Terlipressin Infusion in Variceal Hemorrhage

Study Overview
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Brief Summary
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Randomized, open label study of intravenous terlipressin infusion vs. bolus for the treatment of variceal hemorrhage. 24 hour regimen consisting of intravenous terlipressin will be used either at a rate of 0.5mg/hour or 2mg bolus every 4 hourly. Participants will be randomized into intervention and control arm using block randomization by computer generated random numbers. Efficacy will be assessed by clinical improvement in symptoms and signs of GI bleed. To assess safety, frequency and degree of adverse reactions will be observed. Periodic assessments until 5 days will be done consisting of physical examination, safety assessments, vital signs and lab tests.

Detailed Description
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Randomized, open label trial, conducted on patients admitted with acute variceal hemorrhage at The Aga Khan University Hospital, Karachi (AKUH). Patients will be followed in clinic after discharge to assess survival for 6 weeks. Intravenous terlipressin will be obtained from Clinical Trials Unit, AKUH pharmacy in standard IV infusion form. Following complete clinical and laboratory evaluation, assessing the patient for eligibility, informed consent will be obtained from all the participants who are willing to be part of this study. After obtaining the informed consent, study participants will be randomized into the intervention arm (continuous infusion of Terlipressin) or the control arm (bolus form of Terlipressin). Participants who are randomized to the intervention arm will be administered a continuous infusion of Terlipressin at a rate of 0.5mg/hour for the first 24 hours. Participants randomized into the control group will be administered a bolus form of Terlipressin at a rate of 2mg every six hourly for the first 24 hours respectively. In case of weekends/public holidays intravenous terlipressin will be obtained from the main pharmacy of AKUH. The trial will be conducted in in-patient units of AKUH where eligible patients are admitted. It may include emergency room, special care unit and general ward. Moreover, patients will be followed up by phone calls and in outpatient's clinics to assess survival six weeks post discharge.

Official Title
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Terlipressin Bolus Versus Continuous Infusion in Patients With Variceal Hemorrhage

Conditions
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Terlipressin Adverse Reaction

Intervention / Treatment
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* Drug: Terlipressin Injectable Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 to 60 years Either gender A diagnosis of liver cirrhosis; Initial presentation with acute gastroesophageal variceal bleeding Willing to provide informed consent to participate in the study (by study subject or next of kin) Exclusion Criteria: Age < 18 or > 60 years Not willing to provide consent due to any reason No liver cirrhosis Acute upper gastrointestinal bleeding unrelated to varices; Use of somatostatin or octreotide. Hepatocellular Carcinoma (HCC)outside Milan's criteria Advance cardiovascular, pulmonary or renal disease (e.g. asthma, hypertension, arrhythmia, renal insufficiency) History of hypersensitivity to Terlipressin Pregnancy Patients already admitted at AKUH who develop upper GI bleed during admission.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Experimental Arm: Standard of care being given at AKUH + Continuous infusion of Terlipressin at a rate of 0.5mg/hour for the first 24 hours Comparator Arm: Standard of care being given at AKUH + Bolus infusion of Terlipressin at a frequency of 2mg every six hourly for first 24 hours
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Terlipressin Continuous Infusion<br>Standard of care being given at AKUH + Continuous infusion of Terlipressin (Terlipressin Injectable Product) at a rate of 0.5mg/hour for the first 24 hours | Drug: Terlipressin Injectable Product<br>* Intravenous terlipressin will be obtained from Clinical Trials Unit, AKUH pharmacy in standard IV infusion form. Participants who are randomized to the intervention arm will be administered a continuous infusion of Terlipressin at a rate of 0.5mg/hour for the first 24 hours. Participants randomized into the control group will be administered a bolus form of Terlipressin at a rate of 2mg every six hourly for the first 24 hours respectively. In case of weekends/public holidays intravenous terlipressin will be obtained from the main pharmacy of AKUH.<br>* Other names: Novapressin;|
| Active Comparator: Terlipressin Bolus Infusion<br>Standard of care being given at AKUH + Bolus infusion of Terlipressin (Terlipressin Injectable Product) at a frequency of 2mg every six hourly for first 24 hours | Drug: Terlipressin Injectable Product<br>* Intravenous terlipressin will be obtained from Clinical Trials Unit, AKUH pharmacy in standard IV infusion form. Participants who are randomized to the intervention arm will be administered a continuous infusion of Terlipressin at a rate of 0.5mg/hour for the first 24 hours. Participants randomized into the control group will be administered a bolus form of Terlipressin at a rate of 2mg every six hourly for the first 24 hours respectively. In case of weekends/public holidays intravenous terlipressin will be obtained from the main pharmacy of AKUH.<br>* Other names: Novapressin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in tachycardia, measured through heart rate (>100 bpm) being displayed in the electronic monitors in wards, emergency room and out-patient clinics | It will be assessed by trained research coordinator as; the number of study participants with 20% reduction in tachycardia as compared to the baseline between the two arms. | 6 weeks (Overall length of follow-up) | 
| Improvement in mean arterial pressure, being displayed in the electronic monitors in wards, emergency room and out-patient clinics | It will be assessed by trained research coordinator as; the number of study participants with 20% improvement in mean arterial pressure as compared to the baseline between the two arms. Adverse events related to terlipressin, such as hyponatremia, diarrhea, abdominal pain; arterial hypertension should be reported to the primary gastroenterologist between the two arms. | 6 weeks (Overall length of follow-up) | 
| In-patient hospital mortality, assessed through medical records. | It will be assessed through medical records, by a trained research coordinator as the number of study participants dying within the hospital between the two arms. | Admission of patient till death in the hospital | 
| Failure to control bleeding as assessed by physiological parameters in the blood | It will be assessed by a trained research coordinator as the number of participants having fresh hematemesis and 3 gm drop in hemoglobin (9% drop in hematocrit) within a 24 hours' time period between the two arms. | Admission of patient till discharge from the hospital | 
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | It will be assessed by trained research coordinator as; the number of participants having experienced any adverse events such as hyponatremia, diarrhea, abdominal pain, arterial hypertension, 5 days after having terlipressin drug, between the two arms. | 6 weeks (Overall length of follow-up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Out of hospital mortality assessed through telephonic interviews from patient's caregiver | It will be assessed by trained research coordinator as; the number of participants dying after being discharged from the hospital between the two arms within the follow-up time period of the study. | 5 weeks after being discharged from the hospital | 
| Failure to control bleeding as assessed by physiological parameters in the blood | It will be assessed by trained research coordinator as the number of participants having fresh hematemesis and 3 gm drop in hemoglobin (9% drop in hematocrit) after being discharged from the hospital till three subsequent follow-up visits between the two arms. | 5 weeks after being discharged from the hospital | 
| Prolong hospital stay (> 5 days) as assessed through medical records and pre-designed questionnaire | It will be assessed by trained research coordinator as; the number of participants having stayed in the hospital for more than five days between the two arms. | 5 days after admission till being discharged from the hospital | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Terlipressin Drug, Continuous Infusion, Bolus Form