Hematological Malignancy, Invasive Fungal Infection
Conditions
Keywords
Invasive fungal infection, hematological malignancy, voriconazole, therapeutic drug monitoring
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.
Interventions
DRUGvoriconazole
TDM (through level of 2-5mg/L).
DRUGvoriconazole (dosing according to the SPC)
No serum concentrations are determined
Sponsors
University Medical Center Nijmegen
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Amsterdam UMC, location VUmc
Leiden University Medical Center
UMC Utrecht
Erasmus Medical Center
St. Antonius Hospital
Meander Medical Center
Haga Hospital
Klinikum Oldenburg gGmbH
Jan-Willem C Alffenaar
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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. | 28 days |
Secondary
| Measure | Time frame |
|---|---|
| % of serum concentrations within 2-5mg/L | 7 and 28 days; 12 weeks |
| % switched to salvage therapy or measured concentration level in control arm | 7 and 28 days; 12 weeks |
| Overall mortality | 7 and 28 days; 12 weeks |
| Time to global response | 7 and 28 days; 12 weeks |
| Cost-effectiveness of TDM | 7 and 28 days; 12 weeks |
| Side effects | 7 and 28 days; 12 weeks |
Countries
Netherlands
Outcome results
None listed