Assessment of Liver Fibrosis Staging Using 68Ga-FAPI-46 PET/CT Imaging in Patients Undergoing Biopsy for Suspected or Confirmed Nonalcoholic Steatohepatitis

The primary objective of this study is to demonstrate that the **intensity** of 68Ga-FAPI-46 uptake, measured via PET/CT at biopsied hepatic sites, varies according to four histological stages of fibrosis. These stages are defined based on biopsy analyses: stage 4 (cirrhosis), stage 3 (fibrous septa), stage 2 (portal and perisinusoidal fibrosis), and stage <2 (perisinusoidal or periportal fibrosis, or absence of fibrosis). This is clinically relevant as it aims to provide a non-invasive method to assess liver fibrosis stages in patients with suspected or proven non-alcoholic steatohepatitis, potentially improving diagnostic accuracy and patient management.

Secondary objectives include: - Determining threshold values of hepatic 68Ga-FAPI-46 uptake intensity on PET/CT associated with each of the four histological fibrosis stages. - Describing the topographical distribution of hepatic 68Ga-FAPI-46 uptake intensity throughout the liver volume. - Describing 68Ga-FAPI-46 uptake in the entire imaged volume (whole-body PET/CT), particularly in sites with excessive uptake, which may indicate fibrosis, inflammation, or cancer. - Estimating inter- and intra-observer reproducibility of 68Ga-FAPI-46 hepatic uptake intensity measurements. - Evaluating the specific contribution of 68Ga-FAPI-46 PET/CT in characterizing the stage of hepatic fibrosis, in addition to usual clinico-biological scores and pulse elastometry.

The clinical trial involves participants diagnosed with **non-alcoholic hepatic steatosis** and alcoholic hepatic steatosis. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants are required to have undergone a recent liver biopsy for suspected or confirmed non-alcoholic steatohepatitis (NASH). The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include individuals of legal age who have been fully informed about the research and have signed an informed consent form. Participants must be affiliated with a social security scheme or be beneficiaries of such a scheme and have undergone a preliminary clinical examination appropriate to the research. The histological stage of fibrosis obtained at biopsy is a key factor, with an equivalent number of patients with histological stages greater than 2 and less than or equal to 2 required to be recruited in each center. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.

The clinical trial is designed to evaluate the efficacy of **68Ga-FAPI-46** in assessing liver fibrosis stages in patients with suspected or confirmed non-alcoholic steatohepatitis (NASH). This study employs a **randomized, double-blind, controlled** methodology to ensure the reliability and validity of the results. The trial is expected to commence on January 1, 2025, and conclude by August 1, 2027, with a total duration of approximately 32 months. Participants will be involved in the study for a period that aligns with the trial's timeline, with specific involvement duration depending on individual circumstances and response to the investigational product.

The sequence of study visits begins with an inclusion (screening) visit, where potential participants undergo a preliminary clinical examination to confirm eligibility based on the inclusion criteria, such as having a recent liver biopsy for NASH and being of legal age. Following successful screening, participants will be randomized to receive the investigational product via **intravenous infusion**. Subsequent follow-up visits will be scheduled to monitor the uptake intensity of **68Ga-FAPI-46** using PET/CT scans, focusing on biopsy sites to classify fibrosis stages. The primary endpoint is the measurement of uptake intensity, with secondary endpoints including SUV threshold values and the identification of abnormal uptake zones outside normal elimination areas.

The end-of-study visit will involve a comprehensive assessment to evaluate the outcomes and any adverse events experienced during the trial. Participants may be subject to early termination from the study if they experience significant adverse reactions, withdraw consent, or fail to comply with study protocols. The trial aims to recruit a balanced number of participants across different fibrosis stages, with at least 16 patients in each of the four histological stage groups. The study's findings will contribute to understanding the potential of **68Ga-FAPI-46** in non-invasive liver fibrosis assessment, potentially offering a novel diagnostic tool for NASH management.

The clinical trial involves the use of an experimental medication known as **68Ga-FAPI-46**, a **radiopharmaceutical precursor**. This compound is chemically designated as (S)-2,2',2''-(10-(2-(4-(3-((4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)-quinolin-6-yl)(methyl)amino)-propyl)piperazin-1-yl)-2-oxoethyl)-68Ga-[1,4,7,10]-tetraazacyclododecane-1,4,7-triyl)triacetate. The pharmaceutical form of this medication is a radiopharmaceutical precursor, and it is administered via **intravenous infusion**. The dosage is calculated based on the patient's body weight, with a maximum daily and total dose of 2.5 MBq/kg. The treatment period is limited to a single day.

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 68Ga-FAPI-46 to assess its efficacy in liver fibrosis stage assessment in patients with suspected or proven nonalcoholic steatohepatitis. Participant compliance with the dosing schedule is monitored to ensure accurate and reliable data collection. The trial aims to demonstrate the differential uptake intensity of 68Ga-FAPI-46 in hepatic sites biopsied, corresponding to various fibrosis stages as defined by biopsy analyses.

Efficacy in this clinical trial will be assessed by evaluating the uptake intensity of **68Ga-FAPI-46** using PET/CT imaging. The primary endpoint involves measuring the Standardized Uptake Values maximum (SUVmax), average (SUVmean), and peak (SUVpeak) in areas centered on liver biopsy sites. These measurements will be referenced against a classification of fibrosis stages determined by centralized biopsy rereading, categorized into stages 4, 3, 2, and less than 2, as per the Kleiner and Bedossa criteria.

Secondary endpoints include determining SUV threshold values associated with each fibrosis stage group using a naive Bayes classifier, identifying the location of maximum uptake zones, and assessing the homogeneity of SUV distribution across the liver volume. Additionally, the trial will search for **68Ga-FAPI-46** uptake foci outside normal elimination zones, which may indicate abnormal fibrosis, inflammation, or cancer. Intra-class correlation coefficients and their 95% confidence intervals will be calculated to assess reliability. The trial will also evaluate the variation in prediction accuracy of fibrosis stages when PET/CT variables are combined with traditional clinico-biological scores and pulse elastometry. The reference for these assessments will be the histological fibrosis score determined in the SAF score, with patients grouped into quartiles based on this score.