Evaluation of Diagnostic Efficacy of 18F-labelled Tracer SYN2 in Positron Emission Tomography for Suspected Coronary Artery Disease Using Adenosine and Regadenoson

The primary objective of this Phase III prospective, multicenter, open-label study is to evaluate the **diagnostic performance** of the novel 18F-labelled tracer, SYN2, for **positron emission tomography** (PET) myocardial perfusion imaging (MPI) in detecting significant **coronary artery disease** (CAD) against the reference standard in subjects with suspected CAD. This is clinically relevant as accurate detection of significant CAD is crucial for timely and appropriate management of the disease, potentially reducing the risk of adverse cardiovascular events.

Secondary objectives include:

• Assessing the diagnostic performance of quantitative perfusion analysis of SYN2 injection PET MPI in detecting significant CAD against the reference standard in subjects with suspected CAD.
• Evaluating the safety of SYN2 PET MPI in detecting significant CAD in subjects with suspected CAD.
• Determining the diagnostic performance of qualitative perfusion analysis of SYN2 PET MPI in detecting significant CAD by invasive coronary angiography (ICA) alone, defined by >70% stenosis in a major branch, in subjects with suspected CAD.
• Assessing the diagnostic performance of quantitative perfusion analysis of SYN2 PET MPI in detecting significant CAD by ICA alone, defined by >70% stenosis in a major branch, in subjects with suspected CAD.

The clinical trial focuses on evaluating the diagnostic performance of SYN2 PET MPI in detecting significant **Coronary Artery Disease** (CAD) in subjects with suspected CAD. The study population includes both male and female participants aged over 18 years. Participants are required to have been scheduled for an invasive coronary angiography for CAD assessment at the time of enrollment. The trial includes individuals capable of undergoing pharmacological or exercise stress imaging protocols. Lifestyle considerations, such as adherence to effective contraception methods for both males and females of reproductive potential, are emphasized throughout the study duration. The trial population selection criteria ensure that participants are willing to comply with all study procedures and are available for the study's duration. However, the sponsor has not provided information regarding the total number of participants involved in the trial.

The clinical trial is a **Phase III** prospective, multicenter, open-label study designed to assess the diagnostic efficacy of a novel 18F-labelled tracer, SYN2, for positron emission tomography (PET) in subjects with suspected **coronary artery disease** (CAD). The trial employs a controlled design with a primary objective to evaluate the diagnostic performance of SYN2 PET myocardial perfusion imaging (MPI) in detecting significant CAD against a reference standard. The study is expected to commence recruitment on October 1, 2023, and conclude by January 1, 2025, with an estimated duration of participant involvement being approximately one month.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, willingness to comply with study procedures, and scheduled invasive coronary angiography. The trial includes follow-up visits for the administration of the investigational medicinal product (IMP) and subsequent imaging procedures. The end-of-study visit will involve final assessments to evaluate the primary and secondary endpoints, including diagnostic performance metrics and safety evaluations.

The trial's design incorporates a sequence of visits to ensure comprehensive data collection and participant safety. The inclusion visit will involve obtaining informed consent and verifying eligibility criteria. Follow-up visits will be scheduled for the administration of SYN2 and the performance of PET MPI. The end-of-study visit will focus on collecting data for primary endpoints, such as sensitivity and specificity of SYN2 PET MPI, and secondary endpoints, including adverse event monitoring and quantitative analysis of diagnostic performance.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as withdrawal of consent or the occurrence of significant adverse events. The trial's methodology ensures rigorous assessment of SYN2's diagnostic capabilities while maintaining participant safety and adherence to ethical standards.

The clinical trial involves the administration of **Adenosine** 6 mg/2 ml solution for injection, which is utilized as an auxiliary treatment. This pharmaceutical form is a solution for injection, and the active substance is adenosine, a chemical compound. The maximum daily and total dose is 6 mg, administered via **infusion**. The treatment period is limited to one day. Adenosine is provided by HIKMA FARMACÊUTICA (PORTUGAL), S.A., and is not a paediatric formulation nor an orphan drug.

The experimental medication in this study is **SYN2**, a novel 18F-labelled tracer used for positron emission tomography (PET) in subjects with suspected coronary artery disease. SYN2 is also a solution for injection, with the active substance being a chemical compound named SYN2. The maximum daily and total dose is 610 MBq, administered as a solution for injection. The treatment period is restricted to one day. SYN2 is provided by SYNEKTIK S.A. and is classified as a test product in the trial.

Additionally, **Rapiscan** 400 microgram solution for injection is used as an auxiliary treatment. The active substance in Rapiscan is **regadenoson**, a chemical compound. The pharmaceutical form is a solution for injection, with a maximum daily and total dose of 400 micrograms, administered via infusion. The treatment period is limited to one day. Rapiscan is provided by GE HEALTHCARE AS and is not a paediatric formulation nor an orphan drug.

The efficacy of the clinical trial will be assessed by evaluating the diagnostic performance of the novel 18F-labelled tracer, SYN2, used in Positron Emission Tomography (PET) for detecting significant **Coronary Artery Disease (CAD)**. The primary endpoint focuses on the diagnostic performance in terms of sensitivity and specificity of qualitative expert assessment of SYN2 PET Myocardial Perfusion Imaging (MPI) against a reference standard. Secondary endpoints include the diagnostic performance measured by the area under the receiver operating characteristics (AUC-ROC) of quantitative analysis of SYN2 PET MPI, which will be estimated using the trapezoidal rule. Additionally, the trial will monitor adverse events and reportable serious adverse rates during the resting study, as defined by the NCI Common Toxicity Criteria for Adverse Events (CTCAE v.5.0), including changes in laboratory parameters, ECG parameters, physical examination, and vital signs. The efficacy assessments will be conducted through expert evaluations and quantitative analyses, ensuring a comprehensive evaluation of SYN2's diagnostic capabilities in subjects with suspected CAD.