Pentoxifylline Plus Carvedilol vs Carvedilol Monotherapy in Preventing New Decompensation in Stable Cirrhotic Patients With Prior Decompensation

Study Overview
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Brief Summary
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Cirrhotics with decompensation have increased risk of morbidity and mortality. There is increased portal pressure leading to decompensation. Carvedilol is a standard therapy given to cirrhotic patient with clinically significant portal hypertension to reduce portal pressure. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with anti-inflammatory properties. It reduces portal hypertension, decreases lipopolysaccharide-induced liver injury, improves nonalcoholic steatohepatitis, prevents development of HRS in ascites and SAH, prevents hepatopulmonary syndrome. Investigator want to study whether addition of pentoxifylline to carvediolol vs carvedilol monotherapy reduces the risk of mortality and further decompensation in cirrhotics with prior decompensation.

Detailed Description
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Study population: Cirrhotic patients with prior decompensation at least 3 months ago Study design: A Open label randomized controlled trial Sample size Assuming decompensation in Arm 1 as 25%, and 10% in Arm 2, alpha error- 5, power - 80, 160 patients, 10 % lost to follow up - 180, Each arm 90 patients. Intervention Arm 1 : Carvedilol Arm 2 : Pentoxiphylline plus Carvedilol Monitoring and assessment At enrollment: - Complete history and physical examination Prior ascites, Hepatic encephalopathy, acute variceal bleed. Time to prior decompensation Pattern and number of prior decompensation Prior spontaneous bacterial peritonitis, hydrothorax, Acute on chronic liver failure, acute kidney injury Use of Non selective beta blockers, norfloxaxin, rifaximin and albumin Recent herbal/drugs intake History of EVL or other endotherapy History of hypertension, diabetes mellitus Fever , signs of sepsis Examination- Sarcopenia, fraility, icterus, pedal edema At follow-up (at 3 month, 6 month, 9 month, 12 month): Physical (preferably) • Complete history and physical examination New onset ascites, Hepatic encephalopathy, acute variceal bleed, clinical Jaundice Time to new decompensation from enrollment Pattern and number of new decompensation Other complications - Spontaneous bacterial peritonitis, hydrothorax, Acute on chronic liver failure, acute kidney injury. Recent herbal/drugs intake History of EVL or other endotherapy Hypertension, Diabetes control Fever , signs of sepsis Examination- Sarcopenia, fraility, icterus, pedal edema, ascites, Hepatic encephalopathy Clinical evaluation Etiology of chronic liver disease (Baseline) Control of etiological factor (Baseline, 3 monthly) Alcohol - No relapse, if relapse - severity HBV - on antivirals, HBV DNA -ve HCV - HCV RNA -ve Metabolic risk factors control- DM, HT, weight etc. Severity of liver disease (Baseline, 3 monthly) MELD score, MELD-Na score, CTP score Complications (at 3 month, 6 month, 9 month, 12 month): Overt Hepatic Encephalopathy, Portal hypertension related bleed, clinical jaundice, ascites, hyponatremia, Acute kidney injury, spontaneous bacterial peritonitis, Infections Laboratory parametres Baseline (at enrollment) - Blood : KFT, LFT, CBC, INR, AFP, TNF-a, IL-6, CRP, VWF, ADAM TS 13 Imaging : USG abdomen, LSM, SSM, ECHO Hemodynamics : HVPG (not mandatory) At 3 and 6 month - Blood : KFT, LFT, CBC, INR Imaging : USG abdomen, LSM, SSM At 1 year (end of follow-up) Blood : KFT, LFT, CBC, INR, AFP, TNF-a, IL-6, CRP, VWF, ADAM TS 13 Imaging : USG abdomen, LSM, SSM Hemodynamics : HVPG ( not mandatory) - STATISTICAL ANALYSIS: Data will be reported as mean + SD. Categorical variables will be compared using the chi-square test or Fisher exact test Normal continuous variables will be compared using the Student's t test Non normal continuous variables will be compared using the Mann-Whitney rank-sum test (unpaired data) or the Wilcoxon test (paired data). The actuarial probability of survival will be calculated by the Kaplan-Meier method and compared using the log-rank test. A Cox regression analysis will be performed to identify independent prognostic factors for survival. Univariate and multivariate analysis will be used whenever applicable. - Adverse effects Carvedilol - Bradycardia, hypotension, giddiness, diarrhea, insomnia, hyperglycemia, weight gain, increased BUN, increased nonprotein nitrogen (NPN), increased cough, abnormal vision. Pentoxiphylline - Abdominal discomfort, bloating, diarrhea, Dizziness, headache, flushing, chest pain, arrhythmias, hypertension, dyspnea, tachycardia, and hypotension. - Stopping rule If primary end point achieved or any adverse event due to drug

