Clinical trial NCT02123576
Conditions: Hepatorenal Syndrome
Keywords: Hepatorenal syndrome Renal failure Pentoxyfylline Liver transplantation Cirrhosis
Sponsor: Patrick Northup, MD
Start date: 2014-04-01; Completion date: 2017-12-31
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Arms: arm 1: 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 arm 2: This is a standard placebo pill.
Interventions: intervention 1: Pentoxyfylline intervention 2: Placebo intervention 3: AMO Therapy
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Albumin, midodrine and octreotide therapy (standard of care for HRS)

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 17 
Treatment of acute renal failure in patients with decompensated cirrhosis with 
pentoxyfylline: A placebo controlled, blinded pilot study
Clinical Trial Protocol Version: 1.3 
Date:  6/30/2015 
NTC02123576
Principal Investigator: Jonathan G. Stine M.D. 
Division of Gastroenterology and Hepatology 
University of Virginia  
1215 Lee Street 
PO Box 800708 
Charlottesville, Virginia, USA 22908-0708 
434.924.2959 (office) 
434.244.7542 (fax) 
Jgs9f@virginia.edu 
Sub investigators:  Amy Doran M.D., Sean Rudnick M.D., Zach Henry M.D., Nic Intagliata 
M.D. MSc, Curtis Argo M.D. MSc, Neeral Shah M.D., Stephen Caldwell M.D., Patrick 
Northup M.D.  MHS
Primary Study Coordinator and Administrative Duties:  Jonathan G. Stine, M.D. 
Faculty Mentor: Patrick Northup, M.D., MHS 
Medical Monitor: Brian Behm, M.D. MSc 


Page 2 of 17 
Brief Study Synopsis 
 
Study Phase: Pilot 
 
Primary hypothesis: Pentoxyfylline (PTX) therapy at 1200 mg per day or the renally 
dose equivalent in addition to standard of care is superior to placebo in the treatment of 
acute renal failure (ARF) not responsive to volume resuscitation in hospitalized 
patients with cirrhosis.  
 
Study design: Prospective, placebo-controlled, randomized pilot trial.  
 
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.   
 
ARF will be defined according to the definition put forth by and validated prospectively 
by collaboration between the International Ascites Club (IAC) and the Acute Dialysis 
Quality Initiative as a rise in creatinine of 0.3 mg/dl or 50% from baseline creatinine, 
which will be defined as the most recent stable measurement before admission.[1] 
 
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 PTX 400mg three times a day or 
400mg twice a day for eGFR 10-50 and 400mg once a day for eGFR <10 for 14 days in 
addition to standard inpatient care.  Treatment will be continued for 14 days unless a 
study endpoint has been reached at which time either PTX or placebo will be stopped.  
 
Total study subjects expected: 30 patients with cirrhosis hospitalized ARF 
 
Duration of study: 180 days 
 
Study Drugs: PTX 400 mg tablets and placebo. The study team will not be pursuing a 
change in labeling or an FDA approved indication for this drug as a part of this proposal.  
Standard placebo provided in similar tablet forms.  All investigational drugs will be 
prepared by the Investigational Pharmacy by inserting the active drug/placebo into 
larger cloaking capsules.   Standard corn starch will be used inside the placebo capsule. 
 
Randomization will be 1:1.  The Investigational Pharmacy will be performing 
randomization and will generate the block randomization scheme. 
 
 


Page 3 of 17 
Endpoints: The primary endpoint is resolution of ARF, defined as a return to baseline 
creatinine for 24 hours.  
 
 
The secondary endpoints of progression of ARF to a different stage as defined by AKIN 
criteria will be assessed.[3]  If a patient is enrolled at stage III ARF, they will considered 
to have progressed should they be started on renal replacement therapy (RRT).  Other 
secondary endpoints that will be assessed include change in serum creatinine from 
baseline to day 14, combined increase of treatment success and “partial response” 
which we define as serum creatinine level decreased by >50% from baseline but not to 
baseline without dialysis or HRS recurrence, transplant free survival at day 30 and 180, 
overall survival at day 30 and 180, composite survival index at day 30 and 180. 
 
