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

• ClinicalTrials.gov Identifier: NCT02649335
• Recruitment Status: Unknown
• First Posted: January 7, 2016
• Last Update Posted: January 7, 2016
• Sponsor: Postgraduate Institute of Medical Education and Research
• Information provided by (Responsible Party): Dr.Virendra Singh, Postgraduate Institute of Medical Education and Research

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Ascites	Drug: Propranolol; Procedure: Endoscopic variceal ligation (EVL)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 190 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: To Study the Effect of Nonselective Beta Blockers in Advanced Stage Liver Disease With Ascites
• Study Start Date: July 2015
• Estimated Primary Completion Date: December 2016
• Estimated Study Completion Date: December 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Propranolol; 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; 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
Active Comparator: Endoscopic variceal ligation (EVL); 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); 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) .

Outcome Measures

Primary Outcome Measures :

1. Survival [ Time Frame: Upto 48 weeks ]
   It is a categorical variable-patient dead/alive

Secondary Outcome Measures :

1. Acute kidney injury (AKI) [ Time Frame: Upto 48 weeks ]
   Occurence of AKI will be noted in each group during 48 weeks follow up. The event, AKI is defined as Increase in sCr ≥0.3 mg/dl (≥26.5 μmol/L) within 48 hours; or,A percentage increase sCr ≥50% from baseline which is known, or presumed, to have occurred within the prior 7 days during study period. AKI will be treated accordingly.
2. Spontaneous bacterial peritonitis [ Time Frame: 1 year ]
   The diagnosis is based on neutrophil count in ascitic fluid of >250/mm3 as determined by microscopy. Incidence will be noted at each follow up
3. Hepatorenal syndrome( HRS) [ Time Frame: 1 year ]

   HRS is defined as the occurrence of renal failure in a patient with advanced liver disease in the absence of an identifiable cause of renal failure. Criteria for the diagnosis include-

   • Cirrhosis with ascites
   • Serum creatinine >1.5 mg/dl (133 lmol/L)
   • Absence of shock

   • Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 lmol/L) following at least 2 days of diuretic withdrawal (if on diuretics), and volume expansion with albumin at

     1 g/kg/day up to a maximum of 100 g/day

   • No current or recent treatment with nephrotoxic drugs
   • Absence of parenchymal renal disease as defined by proteinuria <0.5 g/day, no microhaematuria (<50 red cells/high powered field), and normal renal ultrasonography.

   Incidence of HRS will be noted at each follow up.

4. Control of ascites [ Time Frame: Upto 48 weeks ]

   Control of ascites will be assesed by clinical examination in each follow up and response to therapy will be defined as follows:

   1. Complete Response - Elimination of ascites
   2. Partial Response- Presence of ascites not requiring paracentesis.
   3. Absence of response - Persistence of ascites requiring paracentesis

   This parameter will be noted during follow up.

5. Incidence of variceal hemorrhage in each group [ Time Frame: 1 year ]
   Occurence of variceal hemorrhage during follow up period will be noted
6. Incidence of Paracentesis induced circulatory dysfunction (PICD) in different groups during LVP [ Time Frame: Upto 48 weeks ]
   PICD is defined as Increase in plasma renin activity of >50% of the pretreatment value on day 7 after each large volume paracentesis.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion

1. Active infection or recent infection < 2 weeks
2. Hepatic encephalopathy grade 2 or higher
3. Renal dysfunction at the time of inclusion
4. Presence of hepatocellular carcinoma or portal vein thrombosis
5. Active alcoholism
6. Pregnancy
7. HIV infection
8. Severe heart, respiratory or contraindications for beta blockers(severe chronic obstructive pulmonary disease, severe asthma, severe insulin-dependent diabetes mellitus, bradyarrhythmia)
9. Not giving consent

Contacts and Locations

Contacts

Contact: Virendra Singh, MD,DM; 7087006338; virendrasingh100@hotmail.com

Contact: Pramod Kumar, MD; 7087008641; dapramod@gmail.com

Locations

India

Department of Hepatology,Postgraduate Institute of Medical Education and Research; Recruiting

Chandigarh, India

Contact: Virendra Singh 7087006338 virendrasingh100@hotmail.com

Contact: Pramod Kumar 7087008641 dapramod@gmail.com

Sponsors and Collaborators

Postgraduate Institute of Medical Education and Research

Investigators

• Principal Investigator: Virendra Singh, MD,DM; Professor of Hepatology,PGIMER,Chandigarh

More Information

• Responsible Party: Dr.Virendra Singh, Professor of hepatology, Postgraduate Institute of Medical Education and Research
• ClinicalTrials.gov Identifier: NCT02649335
• Other Study ID Numbers: NSBB in cirrhotic ascites
• First Posted: January 7, 2016
• Last Update Posted: January 7, 2016
• Last Verified: January 2016

Keywords provided by Dr.Virendra Singh, Postgraduate Institute of Medical Education and Research:

Non selective beta blockers; Ascites

Additional relevant MeSH terms:

Liver Diseases; Ascites; Digestive System Diseases; Pathologic Processes; Propranolol; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents