Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury



Status:Completed
Conditions:Hospital, Gastrointestinal
Therapuetic Areas:Gastroenterology, Other
Healthy:No
Age Range:18 - 65
Updated:11/1/2018
Start Date:June 2012
End Date:February 23, 2017

Use our guide to learn which trials are right for you!

A Phase 2a Study to Evaluate the Safety and Tolerability of OCR-002 (Ornithine Phenylacetate) in the Treatment of Patients With Acute Liver Failure/Severe Acute Liver Injury

This Phase 2a clinical study is designed to provide data on OCR-002 in patients with acute
liver failure/acute liver injury (ALF/ALI) in regard to:

- safety and tolerability;

- metabolism of the compound to glutamine and phenylacetylglutamine (PAGN);

- its effect on circulating ammonia levels and neurological function in patients with and
without impaired renal function after continuous infusion at different infusion rates.

Subjects will receive up to 120 hours (5 days) of drug infusion, followed by a 30 day
follow-up visit post infusion. It is anticipated that this early safety and tolerability
study, with appropriate PK/PD data, will lead to a development program for the use of OCR-002
in the treatment of hyperammonemia either due to ALF or possibly other liver conditions. The
hypotheses are:

- Treatment with OCR-002 is safe and tolerable in patients with acute liver failure/acute
liver injury due to acetaminophen overdose or drug-induced liver injury, autoimmune
hepatitis, viral hepatitis or indeterminate etiologies.

- A dose of 10-20g/24h (0.42-.83g/h) will achieve steady state plasma concentrations
within 6-12h with little additional accumulation in the ALI/ALF setting.

- Treatment with OCR-002 will reduce ammonia and improve neurological function in patients
with acute liver failure/severe acute liver injury.

There is strong experimental and clinical rationale for the use of ammonia-lowering therapies
in ALF. Ammonia is normally produced in the gut and transformed by the liver into urea. As
the liver fails, ammonia increases in the systemic circulation and enters into the brain. The
result of a rapid rise in ammonia or related compounds in the cerebral circulation is hepatic
encephalopathy (HE), a reversible neuropsychiatric condition that ranges in severity from
mild impairment in attention, to delirium, the development of cerebral edema, coma and death.
This is a Phase 2a, multi-center, open-label study, conducted in two cohorts in patients
diagnosed with acute liver failure/acute liver injury (ALF/ALI) who meet inclusion/exclusion
criteria. This study is designed to provide data on OCR-002 with regards to

- the effect on circulating ammonia levels in patients with acute liver failure with and
without impaired renal function at different doses after single and continuous infusion

- safety and dose tolerability as well as

- providing data on the metabolites, glutamine and phenylacetylglutamine in this patient
population.

It is anticipated that this early efficacy, safety, tolerability,
Pharmacokinetic/Pharmacodynamic (PK/PD) and dose-ranging study will lead to a Phase 3
development program for the use of OCR-002 in the treatment of hyperammonemia due to ALF. No
clinical outcome measures will be formally studied because of the small sample size.

Inclusion Criteria:

1. Men and women, ages 18-65 (have not reached their 66th birthday).

2. Acute liver failure, defined as the development of coagulopathy (International
normalized ratio [INR] ≥1.5) with encephalopathy in a patient with no prior history of
liver disease, with onset of symptoms within 28 days of the inciting event. Patients
may have either a history of acetaminophen overdose (defined as >4 g/day within 7 days
of presentation) and/or detectable acetaminophen levels in the serum, with a pattern
of liver function tests typical for acetaminophen toxicity (bilirubin < 10 mg/dL and
alanine aminotransferase (ALT) ≥1000 IU/L), or a diagnosis of hepatitis A, hepatitis
B, drug-induced liver injury, autoimmune hepatitis or indeterminate cause based on
standard criteria.

3. ALI patients may also be enrolled (those meeting the above criteria plus coagulopathy
(INR ≥ 2.0) and no evidence of encephalopathy)

4. Written informed consent from the patient (ALI) or patient's legally authorized
representative or family member if he/she is considered encephalopathic (ALF).

5. Ammonia level ≥60 μmol/L at baseline (within 8h prior to T0/initiation of infusion).

6. Serum creatinine levels as follows:

1. Cohort 1: Creatinine ≤1.5 mg/dL; and

2. Cohort 2: Creatinine >1.5 mg/dL and <10mg/dL.

7. Mean arterial pressure of >65 mmHg.

Exclusion Criteria:

1. History of chronic liver disease.

2. Signs of overt cerebral herniation, or uncontrolled intracranial hypertension by
intracranial pressure (ICP) monitoring (if applicable).

