Efficacy and Safety of Carvedilol in Cirrhosis Patients With Uncomplicated Ascites Without High Risk Esophageal Varices

Liver Cirrhosis Clinical Trial

Official title:

Efficacy and Safety of Carvedilol in Cirrhosis Patients With Uncomplicated Ascites Without High Risk Esophageal Varices- A Randomised Controlled Trial"

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05057572
• Other study ID #: ILBS-Cirrhosis-44
• Status: Recruiting
• Phase: N/A
• Start date: October 1, 2021
• Est. completion date: August 30, 2023

Study information

• Verified date: August 2021
• Source: Institute of Liver and Biliary Sciences, India
• Contact: Dr Rahul khauria, MD
• Phone: 01146300000
• Email: dr.rahulkhajuria[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The cumulative risk of refractory ascites is in the order of 20% within five years of the development of ascites. An elevated sinusoidal pressure is essential for the development of ascites, as fluid accumulation does not develop at portal pressure gradient below 8 mm Hg, and rising corrected sinusoidal pressure correlates with decreased 24-hour urinary excretion of sodium.More recently, it has been hypothesised that bacterial translocation associated with portal hypertension in cirrhosis and related pathogen-associated, molecular pattern activated innate immune responses lead to systemic inflammation.This is associated with vasodilatation as well as release of proinflammatory cytokines, reactive oxygen and nitrogen species, contributing to organ dysfunction.This activates sympathetic nervous system stimulating reabsorption of sodium in proximal,distal tubules, loop of Henle and collecting duct as well as the renin-angiotensin-aldosterone system, leading to sodium absorption from distal tubule and collecting duct.[5]Renal sodium retention and eventual free water clearance due to non-osmoticrelease of arginine-vasopressin and its action on V2 receptor in the collectingduct underlie the fluid retention associated with oedema and ascites in cirrhosis.The lowering of portal pressure using non selective beta blocker has also been shown to reduce the development of ascites, refractory ascites and hepatorenal syndrome.Furthermore, the effect of non slective beta blocker on intestinal permeability, bacterial translocation and inflammatory response has been proposed to mitigate the risk of developing spontaneous bacterial peritonitis.

Description:

AIM-To compare the safety and efficacy of addition of carvedilol to SMT (diuretics +/- albumin) compared to SMT alone in the prevention of complicated ascites (refractory ascites, AKI-HRS, SBP or severe hyponatremia) at 1year.

Methodology:

Study population: Patient of liver cirrhosis presenting with uncomplicated ascites and without high risk esophageal varices.

Study design:

• A prospective, randomized, single center open label study.

• The study will be conducted on the consecutive patients presenting with uncomplicated ascites and low risk esophageal varices seen at the outpatient clinics/wards of Department of Hepatology, ILBS, New Delhi from July 2021 to June 2023.

Study period: 2years from the date of ethics approval

Sample size with justification:

• Assuming that the complication rate in carvedilol group is 8% and placebo 30% so the complication free rate of 92% and 70 % further assuming alpha -5%, power 80%.

• Investigator need to enrol 108 cases in two groups further with 10% drop out rate it was decided to enroll 120 cases

• Randomisation into two groups by block randomisation method,taking block size 8

Intervention:

• Patients will be randomized into two Arms A & B.

• Arm A will receive carvedilol plus standard medical therpy,Carvedilol: will be started with initial dose of 3.125 mg BD then After 3 days, increase the dose to 6.25 mg BD, Maximum dose would be 12.5 mg BD, the same shall be switch to Maximum tollrated dose if SBP >90, HR >55.

• Arm B will receive standard medical therapy.SMT (as described) that is

• Grade II ascites - Lasilactone (20/50) OD then Change after 1 week as per response, monitor diuretic intolerance.

• Grade III ascites will undergo large volume paracentesis, lasilactone (20/50) OD Both groups will receive albumin as indicated (LT references as per protocol will be send for eligible patients)

• For Diuretic intolerance -Na, K, urea, creatnine will be monitred first weekly then once monthly then SOS as per need

• For Carvedilol heart rate will be monitored first weekly then monthly then SOS as per need

• Dose of carvedilol will be adjusted as per protocol.

• Other treatments given: Alumbin infusion to both group, lasilactone.

• Complications / Organ failures (3m, 6m, 1y or detected during tele/online consult or on opd basis

• Data to be collected

• Baseline -

• Blood : KFT, LFT, CBC, INR, IL-6, CRP,TNF Alpha

• Imaging : USG upper abdomen and doppler for renal blood flow,

• 2D ECHO

• Urine : Urine R/E, Urine Na,AFP

• A/F analysis - for SBP

• HVPG, UGIE

• At 3 months, 6 months.

• Blood : LFT, KFT, INR,AFP

• At 1 year

• Blood : KFT, LFT, CBC, INR, TNF alpha,IL-6, CRP,AFP

• Imaging : USG upper abdomen

• Urine : Urine Na

• HVPG, UGIE

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 testNon 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:

Hypotension (2.6-17.6%) with minor side effets as fainting, shortness of breath, weight gain, swelling of the arms, hands, feet, ankles, or lower legs, chest pain, slow or irregular heartbeat, rash, itching, difficulty breathing and swallowing tiredness, weakness, lightheadedness, dizziness, headache, diarrhea, nausea, vomiting, vision change, joint pain difficulty falling asleep or staying asleep, cough dry eyes, numbness, burning, or tingling in the arms or legs.

