Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis

Males and females of greater than 12 years of age with any of the following conditions: Allogeneic or autologous bone marrow/ peripheral stem cell transplant. Hematological malignancy (including lymphoma). Aplastic anemia and myelodysplastic syndromes (currently on immunosuppressive treatment). Solid organ transplantation. Solid organ malignancy (after cytotoxic chemotherapy). HIV infection/AIDS. High dose prolonged corticosteroid therapy (greater than or equal to 20 mg daily of prednisone or equivalent for greater than 3 weeks) or prolonged therapy with other immunosuppressive agents (e.g., azathioprine, methotrexate). WITH a diagnosis of definite or probable acute invasive aspergillosis. The fungal infection at baseline should represent a new episode of acute invasive aspergillosis. Any course of systemic treatment with amphotericin B (conventional or lipid formulation) or itraconazole should have been completed at least 8 weeks prior to study entry. Signed informed consent must be obtained prior to study participation (patient, relative or legal representative). For patients aged 12-17 years, the written informed consent of the parents or legal guardian must also be obtained. Women of child bearing potential must have a negative pregnancy test at entry and must agree to use barrier methods of contraception throughout the study. No patients with sarcoidosis, aspergilloma or allergic bronchopulmonary aspergillosis. No patients with chronic invasive aspergillosis with a duration of symptoms or radiological findings for more than 4 weeks prior to study entry. No patients that have received systemic antifungal therapy 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, for more than 96 hours during the two week period prior to study entry. No patients with a diagnosis of CMV pneumonia. No pregnant or lactating females. No patients with a history of hypersensitivity or intolerance to azole antifungal agents including miconazole, ketoconazole, fluconazole, or itraconazole. No patients with a history of hypersensitivity or severe intolerance (despite supportive therapy) to conventional or a lipid formulation of amphotericin B. No subjects who are receiving and cannot discontinue the following drugs at least 24 hours prior to randomization: Terfenadine, cisapride and astemizole (due to the possibility of QTc prolongation); Sulphonylureas (as these compounds have a narrow therapeutic window and an increase in plasma levels may lead to hypoglycemia). No subjects who have received the following drugs within 14 days prior to randomization: Rifampin, carbamazepine and barbiturates as these are potent inducers of hepatic enzymes and will result in undetectable levels of voriconazole. No patients who are receiving or are likely to received any investigational drug (any unlicensed new chemical entity), except one of the following classes of medications: cancer chemotherapeutic agents, antiretrovirals, therapies for HIV/AIDS-related opportunistic infections. No patients who are receiving the following medications or treatments during the study period: G-CSF or GM-CSF (for other than of granulocytopenia) any systemic antifungal medication active against Aspergillus white blood cell transfusions. No patients with the following abnormalities of liver function tests: AST, ALT greater than 5x ULN (upper limit normal); alkaline phosphatase, total bilirubin greater than 5x ULN. No patients with renal insufficiency that would contraindicate treatment with initial randomized therapy (serum creatinine greater than 2.5 mg/dl). No patients with a life expectancy of less than 72 hours. No patients on artificial ventilation, unlikely to be extubated within 24 hours of study entry. No patients for whom written informed consent cannot be obtained. No patients that have already participated in this trial. No patients with any condition which, in the opinion of the investigator, could affect patient safety, preclude evaluation of response, or render it unlikely that the contemplated course of therapy can be completed.