Extension Study (Extended Access) of Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans
Condition: Bronchiolitis Obliterans; Constructive Bronchiolitis; Graft Versus Host Disease; Bronchiolitis, Exudative; Bronchiolitis, Proliferative; Graft-Versus-Host Disease
MeSH terms: Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Cyclosporine Inhalation Solution (CIS)
Intervention type(s): Drug
Intervention description(s): CIS is a sterile, clear, colorless, preservative-free solution of cyclosporine (USP) in propylene glycol developed specifically for administration by oral inhalation.
Intervention MeSH terms: Cyclosporine; Cyclosporins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Peripheral Blood Stem Cell Transplant; Inhaled Cyclosporine; Graft-Versus-Host Disease