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

• ClinicalTrials.gov Identifier: NCT06041932
• Recruitment Status: Not yet recruiting
• First Posted: September 18, 2023
• Last Update Posted: October 3, 2023
• Sponsor: Institute of Liver and Biliary Sciences, India
• Information provided by (Responsible Party): Institute of Liver and Biliary Sciences, India

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Liver Cirrhosis	Drug: Carvedilol; Drug: Pentoxifylline	Not Applicable

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pentoxifylline Plus Carvedilol vs Carvedilol Monotherapy in Preventing New Decompensation in Stable Cirrhotic Patients With Prior Decompensation, an Open Label Randomised Control Trial
• Estimated Study Start Date: November 1, 2023
• Estimated Primary Completion Date: August 31, 2024
• Estimated Study Completion Date: August 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pentoxiphylline plus Carvedilol; Pentoxiphylline plus Carvedilol	Drug: Carvedilol; Carvedilol; Drug: Pentoxifylline; Pentoxiphylline
Active Comparator: Carvedilol; PCarvedilol	Drug: Carvedilol; Carvedilol

Outcome Measures

Primary Outcome Measures :

1. Incidence of New onset clinical decompensation (any of overt HE, variceal bleed, clinical jaundice and ascites) at 1 year in two groups. [ Time Frame: 1 year ]

Secondary Outcome Measures :

1. Precipitants, timing of new-onset decompensation at 6 months in two groups. [ Time Frame: 6 months ]
2. Mortality at 6 months [ Time Frame: 6 months ]
3. Precipitants, timing of new-onset decompensation at 12 months in two groups [ Time Frame: 12 months ]
4. Mortality at 12 months in two groups. [ Time Frame: 12 months ]
5. Changes in Liver stiffness measured by Fibroscan at 6 months [ Time Frame: 6 months ]
6. Changes in Liver stiffness measured by Fibroscan at 12 months [ Time Frame: 12 months ]
7. Change in ESR at 6 months in both groups [ Time Frame: 6 months ]
8. Change in CRP at 6 months in both groups [ Time Frame: 6 months ]
9. Change in IL 6 at 6 months in both groups [ Time Frame: 6 months ]
10. Change in TNF Alpha at 6 months in both groups [ Time Frame: 6 months ]
11. Change in Von Willebrand factor at 6 months in both groups [ Time Frame: 6 months ]
12. Change in ADAM TS 13 at 6 months in both groups [ Time Frame: 6 months ]
13. Change in ESR at 12 months in both groups. [ Time Frame: 12 months ]
14. Change in CRP at 12 months in both groups [ Time Frame: 12 months ]
15. Change in IL 6 at 12 months in both groups [ Time Frame: 12 months ]
16. Change in TNF Alpha at 12 months in both groups [ Time Frame: 12 months ]
17. Change in Von Willebrand factor at 12 months in both groups [ Time Frame: 12 months ]
18. Change in ADAM TS 13 at 12 months in both groups [ Time Frame: 12 months ]
19. Dose of Pentoxifylline and Carvedilol at 6 months. [ Time Frame: 6 months ]
20. Dose of Pentoxifylline and Carvedilol at 12 months [ Time Frame: 12 months ]
21. Number of patients with change in CTP in both groups. [ Time Frame: 3 month, 6 month, 9 month and at end of 1 year ]
22. Number of patients with change in MELD score in both groups. [ Time Frame: 3 month, 6 month, 9 month and at end of 1 year ]
    MELD minimum value=6 and maximum value=40
23. Incidence of Hepatocellular carcinoma at 6 months between two groups. [ Time Frame: 6 months ]
24. Incidence of Hepatocellular carcinoma at 12 months between two groups. [ Time Frame: 12 months ]
25. Incidence of Portal vein thrombosis at 6 months between two groups. [ Time Frame: 6 months ]
26. Incidence of Portal vein thrombosis at 12 months between two groups. [ Time Frame: 12 months ]
27. Number of patients with adverse events in both the groups. [ Time Frame: 6 months and 12 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Dr Jaifrin Daniel, MD; 01146300000; jdaniel.m07@gmail.com

Locations

India

Institute of Liver & Biliary Sciences.

New Delhi, Delhi, India, 110070

Contact: Dr Jaifrin Daniel, MD +91-011-46300000 jdaniel.m07@gmail.com

Sponsors and Collaborators

Institute of Liver and Biliary Sciences, India

More Information

• Responsible Party: Institute of Liver and Biliary Sciences, India
• ClinicalTrials.gov Identifier: NCT06041932
• Other Study ID Numbers: ILBS-Cirrhosis-62
• First Posted: September 18, 2023
• Last Update Posted: October 3, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Cirrhosis; Fibrosis; Pathologic Processes; Liver Diseases; Digestive System Diseases; Carvedilol; Pentoxifylline; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Antihypertensive Agents; Antioxidants; Protective Agents; Calcium Channel Blockers; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Vasodilator Agents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Radiation-Protective Agents; Free Radical Scavengers