Clinical trial NCT02404376: COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial
Official title: COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: 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
Lead sponsor: Hospital Universitari Vall d'Hebron Research Institute
Sponsor class: OTHER
First posted: 2015-03-31
Enrollment: 378
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Myocardial Infarct Size
timeFrame: 3-7 days after pPCI
Secondary outcomes:
measure: Myocardial salvage index
timeFrame: 3-7 days after pPCI
measure: Transmurality index
timeFrame: 3-7 days after pPCI
measure: Ventricular volumes
timeFrame: 3-7 days after pPCI
measure: Microvascular obstruction
timeFrame: 3-7 days after pPCI
measure: Markers of successful reperfusion
timeFrame: First 90 min after reperfusion
measure: Major adverse cardiac events (MACE)
timeFrame: Hospital discharge and expected average of 1 week, one year follow-up
Other outcomes:
measure: Substudy: Biomarker analysis in Hospital Universitari Vall d'Hebron Biobank (HUVH Biobank)
timeFrame: pre- pPCI
measure: PRESPECIFIED SUBGROUP ANALYSIS ACCORDING TO TOTAL ISCHEMIC TIME
timeFrame: 3-7 days after pPCI
Locations:
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago de Compostela
state: La Coruña
city: Barcelona
country: Spain
facility: Hospital Universitario Valle de Hebron
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Tarragona
country: Spain
facility: Hospital Universitari de Tarragona Joan 23
Study officials:
affiliation: Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca
name: Ignacio Ferreira González, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.