Evaluation of [18F]RO6958948 PET Imaging for Early Detection and Tau Pathology Mapping in Neurodegenerative Diseases

The primary objective of the study is to establish and validate the use of **tau PET** for the early identification of subjects at risk of developing a **neurodegenerative disease** and for mapping tau pathology over different disease stages. This is clinically relevant as early detection and accurate mapping of tau pathology can significantly enhance the understanding and management of neurodegenerative diseases, potentially leading to improved patient outcomes.

Secondary objectives include: examining interrelationships of tau PET measures with changes in cognition and other novel and established biomarkers for neurodegenerative diseases; understanding differences between dementia disorders in terms of underlying tau-related pathogenic processes; mapping the longitudinal development of tau-related pathogenic processes over different disease stages; defining spatial and temporal differences between purely age-related and disease-related tau aggregation; and establishing tau PET as a tool to evaluate potential treatment outcomes in neurodegenerative diseases associated with tau pathology.

The clinical trial focuses on **neurodegenerative diseases** and involves a study population that includes both male and female participants. The age range of the participants spans from 18 years and older, with specific emphasis on individuals who are part of existing studies such as H75, H70 Clinical Study, Epilepsy Study, BioMin Study, and SWEDOWN study. Participants must be able to speak and understand Swedish without the need for an interpreter. The trial includes a vulnerable population, and participants are required to provide signed informed consent. Fertile women participating in the study are required to use highly effective contraception for 90 days following each administration, and male participants with female reproductive partners must also adhere to contraceptive measures unless their partners are using effective contraceptive methods. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the use of **tau PET** imaging for the early identification of individuals at risk of developing **neurodegenerative diseases** and to map tau pathology across different stages of these diseases. This is a Phase IV, randomized, double-blind, controlled trial, with an estimated duration from January 1, 2018, to June 30, 2025. The trial involves the administration of the investigational product, **RO948 (18F)**, a **solution for injection**, with a maximum daily dose of 370 MBq and a total dose not exceeding 1110 MBq over a treatment period of 48 weeks.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (≥18 years), ability to understand study information, and language proficiency in Swedish. The inclusion visit will involve obtaining informed consent and baseline assessments. Follow-up visits will be scheduled to monitor the uptake of the investigational product using standardized uptake value ratios in selected cortical brain regions, as well as secondary endpoints including CSF and plasma biomarkers, MRI-derived structural and functional measures, and cognitive performance. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of all study parameters.

Participant involvement is expected to last up to 48 weeks, with conditions for early termination including withdrawal of consent, adverse events, or protocol non-compliance. The trial aims to provide valuable insights into the progression of neurodegenerative diseases and the potential of tau PET imaging as a diagnostic tool.

The clinical trial involves the administration of **RO948 (18F), Sahlgrenska**, a novel investigational radiopharmaceutical. The active substance in this experimental medication is **2-(6-[18F]FLUORO-PYRIDIN-3-YL)-9H-DIPYRIDO[2,3-B:3',4'-D]PYRROLE**, also known by its synonyms **[18F]RO6958948** and **[18F]RO-948**. This compound is chemically synthesized and is provided in the form of a **solution for injection**. The administration route is via **injection**, with a maximum daily dose of 370 MBq (megabecquerels) and a cumulative maximum dose of 1110 MBq over the course of the study. The treatment period is limited to a maximum of 48 hours. The investigational product is not formulated for pediatric use and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the investigational product, **RO948 (18F), Sahlgrenska**, to assess its efficacy in mapping tau pathology in neurodegenerative disorders. Participant compliance with the dosing schedule is monitored through standard clinical trial procedures to ensure adherence to the protocol. The trial aims to validate the use of tau PET imaging for early identification of individuals at risk of developing neurodegenerative diseases and to map tau pathology across different stages of these diseases.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint involves the evaluation of **standardized uptake value ratios** of [18F]RO948 in selected cortical brain regions, normalized to a reference region. This measurement will be used to assess the uptake and distribution of the PET ligand, providing insights into tau pathology associated with neurodegenerative diseases.

Secondary endpoints include a range of biomarkers and imaging measures. These encompass cerebrospinal fluid (CSF) measures of proteins and peptides such as sAPPalpha, sAPPbeta, Aβ38, Aβ40, Aβ42, p-tau181, p-tau231, total tau, neurofilament light (NFL), and others. Additionally, structural and functional measures derived from MRI, including cortical volumes, thickness, BOLD signal in selected brain regions, and changes in white matter and vascular structures, will be analyzed. Cognitive performance will be assessed through neuropsychological testing, and plasma measures of Aβ40, Aβ42, NFL, and p-tau will also be evaluated.

The collection and analysis of these efficacy parameters will be conducted at various timepoints throughout the trial, with specific methods and schedules determined by the study protocol. The use of validated scales and laboratory tests will ensure the reliability and accuracy of the data collected. The trial aims to establish and validate the use of tau PET imaging for early identification of individuals at risk of developing neurodegenerative diseases and to map tau pathology across different disease stages.