Phase 3 Multicenter Study of 18F-Florbetaben PET/CT for Non-Invasive Diagnosis of Cardiac AL Amyloidosis in Patients with Monoclonal Component

Trial ID: 2024-517942-33-03
Protocol: PETAL
Sponsor: Fondazione Toscana Gabriele Monasterio

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Diseases & Conditions

Cardiac amyloidosis

Objectives

The primary objective of this study is to define the **concordance** (with a 95% confidence interval) between two diagnostic pathways for cardiac amyloidosis (AL-CA) in patients with a monoclonal component. The study compares the traditional invasive diagnostic pathway with a non-invasive pathway using PET/CT with 18F-florbetaben through visual assessment. This is clinically relevant as it may offer a less invasive and potentially safer diagnostic alternative for patients suspected of having AL-CA.

Secondary objectives include:

To define the diagnostic performance of PET/CT with 18F-florbetaben in terms of sensitivity, specificity, positive and negative predictive value.
To establish cut-offs from myocardial uptake quantification to confirm or discard AL-CA among patients with suspected cardiac amyloidosis and a monoclonal protein, compared to the standard diagnostic algorithm, using quantitative uptake values.
To assess changes in the degree of myocardial 18F-florbetaben uptake over 12 months in patients with AL-CA.
To evaluate the safety and tolerability of PET/CT with 18F-florbetaben in patients evaluated for suspected cardiac amyloidosis.

Participants

The clinical trial focuses on patients diagnosed with **cardiac amyloidosis**. The study population includes both male and female participants aged over 18 years. The sponsor has not provided the total number of participants. Participants were selected based on their ability to understand, sign, and date the informed consent, and specific clinical criteria such as NT-proBNP values greater than 332 ng/L in the absence of renal insufficiency or atrial fibrillation, or left ventricular mean wall thickness greater than 12 mm on echocardiogram. The trial includes a vulnerable population, indicating that special considerations are in place for the protection of these participants. Lifestyle factors such as diet, physical activity, or habits have not been specified by the sponsor.

Plans and Procedures

The clinical trial is a multi-center, phase III study designed to evaluate the efficacy of **18F-florbetaben** positron emission tomography/computed tomography (PET-CT) in the non-invasive diagnosis of cardiac amyloidosis. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from December 1, 2022, to February 28, 2025, allowing for comprehensive data collection and analysis.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age over 18 years and certain biomarker levels. Following successful screening, participants will be randomized to either the traditional invasive diagnostic pathway or the non-invasive PET-CT pathway using **18F-florbetaben**. The primary endpoint is the concordance of these two diagnostic pathways, with secondary endpoints including sensitivity, specificity, and safety assessments.

Throughout the trial, participants will attend follow-up visits to monitor the progression of cardiac amyloidosis and the safety of the imaging procedure. These visits will include assessments of myocardial uptake of **18F-florbetaben** and evaluations of any adverse events. The end-of-study visit will conclude the participant's involvement, summarizing the findings and ensuring the participant's well-being.

The expected length of participant involvement is approximately 12 months, with conditions for early termination including withdrawal of consent, adverse events, or protocol non-compliance. The trial aims to provide valuable insights into the diagnostic capabilities of **18F-florbetaben** PET-CT, potentially offering a less invasive alternative for diagnosing cardiac amyloidosis.

Treatment

The clinical trial involves the use of **Neuraceq**, a **300 MBq/mL solution for injection**. The active substance in this experimental medication is **florbetaben (18F)**, a chemical compound used for diagnostic imaging. Neuraceq is administered as a solution for injection, specifically designed for **intravenous** use. The maximum daily and total dose is set at **300 MBq**, with a treatment period limited to a single day. The administration of Neuraceq is conducted under controlled conditions to ensure precise dosing and participant safety. The pharmaceutical form of Neuraceq is a solution for injection, and it is not formulated for pediatric use. The product is manufactured by Life Molecular Imaging GmbH and is authorized under the marketing authorization number EU/1/13/906/001.

In this study, Neuraceq is utilized as part of a non-invasive diagnostic pathway using **positron emission tomography/computed tomography (PET-CT)** to diagnose cardiac AL amyloidosis. The trial aims to compare this non-invasive method with traditional invasive diagnostic pathways. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol and to maintain the integrity of the trial results.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the **concordance** of two diagnostic pathways for cardiac AL amyloidosis (AL-CA) in patients with a monoclonal component. The primary endpoint is the concordance, with a 95% confidence interval, between the traditional invasive diagnostic pathway and a non-invasive pathway using 18F-florbetaben PET/CT, assessed through visual evaluation. Secondary endpoints include the sensitivity, specificity, and predictive values of the PET/CT with 18F-florbetaben compared to the current diagnostic standard. Additionally, the trial will assess the diagnostic cut-off for AL-CA using quantitative analysis of PET/CT with 18F-florbetaben, variation in myocardial uptake intensity over 12 months, and the safety and tolerability of the imaging procedure.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Men and women aged >18 years
Ability to understand, sign and date the informed consent
NT-proBNP values >332 ng/L in the absence of renal insufficiency or atrial fibrillation or left ventricular mean wall thickness >12 mm on echocardiogram and/or a pattern of circumferential or diffuse subendocardial late gadolinium enhancement and/or BNP >81 ng/L, in a clinical setting judged compatible with CA by experienced clinicians

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Exclusion Criteria

Hypersensitivity to the active principle or any excipient listed in the paragraph 6.1 of the Summary of Product Characteristics (RCP) of Neuraceq®
Chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1,73 m2)
Liver disease [elevation >2 times above the upper reference limit of AST (normal range: males 34 UI/L, females 30 UI/ L), ALT (normal range: males 40 UI/L, females 35 UI/L), gamma-GT (normal range: 64 UI/L)
Performing a PET/CT or scintigraphic exam within 24 hours
Impossibility to lay flat for about 60 minutes
New York Heart Association (NYHA) class IV
Pregnancy or breastfeeding, women with childbearing potential and sexually active not employing highly effective contraceptive methods with a low dependency on the user (from the screening to the end of visit 1), which include: i. abstinence, ii. sexual intercourse only with same-sex partners, iii. monogamous relationship with a partner with prior vasectomy, iv. intrauterine device, v. combined hormonal contraception including estrogens and progesteron-like hormones plus the inhibition of ovulation (oral, intravaginal or transdermal), vi. hormonal contraception based on progesterone- like compounds plus the inhibition of ovulation (oral, injectable, implantable), viii. intrauterine device with hormone release. The highly effective contraceptive measures above are not required for women made sterile by surgical means (for example through tube ligation, hysterectomy, bilateral salpingectomy, bilateral ovariectomy) or after the menopause, defined as 12 months of spontaneous amenorrhea without another clinical cause and with elevated FSH levels in agreement with the expected values for the menopause. For patients with true abstinence or with just same-sex partners, contraception is not required, as far as this is in line with their preferred and habitual lifestyle. Periodical abstinence (for example, estimate of the timing of ovulation or assessment of body temperature) and coitus interruptus are not acceptable contraceptive methods. If a patient stops to be abstinent, she must use the highly effective contraceptive methods above. The pregnancy status in women potentially fertile will be checked through the measurement of beta human gonadotropin on the serum and repeated at the end of the study
Participation to a study involving the administration of an experimental drug within 30 days from the screening or 5 half-lives of the study drug, whichever the longest
Lack of informed consent or impossibility to complete study procedures