68Ga-NODAGA-RGD PET in Patients With an Occluded Coronary Artery (RGDHeart)

68Ga-NODAGA-RGD Cardiac PET in Patients With Acute Myocardial Infarction or Chronic Total Coronary Occlusion

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.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Diagnostic test: 68Ga-NODAGA-RGD PET-imaging

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Antti Saraste, MD, PhD; Phone Number: +35823130000; Email: antti.saraste@utu.fi

Study Locations

• Finland
  • Turku, Finland, 20520
    • Recruiting
    • Turku University Hospital
    • Contact: Antti Saraste, MD, PhD; Phone Number: +3582313000; Email: antti.saraste@utu.fi
    • Sub-Investigator: Christian Paunonen, BM
    • Sub-Investigator: Juhani Knuuti, MD, PhD
• Netherlands
  • Leiden, Netherlands
    • Active, not recruiting
    • Leiden Medical Center
• Switzerland
  • Lausanne, Switzerland, CH-1011
    • Recruiting
    • University of Lausanne Hospitals
    • Contact: John Prior, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acute ST-elevation myocardial infarction or chronic coronary artery occlusion; 68-Ga-NODAGA-RGD PET after acute ST-elevation myocardial infarction or before and after re-opening of a chronic coronary artery occlusion	Diagnostic test: 68Ga-NODAGA-RGD PET-imaging; Patients will undergo cardiac 68Ga-NODAGA-RGD PET in order to detect myocardial αVβ3 integrin expression 3-14 days after an acute myocardial infarction or within 4 weeks before and 2 weeks after re-opening of chronic coronary occlusion. Echocardiography of cardiac function will be performed at the time of PET imaging and repeated 6 months later.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial uptake of 68Ga-NODAGA-RGD after acute myocardial infarction	68Ga-NODAGA-RGD uptake in PET images in the myocardial territory supplied by the occluded coronary artery vs. remote myocardium after an acute myocardial infarction	3 to 14 days after acute myocardial infarction
Myocardial uptake of 68Ga-NODAGA-RGD before and after opening of chronic coronary occlusion	Change in 68Ga-NODAGA-RGD uptake in PET images in the myocardial territory supplied by the occluded coronary artery before and after opening of a chronic coronary occlusion	Within 4 weeks before and 2 weeks after re-opening of a chronic coronary occlusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global left ventricle systolic function	Left ventricle ejection fraction (%) assessed by echocardiography	At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up
Regional left ventricle systolic function	Regional myocardial strain (%) assessed by echocardiography	At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up
Myocardial perfusion reserve	Assessed by PET myocardial perfusion imaging before and after re-opening of chronic coronary occlusion	At the time of 68Ga-NODAGA-RGD PET imaging within 4 weeks before and 2 weeks after re-opening of a chronic coronary occlusion
Adverse cardiac events	Number of patients with myocardial infarction, unstable angina pectoris, repeat revascularization, heart failure hospitalization or death	After 2 years of follow-up
Blood biomarker of heart failure	pro-BNP (ng/L)	At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up
Blood biomarker of myocardial injury	Cardiac troponin T (ng/L)	At the time of 68Ga-NODAGA-RGD PET imaging and after 6 months of follow-up

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Collaborators: University of Lausanne Hospitals; Leiden University Medical Center
• Investigators: Principal Investigator: Antti Saraste, MD, PhD, Turku University Hospital

Publications and helpful links

General Publications

• 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.
• Buchegger F, Viertl D, Baechler S, Dunet V, Kosinski M, Poitry-Yamate C, Rüegg C, Prior JO. 68Ga-NODAGA-RGDyK for αvβ3 integrin PET imaging. Preclinical investigation and dosimetry. Nuklearmedizin. 2011;50(6):225-33. doi: 10.3413/Nukmed-0416-11-06. Epub 2011 Oct 11.
• Grönman M, Tarkia M, Kiviniemi T, Halonen P, Kuivanen A, Savunen T, Tolvanen T, Teuho J, Käkelä M, Metsälä O, Pietilä M, Saukko P, Ylä-Herttuala S, Knuuti J, Roivainen A, Saraste A. Imaging of α(v)β(3) integrin expression in experimental myocardial ischemia with [(68)Ga]NODAGA-RGD positron emission tomography. J Transl Med. 2017 Jun 19;15(1):144. doi: 10.1186/s12967-017-1245-1.
• 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.
• Jenkins WS, Vesey AT, Stirrat C, Connell M, Lucatelli C, Neale A, Moles C, Vickers A, Fletcher A, Pawade T, Wilson I, Rudd JH, van Beek EJ, Mirsadraee S, Dweck MR, Newby DE. Cardiac alphaVbeta3 integrin expression following acute myocardial infarction in humans. Heart. 2017 Apr;103(8):607-615. doi: 10.1136/heartjnl-2016-310115. Epub 2016 Dec 7.
• 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.
• 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.
• 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 αvβ3 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2018
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: January 14, 2021
• First Submitted That Met QC Criteria: May 3, 2021
• First Posted (Actual): May 4, 2021

Study Record Updates

• Last Update Posted (Actual): March 22, 2022
• Last Update Submitted That Met QC Criteria: March 20, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Positron Emission Tomography; Myocardial Infarction
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease
• Other Study ID Numbers: T02/011/18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: May be shared upon reasonable request to the PI

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No