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.

Condition	Treatment or Intervention	Phase
Infection Pulmonary Complications	Drug: amphotericin B  Drug: voriconazole	Phase III

Further Study Details: 

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.

PROTOCOL 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.

Ages Eligible for Study:  12 Years and above

Criteria

PROTOCOL ENTRY 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

--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)

--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

Connecticut
      Hartford Medical Group, Wethersfield,  Connecticut,  06109,  United States
Australia, New South Wales
      St. Vincent's Hospital, Sydney,  New South Wales,  2010,  Australia
Australia, Queensland
      Royal Brisbane Hospital, Brisbane,  Queensland,  4029,  Australia
Australia, Victoria
      Alfred Hospital, Melbourne,  Victoria,  3181,  Australia
      Royal Melbourne Hospital, Parkville,  Victoria,  3050,  Australia
Belgium
      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
France
      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
Germany
      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
Hungary
      County Hospital, Kaposvar,  H-7400,  Hungary
      National Institute of Haematology and Immunology, Budapest,  H-1519,  Hungary
      Szent Laszlo Korhaz, Budapest,  1097,  Hungary
Ireland
      St. James's Hospital, Dublin,  8,  Ireland
Israel
      Hadassah University Hospital, Jerusalem,  91120,  Israel
Italy
      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
Luxembourg
      Centre Hospitalier de Luxembourg, Luxembourg,  1210,  Luxembourg
Netherlands
      Leiden University Medical Center, Leiden,  2300 ZA,  Netherlands
      University Medical Center Nijmegen, Nijmegen,  NL-6252 HB,  Netherlands
Spain
      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
Sweden
      Huddinge Hospital, Stockholm,  S-141 86,  Sweden
      Karolinska Hospital, Stockholm,  S-171 76,  Sweden
Switzerland
      Centre Hospitalier Universitaire Vaudois, Lausanne,  CH-1011,  Switzerland
      Hopital Cantonal Universitaire de Geneva, Geneva,  CH-1211,  Switzerland
      University Hospital, Basel,  CH-4031,  Switzerland
United Kingdom
      North Manchester Healthcare NHS Trust, Manchester,  M8 6RB,  United Kingdom
      Royal Bournemouth Hospital, Bournemouth,  BH7 7DW,  United Kingdom
United Kingdom, England
      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
United Kingdom, Scotland
      Aberdeen Royal Infirmary, Aberdeen,  Scotland,  AB25 2ZN,  United Kingdom

Study chairs or principal investigators

R. Herbrecht,  Study Chair,  EORTC Invasive Fungal Infections Cooperative Group   

Study ID Numbers:  CDR0000065627; EORTC-19961; PFIZER-150-307-000
Record last reviewed:  May 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00003031
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08