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

  • STATUS
    Recruiting
  • End date
    Aug 30, 2023
  • participants needed
    120
  • sponsor
    Institute of Liver and Biliary Sciences, India
Updated on 6 November 2021
hypertension
ascites
cytokines
carvedilol
vasopressin
spontaneous bacterial peritonitis
paracentesis
esophageal varices
vasodilatation

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.

Details
Condition Liver Disorders, Liver Disease, LIVER DISEASE, Cirrhosis, liver cirrhosis, Hepatic Fibrosis, hepatic cirrhosis
Treatment Carvedilol, Standard Medical Treatment
Clinical Study IdentifierNCT05057572
SponsorInstitute of Liver and Biliary Sciences, India
Last Modified on6 November 2021

Eligibility

Yes No Not Sure

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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer  to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note