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Randomized Controlled Trial
. 2008 May;134(5):1360-8.
doi: 10.1053/j.gastro.2008.02.014. Epub 2008 Feb 13.

A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome

Arun J Sanyal  1 , Thomas Boyer, Guadalupe Garcia-Tsao, Frederick Regenstein, Lorenzo Rossaro, Beate Appenrodt, Andres Blei, Veit Gülberg, Samuel Sigal, Peter Teuber; Terlipressin Study Group
Affiliations
Randomized Controlled Trial

A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome

Arun J Sanyal et al. Gastroenterology. 2008 May.

Abstract

Background & aims: Hepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS.

Methods: A prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to </=1.5 mg/dL for at least 48 hours by day 14 without dialysis, death, or relapse of HRS type 1.

Results: Fifty-six subjects were randomized to each arm. Treatment success with terlipressin was double that with placebo (25% vs 12.5%, P = .093). SCr level improved from baseline to day 14 on terlipressin (-0.7 mg/dL) as compared with placebo (0 mg/dL), P < .009. Terlipressin was superior to placebo for HRS reversal (34% vs 13%, P = .008), defined by decrease in SCr level </=1.5 mg/dL. Overall and transplantation-free survival was similar between study groups; HRS reversal significantly improved survival at day 180. One nonfatal myocardial infarction occurred with terlipressin, but the total adverse event rate was similar to placebo.

Conclusions: Terlipressin is an effective treatment to improve renal function in HRS type 1.

Trial registration: ClinicalTrials.gov NCT00089570.

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Conflict of interest statement

Conflicts of interest and financial disclosures: Arun J. Sanyal, MBBS, MD: Stipends paid by Orphan Therapeutics to maintain the 24-hour study Medical Hotline (June 2004, $12,000; May 2005, $12,000). Reimbursement for travel costs and data reviews for FDA meetings (2006, $501.90; April 2007, $251.67). Thomas Boyer, MD: Reimbursement for travel costs and data reviews for FDA meetings (February 2004, $1157.90; June 2006, $377.70; October 2006, $699.20; March 2007, $389.60). Honorarium for OT-0401 Steering Committee in 2004 ($1350.00). Guadalupe Garcia-Tsao, MD: Honorarium for OT-0401 Steering Committee in 2004 ($750.00). Frederick Regenstein, MD: Honorarium for OT-0401 Steering Committee in 2004 ($750.00). Lorenzo Rossaro, MD: Honorarium for OT-0401 Steering Committee in 2004 ($750.00). Andres Blei, MD: None. Veit Gülberg, MD: None. Beate Appenrodt, MD: None. Samuel Sigal, MD: None. Peter Teuber, PhD: President and Managing Partner of Orphan Therapeutics, LLC (OT-0401 study cosponsor).

Figures

Figure 1
Figure 1
Cumulative incidence of HRS reversal by day. Treatment was begun on day 1.
Figure 2
Figure 2
Mean change from baseline in SCr (mg/dL) to end of treatment. Data include all patients in the ITT population at each time point. The mean change from baseline values represents the change from baseline to end of treatment using the last observation carried forward in the ITT population.
Figure 3
Figure 3
Kaplan–Meier plot of overall survival up to day 180. Observations were censored at the last time a patient was known to be alive (represented by open circles).
Figure 4
Figure 4
Overall survival for HRS reversal vs no HRS reversal. Observations were censored at the last time a patient was known to be alive (represented by open circles). All patients are included irrespective of treatment.
See this image and copyright information in PMC

Comment in

References

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