Comparative Evaluation of [18F]RO6958948, [18F]PI-2620, and [18F]MK-6240 PET Tracers in Cognitive Impairment: A Longitudinal Multicenter Study

The primary objective of this study is to compare the **cross-sectional** and **longitudinal** measures of tau obtained with three second-generation PET tau tracers: [18F]RO948, [18F]PI2620, and [18F]MK-6240. This comparison is conducted directly in the same volunteers to elucidate the advantages and limitations of their use in research cohorts, clinical trials, and clinical practice. This is clinically relevant as it aims to enhance the understanding of tau pathology in cognitive impairment, potentially improving diagnostic accuracy and therapeutic strategies.

Secondary objectives include:

• Comparing the cross-sectional features of tau PET tracers.
• Comparing the longitudinal progression of tau PET tracers over 18-24 months.
• Testing the associations between tau PET tracers and plasma biomarker values.

The clinical trial involves participants with **cognitive impairment**, including conditions such as Mild Cognitive Impairment (MCI), Alzheimer's Disease (AD), Frontotemporal Dementia, Primary Progressive Aphasia, Progressive Supranuclear Palsy, Corticobasal Degeneration, Dementia with Lewy Bodies, and Down's Syndrome. The study population comprises both male and female subjects, with an age range primarily between 50 to 90 years, although individuals over 18 years are also included for certain conditions. The trial includes a vulnerable population, and the selection criteria encompass various clinical criteria specific to each condition. The sponsor has not provided the total number of participants. Participants' general health status and lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of three second-generation PET tau tracers in individuals with **cognitive impairment**. This study employs a **randomized**, **double-blind**, and **controlled** methodology to ensure the reliability and validity of the results. The trial is expected to span from July 2024 to May 2027, with participant involvement lasting approximately one year. The primary objective is to compare cross-sectional and longitudinal measures of tau using the tracers [18F]RO948, [18F]PI2620, and [18F]MK-6240, with the main outcome being the Standardized Uptake Value Ratio (SUVR) derived from PET tau images co-registered with structural MRI images.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age and clinical diagnosis. Follow-up visits will be scheduled to monitor the administration of the radiopharmaceuticals and to collect imaging data. The end-of-study visit will conclude the trial, where final assessments and data collection will occur. The study includes several follow-up visits to ensure comprehensive data collection and participant safety.

Participants are expected to remain in the study for its entire duration unless specific conditions necessitate early termination. These conditions include adverse reactions to the investigational products, withdrawal of consent, or any significant protocol deviations. The trial aims to provide valuable insights into the diagnostic performance and associations of tau tracers with various clinical and biomarker outcomes, contributing to the understanding of their potential use in research and clinical settings.

The clinical trial involves the administration of several **experimental medications** in the form of solutions for injection. The first experimental medication is **florquinitau F-18**, also known by its sponsor product code **[18F]MK-6240**. This compound is a chemical substance administered as a solution for injection. The maximum daily and total dose is 185 MBq, delivered via **intravenous injection**. The treatment period is limited to a single day. Participant compliance is monitored to ensure adherence to the dosing schedule.

The second experimental medication is **2-(6-[18F]FLUORO-PYRIDIN-3-YL)-9H-DIPYRIDO[2,3-B:3',4'-D]PYRROLE**, with the sponsor product code **[18F]RO6958948**. This chemical substance is also provided as a solution for injection. The maximum daily and total dose is 370 MBq, administered through intravenous injection, with a treatment period of one day. Compliance monitoring is implemented to ensure proper administration.

**VIZAMYL 400 MBq/mL solution for injection** is used as a **comparator treatment** in the study. The active substance in this solution is **flutemetamol (18F)**. The maximum daily and total dose is 150 MBq, administered via intravenous injection, with a treatment period of one day. This comparator is utilized to evaluate the efficacy of the experimental medications against a known standard.

The final experimental medication is **[18F]PI-2620**, containing the active substance **izaflortaucipir (18F)**. This chemical compound is administered as a solution for injection. The maximum daily and total dose is 185 MBq, delivered through intravenous injection, with a treatment period of one day. Participant compliance is closely monitored to ensure accurate dosing.

Efficacy in this clinical trial will be assessed primarily through the measurement of the **Standardized Uptake Value Ratio (SUVR)** derived from PET tau images. These images will be co-registered with structural MRI images, using the lower cerebellar cortex as a reference region. This primary endpoint will provide a quantitative measure of tau deposition in the brain, which is crucial for evaluating the effectiveness of the radiopharmaceuticals under investigation.

Secondary endpoints will include a variety of analyses to further elucidate the efficacy of the tau PET tracers. These will involve SUVR values obtained for different tracers, voxel-wise and regional correlation analysis, and the transformation of values to standardize tau PET tracers to a common scale. Additionally, the trial will assess diagnostic performance among different groups and explore associations of tau tracers with amyloid, brain atrophy, cognition, and plasma tau biomarkers such as p-tau181, p-tau-217, and p-tau231. Longitudinal tau accumulation rates among tracers will also be evaluated, along with associations between longitudinal changes in tau and amyloid deposition, brain atrophy, and cognitive progression.