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COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial (COMBAT-MI)

Primary Purpose

ST Elevation Acute Myocardial Infarction

Status
Completed
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Exenatide
Remote Ischemic Conditioning (RIC)
Placebo
Sponsored by
Hospital Universitari Vall d'Hebron Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ST Elevation Acute Myocardial Infarction focused on measuring STEMI, Reperfusion Injury, Myocardial Infarction, Myocardial Ischemia, Remote Ischemic Conditioning, Exenatide, Glucagon-Like Peptide-1 (GLP-1), Acute Coronary Syndrome, Cardioprotection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men or women ≥18 years of age
  • STEMI characterized by 2 mm ST segment elevation in 2 or more V1 through V4 leads or presumed new left bundle branch block with minimum of 1 mm concordant ST elevation or 1 mV(millivolt) ST segment elevation in the limb leads (II, III and aVF leads, I, aVL leads) and V4-V6.
  • Patients presenting within 6 hours of chest pain.

Exclusion Criteria:

  • Known hypersensitivity to exenatide or any of the excipients
  • Known contraindication to CMR imaging such as significant claustrophobia, severe allergy to gadolinium chelate contrast, severe renal insufficiency (defined as estimated glomerular filtration rate [eGFR] (epidermal growth factor receptor) <30 mL/min/1.73 m2), presence of CMRI contraindicated implanted devices (e.g., pacemaker, implanted cardiac defibrillator, cardiac resynchronization therapy device, cochlear implant), embedded metal objects (e.g., shrapnel), or any other contraindication for CMRI.
  • Assumed life expectancy < 1 year e.g. due to non-cardiac disease.
  • TIMI flow grade > 1 at the time of diagnostic coronary angiography. These patients will be excluded from the analysis of infarct size but will be included in the safety analysis.
  • Pregnant women
  • Patients with loss of consciousness or confused, not able to read the information and to sign the writting consent
  • Patients with oro-tracheal intubation
  • Patients with cardiogenic shock persisting 48h after reperfusion

Sites / Locations

  • Hospital Universitari Germans Trias i Pujol
  • Hospital Clínico Universitario de Santiago de Compostela
  • Hospital Universitario Valle de Hebron
  • Hospital Universitario Arnau de Vilanova
  • Hospital Universitario Fundación Jiménez Díaz
  • Hospital Universitari de Tarragona Joan 23

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Active Comparator

Arm Label

Remote Ischemic Conditioning

Combined treatment

Placebo

Exenatide

Arm Description

Remote Ischemic Conditioning + placebo

Remote Ischemic Conditioning + exenatide

Sham Remote Ischemic Conditioning + placebo

Sham Remote Ischemic Conditioning + exenatide

Outcomes

Primary Outcome Measures

Myocardial Infarct Size
MI, measured by late gadolinium enhancement in CMRI 3-7 days after pPCI, and expressed as percent of left ventricular mass.

Secondary Outcome Measures

Myocardial salvage index
Myocardial salvage index defined as the difference between infarct size and area at risk, defined by the T2 CMRI and expressed as a percent of total LV (Left Ventricular) mass, divided by the area at risk.
Transmurality index
Transmurality index, defined as the ratio of the mass of myocardium showing late gadolinium enhancement to the mass of the myocardial segment containing it.
Ventricular volumes
LV (Left Ventricular) end-diastolic volume and LVEF (Left Ventricular Ejection Fraction), as determined by CMRI.
Microvascular obstruction
Volume of myocardium with microvascular obstruction determined by late gadolinium enhancement expressed as percent of infarct size.
Markers of successful reperfusion
Markers of successful myocardial reperfusion: ST segment resolution 90 minutes post-pPCI , TIMI flow and frame-count post-pPCI , and TIMI blush grade .
Major adverse cardiac events (MACE)
MACE rate during hospitalization, defined as death, non-fatal myocardial rupture, or appearance or worsening of heart failure during the hospitalization period and after 1 year of follow-up

Full Information

First Posted
March 20, 2015
Last Updated
November 2, 2020
Sponsor
Hospital Universitari Vall d'Hebron Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT02404376
Brief Title
COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial
Acronym
COMBAT-MI
Official Title
COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
March 2016 (Actual)
Primary Completion Date
August 2019 (Actual)
Study Completion Date
June 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospital Universitari Vall d'Hebron Research Institute

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Remote ischemic conditioning (RIC) and intravenous exenatide administered immediately before primary angioplasty have been found to limit infarct size in patients with STEMI (ST segment elevation myocardial infarction), but the reduction is limited. This study investigates whether a combination therapy including both therapies is more effective.
Detailed Description
COMBAT-MI is an investigator-driven, randomized, double-blind and placebo-controlled clinical trial aimed at evaluating the effect of Remote Ischemic Conditioning and exenatide, alone and in combination, on Myocardial Infarct size in 428 STEMI patients (107 per group) (ST segment elevation myocardial infarction). Patients with TIMI (Thrombolysis in Myocardial Infarction) flow grade > 1 will be excluded. The study has a 2 x 2 factorial design (Remote Ischemic Conditioning , Exenatide, both or neither). The primary end-point will be Myocardial Infarct size measured by Cardiac Magnetic Resonance Imaging (CMRI) performed 3 - 7 days after primary Percutaneous Coronary Intervention (pPCI) (expressed as % of left ventricular (LV) mass). Sample size has been calculated in 274 patients with TIMI 0-1 available for analysis of the primary end-point, and inclusion will end when this number is reached, which will require, according to the current rate of TIMI 0-1 in our STEMI population, to randomize 428 patients. Secondary end-points will include myocardial salvage index, based on angiographic and CMRI derived estimations of the area at risk, and frequency of Major Adverse Cardiovascular Events (MACE) and of major adverse events during admission.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ST Elevation Acute Myocardial Infarction
Keywords
STEMI, Reperfusion Injury, Myocardial Infarction, Myocardial Ischemia, Remote Ischemic Conditioning, Exenatide, Glucagon-Like Peptide-1 (GLP-1), Acute Coronary Syndrome, Cardioprotection

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
378 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Remote Ischemic Conditioning
Arm Type
Active Comparator
Arm Description
Remote Ischemic Conditioning + placebo
Arm Title
Combined treatment
Arm Type
Active Comparator
Arm Description
Remote Ischemic Conditioning + exenatide
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Sham Remote Ischemic Conditioning + placebo
Arm Title
Exenatide
Arm Type
Active Comparator
Arm Description
Sham Remote Ischemic Conditioning + exenatide
Intervention Type
Drug
Intervention Name(s)
Exenatide
Intervention Description
Intravenous administration of Exenatide
Intervention Type
Other
Intervention Name(s)
Remote Ischemic Conditioning (RIC)
Intervention Description
Remote ischemic conditioning with a cuff in the arm
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Intrevenous administration of Placebo
Primary Outcome Measure Information:
Title
Myocardial Infarct Size
Description
MI, measured by late gadolinium enhancement in CMRI 3-7 days after pPCI, and expressed as percent of left ventricular mass.
Time Frame
3-7 days after pPCI
Secondary Outcome Measure Information:
Title
Myocardial salvage index
Description
Myocardial salvage index defined as the difference between infarct size and area at risk, defined by the T2 CMRI and expressed as a percent of total LV (Left Ventricular) mass, divided by the area at risk.
Time Frame
3-7 days after pPCI
Title
Transmurality index
Description
Transmurality index, defined as the ratio of the mass of myocardium showing late gadolinium enhancement to the mass of the myocardial segment containing it.
Time Frame
3-7 days after pPCI
Title
Ventricular volumes
Description
LV (Left Ventricular) end-diastolic volume and LVEF (Left Ventricular Ejection Fraction), as determined by CMRI.
Time Frame
3-7 days after pPCI
Title
Microvascular obstruction
Description
Volume of myocardium with microvascular obstruction determined by late gadolinium enhancement expressed as percent of infarct size.
Time Frame
3-7 days after pPCI
Title
Markers of successful reperfusion
Description
Markers of successful myocardial reperfusion: ST segment resolution 90 minutes post-pPCI , TIMI flow and frame-count post-pPCI , and TIMI blush grade .
Time Frame
First 90 min after reperfusion
Title
Major adverse cardiac events (MACE)
Description
MACE rate during hospitalization, defined as death, non-fatal myocardial rupture, or appearance or worsening of heart failure during the hospitalization period and after 1 year of follow-up
Time Frame
Hospital discharge and expected average of 1 week, one year follow-up
Other Pre-specified Outcome Measures:
Title
Substudy: Biomarker analysis in Hospital Universitari Vall d'Hebron Biobank (HUVH Biobank)
Description
To find biomarkers of increased myocardial susceptibility to reperfusion injury in blood samples obtained before PCI
Time Frame
pre- pPCI
Title
PRESPECIFIED SUBGROUP ANALYSIS ACCORDING TO TOTAL ISCHEMIC TIME
Description
The effects of treatments will be analysed in the subgroup of patients with a total ischemic time of less than 3 hours and of 3 hours of longer.
Time Frame
3-7 days after pPCI

