Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure Due to Acetaminophen (STOP-ALF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by University of Texas Southwestern Medical Center
Sponsor:
Collaborators:
Medical University of South Carolina
Ocera Therapeutics
Information provided by (Responsible Party):
William Lee, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT01548690
First received: February 24, 2012
Last updated: February 6, 2014
Last verified: February 2014
  Purpose

This Phase 2a clinical study is designed to provide data on OCR-002 in patients with acute liver failure/acute liver injury (ALF/ALI)secondary to acetaminophen toxicity 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.
  • A dose of 10g/24h (0.42g/h) will achieve steady state plasma concentrations within 6-12h with little additional accumulation in the ALI/ALF setting.
  • Treatment with OCR-002 will improve neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.

Condition Intervention Phase
Acute Liver Failure
Acute Liver Injury
Drug: Ornithine phenylacetate
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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 Due to Acetaminophen Overdose

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 30 Days ] [ Designated as safety issue: Yes ]
    To evaluate the safety and tolerability of OCR-002 in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose


Secondary Outcome Measures:
  • Measurement of OCR-002 Plasma Concentration [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    To evaluate the steady state pharmacokinetic and pharmacodynamic profile of OCR-002 in patients with impaired and intact renal function using urinary PAGN as a surrogate marker

  • Change in Venous Ammonia [ Time Frame: 30 Days ] [ Designated as safety issue: No ]
    To evaluate the effect of OCR-002 on venous ammonia levels in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose

  • Neurological Function measured by the Glasgow Coma Scale (GCS) [ Time Frame: 30 Days ] [ Designated as safety issue: No ]
    To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.

  • Neurological Function measured by the West Haven Criteria (WHC) [ Time Frame: 30 Days ] [ Designated as safety issue: No ]
    To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.

  • Neurological Function measured by the Orientation log (O-log) [ Time Frame: 30 Days ] [ Designated as safety issue: No ]
    To evaluate the effect of OCR-002 on neurological function in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose.


Estimated Enrollment: 24
Study Start Date: June 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ornithine Phenylacetate
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

Subjects [12 with minimal renal dysfunction (Cohort1) or ~12 with comprised renal function (Cohort 2)] will be stratified sequentially to 3 escalating dose levels of OCR-002 for assessment of pharmacokinetics (pk). Escalation is contingent upon safety and tolerability of the preceding dose level by Safety Review Committee (SRC) .

OCR-002 will be administered in the vein 5 days total:

  • Dose Level 1(DL1) - 3.33 g/24 hours
  • Dose Level 2 (DL2) -3.33 g/24 hours for 12 hours; if that dose is tolerated, the dose is increased to 6.65 g/24 hours for the next 4 and a half days
  • Dose Level 3 (DL3) -3.33 g/24 hours for 12 hours; if that dose is tolerated, the dose is increased to 6.65 g/24 hours for 12 hours; if that dose is tolerated, the dose is increased to 10 g/24 hours for 4 days

Below is the schedule and number of subjects (n):

  • Cohort 1 DL1 (3)
  • Cohort 1 DL2 (3)
  • SRC review (6)
  • Cohort 1 DL3 (~6)
  • Cohort 2 DL1 (3)
  • Cohort 2 DL2 (3)
  • SRC review (~12)
  • Cohort 2 DL3 (~6)
Other Name: OCR-002

Detailed 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) due to acetaminophen overdose 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 escalation 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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women, ages 18-65 (have not reached their 66th birthday).
  2. Acute liver failure secondary to presumed acetaminophen toxicity, 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 7 days of the inciting event and with 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).
  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. Venous ammonia level >60 µmol/L at baseline (within 8h prior to T0/initiation of infusion).
  6. Serum creatinine levels as follows:

    • Cohort 1: Creatinine < 1.5 mg/dL.
    • Cohort 2 only: Creatinine ≥ 1.5 mg/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 ICP monitoring (if applicable).
  3. Evidence of Wilson's disease, autoimmune hepatitis, alcoholic hepatitis, biliary obstruction, viral hepatitis A, B, or C, ischemic hepatitis, drug-induced liver injury other than acetaminophen, 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 or the use of vasopressors to support blood pressure.
  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. Use of rifaximin/lactulose more than 8 hours prior to initial infusion will not be an exclusion.
  11. Any other health condition that would preclude participation in the study in the judgment of the principal investigator.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01548690

Contacts
Contact: William M. Lee, MD 214-645-6110 william.lee@utsouthwestern.edu

Locations
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94107
Contact: Oren Fix, MD    415-476-6160    Oren.Fix@ucsf.edu   
Principal Investigator: Oren Fix, MD         
United States, Illinois
Northwestern University Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Daniel R Ganger, MD    312-695-4496    DGanger@nmff.org   
Principal Investigator: Daniel R Ganger, MD         
United States, Michigan
University of Michigan Medical Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Robert Fontana, M.D    734-936-4780    rfontana@med.umich.edu   
Principal Investigator: Robert Fontana, MD         
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Raj Reddy, M.D.    215-662-4276    rajender.reddy@uphs.upenn.edu   
Principal Investigator: Rajender Reddy, MD         
Principal Investigator: Kimberly Forde, MD         
United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: David Koch, MD    843-792-6901    kochd@musc.edu   
Contact: Adrian Reuben, MBBS    (843) 792-6901    reubena@musc.edu   
Principal Investigator: David Koch, MD         
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: William M Lee, M.D.    214-645-6110    William.Lee@utsouthwestern.edu   
Principal Investigator: William M Lee, MD         
United States, Virginia
Virginia Commonwealth University Not yet recruiting
Richmond, Virginia, United States, 23298
Contact: Richard T Stravitz, M.D.    804-828-8514    rstravit@vcu.edu   
Principal Investigator: Richard T Stravitz, MD         
Sponsors and Collaborators
William Lee
Medical University of South Carolina
Ocera Therapeutics
Investigators
Principal Investigator: William M Lee, MD UT Southwestern Medical Center
  More Information

Additional Information:
Publications:

Responsible Party: William Lee, Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01548690     History of Changes
Other Study ID Numbers: ALFSG-OCR-002, U01DK058369
Study First Received: February 24, 2012
Last Updated: February 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Texas Southwestern Medical Center:
ornithine
phenylacetate
acetaminophen toxicity
acute liver failure

Additional relevant MeSH terms:
Liver Failure
Liver Failure, Acute
Liver Diseases
Digestive System Diseases
Hepatic Insufficiency
Acetaminophen
Phenylacetic acid
Analgesics
Analgesics, Non-Narcotic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antipyretics
Central Nervous System Agents
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014