Stopping rule of study:

• Severe complications requiring discontinuation of therapy severe Respiratory distress, severe bradycardia heart block not responding to dose reduction.

• Patient refusal to further participate in study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: August 30, 2023
• Est. primary completion date: August 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age 18-65 years

• Liver cirrhosis

• Grade II-III high SAAG ascites

• Small low risk or no esophageal varices

• CTP 7-12

Exclusion Criteria:

• Age <18 years

• AKI at enrollement (Prior transient volume responsive AKI stage I included)

• Post renal or liver transplantation

• History of CAD, PVD, ventricular arrythmia, Bronchial asthma

• SBP at diagnosis

• Severe Hyponatremia (Na <125 MEq/L)

• Grade II/III/IV HE

• Advanced HCC (BCLC C,D), PVTT, Pregnancy or Lactating mother

• High risk varices (Large varices or small high risk varices)

• CTP >12

• ACLF

• Mixed / TB ascites

• Bilirubin >5 mg/dl

• Known CKD, obstructive uropathy

• Patient on MV, NIV, systemic sepsis and shock

• Lack of informed consent

• Prior intolerance or S/E to carvedilol or diuretics

Related Conditions & MeSH terms

• Ascites
• Esophageal and Gastric Varices
• Fibrosis
• Liver Cirrhosis

Intervention

Drug:
• Carvedilol
- Arm A will receive carvedilol plus standard medical therpy,Carvedilol: will be started with initial dose of 3.125 mg BD then After 3 days, increase the dose to 6.25 mg BD, Maximum dose would be 12.5 mg BD, the same shall be switch to Maximum tollrated dose if SBP>90, HR >55.
• Standard Medical Treatment
Arm B will receive standard medical therapy.SMT (as described) that is Grade II ascites - Lasilactone (20/50) OD then Change after 1 week as per response, monitor diuretic intolerance. Grade III ascites will undergo large volume paracentesis, lasilactone (20/50) OD Both groups will receive albumin as indicated (LT references as per protocol will be send for eligible patients)

Locations

Country	Name	City	State
India	Institute of Liver & Biliary Sciences	New Delhi	Delhi

Sponsors (1)

Lead Sponsor	Collaborator
Institute of Liver and Biliary Sciences, India

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complicated ascites (any of refractory ascites, SBP, AKI-HRS)		1 year
Secondary	Ascites resolution in both groups	Ascites well controlled with appropriate medical treatment, i.e, the minimum diuretic dose necessary to control weight gain and ascites formation that did not lead to diuretic-induced complications, such as renal impairment, hyponatremia, hypokalemia or hyperkalemia, or HE	3 Months
Secondary	Ascites resolution in both groups	Ascites well controlled with appropriate medical treatment, i.e, the minimum diuretic dose necessary to control weight gain and ascites formation that did not lead to diuretic-induced complications, such as renal impairment, hyponatremia, hypokalemia or hyperkalemia, or HE	6 Months
Secondary	Ascites resolution in both groups	Ascites well controlled with appropriate medical treatment, i.e, the minimum diuretic dose necessary to control weight gain and ascites formation that did not lead to diuretic-induced complications, such as renal impairment, hyponatremia, hypokalemia or hyperkalemia, or HE	1 year
Secondary	Need and frequency of Large Volume Paracentesis		1 year
Secondary	Incidence of PICD in 1 year		1 year
Secondary	Mortality		1 year
Secondary	Change in grade of varices in both groups	Change is defined as from garde I to garde II/ grade III	1 year
Secondary	Reduction in HVPG in both groups		1 year
Secondary	Change in MELD score in both groups	Minimum MELD=6 Maximum MELD=40	3 months
Secondary	Change in MELD score in both groups	Minimum MELD=6 Maximum MELD=40	6 months
Secondary	Change in MELD score in both groups	Minimum MELD=6 Maximum MELD=40	1 year
Secondary	Change in CTP score in both groups	CTP Change is CTP- C to CTP- B & CTP- B to CTP- A	3 months
Secondary	Change in CTP score in both groups	CTP Change is CTP- C to CTP- B & CTP- B to CTP- A	6 months
Secondary	Change in CTP score in both groups	CTP Change is CTP- C to CTP- B & CTP- B to CTP- A	1 year
Secondary	Incidence of HE in both groups		6 months
Secondary	Incidence of HE in both groups.		1 year
Secondary	Incidence of variceal bleed in both groups		6 months
Secondary	Incidence of variceal bleed in both groups		1 year
Secondary	Incidence of AKI in both groups		6 months
Secondary	Incidence of AKI in both groups		1 year
Secondary	Incidence of SBP in both groups		6 months
Secondary	Incidence of SBP in both groups		1 year
Secondary	Incidence of severe hyponatremia in both groups		6 months
Secondary	Incidence of severe hyponatremia in both groups		1 year
Secondary	Incidence of refractory ascites in both groups		6 months
Secondary	Incidence of refractory ascites in both groups		1 year
Secondary	Maximum tolerated dose of carvedilol		1 year
Secondary	Tretament (carvedilol) related adverse events and their grades	Adverse Events are defined as incidence of Bradycardia,Hypotension,Breathlessness	1 year