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
Intervention: Cyclosporine Inhalation Solution
Intervention description: sterile, clear, colorless, preservative-free solution of cyclosporine (USP) in propylene glycol developed specifically for administration by oral inhalation.
Intervention MeSH terms: Cyclosporine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 10 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Peripheral Blood Stem Cell Transplant; Inhaled Cyclosporine; Graft-Versus-Host Disease; GVHD; Bronchiolitis Obliterans; Lung

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        History of:<TAB>

        -Hematopoietic stem cell transplant recipients at least 99 days post transplant (group A)

        Or

          -  Lung transplant recipients at least 6 months post transplant (Group B)

          -  Biopsy proven bronchiolitis obliterans (confirmed by NIH pathology department) or
             Bronchiolitis Obliterans Syndrome (BOS) as defined by:

          -  FEV1 less than 75 percent predicted and

          -  No evidence of pulmonary infection as a causative etiology to lung dysfunction or
             other causative etiology

          -  Decline in FEV1 (The FEV1 values used to determine BOS will be the average of 2
             measurements of FEV1 taken sequentially at least 3 weeks apart up to 6 months apart)
             compared to pre-transplant baseline for group A or compared to best post-transplant
             measurement in group B.

          -  For hematopoietic transplant patients, FEV1 must have declined less than 10 percent
             from pre-transplant baseline (group A)

          -  For lung transplant patients, FEV1 must have declined greater than 20 percent from
             best post-transplant measurement (group B)

        And one of the following:

          -  FEV1/FVC less than 0.7

          -  Air trapping seen on CT scan or RV greater than 20 percent predicted

          -  Evidence of cGVHD affecting at least one other organ system (group A)

          -  Age 10-80 years

          -  Progressive disease or stable disease (active BOS, stable by FEV1 criteria) on
             immunosuppressants at study entry

          -  Progressive disease at study entry: Diagnosis of BO or BOS with evidence of a
             progressive decline in FEV1. A documented decline (greater than or equal 10 percent)
             in FEV1 has occurred within 18 weeks (minimum documentation of 3 weeks) preceding
             study enrollment

          -  Stable disease at study entry: Diagnosis of BO or BOS on immunosuppressive therapy
             with evidence of stable disease (active BOS, stable by FEV1 criteria), as documented
             by a stable FEV1 (increase <5% and decrease <10%) within 18 weeks (minimum
             documentation of 3 weeks) preceding study enrollment

          -  Patients on calcineurin inhibitors at study entry will be required to be on a stable
             dose of the calcineurin inhibitor for 4 weeks prior to study enrollment

        EXCLUSION CRITERIA:

          -  Evidence of uncontrolled, pulmonary infection

          -  Patients with unstable coronary insufficiency, severe cardiac arrhythmias, and/or
             uncontrolled hypertension.

          -  History of hypersensitivity to propylene glycol

          -  History of allergic reaction or hypersensitivity to Technetium- 99m sulfur colloid,
             used in lung deposition studies

          -  ECOG performance status greater than or equal to 3

          -  Serum creatinine >2.5 mg/dl

          -  Documented allergy or intolerance to cyclosporine

          -  Patient pregnant or breast feeding or not willing to use an approved method of birth
             control

          -  Inability to comprehend the investigational nature of the study and provide informed
             consent

          -  Life expectancy less than 18 weeks.

          -  An increase greater than or equal to 5% and an absolute increase greater than or equal
             to 0.05 in FEV1 in the 18 weeks (minimum documentation of 3 weeks) preceding study
             enrollment

          -  Subjects who have had prior administration of inhaled cyclosporine.