A Prospective, Randomized Trial Comparing the Efficacy and Safety of Voriconazole Administered With Therapeutic Drug Monitoring vs. Standard Dosing
12 Years
N/A
Both
Fungal Infection
Trial Information
A Prospective, Randomized Trial Comparing the Efficacy and Safety of Voriconazole Administered With Therapeutic Drug Monitoring vs. Standard Dosing
This is a prospective study of patients who receive voriconazole as treatment for an IMI
(proven, probable, and possible by the EORTC/MSG definitions), other than zygomycosis.
Patients will be randomized to receive either standard dosing or dosing based on TDM,
stratified by whether initial voriconazole therapy is PO or IV. Assessment of outcomes will
be made 42 days after start of voriconazole. An additional follow up for safety reporting
will be performed 4weeks after completion of voriconazole
The patients will be randomized to:
- Prospective TDM: voriconazole dose will be adjusted based on per protocol obtained TDM
levels, and
- Standard dosing: standard doses of voriconazole will be used.
In the prospective TDM arm, voriconazole TDM will be performed in real time at each site and
results will be reported to treating physicians for dose adjustment. All efforts will be
taken to obtain results within 24 hours of blood sample collection. In the standard dosing
arm, blood samples will be collected, stored, and batched for voriconazole levels to be
tested retrospectively. Voriconazole plasma levels will be measured by validated high
performance liquid chromatography (HPLC) assays as detailed. Voriconazole trough levels will
be performed on Day Baseline/Screening, 5, 14, 28, and 42.
Voriconazole peak level will be measured on Day 5. Trough voriconazole levels will be
obtained in case of an event, defined as suspected drug-associated toxicity and/or clinical
failure.
Assessment of AEs for all patients will be monitored during the study and response to
treatment will be assessed. The composite of overall AE/clinical failure will be assessed on
day 42.
Inclusion Criteria:
- Indication for voriconazole administration: proven, probable, or possible IMI,
excluding zygomycosis (based on the revised EORTC/MSG consensus definitions) [De
Pauw, Clin Infect Dis. 2008; 46:1813].
- Male or female ≥12 years of age.
- Evidence of a personally signed and dated informed consent document in accordance
with local regulatory and legal requirements indicating that the subject (or a
legally acceptable representative) has been informed of all pertinent aspects of the
study.
- Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
Exclusion Criteria:
- Known history of allergy, hypersensitivity or serious reaction to azole antifungals.
- Patients with aspergilloma or allergic bronchopulmonary aspergillosis (ABPA).
- Patients with chronic invasive aspergillosis with duration of symptoms or
radiological finding for more than 4 weeks prior to study entry.
- Patients who are receiving and cannot discontinue the following drugs at least 24
hours prior to randomization: terfenadine, pimozide or quinidine (because of the
possibility of QT prolongation), St John's wort preparation.
- Patients receiving any of the following medications: sirolimus, rifampin, rifabutin,
carbamazepine, long acting barbiturates (e.g., phenobarbital, mephobarbital),
ritonavir, efavirenz, or ergot alkaloids (e.g., ergotamine, dihydroergotamine).
- Receipt of more than 5 days of voriconazole as treatment prior to enrollment.
- Receipt of 7 days or more of systemic antifungal treatment for the current episode of
IMI.
- Severe liver dysfunction (defined as total bilirubin, AST, ALT, or alkaline
phosphatase >5x upper limit of normal). Local laboratory results may be used to
qualify individuals for enrollment.
- Patients with any condition which, in the opinion of the investigator, could affect
patient safety, preclude evaluation of response, or make it unlikely that the
proposed course of therapy can be completed.
- Patients who have already participated in this trial within the last 30 days.
- Patients with a high likelihood of death due to factors unrelated to IA (e.g., due to
relapsed malignancy, severe GVHD, other underlying diseases, etc.) within 30 days
following planned enrollment (investigator's discretion).
- Patients that weigh <45 and >120 kg, respectively, upon enrollment. If patients'
weight is beyond those limits upon serial assessments during the study period, the
study monitor should be contacted and decisions to keep or withdraw subject from the
study will be made.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Treatment failure
Outcome Description:
The primary endpoint of the study will be a binary outcome, called Failure, defined as one of the following: measured at 42 days from initiation of drug administration: Progression of underlying infection (clinical failure) Death Development of a voriconazole-associated SAE: LFTs, Rash, Visual disturbance, Neurologic abnormality (e.g: hallucinations)
Outcome Time Frame:
42 days
Safety Issue:
Yes
Principal Investigator
Kieren Marr, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Johns Hopkins University
Authority:
United States: Food and Drug Administration
Study ID:
NA_00041916
NCT ID:
NCT01416025
Start Date:
January 2012
Completion Date:
June 2014
Related Keywords:
- Fungal Infection
- Voriconazole
- Therapeutic drug monitoring
- Hematopoietic stem cell transplant
- Hematologic malignancy
- Invasive mould infection
- Mycoses
Name | Location |
|---|---|
| University of Florida College of Medicine | Gainesville, Florida 32610 |
