Trial Information

Extension Study (Extended Access) of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans

Bronchiolitis Obliterans (BO) is an obstructive lung disease that can affect individuals
that have undergone a lung or hematopoietic stem cell transplant. BO has been studied most
extensively in lung transplant recipients, where it is considered to represent chronic lung
rejection. It is the leading cause of death after lung transplant, with mortality rates up
to 55 percent. In hematopoietic stem cell transplantation, BO is thought to be a
manifestation of chronic graft-vs-host disease (GVHD). Up to 45 percent of patients
undergoing hematopoietic stem cell transplantation at the NHLBI develop a decline in
pulmonary function. Conventional therapy for patients who develop BO consists of
augmentation of systemic immunosuppressants. Systemic immunosuppression has limited
efficacy for BO and is associated with deleterious consequences including increased risk of
infections and decreased graft-versus tumor/leukemia effects.

Recently, cyclosporine inhalation solution (CIS) in solution with propylene glycol has been
shown to improve overall survival and chronic rejection-free survival in lung transplant
patients. These findings suggest targeted delivery of immunosuppressive therapy to the
diseased organ warrants further investigation as this may minimize the morbidity associated
with systemic immunosuppression. However, there currently exists limited data regarding the
overall efficacy of inhaled cyclosporine to treat established BO following lung
transplantation. Furthermore, inhaled cyclosporine has not been studied in the treatment of
BO following hematopoietic stem cell transplantation.

Here, we propose to evaluate the long-term safety and efficacy, of inhaled CIS for the
treatment of BO. Enrollment will be offered to subjects who have completed the end of study
(week 18 visit) for the initial protocol (Phase II Trial of CIS in lung transplant and
hematopoietic stem cell transplant recipients for treatment of Bronchiolitis Obliterans) and
who have shown evidence of benefit (either an improvement or stabilization) in BO/BOS with
CIS treatment.

Clinical parameters, including pulmonary function tests, will be measured in addition to
laboratory markers of the anti-inflammatory response to CIS. Adverse events associated with
extended treatment with CIS will be recorded.

The primary objective is to provide long-term safety and efficacy data for the use of CIS in
hematopoietic transplant patients and lung transplant patients with established BO.

Secondary objectives include investigation of the inflammatory pathways that lead to chronic
BO and ascertainment of the long term anti-inflammatory effects of this CSA preparation ex
vivo and in vivo.

Primary endpoint is the efficacy of extended use CIS for BO/BOS. Secondary endpoints include
the toxicity profile (adverse events), improvement in high resolution chest CT images,
results of peripheral blood and bronchoalveolar cytokine arrays to assess secondary markers
of inflammation, and functional capacity measurements using a six-minute walk test.