Safety Assessment of Endobronchial Administration of Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells in Lung Transplant Chronic Rejection

The primary objective of this clinical trial is to evaluate the **safety** of endobronchial administration of allogeneic mesenchymal stromal cells (MSCs) in patients experiencing chronic rejection following a lung transplant, specifically those diagnosed with bronchiolitis obliterans (BO). This is clinically relevant as BO is a significant complication post-lung transplantation, leading to progressive airflow obstruction and graft failure. Ensuring the safety of MSC administration could provide a novel therapeutic approach to manage or mitigate this condition.

Secondary objectives include assessing the efficacy of the endobronchial administration of allogeneic MSCs in the progression of BO. This evaluation is crucial as it may offer insights into the potential therapeutic benefits of MSCs in slowing or altering the course of BO, thereby improving patient outcomes and extending graft survival.

The clinical trial involves **adult** participants aged 18 years and older, comprising both **male** and **female** subjects. The study population includes patients who have undergone a **lung transplant**, either unilateral or bilateral, and have an established diagnosis of **Bronchiolitis Obliterans Syndrome (BOS)** stage ≥ 0p, characterized by FEV1 ≤ 90% and/or FEF 25-75% ≤ of the baseline value with no other justifying cause, within the last six months. The trial does not include a vulnerable population. Participants were required to provide written informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as an **open-label**, randomized, controlled study to evaluate the safety of endobronchial administration of allogeneic mesenchymal stromal cells in patients with lung transplant chronic rejection. The trial is set to run from February 22, 2023, to February 22, 2027, with recruitment having commenced on September 15, 2023. The study involves the administration of PDH-MSC-TxP, a suspension for injection containing **allogeneic bone marrow-derived mesenchymal adult stromal cells, ex-vivo expanded**, via endotracheopulmonary use. The primary objective is to assess the safety of this administration in patients diagnosed with bronchiolitis obliterans syndrome (BOS) following lung transplantation.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), consent, and a recent diagnosis of BOS. Following randomization, participants will receive the investigational product and be monitored for early onset adverse events within 24 hours, including desaturation, hypotension, and fever. Subsequent follow-up visits will occur at regular intervals to monitor for adverse events of special interest, such as lower respiratory tract infections and acute rejection, as well as to assess secondary endpoints like changes in FEV1 and all-cause mortality rate. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 12 months from the time of randomization.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial's methodology ensures rigorous monitoring and data collection to evaluate both the primary and secondary endpoints effectively. The study's design, including its randomized and controlled nature, aims to provide robust data on the safety profile of the investigational product in the specified patient population.

The clinical trial involves the administration of the experimental medication **PDH-MSC-TxP**, which is a **suspension for injection**. This investigational product contains **allogeneic bone marrow-derived mesenchymal adult stromal cells, ex-vivo expanded**. The pharmaceutical form is specifically designed for **endotracheopulmonary use**, allowing for direct administration into the respiratory system. The maximum daily dose is set at 3,300,000 U/ml, with a total maximum dose of 6,600,000 U/ml over the treatment period. The treatment duration is limited to a maximum of two weeks. The administration schedule and dosage are carefully monitored to ensure participant compliance and safety throughout the trial.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, depending on the specific design of the trial. These treatments are used to provide a baseline for evaluating the efficacy and safety of the investigational product. The administration of these non-experimental treatments follows established protocols to maintain consistency and reliability in the trial outcomes.

The efficacy of the clinical trial assessing the safety of endobronchial administration of allogeneic mesenchymal stromal cells in patients with lung transplant chronic rejection will be evaluated using both primary and secondary endpoints. The primary endpoints focus on the incidence of early onset adverse events within 24 hours following the administration of mesenchymal stromal cells, including desaturation, hypotension, radiological infiltrates, fever, or changes in oxygen therapy requirements. Additionally, the incidence of adverse events of special interest since randomization, such as lower respiratory tract infections, acute rejection, and worsening of **Bronchiolitis Obliterans Syndrome (BOS)**, will be monitored.

Secondary endpoints include a range of measures to assess the progression and impact of the treatment over a 12-month period. These include mean changes in Forced Expiratory Volume in 1 second (FEV1) from baseline, the proportion of patients with a greater than 10% decrease in FEV1, and the time to such a decrease. Other secondary measures include the proportion of patients progressing to grade 3 BOS, mean changes in Forced Vital Capacity (FVC), all-cause mortality rate, and re-transplant or CLAD-related mortality rate. The rate of acute rejection, incidence of specific antibodies against donor HLA, and CLAD progression are also evaluated. Additional assessments involve mean changes in the modified Medical Research Council (mMRC) Scale, total hospitalization days, and the proportion of patients requiring ambulatory oxygen therapy.