A Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis After Hematopoietic Transplant (BOSTON-4)
Condition: Bronchiolitis Obliterans Syndrome (BOS); GVHD, Chronic; Stem Cell Transplant Complications
MeSH terms: Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome; Syndrome
Intervention: Liposomal Cyclosporine A; Liposomal Placebo
Intervention description: Liposomal Cyclosporine A is administered at different dosages in the first two arms (10 mg bid and 5 mg bid, respectively) with a new technology of nebulizing liquid drugs, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm; Liposomal Placebo is administered with the same new technology of nebulizing liquid drugs used for L-CsA, creating an aerosol with a low ballistic momentum and a high percentage of droplets in a respirable size range of 3-5 μm
Intervention MeSH terms: Cyclosporine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Masking description: This was a single-blind trial. Due to the different appearance of the 3 tested strengths of IMP, a full blinding of the study was not possible. Only the randomized study patients were blinded to study treatment assignment.
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stem cell; hematopoietic transplant

Summary:

      Primary Objective:

      The primary objective of this study is to assess the tolerability and safety of two dose
      levels of aerosolized L-CsA vs placebo in addition to SoC therapy for BOS in adult allo-HSCT
      recipients.

      Secondary Objectives:

      The secondary objectives of this study are to assess PK and exploratory efficacy and quality
      of life of two dose levels of aerosolized L-CsA vs placebo in addition to SoC therapy for BOS
      in adult allo-HSCT recipients.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age >/= 18 years

          2. Patient must have a history of allogeneic HSCT, regardless of source of stem cell or
             donor or indication for allogeneic HSCT

          3. Documented diagnosis of chronic Graft versus Host Disease (cGvHD) in any organ other
             than the lung. If BOS is the only manifestation of cGvHD, lung biopsy must have been
             performed before entering the trial to confirm BOS diagnosis.

          4. Confirmed diagnosis of BOS Score 1 [Jagasia et al. 2015] within > 6 months and < 3
             years after allo-HSCT:

             FEV1/FVC < 0.7 at Screening Visit AND Post-bronchodilator FEV1 >/= 60 and ≤ 79%
             predicted at Screening Visit AND

               -  10% decline of FEV1 % predicted within 24 months prior to Screening Visit AND
                  Absence of acute infection in the respiratory tract.

          5. Patient must be capable of understanding the purposes and risks of the study, has
             given written informed consent, and agrees to comply with the study requirements.

          6. Patient is capable of aerosol inhalation.

          7. Women of childbearing potential must have a negative serum or urine pregnancy test at
             screening and at randomization visit.

        Exclusion Criteria:

          1. Active bacterial, viral (as confirmed by multiplex PCR) or fungal infection not
             successfully resolved at least 4 weeks prior to the Screening Visit.

          2. Chronic renal dysfunction with serum creatinine >/= 2.5 mg/dL or need for renal
             dialysis.

          3. Chronic hepatic dysfunction with serum total bilirubin > 5x upper limit of normal
             (ULN), transaminases > 5x ULN, or alkaline phosphatase > 5x ULN.

          4. Evidence of relapse of the primary malignancy which warranted allogeneic bone marrow
             transplant.

          5. Use of azithromycin within 4 weeks prior to Randomization (Visit 1).

          6. Use of zafirlukast during the study period.

          7. Chronic oxygen use or use of non-invasive ventilation.

          8. Active smokers (i.e. any kind of inhaled nicotine consumption).

          9. Pregnant women or women who are unwilling to use appropriate birth control to avoid
             pregnancy over the course of the clinical trial.

         10. Women who are currently breastfeeding.

         11. Known hypersensitivity to L-CsA or to cyclosporine A.

         12. Patients who do not tolerate administration of inhaled bronchodilators (e.g.,
             salbutamol).

         13. Patients with life-expectancy of less than 6 months.

         14. Treatments with other Investigational Medicinal Products (IMPs) or previous therapies
             within four weeks or five times half-life of the drug, whichever is longer prior to
             screening and during the study. Participation in registries, considering the before,
             is allowed.

         15. Psychiatric disorders or altered mental status precluding understanding of the
             informed consent process and/or completion of the necessary procedures.

         16. Any co-existing medical condition that in the Investigator's judgment will
             substantially increase the risk associated with the patient's participation in the
             clinical trial.

         17. Pre-scheduled hospitalizations, surgeries or interventions planned to be performed
             after obtaining Informed Consent for this study.