Treatment of Type I Hepatorenal Syndrome (HRS) With Pentoxyfylline

Treatment of Type I Hepatorenal Syndrome (HRS) With Pentoxyfylline: A Placebo Controlled, Blinded Pilot Study

Pentoxyfylline therapy in addition to the standard of care of albumin, midodrine and octreotide therapy is superior to the standard of care alone in the treatment of Type I hepatorenal syndrome in the first 14 days of hospitalization.

Study Overview

• Status: Terminated
• Conditions: Hepatorenal Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Pentoxyfylline; Drug: AMO Therapy

Detailed Description

Each hospitalized subject will undergo pre-dosing screening with review of his or her history and physical exam from the day of enrollment and safety assessment to ensure no contraindication to use of PTX. Type I HRS will be defined according to the criteria put forth by the American Association for the Study of Liver Disease as (1) cirrhosis with ascites; (2) serum creatinine greater than 1.5 mg/dL; (3) no improvement of serum creatinine (decrease to a level of 1.5 mg/dL or less) after at least two days with diuretic withdrawal and volume expansion with albumin; (4) absence of shock; (5) no current or recent treatment with nephrotoxic drugs; and (6) absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells per high power field), and/or abnormal renal ultrasonography. Baseline testing will be obtained from hospitalization records, including but not limited to chemistry panel, liver function testing, urinalysis, urine electrolytes, coagulation studies, blood cultures, chest x-ray, diagnostic paracentesis, abdominal ultrasound with Doppler.

Subjects will take either placebo three times a day or pentoxyfylline 400mg three times a day or 400mg twice a day for eGFR 10-50 and 400mg once a day for eGFR <10 for 90 days in addition to standard AMO therapy. Treatment will be continued for 14 days unless a study endpoint has been reached at which time either PTX or placebo will be stopped

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System

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:

• Hospitalized patients with acute or chronic liver disease
• Type I HRS
• Aged greater than or equal to 18
• Non-pregnant

Exclusion Criteria:

• Allergy or hypersensitivity to PTX or intolerance to methylxanthines (e.g. caffeine, theophylline)
• Concurrent use of nephrotoxic drugs
• Age less than 18
• Pregnancy
• Uncontrolled bacterial infection
• Renal parenchymal disease (e.g. acute tubular necrosis, glomerular disease, interstitial nephritis and urinary obstruction)
• Shock
• TNF alpha antagonist use
• Subject is institutionalized or a prisoner
• Recent cerebral or retinal hemorrhage (contraindication to PTX)
• Severe or poorly controlled cardiovascular disease as determined by the principal investigator to hinder the ability to adhere to study protocols

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Pentoxyfylline 400mg three times a day or 400mg twice a day for eGFR 10-50 and 400mg once a day for eGFR <10 for 90 days in addition to standard AMO therapy	Drug: Pentoxyfylline; Drug: AMO Therapy; Albumin, midodrine and octreotide therapy (standard of care for HRS)
Placebo Comparator: Placebo; This is a standard placebo pill.	Drug: Placebo; Drug: AMO Therapy; Albumin, midodrine and octreotide therapy (standard of care for HRS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Success	We define this as a decrease in serum creatinine level to <1.5 mg/dL without dialysis or death	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Creatinine From Baseline		baseline and 14 days
Incidence of Treatment Failure	Defined as creatinine level above baseline value after day 7, dialysis or death	up to day 14
Number of Participants With Combined Outcome of Treatment Success and Partial Response	We define as serum creatinine level decreased by >50% from baseline but not to <1.5 mg/dL, without dialysis or HRS recurrence	14 days
Transplant Free Survival		day 30 and 180
Overall Survival	This will be the combination of transplant free survival and those patients who received liver transplant	up to 1 year

Collaborators and Investigators

• Sponsor: Patrick Northup, MD
• Investigators: Study Director: Patrick G Northup, MD MHS, University of Virginia; Principal Investigator: Jonathan G Stine, MD, University of Virginia

Publications and helpful links

General Publications

• Morgan TR, McClain CJ. Pentoxifylline and alcoholic hepatitis. Gastroenterology. 2000 Dec;119(6):1787-91. doi: 10.1053/gast.2000.20826. No abstract available.
• Angeli P. beta-blockers and refractory ascites in cirrhosis: the message of a team of true scientists. J Hepatol. 2011 Oct;55(4):743-4. doi: 10.1016/j.jhep.2011.02.026. Epub 2011 Mar 10. No abstract available.
• Lott JP. Renal failure in cirrhosis. N Engl J Med. 2010 Jan 7;362(1):79; author reply 80-1. doi: 10.1056/NEJMc0910190. No abstract available.
• Spring FA, Dalchau R, Daniels GL, Mallinson G, Judson PA, Parsons SF, Fabre JW, Anstee DJ. The Ina and Inb blood group antigens are located on a glycoprotein of 80,000 MW (the CDw44 glycoprotein) whose expression is influenced by the In(Lu) gene. Immunology. 1988 May;64(1):37-43.
• Fallon E, Ehrenwald E, Nazarian GK, Smith CI. TIPS with a polytetrafluoroethylene-lined stent graft and associated haemolytic anaemia. Gut. 2008 Aug;57(8):1180-1. No abstract available.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: April 18, 2014
• First Submitted That Met QC Criteria: April 23, 2014
• First Posted (Estimate): April 25, 2014

Study Record Updates

• Last Update Posted (Actual): May 29, 2019
• Last Update Submitted That Met QC Criteria: May 8, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Liver transplantation; Cirrhosis; Renal failure; Hepatorenal syndrome; Pentoxyfylline
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Syndrome; Hepatorenal Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: 17365