Efficacy Study of Azithromycin-based Therapy for Bronchiolitis Obliterans

NCT01327625 | Terminated

• 1 other identifier: AMC-ALLO-041
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

\[Study Objectives\]

• 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.

Conditions

Graft vs Host Disease; Bronchiolitis Obliterans

Keywords

Allogeneic hematopoietic cell transplantation; Graft versus host disease; Bronchiolitis obliterans; Azithromycin; N-acetylcystein; Fluticasone; Inhaled steroid

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Clinical benefit rate based on the degree of change in FEV1

  6 months

• change in FEV1 compared with pretreatment level

  6 months after treatment initiation

• Reduction rate in immunosuppressive agent / systemic corticosteroid

  6 months after treatment initiation

• Discontinuation rate in immunosuppressive agent / systemic corticosteroid

  6 months after treatment initiation

• Change in dose-intensity of immunosuppressive agent / systemic corticosteroid compared with pretreatment dose-intensity

  6 months after treatment initiation

Study Arms (1)

Azithromycin

EXPERIMENTAL

Patient who are diagnosed as bronchiolitis obliterans according to the WHO criteria

Drug: azithromycin + N-acetylcystein + inhaled corticosteroid

Interventions

azithromycin + N-acetylcystein + inhaled corticosteroid DRUG

* 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

Also known as: Zithromax

Azithromycin

Eligibility Criteria

• Age: 15 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 ㎎/㎗).

You may not qualify if:

• 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)

Sponsors & Collaborators

• Asan Medical Center: lead

Study Sites (1)

Asan Medical Center

Seoul, 138-736, South Korea

Location

Related Publications (26)

• 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.

  PMID: 19442201 BACKGROUND

• 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.

  PMID: 16791762 BACKGROUND

• 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.

  PMID: 19349954 BACKGROUND

• 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.

  PMID: 19602690 BACKGROUND

• 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.

  PMID: 18707652 BACKGROUND

• 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.

  PMID: 18297116 BACKGROUND

• 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.

  PMID: 17488669 BACKGROUND

• 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.

  PMID: 16953211 BACKGROUND

• 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.

  PMID: 15852024 BACKGROUND

• 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.

  PMID: 16002929 BACKGROUND

• 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.

  PMID: 19059110 BACKGROUND

• 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.

  PMID: 18158963 BACKGROUND

• 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.

  PMID: 16709871 BACKGROUND

• 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.

  PMID: 12691702 BACKGROUND

• 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.

  PMID: 11889437 BACKGROUND

• 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.

  PMID: 11518728 BACKGROUND

• 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.

  PMID: 12614277 BACKGROUND

• 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.

  PMID: 14569562 BACKGROUND

• 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.

  PMID: 19896545 BACKGROUND

• 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.

  PMID: 19430505 BACKGROUND

• 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.

  PMID: 18192909 BACKGROUND

• 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.

  PMID: 15167610 BACKGROUND

• 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.

  PMID: 15738293 BACKGROUND

• 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.

  PMID: 17275508 BACKGROUND

• 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.

  PMID: 20186101 BACKGROUND

• 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.

  PMID: 14734137 BACKGROUND

MeSH Terms

Conditions

Graft vs Host Disease; Bronchiolitis Obliterans

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Immune System Diseases; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Dae-Young Kim, M.D.

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: March 31, 2011
• First Posted: April 1, 2011
• Study Start: March 1, 2011
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: July 9, 2014

Record last verified: 2014-07

Locations

KR (1)