Clinical trial NCT04871217: 68Ga-NODAGA-RGD PET in Patients With an Occluded Coronary Artery
Official title: 68Ga-NODAGA-RGD Cardiac PET in Patients With Acute Myocardial Infarction or Chronic Total Coronary Occlusion
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Coronary Artery Disease
Keywords: Positron Emission Tomography
Myocardial Infarction
Lead sponsor: Turku University Hospital
Sponsor class: OTHER_GOV
Collaborators: name: University of Lausanne Hospitals
name: Leiden University Medical Center
First posted: 2021-05-04
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: Background: In patients with coronary artery disease, acute or chronic coronary artery occlusion is associated with various degrees of ischemic myocardial injury and left ventricle dysfunction. The integrin αVβ3 plays a role in angiogenesis, i.e. formation of new capillaries from pre-existing blood vessels that is increased during repair of ischemic myocardial injury. 68Ga-NODAGA-RGD is a radiopharmaceutical for positron emission tomography (PET) imaging of αVβ3 integrin expression.

Aim: This study aims at evaluating the feasibility of imaging myocardial αVβ3 integrin expression using 68-Ga-NODAGA-RGD PET and whether 68Ga-NODAGA-RGD uptake is associated with myocardial contractile function in patients with an acute or chronic coronary artery occlusion.

Study design: An academic, prospective, open-label study in 60 patients with an acute or chronic coronary occlusion.

Study population: 30 patients with an ST-elevation acute myocardial infarction weeks and left ventricular ejection fraction \<50%. 30 patients with planned percutaneous re-opening of a chronic coronary total occlusion and left ventricular ejection fraction \<50%.

Study procedures: Patients will undergo cardiac 68Ga-NODAGA-RGD PET within 3 to 14 days after an ST-elevation acute myocardial infarction or within 4 weeks before and 2 weeks after planned percutaneous re-opening of chronic coronary total occlusion. Myocardial perfusion reserve will be evaluated in patients with chronic total occlusion by PET. Echocardiography will be performed at the time of PET imaging and repeated 6 months later to evaluate global and regional left ventricle contractile function. Data on relevant cardiovascular clinical history and blood sample will be obtained at imaging visits. Cardiac events will be evaluated after two years.

End-points: Primary: Myocardial uptake of 68-Ga-NODAGA-RGD after an acute myocardial infarction or before and after opening of chronic coronary occlusion. Secondary: Global and regional left ventricle systolic function. Blood biomarkers of myocardial injury and heart failure. Myocardial perfusion reserve. Adverse cardiac events including death, myocardial infarction, unstable angina pectoris, repeat revascularization and heart failure hospitalizations.

Detailed description: Background: In patients with coronary artery disease, acute or chronic coronary artery occlusion is associated with various degrees of ischemic myocardial injury and left ventricle dysfunction. The integrin αVβ3 plays a role in angiogenesis (Brooks 1994), i.e. formation of new capillaries from pre-existing blood vessels that is increased during repair of ischemic myocardial injury (Meoli 2004, Higuchi 2008, Sherif 2012, Sun 2003, Jenkins 2017). 68Ga-NODAGA-RGD is a radiopharmaceutical for positron emission tomography (PET) imaging of αVβ3 integrin expression (Grönman 2017, Buchegger 2011, Pohle 2012, Gnesin 2017).

Aim: This study aims at evaluating the feasibility of imaging myocardial αVβ3 integrin expression using 68-Ga-NODAGA-RGD PET and whether 68Ga-NODAGA-RGD uptake is associated with myocardial contractile function in patients with an acute or chronic coronary artery occlusion.

Study design: An investigator-initiated, prospective, open-label study in 60 patients with an acute or chronic coronary occlusion.

Study population: 30 patients with an ST-elevation acute myocardial infarction weeks and left ventricular ejection fraction \<50%. 30 patients with planned percutaneous re-opening of a chronic coronary total occlusion and left ventricular ejection fraction \<50%.

Study procedures: Patients will undergo cardiac 68Ga-NODAGA-RGD PET within 3 to 14 days after an ST-elevation acute myocardial infarction or within 4 weeks before and 2 weeks after planned percutaneous re-opening of chronic coronary total occlusion. Myocardial perfusion reserve will be evaluated in patients with chronic total occlusion by PET myocardial perfusion imaging. Complete echocardiography will be performed at the time of PET imaging and repeated 6 months later to evaluate global and regional left ventricle contractile function. Data on relevant cardiovascular clinical history and blood sample will be obtained at imaging visits. Cardiac events will be evaluated after two years.

Primary end-point: Myocardial uptake of 68-Ga-NODAGA-RGD after an acute myocardial infarction or before and after opening of chronic coronary occlusion. Secondary end-points: Global and regional left ventricle systolic function. Blood biomarkers of myocardial injury (troponin) and heart failure (pro-BNP). Myocardial perfusion reserve. Adverse cardiac events including death, myocardial infarction, unstable angina pectoris, repeat revascularization and heart failure hospitalizations.

Sample size: This is an exploratory study and formal power calculation cannot be performed.

