Voriconazole to Prevent Systemic Fungal Infections in Children
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Aspergillosis; Candidiasis; Fungal Diseases; Mycoses
Intervention: Voriconazole (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: National Cancer Institute (NCI)
Summary
This study will examine how children's bodies metabolize and eliminate the anti-fungal drug
voriconazole. The results will yield information needed to make recommendations for safe and
effective dosing of the drug in children. Children with reduced immune function-such as
those receiving drugs for cancer treatment-are at high risk for serious fungal infections.
Children between 2 and 12 years old who need treatment to prevent fungal infections may be
eligible for this study. Candidates will be screened with a physical examination, eye
examination, and blood and urine tests.
Children in the study will be hospitalized for 21 days. They will receive voriconazole twice
a day (every 12 hours) for 8 days, infused through a vein over a period of 1 to 2 hours. The
dose will be determined based on the individual child's weight. Blood samples will be
collected at various intervals before and after the infusions on days 1, 2, 4 and 8 to
determine the amount of drug in the blood. On day 8, the child will have another physical
and eye examination, as well as additional blood and urine tests. If additional treatment is
required, voriconazole may be continued for up to day 21. (Children who require the drug for
more than 21 days may receive it under another research protocol.) On the last day of
treatment, the child will have another physical examination, and blood and urine tests.
These procedures will be repeated again at 30 to 35 days following the last dose of drug. A
small sample of blood will also be analyzed for genetic information related to the rate of
metabolism of voriconazole-that is, how fast or slow it is cleared (eliminated) by the
liver.
Voriconazole is effective against several different fungi. It may protect children against
serious fungal infections with fewer side effects than standard available therapy.
Clinical Details
Official title: An Open Intravenous Multiple Dose, Multi-Center Study to Investigate the Pharmacokinetics, Safety and Toleration of Voriconazole in Children Aged 2-12 Years Who Require Treatment for the Prevention of Systemic Fungal Infection
Study design: Treatment, Safety Study
Detailed description:
The objective of this study is to evaluate the serum levels and pharmacokinetic parameters
achieved following two dosage levels of voriconazole. In addition, the safety and toleration
of intravenous voriconazole at two dosage levels in an immunocompromised pediatric patient
population will be evaluated. Also, the plasma concentrations of the major metabolite of
voriconazole (N-oxide) in these patients will be performed. The study is designed as a
multi-center, open label multi-dose study of intravenous voriconazole. Intravenous
voriconazole will be administered prophylactically twice daily to immunocompromised children
at high risk for invasive mycoses. The patient population consists of children ages 2 years
to 12 years of age; two age groups will be studied (2-<6, 6-12). Initial dosage levels will
be 3mg/kg q12h and 4mg/kg q12h. The planned sample size is 24 children. For those children
who do not complete the full 8 days of kinetics, a replacement patient will be added.
Immunocompromised children at high risk for invasive mycoses will receive voriconazole
prophylactically. Therapy will be initiated within 48 hours after completion of
chemotherapy. Voriconazole therapy will continue until recovery from neutropenia. The first
12 children will initially receive a loading dose of 6mg/kg X 2 doses followed by 3mg/kg BID
through day 4 of therapy. Twelve hour pharmacokinetics will be collected on day 4. Children
will then receive 4mg/kg starting on the second dose of day 4 and will continue at that
dosage level until recovery from neutropenia. Kinetics will again be collected at the 4mg/kg
dosage level on day 8 of therapy. If the mean peak plasma concentration of voriconazole in
the first 12 patients following 4mg/kg q12h dosing is less than 4,000ng/ml., the remaining 12
patients will receive voriconazole after day 4 at a dosage of 5mg/kg.
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Children (male or female) ages 2-12 years who require treatment for the prevention of
systemic fungal infection.
Children who are expected to develop neutropenia lasting for more than 10 days following
chemotherapy for one of the following conditions: leukemia, lymphoma, aplastic anemia, or
as the preparative regimen for bone marrow transplantation.
Patients who are anticipated to live more than 3 months.
Females of child-bearing potential (post-menarchal) must have a negative pregnancy test at
entry.
Informed consent of the parent or legally authorized representative obtained prior to
entry.
Assent will be obtained from minors capable of understanding.
No patients who are receiving and cannot discontinue the following drugs at least 24 hours
prior to study start: terfenadine and cisapride (due to the possibility of QTc
prolongation). Omegprazole (an inhibitor of CYP2C19) which is known to increase plasma
voriconazole levels.
No patients who have received the following drugs within 14 days prior to study entry:
rifampicin, rifabutin, carbamazepine, phenytoin, nevirapine and barbiturates as these are
potent inducers of hepatic enzymes and will result in undetectable levels of voriconazole.
No patients who have received astemizole within the previous 60 days.
No patients who are taking or are likely to receive any investigational drugs except: used
for cancer treatment, antiretroviral agents, and drugs used for treatments of any AIDS
defining opportunistic infections.
No patients with a history or hypersensitivity to or severe intolerance of azole antifungal
agents.
No patients who have already been entered onto this protocol once.
No patient with medical history or evidence of cardiac arrhythmia.
No patients with AST and ALT greater than or equal to 5XULN.
No patients with moderate and severe renal impairment (i. e., calculated creatine clearance
less than 30ml/min). If creatinine clearance is reduced to less than 30 ml/min at any time
during the study, the patient must be discontinued from the study. Creatine clearance will
be calculated using the following equation: 0. 55 X height (cm)/serum creatinine (mg/dL).
Any other condition which, in the opinion of the investigator, would make the patient
unsuitable for enrollment.
Locations and Contacts
National Cancer Institute (NCI), Bethesda, Maryland 20892, United States
Additional Information
Related publications: Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. 1996 Jun;10(2):365-400. Review. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med. 1982 Jan;72(1):101-11. No abstract available. Walsh TJ, Gonzalez C, Lyman CA, Chanock SJ, Pizzo PA. Invasive fungal infections in children: recent advances in diagnosis and treatment. Adv Pediatr Infect Dis. 1996;11:187-290. Review. No abstract available.
Starting date: June 2000
Ending date: January 2001
Last updated: March 3, 2008
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