An open-label, multi-center, non-randomized pivotal Phase 3 study to evaluate the efficacy and safety of [18F]florbetaben Positron Emission Tomography (PET) imaging to diagnose cardiac AL amyloidosis

The primary objective of this study is to determine the **sensitivity** and **specificity** of the visual assessment of [18F]florbetaben PET images for diagnosing cardiac AL amyloidosis, utilizing the standard of care clinical diagnosis. This is clinically relevant as accurate diagnosis of cardiac AL amyloidosis is crucial for timely and appropriate management of the condition, potentially improving patient outcomes.

Secondary objectives include:

• Determining the sensitivity and specificity of the quantitative [18F]florbetaben PET scan analysis for the diagnosis of cardiac AL amyloidosis.
• Evaluating the correlation of quantitative [18F]florbetaben PET results with left ventricular ejection fraction (LV EF) and left ventricular mass (LV mass).
• Assessing the correlation of the PET results with AL cardiac amyloidosis disease stage I-IV.
• Evaluating the impact of [18F]florbetaben PET (AL-CA vs non AL-CA) on diagnostic thinking and patient management.
• Assessing the preference of patients for endomyocardial biopsy versus [18F]florbetaben PET imaging.
• Evaluating the safety and tolerability of [18F]florbetaben PET in patients with suspected cardiac amyloidosis.

The clinical trial involves a total of **91 participants** diagnosed with or being considered for a possible diagnosis of **cardiac amyloidosis**, including **AL amyloidosis** and **ATTR amyloidosis**. The study population comprises both male and female subjects aged **18 years and older**. Participants were selected based on their potential diagnosis of cardiac amyloidosis, with specific criteria such as established systemic amyloidosis without proven cardiac involvement, known plasma cell dyscrasia, or pathological free light chain levels. Additionally, participants may present with heart failure with preserved ejection fraction and specific echocardiographic or biomarker findings indicative of cardiac involvement. The trial does not include a vulnerable population. Lifestyle considerations include the requirement for female participants of childbearing potential to use highly effective contraception for one week post-PET scan, while male participants and their partners must adhere to contraception for 90 days post-scan. The trial population was selected to ensure the inclusion of individuals who can provide informed consent and are undergoing planned diagnostic procedures to establish cardiac involvement.

The clinical trial is a pivotal Phase 3 study designed to evaluate the efficacy and safety of **[18F]florbetaben** Positron Emission Tomography (PET) imaging for diagnosing cardiac AL amyloidosis. The trial employs an open-label, multi-center, non-randomized design. The primary objective is to determine the sensitivity and specificity of the visual assessment of **[18F]florbetaben** PET images compared to the standard of care clinical diagnosis. The trial is expected to run from September 2022 to June 2025, with participant involvement lasting up to one year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, informed consent, and specific medical conditions indicative of cardiac amyloidosis. The inclusion criteria require participants to be at least 18 years old and capable of providing informed consent. Key conditions for inclusion involve established systemic amyloidosis without proven cardiac involvement or known plasma cell dyscrasia, among others. The screening visit will also involve planned diagnostic procedures to confirm cardiac involvement.

Following the screening, participants will attend follow-up visits for PET imaging and additional assessments. The primary endpoints focus on the sensitivity and specificity of the PET images, while secondary endpoints include quantitative image analysis and correlations with left ventricular ejection fraction and mass, as well as AL-CA prognostic values. The impact of PET imaging on diagnostic thinking and patient management will also be evaluated through physician questionnaires.

The end-of-study visit will conclude the trial for each participant, ensuring all necessary data is collected and any remaining health assessments are completed. Participants may be terminated early from the study if they withdraw consent, experience adverse events, or fail to comply with study procedures. The trial aims to provide valuable insights into the diagnostic capabilities of **[18F]florbetaben** PET imaging for cardiac AL amyloidosis, potentially influencing future clinical practices.

The clinical trial involves the administration of **Neuraceq**, a **300 MBq/mL solution for injection**. The active substance in Neuraceq is **florbetaben (18F)**, a chemical compound used for diagnostic imaging. The pharmaceutical form of Neuraceq is a solution intended for injection, and it is administered via the injection route. The maximum daily dose and total dose amount are both set at 360 MBq, with a maximum treatment period of one day. The administration of Neuraceq is conducted under the supervision of qualified healthcare professionals to ensure accurate dosing and participant safety. Compliance with the dosing schedule is monitored throughout the trial to maintain the integrity of the study results.

In this study, Neuraceq is used as the experimental medication to evaluate its efficacy and safety in diagnosing cardiac AL amyloidosis through Positron Emission Tomography (PET) imaging. The trial is designed as an open-label, multi-center, non-randomized pivotal Phase 3 study. The primary objective is to determine the sensitivity and specificity of the visual assessment of [18F]florbetaben PET images compared to the standard of care clinical diagnosis. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial strictly adheres to the protocol to ensure the reliability and validity of the collected data.

The efficacy of the clinical trial will be assessed by evaluating the sensitivity and specificity of the visual assessment of **[18F]florbetaben** Positron Emission Tomography (PET) images for diagnosing cardiac AL amyloidosis. The primary endpoints include the co-primary efficacy variables of sensitivity and specificity, which will be determined through visual assessment. Secondary endpoints will involve quantitative image analysis to further determine sensitivity and specificity. Additionally, correlations will be made between quantitative **[18F]florbetaben** PET results and left ventricular ejection fraction (LV EF), left ventricular mass (LV mass), and AL-CA prognostic values based on FLC-diff, cTnT, and NT-proBNP levels.

The impact of PET imaging on diagnostic thinking and patient management will also be assessed using physician questionnaires administered before and after the diagnostic work-up, as well as after the receipt of PET results. These assessments will provide insights into how PET imaging influences clinical decision-making and patient care. The trial is designed as an open-label, multi-center, non-randomized pivotal Phase 3 study, with the main objective of determining the diagnostic efficacy of **[18F]florbetaben** PET imaging in patients with suspected cardiac amyloidosis.