Efficacy of Melatonin in Patients With Severe Sepsis or Septic Shock

Phase III, Prospective, Randomized, Double-blind Clinical Trial to Evaluate the Efficacy of Melatonin in Patients With Severe Sepsis or Septic Shock

OBJECTIVES. To establish the therapeutic efficiency of melatonin in adult patients with severe sepsis and septic shock.

Specifically:

1. To evaluate the survival to 28 days of mechanical assisted ventilation, days with vasoactive drugs, need of hemodialysis-hemofiltration, superinfection and evolution towards the failure of other organs.

2. To evaluate, waiting for reduction under the influence of the treatment with melatonin, :

   1. clinical - analytical parameters of sepsis;
   2. levels of cytokines;
   3. oxidative and nitrosative stress;
   4. acute-phase proteins (APP), specially of the ITIH4;
   5. immune response;
   6. endocrine response.

METHODOLOGY. Patients will be randomized in two groups, n = 55 in each group: 1) treatment with melatonin 30mg/12 hours 28 days; 2) placebo.

Determinations: a) clinical - analytical parameters relative to the sepsis; b) melatonin plasmatic levels; c) quantification of malonyldialdehyde and 4-hydroxynonenal, protein carbonyl content, nitrites, erythrocyte membrane fluidity, and superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase activity; d) Interleukins-1,2,4,5, 6, 7,8,10,12,13, IFN-γ; TNF-α and GM-CSF; e) acute-phase proteins: PCR, haptoglobin, Apo A-I, α1-GPA and ITIH4; f) lymphocytes T, B, NK, T CD4, and T CD8, and immunoglobulins; g) cortisol, aldosterone, ACTH, ADH, insulin, glucagon and 25-hydroxyvitamin D3. Data will be analyzed following a prospectively define plan and by intention-to-treat (ITT) analysis.

Study Overview

• Status: Unknown
• Conditions: Septic Shock; Severe Sepsis
• Intervention / Treatment: 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): 110
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• patients (males and females) over 18 years who meet the diagnostic criteria for severe sepsis or septic shock secondary to community-acquired pneumonia or hospital and or intra-abdominal infection

Exclusion Criteria:

• Patient with more than 24 hours from the first documentation of organ dysfunction

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; saline every 12 hours for 28 days
Experimental: Melatonin; Oral 30mg/12hours melatonin 28 days	Drug: Melatonin; Administration via oral or via a nasogastric tube followed by 20mL saline; Other Names: Liquid 1 mg/mL Melatonin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality at 28 days of study entry.	1 month
Clinical evolution parameters	Days of mechanical ventilation. Days with vasoactive drugs. Days with hemodialysis or hemofiltration. Superinfection of organs other than the initial cause of the sepsis. Progression to other organs fail after starting the treatment.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical evolution	clinical - analytical parameters relative to the sepsis	1 month
Oxidative-nitrosative parameters	Melatonin plasmatic levels Quantification of malonyldialdehyde and 4-hydroxynonenal Protein carbonyl content Nitrites Erythrocyte membrane fluidity Superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase activity	1 month
Inflammatory parameters	Interleukins-1,2,4,5, 6, 7,8,10,12,13, IFN-γ; TNF-α and GM-CSF	1 month
Acute phase proteins	PCR, haptoglobin, Apo A-I, α1-GPA and ITIH4	1 month
Immune parameters	Lymphocytes T, B, NK, T CD4, and T CD8, and immunoglobulins	1 month
Endocrine parameters	Cortisol, aldosterone, ACTH, ADH, insulin, glucagon and 25-hydroxyvitamin D3	1 month

Collaborators and Investigators

• Sponsor: Aragon Institute of Health Sciences
• Collaborators: Ministerio de Sanidad, Servicios Sociales e Igualdad
• Investigators: Principal Investigator: Francisco A García-Gil, Physician, Hospital Clinico 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 17, 2013
• First Posted (Estimate): May 21, 2013

Study Record Updates

• Last Update Posted (Estimate): May 21, 2013
• Last Update Submitted That Met QC Criteria: May 17, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: TRA-172