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
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Mycoses
Intervention: Voriconazole (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)
Summary
Invasive fungal infections are often life-threatening in persons with immunocompromise.
Persons with prolonged neutropenia secondary to cytotoxic chemotherapies are at high risk
for these infections. Patients undergoing bone marrow transplantation, receiving prolonged
corticosteroid or other immunosuppressive therapies, and persons with HIV infection and AIDS
are also at risk. With the use of currently approved antifungal therapy, many of these
infections may still be associated with a high mortality. Amphotericin B in its
conventional form, is the current standard treatment for most life-threatening fungal
infections. Because of its nephrotoxicity and other adverse effects, alternatives to
conventional amphotericin B have been sought. Alternated agents include three lipid
formulations of amphotericin B, fluconazole, itraconazole. Although all of these agents are
associated with a decrease in adverse effects, their efficacy in most life-threatening
fungal infections has not been shown to be equivalent to conventional amphotericin B.
Voriconazole is an investigational antifungal drug currently being brought to phase III
trials in the US. This azole has been shown active against many fungal pathogens in vitro.
In animal models and early human trials this new agent has been shown to be effective
against aspergillosis. It has been shown to be well-tolerated and is available in an
intravenous and oral formulation.
This is a non-comparative, open label study to evaluate the efficacy, safety and toleration
of voriconazole in the treatment of invasive fungal infections. This agent will be used as
primary therapy in those fungal infections in which no antifungal agent is currently
approved or in patients unable to tolerate the approved agent. Voriconazole will also be
used as a secondary treatment in those patients who have failed therapy with the primary
approved agent or are unable to tolerate that agent or have unacceptable toxicity.
Clinical Details
Official title: 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
Study design: Endpoint Classification: Efficacy Study, Primary Purpose: Treatment
Detailed description:
Invasive fungal infections are often life-threatening in persons with immunocompromise.
Persons with prolonged neutropenia secondary to cytotoxic chemotherapies are at high risk
for these infections. Patients undergoing bone marrow transplantation, receiving prolonged
corticosteroid or other immunosuppressive therapies, and persons with HIV infection and AIDS
are also at risk. With the use of currently approved antifungal therapy, many of these
infections may still be associated with a high mortality. Amphotericin B in its
conventional form, is the current standard treatment for most life-threatening fungal
infections. Because of its nephrotoxicity and other adverse effects, alternatives to
conventional amphotericin B have been sought. Alternate agents include three lipid
formulations of amphotericin B, fluconazole, and itraconazole. Although all of these agents
are associated with a decrease in adverse effects, their efficacy in most life-threatening
fungal infections has not been shown to be equivalent to conventional amphotericin B.
Voriconazole is an investigational antifungal drug currently being brought to phase III
trials in the US. This azole has been shown active against many fungal pathogens in vitro.
In animal models and early human trials this new agent has been shown to be effective
against aspergillosis. It has been shown to be well-tolerated and is available in an
intravenous and oral formulation.
This is a non-comparative, open label study to evaluate the efficacy, safety, and toleration
of voriconazole in the treatment of invasive fungal infections. This agent will be used as
primary therapy in those fungal infections in which no antifungal agent is currently
approved or in patients unable to tolerate the approved agent. Voriconazole will also be
used as a secondary treatment in those patients who have failed therapy with the primary
approved agent or are unable to tolerate that agent or have unacceptable toxicity.
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Males or (non-pregnant) females must be at least 18 Years of age.
Subjects must have one of the following systemic or invasive fungal infections at
baseline: (1) systemic or invasive infection due to a fungal pathogen for which there is
no currently licensed treatment; (2) systemic or invasive fungal infection, with evidence
of failure and/or intolerance/toxicity to treatment with approved systemic antifungal
agents. Definition of failure to treatment with approved systemic antifungal agents: a)
for invasive aspergillosis and other invasive fungal infections: lack of clinical
response after at least 7 days of systemic antifungal treatment at adequate doses; or b)
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: a)
intolerance to the infusion-related toxicities of amphotericin B preparations despite
appropriate supportive therapy; b) nephrotoxicity defined as a serum creatinine that had
increased by greater than or equal to 1. 5 mg/dl while receiving amphotericin B therapy or
c) preexisting renal impairment defined as a serum creatinine that increased to greater
than or equal to 2. 0 mg/dl due to reasons other than amphotericin B.
The systemic or invasive fungal infection must be present at baseline and documented
within four weeks preceding study entry as follows: (1) positive histopathology with
evidence of tissue invasion by fungal elements, or (2) positive serology where diagnostic
(CSF cryptococcal antigen; serum or CSF Coccidioides antibody; serum, CSF or urine
Histoplasma antigen), or (3) 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.
Medical history must be obtained at baseline.
Signed written informed consent must be obtained at baseline.
Subjects must not have previously participated in this trial.
Subjects must not be taking and are unable to discontinue the following drugs at least 24
hours prior to randomization: terfenadine, cisapride, astemizole, and sulphonylureas.
Subjects must not have received any of 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.
Subjects must not have the following abnormalities of liver function tests (LFT's): AST,
ALT greater than 5 times upper limit normal; alkaline phosphatase, total bilirubin greater
than 5 times upper limit normal.
Subjects must not have a serum creatinine greater than 3. 5 mg/dl or end-stage renal
disease requiring chronic dialysis.
Subjects must not have allergic bronchopulmonary aspergillosis, aspergilloma, zygomycoses,
candiduria, and/or catheter- or device-related candidemia.
Subjects must not have fungal infections which are not considered to be invasive or
systemic including dermatophytosis and oropharyngeal candidiasis.
Subjects must not be receiving or are likely to receive 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.
Subjects must not be receiving or are 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 or white blood cell transfusions.
Subjects must not have a history of hypersensitivity or intolerance to azole antifungal
agents including miconazole, ketoconazole, fluconazole, or itraconazole.
Subjects must not have a life expectancy of less than 72 hours.
Subjects must 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.
Locations and Contacts
National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland 20892, United States
Additional Information
Starting date: November 1997
Last updated: March 3, 2008
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