Terlipressin + Albumin Versus Midodrine + Octreotide in the Treatment of Hepatorenal Syndrome

Terlipressin + Albumin Versus Midodrine + Octreotide in the Treatment of Hepatorenal Syndrome (HRS): An Open Multicentric Randomized Study

From 1999, several studies have showed that the use of vasoconstrictors in association with albumin are effective in the treatment of hepatorenal syndrome (HRS). The rationale of the use of vasoconstrictors together with albumin in the treatment of this severe complication of portal hypertension in patients with cirrhosis is to correct the reduction of the effective circulating volume due to the splanchnic arterial vasodilatation.In most of these studies terlipressin, a derivate of vasopressin, has been used as vasoconstrictor as intravenous boluses moving from an initial dose of 0.5-1 mg/4 hr. In some studies midodrine, an alpha-adrenergic agonist, given by mouth has been used as vasoconstrictor at a dose ranging from 2.5 up to 12.5 tid together with octreotide, an inhibitor of the release of glucagon, given subcutaneously at a dose ranging from 10 µg upt to 200 µg tid. To the day, there isn't a study comparing terlipressin + albumin versus midodrine + octreotide + albumin in the treatment of HRS in patients with cirrhosis.Thus, the aim of the study is to compare terlipressin + albumin vs midodrine + octreotide + albumin in the treatment of the HRS in patients with cirrhosis.

Study Overview

• Status: Terminated
• Conditions: Cirrhosis; Hepatorenal Syndrome
• Intervention / Treatment: Drug: Terlipressin plus albumin; Drug: Midodrine plus octreotide plus human albumin

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Italy
  • Padova, Italy, 35100
    • Dept. of Clinical and Experimental Medicine, University of Padova

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with cirrhosis and diagnosis of HRS type 1 or 2,serum creatinine > 2.5 mg/dl

Exclusion Criteria:

• Diagnosis of HCC with a staging beyond the Milan Criteria di Milano
• Septic shock (systolic arterial pressure < 90 mmHg
• Significant heart or respiratory failure
• Peripheral arteriophaty clinically significant
• Previous heart stroke or significant alteration of the ECG

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Fifty patients with cirrhosis and HRS will be randomly assigned to arm 1.	Drug: Terlipressin plus albumin; The terlipressin will be give at the initial dose of 3 mg/24 hours by intravenous continuous infusion. If during the following 48 hours the serum value of creatinine will not change or will go down less than 25%, the dose of terlipressin will be increased to 6 mg/24 hours. If no response will ensue, the dose of terlipressin will be increased to the maximal dose of 12 mg/24 hours. Twenty percent human albumin solution will be administrate together with terlipressin at the dosage of 1 g/Kg of body weight, on first day, and then, to the dosage of 20-40 g/Kg in order to maintain the central venous pressure (CVP) between 10 and 15 cm H2O.The treatment with terlipressin and albumin will be maintained for 24 hours after complete or incomplete resolution. The length of the study in patients with complete and incomplete resolution will reach a maximum of 15 days. In the patients without response the treatment with the high dosage of terlipressin will go on for a maximum of 7 days.
Experimental: 2; Fifty patients with cirrhosis and HRS will be randomly assigned to arm 2.	Drug: Midodrine plus octreotide plus human albumin; Midodrine will be give orally at the initial dose 7.5 tid together with octreotide at the initial dosage of 100 µg subcutaneously tid. If during the following 96 hours the serum value of creatinine will not change or will go down less than 25%, the dose of midodrine will be increased to 12.5 mg tid Twenty percent human albumin solution will be administrate together with midodrine and octreotide at the dosage of 1 g/Kg of body weight, on first day, and then, to the dosage of 20-40 g/Kg in order to maintain the central venous pressure (CVP) between 10 and 15 cm H2O.The treatment with terlipressin and albumin will be maintained for 24 hours after complete or incomplete resolution. The length of the study in patients with complete and incomplete resolution will reach a maximum of 15 days. In the patients without response the treatment with the high dosage of terlipressin will go on for a maximum of 7 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary end-point of the study is the complete reform of the renal function (serum creatinine < 1.5 mg/dl. The primary end point will be evaluated at the end of the treatment.	The treatment will be continued for a maximum of 15 days

Collaborators and Investigators

• Sponsor: University of Padova

Publications and helpful links

General Publications

• Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007 Sep;56(9):1310-8. doi: 10.1136/gut.2006.107789. Epub 2007 Mar 27. No abstract available.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: August 26, 2008
• First Submitted That Met QC Criteria: August 26, 2008
• First Posted (Estimate): August 27, 2008

Study Record Updates

• Last Update Posted (Estimate): October 15, 2014
• Last Update Submitted That Met QC Criteria: October 11, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: cirrhosis; hepatorenal syndrome; terlipressin; midodrine; octreotide; human albumin; effective circulating volume; The criteria which will be used for the diagnosis of HRS will be the criteria which were recently published by the International Ascites Club; Patients with cirrhosis and type 2 HRS only with serum creatinine value > 2.5 mg/dl; All patients with cirrhosis and type 1 HRS
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Fibrosis; Syndrome; Liver Cirrhosis; Hepatorenal Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Adrenergic alpha-1 Receptor Agonists; Octreotide; Terlipressin; Midodrine
• Other Study ID Numbers: 1264P

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No