Impact of Melatonin in the Pretreatment of Organ Donor and the Influence in the Evolution of Liver Transplant.

Impact of Melatonin in the Pretreatment of Organ Donor and the Influence in the Evolution of Liver Transplant: a Prospective, Randomised Double-blind Study.

Impact of melatonin on organ donor pretreatment and liver transplant recipient: prospective, randomized, double-blind trial.

OBJECTIVES. To establish the efficacy of the melatonin administered to encephalic death donors (EDD) in liver transplantation. The aim is to improve the functional quality of the retrieved organs, attenuate lesions and ischemia-reperfusion mediators, and provide grafts with greater resistance to post-transplant aggression.

METHODOLOGY. Prospective, randomized, double-blind, pilot trial to evaluate preconditioning with melatonin versus placebo in EDDs. Two groups, melatonin and control-placebo, n=30 per group. Administration to donor via NG tube of 30mg of melatonin or placebo (lactose) upon inclusion in the trial, 60 minutes prior to commencement of surgery and following laparotomy during extraction. Evaluation of response to treatment: A) Conventional clinical, hemodynamic, analytical and histopathological parameters in donor and recipient. B) Plasma determinations for: oxidative/nitrosative stress; acute phase proteins; cellular and humoral immunity; NT-proBNP and cystatin C; endocrine profile; melatonin levels. C) Determinations in liver tissue: quantification of malonyldialdehyde-4hydroxyalkenals and protein carbonyl content; cellular and mitochondrial membrane fluidity; markers of tissue-vascular damage and proliferation: transforming growth factor-beta (TGF-β); hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF). Data will be analyzed following a prospectively define plan and by intention-to-treat analysis.

Study Overview

• Status: Unknown
• Conditions: Evidence of Liver Transplantation
• Intervention / Treatment: Drug: Placebo; Drug: Melatonin

Detailed Description

This study will be done in the Hospital Clinico Lozano Blesa (Zaragoza, Spain), promoted by the Health Science Aragon Institute and its principal investigator is F. Agustín García Gil (Surgical Service). It will start in April-May 2013 and will finish 12 months later approximately. The study sponsor is I+CS (Aragon Institute of Health Sciences).

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Zaragoza, Spain, 50009
    • Hospital Clínico Universitario Lozano Blesa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

A) Donors

1. Encephalic-death (ED) organ donor who is situated in the ICUs of accredited hospitals in Zaragoza and meets each and every one of the following criteria.
2. Being 16 years old or older.
3. Informed consent for the donation signed by the immediate family.
4. Informed consent for inclusion of the donor in the study .
5. Receive intensive treatment and standard maintenance of the donor in ED, in accordance with universally accepted protocols of the Organizacion Nacional de Trasplantes (ONT), of the Aragon Autonomous Transplant Coordination, and of the ICUs and the participating hospitals in the study.

B) Liver transplant recipients

1. Being 18 years old or older and being less than 68 years of age.
2. Informed consent for the procedure of LT signed.
3. Informed consent for patient inclusion in the study, signed the same day that consent to the LT.

Exclusion Criteria:

A) Donors

A potential encephalic-death organ donor will not be included in the study if either of the following criteria:

1. Absence of either signed informed consent: for organ donation or for inclusion in the study.
2. No standard concomitant treatment and management of donor in ED.

B) Liver transplant recipients

1. Absence of either signed informed consent: for liver transplantation or for inclusion in the study.
2. Split, domino or multiorgan transplantation.
3. Grafts removed by other surgical teams.
4. Pregnant women or fertile not using contraceptive measures highly effective.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Solution for infusion; Solution for infusion administrated via nasogastric tube	Drug: Placebo
Experimental: Melatonin; 30 mg melatonin administrated via nasogastric tube in the Intensive Care Unit when included in the study and 30 mg melatonin 60 minutes before transfer to the operating room.	Drug: Melatonin; Melatonin 2 mg prolonged-release tablet, administration via nasogastric tube.; Other Names: Circadin (Neurim Pharmaceuticals)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AST levels	Aspartate transaminase (AST) levels will be measured.	Between days 1 and 10 postoperatively.
ALT	Alanine transaminase (ALT) levels will be measured.	Between days 1 and 10 postoperatively
Bilirubin levels	Bilirubin levels will be measured.	Between days 1 and 10 postoperatively
Prothrombin levels	Prothrombin levels will be measured.	Between days 1 and 10 postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-reperfusion syndrome	Post-reperfusion syndrome	Transplant day
No primary function and primary graft dysfunction	No primary function and primary graft dysfunction	Transplant day
Survival of the graft	Survival of the graft	From day 0 to 3 months
Patient survival	Patient survival	Day 0 to 3 months
Donor and recipient serological parameters	Donor and recipient serological parameters	Between days 1 and 10 postoperatively
Morphological and functional quality of the liver graft evaluated by histological parameters of ischemia-reperfusion and tissue biochemical markers	Morphological and functional quality of the liver graft evaluated by histological parameters of ischemia-reperfusion and tissue biochemical markers	Day 0 and day 1

Collaborators and Investigators

• Sponsor: Aragon Institute of Health Sciences
• Collaborators: Fondo de Investigacion Sanitaria
• Investigators: Principal Investigator: Francisco A. García-Gil, Physician, Hospital Clínico Universitario Lozano Blesa

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Anticipated): December 1, 2013
• Study Completion (Anticipated): December 1, 2013

Study Registration Dates

• First Submitted: May 17, 2013
• First Submitted That Met QC Criteria: May 22, 2013
• First Posted (Estimate): May 23, 2013

Study Record Updates

• Last Update Posted (Estimate): May 23, 2013
• Last Update Submitted That Met QC Criteria: May 22, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Melatonin, liver transplant, oxidative stress
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: PI10/02877