To Study the Effect of Nonselective Beta Blockers in Advanced Stage Liver Disease With Ascites

NCT02649335 | Completed Phase 3 DMC

• 1 other identifier: NSBB in cirrhotic ascites
• Study Type: interventional
• Target: 190
• Locations: 1 country
• Sites: 1

Brief Summary

Cirrhosis is the leading cause of death in India and worldwide and leading causes in developed world include alcoholic liver disease, hepatitis C, and more recently, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH). As cirrhosis advances, portal hypertension develops, resulting in complications such as ascites, hepatic encephalopathy, and variceal hemorrhage. Ascites is the most common major complication of cirrhosis, occurring in 50-60% of patients within ten years of diagnosis . Development of ascites is an ominous landmark in disease progression as 15% of patients with ascites will die within 1 year, and 44% within 5 years. Less than 10% patients develop refractory ascites and is associated with a poor prognosis with a high mortality, approximately 50% within 6 months and 75% at 1 year with the median survival approximately 6 months . Refractory ascites occurs as a result of splanchnic vasodilatation and maximal activation of the sympathetic nervous system (SNS) and the renin - aldosterone system (RAAS) . The therapeutic options available for these patients are serial therapeutic paracentesis, liver transplantation and trans jugular intrahepatic portosystemic shunts .The model for end stage liver disease( MELD) score predicts survival in patients with cirrhosis . However, other factors in patients with cirrhosis and ascites are also associated with poor prognosis, including low mean arterial pressure; low serum sodium, low urine sodium, and high Child-Pugh score . Variceal bleed is the most dreaded complication of cirrhosis and screening endoscopic is recommend in these patients. About 60% of patients with decompensated cirrhosis have varices at the time of diagnosis. Majority of these patients will require non selective beta blockers (NSBB) as standard of care as primary or secondary prophylaxis in prevention of variceal hemorrhage. NSBB reduce portal pressure by decreasing cardiac output and by producing splanchnic vasoconstriction.. Endoscopic variceal band ligation (EVL) is another modality of treatment of esophageal varices and meta-analysis showed EVL to be associated with significantly lower incidence of first variceal hemorrhage without differences in mortality compared to NSBB. NSBB also has shown to improve survival in these patients with nonhemodynamic effects. Some of the patients may progress to end stage liver disease characterized by the development of refractory ascites and other complications. Most of the studies of NSBB comparing to EVL for primary/secondary prevention of variceal hemorrhage included patients of predominantly child A/B cirrhosis with variable number with ascites without any mention of ascites grading and some of trials excluded patient's with refractory ascites. These patients with ascites received diuretics and salt restricted diet as standard of care. However none of these studies mentioned about control of ascites and survival benefit in patients with advanced stage (child B and C) cirrhosis with ascites .In recent years the role of NSBB for prevention of variceal hemorrhage in refractory ascites patients has been questioned because of the deleterious effect on survival.However the use of NSBB in end stage liver disease has shown mixed results and controversial. Therefore this study is being planned to know the effects of NSBB in advanced stage liver disease patients with ascites and varices in preventing variceal hemorrhage ,effect on ascites and survival.

Conditions

Ascites

Keywords

Non selective beta blockers; Ascites

Outcome Measures

Primary Outcomes (1)

• Survival

  It is a categorical variable-patient dead/alive

  Upto 48 weeks

Secondary Outcomes (6)

• Acute kidney injury (AKI)

  Upto 48 weeks

• Spontaneous bacterial peritonitis

  1 year

• Hepatorenal syndrome( HRS)

  1 year

• Control of ascites

  Upto 48 weeks

• Incidence of variceal hemorrhage in each group

  1 year

Study Arms (2)

Propranolol

ACTIVE COMPARATOR

Propranolol will be started at a dose of 40 mg and will be titrated based on pulse rate with target of 55-60 beats per minute or 20-25% reduction in heart rate and maximum tolerated dose.If any patients develop intolerable side effects, they will be withdrawn from the study.

Drug: Propranolol

Endoscopic variceal ligation (EVL)

ACTIVE COMPARATOR

Patients in EVL group will undergo regular sessions of UGIE with EVL till variceal eradication every 2- 4 weekly followed by 3 monthly for initial 6 months and 6 monthly in rest of the study period. If any patient develop acute variceal hemorrhage on follow up , will be treated inpatient with standard medical therapy (SMT) .

Procedure: Endoscopic variceal ligation (EVL)

Interventions

Propranolol DRUG

Propranolol will be started at a dose of 40 mg and will be titrated based on pulse rate with target of 55-60 beats per minute or 20-25% reduction in heart rate and maximum tolerated dose.If any patients develop intolerable side effects, they will be withdrawn from the study

Propranolol

Endoscopic variceal ligation (EVL) PROCEDURE

Patients in EVL group will undergo regular sessions of UGIE with EVL till variceal eradication every 2- 4 weekly followed by 3 monthly for initial 6 months and 6 monthly in rest of the study period. If any patient develop acute variceal hemorrhage on follow up , will be treated inpatient with standard medical therapy(SMT) .

Endoscopic variceal ligation (EVL)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cirrhosis of any etiology with grade 2 ascites including refractory patients and varices/variceal hemorrhage requiring prophylaxis
• Cirrhosis diagnosed by clinical, analytical, and ultrasonographic findings or available histological findings
• Both inpatient and outpatient
• Child B or C status

You may not qualify if:

• Active infection or recent infection \< 2 weeks
• Hepatic encephalopathy grade 2 or higher
• Presence of hepatocellular carcinoma or portal vein thrombosis
• Active alcoholism
• Pregnancy
• HIV infection
• Severe heart, respiratory or contraindications for beta blockers(severe chronic obstructive pulmonary disease, severe asthma, severe insulin-dependent diabetes mellitus, bradyarrhythmia)
• Not giving consent

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

Department of Hepatology,Postgraduate Institute of Medical Education and Research

Chandigarh, India

Location

Related Publications (1)

• Singh V, Kumar P, Verma N, Vijayvergiya R, Singh A, Bhalla A. Propranolol vs. band ligation for primary prophylaxis of variceal hemorrhage in cirrhotic patients with ascites: a randomized controlled trial. Hepatol Int. 2022 Aug;16(4):944-953. doi: 10.1007/s12072-022-10361-4. Epub 2022 Jun 7.

  PMID: 35672572 DERIVED

MeSH Terms

Conditions

Ascites

Interventions

Propranolol

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Study Officials

• Virendra Singh, MD,DM

  Professor of Hepatology,PGIMER,Chandigarh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of hepatology

Study Record Dates

• First Submitted: December 5, 2015
• First Posted: January 7, 2016
• Study Start: July 1, 2015
• Primary Completion: December 30, 2016
• Study Completion: December 30, 2016
• Last Updated: May 9, 2023

Record last verified: 2023-05

Locations

IN (1)