Clinical trial NCT06041932: Pentoxifylline Plus Carvedilol vs Carvedilol Monotherapy in Preventing New Decompensation in Stable Cirrhotic Patients With Prior Decompensation
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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Liver Cirrhosis
Lead sponsor: Institute of Liver and Biliary Sciences, India
Sponsor class: OTHER
First posted: 2023-09-18
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Incidence of New onset clinical decompensation (any of overt HE, variceal bleed, clinical jaundice and ascites) at 1 year in two groups.
timeFrame: 1 year
Secondary outcomes:
measure: Precipitants, timing of new-onset decompensation at 6 months in two groups.
timeFrame: 6 months
measure: Mortality at 6 months
timeFrame: 6 months
measure: Precipitants, timing of new-onset decompensation at 12 months in two groups
timeFrame: 12 months
measure: Mortality at 12 months in two groups.
timeFrame: 12 months
measure: Changes in Liver stiffness measured by Fibroscan at 6 months
timeFrame: 6 months
measure: Changes in Liver stiffness measured by Fibroscan at 12 months
timeFrame: 12 months
measure: Change in ESR at 6 months in both groups
timeFrame: 6 months
measure: Change in CRP at 6 months in both groups
timeFrame: 6 months
measure: Change in IL 6 at 6 months in both groups
timeFrame: 6 months
measure: Change in TNF Alpha at 6 months in both groups
timeFrame: 6 months
measure: Change in Von Willebrand factor at 6 months in both groups
timeFrame: 6 months
measure: Change in ADAM TS 13 at 6 months in both groups
timeFrame: 6 months
measure: Change in ESR at 12 months in both groups.
timeFrame: 12 months
measure: Change in CRP at 12 months in both groups
timeFrame: 12 months
measure: Change in IL 6 at 12 months in both groups
timeFrame: 12 months
measure: Change in TNF Alpha at 12 months in both groups
timeFrame: 12 months
measure: Change in Von Willebrand factor at 12 months in both groups
timeFrame: 12 months
measure: Change in ADAM TS 13 at 12 months in both groups
timeFrame: 12 months
measure: Dose of Pentoxifylline and Carvedilol at 6 months.
timeFrame: 6 months
measure: Dose of Pentoxifylline and Carvedilol at 12 months
timeFrame: 12 months
measure: Number of patients with change in CTP in both groups.
timeFrame: 3 month, 6 month, 9 month and at end of 1 year
measure: Number of patients with change in MELD score in both groups.
timeFrame: 3 month, 6 month, 9 month and at end of 1 year
measure: Incidence of Hepatocellular carcinoma at 6 months between two groups.
timeFrame: 6 months
measure: Incidence of Hepatocellular carcinoma at 12 months between two groups.
timeFrame: 12 months
measure: Incidence of Portal vein thrombosis at 6 months between two groups.
timeFrame: 6 months
measure: Incidence of Portal vein thrombosis at 12 months between two groups.
timeFrame: 12 months
measure: Number of patients with adverse events in both the groups.
timeFrame: 6 months and 12 months
Other outcomes:
Locations:
city: New Delhi
country: India
facility: Institute of Liver & Biliary Sciences.
state: Delhi
Study officials:
References: