A Phase III Clinical Trial to Demonstrate Efficacy / Safety of Liposomal Cyclosporine A + Standard of Care (SoC) vs SoC Alone in Treating Chronic Lung Allograft Dysfunction / Bronchiolitis Obliterans in Patients Post Double Lung Transplant

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.