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

NCT01548690 | Completed Phase 2 Results DMC

• 2 other identifiers: ALFSG-OCR-002U01DK058369
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 11

Brief Summary

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.

Conditions

Acute Liver Failure; Acute Liver Injury

Keywords

ornithine; phenylacetate; acetaminophen toxicity; acute liver failure; hepatitis B; autoimmune hepatitis; drug-induced liver injury

Outcome Measures

Primary Outcomes (1)

• Number of Participants That do Not Tolerate the Administered Dose and Had Grade 3 or 4 Treatment Emergent Adverse Events as a Measure of Safety and Tolerability

  To evaluate the safety and tolerability of OCR-002 in patients with acute liver failure/severe acute liver injury

  30 Days

Secondary Outcomes (4)

• Measurement of OCR-002 Plasma Concentration

  24 Hours after last infusion

• Change in Ammonia

  Baseline and 72 Hours

• Neurological Function Measured by the West Haven Criteria (WHC) for Hepatic Encephalopathy

  120 hours from start of infusion

• Neurological Function Measured by the Orientation Log (O-log)

  30 Days

Study Arms (1)

Ornithine·Phenylacetate

EXPERIMENTAL

Ornithine Phenylacetate is administered intravenously, through a peripheral venous catheter. Each infusion should will be administered over a period of 120 hours.

Drug: Ornithine Phenylacetate

Interventions

Ornithine Phenylacetate DRUG

Up to 36 patients will be enrolled into 2 groups \[\~18 with minimal renal dysfunction (Cohort 1) \& \~18 w/ comprised renal function (Cohort 2)\] and receive OCR-002 infusion for at least 72 hrs. OCR-002 will be administered in the vein and pharmacokinetics (pk) assessed for all subjects who receive the infusion. The first 24 enrolled subjects received OCR-002 at 3 ascending dose levels (DLs 1-3) with a maximum target infusion rate equivalent to 10g/24h. The remaining 12 patients (\~6 Cohort 1 \& \~6 Cohort 2) will be enrolled and receive identical quantities of OCR-002 at 20g/24hr continuously for 5 days (Dose Level 4).

Also known as: OCR-002

Ornithine·Phenylacetate

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women, ages 18-65 (have not reached their 66th birthday).
• 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.
• ALI patients may also be enrolled (those meeting the above criteria plus coagulopathy (INR ≥ 2.0) and no evidence of encephalopathy)
• Written informed consent from the patient (ALI) or patient's legally authorized representative or family member if he/she is considered encephalopathic (ALF).
• Ammonia level ≥60 μmol/L at baseline (within 8h prior to T0/initiation of infusion).
• Serum creatinine levels as follows:
• Cohort 1: Creatinine ≤1.5 mg/dL; and
• Cohort 2: Creatinine \>1.5 mg/dL and \<10mg/dL.
• Mean arterial pressure of \>65 mmHg.

You may not qualify if:

• History of chronic liver disease.
• Signs of overt cerebral herniation, or uncontrolled intracranial hypertension by intracranial pressure (ICP) monitoring (if applicable).
• 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.
• Significant gastrointestinal bleeding (coffee grounds per nasogastric tube and/or melena).
• Hemodynamic instability, defined by a mean arterial pressure of \<65 mmHg.
• Cardiopulmonary complications such as pulmonary edema, aspiration pneumonia, heart failure.
• QT interval of \>500msec at baseline EKG.
• Pregnancy.
• 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.
• 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.
• Any other health condition that would preclude participation in the study in the judgment of the principal investigator.

Sponsors & Collaborators

• William Lee: lead
• Medical University of South Carolina: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• Ocera Therapeutics: collaborator

Study Sites (11)

University of California, San Francisco

San Francisco, California, 94107, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06520, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Related Publications (34)

• Lee WM. Etiologies of acute liver failure. Semin Liver Dis. 2008 May;28(2):142-52. doi: 10.1055/s-2008-1073114.

  PMID: 18452114 BACKGROUND

• Roberts MS, Angus DC, Bryce CL, Valenta Z, Weissfeld L. Survival after liver transplantation in the United States: a disease-specific analysis of the UNOS database. Liver Transpl. 2004 Jul;10(7):886-97. doi: 10.1002/lt.20137.

