Evaluation of [18F]MNI-659 as a Biomarker for Monitoring Disease Progression in Symptomatic and Pre-symptomatic Huntington's Disease Patients

The primary objective of the study is to identify **biomarkers**, used singly or in combination, that enable sensitive measurement of the progression of **Huntington's disease** from the presymptomatic stages onwards, within the framework of clinical trials. This is clinically relevant as it aims to enhance the understanding of disease progression, potentially leading to improved patient management and therapeutic strategies.

Secondary objectives include:

• Identifying patient profiles and Huntington's disease progression trajectories through unsupervised analyses.
• Identifying the best predictive biomarkers, individually or in combination, and establishing their prognostic value on disease progression through supervised analyses.

The clinical trial involves **patients with symptomatic and pre-symptomatic Huntington's disease**. The study population includes both male and female participants, aged between 18 and 65 years. The sponsor has not provided the total number of participants. Participants were selected based on specific inclusion criteria, which required them to be physically able to provide written consent and affiliated with a social security plan. The trial includes healthy volunteers as a control group, who have no known genetic disease and no direct relationship to a Huntington's disease patient. The study does not involve a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate **biomarkers** for predicting the progression of **Huntington's disease** in both symptomatic and pre-symptomatic patients. This study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to span approximately four years, with an estimated recruitment start date in March 2024 and an anticipated end date in January 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age between 18 and 65 years, and the ability to provide informed consent. The trial will include follow-up visits at various intervals, specifically at Day 0 (D0), Month 1 (M1), Month 1 bis (M1 bis), Month 12 (M12), Month 24 (M24), and Month 24 bis (M24 bis). These visits are structured to monitor the progression of the disease and the effect of the intervention, with the primary endpoint being the effect size assessed by the standardized mean difference (Cohen's d) for each biomarker over a two-year follow-up period.

The expected length of participant involvement is up to two years, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that may compromise participant safety. Secondary endpoints will involve analyzing patient profiles and progression trajectories, utilizing socio-demographic data, clinical scores, and statistical methods to identify optimal biomarkers for predicting disease progression. The study will employ both conventional regression and machine learning techniques to evaluate the predictive performance of these biomarkers.

The clinical trial involves the administration of the experimental medication **[18F]MNI-659**, which is a **solution for injection**. The active substance in this medication is **2-[2-[3-[4-(2-(18F)fluoranylethoxy)phenyl]-7-methyl-4-oxoquinazolin-2-yl]ethyl]-4-propan-2-yloxyisoindole-1,3-dione**. This compound is of chemical origin and is administered via **intravenous administration**. The maximum daily dose of **[18F]MNI-659** is 5 micrograms, with a total maximum dose of 10 micrograms over the course of the treatment period. The treatment period is limited to a maximum of 2 days. The pharmaceutical form of the medication is a solution specifically designed for injection, ensuring precise delivery of the active compound.

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 administration of the experimental medication **[18F]MNI-659**. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol, although specific compliance monitoring methods are not detailed in the provided data. The trial aims to identify biomarkers that can sensitively measure the progression of Huntington's disease from presymptomatic stages onwards, using innovative imaging and cognitive biomarkers.

Efficacy in the clinical trial titled "I2BIO-HD. Innovative Imaging and cognitive BIOmarkers to predict Huntington’s Disease progression" will be assessed using both primary and secondary endpoints. The primary endpoint involves evaluating the effect size, which will be determined by the standardized mean difference (Cohen's d) for each **biomarker**. This will be measured by comparing the initial values with those obtained at a 2-year follow-up. Secondary endpoints include the analysis of patient profiles and progression trajectories, which will be assessed at multiple timepoints: D0, M1, M1 bis, M12, M24, and M24 bis. This analysis will incorporate socio-demographic characteristics, initial clinical and paraclinical scores, and their evolution over time. Clustering analyses will be employed, utilizing statistical validation indices to determine the optimal number of clusters and assess cluster quality. Additionally, the identification of the most predictive biomarkers for an unfavorable disease course will be conducted using conventional regression and machine learning methods. The discrimination and calibration performances of each model will be systematically evaluated and compared.