Liver Cirrhosis Network (LCN) Rosuvastatin Efficacy and Safety for Cirrhosis in the United States (RESCU): A Double-Blind Randomized, Placebo-Controlled Phase 2 Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 256
- 试验地点
- 13
- 主要终点
- Mean change in liver stiffness
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
- •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 ≥15 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 ≥ 15 kilopascal.
- •The two measures must be at least 2 hours apart and no more than 60 days apart from one another.
- •The mean of two measurements must be ≥ 15 kilopascal.
- •Additionally, both screening and open-label dispense liver stiffness measures must be ≤50 kPa
- •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.
排除标准
- •Currently on a statin or any statin exposure within 24 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) total score of ≥8 at screening.
- •Patients with limitations in attending study visits.
- •Known prior or current hepatocellular carcinoma (HCC) or cholangiocarcinoma.
- •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:
- •methotrexate
- •Current (in past 24 weeks prior to consenting) use of medications which may increase risk for rosuvastatin-related myositis or DILI, defined as:
- •fenofibrate
- •erythromycin
- •gemfibrozil
- •niacin (500 mg or more)
- •HIV protease inhibitors (darunivar, indinavir, nelfinavir, amprenavir) in patients of East Asian descent
- •cyclosporin
- •Additional medications that will be excluded:
- •atazanavir/ritonavir capmatinib darolutamide dasabuvir/ombitasvir/paritaprevir/ritonavir ledipasvir/sofosbuvir elbasvir/grazoprevir erythromycin glecaprevir/pibrentasvir lopinavir/ritonavir regorafenib ritonavir, in any combination simeprevir sofbuvir/velpatasvir/voxilaprevir sofosbuvir/velpatasvir tafamidis teriflunomide
- •*If exposure was for 7 or less days for one of these medications can consider enrollment after 28 days from final dose.
- •Presence of portal or hepatic vein thrombosis
- •Diagnosis of untreated hypothyroidism or on unstable treatment regimen for hypothyroidism
- •Receiving an elemental diet or parenteral nutrition
- •Chronic pancreatitis or pancreatic insufficiency
- •Etiology of cirrhosis other than ALD, NAFLD, or viral hepatitis (excluded diagnoses include cryptogenic immune-mediated such as AIH, PSC and PBC, cardiac cirrhosis or Fontan-associated liver disease, A1AT, Wilson's disease, etc.)
- •Conditions which may confound study outcome:
- •Unstable or active inflammatory bowel disease
- •Active infection
- •Any malignant disease (other than squamous or basal cell carcinoma of the skin) within previous 3 years
- •Prior solid organ or hematopoietic cell transplant
- •Bariatric surgery in the last 24 weeks prior to consent or planned bariatric surgery within the next 96 weeks
- •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:
- •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)
- •Direct bilirubin ≥ 0.9
- •Uncontrolled diabetes (HbA1c ≥ 9.5%) within past 90 days.
- •Kidney function abnormalities including:
- •Baseline eGFR < 30 cc/min with CKD-Epi equation
- •Known nephrotic proteinuria, defined as 3g or greater of protein in 24-hour urine collection
- •Recent (within 48 weeks) or present hepatic decompensation with ascites/hydrothorax, hepatic encephalopathy or variceal bleeding
- •Untreated chronic hepatitis B or C infection
- •HCV eligible for enrollment if HCV RNA negative at baseline or documentation of prior SVR12
- •HBV eligible if an HBV DNA <100 IU/mL within the last 48 weeks and on treatment
- •Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 200 U/L, or alkaline phosphatase (ALP) ≥ 300 within the past 24 weeks.
- 另有 7 项未显示
研究组 & 干预措施
Active
Open-label lead-in period of 4 weeks on 20 mg (10 mg for participants of East ancestry or on a protease inhibitor) 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 or on a protease inhibitor).
干预措施: Rosuvastatin (Drug)
Placebo
Open-label lead-in period of 4 weeks on 20 mg (10 mg for participants of East ancestry or on a protease inhibitor) rosuvastatin by mouth once daily, followed by a period of 96 weeks placebo.
干预措施: Rosuvastatin (Drug)
结局指标
主要结局
Mean change in liver stiffness
时间窗: 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
次要结局
- Time to disease progression(96 weeks)
- All-cause mortality(96 weeks)
- Time to development of ascites(96 weeks)
- Time to development of overt hepatic encephalopathy(96 weeks)
- Time to development of variceal bleed(96 weeks)
- Time to development of hepatocellular carcinoma(96 weeks)
- Change in spleen stiffness as measured by Vibration-Controlled Transient Elastography (VCTE)(96 weeks)
- Change in Child-Turcotte-Pugh score(96 weeks)
- Change in Model for End Stage Liver Disease - Sodium (MELD-Na)(96 weeks)
- Change in liver stiffness via Magnetic Resonance Elastography(96 weeks)
- Change in Enhanced Liver Fibrosis test(96 weeks)
- Change in Fibrosis-4(96 weeks)
- Change in patient-reported quality of life scores(96 weeks)
- Rate of adverse events(96 weeks)
- Rate of serious adverse events(96 weeks)
- Rate of adverse events of special interest(96 weeks)
- Time to cardiovascular events(96 weeks)
- Time to new onset diabetes(96 weeks)