  PMID: 15237373 BACKGROUND

• Stravitz RT, Kramer DJ. Management of acute liver failure. Nat Rev Gastroenterol Hepatol. 2009 Sep;6(9):542-53. doi: 10.1038/nrgastro.2009.127. Epub 2009 Aug 4.

  PMID: 19652652 BACKGROUND

• Blei AT. Pathogenesis of brain edema in fulminant hepatic failure. Prog Liver Dis. 1995;13:311-30. No abstract available.

  PMID: 9224508 BACKGROUND

• Jalan R. Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure. Neurochem Int. 2005 Jul;47(1-2):78-83. doi: 10.1016/j.neuint.2005.04.010.

  PMID: 15927306 BACKGROUND

• Larsen FS, Wendon J. Prevention and management of brain edema in patients with acute liver failure. Liver Transpl. 2008 Oct;14 Suppl 2:S90-6. doi: 10.1002/lt.21643.

  PMID: 18825686 BACKGROUND

• Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology. 1999 Mar;29(3):648-53. doi: 10.1002/hep.510290309.

  PMID: 10051463 BACKGROUND

• Blei AT, Larsen FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol. 1999 Oct;31(4):771-6. doi: 10.1016/s0168-8278(99)80361-4. No abstract available.

  PMID: 10551405 BACKGROUND

• Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut. 2006 Jan;55(1):98-104. doi: 10.1136/gut.2004.061754. Epub 2005 Jul 15.

  PMID: 16024550 BACKGROUND

• Traber PG, Dal Canto M, Ganger DR, Blei AT. Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure: ultrastructure and integrity of the blood-brain barrier. Hepatology. 1987 Nov-Dec;7(6):1272-7. doi: 10.1002/hep.1840070616.

  PMID: 3679092 BACKGROUND

• Cordoba J, Gottstein J, Blei AT. Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema. Hepatology. 1996 Oct;24(4):919-23. doi: 10.1002/hep.510240427.

  PMID: 8855198 BACKGROUND

• Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF. L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology. 1999 Sep;30(3):636-40. doi: 10.1002/hep.510300311.

  PMID: 10462368 BACKGROUND

• Rose C, Michalak A, Pannunzio M, Chatauret N, Rambaldi A, Butterworth RF. Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure. Hepatology. 2000 Apr;31(4):872-7. doi: 10.1053/he.2000.5923.

  PMID: 10733542 BACKGROUND

• Jalan R, Wright G, Davies NA, Hodges SJ. L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses. 2007;69(5):1064-9. doi: 10.1016/j.mehy.2006.12.061. Epub 2007 Apr 27.

  PMID: 17467190 BACKGROUND

• Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology. 2005 May;41(5):1179-97. doi: 10.1002/hep.20703. No abstract available.

  PMID: 15841455 BACKGROUND

• Sterling RK, Luketic VA, Sanyal AJ, Shiffman ML. Treatment of fulminant hepatic failure with intravenous prostaglandin E1. Liver Transpl Surg. 1998 Sep;4(5):424-31. doi: 10.1002/lt.500040501.

  PMID: 9724481 BACKGROUND

• O'Grady JG, Gimson AE, O'Brien CJ, Pucknell A, Hughes RD, Williams R. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology. 1988 May;94(5 Pt 1):1186-92. doi: 10.1016/0016-5085(88)90011-x.

  PMID: 3280388 BACKGROUND

• Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004 Nov;127(5):1338-46. doi: 10.1053/j.gastro.2004.08.005.

  PMID: 15521003 BACKGROUND

• Stravitz RT, Larsen FS. Therapeutic hypothermia for acute liver failure. Crit Care Med. 2009 Jul;37(7 Suppl):S258-64. doi: 10.1097/CCM.0b013e3181aa5fb8.

  PMID: 19535956 BACKGROUND

• Randomised trial of steroid therapy in acute liver failure. Report from the European Association for the Study of the Liver (EASL). Gut. 1979 Jul;20(7):620-3. doi: 10.1136/gut.20.7.620.

  PMID: 385456 BACKGROUND

• Kumar M, Satapathy S, Monga R, Das K, Hissar S, Pande C, Sharma BC, Sarin SK. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology. 2007 Jan;45(1):97-101. doi: 10.1002/hep.21486.

