Safety Study of Aztreonam Lysine for Inhalation (AZLI) in the Treatment of Early Bronchiolitis Obliterans Syndrome (BOS) (AZLI)

• ClinicalTrials.gov Identifier: NCT01469364
• Recruitment Status: Completed
• First Posted: November 10, 2011
• Results First Posted: November 26, 2015
• Last Update Posted: January 29, 2016
• Sponsor: Duke University
• Collaborator: Gilead Sciences
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

This study is a pilot two- center study to determine if aztreonam lysine for inhalation AZLI can be safely and self-administered in lung transplant recipients with newly diagnosed bronchiolitis obliterans syndrome, grade 1 (BOS) and obtain pilot data regarding its effect on lung function in order to appropriately design and power a larger multicenter randomized study.

The hypothesis is that AZLI is a safe and effective treatment for declining lung function in lung transplant recipients with early stage BOS.

Condition or disease	Intervention/treatment	Phase
Complication of Transplanted Lung	Drug: Aztreonam Lysine for Inhalation (AZLI); Procedure: Status Post Lung Transplant	Phase 4

Detailed Description:

Lung transplantation is increasingly employed as a therapy for patients with advanced lung disease including cystic fibrosis, idiopathic pulmonary fibrosis or emphysema. Despite significant short-term improvements in life quality and measures of lung function after lung transplantation, long-term outcomes are disappointing primarily due to the development of a condition of airway fibrosis known as bronchiolitis obliterans (BO). It is hypothesized that aztreonam lysine for inhalation (AZLI) is a safe and effective treatment for declining lung function in lung transplant recipients with early stage BOS. In order to test the hypothesis, the investigators seek to establish the safety of AZLI in a two-center cohort of 30 lung transplant recipients with BOS treated intermittently for 5 consecutive study months and determine if this treatment leads to improvement or stabilization of lung function. The intervention will involve open label treatment with AZLI, in addition to usual transplant care, administered for 3 intermittent courses, 28 days each, over a 5 month study period.. Bronchoscopy, pulmonary function testing, and laboratory testing will be performed on a regular basis during study enrollment consistent with each center's usual standard clinical care. Patients will have a baseline screening visit, one month and five month study visit.. The study will take two years to complete from the start of funding. After a start-up period of 2 months, a total of 30 patients will be enrolled over 12 months across the two centers (15 patients each at DUMC and UCLA). Each enrolled patient will complete 5 months of intermittent therapy, and complete baseline, month 1 and month 5 visits. Over the next 6 months the study database will be finalized, statistical analysis will for primary and secondary outcomes will be performed leading to the generation of either a study abstract or manuscript.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Aztreonam Lysine for Inhalation (AZLI) in the Treatment of Early Bronchiolitis Obliterans Syndrome (BOS) After Lung Transplantation
• Study Start Date: March 2013
• Actual Primary Completion Date: March 2015
• Actual Study Completion Date: April 2015

Arms and Interventions

Arm

Intervention/treatment

Experimental: Aztreonam Lysine for Inhalation (AZLI); Patients to received Aztreonam Lysine(AZLI)

Drug: Aztreonam Lysine for Inhalation (AZLI); The intervention will involve open label treatment with AZLI inhaled 75mg TID self-administered intermittently for 28 days on study drug and 28 days off study drug over a study period of 5 consecutive months (on/off/on/off/on AZLI); Procedure: Status Post Lung Transplant; Bronchoscopy, pulmonary function testing, and laboratory testing will be performed on a regular basis during study enrollment consistent with each center's usual standard clinical care.; Other Name: Standard Post Lung Transplant Care

Outcome Measures

Primary Outcome Measures :

