Effect of long-term carvedilol to prevent decompensation or death in patients with asymptomatic Child-Pugh A5 to B8 cirrhosis and clinically significant portal hypertension: a multicenter, double-blind, randomized controlled trial.
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 25
- 主要终点
- Primary endpoint will be the occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death.
研究概览
简要总结
To evaluate the effect of low dose carvedilol (<=12.5 mg per day) versus placebo on the occurrence of decompensation of cirrhosis or liverrelated death at 36 months in patients with asymptomatic Child-Pugh class A5 to B8 cirrhosis with TE-LSM ≥ 25 kPa without high-risk varices.
详细描述
Decompensation of cirrhosis is a turning point in cirrhosis course, as associated with a marked decrease in life expectancy. Thus, prevention of decompensation is crucial.
Portal hypertension (PH) is the strongest predictor of decompensation. Hepatic venous pressure gradient (HVPG) is the reference standard for the evaluation of PH. HVPG ≥10 mm Hg, called "clinically significant portal hypertension", identifies a population with a high risk of decompensation. HVPG measurement is an invasive procedure, only routinely available in expert centers. Liver stiffness measurement (LSM) using transient elastography (TE) (referred as TE LSM) using Fibroscan can provide an indirect estimate of HVPG. TE-LSM ≥ 25 kPa can rule-in HVPG ≥10 mm Hg with a specificity >90%.
Nonselective beta-blockers (NSBBs) lower portal pressure by decreasing portal venous inflow. Carvedilol also decreases intrahepatic vascular resistance, and thereby achieves a greater reduction in portal pressure than propranolol. At low-dose (≤12.5 mg/day), carvedilol is safe in patients with compensated cirrhosis.
In patients with asymptomatic cirrhosis, NSBBs were recommended when medium or large varices (high-risk varices) are present for prophylaxis of variceal bleeding. In a recent randomized controlled trial, the PREDESCI study (NCT01059396), NSBBs reduced incidence of decompensation or death in patients with compensated cirrhosis with clinically significant portal hypertension. In the PREDESCI study, the diagnosis of clinically significant portal hypertension was based on invasive HVPG measurement, so that its results are not applicable in clinical practice.
The usefulness of carvedilol to prevent decompensation of cirrhosis in patients with TE-LSM ≥25 kPa as a surrogate marker for clinically significant portal hypertension, has never been evaluated in a randomized controlled trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 主要目的
- Follow-up assessments and visit
- 盲法
- Double (Subject, Analyst, Monitor, Investigator)
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Male or female≥ 18 years of age
- •Cirrhosis related to hepatitis C or hepatitis B virus without viral replication for at least 2 years. Or Cirrhosis related to alcohol consumption (active or abstinent) Or Cirrhosis related to metabolic syndrome or cryptogenic with BMI < 30 kg/m2
- •2 TE-LSM (Fibroscan®) performed in fasting conditions, using either the M or the XL probe >=25 kPa, within 12 months before inclusion
- •Absence of medium or large varices or small varices with red signs at endoscopy within 3 months before inclusion
- •Child-Pugh A5 to B8
- •Affiliation to a French social security system.
- •Written informed consent obtained from the participant or participant’s legal representative
- •For child-bearing aged women, contraception using oral contraceptive, or intrauterine device or mechanical contraception
排除标准
- •History of overt ascites or encephalopathy <12 months before inclusion
- •Known hypersensitivity to carvedilol
- •Concomitant use of Cimétidin
- •Concomitant use of class I antiarythmic agents (except lidocaïn) (i.e.cibenzoline, disopyramide, flécaı̈nide, hydroquinidine méxilétine, propafenone, quinidine)
- •Concomitant use of calcium antagonists: diltiazem, vérapamil and bépridil
- •Concomitant use of clonidine, méthyldopa, guanfacine, moxonidine, rilménidine
- •Concomitant use of fingolimod
- •Concomitant use of potent inhibitors (e.g. ketoconazole, HIV protease inhibitors) or inductors (e.g. rifampin, carbamazepine, phenytoin) of CYP3A4 (see appendix 7)
- •Pregnancy or breastfeeding
- •Non ability for participant to comply with the requirements of the study
- •Life expectancy <12 months
- •Treatment with either diuretics or lactulose or rifaximin <3 months before inclusion
- •Any history of portal hypertension related bleeding
- •Baseline heart rate <65/min or systolic blood pressure <100 mm Hg
- •Previous transjugular intrahepatic portosystemic shunt (TIPSS) or liver transplantation
- •Previous history or active hepatocellular carcinoma
- •Glomerular filtration rate (CKD-Epi) < 30 mL/min
- •Strict indication to selective or nonselective beta-blockers: history of acute myocardial infarction, congestive heart failure
- •Strict contraindication to selective or nonselective beta-blockers: o decompensated congestive heart failure o grade 2 or 3 atrioventricular block o sinus node dysfunction without pacemaker o severe asthma according to WHO classification [63] o severe Chronic Obstructive Pulmonary Disease, defined stage 3 or 4 of the GOLD classification, i.e.FEV1<50% of the predicted value (https://goldcopd.org/) o severe Raynaud disease, defined as repetitive episodes of biphasic colour (at least two) of pallor, cyanosis, erythema, in addition to paresthesia or numbness, occurring in both cold and normal environments [64].
结局指标
主要结局
Primary endpoint will be the occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death.
Primary endpoint will be the occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death.
次要结局
- 1. Safety of carvedilol (<=12.5 mg per day) on: (a) Systemic hemodynamics (heart rate, blood pressure), (b) Cardiac function (c) any other adverse effects and reactions within 36 months after inclusion
- Effect of low dose carvedilol (<=12.5 mg per day), within 36 months after randomization
- 3. To assess treatment compliance: record of unused packaging and information about compliance in a patient notebook
- 4. To identify potential predictors of decompensation in the control group: - Levels of liver and spleen stiffness at baseline and at month 12 - Liver surface nodularity at baseline
- 5. To identify potential predictors of response to carvedilol (in the group receiving carvedilol): - Levels and variation of liver and spleen stiffness at baseline, and week 2 - Heart rate, systolic and mean blood pressure and its variation at baseline and week 2
- 6. Occurrence, within 36 months after inclusion, of either decompensation of cirrhosis or liver-related death according to subgroups (a) main etiology of cirrhosis (alcohol, viral, or metabolic) (b) history of previous decompensation (c) alcohol consumption (d) features of metabolic syndrome
研究者
Coordonateur
Scientific
Centre Hospitalier Regional Universitaire De Tours