), University of Southern California (Other)

256

Enrollment

Locations

Arms

Anticipated Duration (Months)

19.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Rosuvastatin	Phase 2

Detailed Description

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

256 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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 (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

The drug manufacturer and bottler will be unblinded, as will a few members of the Scientific and Data Coordinating Center. All other study team members will remain blinded.

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Jul 31, 2028

Anticipated Study Completion Date :

Jul 31, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active 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 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. Other Names: Rosuvastatin 20 mg Rosuvastatin 10 mg
Placebo Comparator: Placebo 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 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. Other Names: Rosuvastatin 20 mg Rosuvastatin 10 mg

Arm

Intervention/Treatment

Experimental: Active

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

Other Names:

Rosuvastatin 20 mg

Rosuvastatin 10 mg

Placebo Comparator: Placebo

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

Other Names:

Rosuvastatin 20 mg

Rosuvastatin 10 mg

Outcome Measures

Primary Outcome Measures

Mean change in liver stiffness [96 weeks]
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

Secondary Outcome Measures

Time to disease progression [96 weeks]
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.
All-cause mortality [96 weeks]
All-cause mortality: time-to-event, binary if low counts
Time to development of ascites [96 weeks]
Ascites: time-to-event, binary if low counts
Time to development of overt hepatic encephalopathy [96 weeks]
Time to development of overt hepatic encephalopathy: time-to-event, binary if low counts
Time to development of variceal bleed [96 weeks]
Variceal bleed: time-to-event, binary if low counts
Time to development of hepatocellular carcinoma [96 weeks]
Hepatocellular carcinoma: time-to-event, binary if low counts
Change in Child-Turcotte-Pugh score [96 weeks]
Ordinal score from 5 to 15; higher score indicates further disease progression
Change in Model for End Stage Liver Disease - Sodium (MELD-Na) [96 weeks]
Unitless; Range: 6-40; higher score indicates further disease progression
Change in spleen stiffness as measured by Vibration-Controlled Transient Elastography (VCTE) [96 weeks]
Units: kilopascal; Range: 5 to 100 kilopascal; higher stiffness indicates increased disease progression
Change in liver stiffness via Magnetic Resonance Elastography [96 weeks]
Units: kilopascal; Range: 0 to 20; higher stiffness indicates increased disease progression
Change in Enhanced Liver Fibrosis test [96 weeks]
Unitless; Range: 5 to 11; Higher score is worse
Change in Fibrosis-4 [96 weeks]
Unitless; Range: 0 to 10; higher score indicates more stiffness
Time to new onset diabetes [96 weeks]
New onset diabetes: time-to-event, binary if low counts
Time to cardiovascular events [96 weeks]
Cardiovascular events: time-to-event, binary if low counts
Change in patient-reported quality of life scores [96 weeks]
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)
Rate of adverse events [96 weeks]
Count
Rate of serious adverse events [96 weeks]
Count
Rate of adverse events of special interest [96 weeks]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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
Myocardial infarction, Unstable angina, transient ischemic events, or stroke within 24 weeks of screening.
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.
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:

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
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:

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
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.

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.
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:

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.
Significant existing muscle pain or tenderness as determined by a site physician.
Failure or inability to provide informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego NAFLD Research Center	La Jolla	California	United States	92035
2	Keck Medical Center of USC	Los Angeles	California	United States	90033
3	LAC + USC Medical Center	Los Angeles	California	United States	90033
4	UCSF/Zuckerberg San Francisco General Hospital and Trauma Center	San Francisco	California	United States	94110
5	UCSF Medical Center	San Francisco	California	United States	94143
6	University of Miami Health System	Miami	Florida	United States	33122
7	University of Michigan	Ann Arbor	Michigan	United States	48109
8	Mayo Clinic	Rochester	Minnesota	United States	55901
9	New York Presbyterian/Weill Cornell	New York	New York	United States	10021
10	Columbia University Iriving School of Medicine	New York	New York	United States	10031
11	Duke Liver Center	Durham	North Carolina	United States	27710
12	Cleveland Clinic	Cleveland	Ohio	United States	44192
13	Virginia Commonwealth University	Richmond	Virginia	United States	23298