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Role of Immune Responses After Acute Myocardial Infarction (BATTLE-AMI)

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ClinicalTrials.gov Identifier: NCT02428374
Recruitment Status : Recruiting
First Posted : April 28, 2015
Last Update Posted : June 11, 2015
Sponsor:
Collaborator:
FAPESP - Fundação de Apoio à Pesquisa do Estado de São Paulo
Information provided by (Responsible Party):
Francisco Antonio Helfenstein Fonseca, Federal University of São Paulo

Brief Summary:
The fascinating role of lymphocyte subtypes in the development of coronary artery disease may be a new strategic target for understanding and therapy of acute myocardial infarction. The determinants of cell viability are unknown, postulating that they arise from factors not only related to microcirculation or energy expenditure, but also to inflammatory and immune responses. Furthermore, the intense mobilization of progenitor cells secondary to myocardial infarction triggers large lymphocyte proliferation that colonizes plaques in development, contributing to recurrent ischemic outcomes. This project aims to evaluate the immune and metabolic mechanisms involved in the recovery of the ischemic myocardium and coronary disease progression.

Condition or disease Intervention/treatment Phase
Myocardial Fibrosis Drug: Rosuvastatin plus clopidogrel Drug: Rosuvastatin plus ticagrelor Drug: Simvastatin plus clopidogrel Drug: Simvastatin plus ticagrelor Phase 4

Detailed Description:

Specifically, the investigators will study the innate and adaptive immunity, with emphasis on lymphocytes subtypes involved in the early and late surrogate outcomes of patients with acute myocardial infarction, their characterization (B1, B2 and T lymphocytes) in cell culture and by flow-cytometry, and immune responses (IgM and IgG for oxLDL and specific epitopes of apoB). In addition, the project will evaluate new biomarkers identified by studies of metabolomics, as well as the corresponding signaling pathways. Therapeutic pharmacological strategies and changes on intestinal microbiota will be evaluated since the acute phase of myocardial infarction up to 6 months.

In the study, the investigators will compared four arms of combined therapy: clopidogrel with rosuvastatin; or clopidogrel with simvastatin; or ticagrelor with rosuvastatin; or ticagrelor with simvastatin. The investigator's hypothesis is that the improvement of microcirculation with rosuvastatin and ticagrelor (synergic pleiotropic effects) may decrease the infarcted mass area, resulting in better left ventricular ejection fraction when compared to the other combined therapies.

The monitoring and genotype of microbiota will be examined together the metabolomics and cardiac MRIs obtained at the acute phase of MI and after 1-mo and 6-mo FU.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Role of Innate and Adaptive Immunity After Acute Myocardial Infarction BATTLE-AMI Study (B And T Types of Lymphocytes Evaluation in Acute Myocardial Infarction)
Study Start Date : May 2015
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : July 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Attack

Arm Intervention/treatment
Active Comparator: rosuvastatin plus clopidogrel
rosuvastatin 40 mg and clopidogrel 75 mg
Drug: Rosuvastatin plus ticagrelor
Crestor 40 mg plus Brilinta 180 mg (initial dosis) and 90 mg bid up to 6-mo
Other Name: Crestor & Brilinta

Drug: Simvastatin plus clopidogrel
Zocor 40 mg plus Plavix 600 mg (initial dosis) and 75 mg daily up to 6-mo
Other Name: Zocor plus Plavix

Drug: Simvastatin plus ticagrelor
Zocor 40 mg plus Brilinta 180 mg (initial dosis) and 90 mg bid up to 6-mo
Other Name: Zocor & Brilinta

Active Comparator: Rosuvastatin plus ticagrelor
Rosuvastatin 40 mg plus ticagrelor 90 mg bid
Drug: Rosuvastatin plus clopidogrel
Crestor 40 mg daily plus Plavix 600 mg (initial dosis) and 75 mg daily up to 6-mo
Other Name: Crestor & Plavix

Drug: Simvastatin plus clopidogrel
Zocor 40 mg plus Plavix 600 mg (initial dosis) and 75 mg daily up to 6-mo
Other Name: Zocor plus Plavix

Drug: Simvastatin plus ticagrelor
Zocor 40 mg plus Brilinta 180 mg (initial dosis) and 90 mg bid up to 6-mo
Other Name: Zocor & Brilinta

Active Comparator: simvastatin plus clopidogrel
Simvastatin 40 mg plus clopidogrel 75 mg
Drug: Rosuvastatin plus clopidogrel
Crestor 40 mg daily plus Plavix 600 mg (initial dosis) and 75 mg daily up to 6-mo
Other Name: Crestor & Plavix