Statistical Methods:  All analyses will be conducted based on the intention to treat 
population.  Results will be expressed as means with standard deviations.   Chi-squared 
and Fisher’s exact test will be used to analyze our categorical endpoints.  Student’s t test 
and Mann-Whitney Rank Sum test will be used for secondary analysis of differences in 
numerical lab data. Kaplan-Meier curves will be constructed and compared by a log-
rank test to assess our secondary endpoints of survival.  A p value of <0.05 will be 
significant.  Subgroup analysis will be performed by stratifying on initial AKIN stage. 
 
Future Study: If there is a treatment benefit with using PTX for treatment of ARF in 
patients with cirrhosis, we would apply for an orphan grant from the NIH or foundation 
awards from the American Association for the Study of Liver Diseases for a multi or single 
center, randomized, double blinded placebo controlled trial.  Ideally we could combine this 
with translational research to help better determine a mechanism of action. 
 
 


Page 4 of 17 
1. Introduction and Study Rationale 
 
Chronic liver disease (CLD) is the 12th leading cause of death in the U.S.[8] and is a 
significant cause of morbidity and hospitalizations across the world. It has been 
estimated that chronic liver disease represents yearly economic costs in upwards of $2 
billion.[9, 10]  Acute renal failure (ARF) is one of the most common complications in 
patients with cirrhosis and leads to poorer outcomes.[11]  The onset of ARF is typically 
in association with other manifestations of hepatic decompensation including 
gastroesophageal 
variceal 
bleeding, 
spontaneous 
bacteria 
peritonitis 
(SBP), 
hyponatremia and issues with volume status and can occur in up to 19% of patients 
hospitalized with cirrhosis.[12]  ARF in patients with cirrhosis can be further subtyped 
into pre-renal azotemia (PRA), acute tubular necrosis (ATN) or Type I or II hepatorenal 
syndrome (HRS).[13]  
 
HRS is a feared complication of CLD and cirrhosis and presents a unique challenge to 
physicians and their management.  The incidence of HRS in patients with cirrhosis and 
ascites is 18 and 39 percent at one and five years, respectively.[14]  HRS occurs in the 
absence of underlying kidney disease and leads to renal failure secondary to 
compensatory renal vasoconstriction due to an ineffective interarteriolar blood volume 
resultant from splanchnic arterial vasodilation.[15, 16]  The prognosis of type 1 HRS is 
so poor with life expectancy less than 2 weeks.[7]  Patients often decompensate and die 
prior to liver transplant (LT) 
 
The standard of care to treat type I HRS is the combination of albumin, octreotide and 
midodrine.[17]  Terlipressin in combination with albumin is also effective, however, 
this is not FDA approved or available currently in the U.S.[18]  Noradrenalin and 
albumin may also be used however this requires ICU level care and is not applicable for 
all patients or all hospitals. [19]  Patients who develop HRS and survive are more likely 
to develop HRS recurrence.  After the withdrawal of treatment for type 1 HRS, 
recurrence can occur in up to 20% of cases.[17]  Treatment for PRA or ATN is largely 
supportive with careful attention to volume status and avoidance of nephrotoxins. 
 
Pentoxifylline (PTX) is a phosphodiesterase inhibitor with anti-inflammatory 
capabilities that lowers blood viscosity and improves erythrocyte flexibility.  
Proinflammatory cytokines, including TNF-a and interleukin-6 are elevated in patients 
with chronic liver disease and cirrhosis in response to circulating endotoxemia.[20, 21] 
These cytokines lead to a proinflammatory, hyperdynamic state in cirrhosis. 
 
PTX has been shown to decrease levels of TNF-a[22] and has also been shown to 
increase systemic vascular resistance to oppose the splanchnic vasodilation seen in 
cirrhosis, but has not had a documented effect on portal pressures.[23]  
 
PTX has is effective in preventing HRS in acute alcoholic hepatitis.[24]  In their study of 
101 patients, Akriviadis et al demonstrated that compared to placebo, patients 
randomized to 400mg PTX orally three times a day not only had improved survival 


Page 5 of 17 
(24.5% versus 46.1% mortality, p = 0.037; RR 0.59, 95% CI 0.35-0.97) but a decreased 
risk of developing HRS as a cause of death (50% versus 91.7% respectively, p = 0.009; 
RR 0.29; 95% CI 0.13-0.65).  Interestingly, the authors noted that increasing TNF-a 
levels during the hospital course were associated with an increase in mortality rate. 
 
