Efficacy of Continuous Terlipressin Therapy After Endoscopic Variceal Ligation (TERLEVL)

Efficacy of Continuous Terlipressin Therapy After Endoscopic Variceal Ligation in Acute Variceal Haemorrhage: A Randomised Control Clinical Trial

Upper gastrointestinal (UGI) bleed of variceal origin is a common medical emergency. Prompt endoscopic variceal ligation (EVL) is therapeutic as well as diagnostic. Terlipressin, a vasopressin analog (intravenous, 2 mg q 4 hourly), is widely used promptly in any suspicious cases of variceal haemorrhage (VH) before endoscopic intervention, along with volume and blood resuscitative measures.

As per guideline, after EVL Terlipressin therapy (1 mg IV q 4 hourly) is advised to continue for 2-5 day to prevent re-bleed and mortality [1]. But the prolong use of Terlipressin is not completely safe as well as it is expensive also in resource constraint setting. At present, no randomized control clinical trial (RCT) is available to prove the efficacy of post-EVL Terlipressin therapy in preventing re-bleed and mortality in acute variceal haemorrhage.

During the post marketing surveillance Terlipressin therapy was found to be associated with life threatening complication like cardiac arrhythmia, myocardial ischemia, critical vasoconstriction of peripheral as well as internal organ leading to ischemia or gangrene, severe hyponatremia, hypertension, fluid overload and pulmonary oedema (2-4).

So the justification of continuing Terlipressin for 5 days after EVL is questionable, as the haemostasis is primarily achieved by EVL and the risk versus benefit of Trelipressin therapy after EVL is still unknown. Continue IV Terlipressin therapy also prolongs in-hospital care causing further increase of health care burden.

As per recently concluded institutional study, continuing Terlipressin after EVL in acute VH did not prevent re-bleed or mortality, rather it increased the risk of ADR, duration of hospital stay, in-hospital complications and cost of the therapy [5]. But the study was open level with relatively smaller sample size.

There is still lack of RCT on post-EVL Terlipressin therapy, regarding its efficacy in preventing re-bleed and mortality. So, we have planned this study to evaluate the efficacy of continuous Terlipressin therapy after EVL, in acute VH.

It will be a double blind randomized controlled clinical trial. The study will be carried out in the 2 arms; denoting the duration of Terlipressin therapy after EVL. Participant with acute VH will be randomized into two study groups after successful EVL.

The treatment group will receive injection Terlipressin (1 mg IV bolus q 4 hourly) for 2 days and the control group will receive 10 ml of 0.9% normal saline (NS) IV bolus q 4 hourly instead of Terlipressin for 2 days. Both the group will receive standard care of therapy and will be followed up for 8 weeks. The participants and the recruiter/PI will be unaware of intervention (terlipressin or NS) receiving.

The study will enlighten us regarding efficacy of continuous Terlipressin therapy after EVL to prevent re- bleed and mortality in acute VH. The study will also generate significant data regarding adverse drug events (ADE) and cost effectiveness or pharmaco- economics of continue Terlipressin therapy after EVL.

In the Indian population there is no study to determine the role gene related to variceal bleed or re-bleed. Endothelial dysfunction is the major contributor for the development of portal hypertension and subsequent varices formation in patient with cirrhosis. Development of blood vessel and endothelial function, endothelial proliferation and neoangiogenesis are regulated by vascular endothelial growth factor (VEGF) family genes. In a recently published study, VEGF C(+405)G(rs2010963) single nucleotide polymorphism (SNP) genotype was found to be associated with higher risk of esophageal and gastric varices and bleeding [10]. Since VEGF is the major factor to endothelial proliferation and neoangiogenesis. So, in this study, as a secondary objective, we will also try to explore the association of VEGF genotype with variceal bleed/ re-bleed and mortality.

Study Overview

• Status: Not yet recruiting
• Conditions: Variceal Hemorrhage
• Intervention / Treatment: Drug: Terlipressin; Other: 0.9% normal saline (NS)

• Study Type: Interventional
• Enrollment (Estimated): 165
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Deba P Dhibar, MD; Phone Number: 9530881462; Email: drdeba_prasad@yahoo.co.in

Study Locations

• India
  • Chandigarh, India, 160012
    • Department of Internal Medicine, Post Graduate Institute of Medical Education and Research,
    • Contact: P; Phone Number: +911722756670; Email: pgimerinternalmed@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Irrespective of gender
• age ≥ 18 years
• all the patients with endoscopy proven acute VH with successful EVL done

Exclusion Criteria:

• Patients not receiving pre-EVL Terlipressin therapy
• not achieving haemostasis during EVL
• EVL done beyond 48 hours of admission because of hemodynamic instability or encephalopathy
• Patients with chronic kidney disease
• Patients with pregnancy
• Patients who are receiving blood thinners like anti-platelets, anti-coagulation agents within 4 weeks of presentation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment; After successful Endoscopic variceal ligation (EVL) the treatment group will receive injection Terlipressin (1 mg IV bolus q 4 hourly) for 2 days. Both the group will receive standard care of therapy.	Drug: Terlipressin; After successful Endoscopic variceal ligation (EVL) The treatment group will receive injection Terlipressin (1 mg IV bolus q 4 hourly) for 2 days; Other Names: Standard care of therapy; Endoscopic variceal ligation (EVL)
Placebo Comparator: Control; After successful Endoscopic variceal ligation (EVL) the control group will receive 10 ml of 0.9% normal saline (NS) IV bolus q 4 hourly instead of Terlipressin for 2 days. Both the group will receive standard care of therapy.	Other: 0.9% normal saline (NS); After successful Endoscopic variceal ligation (EVL) the control group will receive 10 ml of 0.9% normal saline (NS) IV bolus q 4 hourly instead of Terlipressin for 2 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Re-bleed	Re-bleed is defined as any significant UGI haemorrhage after EVL, leading to repeat endoscopy, haemodynamic instability and significant drop of haemoglobin requiring blood transfusion.	7 days
Mortality	Incidence of episode of mortality	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of hospital stay	Number of days of stay in the hospital	1 week
need for blood transfusions	After successful EVL, requirement of blood transfusion	1 week
Adverse drug reaction (ADR)	Incidence of adverse drug reaction (ADR)	1 week

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2023
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 31, 2023
• First Submitted That Met QC Criteria: August 31, 2023
• First Posted (Actual): September 7, 2023

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Antihypertensive Agents; Vasoconstrictor Agents; Terlipressin
• Other Study ID Numbers: IEC-INT/2023/Study-865

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No