Evaluation of [18F]FAPI-74 PET/CT Imaging for Early Detection of Progressive Lung Fibrosis in Connective Tissue Disease-Associated Interstitial Lung Disease

The primary objective of this study is to compare baseline **FAPI PET/CT** measures in patients with connective tissue diseases at high risk of interstitial lung disease (CTD-ILD) who will and will not experience lung functional progression at a 12-month follow-up. This objective is clinically relevant as it aims to identify early markers of progressive lung fibrosis, which can significantly impact patient management and outcomes in systemic rheumatic diseases.

Secondary objectives include:

• Correlating FAPI PET/CT measures with AI-read high-resolution computed tomography (HRCT) outputs and circulating extracellular vesicle (EV) proteomic and transcriptomic characteristics.
• Exploratory objective: Correlating FAPI PET/CT measures with bronchoalveolar lavage fluid (BALF) EV proteomic and transcriptomic characteristics.

The clinical trial involves **patients with connective tissue diseases** at high risk of interstitial lung disease. The study population includes both female and male participants aged between 18 and 75 years. Participants are required to have a clinical diagnosis of systemic sclerosis (SSc), rheumatoid arthritis (RA), Sjögren's syndrome (SS), idiopathic inflammatory myopathies (IIM), or undifferentiated connective tissue disease (UCTD), adhering to internationally accepted classification criteria. The trial does not involve a vulnerable population. Participants must exhibit evidence of interstitial lung disease (ILD) based on high-resolution computed tomography (HRCT) documenting interstitial changes involving at least 10% of the parenchyma within the previous six weeks. They should either be naive to immunosuppressants or have been on a stable immunosuppressive regimen for the three months preceding the FAPI PET/CT. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified. The trial population was selected based on specific autoantibody profiles and evidence of ILD, with additional criteria for those undergoing bronchoalveolar lavage fluid (BALF) collection. The sponsor did not provide information on the total number of participants.

The clinical trial is designed to evaluate the efficacy of **[18F]FAPI-74** in the functional characterization of patients with connective tissue diseases at high risk of interstitial lung disease (CTD-ILD) using PET/CT imaging. This is a non-randomized, phase II, monocentric interventional study. The trial aims to compare baseline FAPI PET/CT measures in CTD-ILD patients who will and will not experience lung functional progression at a 12-month follow-up. The primary endpoints include the evaluation of FAPI uptake patterns, mean and maximum Standardized Uptake Value (SUV mean and SUV max) of pulmonary fibrotic lesions, fibrotic active volume (FAV), total fibrosis, and uptake ratio between fibrotic and healthy lung tissue. Secondary endpoints involve AI-collected measures of lung anatomy and serum extracellular vesicle (EV) single-protein quantity and RNA expression measures, with an exploratory endpoint focusing on bronchoalveolar lavage fluid (BALF) EV measures.

The trial is expected to commence recruitment on November 4, 2024, and conclude by September 4, 2026. Participants will be involved in the study for a duration of 12 months. The study visits will include an initial screening visit to confirm eligibility based on inclusion criteria such as age, informed consent, clinical diagnosis, and evidence of interstitial lung disease (ILD). Follow-up visits will be scheduled to monitor the progression of lung function and collect necessary imaging and biological data. The end-of-study visit will assess the final outcomes and gather data for endpoint analysis. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or adverse events that compromise participant safety.

The clinical trial involves the administration of the experimental medication **[18F]FAPI-74**, which is a **solution for injection**. This investigational product is utilized to assess its efficacy in the early recognition of progressive lung fibrosis in systemic rheumatic diseases. The active substance, **[18F]FAPI-74**, is of chemical origin and is administered intravenously. The dosage is measured in megabecquerels (MBq), with a maximum daily and total dose of 259 MBq. The treatment period is limited to 259 days. The administration of the drug is conducted under controlled conditions to ensure participant safety and compliance with the study protocol.

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, **[18F]FAPI-74**, to evaluate its potential in the specified clinical context. Participant compliance is monitored through regular assessments and adherence to the dosing schedule, ensuring the integrity of the trial data. The trial is conducted in accordance with regulatory standards and ethical guidelines to ensure the safety and well-being of all participants.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints involve the evaluation of FAPI PET-CT measures, which include the pattern and distribution of **FAPI** uptake, mean and maximum Standardized Uptake Value (SUV mean and SUV max) of pulmonary fibrotic lesions, fibrotic active volume (FAV), total fibrosis (calculated as the product of SUV mean and the fibrotic active volume), and the uptake ratio between fibrotic and healthy lung tissue. These measures will be compared between patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) who exhibit progressive phenotypes and those who do not at the 12-month follow-up.

Secondary endpoints will include AI-collected measures of lung anatomy, such as lung texture, airway, and vascular measures, as well as serum extracellular vesicle (EV) single-protein quantity and RNA expression measures. An exploratory endpoint will assess bronchoalveolar lavage fluid (BALF) EV single-protein quantity and RNA expression measures. The trial is designed to functionally characterize patients using the drug [18F]FAPI-74 in PET/CT evaluations, with the aim of identifying early recognition of progressive lung fibrosis in systemic rheumatic diseases.