Efficacy Study of Azithromycin-based Therapy for Bronchiolitis Obliterans

Graft vs Host Disease Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01327625
• Other study ID #: AMC-ALLO-041
• Status: Terminated
• Phase: N/A
• First received: March 31, 2011
• Last updated: July 8, 2014
• Start date: March 2011
• Est. completion date: June 2013

Study information

• Verified date: July 2014
• Source: Asan Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: South Korea: Korea Food and Drug Administration (KFDA)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years to 75 Years

Eligibility

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 Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bronchiolitis
• Bronchiolitis Obliterans
• Graft vs Host Disease

Intervention

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

Locations

Country	Name	City	State
Korea, Republic of	Asan Medical Center	Seoul

Sponsors (1)

Lead Sponsor	Collaborator
Asan Medical Center

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (26)

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

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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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. — View Citation

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. Review. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response rate based on the improvement of FEV1	Response rate at 6 months after treatment initiation based on the improvement of FEV1	6 months	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	event-free survival		1 year	No
Secondary	overall survival		1year	No