PTX has been 
used to 
treat renal 
failure 
from idiopathic 
membranous 
glomerularnephropathy[25] and to prevent GFR decline in high-risk chronic kidney 
disease patients when compared to placebo and thus may have a role in intrinsic kidney 
disease as well.[26]  
 
Two studies have examined using PTX for HRS prevention in all cirrhotics.  In their 
randomized controlled trial of 335 patients with advanced cirrhosis (Child-Pugh class 
C), Lebrec et al[27] demonstrated that the proportions of patients without a composite 
of complications, including HRS, were higher in the PTX group than the placebo group 
at two (78.6% vs. 63.4%, p = .006) and six months (66.8% vs. 49.7%, p = .002) 
respectively.  Furthermore, the probability of being free of renal failure was statistically 
significant at 6 months in the PTX group (90.9%, 95% CI 86.1-95.6) versus the placebo 
group (79.4%, 95% CI 72.6-86.1%), p = 0.02.  However, there was no appreciable 
survival difference at 2 and 6 months between these two groups. 
In their landmark study, Tyagi et al[28] demonstrated that PTX is effective in 
preventing HRS in cirrhotic patients with ascites.  In their randomized placebo 
controlled trial of 70 patients, 35 were given PTX with improvements in serum sodium, 
mean arterial pressure and preservation of creatinine.  Of the 12 patients who 
developed HRS, two patients were in the PTX arm (type-1 HRS, n = 2) (P = 0.01).  The 
authors noted that patients with HRS had higher baseline TNF-α (15.3±5.8 vs. 10.9±4.8 
pg/ml, P = 0.01), lower MAP (68.0±3.8 vs. 77.8±6.5 mmHg, P = 0.01), and sodium level 
(131.2±3.0 vs. 135.6±4.7 mmol/l, P = 0.003) than those who did not develop HRS. 
To our knowledge, no study to date has investigated adding PTX to the treatment 
algorithm for the treatment of ARF in patients with cirrhosis despite the previously 
demonstrated benefit of PTX as primary prophylaxis to prevent HRS, a subtype of 
ARF.[27] 
For all of these reasons, we propose a double blind, randomized, placebo controlled 
pilot trial with PTX to investigate the efficacy of PTX in treating ARF in patients with 
cirrhosis. 
 
 
 


Page 6 of 17 
2. Study Design 
 
The proposed study is a blinded prospective, placebo controlled, randomized pilot 
study. Figure 1 shows the study design schematic. Subjects will be identified during 
their hospitalization with ARF.  Each subject will undergo screening and a pre-dosing 
history and physical exam, and safety assessment, which will include reviewing basic 
blood work results and imaging from their hospitalization (CBC, CMP, INR, Blood 
cultures, UA and urine culture, Urine lytes, Chest x-ray, Abdominal ultrasound with 
dopplers, diagnostic paracentesis if ascites is present) and performing urine pregnancy 
testing in women of child bearing potential.    Subjects will be randomized 1:1 by the 
Investigational Pharmacy. 
 
Subjects will then take a 14-day course of PTX 400 mg three times a day. On day 3 there 
will be an in-person assessment and review of side effect profile.  If there have been no 
serious adverse events, PTX will be continued.  Additional safety assessments will be 
completed at day 7,10,14. 
 
Patients will also be seen in the hospital to assess for treatment response at day 
3,7,10,14.  At these visits, they will have repeat blood work at the discretion of the 
treating physicians (e.g. CBC, CMP, INR, UA with reflex urine culture, Urine lytes,).   
During each assessment, primary and secondary endpoints will be measured.  If an 
endpoint is obtained, the patient will be instructed to stop therapy.   
Survival will be assessed at 30 and 180 days by telephone interviews.  If subjects are 
discharged prior to completing 14 days of therapy, they most likely has met an endpoint 
(resolution, death, transplant, etc).  If in the unlikely event the patient is to be 
discharged and they have not met an endpoint, they will be withdrawn from the study. 
Once the patient is discharged there will be no in person follow up evaluations. 
 
