Clinical trial NCT00003031: Comparison of Voriconazole and 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection
Pulmonary Complications
Keywords: infection
pulmonary complications
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2004-05-27
Enrollment: 212
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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.

Eligibility 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)

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Wethersfield
country: United States
facility: Hartford Medical Group
state: Connecticut
city: Sydney
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Antwerp
country: Belgium
facility: Algemeen Ziekenhuis Middelheim
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Ghent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Mont-Godinne Yvoir
country: Belgium
facility: Clinique Universitaire De Mont-Godinne
city: Besancon
country: France
facility: CHR de Besancon - Hopital Jean Minjoz
city: Creteil
country: France
facility: Centre Hospitalier Universitaire Henri Mondor
city: Dijon
country: France
facility: Hopital Du Bocage
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Marseille
country: France
facility: Institut J. Paoli and I. Calmettes
city: Nantes
country: France
facility: CHR Hotel Dieu
city: Paris
country: France
facility: Hopital De L'Institut Pasteur
city: Paris
country: France
facility: Hopital Robert Debre
city: Paris
country: France
facility: Hotel Dieu de Paris
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: Hopital Necker
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Vandoeuvre-Les-Nancy
country: France
facility: CHRU de Nancy - Hopitaux de Brabois
city: Berlin
country: Germany
facility: Universitaetsklinikum Benjamin Franklin
city: Berlin
country: Germany
facility: Virchow Klinikum Humboldt Universitaet Berlin
city: Bonn
country: Germany
facility: Universitaetskliniken Bonn
city: Dresden
country: Germany
facility: Medizinische Klinik I
city: Duisburg
country: Germany
facility: Staedtische Kliniken Duisburg
city: Essen
country: Germany
facility: Evangelisches Krankenhaus Essen Werden
city: Freiburg
country: Germany
facility: University Medical Center
city: Halle Saale
country: Germany
facility: Martin Luther Universitaet
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Idar-Oberstein
country: Germany
facility: Stefan Morsch Stiftung
city: Munich
country: Germany
facility: Klinikum Grosshadern
city: Munich
country: Germany
facility: Klinikum Rechts Der Isar/Technische Universitaet Muenchen
city: Nuremberg (Nurnberg)
country: Germany
facility: Klinikum Nurnberg
city: Tubingen
country: Germany
facility: Eberhard Karls Universitaet
city: Ulm
country: Germany
facility: Klinikum der Universitaet Ulm
city: Budapest
country: Hungary
facility: Szent Laszlo Korhaz
city: Budapest
country: Hungary
facility: National Institute of Haematology and Immunology
city: Kaposvar
country: Hungary
facility: County Hospital
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Jerusalem
country: Israel
facility: Hadassah University Hospital
city: Bologna
country: Italy
facility: Ospedale San Orsola
city: Genoa
country: Italy
facility: Istituto Nazionale per la Ricerca sul Cancro
city: Milan
country: Italy
facility: Ospedale Maggiore Ca Granda
city: Pavia
country: Italy
facility: University and I.R.C.C.S. Policlinico San Matteo
city: Perugia
country: Italy
facility: Policlinico Monteluce
city: Pescara
country: Italy
facility: Ospedale Civile Pescara
city: Rome
country: Italy
facility: Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore
city: Luxembourg
country: Luxembourg
facility: Centre Hospitalier de Luxembourg
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen
city: Barakaldo, Bilbao
country: Spain
facility: Hospital de Cruces
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Hospital Clinic y Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital General Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitasrio San Carlos
city: Salamanca
country: Spain
facility: University Hospital - Salamanca
city: Sevilla
country: Spain
facility: Hospital Universidad Virgen Del Rocio
city: Stockholm
country: Sweden
facility: Huddinge Hospital
city: Stockholm
country: Sweden
facility: Karolinska Hospital
city: Basel
country: Switzerland
facility: University Hospital
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneva
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands and Solihull NHS Trust (Teaching)
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's NHS Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital
state: England
city: London
country: United Kingdom
facility: University College Hospital
state: England
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Manchester
country: United Kingdom
facility: North Manchester Healthcare NHS Trust
Study officials:
affiliation: Hopital Universitaire Hautepierre
name: R. Herbrecht, MD
role: STUDY_CHAIR
References: