Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury (STOP-ALF)

October 1, 2018 updated by: William Lee

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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) 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.

Study Type

Interventional

Enrollment (Actual)

47

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94107
        • University of California, San Francisco
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Yale University School Of Medicine
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern University
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • University of Kansas Medical Center
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan Medical Center
    • Ohio
      • Columbus, Ohio, United States, 43210
        • The Ohio State University
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina
    • Texas
      • Dallas, Texas, United States, 75390
        • University of Texas Southwestern Medical Center
    • Virginia
      • Richmond, Virginia, United States, 23298
        • Virginia Commonwealth University
    • Washington
      • Seattle, Washington, United States, 98195
        • University of Washington

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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

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 Names:
  • OCR-002

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: 30 Days
To evaluate the safety and tolerability of OCR-002 in patients with acute liver failure/severe acute liver injury
30 Days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measurement of OCR-002 Plasma Concentration
Time Frame: 24 Hours after last infusion
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
Change in Ammonia
Time Frame: Baseline and 72 Hours
To evaluate the effect of OCR-002 on ammonia levels in patients with acute liver failure/severe acute liver injury
Baseline and 72 Hours
Neurological Function Measured by the West Haven Criteria (WHC) for Hepatic Encephalopathy
Time Frame: 120 hours from start of infusion
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
Neurological Function Measured by the Orientation Log (O-log)
Time Frame: 30 Days
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

William Lee

Collaborators

Medical University of South Carolina
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Ocera Therapeutics

Investigators

  • Principal Investigator: William M Lee, MD, UT Southwestern Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2012

Primary Completion (Actual)

February 23, 2017

Study Completion (Actual)

February 23, 2017

Study Registration Dates

First Submitted

February 24, 2012

First Submitted That Met QC Criteria

March 7, 2012

First Posted (Estimate)

March 8, 2012

Study Record Updates

Last Update Posted (Actual)

October 30, 2018

Last Update Submitted That Met QC Criteria

October 1, 2018

Last Verified

October 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ALFSG-OCR-002
  • U01DK058369 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

De-identified data for the overall study will be shared once the study is completed.

IPD Sharing 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.

IPD Sharing Access Criteria

The STOP-ALF PUDS will be made available without cost to researchers and analysts.

IPD Sharing Supporting Information Type

  • Study Protocol

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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