Clinical trial NCT00893555: Pharmacologic Optimization of Voriconazole
Official title: Pharmacologic Optimization of Voriconazole - a Prospective Clustered Group-randomized Cross-over Trial of Therapeutic Drug Monitoring
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Invasive Fungal Infection
Hematological Malignancy
Keywords: Invasive fungal infection
hematological malignancy
voriconazole
therapeutic drug monitoring
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: University Medical Center Nijmegen
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Amsterdam UMC, location VUmc
name: Leiden University Medical Center
name: UMC Utrecht
name: Erasmus Medical Center
name: St. Antonius Hospital
name: Meander Medical Center
name: Haga Hospital
name: Klinikum Oldenburg gGmbH
First posted: 2009-05-06
Enrollment: 189
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The objective of this study proposal is to determine whether pharmacologic optimization of voriconazole by means of therapeutic drug monitoring (TDM) results in improved patient outcomes (efficacy and safety) and is more cost-effective compared to the current standard of care.

Detailed description: Patients with haematological malignancies and chemotherapy-induced prolonged neutropenia are at risk for severe bacterial and fungal infections. These opportunistic infections can result in prolonged hospital stay, increases costs and greater mortality. Voriconazole has now been recommended as the first line agent for invasive pulmonary aspergillosis. Retrospective observational studies of voriconazole serum concentration suggest that serum concentration correlate with toxicity and clinical response. These observations were however made in small series of patients and data were collected retrospectively. These inherent methodological flaws make it impossible to draw definite conclusions about the effect of voriconazole serum level monitoring on the outcome of IA, and therefore considered insufficient proof to recommend voriconazole concentration determination in blood as standard of care. The impact that so called serum concentration guided dosing of voriconazole will have on treatment success can only be evaluated through a prospective randomized clinical trial.

For this purpose, we designed a prospective stratified cluster randomized cross-over trial of therapeutic drug monitoring in patients with haematological disease who have developed IA. The order of periods (TDM or standard of care, each 12 months) will be randomized per centre. During the TDM episode, the voriconazole dosage will be adjusted to achieve trough blood concentrations in a predefined window of 2-5 mg/L. A sample size of n=192 is needed to detect a 20% absolute reduction in the number of treatment failures (40% to 20 %) compared to control.

Eligibility criteria: Inclusion Criteria:

* are at least 18 years of age
* have received chemotherapy for haematological malignancies or have received a hematopoietic stem cell transplant
* proven, probable or possible invasive fungal disease according to the EORTC/MSG criteria
* treatment with voriconazole

Exclusion Criteria:

* allergic to voriconazole or its excipients
* age below 18 years

Primary outcomes:
measure: The primary clinical endpoint will be a global response consisting of a combined endpoint of toxicity and response to therapy (clinical, microbiologic and radiologic responses) 28 days after starting treatment with voriconazole.
timeFrame: 28 days
Secondary outcomes:
measure: Overall mortality
timeFrame: 7 and 28 days; 12 weeks
measure: % of serum concentrations within 2-5mg/L
timeFrame: 7 and 28 days; 12 weeks
measure: % switched to salvage therapy or measured concentration level in control arm
timeFrame: 7 and 28 days; 12 weeks
measure: Side effects
timeFrame: 7 and 28 days; 12 weeks
measure: Time to global response
timeFrame: 7 and 28 days; 12 weeks
measure: Cost-effectiveness of TDM
timeFrame: 7 and 28 days; 12 weeks
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: University Medical Center Groningen
name: J GW Kosterink, PharmD, PhD
role: STUDY_CHAIR
affiliation: University Medical Center Groningen
name: J WC Alffenaar, PharmD PhD
role: PRINCIPAL_INVESTIGATOR
References: