Treatment of Type I Hepatorenal Syndrome (HRS) With Pentoxyfylline

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Hepatorenal Syndrome

Intervention / Treatment
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* Drug: Pentoxyfylline
* Drug: Placebo
* Drug: AMO Therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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<br> <br> Drug: AMO Therapy<br>* Albumin, midodrine and octreotide therapy (standard of care for HRS)<br>|
| Placebo Comparator: Placebo<br>This is a standard placebo pill. | Drug: Placebo<br> <br> Drug: AMO Therapy<br>* Albumin, midodrine and octreotide therapy (standard of care for HRS)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatorenal syndrome, Renal failure, Pentoxyfylline, Liver transplantation, Cirrhosis