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

NCT ID: NCT01434108

Last Updated: 2015-03-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2015-03-31

Brief Summary

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.

Conditions

Gastrointestinal Bleeding; Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ornithine-phenylacetate

Administration of OP (OCR-002) during 5 days in addition to standard treatment of gastrointestinal bleeding.

Group Type: EXPERIMENTAL

Ornithine-phenylacetate

Intervention Type: DRUG

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.

Saline iv

Administration of control infusion (saline infusion) during 5 days in addition to standard treatment of gastrointestinal bleeding.

Group Type: PLACEBO_COMPARATOR

Ornithine-phenylacetate

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

OCR-002

Eligibility 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.

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospital Universitari Vall d'Hebron Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joan Genescà, MD

Role: PRINCIPAL_INVESTIGATOR

EASL

Locations

Hospital Vall Hebron

Barcelona, Barcelona, Spain

Countries

Spain

Other Identifiers

2009-017819-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

OP_GIB

Identifier Type: -

Identifier Source: org_study_id