To Study the Hemodynamic Response of Early Addition of Carvedilol to Terlipressin in Acute Variceal Bleed in Child's B and C Cirrhosis

NCT ID: NCT05699824

Last Updated: 2023-08-01

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-07-01
• Study Completion Date: 2024-06-30

Brief Summary

Management of Acute variceal bleeding includes endoscopic variceal ligation (EVL) along with vasoactive agents. Inspite of successful hemostasis, this is associated with high variceal rebleeding (VRB) in Child B and C cirrhosis and have higher 6-week mortality rates. Pre-emptive TIPS has shown to prevent rebleed and improve survival in child B and C patients but is associated with liver related complications in advanced disease. HVPG guided therapy and treatment response is known to improve rebleeding and associated with improved survival. This is based on achieving hemodynamic response defined as HVPG reduction of ≥20% from baseline or absolute reduction of HVPG </= 12 mmHg for secondary prophylaxis for prevention of rebleeding. Studies have shown the safety of giving terlipressin in patients receiving beta- blockers. We aim to achieve hemodynamic response with addition of carvedilol with vasoactive agent for reduction of portal blood flow to decreases rebleeding episodes and reduce mortality.

Detailed Description

Aim and Objective To compare the hemodynamic response of early addition of carvedilol with terlipressin in patients with cirrhosis presenting with acute esophageal variceal bleeding.

Primary objective • To study the hemodynamic response (HVPG reduction of ≥20% from baseline or absolute reduction of HVPG </= 12 mmHg) in the groups at 5-days.

Secondary objective

• Rebleeding rate in the two groups at 5-days
• Rebleeding rate at 6-weeks
• Reduction of HVPG <16mm Hg in both groups at 5-days
• Salvage treatment, TIPS in both groups at 5-days and at 6-weeks
• Salvage treatment, SEMS, SB tube placement in-between groups at 5-days and at 6- weeks
• Survival at 6-weeks
• Liver related decompensation in-between groups at 6-weeks
• Adverse events between the groups at 6-weeks

Methodology:

Study population: Patients with Child's B and C cirrhosis who present with acute esophageal variceal bleed, between 18-75 years will be enrolled and randomized based on inclusion and exclusion criteria.

Study design- Prospective open label RCT

Study period - 1.5 years

Sample Size:Sample size will be calculated assuming that baseline characteristics (22.2±5.0 mmHg) are same and HVPG reduction on 5th day with terlipressin is 19.1±5 mmHg [7] and estimating a further reduction of 15% with addition of carvedilol [14] (16.3±4.3 mmHg), with an alpha value equal to 5 % and power of 80%, we need to enrol 45 cases in both arms. Assuming an attrition rate of 10%, it was decided to enrol 100 cases, 50 in each group, randomly allocated by block randomization method with block size of 10.

Intervention: All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol

Arm A- Carvedilol will be initiated on day 2, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

Arm B- Carvedilol will be initiated on day 6, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

• Monitoring and assessment: Patients will be admitted in GI-bleed ICU and will be randomized into the study groups after successful endoscopic control of the bleed. Each patient will be monitored as per the institutional protocol for management of upper GI bleed. A detailed clinical history will be taken, and blood investigations and other relevant investigations required will be done as mentioned in the table 2. Patient will undergo HCC surveillance as per the guideline. Once discharged, patient will be called for OPD visits and routine investigations as planned will be done. Patient will be assessed for the tolerance of carvedilol and dose escalation to a maximum dose of 6.25mg twice a day (12.5mg/day) will be achieved. Each patient will maintain a "patient diary" for ease in recording details.

Table 2: Investigations

Day 0-5 Complete physical evaluation Hemogram, Kidney function test, Liver function test, INR Ultrasound abdomen with spleno-portal axis doppler Fibroscan-liver and spleen Coagulation parameter, vWF, ADAMTS-13 2D-ECHO, ECG Rest investigation, monitoring, antibiotics as per hospital protocol HVPG on Day 1 and at Day 5 Planned OPD visits on day 7, 14, 28, 42 Hemogram, Kidney function test, Liver function test, INR Follow-up visits Repeat upper GI endoscopy every 3 weeks till variceal eradication

Expected outcome of the project:

HVPG guided treatment and achieving hemodynamic response post bleed will reduce rebleeding rates and will prevent further decompensation and reduce mortality in patients with Child B and C cirrhosis.

Conditions

Liver Cirrhosis

Study Design

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

Study Groups

Carvedilol at Day2 + Standard Medical Treatment

Arm A- Carvedilol will be initiated on day 2, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol

Group Type: EXPERIMENTAL

Carvedilol Day2

Intervention Type: DRUG

Carvedilol will be initiated on day 2, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

Standard Medical Treatment

Intervention Type: OTHER

All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol. Standard Medical Treatment

Carvedilol at Day6 + Standard Medical Treatment

Arm B- Carvedilol will be initiated on day 6, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol

Group Type: ACTIVE_COMPARATOR

Standard Medical Treatment

Intervention Type: OTHER

All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol. Standard Medical Treatment

Carvedilol Day6

Intervention Type: DRUG

Carvedilol will be initiated on day 6, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

Interventions

Carvedilol Day2

Carvedilol will be initiated on day 2, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

Intervention Type: DRUG

Standard Medical Treatment

All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol. Standard Medical Treatment

Intervention Type: OTHER

Carvedilol Day6

Carvedilol will be initiated on day 6, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Cirrhosis with Acute Variceal Bleed
• Child's B and C cirrhosis (CTP ≤ 12)
• Patients age between 18 to 75 years

Exclusion Criteria

• Gastric variceal bleed
• Bleeding related to coagulopathy
• Other causes of portal hypertensive bleeding
• Acute on chronic liver failure
• Sepsis
• Shock(persistence of hypotension)
• Acute kidney injury (>1.5 mg%)
• Grade 3 Ascites
• Hyponatremia (Na < 125 mEq/L)
• Complete portal vein thrombosis
• Hepatocellular carcinoma (>3cm lesion)
• Tumoral portal vein thrombosis
• Chronic kidney disease
• Coronary artery disease
• Valvular heart disease
• Sick sinus syndrome/ Pacemaker
• Arrythmia
• Uncontrolled hypothyroidism and hyperthyroidism
• Pregnancy
• Failure to give consent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 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

Site Status: RECRUITING

Countries

India

Central Contacts

Dr Ibrar Ahmed, MD

Role: CONTACT

ibrarkhangmc29@gmail.com

01146300000

Facility Contacts

Dr Ibrar Ahmed, MD

Role: primary

ibrarkhangmc29@gmail.com

01146300000

Other Identifiers

ILBS-Cirrhosis-53

Identifier Type: -

Identifier Source: org_study_id