Effects of the Administration of Ornithine Phenylacetate in Patients With Cirrhosis and Upper Gastrointestinal Bleeding

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Hospital Universitari Vall d'Hebron Research Institute
Sponsor:
Information provided by (Responsible Party):
Hospital Universitari Vall d'Hebron Research Institute
ClinicalTrials.gov Identifier:
NCT01434108
First received: September 12, 2011
Last updated: March 31, 2014
Last verified: March 2014
  Purpose

The main objective is to evaluate the effectiveness of the experimental drug to reduce plasma ammonia concentration at a dose that is safe and well tolerated. Ammonia usually rises significantly in the hours after gastrointestinal bleeding in patients with cirrhosis of the liver. This increase in the concentration of ammonia facilitates the development of hepatic encephalopathy.

The study will be divided in two parts:

Part A: Open-label, dose-escalating, single cohort study. The goal of this phase is to confirm the tolerance and safety of the dose of OP that is being proposed for the study according to the results of phase I and phase II studies in healthy subjects and stable outpatients with cirrhosis.

Part B: Multi-center (2 University Hospitals), double-blind, randomized, parallel-group trial. Assignment of treatment will be done according to a list (one at each study site) of random numbers in blocks that will be concealed until the end of the study. The control group will be assigned to placebo on a 1:1 ratio. The placebo and treatment will be masked.


Condition Intervention Phase
Gastrointestinal Bleeding
Cirrhosis
Drug: Ornithine-phenylacetate
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of the Administration of Ornithine Phenylacetate in Patients With Cirrhosis and Upper Gastrointestinal Bleeding

Resource links provided by NLM:


Further study details as provided by Hospital Universitari Vall d'Hebron Research Institute:

Primary Outcome Measures:
  • Ammonia plasma concentration umol/L. [ Time Frame: 6 days ] [ Designated as safety issue: No ]
    Venous plasma ammonia will be assessed within 60 minutes of extraction in samples withdrawn every 12 hours during the first 48 hours and once a day during the second 72 hours. The concentration of ammonia will be used to decide: a)dose escalating in the initial phase (first 48 hours) of part A and b)discontinuation of treatment in the second phase (second 72 hours) of part B. Blood samples will be processed immediately after being withdrawn to separate plasma under cold conditions. Ammonia will be measured enzymatically in a Cobas Integra analyzer.


Secondary Outcome Measures:
  • Hepatic encephalopathy [ Time Frame: 6 days ] [ Designated as safety issue: No ]
    Hepatic encephalopathy (HE) is a common complication of cirrhosis,characterized by a myriad of neurological manifestations,diverse underlying liver disorders, and a variety of precipitating factors. For evaluated the presence and severity of HE the CHESS, and WEST-HAVEN scales will be performe because are adequate for clinical trials.


Estimated Enrollment: 48
Study Start Date: October 2011
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
Administration of OP (OCR-002) during 5 days in addition to standard treatment of gastrointestinal bleeding.
Drug: Ornithine-phenylacetate

Phase A: Open-label scalating dose of OP. Treatment will be initiated at 1/3 of the final dose and will be scalated every 12 hours up to the full dose, except if there are problems of tolerance. Duration of the infusion 5 days.

Phase B: Comparative study of experimental drug vs placebo for 5 days OP (OCR-002) at a dose of 10 g diluted in 150 ml of water for injection administered as a continuous i.v. infusion for 24 hours (8.3 ml/h)during 5 days.

Other Name: OCR-002
Placebo Comparator: Saline iv
Administration of control infusion (saline infusion) during 5 days in addition to standard treatment of gastrointestinal bleeding.
Drug: Ornithine-phenylacetate

Phase A: Open-label scalating dose of OP. Treatment will be initiated at 1/3 of the final dose and will be scalated every 12 hours up to the full dose, except if there are problems of tolerance. Duration of the infusion 5 days.

Phase B: Comparative study of experimental drug vs placebo for 5 days OP (OCR-002) at a dose of 10 g diluted in 150 ml of water for injection administered as a continuous i.v. infusion for 24 hours (8.3 ml/h)during 5 days.

Other Name: OCR-002

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Cirrhosis of the liver; diagnosed by clinical, laboratory or radiological findings.
  • Upper gastrointestinal bleeding, as judged by clinical signs (hematemesis, melena, anemia) combined with endoscopic data.
  • Bleeding that has been active within 24 hours prior to inclusion; signs of activity are defined by the presence of blood in the gastrointestinal tract and symptoms attributable to bleeding (hypotension, tachycardia, etc.).
  • Age between 18 and 75 years.
  • Informed consent by the patient. In case of inability to provide informed consent due to impaired mental status secondary to hepatic encephalopathy the informed consent should be provided by the next of kin and should be confirmed by the patient when he/she recovers from hepatic encephalopathy.
  • Absence of exclusion criteria.

Exclusion criteria

  • Terminal illness (e.g. advanced hepatocellular carcinoma).
  • Need for mechanical ventilation.
  • Renal impairment, defined by a creatinine > 1.5 mg/dl or need of hemodialysis.
  • Pregnant or breast-feeding. Pre-menopausal women capable of bearing children should be following a reliable method of birth control and should have a negative result in a pregnancy test prior to inclusion.
  • Known or suspected hypersensitivity or allergic reaction to ornithine or phenylacetate.
  • Use of medications known to interfere with the clearance of either ornithine and/or phenylacetate, such as antibiotics of the penicillin group and probenicid.
  • Use of medications that may induce hyperammonemia; such as haloperidol, valproic acid, and systemic corticosteroids.
  • History or known infection with human immunodeficiency virus (HIV).
  • Neurological comorbidities that impair mental status and do not allow to adequately assess the presence or outcome of hepatic encephalopathy.
  • The presence in the electrocardiogram of a QTcF >500 msec
  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: NCT01434108

Contacts
Contact: Joan Genescà, MD +34 93 274 6140 jgenesca@vhebron.net
Contact: Meritxell Ventura, MD +34 93 274 6240 txell.ventura.cots@gmail.com

Locations
Spain
Hospital Vall Hebron Recruiting
Barcelona, Spain, 08035
Contact: Joan Genescà, MD    +34 93 274 6140    jgenesca@vhebron.net   
Contact: Meritxell Ventura, MD    +34 93 274 6240    txell.ventura.cots@gmail.com   
Principal Investigator: Joan Genescà, MD         
Sponsors and Collaborators
Hospital Universitari Vall d'Hebron Research Institute
Investigators
Principal Investigator: Joan Genescà, MD EASL
  More Information

No publications provided

Responsible Party: Hospital Universitari Vall d'Hebron Research Institute
ClinicalTrials.gov Identifier: NCT01434108     History of Changes
Other Study ID Numbers: OP_GIB, 2009-017819-16
Study First Received: September 12, 2011
Last Updated: March 31, 2014
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Hospital Universitari Vall d'Hebron Research Institute:
cirrhosis, gastrointestinal bleeding

Additional relevant MeSH terms:
Gastrointestinal Hemorrhage
Hemorrhage
Liver Cirrhosis
Fibrosis
Gastrointestinal Diseases
Digestive System Diseases
Pathologic Processes
Liver Diseases
Phenylacetic acid
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 01, 2014