3. Evidence of Wilson's disease, alcoholic hepatitis, biliary obstruction, ischemic
hepatitis, severe acute renal tubular necrosis (ATN) due to shock, or any patient with
ongoing hypotension.

4. Significant gastrointestinal bleeding (coffee grounds per nasogastric tube and/or
melena).

5. Hemodynamic instability, defined by a mean arterial pressure of <65 mmHg.

6. Cardiopulmonary complications such as pulmonary edema, aspiration pneumonia, heart
failure.

7. QT interval of >500msec at baseline EKG.

8. Pregnancy.

9. History of malignancy that has not been cured or any cancer in remission for less than
1 within the past 5 year. Non-melanoma skin cancers do not preclude participation in
the trial.

10. Concomitant administration of drugs known to interfere with renal excretion of
phenylacetylglutamine or those medications that may induce hyperammonemia such as
haloperidol, valproic acid and systemic corticosteroids (prohibited during the study).
Alternative ammonia modifying agents such as lactulose and rifaximin are not
considered standard of care and are prohibited during the study period.

11. Any other health condition that would preclude participation in the study in the
judgment of the principal investigator.
We found this trial at
11
sites
Seattle, Washington 98104
(206) 543-2100
Principal Investigator: Iris Liou, MD
Phone: 206-598-4908
Univ of Washington Founded in 1861 by a private gift of 10 acres in what...
?
mi
from
Seattle, WA
Click here to add this to my saved trials
201 Dowman Dr
Atlanta, Georgia 30303
(404) 727-6123
Principal Investigator: Ram Subramanian, MD
Phone: 404-712-3833
Emory University Emory University, recognized internationally for its outstanding liberal artscolleges, graduate and professional schools,...
?
mi
from
Atlanta, GA
Click here to add this to my saved trials
Ann Arbor, Michigan 48109
Principal Investigator: Robert Fontana, MD
Phone: 734-936-4780
?
mi
from
Ann Arbor, MI
Click here to add this to my saved trials
171 Ashley Avenue
Charleston, South Carolina 29425
843-792-1414
Principal Investigator: David Koch, MD
Phone: 843-792-6901
Medical University of South Carolina The Medical University of South Carolina (MUSC) has grown from...
?
mi
from
Charleston, SC
Click here to add this to my saved trials
303 East Superior Street
Chicago, Illinois 60611
Principal Investigator: Daniel R Ganger, MD
Phone: 312-695-4496
?
mi
from
Chicago, IL
Click here to add this to my saved trials
281 W. Lane Ave
Columbus, Ohio 43210
(614) 292-6446
Principal Investigator: James Hanje, MD
Phone: 614-293-6255
Ohio State University The Ohio State University’s main Columbus campus is one of America’s largest...
?
mi
from
Columbus, OH
Click here to add this to my saved trials
1801 Inwood Rd
Dallas, Texas 75390
(214) 645-3300
Principal Investigator: William M Lee, MD
Phone: 214-645-6110
University of Texas Southwestern Medical Center UT Southwestern is an academic medical center, world-renowned for...
?
mi
from
Dallas, TX
Click here to add this to my saved trials
3901 Rainbow Blvd
Kansas City, Kansas 66160
(913) 588-5000
Principal Investigator: Jody Olson, MD
Phone: 913-588-1591
University of Kansas Medical Center The University of Kansas Medical Center serves Kansas through excellence...
?
mi
from
Kansas City, KS
Click here to add this to my saved trials
333 Cedar St
New Haven, Connecticut 06504
(203) 432-4771
Phone: 203-785-1952
Yale University School of Medicine Founded in 1810, the Yale School of Medicine is a...
?
mi
from
New Haven, CT
Click here to add this to my saved trials
Richmond, Virginia 23298
(804) 828-0100
Principal Investigator: Richard T Stravitz, MD
Phone: 804-828-8514
Virginia Commonwealth University Since our founding as a medical school in 1838, Virginia Commonwealth University...
?
mi
from
Richmond, VA
Click here to add this to my saved trials
San Francisco, California 94143
Principal Investigator: Bilal Hameed, MD
Phone: 415-476-6160
?
mi
from
San Francisco, CA
Click here to add this to my saved trials