Efficacy Study of Azithromycin-based Therapy for Bronchiolitis Obliterans

A Pilot Study Evaluating the Efficacy of Azithromycin, N-acetylcystein and Inhaled Corticosteroid Combination Therapy for Bronchiolitis Obliterans After Allogeneic Hematopoietic Cell Transpantation

[Study Objectives]

• To evaluate the efficacy of azithromycin, N-acetylcystein, and inhaled corticosteroid combination therapy in patients with bronchiolitis obliterans as a complication of allogeneic hematopoietic cell transplantation in terms of response rate at 6 months after treatment initiation based on the improvement of FEV1.

Study Overview

• Status: Terminated
• Conditions: Bronchiolitis Obliterans; Graft vs Host Disease
• Intervention / Treatment: Drug: azithromycin + N-acetylcystein + inhaled corticosteroid

Detailed Description

• Bronchiolitis obliterans (BO) is a graft-versus-host disease of respiratory organs.
• Prognosis of BO is very poor, and the overall outcome of patients who are involved in BO is very dismal.
• The mechanism of BO has been known to be associated with immune / non-immune response.
• Corticosteroid and immunosuppressants are recommended as a best current treatment options for BO, which have been not satisfactory.
• Many treatment options have been tried to improve the outcome of BO.
• Azithromycin, as an immune modulating agent, has been tried for the treatment of BO, and has been reported to show hopeful results.
• N-acetylcystein, as an antioxidative agent, has been tried for BO.
• Inhaled corticosteroid may help to improve airway inflammation and decrease the amount of systemic corticosteroid.
• These 3 drugs are widely used for other respiratory disease, have been proven to be safe, and have shown some efficacy for BO in various depth of evidence.
• In these rationale, we'd like to try the 3-drug combination for BO, to assess the efficacy and safety of these drug combination.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 75 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients who previously received allogeneic hematopoietic cell transplantation due to hematologic malignancy, bone marrow failure syndrome, and other compatible disease.
• Patients who are diagnosed as bronchiolitis obliterans (BO) according to the NIH diagnostic guideline which is suggested as below.
• Patients should be 15 years of age or older, but younger than 75 years.
• Patients should have estimated life expectancy of more than 3 months.
• Patients must have adequate hepatic function (bilirubin less than 3.0 ㎎/㎗, AST and ALT less than three times the upper normal limit).
• Patients must have adequate renal function (creatinine less than 2.0 ㎎/㎗).

Exclusion Criteria:

• Presence of significant active infection
• Presence of uncontrolled bleeding
• Any coexisting major illness or organ failure
• Patients with a psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible.
• Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception
• Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Azithromycin; Patient who are diagnosed as bronchiolitis obliterans according to the WHO criteria	Drug: azithromycin + N-acetylcystein + inhaled corticosteroid; Azithromycin 500mg qd x 1 week --> 250mg qod x 6 months; N-acetylcystein 200mg tid x 6 months; Fluticasone 250mcg puff x2/day x 6 months; Other Names: Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate based on the improvement of FEV1	Response rate at 6 months after treatment initiation based on the improvement of FEV1	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical benefit rate based on the degree of change in FEV1	Clinical benefit rate at 6 months after treatment initiation based on the degree of change in FEV1	6 months
change in FEV1 compared with pretreatment level	Change in FEV1 at 6 months after treatment initiation compared with pretreatment level	6 months after treatment initiation
Reduction rate in immunosuppressive agent / systemic corticosteroid	Reduction rate in immunosuppressive agent / systemic corticosteroid at 6 months after treatment initiation	6 months after treatment initiation
Discontinuation rate in immunosuppressive agent / systemic corticosteroid	Discontinuation rate in immunosuppressive agent / systemic corticosteroid at 6 months after treatment initiation	6 months after treatment initiation
Change in dose-intensity of immunosuppressive agent / systemic corticosteroid compared with pretreatment dose-intensity	Change in dose-intensity of immunosuppressive agent / systemic corticosteroid at 6 month after treatment initiation compared with pretreatment dose-intensity	6 months after treatment initiation
event-free survival		1 year
overall survival		1year

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Investigators: Principal Investigator: Dae-Young Kim, M.D., Asan Medical Center

Publications and helpful links

General Publications

• Chien JW, Duncan S, Williams KM, Pavletic SZ. Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S106-14. doi: 10.1016/j.bbmt.2009.11.002. Epub 2009 Nov 5.
• Patriarca F, Poletti V, Costabel U, Battista ML, Sperotto A, Medeot M, Toffoletti E, Fanin R. Clinical presentation, outcome and risk factors of late-onset non-infectious pulmonary complications after allogeneic stem cell transplantation. Curr Stem Cell Res Ther. 2009 May;4(2):161-7. doi: 10.2174/157488809788167436.
• Afessa B, Peters SG. Major complications following hematopoietic stem cell transplantation. Semin Respir Crit Care Med. 2006 Jun;27(3):297-309. doi: 10.1055/s-2006-945530.
• Nishio N, Yagasaki H, Takahashi Y, Muramatsu H, Hama A, Tanaka M, Yoshida N, Watanabe N, Kudo K, Yoshimi A, Kojima S. Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 2009 Sep;44(5):303-8. doi: 10.1038/bmt.2009.33. Epub 2009 Apr 6.
• Williams KM, Chien JW, Gladwin MT, Pavletic SZ. Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. JAMA. 2009 Jul 15;302(3):306-14. doi: 10.1001/jama.2009.1018.
• Sato M, Keshavjee S. Bronchiolitis obliterans syndrome: alloimmune-dependent and -independent injury with aberrant tissue remodeling. Semin Thorac Cardiovasc Surg. 2008 Summer;20(2):173-82. doi: 10.1053/j.semtcvs.2008.05.002.
• Duncan CN, Buonanno MR, Barry EV, Myers K, Peritz D, Lehmann L. Bronchiolitis obliterans following pediatric allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008 Jun;41(11):971-5. doi: 10.1038/bmt.2008.19. Epub 2008 Feb 25.
• Ditschkowski M, Elmaagacli AH, Trenschel R, Peceny R, Koldehoff M, Schulte C, Beelen DW. T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors. Haematologica. 2007 Apr;92(4):558-61. doi: 10.3324/haematol.10710.
• Huisman C, van der Straaten HM, Canninga-van Dijk MR, Fijnheer R, Verdonck LF. Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease. Bone Marrow Transplant. 2006 Oct;38(8):561-6. doi: 10.1038/sj.bmt.1705484. Epub 2006 Sep 4.
• Yoshihara S, Tateishi U, Ando T, Kunitoh H, Suyama H, Onishi Y, Tanosaki R, Mineishi S. Lower incidence of Bronchiolitis obliterans in allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning compared with myeloablative conditioning. Bone Marrow Transplant. 2005 Jun;35(12):1195-200. doi: 10.1038/sj.bmt.1704985.
• Santo Tomas LH, Loberiza FR Jr, Klein JP, Layde PM, Lipchik RJ, Rizzo JD, Bredeson CN, Horowitz MM. Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia. Chest. 2005 Jul;128(1):153-61. doi: 10.1378/chest.128.1.153. Erratum In: Chest. 2006 Jan;129(1):216.
• Xu J, Torres E, Mora AL, Shim H, Ramirez A, Neujahr D, Brigham KL, Rojas M. Attenuation of obliterative bronchiolitis by a CXCR4 antagonist in the murine heterotopic tracheal transplant model. J Heart Lung Transplant. 2008 Dec;27(12):1302-10. doi: 10.1016/j.healun.2008.08.010.
• Hildebrandt GC, Granell M, Urbano-Ispizua A, Wolff D, Hertenstein B, Greinix HT, Brenmoehl J, Schulz C, Dickinson AM, Hahn J, Rogler G, Andreesen R, Holler E. Recipient NOD2/CARD15 variants: a novel independent risk factor for the development of bronchiolitis obliterans after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008 Jan;14(1):67-74. doi: 10.1016/j.bbmt.2007.09.009.
• Medoff BD, Wain JC, Seung E, Jackobek R, Means TK, Ginns LC, Farber JM, Luster AD. CXCR3 and its ligands in a murine model of obliterative bronchiolitis: regulation and function. J Immunol. 2006 Jun 1;176(11):7087-95. doi: 10.4049/jimmunol.176.11.7087.
• Jaramillo A, Smith CR, Maruyama T, Zhang L, Patterson GA, Mohanakumar T. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol. 2003 May;64(5):521-9. doi: 10.1016/s0198-8859(03)00038-7.
• Belperio JA, DiGiovine B, Keane MP, Burdick MD, Ying Xue Y, Ross DJ, Lynch JP 3rd, Kunkel SL, Strieter RM. Interleukin-1 receptor antagonist as a biomarker for bronchiolitis obliterans syndrome in lung transplant recipients. Transplantation. 2002 Feb 27;73(4):591-9. doi: 10.1097/00007890-200202270-00020.
• Belperio JA, Keane MP, Burdick MD, Lynch JP 3rd, Xue YY, Berlin A, Ross DJ, Kunkel SL, Charo IF, Strieter RM. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. J Clin Invest. 2001 Aug;108(4):547-56. doi: 10.1172/JCI12214.
• Vilchez RA, Dauber J, Kusne S. Infectious etiology of bronchiolitis obliterans: the respiratory viruses connection - myth or reality? Am J Transplant. 2003 Mar;3(3):245-9. doi: 10.1034/j.1600-6143.2003.00056.x.
• Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant. 2003 Oct;9(10):657-66. doi: 10.1016/s1083-8791(03)00242-8.
• Maimon N, Lipton JH, Chan CK, Marras TK. Macrolides in the treatment of bronchiolitis obliterans in allograft recipients. Bone Marrow Transplant. 2009 Jul;44(2):69-73. doi: 10.1038/bmt.2009.106. Epub 2009 May 11.
• Gottlieb J, Szangolies J, Koehnlein T, Golpon H, Simon A, Welte T. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2008 Jan 15;85(1):36-41. doi: 10.1097/01.tp.0000295981.84633.bc.
• Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2004 May 15;77(9):1465-7. doi: 10.1097/01.tp.0000122412.80864.43.
• Khalid M, Al Saghir A, Saleemi S, Al Dammas S, Zeitouni M, Al Mobeireek A, Chaudhry N, Sahovic E. Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J. 2005 Mar;25(3):490-3. doi: 10.1183/09031936.05.00020804.
• Meloni F, Cascina A, Miserere S, Perotti C, Vitulo P, Fietta AM. Peripheral CD4(+)CD25(+) TREG cell counts and the response to extracorporeal photopheresis in lung transplant recipients. Transplant Proc. 2007 Jan-Feb;39(1):213-7. doi: 10.1016/j.transproceed.2006.10.227.
• Duncan CN, Barry EV, Lehmann LE. Tolerability of pravastatin in pediatric hematopoietic stem cell transplant patients with bronchiolitis obliterans. J Pediatr Hematol Oncol. 2010 Apr;32(3):185-8. doi: 10.1097/MPH.0b013e3181d32184.
• Wuyts WA, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE, Demedts MG, Verleden GM. N-acetylcysteine inhibits interleukin-17-induced interleukin-8 production from human airway smooth muscle cells: a possible role for anti-oxidative treatment in chronic lung rejection? J Heart Lung Transplant. 2004 Jan;23(1):122-7. doi: 10.1016/s1053-2498(03)00099-8.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (ACTUAL): June 1, 2013
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: March 31, 2011
• First Submitted That Met QC Criteria: March 31, 2011
• First Posted (ESTIMATE): April 1, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): July 9, 2014
• Last Update Submitted That Met QC Criteria: July 8, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: Azithromycin; Graft versus host disease; Fluticasone; Allogeneic hematopoietic cell transplantation; N-acetylcystein; Bronchiolitis obliterans; Inhaled steroid
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Bronchiolitis; Bronchiolitis Obliterans; Graft vs Host Disease; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: AMC-ALLO-041