Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury
NCT ID: NCT01548690
Last Updated: 2018-10-30
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
47 participants
INTERVENTIONAL
2012-06-30
2017-02-23
Brief Summary
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* 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.
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Detailed Description
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* 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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Ornithine·Phenylacetate
Ornithine Phenylacetate is administered intravenously, through a peripheral venous catheter. Each infusion should will be administered over a period of 120 hours.
Ornithine Phenylacetate
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).
Interventions
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Ornithine Phenylacetate
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).
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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.
18 Years
65 Years
ALL
No
Sponsors
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Medical University of South Carolina
OTHER
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH
Ocera Therapeutics
INDUSTRY
William Lee
OTHER
Responsible Party
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William Lee
Professor
Principal Investigators
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William M Lee, MD
Role: PRINCIPAL_INVESTIGATOR
UT Southwestern Medical Center
Locations
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University of California, San Francisco
San Francisco, California, United States
Yale University School of Medicine
New Haven, Connecticut, United States
Emory University
Atlanta, Georgia, United States
Northwestern University
Chicago, Illinois, United States
University of Kansas Medical Center
Kansas City, Kansas, United States
University of Michigan Medical Center
Ann Arbor, Michigan, United States
The Ohio State University
Columbus, Ohio, United States
Medical University of South Carolina
Charleston, South Carolina, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Virginia Commonwealth University
Richmond, Virginia, United States
University of Washington
Seattle, Washington, United States
Countries
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References
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Lee WM. Etiologies of acute liver failure. Semin Liver Dis. 2008 May;28(2):142-52. doi: 10.1055/s-2008-1073114.
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.
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.
Blei AT. Pathogenesis of brain edema in fulminant hepatic failure. Prog Liver Dis. 1995;13:311-30. No abstract available.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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.
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.
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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.
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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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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Acute Liver Failure Study Website
Instructional STOP-ALF YouTube Video
Other Identifiers
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ALFSG-OCR-002
Identifier Type: -
Identifier Source: org_study_id
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