Aerosol Liposomal Cyclosporine for Chronic Rejection in Lung Transplant Recipients

This is a randomized single-center pilot study to investigate the efficacy and safety of aerosolized liposomal cyclosporine A (L-CsA) in the treatment of chronic rejection in lung transplant recipients with Grade 1 or 2 BOS.

The primary endpoints will include:

* Improvement or stabilization of pulmonary function test (FEV1) from baseline
* Stabilization of histology (no deterioration from baseline)
* Safety of the preparation

The secondary endpoints will include:

* Pharmacokinetics and distribution of CsA in blood -
* Change in cytokine levels from BAL specimens.

• Liposomal aerosol cyclosporine (Drug), also known as cyclosporine: inhaled form of immune suppression
• standard immune suppression, oral (Other), also known as tacrolimus, rapamycin, sirolimus: conventional drug Conventrional oral immune suppression as standard of care thus consists of tacrolimus, mycophenolate mofetil prednisone and rapamycin

Primary outcomes

• Number Of Participants With Chronic Rejection Who Met Primary Combined End-point [approximately 1 year]: Treatment failure defined as: BOS progression (> 20% decline lung function), re-transplant, or death

Secondary outcomes

• Cytokine Analysis From BAL Fluid in Lung [baseline to approximately 1 year]: Multiple cytokines were assessed as markers of lung inflammation that may be used in addition to biopsy data, collected per patient as clinically indicated during the follow-up interval. Values are reported as mean change from baseline in each group, per week
• Overall Survival at 5 Years Follow-up [5 years]: Number of participants surviving at 5 year follow-up

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Chronic rejection

1. Bronchiolitis obliterans diagnosed by bronchiolitis obliterans syndrome and > 20% decline from the individual patient's best FEV1 is observed
2. Recipient of a double or single lung transplant
3. Receiving immunosuppressive treatment according to institutional standards

Exclusion criteria:

1. Active invasive bacterial, viral or fungal infection
2. Current mechanical ventilation
3. Pregnant or breast-feeding woman
4. Known hypersensitivity to cyclosporine A
5. Serum creatinine value of more than 265 μmol/L (3 mg/dL) or chronic dialysis
6. Receipt of an investigational drug as part of a clinical trial

Participant flow

Outcome results

• Number Of Participants With Chronic Rejection Who Met Primary Combined End-point (Primary), Count of participants, Participants: Liposomal Aerosol Cyclosporine 2; Conventional Oral Immune Suppression 5 (p 0.03)
• Cytokine Analysis From BAL Fluid in Lung (Secondary), Mean, pg/mL: Liposomal Aerosol Cyclosporine -2 (-9.3 to 5.3); Conventional Oral Immune Suppression 3.3 (-4.3 to 10.9)
• Overall Survival at 5 Years Follow-up (Secondary), Count of participants, Participants: Liposomal Aerosol Cyclosporine 5; Conventional Oral Immune Suppression 0

Adverse events

Time frame: Serious and non-serious adverse events monitored for one year as described in the IND. All cause mortality monitored out to 5 years.

Serious adverse events by term

Other adverse events by term

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• Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, Fung JJ, Burckart GJ, McCurry KR, Griffith BP. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med. 2006 Jan 12;354(2):141-50. doi: 10.1056/NEJMoa043204. PMID 16407509

• Aldo T Iacono, MD, Principal investigator, University of Maryland