Ethical aspects: The study conforms to the World Medical Association Declaration of Helsinki. Written statement will be obtained from the ethics committee (the Ethical Board of the South-Western Finland). Permissions from regulatory authorities (the Finnish Medicines Agency Fimea) and the Turku University Hospital for conducting the study will be obtained. Signed and dated informed consent will be obtained from patients before conducting any study specific procedures.

Eligibility criteria: Inclusion Criteria:

* ST-elevation acute myocardial infarction within 3-14 days
* Planned elective percutaneous revascularization of angiographically documented coronary chronic total occlusion (CTO)
* Left ventricular ejection fraction \< 50% when hospitalized for index acute myocardial infarction or within 12 months before planned revascularization of coronary CTO
* Provision of signed and dated informed consent prior to study specific procedures

Exclusion Criteria:

* Current unstable angina
* Significant valvular heart disease
* NYHA IV heart failure symptoms
* Severe untreated hypertension (\>180/110 mmHg)
* Female not post-menopausal
* Contraindications for adenosine infusion (in patients with CTO):
* Severe renal failure (estimated glomerular filtration rate \< 30 ml/min)
* Atrial fibrillation with ventricular response \> 110 bpm
* No acoustic window for left ventricle assessment by echocardiography
* Previous cardiac surgery

Primary outcomes:
measure: Myocardial uptake of 68Ga-NODAGA-RGD after acute myocardial infarction
timeFrame: 3 to 14 days after acute myocardial infarction
measure: Myocardial uptake of 68Ga-NODAGA-RGD before and after opening of chronic coronary occlusion
timeFrame: Within 4 weeks before and 2 weeks after re-opening of a chronic coronary occlusion
Secondary outcomes:
measure: Global left ventricle systolic function
timeFrame: At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up
measure: Regional left ventricle systolic function
timeFrame: At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up
measure: Myocardial perfusion reserve
timeFrame: At the time of 68Ga-NODAGA-RGD PET imaging within 4 weeks before and 2 weeks after re-opening of a chronic coronary occlusion
measure: Adverse cardiac events
timeFrame: After 2 years of follow-up
measure: Blood biomarker of heart failure
timeFrame: At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up
measure: Blood biomarker of myocardial injury
timeFrame: At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up
Other outcomes:
Locations:
city: Turku
country: Finland
facility: Turku University Hospital
city: Leiden
country: Netherlands
facility: Leiden Medical Center
city: Lausanne
country: Switzerland
facility: University of Lausanne Hospitals
Study officials:
affiliation: Turku University Hospital
name: Antti Saraste, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994 Apr 22;264(5158):569-71. doi: 10.1126/science.7512751.
citation: Buchegger F, Viertl D, Baechler S, Dunet V, Kosinski M, Poitry-Yamate C, Ruegg C, Prior JO. 68Ga-NODAGA-RGDyK for alphavbeta3 integrin PET imaging. Preclinical investigation and dosimetry. Nuklearmedizin. 2011;50(6):225-33. doi: 10.3413/Nukmed-0416-11-06. Epub 2011 Oct 11.
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citation: Higuchi T, Bengel FM, Seidl S, Watzlowik P, Kessler H, Hegenloh R, Reder S, Nekolla SG, Wester HJ, Schwaiger M. Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography. Cardiovasc Res. 2008 May 1;78(2):395-403. doi: 10.1093/cvr/cvn033. Epub 2008 Feb 6.
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citation: Meoli DF, Sadeghi MM, Krassilnikova S, Bourke BN, Giordano FJ, Dione DP, Su H, Edwards DS, Liu S, Harris TD, Madri JA, Zaret BL, Sinusas AJ. Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction. J Clin Invest. 2004 Jun;113(12):1684-91. doi: 10.1172/JCI20352.
citation: Pohle K, Notni J, Bussemer J, Kessler H, Schwaiger M, Beer AJ. 68Ga-NODAGA-RGD is a suitable substitute for (18)F-Galacto-RGD and can be produced with high specific activity in a cGMP/GRP compliant automated process. Nucl Med Biol. 2012 Aug;39(6):777-84. doi: 10.1016/j.nucmedbio.2012.02.006. Epub 2012 Mar 22.
citation: Sherif HM, Saraste A, Nekolla SG, Weidl E, Reder S, Tapfer A, Rudelius M, Higuchi T, Botnar RM, Wester HJ, Schwaiger M. Molecular imaging of early alphavbeta3 integrin expression predicts long-term left-ventricle remodeling after myocardial infarction in rats. J Nucl Med. 2012 Feb;53(2):318-23. doi: 10.2967/jnumed.111.091652.
citation: Sun M, Opavsky MA, Stewart DJ, Rabinovitch M, Dawood F, Wen WH, Liu PP. Temporal response and localization of integrins beta1 and beta3 in the heart after myocardial infarction: regulation by cytokines. Circulation. 2003 Feb 25;107(7):1046-52. doi: 10.1161/01.cir.0000051363.86009.3c.
citation: Gnesin S, Mitsakis P, Cicone F, Deshayes E, Dunet V, Gallino AF, Kosinski M, Baechler S, Buchegger F, Viertl D, Prior JO. First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK. EJNMMI Res. 2017 Dec;7(1):43. doi: 10.1186/s13550-017-0288-x. Epub 2017 May 18.