BACKGROUND: Chronic rejection, manifesting as bronchiolitis obliterans, is the leading cause of death in lung transplant recipients. In our previously reported double-blinded, placebo-controlled trial comparing inhaled cyclosporine (ACsA) to aerosol placebo, the rate of bronchiolitis-free survival improved. However, an independent analysis of pulmonary function, a secondary endpoint of the trial, was not performed. We sought to determine the effect of ACsA, in addition to systemic immunosuppression, on pulmonary function. METHODS:From 1998-2001, 58 patients were randomly assigned to inhale either 300 mg of ACsA (28 patients) or placebo aerosol (30 patients) 3 days a week for the first 2 years after transplantation. Longitudinal changes in pulmonary function of ACsA patients were compared to aerosol placebo patients. In another analysis, the rate of decline from 6-month maximum FEV(1) in randomized patients was compared to the rate of decline in patients receiving conventional immunosuppression from the Novartis transplant database (644 patients, 12 centers worldwide, transplanted from 1990-1995). RESULTS: The average duration of ACsA and aerosol placebo was 400 days +/- 306 and 433 +/- 256, respectively. The change in FEV(1) of ACsA patients (adjusted for Cytomegalovirus (CMV) mismatch and transplant type, followed for a maximum duration of 4.6 years) was superior to the aerosol placebo controls (9.0 +/- 71.4 mL/year vs. -107.9 +/- 55.3, p = 0.007). The FEF(25-75) decreased by -220.3 +/- 117.7 L/(second x year) vs. -412.2 +/- 139.2, p = 0.07, respectively. Similarly, percent FEV(1) decline from maximal values was improved in ACsA patients compared to aerosol placebo and Novartis controls (ACsA -0.43 +/- 1.12%/year vs. aerosol placebo -4.08 +/- 1.4, p = 0.04; ACsA vs. Novartis -4.7 +/- 0.31, p = 0.007). Single-lung recipients receiving ACsA showed improvement in FEV(1) compared to Novartis controls (FEV(1) -0.8 +/- 1.8%/year vs. -4.94 +/- 0.4, p = 0.03) but double-lung recipients showed improvement compared to aerosol placebo controls only (FEV(1) -0.28 +/- 1.22%/year vs. -8.53 +/- 5.95, p = 0.048). CONCLUSIONS: In this single center trial, ACsA appears to ameliorate important pulmonary function parameters in lung transplant recipients compared to aerosol placebo and historical control patients. Single- and double-lung transplant recipients may not respond uniformly to treatment, and ongoing randomized trials in lung transplant recipients using ACsA may help elucidate our findings.
RCT Entities:
BACKGROUND: Chronic rejection, manifesting as bronchiolitis obliterans, is the leading cause of death in lung transplant recipients. In our previously reported double-blinded, placebo-controlled trial comparing inhaled cyclosporine (ACsA) to aerosol placebo, the rate of bronchiolitis-free survival improved. However, an independent analysis of pulmonary function, a secondary endpoint of the trial, was not performed. We sought to determine the effect of ACsA, in addition to systemic immunosuppression, on pulmonary function. METHODS: From 1998-2001, 58 patients were randomly assigned to inhale either 300 mg of ACsA (28 patients) or placebo aerosol (30 patients) 3 days a week for the first 2 years after transplantation. Longitudinal changes in pulmonary function of ACsApatients were compared to aerosol placebo patients. In another analysis, the rate of decline from 6-month maximum FEV(1) in randomized patients was compared to the rate of decline in patients receiving conventional immunosuppression from the Novartis transplant database (644 patients, 12 centers worldwide, transplanted from 1990-1995). RESULTS: The average duration of ACsA and aerosol placebo was 400 days +/- 306 and 433 +/- 256, respectively. The change in FEV(1) of ACsApatients (adjusted for Cytomegalovirus (CMV) mismatch and transplant type, followed for a maximum duration of 4.6 years) was superior to the aerosol placebo controls (9.0 +/- 71.4 mL/year vs. -107.9 +/- 55.3, p = 0.007). The FEF(25-75) decreased by -220.3 +/- 117.7 L/(second x year) vs. -412.2 +/- 139.2, p = 0.07, respectively. Similarly, percent FEV(1) decline from maximal values was improved in ACsApatients compared to aerosol placebo and Novartis controls (ACsA -0.43 +/- 1.12%/year vs. aerosol placebo -4.08 +/- 1.4, p = 0.04; ACsA vs. Novartis -4.7 +/- 0.31, p = 0.007). Single-lung recipients receiving ACsA showed improvement in FEV(1) compared to Novartis controls (FEV(1) -0.8 +/- 1.8%/year vs. -4.94 +/- 0.4, p = 0.03) but double-lung recipients showed improvement compared to aerosol placebo controls only (FEV(1) -0.28 +/- 1.22%/year vs. -8.53 +/- 5.95, p = 0.048). CONCLUSIONS: In this single center trial, ACsA appears to ameliorate important pulmonary function parameters in lung transplant recipients compared to aerosol placebo and historical control patients. Single- and double-lung transplant recipients may not respond uniformly to treatment, and ongoing randomized trials in lung transplant recipients using ACsA may help elucidate our findings.
Authors: Marc Estenne; Janet R Maurer; Annette Boehler; James J Egan; Adaani Frost; Marshall Hertz; George B Mallory; Gregory I Snell; Samuel Yousem Journal: J Heart Lung Transplant Date: 2002-03 Impact factor: 10.247
Authors: A T Iacono; T E Corcoran; B P Griffith; W F Grgurich; D A Smith; A Zeevi; G C Smaldone; K R McCurry; B A Johnson; J H Dauber Journal: Eur Respir J Date: 2004-03 Impact factor: 16.671
Authors: T E Corcoran; G C Smaldone; J H Dauber; D A Smith; K R McCurry; G J Burckart; A Zeevi; B P Griffith; A T Iacono Journal: Eur Respir J Date: 2004-03 Impact factor: 16.671
Authors: R D Dowling; M Zenati; G J Burckart; S A Yousem; M Schaper; R L Simmons; R L Hardesty; B P Griffith Journal: Surgery Date: 1990-08 Impact factor: 3.982
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Authors: R J Keenan; A J Duncan; S A Yousem; M Zenati; M Schaper; R D Dowling; Y Alarie; G J Burckart; B P Griffith Journal: Transplantation Date: 1992-01 Impact factor: 4.939
Authors: Oscar Okwudiri Onyema; Yizhan Guo; Bayan Mahgoub; Qing Wang; Amir Manafi; Zhongcheng Mei; Anirban Banerjee; Dongge Li; Mark H Stoler; Melissa T Zaidi; Adam G Schrum; Daniel Kreisel; Andrew E Gelman; Elizabeth A Jacobsen; Alexander Sasha Krupnick Journal: JCI Insight Date: 2019-06-06
Authors: Yi-Bo Wang; Alan B Watts; Jay I Peters; Sha Liu; Ayesha Batra; Robert O Williams Journal: AAPS PharmSciTech Date: 2014-05-14 Impact factor: 3.246