This was a Phase III, open-label, prospective, multicenter, randomized, controlled clinical trial of L-CsA for the treatment of BOS in adults following DLT. The patient population was recipients of a double pulmonary allograft, \> or = 18 years old, with clinically defined CLAD--BOS with screening FEV1 \>or = 51% of personal best FEV1 value post-transplant during the Screening period.
The rationale for an open-label study was driven by concerns that a sucrose-containing placebo formulation could increase a potential risk of pulmonary infection without the benefit of L-CsA. Sucrose is a lyoprotectant in the manufacturing process. After carefully considering alternative options for lyoprotection, no sugar-free alternatives that would qualify as a real placebo (i.e., undistinguishable by means of appearance, taste, or smell) could be identified.
Therefore, an open-label, randomized controlled trial versus SoC was the only suitable alternative.
An open-label clinical trial generally bears the potential for bias in patient treatment and care, and thus trial outcome. However, for this trial the risk of bias is considered low because of the following reasons:
* During the trial, the general treatment of BOS was use of immunosuppressive therapy to the highest tolerable level unless limited by systemic toxicity. As inhaled L-CsA has not been associated with additional systemic drug burden, dose reductions or adaptations of other components of the immunosuppressive cocktail would not be required and were not desired.
* The selected primary endpoint FEV1 is an objective parameter and its measurement was performed according to recommended guidelines of American Thoracic Society (ATS)/European Respiratory Society (ERS) which had to be respected by each participating center. Following this methodology, a subjective and intentional manipulation of outcome was highly unlikely even if healthcare professional and patient were aware of the treatment allocation.
* Pulmonary function technicians, respiratory therapists, or physiotherapists who performed spirometry at each site were blinded to each patient's study treatment assignment.
* Finally, the correctness and validity of individual FEV1 curves and their resulting value had to be approved in a central and blinded reading by a pulmonary expert who was independent and not involved in patient care or treatment. The implementation of these measures should have ensured that the reported data of the primary outcome was as free as possible of bias induced by the open-label trial design.
Stratification prior to randomization was performed to limit imbalances between treatment arms with respect to key variables and potential confounders.
There were major recruitment issues in both the BOSTON-1 trial (SLT recipients) and the present BOSTON-2 trial, in part due to Coronavirus disease-2019 (COVID-19) and specifically in BOSTON-1 due to a marked decline over time in the use of SLT. Following FDA recommendation to obtain an adequately sized safety database for inhaled L-CsA and reach the originally planned sample size for BOSTON-1 and BOSTON-2 trials combined, it was planned to stop randomization into the two Phase III clinical trials upon achievement of a combined total of approximately 220 patients, of which approximately 160 to 170 patients were planned for enrollment in BOSTON-2. To assure balance between treatment arms with regard to key variables and potential confounders, stratification prior to randomization was performed. Within each of the 8 strata, using a permuted blocks randomization, patients were randomly assigned with equal probability (1:1) to receive either L-CsA (10 mg) via the PARI eFlow Nebulizer System twice daily (BID) plus SoC treatment or SoC alone, for a period of 48 weeks. Patients were monitored every 4 to 8 weeks over 48 weeks for efficacy parameters and for all safety evaluations. All patients were eligible to continue in an open-label extension trial of L-CsA, BOSTON-3 (Study BT-L-CsA-303-FU) following completion of either BOSTON-1 or BOSTON-2.
Up to 11 visits (Screening, V1 through V10) were planned during the clinical trial. After informed consent had been obtained, a Screening Visit was carried out to check general eligibility for participation. At the Baseline Visit (V1, Randomization Visit), inclusion and exclusion criteria were re-checked, and Baseline serial spirometry was performed. During the 48-week treatment period, visits were scheduled every 4 to 8 weeks (V2 to V9). Visit 9 (End of Treatment \[EoT) was scheduled to occur 48 weeks after Visit 1. If a patient had an event that met the first criterion for progression of BOS, progression of BOS must have been confirmed by measurements that were taken with COMPACT spirometer at least 2 weeks apart. Visit 10 (EoS) was a safety follow-up visit performed 4 weeks after Visit 9/EoT only in patients not rolling over to the extension study (BOSTON-3). For patients who rolled over to BOSTON-3, the EoT Visit was the EoS Visit. Every effort was made to have all planned and unscheduled visits at the study site. However, if one of the visits from Visit 2 to Visit 8 and discontinuation visits could not be performed at the site due to COVID-19, remote visits (e.g., by telephone) were possible. Mandatory on-site visits were Screening Visit, Visit 1, and Visit 9.
