Evaluation of Amyloid PET Imaging with Florbetaben (18F) and Flutemetamol (18F) in Dementia-Related Morbidity Outcomes

The primary objective of this study is to demonstrate a patient-relevant benefit of **amyloid PET** imaging compared to S3 guideline diagnostics without amyloid PET on dementia-relevant morbidity endpoints. This is clinically significant as it aims to establish the added value of amyloid PET imaging in the diagnostic process for various forms of **dementia**, potentially leading to improved patient outcomes and more tailored therapeutic strategies. The study focuses on several types of dementia, including Alzheimer's disease, vascular dementia, and dementia associated with other conditions such as Parkinson's disease and HIV. The evaluation of amyloid PET imaging could provide critical insights into its role in enhancing diagnostic accuracy and influencing clinical decision-making in dementia care.

The clinical trial involves a study population comprising both **male** and **female** participants aged 50 years and older, with a focus on individuals experiencing mild to moderate **dementia**. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on specific criteria, including the presence of an unclear diagnosis of dementia or uncertain diagnosis of Alzheimer's disease, with a diagnostic certainty of less than 85%. The study population includes individuals who are part of a vulnerable group, as they are affected by various forms of dementia, such as Alzheimer's disease, vascular dementia, and dementia associated with other conditions like Parkinson's disease and HIV. Participants are required to have valid insurance coverage from a German compulsory health insurance and must be accompanied by an informant authorized to provide information. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial aims to demonstrate the benefit of amyloid PET diagnostics compared to standard guideline diagnostics on dementia-relevant morbidity endpoints.

The clinical trial is designed to evaluate the **patient-relevant benefit** of amyloid PET imaging compared to standard S3 guideline diagnostics without amyloid PET in patients with various forms of **dementia**, including Alzheimer's disease. 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 September 2024 to March 2028, with participant involvement expected to last up to 104 weeks from randomization.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, insurance coverage, and dementia diagnosis. Following randomization, participants will be assigned to either the amyloid PET arm or the control arm. The primary endpoint will be assessed 78 weeks after randomization, focusing on the ability to manage activities of daily living as measured by the Amsterdam Instrumental Activities of Daily Living Questionnaire. Secondary endpoints will be evaluated at various intervals, including 26, 52, 78, and 104 weeks, and will encompass cognitive performance, quality of life, and the incidence of adverse events.

The trial will include follow-up visits to monitor the participants' health status and any changes in their condition. The end-of-study visit will occur at the conclusion of the participant's involvement, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, withdraw consent, or if the investigator deems it necessary for their safety. The trial aims to provide valuable insights into the benefits of amyloid PET imaging in the management of dementia, potentially influencing future diagnostic and therapeutic strategies.

The clinical trial involves the administration of **Neuraceq**, a **solution for injection** containing the active substance **florbetaben (18F)**. This radiopharmaceutical is provided at a concentration of 300 MBq/mL and is administered via **intravenous injection**. The maximum daily and total dose is 360 MBq, with a treatment period limited to a single day. The product is manufactured by Life Radiopharma Berlin GmbH and is not formulated for pediatric use. The chemical origin of the active substance ensures its suitability for the intended diagnostic application in amyloid PET imaging.

Additionally, the trial includes the use of **VIZAMYL**, another **solution for injection** with the active substance **flutemetamol (18F)**. This product is available at a concentration of 400 MBq/mL and is also administered through **intravenous injection**. The maximum daily and total dose for VIZAMYL is 185 MBq, with a treatment period restricted to one day. GE Healthcare AS is the manufacturer of this radiopharmaceutical, which, like Neuraceq, is not designed for pediatric use. The chemical nature of flutemetamol (18F) supports its application in the study's diagnostic objectives.

Both Neuraceq and VIZAMYL are utilized as test products in the trial, with no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments being employed. The administration of these radiopharmaceuticals is carefully monitored to ensure participant compliance and adherence to the dosing schedules. The trial aims to demonstrate the patient-relevant benefits of amyloid PET imaging in comparison to standard diagnostics without amyloid PET, focusing on dementia-relevant morbidity endpoints.

Efficacy in the clinical trial titled "Patient- and care-related benefits of amyloid PET imaging (ENABLE)" will be assessed using both primary and secondary endpoints. The primary endpoint is the ability to manage activities of daily living, measured by the Amsterdam Instrumental Activities of Daily Living Questionnaire© (A-IADL-Q) score, evaluated 78 weeks after randomization. This assessment will be conducted by investigators who are blinded to the intervention condition.

Secondary endpoints include several measures: the occurrence of adverse events in the amyloid PET arm during and immediately after the PET examination, and the incidence of adverse and serious adverse events (SAEs), including adverse drug reactions (ARs) and mortality, assessed over the entire trial period. Changes in the aetiological diagnosis of dementia, diagnostic certainty, and management strategies, including medication administration or discontinuation, will be evaluated 26 weeks after randomization and again 78 weeks after randomization. Cognitive performance will be measured using the ADAS-cog and MMSE scales, and quality of life will be assessed using the QOL-AD scale at 26, 52, 78, and 104 weeks after randomization. The need for full inpatient or institutionalized outpatient care, as well as the total duration and frequency of unplanned inpatient stays, will be measured using the FIMA scale. Additionally, the Clinical Dementia Rating (CDR) and Geriatric Depression Scale (GDS) will be evaluated 78 weeks after randomization. Finally, the use of potentially unsuitable medication, as per the PRISCUS list, will be assessed by an independent doctor after database closure.