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

NCT ID: NCT06041932

Last Updated: 2023-10-03

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 180 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-11-01
• Study Completion Date: 2024-08-31

Brief Summary

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

• 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

Conditions

Liver Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Pentoxiphylline plus Carvedilol

Pentoxiphylline plus Carvedilol

Group Type: EXPERIMENTAL

Carvedilol

Intervention Type: DRUG

Carvedilol

Pentoxifylline

Intervention Type: DRUG

Pentoxiphylline

Carvedilol

PCarvedilol

Group Type: ACTIVE_COMPARATOR

Carvedilol

Intervention Type: DRUG

Carvedilol

Interventions

Carvedilol

Carvedilol

Intervention Type: DRUG

Pentoxifylline

Pentoxiphylline

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age 18-70 years

2. Cirrhosis with prior clinical decompensation (ascites, Hepatic encephalopathy, Portal Hypertension related bleed)

3. No current clinical decompensation (for at least 3 months)

Exclusion Criteria

1. Post TIPS/ BRTO/ SAE patients

2. Post renal or liver transplantation

3. History of CAD, ischemic cardiomyopathy, PVD, ventricular arrythmia

4. Presence of clinical ascites, HE, Jaundice

5. Last clinical decompensation within 3 months.

6. Ongoing significant alcohol use

7. Active HCV/HBV infection (Detectable HCV RNA/ HBV DNA)

8. Prior Intolerance to carvedilol and hypersensitivity to Pentoxyfylline

9. Use of Pentoxifylline within last 1 month

10. AIH/PBC

11. Lack of informed consent

12. Hepatocellular carcinoma / Portal vein thrombosis/ Budd Chiari Syndrome

13. Non-cirrhotic portal hypertension

14. Ongoing CAM/Hepatotoxic drug intake

15. Known HIV infection

16. Pregnant women

17. HepatoPulmonary Syndrome

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institute of Liver and Biliary Sciences, India

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Institute of Liver & Biliary Sciences.

New Delhi, National Capital Territory of Delhi, India

Countries

India

Central Contacts

Dr Jaifrin Daniel, MD

Role: CONTACT

jdaniel.m07@gmail.com

01146300000

Facility Contacts

Dr Jaifrin Daniel, MD

Role: primary

jdaniel.m07@gmail.com

+91-011-46300000

Other Identifiers

ILBS-Cirrhosis-62

Identifier Type: -

Identifier Source: org_study_id