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

Primary Purpose

Gastrointestinal Bleeding, Cirrhosis

Status

Completed

Phase

Phase 2

Locations

Spain

Study Type

Interventional

Intervention

Ornithine-phenylacetate

About this trial

This is an interventional treatment trial for Gastrointestinal Bleeding focused on measuring cirrhosis, gastrointestinal bleeding

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Hospital Vall Hebron

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ornithine-phenylacetate

Saline iv

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT01434108

First Posted

September 12, 2011

Last Updated

March 19, 2015

Sponsor

Hospital Universitari Vall d'Hebron Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT01434108

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2015

Overall Recruitment Status

Completed

Study Start Date

October 2011 (undefined)

Primary Completion Date

March 2015 (Actual)

Study Completion Date

March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hospital Universitari Vall d'Hebron Research Institute

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Gastrointestinal Bleeding, Cirrhosis

Keywords

cirrhosis, gastrointestinal bleeding

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

48 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ornithine-phenylacetate

Arm Type

Experimental

Arm Description

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

Arm Title

Saline iv

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Ornithine-phenylacetate

Other Intervention Name(s)

OCR-002

Intervention Description

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.

Primary Outcome Measure Information:

Title

Ammonia plasma concentration umol/L.

Description

Time Frame

6 days

Secondary Outcome Measure Information:

Title

Hepatic encephalopathy

Description

Time Frame

6 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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. 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joan Genescà, MD

Organizational Affiliation

EASL

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hospital Vall Hebron

City

Barcelona

ZIP/Postal Code

08035

Country

Spain

12. IPD Sharing Statement

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

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