Assessment of Ischemia and Viability in Coronary Artery Chronic Total Occlusion Using Theophylline Anhydrous, Gadoteric Acid, and Regadenoson Imaging Modalities

The primary objective of this study is to evaluate the **concordance** between coronary CT angiography with myocardial perfusion imaging at stress and rest, and stress cardiac MRI for the detection of ischemia and viability in patients with **chronic total occlusion** (CTO) of the coronary artery. This is clinically relevant as it aims to determine the effectiveness of non-invasive imaging techniques in identifying ischemic regions and assessing myocardial viability, which are critical for guiding treatment decisions in patients with CTO.

Secondary objectives include:

• Evaluating the concordance between stress cardiac MRI without contrast using native myocardial T1 mapping and conventional stress cardiac MRI with contrast for the detection of ischemia in patients with coronary CTO.
• Comparing the modification of the arrhythmogenic substrate, including both myocardial ischemia and scar characterization, using cardiac MRI before and after percutaneous revascularization of a coronary CTO.

The clinical trial involves participants diagnosed with **coronary artery chronic total occlusion**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a distal vessel to the chronic occlusion with a diameter of at least 2.5 mm. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection of the trial population includes individuals who are capable of providing informed consent and are willing to comply with the follow-up protocol. The study considers a vulnerable population, although specific lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to evaluate the concordance between coronary CT angiography, myocardial perfusion imaging at stress and rest, and stress cardiac MRI for detecting ischemia and viability in patients with **coronary artery chronic total occlusion**. This study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial is expected to span approximately 35 months, with an estimated recruitment start date of January 23, 2023, and an anticipated end date of December 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older), presence of chronic total occlusion in a native coronary artery, and the ability to provide informed consent. Following the screening, participants will attend baseline visits for initial assessments, including cardiac magnetic resonance imaging (CMR) and computed tomography (CT) studies. These imaging studies will be conducted using a 3T system and a dual-source scanner, respectively, to evaluate myocardial viability and ischemia.

Follow-up visits will occur at regular intervals, with a significant assessment at six months post-intervention to monitor changes in myocardial perfusion and viability. The end-of-study visit will involve comprehensive evaluations to determine the primary and secondary endpoints, such as myocardial viability, ischemia, and the classification of chronic total occlusion. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as adverse events or withdrawal of consent.

Throughout the trial, the use of investigational products, including **theophylline anhydrous**, **gadoteric acid**, and **regadenoson**, will be carefully monitored. These products are administered as solutions for injection, with specific dosing regimens tailored to each participant's needs. The trial's primary endpoints focus on the enhancement and myocardial thickness criteria for viability, while secondary endpoints include adverse events and arrhythmogenic substrate evaluation. The study aims to provide valuable insights into the management of coronary artery chronic total occlusion, contributing to improved patient outcomes.

The clinical trial involves the administration of **Eufilina Venosa**, a 200 mg solution for injection containing **theophylline anhydrous** as the active substance. This pharmaceutical form is a solution for injection, administered **intravenously**. The maximum daily dose is 200 mg, with a total treatment period of up to 4 days. Theophylline anhydrous is a chemical substance classified under the ATC code R03DA04, indicating its use as a systemic antiasthmatic. The product is manufactured by ZR PHARMA& GMBH and is not a pediatric formulation.

Another treatment used in the study is **Clariscan**, a 0.5 mmol/mL solution for injection containing **gadoteric acid**. This solution is also administered intravenously, with a maximum daily dose of 0.1 mmol/kg. The treatment period is limited to a single day. Gadoteric acid is a chemical substance with the ATC code V08CA02, used as a contrast agent in imaging procedures. The product is manufactured by GE HEALTHCARE BIO-SCIENCES, S.A.U. and is not formulated for pediatric use.

The trial also includes the administration of **Rapiscan**, a 400 microgram solution for injection with **regadenoson** as the active ingredient. This solution is administered intravenously, with a maximum daily dose of 400 micrograms, and the treatment period is restricted to one day. Regadenoson is a chemical substance used as a coronary vasodilator, manufactured by GE HEALTHCARE AS. This product is not intended for pediatric use.

Throughout the trial, participant compliance with the dosing schedules will be monitored to ensure adherence to the specified treatment regimens. The trial aims to evaluate the concordance between different imaging modalities in detecting ischemia and viability in patients with chronic total occlusion.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the detection of ischemia and viability in patients with chronic total occlusion (CTO). The primary endpoints include the assessment of myocardial viability and ischemia. Viability will be determined using the enhancement criterion, which involves measuring the mean late enhancement in more than 50% of the thickness of the affected myocardial wall using the 17-segment model. The number of segments meeting this criterion will be recorded. Additionally, myocardial thickness will be evaluated, with a focus on segments with motility impairment where the mean myocardial thickness is less than 5 or 3 mm. Myocardial ischemia will be identified by an inducible and persistent perfusion defect during the stress study that significantly improves or resolves in the rest study, exceeding the lateral or transmural extent of myocardial scar in the late enhancement study in the same myocardial segment. The number of segments with myocardial ischemia will be documented. CTO will be classified based on the absence of antegrade coronary flow through the coronary stenosis, with classifications of definite or probable based on the duration of the occlusion.

Secondary endpoints include the use of Cardiac Magnetic Resonance Imaging (CMR) and Computed Tomography (CT) as part of routine clinical practice. CMR studies will be conducted at baseline and six months post-intervention using a 3T system (ARCHITECT GE). CT studies will be performed pre-procedurally, incorporating static perfusion assessment at stress and rest, coronary angiography, and late enhancement for viability evaluation using a dual-source scanner with dual-energy capability (Somaton Flash Definition, SIEMENS). Adverse events will be defined according to the Chronic Total Occlusion Academic Research Consortium (CTO-ARC). The arrhythmogenic substrate will be evaluated using late enhancement images obtained through a 3D Inversion-Recovery Gradient Echo sequence, with the ADAS 3D software from Galgo Medical SL. Invasive physiological assessment will be performed in all patients to optimize percutaneous treatment, with follow-up catheterization in patients with distal stenosis to the occlusion ≥ 50%.