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…
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Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
1)mortality at day 28 and week 12 of therapy due to fungal infection, overall
mortality at 28 days and 12
weeks.
2)resolution of neutropenic fever, defined as percentage of patients with a
oral temperature of <38 °C at
day 7 of voriconazole treatment [17]; time (in days) to resolve fever is also
noted.
3) percentage of voriconazole serum concentrations within the targeted window
of 2-5mg/L during
therapy based on repeated measurements in time.
4) percentage switched to salvage therapy (i.e. amphotericin B or one of its
lipid or liposomal
formulations; or echinocandin (e.g., caspofungin) or other triazole (e.g.,
posaconazole); or measured
concentration level in control arm during treatment for toxicity or failure)
5) side effects (visual disturbance and liver enzymes)
Side effects leading to drug discontinuation.
6) time (in days) of to global response as defined under the primary endpoint
definition after the start of
voriconazole
7) The evaluation of cost-effectiveness of voriconazole TDM in patients with
invasive aspergillosis
Background summary
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.
Study objective
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.
Study design
For this purpose, we designed a prospective stratified clusterrandomized
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.
Intervention
The intervention (TDM) consists of taking serum samples at day three of
treatment, measuring the voriconazole serum levels and adjusting the dosage to
reach the therapeutic window. Standard care consists dosing voriconazole
according to the product brochure during the control period.
Study burden and risks
There is no additional risk compared to standard of care. The study is designed
to optimize standard of care by dosing on serum concentration and therefore
possibly preventing side effects and increasing efficacy. The extra sample
needed for TDM are no extra burden as these patients are often monitored for
clinical or pharmacological parameters. The sample is taken during regular
sampling for routine laboratory parameters like electrolyte, hepatic function
etc. The advantage of choosing this sampling moment (early morning) is that no
extra vena puncture has to be performed.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
1) are at least 18 years of age
2) have received chemotherapy for haematological malignancies or have received a hematopoietic stem cell transplant
3) proven, probable or possible invasive fungal disease according to the EORTC/MSG criteria
4) treatment with voriconazole
Exclusion criteria
1) allergic to voriconazole or its excipients
2) age below 18 years
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | CLINICALTRIALS.GOV |
| EudraCT | EUCTR2008-007973-19-NL |
| CCMO | NL25850.042.09 |