An Open Label, Non-Comparative, Multicenter, Phase III Trial of the Efficacy, Safety and Toleration of Voriconazole in the Primary or Secondary Treatment of Invasive Fungal Infections
Males or (non-pregnant) females greater than or equal to 12 years of age.
Patients must have one of the following systemic or invasive fungal infections at
baseline: systemic or invasive infection due to a fungal pathogen for which there is
currently no licensed treatment or systemic or invasive fungal infection, with evidence of
failure and/or intolerance/toxicity to treatment with approved systemic antifungal agents.
Definitions of failure to treatment with approved systemic antifungal agents:
For invasive aspergillosis and other invasive fungal infections - lack of clinical
response after at least 7 days of systemic antifungal treatment at adequate doses;
For candida esophagitis only - lack of clinical response after at least 14 days of
fluconazole at a dose of greater than or equal to 200 mg/day.
Definition of intolerance/toxicity to treatment with approved systemic antifungal agents:
Intolerance to the infusion-related toxicities of amphotericin B preparations despite
appropriate supportive therapy, OR;
Nephrotoxicity defined as a serum creatinine that had increased by greater than 1.5 mg/dl
while receiving amphotericin B therapy, OR;
Pre-existing renal impairment defined as a serum creatinine that increased to greater than
2.0 mg/dl due to reasons other than amphotericin B therapy.
The systemic or invasive fungal infection must be present at baseline and documented
within four weeks preceding study entry as follows: positive histopathology with evidence
of tissue invasion by fungal elements or positive serology where diagnostic (CSF
cryptococcal antigen; serum or CSF Coccidioides antibody; serum, CSF or urine Histoplasma
antigen) or positive mycologic culture from a normally sterile site, taken during the
current episode of infection.
Women of child bearing potential (or less than 2 years post-menopausal) must have a
negative serum pregnancy test at baseline, and must agree to use barrier methods of
contraception during the study. Women may not be pregnant or lactating.
Signed written informed consent must be obtained at baseline.
Assent will be obtained from minors capable of understanding.
Subjects may not have previously participated in this trial.
Patients may not be receiving or be unable to discontinue the following drugs at least 24
hours prior to randomization: terfenadine, cisapride and astemizole (due to the
possibility of QTc prolongation).
Patients may not be receiving or be unable to discontinue sulphonylureas at least 24 hours
prior to randomization (as these compounds have a narrow therapeutic window and an
increase in plasma levels may lead to hypoglycemia).
Patients may not 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.
Patients may not be participating in a blinded trial of any investigational drug.
Patients may not have AST, ALT, total bilirubin or alkaline phosphatase greater than 5
times the upper limit normal.
No patients with a serum creatinine greater than 3.5 mg/dl or with end-stage renal disease
requiring chronic dialysis.
Patients may not have allergic bronchopulmonary aspergillosis, aspergilloma, zygomycoses,
isolated candiduria, and/or catheter-or-device-related candidemia.
Patients may not have fungal infections not considered to be invasive or systemic
including dermatophytosis and oropharyngeal candidiasis.
Patients may not be receiving or likely to receive any investigational drug (any
unlicensed new chemical entity), except one of the following classes of medications:
cancer chemotherapeutic agents, antiretrovirals, or other therapies for HIV/AIDS-related
Patients may not be receiving or likely to receive the following medications or treatments
during the study period:
G-CSF or GM-CSF (for other than treatment of granulocytopenia);
Any systemic antifungal medication;
White blood cell transfusions.
Patients may not have hypersensitivity or intolerance to azole antifungal agents including
miconazole, ketocanazole, fluconazole, or itraconazole.
Patients must have a life expectancy greater than 72 hours.
Patients may not have any condition which, in the opinion of the investigator, could
affect subject safety, preclude evaluation of response, or render it unlikely that the
contemplated course of therapy can be completed.