  PMID: 17187417 BACKGROUND

• Ichai P, Duclos-Vallee JC, Guettier C, Hamida SB, Antonini T, Delvart V, Saliba F, Azoulay D, Castaing D, Samuel D. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl. 2007 Jul;13(7):996-1003. doi: 10.1002/lt.21036.

  PMID: 17370335 BACKGROUND

• Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995 Dec;109(6):1907-16. doi: 10.1016/0016-5085(95)90758-0.

  PMID: 7498656 BACKGROUND

• Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364-72. doi: 10.1002/hep.20948.

  PMID: 16317692 BACKGROUND

• Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, Davern TJ 2nd, Murray NG, McCashland T, Reisch JS, Robuck PR; Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. doi: 10.1053/j.gastro.2009.06.006. Epub 2009 Jun 12.

  PMID: 19524577 BACKGROUND

• Liou IW, Larson AM. Role of liver transplantation in acute liver failure. Semin Liver Dis. 2008 May;28(2):201-9. doi: 10.1055/s-2008-1073119.

  PMID: 18452119 BACKGROUND

• Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH, Mehta RL, Blei AT, Fontana RJ, McGuire BM, Rossaro L, Smith AD, Lee WM; Acute Liver Failure Study Group. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med. 2007 Nov;35(11):2498-508. doi: 10.1097/01.CCM.0000287592.94554.5F.

  PMID: 17901832 BACKGROUND

• Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology. 2009 Jun;136(7):2159-68. doi: 10.1053/j.gastro.2009.02.050.

  PMID: 19505424 BACKGROUND

• Jalan R, Lee WM. Treatment of hyperammonemia in liver failure: a tale of two enzymes. Gastroenterology. 2009 Jun;136(7):2048-51. doi: 10.1053/j.gastro.2009.04.016. Epub 2009 May 3. No abstract available.

  PMID: 19409290 BACKGROUND

• Davies NA, Wright G, Ytrebo LM, Stadlbauer V, Fuskevag OM, Zwingmann C, Davies DC, Habtesion A, Hodges SJ, Jalan R. L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology. 2009 Jul;50(1):155-64. doi: 10.1002/hep.22897.

  PMID: 19437490 BACKGROUND

• Ytrebo LM, Kristiansen RG, Maehre H, Fuskevag OM, Kalstad T, Revhaug A, Cobos MJ, Jalan R, Rose CF. L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology. 2009 Jul;50(1):165-74. doi: 10.1002/hep.22917.

  PMID: 19554542 BACKGROUND

• Zimmerman L, Jornvall H, Bergstrom J. Phenylacetylglutamine and hippuric acid in uremic and healthy subjects. Nephron. 1990;55(3):265-71. doi: 10.1159/000185973.

  PMID: 2370926 BACKGROUND

• Novack, T. (2000). The Orientation Log. The Center for Outcome Measurement in Brain Injury. http://www.tbims.org/combi/olog

  BACKGROUND

• Stravitz RT, Fontana RJ, Karvellas C, Durkalski V, McGuire B, Rule JA, Tujios S, Lee WM; Acute Liver Failure Study Group. Future directions in acute liver failure. Hepatology. 2023 Oct 1;78(4):1266-1289. doi: 10.1097/HEP.0000000000000458. Epub 2023 May 16.

  PMID: 37183883 DERIVED

Related Links

• Acute Liver Failure Study Website
• Instructional STOP-ALF YouTube Video

MeSH Terms

Conditions

Liver Failure, Acute; Hepatitis B; Hepatitis, Autoimmune; Chemical and Drug Induced Liver Injury

Interventions

ornithine phenylacetate

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Hepatitis, Chronic; Autoimmune Diseases; Immune System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Results Point of Contact

• Title: William M. Lee, MD
• Organization: University of Texas Southwestern Medical Center

William.Lee@UTSouthwestern.edu

(214) 645-6110

Study Officials

• William M Lee, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 24, 2012
• First Posted: March 8, 2012
• Study Start: June 1, 2012
• Primary Completion: February 23, 2017
• Study Completion: February 23, 2017
• Last Updated: October 30, 2018
• Results First Posted: September 20, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: The public use dataset (PUDS) will be submitted to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within six months of the primary outcome publication date. The PUDS will be available through the NIDDK Repository for the period of time required under the NIDDK Data Sharing Policy.
• Access Criteria: The STOP-ALF PUDS will be made available without cost to researchers and analysts.

Locations

US (11)