Evaluation of Diagnostic Accuracy of [18F]RO6958948 and Flutemetamol (18F) in Identifying High-Risk Neurodegenerative Disorders with Tau-Pathology

The primary objective of the BioFINDER 2 study is to evaluate the **diagnostic accuracy** of Tau PET using 18F-RO6958948 and Vizamyl (18F-Flutemetamol) in identifying healthy elderly individuals and patients with subjective or objective mild cognitive symptoms who are at high risk of developing dementia due to Alzheimer's disease or other neurodegenerative disorders. This is clinically relevant as early and accurate diagnosis can significantly impact the management and treatment strategies for these conditions, potentially improving patient outcomes.

Secondary objectives include: - Investigating whether Tau pathology or amyloid pathology in non-demented subjects affects functional and structural neuronal connectivity as visualized with MRI techniques. - Examining the association between CSF biomarkers, particularly P-tau, total-tau, and oligomeric tau, with 18F-RO6958948 retention visualized with PET. - Determining whether Tau pathology can precede amyloid pathology in preclinical Alzheimer's disease or if it is always a consequence of amyloid accumulation. - Establishing cut-offs for pathological PET scans in a healthy population. These objectives aim to enhance the understanding of the pathophysiology of cognitive disorders and improve diagnostic criteria.

The clinical trial involves a study population comprising both **male** and **female** participants, aged between 20 and 100 years. The trial focuses on individuals with **neurodegenerative disorders** characterized by Tau-pathology, including Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, and mild cognitive impairment. Participants include healthy elderly individuals with no cognitive symptoms and those with mild cognitive impairment or dementia, as reported by the patient or an informant. The general cognition and functional performance of participants are assessed to ensure they do not meet the criteria for a dementia diagnosis at the baseline visit, except for those in the dementia group. All participants are required to be fluent in Swedish and agree to undergo at least one lumbar puncture, MRI scan of the brain, and neuropsychological testing. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **diagnostic accuracy** of Tau PET using **18F-RO6958948** and **Vizamyl (18F-Flutemetamol)** in identifying healthy elderly individuals and patients with mild cognitive symptoms who are at high risk of developing dementia due to **Alzheimer's disease** or other neurodegenerative disorders. This is a Phase 4, randomized, double-blind, controlled trial with an estimated duration from March 1, 2017, to February 29, 2028. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the detection of specific signals of the radiotracers in patients or healthy volunteers.

The trial includes several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (20-100 years), cognitive performance, and language proficiency in Swedish. Participants must agree to undergo at least one lumbar puncture, MRI scan, and neuropsychological testing. Follow-up visits will be scheduled to monitor the uptake ratios of the radiotracers and their association with other diagnostic methods, including CSF biomarkers and MRI findings. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and analyzed.

Participants may be terminated early from the study if they do not meet the inclusion criteria, withdraw consent, or experience adverse events that compromise their safety. The trial aims to provide insights into the regional differences in the distribution of the radiotracers between different neurodegenerative conditions, contributing to improved diagnostics and understanding of cognitive disorders.

The clinical trial involves the administration of **Vizamyl**, a radiopharmaceutical product containing the active substance **Flutemetamol (18F)**. Vizamyl is provided as a **solution for injection** with a concentration of 400 MBq/mL. The maximum daily and total dose administered to participants is 185 MBq. The administration route is via **injection**, and the treatment period is limited to a single day. Vizamyl is utilized to assess its diagnostic accuracy in identifying individuals at high risk of developing dementia due to Alzheimer's disease or other neurodegenerative disorders. The product is manufactured by GE Healthcare AS and is not a pediatric formulation.

The study also includes the investigational use of **[18F]RO6958948**, a radiolabeled compound with the active substance **2-(6-[18F]Fluoro-pyridin-3-yl)-9H-dipyrido[2,3-b:3',4'-d]pyrrole**. This compound is also provided as a **solution for injection**. The maximum daily and total dose for this investigational product is 370 MBq, administered via **injection**. The treatment period is similarly restricted to a single day. The investigational product is developed by Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau. This compound is being evaluated for its potential in improving diagnostic accuracy for cognitive disorders.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the study protocol. Participant compliance with the dosing schedule is monitored to ensure adherence to the trial's requirements. Both substances are of chemical origin and are used to enhance the understanding of the pathophysiology of cognitive disorders within the context of the BioFINDER 2 study.

Efficacy in the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint involves the detection of specific signals of **18F-RO6958948** or **18F-Flutemetamol** in patients with neurodegenerative diseases or healthy volunteers. This will be measured using Positron Emission Tomography (PET) imaging to evaluate the presence and distribution of these radiotracers in the brain.

Secondary endpoints include the measurement of brain-to-cerebellar uptake ratios of **18F-RO6958948** or **18F-Flutemetamol** using a priori Volume of Interest (VOI) analysis. These ratios will be compared between subjects with neurodegenerative diseases and healthy volunteers. Additionally, the study will explore associations between the brain uptake ratios of these radiotracers and other diagnostic methods, such as cerebrospinal fluid (CSF) biomarkers, cognitive tests, and MRI findings. The trial will also investigate regional differences in the distribution of these radiotracers across different neurodegenerative disease conditions.