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

Cirrhosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01434108
• Other study ID #: OP_GIB
• Secondary ID: 2009-017819-16
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: September 12, 2011
• Last updated: March 19, 2015
• Start date: October 2011
• Est. completion date: March 2015

Study information

• Verified date: March 2015
• Source: Hospital Universitari Vall d'Hebron Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cirrhosis
• Gastrointestinal Bleeding
• Gastrointestinal Hemorrhage
• Hemorrhage
• Liver Cirrhosis

Intervention

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.

Locations

Country	Name	City	State
Spain	Hospital Vall Hebron	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Universitari Vall d'Hebron Research Institute

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ammonia plasma concentration umol/L.	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.	6 days	No
Secondary	Hepatic encephalopathy	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.	6 days	No