1. Change in Pulmonary Function, as Measured by Serial Forced Expiratory Volume in 1 Second (FEV1) on Spirometry [ Time Frame: Baseline, month 1 ]
   Within-subject change to absolute FEV1 month 1 vs. 0. FEV1 was measured 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
2. Change in Pulmonary Function, as Measured by Serial Forced Expiratory Volume in 1 Second (FEV1) on Spirometry [ Time Frame: Baseline, month 5 ]
   Within-subject change to absolute FEV1 month 5 vs 0.
3. Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 [ Time Frame: Baseline, month 1 ]
   The SF-36 is a commonly used, well validated measure of global health related quality of life. The survey was self-administered. There are 8 subscales which combine to form a Physical Component Score (PCS) and a Mental Component Score (MCS). We analyzed within subject changes to the PCS and MCS at month 1 vs. 0. MCS and PCS scores are relative to a US population mean of 50. The higher the score, the better one perceives his quality of life. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference. The SF-36 was completed 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
4. Change in Global Health Related Quality of Life, Measured by Serially Self-administered Short Form 36 Health Survey Questionnaire (SF-36) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 and Month 5. [ Time Frame: Baseline, month 5 ]
   The SF-36 is a commonly used, well validated measure of global health related quality of life. The survey was self-administered. There are 8 subscales which combine to form a Physical Component Score (PCS) and a Mental Component Score (MCS). We analyzed within subject changes to the PCS and MCS at month 5 vs 0. MCS and PCS scores are relative to a US population mean of 50. The higher the score, the better one perceives his quality of life. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference. The SF-36 was completed 14-35 days after the start of months 1 and 5 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
5. Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 [ Time Frame: Baseline, month 1 ]
   The SRGQ measures activities, symptoms, and impacts of living with a pulmonary condition. We analyzed the change to the within-subject Total score month 1 vs. 0. Total score ranges from 0-100 with a smaller value representing better respiratory-specific QOL. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference in the Total Score. The SGRQ was completed 14-35 days after the start of months 1 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
6. Change in Respiratory-specific Health Related Quality of Life, Measured by Serially Self Administered St. George's Respiratory Questionnaire (SGRQ) at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5. [ Time Frame: Baseline, month 5 ]
   The SRGQ measures activities, symptoms, and impacts of living with a pulmonary condition. We analyzed the change to the within-subject Total score month 5 vs 0. Total score ranges from 0-100 with a smaller value representing better respiratory-specific QOL. A change in score of 4 points or more is considered clinically meaningful. Scores represent Median Absolute Difference in theTotal Score. The SGRQ was completed 14-35 days after the start of month 5 AZLI courses and compared to study month 0 (baseline/prior to 1st dose).
7. Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 5. [ Time Frame: Baseline, month 5 ]
   Within-subject change to absolute FEF 25-75 month 5 vs 0. FEF 25-75 was measured 14-35 days after the start of months 5
8. Change in Pulmonary Function, as Measured by Serial Forced Expiratory Flow (FEF25-75) on Spirometry at Baseline (Prior to AZLI First Dose) and During AZLI Therapy at Month 1 [ Time Frame: Baseline, month 1 ]
   Within-subject change to absolute FEF 25-75 month 1 vs. 0. FEF 25-75 was measured 14-35 days after the start of months 1

Secondary Outcome Measures :

1. Change in FEV1 Off AZLI Therapy [ Time Frame: At Study Months 2 and 4 ]
   This will be compared to study month 0 (baseline, when obtained as standard of care (SOC).
2. Change in HRQOL Off AZLI Therapy. [ Time Frame: At study months 2 or 4 ]
   This will be compared to study month 0 (baseline), when obtained at standard of care visit (SOC)
3. Among Patients Colonized With Pseudomonas Aeruginosa, Change in Infection Burden as Measured by the Culture Final Report (0,1+, 2+, 3+, 4+) of in Pseudomonas Aeruginosa Sputum or Bronchoalveolar Fluid. [ Time Frame: Baseline, month 1 ]
   Microbiology data was collected when performed for SOC purposes on BAL or sputum samples. Baseline and 1 month value represents the culture final report value (0,1+, 2+, 3+, 4+) of Pseudomonas aeruginosa. A value of zero represents no Pseudomonas aeruginosa sputum or bronchoalveolar fluid. A value of 4 represents high amounts of Pseudomonas aeruginosa sputum or bronchoalveolar fluid.
4. Bronchoalveolar Lavage Fluid (BALF) Neutrophilia After Treatment, When Performed as Part of Clinical Care (SOC). [ Time Frame: Baseline - defined as a within 90 days of enrollment and After Treatment (5 months) ]
   The study team is measuring the change in neutrophils AFTER treatment. They will compare a SOC BAL taken after AZLI with the BAL taken within 90 days of AZLI initiation (pre or baseline measure). The post AZLI BAL measurement time range is 15 days after first course of AZLI up to last day of the 3rd and final course of AZLI (over a period of 5 consecutive months).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Adult (18 or older at the time of transplant) male or female
• Cadaveric first lung transplant recipient, single or bilateral; or multi-organ lung transplant recipient.

• Current FEV1 66-80% of posttransplant baseline FEV1, and meets all criteria for BOS 1 as defined by the International Society of Heart and Lung Transplantation.

  • Onset of BOS 1 within twelve months of screening

Exclusion Criteria:

• Known allergy to aztreonam
• Retransplant
• Pediatric patients
• Live lobar transplant recipients
• Inability to provide informed consent.
• Patients with advanced BOS (grades 2,3) or established BOS >6 months
• Pregnant Women

Contacts and Locations

Locations

United States, California

David Geffen School of Medicine at UCLA

Los Angeles, California, United States, 90095

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Duke University

Gilead Sciences

Investigators

• Principal Investigator: Scott Palmer, MD; Duke University

More Information

Publications:

Belperio JA, Weigt SS, Fishbein MC, Lynch JP 3rd. Chronic lung allograft rejection: mechanisms and therapy. Proc Am Thorac Soc. 2009 Jan 15;6(1):108-21. doi: 10.1513/pats.200807-073GO. Review.

Weigt SS, Wallace WD, Derhovanessian A, Saggar R, Saggar R, Lynch JP, Belperio JA. Chronic allograft rejection: epidemiology, diagnosis, pathogenesis, and treatment. Semin Respir Crit Care Med. 2010 Apr;31(2):189-207. doi: 10.1055/s-0030-1249116. Epub 2010 Mar 30. Review.

Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, Mallory GB, Snell GI, Yousem S. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002 Mar;21(3):297-310. Review.

Lama VN, Murray S, Lonigro RJ, Toews GB, Chang A, Lau C, Flint A, Chan KM, Martinez FJ. Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients. Am J Respir Crit Care Med. 2007 Jun 1;175(11):1192-8. Epub 2007 Mar 8.

Christie JD, Edwards LB, Kucheryavaya AY, Aurora P, Dobbels F, Kirk R, Rahmel AO, Stehlik J, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report--2010. J Heart Lung Transplant. 2010 Oct;29(10):1104-18. doi: 10.1016/j.healun.2010.08.004.

Finlen Copeland CA, Snyder LD, Zaas DW, Turbyfill WJ, Davis WA, Palmer SM. Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients. Am J Respir Crit Care Med. 2010 Sep 15;182(6):784-9. doi: 10.1164/rccm.201002-0211OC. Epub 2010 May 27.

Vos R, Vanaudenaerde BM, Ottevaere A, Verleden SE, De Vleeschauwer SI, Willems-Widyastuti A, Wauters S, Van Raemdonck DE, Nawrot TS, Dupont LJ, Verleden GM. Long-term azithromycin therapy for bronchiolitis obliterans syndrome: divide and conquer? J Heart Lung Transplant. 2010 Dec;29(12):1358-68. doi: 10.1016/j.healun.2010.05.023. Epub 2010 Jul 8.

Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med. 2003 Jul 1;168(1):121-5. Epub 2003 Apr 2.

Vos R, Vanaudenaerde BM, Geudens N, Dupont LJ, Van Raemdonck DE, Verleden GM. Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation? Eur Respir J. 2008 May;31(5):1037-45. doi: 10.1183/09031936.00128607. Epub 2008 Feb 6.

Jain R, Hachem RR, Morrell MR, Trulock EP, Chakinala MM, Yusen RD, Huang HJ, Mohanakumar T, Patterson GA, Walter MJ. Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2010 May;29(5):531-7. doi: 10.1016/j.healun.2009.12.003. Epub 2010 Feb 4.

McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008 Nov 1;178(9):921-8. doi: 10.1164/rccm.200712-1804OC. Epub 2008 Jul 24.

Oermann CM, Retsch-Bogart GZ, Quittner AL, Gibson RL, McCoy KS, Montgomery AB, Cooper PJ. An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis. Pediatr Pulmonol. 2010 Nov;45(11):1121-34. doi: 10.1002/ppul.21301.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT01469364
• Other Study ID Numbers: Pro00030559; Gilead Sciences, Inc ( Other Identifier: Gileand Sciences, Inc ); Pro00030191 ( Other Identifier: Duke Site Protocol Number )
• First Posted: November 10, 2011
• Results First Posted: November 26, 2015
• Last Update Posted: January 29, 2016
• Last Verified: December 2015

Keywords provided by Duke University:

Lung Transplant; Lung Transplant Recipient

Additional relevant MeSH terms:

Bronchiolitis; Bronchiolitis Obliterans; Respiratory Tract Diseases; Bronchitis; Respiratory Tract Infections; Infections; Bronchial Diseases; Lung Diseases, Obstructive; Lung Diseases; Aztreonam; Anti-Bacterial Agents; Anti-Infective Agents