Evaluation of Cerebral Amyloid and Glucose Metabolism in Alzheimer's Disease Using 18F-Flutemetamol and 18F-Fludeoxyglucose PET in ALFA Project Participants

The primary objective of this study is to determine the **prevalence** and progression of positive 18F-Flutemetamol scans in individuals recruited in the ALFA project. This is clinically relevant as it aids in understanding the early detection and monitoring of Alzheimer's Disease, potentially facilitating timely intervention strategies.

Secondary objectives include:

• To determine the prevalence of the different stages of preclinical Alzheimer's Disease according to the NIA-AA criteria. This objective is crucial for identifying the distribution of disease stages in the population, which can inform targeted therapeutic approaches.

The clinical trial focuses on individuals diagnosed with **Alzheimer's Disease**. The study population includes both male and female participants, with an age range of 45 to 65 years. Participants are required to have a general health status that includes cognition within psychometric normal ranges, as indicated by a Mini Mental State Examination score of 26 or higher and a Verbal Semantic Fluency score of 12 or higher at baseline. Additionally, participants must have a score of 0 on the Clinical Dementia Rating scale at baseline. The trial does not involve a vulnerable population. Participants are expected to have a good knowledge of Spanish or Catalan and be literate. Female participants should be post-menopausal or present a negative pregnancy test at the time of PET realization. The sponsor has not provided information regarding the total number of participants. The trial population was selected from individuals enrolled in the STUDY 45-65 FPM/2012, with the requirement of having a cerebral MRI not suggestive of radiological incidental findings that would constitute an exclusion criterion. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.

The clinical trial is designed to evaluate the **prevalence** and progression of positive **18F-Flutemetamol** scans in individuals with **Alzheimer's Disease**. This is a Phase IV, randomized, double-blind, controlled study, utilizing a parallel-group design. The trial is expected to run from January 2, 2017, to December 30, 2028. Participants will be administered either **VIZAMYL 400 MBq/mL** or **BARNASCAN 3000 MBq/mL** solution for injection, both delivered via **intravenous injection**. The primary endpoint is to classify participants based on their mean cortex activity SUVr (cerebellar cortex) over 1.56 in **18F-Flutemetamol PET** scans, determining the prevalence of positive scans by age, sex, APOE genotype, and family history of Alzheimer's Disease.

Study visits are structured to include an initial screening visit, where eligibility is confirmed through criteria such as informed consent, cognitive assessments, and MRI results. Participants must have a Mini Mental State Examination score of ≥26 and a Clinical Dementia Rating score of 0 at baseline. Follow-up visits will be scheduled to monitor the progression of cerebral amyloid deposition and glucose metabolism. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events. The expected length of participant involvement is approximately one year, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events compromising participant safety.

The clinical trial involves the administration of **VIZAMYL**, a **solution for injection** containing the active substance **flutemetamol (18F)**. This radiopharmaceutical is provided in a concentration of 400 MBq/mL and is administered via **intravenous administration**. The maximum daily and total dose is 185 MBq, with a treatment period limited to a single day. The product is manufactured by GE Healthcare AS and is not formulated for pediatric use. The chemical origin of the active substance ensures its suitability for the intended diagnostic imaging purposes.

Additionally, the trial includes the use of **BARNASCAN**, another **solution for injection** with the active substance **fludeoxyglucose (18F)**. This compound is available at a concentration of 3000 MBq/mL and is administered through **intravenous injection**. The maximum daily and total dose for this product is 400 MBq, also restricted to a one-day treatment period. Produced by Advanced Accelerator Applications Ibérica, S.L.U, BARNASCAN is similarly of chemical origin and is not designed for pediatric patients. Both products are utilized to assess cerebral amyloid deposition and glucose metabolism in the context of the ALFA project.

Efficacy in this clinical trial will be assessed by evaluating the prevalence and progression of positive **18F-Flutemetamol** scans in individuals enrolled in the ALFA project. The primary endpoint involves classifying participants based on their mean cortex activity SUVr (cerebellar cortex) in **18F-Flutemetamol PET** scans. Participants with a mean cortex activity SUVr over 1.56 will be classified as positive for cerebral amyloid deposition, while those with a lower SUVr will be classified as negative. The prevalence of positive **18F-Flutemetamol PET** scans will be further analyzed by age, sex, APOE genotype, and family history of Alzheimer's Disease (AD).