Corticosteroids and Myocardial Injury in CAP (COLOSSEUM TRIAL)

Study Overview
=================
Brief Summary
-----------------
Community-acquired pneumonia (CAP) is often complicated by elevation of cardiac troponin, a marker of myocardial injury, that can be isolated or associated to myocardial infarction (MI). A retrospective study showed that corticosteroid treatment lowers incidence of MI during the hospital-stay. The aim of this clinical trial is to examine whether in-hospital treatment with iv methylprednisolone (20 mg b.i.d) may reduce myocardial injury, as assessed by serum high-sensitivity cardiac T Troponin) and eventually cardiovascular events during a short- and long-term follow-up in patients hospitalized CAP.

Detailed Description
-----------------
Background. Community-acquired pneumonia (CAP) is often complicated by elevation of cardiac troponin, a marker of myocardial injury, that can be isolated or associated to myocardial infarction (MI). A retrospective study showed that corticosteroid treatment lowers incidence of MI during the hospital-stay. No data exist so far on the effect of corticosteroids on myocardial injury in CAP patients. Study design. Double-blind randomized placebo-controlled trial. One hundred twenty-two eligible patients will be randomized to a week treatment with iv methylprednisolone (20 mg b.i.d) or placebo from hospital admission. Serum hs-cTnT will be measured at admission and every day until up 3 days from admission. ECG will be monitored every day until discharge. After dismission, all patients will be followed-up 2 years. Aims of the study. Primary objective of the study is to evaluate if methylprednisolone is able to reduce myocardial injury, as assessed by serum high-sensitivity cardiac T Troponin (hs-cTnT), in a cohort of patients hospitalized for CAP. Secondary aims are to evaluate the potential effect of methylprednisolone on cardiovascular events during hospitalization, at 30 day from hospital admission and during 2 years' follow-up. The trial will also examine whether the potential protective effects of methylprednisolone might be due to platelet activation down-regulation.

Official Title
-----------------
Effect of Corticosteroids On MyocardiaL Injury Among Patients Hospitalized for Community-AcquirEd PneUMonia - COLOSSEUM TRIAL

Conditions
-----------------
Community-acquired Pneumonia

Intervention / Treatment
-----------------
* Drug: Methylprednisolone Sodium Succinate
* Drug: Saline Solution for Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Hospitalization for community-acquired pneumonia Exclusion Criteria: Use of corticosteroids in the previous 30 days Health Care-Associated Pneumonia Reported severe immunosuppression (human immunodeficiency virus infection, immunosuppressive conditions or medications) Preexisting medical condition with a life expectancy of less than 3 months Uncontrolled diabetes mellitus Gastritis with or without major gastrointestinal bleeding within 3 months Any condition requiring acute treatment with glucocorticoids

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 3, multicenter, double-blind, placebo-controlled, randomized, intervention trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment group<br>Methylprednisolone Sodium Succinate (20mg/ml) will be given at the dose of 40 mg/day (20 mg x 2/day). The treatment will last 7 days (or the time of hospitalization if the patient is discharged in a period less or more than 7 days). | Drug: Methylprednisolone Sodium Succinate<br>* During hospitalization, 40 mg of methylprednisolone (20 mg/ml) will be given intravenously twice a day (20 mg every 12 hours).<br>|
| Placebo Comparator: Placebo group<br>Saline Solution for Injection will be given ath the dose of 2 ml/day. The treatment placebo will last 7 days (or the time of hospitalization if the patient is discharged in a period less or more than 7 days). | Drug: Saline Solution for Injection<br>* During hospitalization, 2 ml of Saline Solution for Injection will be given intravenously twice a day (2 ml every 12 hours).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High sensitivity cardiac T troponin (myocardial injury biomarker) | Primary endpoint of the study will be a significant reduction of hs-cTnT increase. Hs-cTnT will be measured . Hs-cTnT levels will be measured by the Elecsys 2010 (Roche Diagnostics, Indianapolis, IN) in a dedicated core laboratory. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum TxB2 (biomarker of platelet activation) | Serum Thromboxane (Tx) B2 will be measured on blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days). | 7 days | 
| sP-selectin (biomarker of platelet activation). | Plasma sP-selectin will be measured on blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days). | 7 days | 
| sCD40L (biomarker of platelet activation). | Plasma sCD40L will be measured on blood sample obtained at admission, after 72 hours and at hospital discharge (within 7 days). | 7 days | 
| High-sensitivity C-Reactive Protein | Serum high-sensitivity C-Reactive Protein will be measured in blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days). | 7 days | 
| Serum sNOX2-dp (biomarker of oxidative stress) | Serum sNOX2-dp will be measured on blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days). Blood levels of soluble NOX2-derived peptide (sNOX2-dp), a marker of NADPH oxidase activation, will be detected by ELISA as previously described (Pignatelli P et al Arterioscler Thromb Vasc Biol 2010;30:360-7). | 7 days | 
| Serum F2-isoprostanes (biomarker of oxidative stress) | Serum F2-isoprostane (8-iso-PGF2α -III) will be measured by the enzyme immunoassay method in blood samples obtained at admission, after 72 horus and at hospital discharge (within 7 days). | 7 days | 
| Urinary F2-isoprostanes (biomarker of oxidative stress) | F2-isoprostanes will be measured in urine samples collected at admission, after 72 horus and at hospital discharge (within 7 days). | 7 days | 
| Cardiovascular events during hospitalization. | This composite outcome will consist in any of the following events during hospitalization: acute myocardial infarction, new or worsening heart failure, new onset atrial fibrillation, stroke, cardiovascular death. | 7 days | 
| Major adverse cardiac and cerebrovascular events (MACCE) at 30 days. | This composite outcome will consist in any of the following events during a 30-days follow-up: cardiovascular death, myocardial infarction and stroke. | 30 days | 
| Major adverse cardiac and cerebrovascular events (MACCE) during a a long-term follow-up. | This composite outcome will consist in any of the following events during a 2-years f follow-up: cardiovascular death, myocardial infarction and stroke. | 2 years | 
| Short-term mortality | Death for any cause during a 30-days follow-up | 30 days | 
| Long-term mortality | Death for any cause during a2 years follow-up | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
corticosteroids