Comparison of Voriconazole and Amphotericin B in Treating Patients With Aspergillosis

Condition(s) targeted: Infection; Pulmonary Complications

Intervention: amphotericin B deoxycholate (Drug); voriconazole (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: European Organization for Research and Treatment of Cancer

Official(s) and/or principal investigator(s):
R. Herbrecht, MD, Study Chair, Affiliation: Hopital Universitaire Hautepierre

RATIONALE: Antifungal therapy with voriconazole or amphotericin B may be an effective treatment for aspergillosis. It is not yet known whether voriconazole is more effective than amphotericin B in treating patients with aspergillosis.

PURPOSE: Randomized phase III trial to compare the effectiveness of voriconazole with amphotericin B in treating patients with aspergillosis.

Official title: An Open Randomised Comparative Multicentre Study of the Efficacy, Safety and Toleration of Voriconazole Versus Amphotericin-B in the Treatment of Acute Invasive Aspergillosis in Immunocompromised Patients

Study design: Supportive Care, Randomized

Detailed description: OBJECTIVES: I. Compare the efficacy, safety, and toleration of voriconazole versus amphotericin B (CAB) in the treatment of acute invasive aspergillosis in immunocompromised patients. II. Compare the efficacy, safety, and toleration of voriconazole versus CAB followed by other antifungal therapy in the treatment of acute invasive aspergillosis in immunocompromised patients. III. Compare survival in patients treated with voriconazole versus CAB with or without other antifungal therapy. IV. Investigate resource utilization in patients treated with voriconazole versus CAB with or without other antifungal therapy.

OUTLINE: This is an open label, randomized, multicenter study. Patients are stratified according to center, site of infection, underlying disease, and baseline neutrophil count. Patients are randomized to one of two treatment arms. Arm I: Patients receive voriconazole IV every 12 hours for 7-28 days and continue with oral voriconazole twice a day for a maximum total duration of 12 weeks of therapy. Arm II: Patients receive intravenous amphotericin B daily for at least 2 weeks; treatment continues for a maximum of 12 weeks. Patients discontinued from study drug treatment because of toxicity, intolerance or clinical failure may receive alternative (nonstudy) antifungal therapy. All patients are monitored for a total of 16 weeks.

PROJECTED ACCRUAL: A sufficient number of patients will be accrued so that 212 patients (106 per study arm) will be eligible for the study.

Minimum age: 12 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS: Patient immunocompromised as the result of any of the following: Allogeneic bone marrow/peripheral stem cell transplant Autologous bone marrow/peripheral stem cell transplant Hematological malignancy (including lymphoma) Aplastic anemia and myelodysplastic syndromes (currently on immunosuppressive treatment) Solid organ transplantation (other than lung) Other solid organ malignancy (after cytotoxic chemotherapy) HIV/AIDS High dose prolonged corticosteroid therapy (at least 20 mg/day of prednisolone or equivalent for more than 3 weeks) or prolonged therapy with other immunosuppressive agents (e. g., azathioprine, methotrexate) Diagnosis of either definite or probable acute invasive aspergillosis Fungal infection represents a new episode of acute invasive aspergillosis Patients with the following are ineligible: Aspergilloma or allergic bronchopulmonary aspergillosis Chronic invasive aspergillosis Sarcoidosis CMV pneumonia

PATIENT CHARACTERISTICS: Age: 12 and over Life expectancy: At least 72 hours Hematopoietic: Not specified Hepatic: Bilirubin no greater than 5 times upper limit of normal (ULN) SGOT/SGPT no greater than 5 times ULN Alkaline phosphatase no greater than 5 times ULN Renal: Creatinine no greater than 2. 5 mg/dL Other: No history of hypersensitivity or intolerance to azole antifungal agents including miconazole, ketoconazole, fluconazole, or itraconazole No history of hypersensitivity or severe intolerance to conventional or lipid formulations of amphotericin B Not pregnant or nursing Fertile women must use effective contraception Negative pregnancy test No prior participation on this trial Not on artificial ventilation and unlikely to be extubated within 24 hours No condition that could affect patient safety, preclude evaluation of response, or make study completion unlikely

PRIOR CONCURRENT THERAPY: At least 8 weeks since prior systemic treatment with amphotericin B or itraconazole At least 2 weeks since prior systemic antifungal therapy for more than 96 hours at doses greater than 0. 5 mg/kg/day for conventional or lipid formulations of amphotericin B or greater than 200 mg/day of itraconazole No concurrent drugs that are metabolized primarily by hepatic cytochrome P-450 enzymes or which induce or inhibit these enzymes, such as terfenadine, loratidine, astemizole, midazolam, triazolam, cisapride, rifampin, rifabutin, barbiturates, carbamazepine, coumarins, sulfonylureas, nivarapine, erythromycin, ritonavir, delaviridine, omeprazole, and phenytoin At least 2 weeks since prior rifampin, rifabutin, carbamazepine, or barbiturates for more than 3 days No concurrent investigational drugs other than cytotoxics, antiretroviral agents, or therapies for AIDS-related opportunistic infection No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) other than for treatment of granulocytopenia No concurrent white blood cell transfusions No concurrent systemic antifungal agents active against Aspergillus spp. (e. g., itraconazole, lipid formulations of amphotericin B, or flucytosine)

