Nebulized Liposomal Amphotericin B Ambisome for Prophylaxis of Invasive Pulmonary Aspergillosis

Acute Myeloid Leukemia Clinical Trial

— AMBINEB  

Official title:

AMBINEB: Clinical Trial to Evaluate Tolerance and Safety of Nebulized Liposomal Amphotericin B Ambisome for Prophylaxis of Invasive Pulmonary Aspergillosis in Patients With Acute Myeloid Leukemia and Allogeneic Haematopoietic Progenitor Cell Transplant (Alo-HPCT)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00391014
• Other study ID #: 2005-000703-34
• Secondary ID: AMBINEB
• Status: Completed
• Phase: Phase 2
• First received: October 20, 2006
• Last updated: May 11, 2009
• Start date: January 2006
• Est. completion date: April 2009

Study information

• Verified date: May 2009
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The trial is planned as a multicentric, national, phase II, open-label trial to evaluate safety and tolerance of nebulized Liposomal Amphotericin B (Ambisome) for LMA patients during the induction therapy ,intensification, plus Allogeneic Haematopoietic Progenitor Cell transplant in due course, as well for patients diagnosed of several malignant haematologic diseases and treated with Allogeneic Haematopoietic Progenitor Cell Transplant

Description:

The invasive fungal infection (IFI) is the most common cause of mortality related to autologous stem cell transplant. Taking into account that Saprophytic Aspergillus is usually acquired by inhalation, to protect the bronchial tree just before the tissue invasion is quite attractive. In haematologic patients, as well as those ones subjected to an Allogeneic haematopoietic progenitor cell transplant, there is another group of patients at high risk of Invasive Pulmonary Aspergillosis (IPA). These are those patients with acute myeloid leucemia (AML), submitted to induction, intensification or consolidation polychemotherapy. The IPA incidence rate in these patients, whenever during their evolution, reaches 18-20%, with usual treatments. Furthermore, unlike allogeneic haematopoietic progenitor cell transplant patients, neutropenia was the only IPA risk factor. Nowadays, pharmacologic prophylaxis against IPA, in patients with allogeneic haematopoietic progenitor cell transplant and patients affected by AML in induction or intensification therapy is far from being optimal, because of problems related to tolerance and drug interactions .

The Nebulized Liposomal Amphotericin B (Ambisome) prophylaxis against IPA has shown good tolerance, safety and efficacy in lung transplant recipients.

Extrapolating the results obtained in lung transplant recipients, we get the conclusion that it would be essential to study safety and tolerance of nebulized AMBISOME in the group of patients with different peculiarities, mucositis secondary to chemotherapy, and high incidence of IPA in order to reach the goal of evaluate its efficacy as prophylaxis against IPA in this kind of patients

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: April 2009
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient has decided voluntary to consent his or her participation signing the consent form before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

• Patients with Acute myeloid Leukemia (AML), that will start induction chemotherapy or those patients submitted to an Allogeneic haematopoietic progenitor cell transplant.

• The patient is >18 years old.

Exclusion Criteria:

• Patient with prior Invasive Pulmonary Aspergillosis (IPA) history.

• History of allergy or hypersensitivity to Amphotericin B.

• Patient with intellectual deficit or patients with psychological alterations that make impossible the trial understanding.

• Pregnancy or breastfeeding.

• Patient has received other investigational drug or non traded product within 30 days before trial beginning.

• Patient is enrolled in another clinical research study or/and is receiving an investigational agent for any reason.

• Patient had major surgery within 4 weeks before enrollment.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Allogeneic Haematopoietic Progenitor Cell Transplant
• Aspergillosis
• Invasive Pulmonary Aspergillosis
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Pulmonary Aspergillosis

Intervention

Drug:
• liposomal Amphotericine B
AML patients in induction chemotherapy treatment will received prophylaxis with nebulized liposomal amphotericin B (24 mg/week). It will be maintained during the intensification chemotherapy and in periods between cycles. If patient required ALO-TPH, the prophylaxis should be followed.

Locations

Country	Name	City	State
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario de la Princesa	Madrid
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario la Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
PETHEMA Foundation

Country where clinical trial is conducted

Spain, 

References & Publications (24)

Behre GF, Schwartz S, Lenz K, Ludwig WD, Wandt H, Schilling E, Heinemann V, Link H, Trittin A, Boenisch O, et al. Aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in neutropenic cancer patients. Ann Hematol. 1995 Dec;71(6):287-91. — View Citation

Cahill BC, Hibbs JR, Savik K, Juni BA, Dosland BM, Edin-Stibbe C, Hertz MI. Aspergillus airway colonization and invasive disease after lung transplantation. Chest. 1997 Nov 5;112(5):1160-4. — View Citation

Calvo V, Borro JM, Morales P, Morcillo A, Vicente R, Tarrazona V, París F. Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group. Chest. 1999 May;115(5):1301-4. — View Citation

Conneally E, Cafferkey MT, Daly PA, Keane CT, McCann SR. Nebulized amphotericin B as prophylaxis against invasive aspergillosis in granulocytopenic patients. Bone Marrow Transplant. 1990 Jun;5(6):403-6. — View Citation

Denning DW. Invasive aspergillosis. Clin Infect Dis. 1998 Apr;26(4):781-803; quiz 804-5. Review. — View Citation

Dubois J, Bartter T, Gryn J, Pratter MR. The physiologic effects of inhaled amphotericin B. Chest. 1995 Sep;108(3):750-3. — View Citation

Erjavec Z, Woolthuis GM, de Vries-Hospers HG, Sluiter WJ, Daenen SM, de Pauw B, Halie MR. Tolerance and efficacy of Amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in haematological patients. Eur J Clin Microbiol Infect Dis. 1997 May;16(5):364-8. — View Citation

Hertenstein B, Kern WV, Schmeiser T, Stefanic M, Bunjes D, Wiesneth M, Novotny J, Heimpel H, Arnold R. Low incidence of invasive fungal infections after bone marrow transplantation in patients receiving amphotericin B inhalations during neutropenia. Ann Hematol. 1994 Jan;68(1):21-6. — View Citation

Kramer MR, Denning DW, Marshall SE, Ross DJ, Berry G, Lewiston NJ, Stevens DA, Theodore J. Ulcerative tracheobronchitis after lung transplantation. A new form of invasive aspergillosis. Am Rev Respir Dis. 1991 Sep;144(3 Pt 1):552-6. — View Citation

Kume H, Yamazaki T, Abe M, Tanuma H, Okudaira M, Okayasu I. Increase in aspergillosis and severe mycotic infection in patients with leukemia and MDS: comparison of the data from the Annual of the Pathological Autopsy Cases in Japan in 1989, 1993 and 1997. Pathol Int. 2003 Nov;53(11):744-50. — View Citation

Lambros MP, Bourne DW, Abbas SA, Johnson DL. Disposition of aerosolized liposomal amphotericin B. J Pharm Sci. 1997 Sep;86(9):1066-9. — View Citation

Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002 Dec 15;100(13):4358-66. Epub 2002 Aug 22. — View Citation

Monforte V, Roman A, Gavalda J, Bravo C, Tenorio L, Ferrer A, Maestre J, Morell F. Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors. J Heart Lung Transplant. 2001 Dec;20(12):1274-81. — View Citation

Monforte V, Roman A, Gavaldá J, López R, Pou L, Simó M, Aguadé S, Soriano B, Bravo C, Morell F. Nebulized amphotericin B concentration and distribution in the respiratory tract of lung-transplanted patients. Transplantation. 2003 May 15;75(9):1571-4. — View Citation

Myers SE, Devine SM, Topper RL, Ondrey M, Chandler C, O'Toole K, Williams SF, Larson RA, Geller RB. A pilot study of prophylactic aerosolized amphotericin B in patients at risk for prolonged neutropenia. Leuk Lymphoma. 1992 Oct;8(3):229-33. — View Citation

Nosari A, Oreste P, Cairoli R, Montillo M, Carrafiello G, Astolfi A, Muti G, Marbello L, Tedeschi A, Magliano E, Morra E. Invasive aspergillosis in haematological malignancies: clinical findings and management for intensive chemotherapy completion. Am J Hematol. 2001 Dec;68(4):231-6. — View Citation

Reichenspurner H, Gamberg P, Nitschke M, Valantine H, Hunt S, Oyer PE, Reitz BA. Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis. Transplant Proc. 1997 Feb-Mar;29(1-2):627-8. — View Citation

Schmitt HJ, Bernard EM, Häuser M, Armstrong D. Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis. Antimicrob Agents Chemother. 1988 Nov;32(11):1676-9. — View Citation

Schwartz S, Behre G, Heinemann V, Wandt H, Schilling E, Arning M, Trittin A, Kern WV, Boenisch O, Bosse D, Lenz K, Ludwig WD, Hiddemann W, Siegert W, Beyer J. Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood. 1999 Jun 1;93(11):3654-61. — View Citation

Siwek GT, Dodgson KJ, de Magalhaes-Silverman M, Bartelt LA, Kilborn SB, Hoth PL, Diekema DJ, Pfaller MA. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis. 2004 Aug 15;39(4):584-7. Epub 2004 Jul 30. — View Citation

Thomas DA, Myers MA, Wichert B, Schreier H, Gonzalez-Rothi RJ. Acute effects of liposome aerosol inhalation on pulmonary function in healthy human volunteers. Chest. 1991 May;99(5):1268-70. — View Citation

Westney GE, Kesten S, De Hoyos A, Chapparro C, Winton T, Maurer JR. Aspergillus infection in single and double lung transplant recipients. Transplantation. 1996 Mar 27;61(6):915-9. — View Citation

Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL, Leitz GJ, Territo MC. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med. 2003 May 6;138(9):705-13. — View Citation

Yeldandi V, Laghi F, McCabe MA, Larson R, O'Keefe P, Husain A, Montoya A, Garrity ER Jr. Aspergillus and lung transplantation. J Heart Lung Transplant. 1995 Sep-Oct;14(5):883-90. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy and safety prophylaxis against IPA in LMA patients.		1 year	Yes

External Links

•   Pethema Foundation web
•   Spanish association of Haematology