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

Summary: 
      Background:

      - Bronchiolitis obliterans or bronchiolitis obliterans syndrome is a lung disorder that
      occurs as a complication of either lung transplantation or bone marrow/blood stem cell
      transplantation. One of the complications of transplant is the occurrence of graft versus
      host disease (in hematopoietic stem cell transplants) and host versus graft disease (in lung
      transplantation). In these diseases, the cells attack the lungs and cause irreversible small
      airway fibrosis referred to as bronchiolitis obliterans syndrome. When a patient develops
      fibrosis of the lungs or bronchioles, the lungs no longer work properly, which causes
      difficulties with breathing that lead to a diminished quality of life and an increased risk
      of death. Treatment typically involves immunosuppressive therapy such as oral cyclosporine or
      steroid therapy, but these treatments are only marginally effective and can cause significant
      toxicities and increase the risk of infections. Inhaled cyclosporine (CIS) achieves higher
      concentrations of cyclosporine in the lungs and lower concentrations of cyclosporine in the
      blood than oral cyclosporine. Therefore, it could have advantages over conventional oral
      immunosuppressive therapies used to treat this disorder. Researchers are interested in
      testing whether inhaled cyclosporine therapy could be used as a safe and effective treatment
      for bronchiolitis obliterans or bronchiolitis obliterans syndrome occurring after bone
      marrow/blood stem cell or lung transplants.

      Objectives:

      - To evaluate whether inhaled cyclosporine (CIS) can improve or stabilize lung function and
      quality of life in individuals with bronchiolitis obliterans.

      Eligibility:

      - Individuals between 10 and 80 years of age who have been diagnosed with bronchiolitis
      obliterans or bronchiolitis obliterans syndrome after blood or lung transplants.

      Design:

        -  Participants will be screened with a full medical history and physical examination, as
           well as blood and urine tests, lung function tests, imaging studies, bronchoalveolar
           lavage samples, and quality of life questionnaires.

        -  Participants will take cyclosporine inhalation solution through a nebulizer. The
           nebulizer generates a mist of cyclosporine inhalation solution (CIS), which is then
           breathed in through a mouthpiece. The process takes approximately 20 minutes. The
           solution will be provided in single-use vials.

        -  Participants will continue to take all medications for post-transplant care as required
           by their doctor and the study researchers. Attempts will be made to reduce the doses and
           types of immunosuppressants given to participants on the study, as long as the treatment
           continues to produce improved or stable lung function.

        -  Participants will have study visits every 3 weeks with blood and urine tests, lung
           function tests, and imaging studies. Participants will undergo repeat bronchoalveolar
           sample at week 9 and 18. Participants will also complete quality of life questionnaires
           as directed. Treatment will continue for a minimum of 18 weeks, followed by a final
           follow-up visit 2 weeks after the end of the study.

        -  Participants who benefit from the inhaled cyclosporine (CIS) may continue to receive
           further therapy with inhaled cyclosporine at the end of the study by participation in a
           separate study extension.
    

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%. In hematopoietic stem cell transplantation, BO is thought to be a manifestation of
      chronic graft-vs-host disease (GVHD). Up to 45% 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 safety, efficacy, and pharmacodynamics of inhaled
      cyclosporine for the treatment of BO. Two distinct patient populations will be offered
      enrollment in this protocol: hematopoietic transplant recipients with BO (group A) and lung
      transplant recipients with BO (group B). Study participants will receive CIS at an initial
      dose of 150mg, three times weekly. Patients will undergo dose titration to a maximum dose of
      300mg, three times weekly. Drug deposition and pharmacokinetic analyses will be performed at
      the initiation of 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 treatment will be recorded.

      The primary objective is to 1) assess the safety and efficacy of inhaled cyclosporine as a
      new therapy in hematopoietic transplant patients and lung transplant patients with
      established BO. Additionally, we seek to promote a better understanding of the pathogenesis
      of BO in these two transplant groups and to assess the anti-inflammatory effects of inhaled
      cyclosporine in patients that develop this complication.

      The primary endpoint of each study group is the best response, FEV1 improvement or
      stabilization from study baseline at week 18 for two successive measures, at least 1 week
      apart, no more than 2 weeks apart. Secondary endpoints include the toxicity profile as
      measured by CTCAE criteria (safety), the study of pharmacokinetics and lung deposition
      characteristics of inhaled cyclosporine, 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
Intervention type(s): Drug
Intervention description(s): 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; GVHD; Bronchiolitis Obliterans; Lung