Hepatorenal Syndrome
Conditions
Keywords
Hepatorenal syndrome, Renal failure, Pentoxyfylline, Liver transplantation, Cirrhosis
Brief summary
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
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
Interventions
DRUGPentoxyfylline
DRUGPlacebo
DRUGAMO Therapy
Albumin, midodrine and octreotide therapy (standard of care for HRS)
Sponsors
Patrick Northup, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Success | 14 days | We define this as a decrease in serum creatinine level to \<1.5 mg/dL without dialysis or death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Creatinine From Baseline | baseline and 14 days | — |
| Incidence of Treatment Failure | up to day 14 | Defined as creatinine level above baseline value after day 7, dialysis or death |
| Number of Participants With Combined Outcome of Treatment Success and Partial Response | 14 days | We define as serum creatinine level decreased by \>50% from baseline but not to \<1.5 mg/dL, without dialysis or HRS recurrence |
| Transplant Free Survival | day 30 and 180 | — |
| Overall Survival | up to 1 year | This will be the combination of transplant free survival and those patients who received liver transplant |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Pentoxyfylline
AMO Therapy: Albumin, midodrine and octreotide therapy (standard of care for HRS) | 6 |
| Placebo This is a standard placebo pill.
Placebo
AMO Therapy: Albumin, midodrine and octreotide therapy (standard of care for HRS) | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Continuous | 57 years | 60.8 years | 58.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 3 / 6 |
| other Total, other adverse events | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 1 / 6 | 0 / 6 |
Outcome results
Primary
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
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Treatment Success | 1 Participants |
| Placebo | Number of Participants With Treatment Success | 1 Participants |
Secondary
Change in Serum Creatinine From Baseline
Time frame: baseline and 14 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment | Change in Serum Creatinine From Baseline | 0.48 g/dL |
| Placebo | Change in Serum Creatinine From Baseline | 0.03 g/dL |
Secondary
Incidence of Treatment Failure
Defined as creatinine level above baseline value after day 7, dialysis or death
Time frame: up to day 14
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Incidence of Treatment Failure | 3 Participants |
| Placebo | Incidence of Treatment Failure | 3 Participants |
Secondary
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
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Combined Outcome of Treatment Success and Partial Response | 1 Participants |
| Placebo | Number of Participants With Combined Outcome of Treatment Success and Partial Response | 2 Participants |
Secondary
Overall Survival
This will be the combination of transplant free survival and those patients who received liver transplant
Time frame: up to 1 year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment | Overall Survival | 102 days |
| Placebo | Overall Survival | 59 days |
Secondary
Transplant Free Survival
Time frame: day 30 and 180
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment | Transplant Free Survival | 80 days |
| Placebo | Transplant Free Survival | 36 days |