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

Acute Liver Failure Clinical Trial

— STOP-ALF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01548690
• Other study ID #: ALFSG-OCR-002
• Secondary ID: U01DK058369
• Status: Completed
• Phase: Phase 2
• Start date: June 2012
• Est. completion date: February 23, 2017

Study information

• Verified date: October 2018
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: February 23, 2017
• Est. primary completion date: February 23, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Liver Failure
• Acute Liver Injury
• Liver Failure
• Liver Failure, Acute
• Wounds and Injuries

Intervention

Drug:
• 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).

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	The Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of California, San Francisco	San Francisco	California
United States	University of Washington	Seattle	Washington

Sponsors (4)

Lead Sponsor	Collaborator
William Lee	Medical University of South Carolina, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Ocera Therapeutics

Country where clinical trial is conducted

United States, 

References & Publications (33)

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. — View Citation

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Blei AT. Pathogenesis of brain edema in fulminant hepatic failure. Prog Liver Dis. 1995;13:311-30. Review. — View Citation

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. — View Citation

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. — View Citation

Davies NA, Wright G, Ytrebø LM, Stadlbauer V, Fuskevåg 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. — View Citation

Ichai P, Duclos-Vallée 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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2007 Apr 27. — View Citation

Jalan R. Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure. Neurochem Int. 2005 Jul;47(1-2):78-83. Review. — View Citation

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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. Review. — View Citation

Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt 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. — View Citation

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. Erratum in: Gastroenterology. 2013 Sep;145(3):695. Dosage error in article text. — View Citation

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

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. Review. — View Citation

Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995 Dec;109(6):1907-16. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

Ytrebø LM, Kristiansen RG, Maehre H, Fuskevåg 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. — View Citation

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* Note: There are 33 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Measurement of OCR-002 Plasma Concentration	To evaluate the steady state pharmacokinetic and pharmacodynamic profile of OCR-002 in patients with impaired and intact renal function using urinary phenylacetylglutamine (PAGN) as a surrogate marker	24 Hours after last infusion
Secondary	Change in Ammonia	To evaluate the effect of OCR-002 on ammonia levels in patients with acute liver failure/severe acute liver injury	Baseline and 72 Hours
Secondary	Neurological Function Measured by the West Haven Criteria (WHC) for Hepatic Encephalopathy	The West Haven Criteria (WHC) for Hepatic Encephalopathy measures the severity of encephalopathy and patient's level of consciousness. The scale ranges from 0 to 4; a minimum score of 0 represents a better outcome, and a maximum total score of 4 represents a worse outcome. A score of 0 corresponds to normal consciousness and behavior and normal neurological examination. A score of 1 corresponds to mild lack of awareness, shortened attention span, and impaired addition or subtraction; mild asterixis or tremor. A score of 2 corresponds to lethargy, disorientated or inappropriate behavior, obvious asterixis; slurred speech. A score of 3 corresponds to somnolent but arousable, gross disorientation or bizarre behavior, muscle rigidity and clonus; hyperreflexia. A score of 4 corresponds to coma and decerebrate posturing.	120 hours from start of infusion
Secondary	Neurological Function Measured by the Orientation Log (O-log)	The orientation log focuses on orientation to place, time, and circumstance. There are 10 items on the orientation log, which are scored 0-3. A spontaneous correct response is awarded 3 points. A spontaneous response that is lacking or incorrect, but a correct response is provided following a logical cue is awarded 2 points. A score of 1 is given if spontaneous and cued responses are lacking or incorrect, but a correct response is provided in a recognition format. A score of 0 is given if the spontaneous, cued, or recognition format does not generate a correct answer. Scores from the 10 items are summed and the final score ranges from 0 to 30.	30 Days

External Links

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