Study Design of Two Phase III, Prospective, Multicenter, Randomized, Controlled Clinical Trials Evaluating the Efficacy and Safety of Liposomal Cyclosporin A for Inhalation(L-CsA-i) in Patients with Bronchiolitis Obliterans Syndrome Post Single- (BOSTON-1) or Double- (BOSTON-2) Lung Transplantation

Abstract

RATIONALE: Bronchiolitis obliterans syndrome (BOS) is the most common form of chronic lung allograft dysfunction, and the major limitation of long-term survival post lung transplantation (LTx). BOS affects up to 50% of LTx recipients within 5 years post-transplant. Currently there are no therapies indicated specifically for BOS. The most common treatment is augmentation of systemic immunosuppression, which has limited efficacy and is associated with deleterious long-term side effects. To address the goal of optimizing immunosuppression as a treatment for BOS, a novel liposomal formulation of cyclosporine A (L-CsA) delivered with an investigational eFlow® Technology nebulizer system (PARI Pharma GmbH) is being investigated. The objective of these two trials is to assess the efficacy and safety of inhaled L-CsA added to standard of Care (SoC) immunosuppression, in adult patients with single (SLT) and double lung transplantation (DLT). METHODS: Adult patients who received a SLT or DLT at least 12 months prior to screening, diagnosed with clinically defined BOS by FEV1 between 85-60% of personal best after transplant are eligible for inclusion. Patients are randomized 1:1 to L-CsA-i (5mg dose for SLT;10mg dose for DLT) twice daily plus SoC or SoC alone. After informed consent has been obtained, a Screening Visit is carried out to check general eligibility for participation. At the Randomization Visit, inclusion and exclusion criteria will be reevaluated and spirometry performed. Safety and tolerability will be assessed by physical examination, vital signs, adverse event reporting, and clinical laboratory parameters at every visit. A total of 11 visits throughout the 48-week treatment period will be performed. At completion of trial period, patients from both treatment groups could be eligible to continue in an open-label extension trial (BOSTON-3). The primary endpoint for both trials is the mean absolute change in FEV1 (mL) from baseline to Week 48 between the treatment groups. Secondary endpoints for both trials include mean change in FEV1/FVC from baseline to Week 48 and time to progression of BOS. The latter endpoint will be assessed in a pooled analysis of both trials. CONCLUSIONS: These phase III trials will help characterize the safety and efficacy of L-CsA-i as add-on therapy to SoC in BOS patients. Despite the COVID-19 pandemic, BOSTON-1 and BOSTON-2 are ongoing, ensuring the integrity of data collection and safety of enrolled patients. .