Evaluation of [68Ga]FAPI-46 PET/CT for Assessing Fibroblast Activity in Patients with Non-Resolving Acute Respiratory Distress Syndrome (ARDS) in the ICU

The primary objective of this study is to assess the relationship between **pulmonary fibroblast activity** in patients with non-resolving Acute Respiratory Distress Syndrome (ARDS), as measured by FAPI-PET/CT, and clinical outcomes such as 28-day mortality, ventilator-free days, and ICU length of stay. This is clinically relevant as it may provide insights into the prognostic value of fibroblast activity in ARDS, potentially guiding therapeutic strategies and improving patient management.

Secondary objectives include:

• Evaluating the PET/CT procedure using an evaluation form and adverse event registration.
• Studying the relationship between pulmonary fibroblast activity and systemic fibrotic and inflammatory blood markers.
• Relating pulmonary fibroblast activity on [68Ga]FAPI PET/CT with respiratory cytopathology and fibrotic and inflammatory mediators collected via bronchoalveolar lavage (BAL).

The clinical trial focuses on patients with **non-resolving ARDS**. The study population includes both male and female adults over the age of 19. Participants are required to be mechanically ventilated and must meet specific criteria for non-resolving ARDS by day 5 of diagnosis, such as a P/F ratio of less than 200 mmHg, a Positive End Expiratory Pressure (PEEP) of 12 cmH20 or more, or static lung compliance of less than 50 ml/cmH20. The trial involves a vulnerable population, and participants must be deemed safe for transport by the attending clinician. Informed consent is required from the patient or their legal representative. For those with COVID-19, a SARS-CoV-2 PCR CT greater than 30 is necessary. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **[68Ga]FAPI-46**, a **solution for injection**, in detecting fibroblast activity in patients with non-resolving acute respiratory distress syndrome (ARDS) using PET/CT imaging. This study is a **randomized, double-blind, controlled** trial, with an estimated duration from September 2024 to January 2026. The primary objective is to correlate pulmonary fibroblast activity with 28-day mortality, ventilator-free days, and ICU length of stay. Secondary endpoints include the relationship between fibroblast activity and respiratory parameters, as well as plasma markers of inflammation.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, mechanical ventilation status, and specific ARDS parameters. Following the screening, eligible participants will receive the investigational product via **intravenous administration**. Subsequent follow-up visits will monitor the uptake of **[68Ga]FAPI-46** and assess clinical outcomes. The end-of-study visit will conclude the participant's involvement, evaluating the overall impact of the treatment.

The expected length of participant involvement is approximately 28 days, aligning with the primary endpoints. Conditions that may lead to early termination from the study include adverse reactions to the investigational product, withdrawal of consent, or any clinical judgment deeming continued participation unsafe. The trial aims to provide valuable insights into the role of fibroblast activity in non-resolving ARDS and its potential as a therapeutic target.

The clinical trial involves the administration of the experimental medication **[68Ga]FAPI-46**, which is a **solution for injection**. This investigational product is designed to detect fibroblast activity in patients with non-resolving acute respiratory distress syndrome (ARDS) in the intensive care unit (ICU). The active substance in **[68Ga]FAPI-46** is chemically synthesized and is identified 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 medication is administered via **intravenous administration**. The maximum daily dose and total dose for the treatment period is 220 megabecquerels (MBq), with the treatment period limited to a single day.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of **[68Ga]FAPI-46** to evaluate its efficacy in detecting fibroblast activity. Participant compliance with the dosing schedule is monitored to ensure accurate assessment of the investigational product's effects. The trial is conducted under the auspices of the University Medical Center Groningen, ensuring adherence to rigorous clinical standards.

Efficacy in this clinical trial will be assessed by evaluating the uptake of **[68Ga]FAPI** in non-resolving Acute Respiratory Distress Syndrome (ARDS) patients. The primary endpoints include the correlation of **[68Ga]FAPI** uptake with 28-day mortality, the length of Intensive Care Unit (ICU) stay, and ventilator-free days at 28 days (VFD-28). These parameters will be measured using FAPI-PET/CT imaging techniques.

Secondary endpoints will explore the relationship between pulmonary fibroblast activity, as measured by FAPI-PET, and clinically determined respiratory parameters such as Positive End Expiratory Pressure (PEEP), peak inspiratory pressure (Ppeak), lung compliance, driving pressure, and mechanical power. Additionally, plasma markers of extracellular matrix and inflammation, including IL-8, IL-6, TNF-alpha, ProC3, and C3M, will be analyzed. Bronchoalveolar lavage (BAL) will be performed to collect respiratory cytology and determine cellular phenotypes using single-cell RNA sequencing (scRNA). The PET/CT procedure will also be evaluated through an evaluation form and adverse event registration.