 
 


Page 7 of 17 
Screening and 
initial 
assessment 
visit in hospital 
Randomized 
1:1 to PTX 
treatment arm 
or placebo arm 
Blinded study 
medication, PTX 
or placebo, 
administered in 
addition standard 
of care 
Daily 
assessment to 
response 
assessed 
Stop medication at 
14 days or sooner 
if end point 
reached 
 
 
Figure 1:  Study protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Subject Selection 
 
This study will enroll 30 patients with cirrhosis hospitalized with acute or chronic liver 
disease and ARF as defined according to the criteria put forth by and validated 
prospectively by collaboration between the International Ascites Club (IAC) and the 
Acute Dialysis Quality Initiative as a rise in creatinine of 0.3 mg/dl or 50% from 
baseline creatinine, which will be defined as the most recent stable measurement 
before admission.[1] 
 
 
All participants will be aged greater than or equal to 18 and non-pregnant because of 
the study drug characteristics.  Patients with labeled contraindications to PTX use will 
be excluded. 
 
All subjects will be initially located on the general medical floor, typically 5 central 
which is a GI and hepatology floor.  If a subject decompensates and requires ICU level 
care then they will be transferred to the ICU at the discretion of the treating physician.  
Admission to the ICU will not impede participation status unless the patient reaches 
and endpoint of death, liver transplant or renal replacement therapy at which time their 
participation in the study will have concluded.  We will not be performing initially 
enrollment of the patient in the ICU.  We will not seek surrogate consent. If a patient is 
still in the ICU at day 14 they will not be considered for therapy beyond that point and 
therefore surrogate consent will not be required. 
If a patient is unable to swallow a pill for 6 consecutive doses they will be withdrawn 
from the study. 
 
Table 1 shows the exclusion criteria.   


Page 8 of 17 
 
Table 1: 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 
Acute or chronic renal replacement therapy at time of enrollment 
Shock 
TNF alpha antagonist use 
Subject is institutionalized or a prisoner 
Recent cerebral or retinal hemorrhage (contraindication to PTX) 
Previous participation in this study 
Severe or poorly controlled cardiovascular disease as determined by the principal 
investigator to hinder the ability to adhere to study protocols 
Creatinine > 4.0 g/dL 
Life expectancy < 72 hours 
 
 
4. Overall Risk Benefit Assessment 
 
This study is designed to assess the efficacy of PTX use in patients with cirrhosis with 
ARF when added to standard of hospitalized care.  Because of the short duration of 
dosing and intensive safety assessments, the risks of this study should be minimal to 
the subjects.  Prior studies in both hospitalized and outpatient populations with liver 
disease have shown PTX to be safe in this population.  The risk benefit ratio is 
minimized in the study design and safety plan. 
 
5. Study Objectives 
 
This study is a randomized placebo controlled trial and is hypothesis based.  Data on 
efficacy will be assessed. 
 
5.1. Primary Objective: PTX is safe and effective in treating ARF in hospitalized 
patients with cirrhosis when added to standard of care 
 
5.2 Secondary and Exploratory Objectives:  Progression of ARF to a different stage 
as defined by AKIN criteria will be assessed.[3]  If a patient is enrolled at stage III 
ARF, they will considered to have progressed should they be started on renal 
replacement therapy (RRT).  Other secondary endpoints that will be assessed 
include change in serum creatinine from baseline to day 14, combined increase of 
treatment success and “partial response” which we define as serum creatinine level 
decreased by >50% from baseline but not to baseline without dialysis or HRS 
recurrence, transplant free survival at day 30 and 180, overall survival at day 30 and 
180, composite survival index at day 30 and 180. 