Official Title
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Pentoxifylline Plus Carvedilol vs Carvedilol Monotherapy in Preventing New Decompensation in Stable Cirrhotic Patients With Prior Decompensation, an Open Label Randomised Control Trial

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Drug: Carvedilol
* Drug: Pentoxifylline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 years Cirrhosis with prior clinical decompensation (ascites, Hepatic encephalopathy, Portal Hypertension related bleed) No current clinical decompensation (for at least 3 months) Exclusion Criteria: Post TIPS/ BRTO/ SAE patients Post renal or liver transplantation History of CAD, ischemic cardiomyopathy, PVD, ventricular arrythmia Presence of clinical ascites, HE, Jaundice Last clinical decompensation within 3 months. Ongoing significant alcohol use Active HCV/HBV infection (Detectable HCV RNA/ HBV DNA) Prior Intolerance to carvedilol and hypersensitivity to Pentoxyfylline Use of Pentoxifylline within last 1 month AIH/PBC Lack of informed consent Hepatocellular carcinoma / Portal vein thrombosis/ Budd Chiari Syndrome Non-cirrhotic portal hypertension Ongoing CAM/Hepatotoxic drug intake Known HIV infection Pregnant women HepatoPulmonary Syndrome

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentoxiphylline plus Carvedilol<br>Pentoxiphylline plus Carvedilol | Drug: Carvedilol<br>* Carvedilol<br>Drug: Pentoxifylline<br>* Pentoxiphylline<br>|
| Active Comparator: Carvedilol<br>PCarvedilol | Drug: Carvedilol<br>* Carvedilol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of New onset clinical decompensation (any of overt HE, variceal bleed, clinical jaundice and ascites) at 1 year in two groups. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Precipitants, timing of new-onset decompensation at 6 months in two groups. |  | 6 months | 
| Mortality at 6 months |  | 6 months | 
| Precipitants, timing of new-onset decompensation at 12 months in two groups |  | 12 months | 
| Mortality at 12 months in two groups. |  | 12 months | 
| Changes in Liver stiffness measured by Fibroscan at 6 months |  | 6 months | 
| Changes in Liver stiffness measured by Fibroscan at 12 months |  | 12 months | 
| Change in ESR at 6 months in both groups |  | 6 months | 
| Change in CRP at 6 months in both groups |  | 6 months | 
| Change in IL 6 at 6 months in both groups |  | 6 months | 
| Change in TNF Alpha at 6 months in both groups |  | 6 months | 
| Change in Von Willebrand factor at 6 months in both groups |  | 6 months | 
| Change in ADAM TS 13 at 6 months in both groups |  | 6 months | 
| Change in ESR at 12 months in both groups. |  | 12 months | 
| Change in CRP at 12 months in both groups |  | 12 months | 
| Change in IL 6 at 12 months in both groups |  | 12 months | 
| Change in TNF Alpha at 12 months in both groups |  | 12 months | 
| Change in Von Willebrand factor at 12 months in both groups |  | 12 months | 
| Change in ADAM TS 13 at 12 months in both groups |  | 12 months | 
| Dose of Pentoxifylline and Carvedilol at 6 months. |  | 6 months | 
| Dose of Pentoxifylline and Carvedilol at 12 months |  | 12 months | 
| Number of patients with change in CTP in both groups. |  | 3 month, 6 month, 9 month and at end of 1 year | 
| Number of patients with change in MELD score in both groups. | MELD minimum value=6 and maximum value=40 | 3 month, 6 month, 9 month and at end of 1 year | 
| Incidence of Hepatocellular carcinoma at 6 months between two groups. |  | 6 months | 
| Incidence of Hepatocellular carcinoma at 12 months between two groups. |  | 12 months | 
| Incidence of Portal vein thrombosis at 6 months between two groups. |  | 6 months | 
| Incidence of Portal vein thrombosis at 12 months between two groups. |  | 12 months | 
| Number of patients with adverse events in both the groups. |  | 6 months and 12 months |