Drug: Rosuvastatin plus ticagrelor
Crestor 40 mg plus Brilinta 180 mg (initial dosis) and 90 mg bid up to 6-mo
Other Name: Crestor & Brilinta

Drug: Simvastatin plus ticagrelor
Zocor 40 mg plus Brilinta 180 mg (initial dosis) and 90 mg bid up to 6-mo
Other Name: Zocor & Brilinta

Active Comparator: Simvastatin plus ticagrelor
Simvastatin 40 mg plus ticagrelor 90 mg bid
Drug: Rosuvastatin plus clopidogrel
Crestor 40 mg daily plus Plavix 600 mg (initial dosis) and 75 mg daily up to 6-mo
Other Name: Crestor & Plavix

Drug: Rosuvastatin plus ticagrelor
Crestor 40 mg plus Brilinta 180 mg (initial dosis) and 90 mg bid up to 6-mo
Other Name: Crestor & Brilinta

Drug: Simvastatin plus clopidogrel
Zocor 40 mg plus Plavix 600 mg (initial dosis) and 75 mg daily up to 6-mo
Other Name: Zocor plus Plavix




Primary Outcome Measures :
  1. Comparison of the left ventricular function (MRI) between the four combined treatments, after STEMI [ Time Frame: 1-mo ]
    The effects of treatments on the left ventricular function will be measured by MRI


Secondary Outcome Measures :
  1. To compare the effects of the four combined therapies on the left ventricular function after STEMI [ Time Frame: 3-d ]
    Variables will be examined by MRI

  2. To compare the effects of the four combined therapies on the left ventricular function after STEMI [ Time Frame: 6-mo ]
    Variables will be examined by MRI

  3. To compare the effects of the four combined therapies on the infarcted mass area after STEMI [ Time Frame: 1-mo ]
    Variables will be examined by MRI

  4. To compare the effects of the four combined therapies on the infarcted mass area after STEMI [ Time Frame: 6-mo ]
    Variables will be examined by MRI

  5. To compare the effects of the four combined therapies on the percentage of subjects with left ventricular ejection fraction < 40% after STEMI [ Time Frame: 1-mo ]
    Variables will be examined by MRI

  6. To compare the effects of the four combined therapies on the percentage of subjects with left ventricular ejection fraction < 40% after STEMI [ Time Frame: 6-mo ]
    Variables will be examined by MRI

  7. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction after STEMI [ Time Frame: 1-d ]
    Lymphocyte subtypes quantified by flow-cytometry and left ventricular ejection fraction by MRI

  8. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction after STEMI [ Time Frame: 1-mo ]
    Lymphocyte subtypes quantified by flow-cytometry and left ventricular ejection fraction by MRI

  9. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction after STEMI [ Time Frame: 6-mo ]
    Lymphocyte subtypes quantified by flow-cytometry and left ventricular ejection fraction by MRI

  10. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with infarcted mass area after STEMI [ Time Frame: 1-d ]
    Lymphocyte subtypes quantified by flow-cytometry and infarcted mass area by MRI

  11. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with infarcted mass area after STEMI [ Time Frame: 1-mo ]
    Lymphocyte subtypes quantified by flow-cytometry and infarcted mass area by MRI

  12. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with infarcted mass area after STEMI [ Time Frame: 6-mo ]
    Lymphocyte subtypes quantified by flow-cytometry and infarcted mass area by MRI

  13. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction <40% after STEMI [ Time Frame: 1-d ]
    Lymphocyte subtypes quantified by flow-cytometry and left ventricular ejection fraction by MRI

  14. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction <40% after STEMI [ Time Frame: 1-mo ]
    Lymphocyte subtypes quantified by flow-cytometry and left ventricular ejection fraction by MRI

  15. To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction <40% after STEMI [ Time Frame: 6-mo ]
    Lymphocyte subtypes quantified by flow-cytometry and left ventricular ejection fraction by MRI


Other Outcome Measures:
  1. Relationship between gut microbiota and diabetes status after STEMI [ Time Frame: 1-3d ]
    Intestinal microbiota will be genotyped and diabetes status (non-diabetic, pre-diabetic or diabetic) according to HbA1c levels.

  2. Relationship between gut microbiota and diabetes status after STEMI [ Time Frame: 1-mo ]
    Intestinal microbiota will be genotyped and diabetes status (non-diabetic, pre-diabetic or diabetic) according to HbA1c levels.

  3. Relationship between gut microbiota and diabetes status [ Time Frame: 6-mo ]
    Intestinal microbiota will be genotyped and diabetes status (non-diabetic, pre-diabetic or diabetic) according to HbA1c levels.

  4. Relationship between gut microbiota and metabolomics [ Time Frame: 1-3d ]
    Intestinal microbiota will be genotyped and metabolomics by LC/MS-MS

  5. Relationship between gut microbiota and metabolomics [ Time Frame: 1-mo ]
    Intestinal microbiota will be genotyped and metabolomics by LC/MS-MS

  6. Relationship between gut microbiota and metabolomics [ Time Frame: 6-mo ]
    Intestinal microbiota will be genotyped and metabolomics by LC/MS-MS

  7. Comparison between the four arm of combined therapies on microparticles and endothelial progenitor cells [ Time Frame: 1-d ]
    Endothelial, platelet, and monocyte-derived microparticles as well as endothelial progenitor cells will be quantified by flow-cytometry

  8. Comparison between the four arm of combined therapies on microparticles and endothelial progenitor cells [ Time Frame: 1-mo ]
    Endothelial, platelet, and monocyte-derived microparticles as well as endothelial progenitor cells will be quantified by flow-cytometry

  9. Comparison between the four arm of combined therapies on microparticles and endothelial progenitor cells [ Time Frame: 6-mo ]
    Endothelial, platelet, and monocyte-derived microparticles as well as endothelial progenitor cells will be quantified by flow-cytometry

  10. Correlation between the severity of coronary disease with antibodies against oxidized LDL and peptide D of apolipoprotein B of LDL [ Time Frame: 1-d ]
    Antibodies IgG and IgM against oxidized LDL as well as against peptide D of LDL will be quantified by ELISA. Coronary disease severity will be quantified by the Gensini Score

  11. Comparison between the four arms of combined therapies on TIMI flow grade and blush grade [ Time Frame: 1-d ]
    TIMI flow grade and blush grade will be determined based on coronary angiogram obtained at baseline by two independent and blinded certified invasive cardiologists

  12. Relationship between no-reflow images obtained at MRI with metabolomics [ Time Frame: 1-d ]
    Metabolomics will be determined by LC/MS-MS and images by MRI

  13. Relationship between no-reflow images obtained at MRI with metabolomics [ Time Frame: 1-mo ]
    Metabolomics will be determined by LC/MS-MS and images by MRI

  14. Relationship between no-reflow images obtained at MRI with metabolomics [ Time Frame: 6-mo ]
    Metabolomics will be determined by LC/MS-MS and images by MRI



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Stable patients with ST elevation myocardial infarction (STEMI) treated with thrombolytics in the first 6h or the initial of symptoms of MI.

Exclusion Criteria:

  1. Contraindication or known intolerance to the study drug protocol
  2. Those with comorbidities such as neoplasm, renal insufficiency (stage 4 or higher)

Patients should be randomized in the first 24 hours of AMI and treated by one of the four combined therapies at least 2h prior to coronary angiogram followed by percutaneous intervention when necessary.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02428374


Contacts
Layout table for location contacts
Contact: Francisco A Fonseca, MD, PhD +55 11 992639082 fahfonseca@terra.com.br
Contact: Maria C Izar, MD, PhD +55 11 mcoizar@terra.com.br

Locations
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Brazil
Hospital Sao Paulo - UNIFESP Recruiting
Sao Paulo, Brazil, 04040001
Contact: Francisco A H Fonseca, MD, PhD    +5511992639082    fahfonseca@terra.com.br   
Sponsors and Collaborators
Federal University of São Paulo
FAPESP - Fundação de Apoio à Pesquisa do Estado de São Paulo
Investigators
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Principal Investigator: Francisco A Fonseca, MD, PhD Federal University of São Paulo

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Francisco Antonio Helfenstein Fonseca, Affiliate Professor of Medicine, Federal University of São Paulo
ClinicalTrials.gov Identifier: NCT02428374     History of Changes
Other Study ID Numbers: EPM/UNIFESP
FAPESP ( Other Grant/Funding Number: Research Foundation of the State of Sao Paulo )
First Posted: April 28, 2015    Key Record Dates
Last Update Posted: June 11, 2015
Last Verified: June 2015

Keywords provided by Francisco Antonio Helfenstein Fonseca, Federal University of São Paulo:
MRI
Ventricular function, left

Additional relevant MeSH terms:
Layout table for MeSH terms
Myocardial Infarction
Myocardial Ischemia
Infarction
Ischemia
Pathologic Processes
Necrosis
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Clopidogrel
Ticagrelor
Rosuvastatin Calcium
Simvastatin
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors