Safety and Efficacy of Inhaled Alpha-1 Antitrypsin in Preventing Bronchiolitis Obliterable Syndrome in Lung Transplant Recipients
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|ClinicalTrials.gov Identifier: NCT01394835|
Recruitment Status : Unknown
Verified July 2011 by Rabin Medical Center.
Recruitment status was: Not yet recruiting
First Posted : July 14, 2011
Last Update Posted : July 14, 2011
Bronchiolitis obliterable syndrome (BOS) is the most common cause of death in long-term survivors after lung transplantation and refractory to most interventions. Many risk factor for BOS were identified in previous studies such as acute cellular rejection, lymphocytic bronchiolitis, cytomegalovirus (CMV) and non-CMV respiratory infections, injury to the allograft or airways, Primary graft dysfunction, HLA mismatching, and organizing pneumonia. (Belperio JA. et al.). Neutrophils and their released products may be involved in the development of BOS. Neutrophilia was repeatedly observed in the bronchoalveolar lavage fluid of patients after lung transplantation. In addition, infiltration of neutrophils into the bronchial epithelium has been detected in patients with higher degrees of active airway damage. Neutrophils are capable of causing severe damage to the lung tissue by releasing toxic proteases and reactive oxygen species if not counterbalanced by the antiprotease/ antioxidant screen of the lung. Based on this background, a causal relationship between neutrophilia and the development of BOS has been proposed. (Hirsch J. et al.) Detection of unopposed Neutrophile elastase (NE) activity in BAL appears to correlate with poor outcome due to refractory BOS. Unopposed NE in these subjects may not only serve as a marker of evolving graft dysfunction but also participate in damaging the airways of the allograft and inhibit adequate bacterial clearance. Prevention of neutrophil sequestration or inhibition of NE may prevent or attenuate airway damage and improve bacterial clearance mechanisms. (Nutley D et al.) These data demonstrate the importance of neutrophils and unopposed NE in the pathogenesis of BOS and call for new approach to prevent or modulate BOS targeting this mechanism.
AAT is the main inhibitor of neutrophil elastase in the lower airways and patients with AAT deficiency have low concentrations of the protein in this region of the lung. This explains the proteinase/antiproteinase theory of the development of emphysema in deficient patients in which the amount of elastase released in the lung exceeds the amount of AAT. The net result is persistence of elastase activity leading to lung destruction and the pathological changes of emphysema. (Abusriwil H. et al.) The administration of the AAT is to address proteinase/antiproteinase imbalance.
Administration of AAT will help to prevent further destruction of the lung architecture and reduce the inflammatory dysregulation that causes pulmonary dysfunction. It is expected that by attacking a specific and previously untreated key component part of the pathophysiological cycle of BOS, AAT therapy would decrease the prevalence of BOS in lung transplant recipients and prolong life expectancy of these patients.
|Condition or disease||Intervention/treatment||Phase|
|Lung Transplantation Bronchiolitis Obliterable Syndrome||Drug: Alpha -1 Antitrypsin Drug: Alpha-1 Antitrypsin Drug: AAT||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Study Start Date :||September 2011|
|Estimated Primary Completion Date :||September 2012|
|Estimated Study Completion Date :||September 2013|
|Experimental: Alpha -1 Antitrypsin||
Drug: Alpha -1 Antitrypsin
Inhalation twice daily of 160mg
Drug: Alpha-1 Antitrypsin
Inhalation twice daily .Dosage 160mg
Inhalation twice daily' 160mg
- Clinical diagnosis of BOS according to Estenne M. et al Treatment of lung transplant recipients to prevent BOS Clinical diagnosis of BOS according to Estenne M. et al. Adverse events and conc [ Time Frame: 12 Month ]
Adverse events and concomitant medication recording and follow up. Safety/tolerability parameters at baseline (Day #1) will be compared with values generated at the following visits every 6 weeks (+/- 10 days).
At all visits, AEs and concomitant medications will be recorded. Additionally, the study coordinator will check occurrence of AE and concomitant medications by a telephone visit
- Change in lung function test [ Time Frame: 12 month ]
Change in lung function FEV%, FEV1, FVC Baseline (Day #1) values of FEV1 and FVC (and FEV%) will be compared to the following visits every 6 weeks (+/- 10 days).
Incidence of Acute cellular rejection. Incidence of respiratory infection leading to antibiotics administration according to the decision of the investigator.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01394835
|Contact: Mordechai Kramer, MDfirstname.lastname@example.org|
|Contact: Liora Yehoshua, Bscemail@example.com|
|Principal Investigator:||Mordechai R Kramer, M.D||Rabin Medical Center|