Efficacy of Melatonin in Patients With Severe Sepsis or Septic Shock

Study Overview
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Brief Summary
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OBJECTIVES. To establish the therapeutic efficiency of melatonin in adult patients with severe sepsis and septic shock. Specifically: 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. To evaluate, waiting for reduction under the influence of the treatment with melatonin, : clinical - analytical parameters of sepsis; levels of cytokines; oxidative and nitrosative stress; acute-phase proteins (APP), specially of the ITIH4; immune response; 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.

Detailed Description
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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).

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

Conditions
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Severe Sepsis, Septic Shock

Intervention / Treatment
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* Drug: Melatonin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis