Efficacy Study of Azithromycin-based Therapy for Bronchiolitis Obliterans

NCT ID: NCT01327625

Last Updated: 2014-07-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-03-31
• Study Completion Date: 2013-06-30

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.

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.

Conditions

Graft vs Host Disease; Bronchiolitis Obliterans

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Azithromycin

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

Group Type: EXPERIMENTAL

azithromycin + N-acetylcystein + inhaled corticosteroid

Intervention Type: 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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Zithromax

Eligibility Criteria

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)

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Asan Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Dae-Young Kim

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dae-Young Kim, M.D.

Role: PRINCIPAL_INVESTIGATOR

Asan Medical Center

Locations

Asan Medical Center

Seoul, , South Korea

Countries

South Korea

References

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.

Reference Type: BACKGROUND

PMID: 19442201 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16791762 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19349954 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19602690 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18707652 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18297116 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17488669 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16953211 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15852024 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16002929 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19059110 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18158963 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16709871 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12691702 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11889437 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11518728 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12614277 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14569562 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19896545 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19430505 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18192909 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15167610 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15738293 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17275508 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20186101 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14734137 (View on PubMed)

Other Identifiers

AMC-ALLO-041

Identifier Type: -

Identifier Source: org_study_id