Algemeen Ziekenhuis Middelheim, Antwerp 2020, Belgium

Clinique Universitaire De Mont-Godinne, Mont-Godinne Yvoir 5530, Belgium

Hopital Universitaire Erasme, Brussels 1070, Belgium

Institut Jules Bordet, Brussels 1000, Belgium

U.Z. Gasthuisberg, Leuven B-3000, Belgium

Universitair Ziekenhuis Antwerpen, Edegem B-2650, Belgium

Universitair Ziekenhuis Gent, Ghent B-9000, Belgium

Centre Hospitalier Universitaire Henri Mondor, Creteil 94010, France

CHR de Besancon - Hopital Jean Minjoz, Besancon 25030, France

CHR Hotel Dieu, Nantes 44093, France

CHRU de Nancy - Hopitaux de Brabois, Vandoeuvre-Les-Nancy 54511, France

Hopital De L'Institut Pasteur, Paris 75015, France

Hopital Du Bocage, Dijon 21034, France

Hopital Edouard Herriot, Lyon 69437, France

Hopital Necker, Paris 75743, France

Hopital Robert Debre, Paris 75019, France

Hopital Saint-Louis, Paris 75475, France

Hopital Universitaire Hautepierre, Strasbourg 67098, France

Hotel Dieu de Paris, Paris 75181, France

Institut J. Paoli and I. Calmettes, Marseille 13273, France

Eberhard Karls Universitaet, Tubingen D-72076, Germany

Evangelisches Krankenhaus Essen Werden, Essen D-45239, Germany

Klinikum der Universitaet Ulm, Ulm D-89081, Germany

Klinikum Grosshadern, Munich D-81377, Germany

Klinikum Nurnberg, Nuremberg (Nurnberg) D-90419, Germany

Klinikum Rechts Der Isar/Technische Universitaet Muenchen, Munich D-81675, Germany

Martin Luther Universitaet, Halle Saale DOH-0-6112, Germany

Medizinische Hochschule Hannover, Hannover D-30625, Germany

Medizinische Klinik I, Dresden D-01307, Germany

Staedtische Kliniken Duisburg, Duisburg D-47055, Germany

Stefan Morsch Stiftung, Idar-Oberstein D-55743, Germany

Universitaetskliniken Bonn, Bonn D-53127, Germany

Universitaetsklinikum Benjamin Franklin, Berlin D-12200, Germany

University Medical Center, Freiburg D-79106, Germany

Virchow Klinikum Humboldt Universitaet Berlin, Berlin D-13353, Germany

County Hospital, Kaposvar H-7400, Hungary

National Institute of Haematology and Immunology, Budapest H-1519, Hungary

Szent Laszlo Korhaz, Budapest 1097, Hungary

St. James's Hospital, Dublin 8, Ireland

Hadassah University Hospital, Jerusalem 91120, Israel

Istituto Nazionale per la Ricerca sul Cancro, Genoa 16132, Italy

Ospedale Civile Pescara, Pescara 65100, Italy

Ospedale Maggiore Ca Granda, Milan 20162, Italy

Ospedale San Orsola, Bologna 40138, Italy

Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore, Rome 00168, Italy

Policlinico Monteluce, Perugia 06122, Italy

University and I.R.C.C.S. Policlinico San Matteo, Pavia 27100, Italy

Centre Hospitalier de Luxembourg, Luxembourg 1210, Luxembourg

Leiden University Medical Center, Leiden 2300 ZA, Netherlands

University Medical Center Nijmegen, Nijmegen NL-6252 HB, Netherlands

Hospital Clinic y Provincial de Barcelona, Barcelona 08036, Spain

Hospital de Cruces, Barakaldo, Bilbao E-48903, Spain

Hospital Del Mar, Barcelona 08003, Spain

Hospital General Gregorio Maranon, Madrid 28007, Spain

Hospital Universidad Virgen Del Rocio, Sevilla E- 41013, Spain

Hospital Universitasrio San Carlos, Madrid 28040, Spain

University Hospital - Salamanca, Salamanca 37007, Spain

Huddinge Hospital, Stockholm S-141 86, Sweden

Karolinska Hospital, Stockholm S-171 76, Sweden

Centre Hospitalier Universitaire Vaudois, Lausanne CH-1011, Switzerland

Hopital Cantonal Universitaire de Geneva, Geneva CH-1211, Switzerland

University Hospital, Basel CH-4031, Switzerland

North Manchester Healthcare NHS Trust, Manchester M8 6RB, United Kingdom

Royal Bournemouth Hospital, Bournemouth BH7 7DW, United Kingdom

Hartford Medical Group, Wethersfield, Connecticut 06109, United States

Addenbrooke's NHS Trust, Cambridge, England CB2 2QQ, United Kingdom

Birmingham Heartlands and Solihull NHS Trust (Teaching), Birmingham, England B9 5SS, United Kingdom

King's College Hospital, London, England SE5 9RS, United Kingdom

University College Hospital, London, England WC1E 6AU, United Kingdom

St. Vincent's Hospital, Sydney, New South Wales 2010, Australia

Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia

Aberdeen Royal Infirmary, Aberdeen, Scotland AB25 2ZN, United Kingdom

Alfred Hospital, Melbourne, Victoria 3181, Australia

Royal Melbourne Hospital, Parkville, Victoria 3050, Australia

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: June 1997
Last updated: May 23, 2008