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men or women ≥18 years of age STEMI characterized by 2 mm ST segment elevation in 2 or more V1 through V4 leads or presumed new left bundle branch block with minimum of 1 mm concordant ST elevation or 1 mV(millivolt) ST segment elevation in the limb leads (II, III and aVF leads, I, aVL leads) and V4-V6. Patients presenting within 6 hours of chest pain. Exclusion Criteria: Known hypersensitivity to exenatide or any of the excipients Known contraindication to CMR imaging such as significant claustrophobia, severe allergy to gadolinium chelate contrast, severe renal insufficiency (defined as estimated glomerular filtration rate [eGFR] (epidermal growth factor receptor) <30 mL/min/1.73 m2), presence of CMRI contraindicated implanted devices (e.g., pacemaker, implanted cardiac defibrillator, cardiac resynchronization therapy device, cochlear implant), embedded metal objects (e.g., shrapnel), or any other contraindication for CMRI. Assumed life expectancy < 1 year e.g. due to non-cardiac disease. TIMI flow grade > 1 at the time of diagnostic coronary angiography. These patients will be excluded from the analysis of infarct size but will be included in the safety analysis. Pregnant women Patients with loss of consciousness or confused, not able to read the information and to sign the writting consent Patients with oro-tracheal intubation Patients with cardiogenic shock persisting 48h after reperfusion
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ignacio Ferreira González, MD, PhD
Organizational Affiliation
Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Universitari Germans Trias i Pujol
City
Badalona
State/Province
Barcelona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Hospital Clínico Universitario de Santiago de Compostela
City
Santiago de Compostela
State/Province
La Coruña
ZIP/Postal Code
15706
Country
Spain
Facility Name
Hospital Universitario Valle de Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Universitario Arnau de Vilanova
City
Lleida
ZIP/Postal Code
25198
Country
Spain
Facility Name
Hospital Universitario Fundación Jiménez Díaz
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Hospital Universitari de Tarragona Joan 23
City
Tarragona
ZIP/Postal Code
43005
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
21920963
Citation
Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, Mathiasen AB, Jorgensen E, Helqvist S, Saunamaki K, Clemmensen P, Holmvang L, Thuesen L, Krusell LR, Jensen JS, Kober L, Treiman M, Holst JJ, Engstrom T. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012 Jun;33(12):1491-9. doi: 10.1093/eurheartj/ehr309. Epub 2011 Sep 14.
Results Reference
background
PubMed Identifier
20189026
Citation
Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727-34. doi: 10.1016/S0140-6736(09)62001-8.
Results Reference
result
PubMed Identifier
25240548
Citation
White SK, Frohlich GM, Sado DM, Maestrini V, Fontana M, Treibel TA, Tehrani S, Flett AS, Meier P, Ariti C, Davies JR, Moon JC, Yellon DM, Hausenloy DJ. Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv. 2015 Jan;8(1 Pt B):178-188. doi: 10.1016/j.jcin.2014.05.015. Epub 2014 Sep 17.
Results Reference
result
PubMed Identifier
25449504
Citation
Garcia-Dorado D, Garcia-del-Blanco B, Otaegui I, Rodriguez-Palomares J, Pineda V, Gimeno F, Ruiz-Salmeron R, Elizaga J, Evangelista A, Fernandez-Aviles F, San-Roman A, Ferreira-Gonzalez I. Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: a randomized controlled clinical trial. Int J Cardiol. 2014 Dec 20;177(3):935-41. doi: 10.1016/j.ijcard.2014.09.203. Epub 2014 Oct 7.
Results Reference
result

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COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial

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