Page 9 of 17 
 
6. Ethical Considerations 
 
6.1. Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonization (ICH) and in accordance 
with the ethical principles underlying European Union Directive 2001/20/EC and 
the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50). The 
study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior 
to initiation of the study. All potential serious breaches must be reported to the local 
IRB as required immediately. A serious breach is a breach of the conditions and 
principles of GCP in connection with the study or the protocol, which is likely to 
affect, to a significant degree, the safety or physical or mental integrity of the 
patients of the study or the scientific value of the study. Study personnel involved in 
conducting this study will be qualified by education, training, and experience to 
perform their respective task(s).  
 
6.2. Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated 
approval/favorable opinion from the IRB/IEC for the protocol, consent form, subject 
recruitment materials/process (e.g., advertisements), and any other written 
information to be provided to patients. The investigator or sponsor should provide 
the IRB/IEC with reports, updates and other information (e.g., expedited safety 
reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
 
6.3. Informed Consent 
Investigators must ensure that patients are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which 
they volunteer to participate.  Surrogate consent will be sought if the patient is 
unable to provide consent due to encephalopathy or lack of capacity. Freely given 
written informed consent must be obtained from every subject prior to clinical 
study participation, including informed consent for any screening procedures 
conducted to establish subject eligibility for the study. The rights, safety, and well 
being of the study patients are the most important considerations and should 
prevail over interests of science and society. The consent process will occur in a 
private room in the hospital.  The PI will carefully discuss the risks and benefits of 
study participation and review study procedures. The PI will make it clear that the 
subject’s standard clinical care will not be affected in any way through participation 
or non-participation in the study. All questions will be answered prior to signing the 
informed consent document and the subject will verbalize understanding at the time 
of consent. The consent process will take approximately 15 minutes. 
 


Page 10 of 17 
 
7. Study Treatments 
 
7.1. Investigational Drug 
PTX is a vasoactive xanthine derivative and phosphodiesterase inhibitor that 
improves peripheral blood flow and enhances peripheral tissue oxygenation.  PTX 
relaxes smooth muscle in peripheral vessels leading to vasodilation.  PTX improves 
red blood cell flexibility, which allows for improved blood flow ability.  Importantly, 
PTX promotes platelet deaggregation and decreases blood viscosity.   The 
summative effects are a decrease in inflammatory mediators.  The investigational 
pharmacy will be used for drug acquisition, storage, and accountability. Subjects will 
start the protocol with 400mg PTX three times a day for 14 days or the renally 
dosed equivalent (400mg BID for eGFR 10-50 and 400mg daily for eGFR <10).  The 
investigators will not seek FDA labeling or approved indications for PTX as part of 
this study; therefore, no IND will be sought for the study drug use in this protocol.   
There are no restrictions on concurrent drugs other than those listed in the 
exclusion criteria in Table 1.  The study drug cannot be crushed or administered 
through a nasogastric tube.  If a patient is NPO but can swallow safely, they may 
receive the drug.  If they are NPO and have a nasogastric tube in place they  will miss 
the dose. 
 
7.2. Study Drug Discontinuation 
Study drug or placebo will be discontinued if a grade 3 adverse event (based on the 
NCI Common Terminology Criteria for Adverse Events, CTCAE, version 4.0) related 
to the study drug at the judgment of the PI and medical monitor.  The PI will notify 
the medical monitor of a grade 3 adverse event over the phone and the medical 
monitor will conduct an independent review with access to the medical record.  The 
medical monitor may interview the patient at the bedside should they deem this 
necessary.  Meetings between the medical monitor and the PI will take place on an 
as needed basis.  One scheduled meeting will take place after 50% enrollment has 
been completed to review all the reported adverse events. 
 
Study drug or placebo will be discontinued if a grade 4 adverse event or pregnancy 
occurs during the study protocol or at the request of the subject. If the subject 
misses a dose and is less than 4 hours late, the subject will be advised to make up 
the dose.  Otherwise, the dose can be omitted and per protocol dosing can resume 
with the next scheduled administration. 
 
7.3. Management of Study Drug Side Effects 
Because of the short duration of study drug administration, side effects are expected 
to be minimal. Side effects will be assessed and managed directly by the study team.  
If severe, the study team will discontinue the study drug.  Common side effects of 
PTX include dyspepsia and nausea.  More serious, rare side effects include a 
hypersensitivity reaction and/or arrhythmia. 
 


Page 11 of 17 
8. Study Assessments 
 
8.1. Schedule of Visits 
The schedule of study assessments and visits is shown in Table 2.  
 
Table 2: Schedule of visits and study protocol assessments 
Visit 
Screening  
initial 
assessment 
Follow up 
assessment 
”Partial 
response” 
assessment 
 
Phone 
Call 
Day 
0 
Day 
3,7,10,14  
Day 14, 28 
 
Day 
30,180 
Initial 
history 
and 
physical exam 
X 
 
 
 
ARF 
response 
assessment 
 
X 
X 
X 
Symptom 
triggered 
physical exam 
 
X 
X 
 
Interim 
safety 
assessment and pill 
count 
 
X 
X 
 
Labs and imaging 
X 
X 
X 
 
 
8.2. Primary Endpoints 
ARF treatment response will be assessed according to Table 2.  The PI or sub-
investigators will perform all assessments and will assess for the presence of side 
effects or toxicities of the study drug by performing a brief history at each visit and 
and by performing a targeted physical exam.  A phone call to assess 30 and 180-day 
survival will be completed. 
 
8.3. Secondary Endpoints 
The secondary endpoints will be assessed by the PI, or sub-investigators, during 
telephone assessments and in-person hospital visits as noted in Table 2. 
 
 


Page 12 of 17 
 
9. Statistical Procedures and Methods 
 
As this is a pilot study and the benefit of PTX in the treatment of ARF has not been 
studied, we estimate a sample size of 30, 15 in each treatment arm, is sufficient to meet 
our primary and secondary endpoints.  Results will be expressed as means with 
standard deviations.   Chi-squared and Fisher’s exact test will be used to analyze our 
categorical endpoints.  Student’s t test and Mann-Whitney Rank Sum test will be used 
for secondary analysis of differences in numerical lab data. Kaplan-Meier curves will be 
constructed and compared by a log-rank test to assess our secondary endpoint of all-
cause mortality.  A p value of <0.05 will be significant.  Intention to treat analysis will be 
performed.  Subgroup analysis will be performed by stratifying on initial AKIN stage. 
 
10. 
Adverse Events, Human Safety Measures, and Oversight 
 
10.1. Definitions 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation 
subject administered an investigational (medicinal) product and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of investigational product, whether or not considered related to the 
investigational product. 
 
10.2. Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
 is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) 
• results in persistent or significant disability/incapacity 
• results in a congenital anomaly/birth defect 
• is an important medical event (defined as a medical event(s) that may not be 
Immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the 
subject or may require intervention [e.g., medical, surgical] to prevent one of 
the other serious outcomes listed in the definition above.) Examples of such 
events include, but are not limited to, intensive treatment in an emergency 
room or at home for severe encephalopathy; seizures or convulsions that do 
not result in hospitalization.) 
 


Page 13 of 17 
All pregnancies, regardless of outcome, will be considered a special adverse event 
(not an SAE).  Although overdose and cancer are not always serious by regulatory 
definition, these events should be reported as an SAE in an expedited manner. 
 
 
10.3. Assignment of Adverse Event Intensity and Relationship to Investigational 
Product 
 
All adverse events, including those that are serious, will be graded according to the 
National Cancer CTCAE version 4.0. The following categories and definitions of 
causal relationship to study drug as determined by a physician should be used for all 
BMS clinical study AEs: 
• Related: There is a reasonable causal relationship to study drug 
administration and the AE 
• Not related: There is not a reasonable causal relationship to study drug 
administration and the AE 
 
The expression "reasonable causal relationship" is meant to convey in general that 
there are facts (e.g., evidence such as de-challenge/re-challenge) or other arguments 
to suggest a positive causal relationship. 
 
10.4. Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting 
bias, patients should not be questioned regarding the specific occurrence of one or 
more AEs.)  If known, the diagnosis of the underlying illness or disorder should be 
recorded, rather than its individual symptoms. The following information should be 
captured for all AEs: onset, duration, intensity, seriousness, relationship to study 
drug, action taken, and treatment required. If treatment for the AE was 
administered, it should be recorded on the appropriate CRF page. The investigator 
shall supply the IRB with any additional requested information, notably for reported 
deaths of patients. Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of 
the study. 
 
10.4.1. Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must 
be collected, including those thought to be associated with protocol-specified 
procedures. All SAEs must be collected that occur within 14 days of 
discontinuation of dosing of the study drug. If applicable, SAEs must be collected 
that relate to any later protocol specified procedure. The investigator will notify 
the local IRB of any SAE occurring after this time period that is believed to be 
related to the study drug or protocol-specified procedure. Serious adverse 
events, whether related or unrelated to study drug, must be reported within 
local regulatory requirements. An SAE report should be completed for any event 
where doubt exists regarding its status of seriousness. 


Page 14 of 17 
 
10.4.2. Nonserious Adverse Events 
The collection of nonserious AE information should begin at initiation of the first 
dose of study drug. Nonserious AE’s will not be required to be reported to the 
local regulatory board but the PI can report these AE’s at his own discretion if an 
unusual trend or novel finding is revealed. Nonserious AEs should be followed to 
resolution or stabilization, or reported as SAEs if they become serious. Follow-up 
is also required for nonserious AEs that cause interruption or discontinuation of 
study drug, or those that are present at the end of study participation. Patients 
with nonserious AEs at study completion should receive post-treatment follow-
up as appropriate through the PI or through referral to the subject’s primary 
care physician or specialist as appropriate. 
 
10.4.3. Overdose 
An overdose is defined as the accidental or intentional ingestion of any dose of a 
product that is considered both excessive and medically important. All 
occurrences of overdose must be reported as an SAE (see above): 
 
10.4.4. Pregnancy 
Women who are pregnant will be excluded from this pilot study.  
 
10.5. Projected Adverse Events 
PTX has been prescribed internationally since 1972 and was first approved by the 
FDA in 1984.  It is generally well tolerated and the incidence of serious adverse 
events is <1%.[29]  Common side effects to commercially available oral PTX include 
dyspepsia (2.8-9.6%), nausea and vomiting (1.2-28.8%), dizziness (1.9-11.9%), 
headache (1.2-6.2%).[29]  In the only study using PTX in cirrhotics with ascites for 
HRS prevention, side effects were statistically similar between the PTX arm and the 
placebo group; dyspepsia occurred in 20% versus 13% (p=0.19), diarrhea and 
headache occurred in 13% versus 6% (p not significant, number not given).[28]  We 
expect to encounter the previously reported rates of common complications 
associated with the use of PTX. 
 
10.6. Study Termination, Monitoring, and Data Security 
Dr. Brian Behm will serve as the independent medical monitor for the study 
subjects.  The PI reserves the right to terminate any subject from the protocol if he 
deems the study subject’s continued participation will hinder the effective execution 
of the protocol or places the subject at risk that is not justified.   If the SAE’s occur in 
more than 25% of participants, the PI will place on hold further enrollment in the 
study until review by an independent local regulatory board composed of a 
Hepatologist, a Gastroenterologist, and another uninvolved physician vote 
unanimously to continue the study with appropriate binding modifications made 
and approved by the local IRB. The study database will be maintained on data 
systems behind secure university firewalls using state-of-the-art data security 
technology.  The PI and sub-investigators will be the only people with access to the 


Page 15 of 17 
study database and all protected personal data will be stored in a “linked and coded” 
dataset.   
 
10.7. Subject Benefit and Payment 
There are potential medical benefits to the subject in participating in this trial in 
that the subject may benefit from the treatment of a rare disease with a poor 
prognosis and limited life expectancy.  There is also a general benefit in increasing 
medical knowledge and potential help of others in future trials.  Subjects will not be 
compensated. 
 
10.8. Inclusion of Women, Children, and Minorities 
This study will not enroll children less than 18 years of age because of limited data 
on PTX use in children.  All women and minorities will be eligible for enrollment 
unless they meet the exclusion criteria in Table 1. The population of chronic liver 
disease patients is predominantly Caucasian males, however. 
 
 


Page 16 of 17 
 
 
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