Evaluation of [18F]-Flutemetamol PET Tracer for Diagnostic Imaging in Cardiac Amyloidosis: A Phase II Monocentric Exploratory Study

Trial ID: 2024-517971-19-01
Protocol: PULSAR
Sponsor: Fondazione Toscana Gabriele Monasterio

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Diseases & Conditions

Cardiac amyloidosis

Objectives

The primary objective of this study is to establish the **affinity** of the tracer [18F]-Flutemetamol for cardiac amyloid deposits in patients with cardiac amyloidosis, specifically in those with ATTRwt, ATTRv, and AL types. This is clinically relevant as it aims to enhance the diagnostic accuracy for cardiac amyloidosis, a condition characterized by the deposition of amyloid proteins in the heart, which can lead to heart failure and other serious complications.

Secondary objectives include:

Comparing the kinetics and extent of radiopharmaceutical cardiac uptake among patients diagnosed with ATTR and AL, and control subjects with non-infiltrative left ventricular hypertrophy.
Checking for any correlation between the radiopharmaceutical uptake entity and the type of TTR mutation.
Evaluating the diagnostic performance of the radiopharmaceutical in patients with reduced or absent cardiac uptake of the osteophilic radiopharmaceutical, as assessed by scintigraphy (Perugini score: 0 - 1).
Evaluating the potential use of the tracer [18F]-Flutemetamol for detecting extra cerebral and extra cardiac amyloid deposits.

Participants

The clinical trial involves participants diagnosed with **cardiac amyloidosis**, specifically ATTRwt, ATTRv, and AL types. The study population includes both male and female subjects aged 18 years and older. Participants are selected based on a clinical suspicion of cardiac amyloidosis, confirmed through various diagnostic methods such as cardiac examination, biomarker assays, and imaging techniques. The trial also includes control subjects with non-infiltrative left ventricular hypertrophy. The study population is characterized by the ability to provide informed consent. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and both genders are represented. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is a **prospective**, monocentric, exploratory phase II study designed to evaluate the diagnostic use of the tracer PET (18F)-Flutemetamol in patients with **cardiac amyloidosis**. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The study is expected to run from January 31, 2023, to July 31, 2025, with participant involvement lasting up to one year. The primary objective is to establish the affinity of the tracer [18F]-Flutemetamol for cardiac amyloid deposits in patients with cardiac amyloidosis ATTRwt, ATTRv, and AL. The primary endpoint involves quantifying myocardial uptake of the tracer using PET parameters.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including a diagnosis of cardiac amyloidosis and the ability to provide consent. Follow-up visits will be scheduled to monitor the tracer's uptake and assess any systemic uptake of the radiopharmaceutical. The end-of-study visit will conclude the participant's involvement, during which final assessments and data collection will occur. The expected length of participant involvement is contingent upon adherence to the study protocol, with early termination possible if adverse events or protocol violations occur.

Inclusion criteria require participants to be male or female, aged 18 years or older, with a confirmed diagnosis of cardiac amyloidosis. Control subjects must have non-infiltrative left ventricular hypertrophy. Exclusion criteria are not specified, but participants must meet all inclusion criteria to be eligible. The study aims to provide quantitative differentiation of myocardial tracer uptake in patients with different ATTRv genotypes and identify any areas of systemic uptake related to amyloid deposits. The trial's design and methodology are structured to ensure comprehensive data collection and analysis, contributing to the understanding of cardiac amyloidosis and the potential diagnostic utility of the tracer.

Treatment

The clinical trial involves the use of **VIZAMYL 400 MBq/mL solution for injection**, an experimental medication containing the active substance **flutemetamol (18F)**. This pharmaceutical form is a **solution for injection** and is administered via **intravenous administration**. The dosage is set at a maximum of 185 MBq per day, with the total dose not exceeding 185 MBq. The treatment period is limited to a single day. The active substance, flutemetamol (18F), is of chemical origin and is utilized for its diagnostic properties in the context of this study. The medication is manufactured by GE Healthcare AS and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are employed. The focus is solely on the evaluation of the diagnostic use of the tracer PET (18F)-Flutemetamol in patients with cardiac amyloidosis. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to establish the affinity of the tracer for cardiac amyloid deposits in patients with cardiac amyloidosis ATTRwt, ATTRv, and AL.

Efficacy

The efficacy of the clinical trial will be assessed through the primary endpoint, which involves the quantification of myocardial uptake of the tracer **[18F] -Flutemetamol** using PET parameters in patients diagnosed with cardiac amyloidosis, including ATTRwt, ATTRv, and AL types. Secondary endpoints will further evaluate the quantification of myocardial uptake in specific subgroups, such as patients with different ATTRv genotypes and those with weakly positive or negative scintigraphy (Perugini 0–1). Additionally, the study will identify and quantify any systemic uptake of the radiopharmaceutical indicative of amyloid deposits, thereby assessing systemic amyloidosis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients with cardiac amyloidosis: male and female, age greater or equal 18 years diagnosed with cardiac amyloidosis. In accordance with the recommendations of the European Society of Cardiology, all of the following conditions must be present: - clinical suspicion of disease based on one or more of the following exams: cardiac examination, biomarker assay (NT-proBNP, HS-TnT, plasma protein electrophoresis, serum and urinary immunofixation, free light chains), baseline EKG, baseline echocardiography, cardiac magnetic resonance; - clearly positive osteophilic radiopharmaceutical scintigraphy (Perugini 2-3) in the absence of serum and/or urinary monoclonal component OR abdominal fat biopsy and/or endomyocardial biopsy showing ATTR or AL amyloidosis; - genetic characterization to identify patients with ATTRv; - ability to provide consent to the study.
Control subjects: male and female, age greater or equal 18 years diagnosed with not-infiltrative left ventricular hypertrophy;
ability to consent to the study.

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Exclusion Criteria

pregnancy confirmed by plasma beta-HCG on 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 samesex 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 at baseline through the measurement of beta human gonadotropin on the serum;
breastfeeding;
known ischemic heart disease;
hypersensitivity to the active substance or to any of the excipients listed in the chapter 6.1 of the simplified IMPD;
severe hepatic insufficiency [alteration in the presence of known chronic liver disease of AST (male normal range> 34 IU / L; female <30 IU / L), ALT (male normal range 10-40 IU / L; female 7-35 IU / L), gamma-GT (normal range 7-64 IU / L), albumin (normal range 3.5-5 g / dl), prothrombin activity (normal range PT 70-120%) and bilirubin (normal range> 1,2 mg/dl)];
severe renal insufficiency [GFR estimated from creatinine and BUN <30 mL/ min/1.73 m2]; PET/CT or scintigraphic examination 24 hours prior to enrolment;
participation in a clinical study with an investigational drug administered within 30 days before the screening or 5 half-lives of the study drug, whichever the longest