Efficacy Study of Azithromycin-based Therapy for Bronchiolitis Obliterans - Full Text View

Purpose

[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.

Condition	Intervention
Graft vs Host Disease Bronchiolitis Obliterans	Drug: azithromycin + N-acetylcystein + inhaled corticosteroid

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Pilot Study Evaluating the Efficacy of Azithromycin, N-acetylcystein and Inhaled Corticosteroid Combination Therapy for Bronchiolitis Obliterans After Allogeneic Hematopoietic Cell Transpantation

Resource links provided by NLM:

MedlinePlus related topics: Steroids

Drug Information available for: Azithromycin Azithromycin dihydrate Azithromycin monohydrate

U.S. FDA Resources

Further study details as provided by Asan Medical Center:

Primary Outcome Measures:

Response rate based on the improvement of FEV1 [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Response rate at 6 months after treatment initiation based on the improvement of FEV1

Secondary Outcome Measures:

Clinical benefit rate based on the degree of change in FEV1 [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Clinical benefit rate at 6 months after treatment initiation based on the degree of change in FEV1
change in FEV1 compared with pretreatment level [ Time Frame: 6 months after treatment initiation ] [ Designated as safety issue: No ]
Change in FEV1 at 6 months after treatment initiation compared with pretreatment level
Reduction rate in immunosuppressive agent / systemic corticosteroid [ Time Frame: 6 months after treatment initiation ] [ Designated as safety issue: No ]
Reduction rate in immunosuppressive agent / systemic corticosteroid at 6 months after treatment initiation
Discontinuation rate in immunosuppressive agent / systemic corticosteroid [ Time Frame: 6 months after treatment initiation ] [ Designated as safety issue: No ]
Discontinuation rate in immunosuppressive agent / systemic corticosteroid at 6 months after treatment initiation
Change in dose-intensity of immunosuppressive agent / systemic corticosteroid compared with pretreatment dose-intensity [ Time Frame: 6 months after treatment initiation ] [ Designated as safety issue: No ]
Change in dose-intensity of immunosuppressive agent / systemic corticosteroid at 6 month after treatment initiation compared with pretreatment dose-intensity
event-free survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
overall survival [ Time Frame: 1year ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	March 2011
Estimated Study Completion Date:	April 2015
Estimated Primary Completion Date:	October 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: Zithromax

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.

Eligibility

Ages Eligible for Study:	15 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01327625

Contacts

Contact: Young-Ah Kang, RN	82-2-3010-6375	kya79@amc.seoul.kr
Contact: Bo Youn Kim, RN	82-2-3010-7289	bykim1018@gmail.com

Locations

Korea, Republic of
Asan Medical Center	Recruiting
Seoul, Korea, Republic of, 138-736
Contact: Bo Youn Kim, RN 82-2-3010-7289 bykim1018@gmail.com
Principal Investigator: Dae-Young Kim, M.D.
Sub-Investigator: Je-Hwan Lee, M.D. & PhD
Sub-Investigator: Jung-Hee Lee, M.D. & PhD.
Sub-Investigator: Kyoo-Hyung Lee, M.D. & PhD.
Sub-Investigator: Sung-Doo Kim, M.D.
Sub-Investigator: Yunsuk Choi, M.D.
Sub-Investigator: Young-Hun Park, M.D.

Sponsors and Collaborators

Asan Medical Center

Investigators

Principal Investigator:

Dae-Young Kim, M.D.

Asan Medical Center

More Information

Publications:

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. Review.

Afessa B, Peters SG. Major complications following hematopoietic stem cell transplantation. Semin Respir Crit Care Med. 2006 Jun;27(3):297-309. Review.

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. 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.

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. Review.

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. 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.

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. 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.

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. 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.

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.

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.

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.

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.

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.

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. Review.

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.

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. Epub 2009 Nov 5. Review.

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. Epub 2009 May 11. Review.

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.

Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2004 May 15;77(9):1465-7.

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.

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.

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.

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.

Responsible Party:	Dae-Young Kim, Assistant Professor, Asan Medical Center
ClinicalTrials.gov Identifier:	NCT01327625 History of Changes
Other Study ID Numbers:	AMC-ALLO-041
Study First Received:	March 31, 2011
Last Updated:	January 3, 2013
Health Authority:	South Korea: Korea Food and Drug Administration (KFDA)

Keywords provided by Asan Medical Center:

Allogeneic hematopoietic cell transplantation
Graft versus host disease
Bronchiolitis obliterans
Azithromycin

N-acetylcystein
Fluticasone
Inhaled steroid

Additional relevant MeSH terms:

Bronchiolitis
Bronchiolitis Obliterans
Graft vs Host Disease
Bronchitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases

Respiratory Tract Infections
Immune System Diseases
Azithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on June 18, 2013