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Pharmacologic Optimization of Voriconazole - a Prospective Clustered Group-randomized Cross-over Trial of Therapeutic Drug Monitoring

Phase 3
18 Years
Open (Enrolling)
Invasive Fungal Infection, Hematological Malignancy

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Trial Information

Pharmacologic Optimization of Voriconazole - a Prospective Clustered Group-randomized Cross-over Trial of Therapeutic Drug Monitoring

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.

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

- treatment with voriconazole

Exclusion Criteria:

- allergic to voriconazole or its excipients

- age below 18 years

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome 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.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

J GW Kosterink, PharmD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

University Medical Centre Groningen


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

April 2009

Completion Date:

April 2013

Related Keywords:

  • Invasive Fungal Infection
  • Hematological Malignancy
  • Invasive fungal infection
  • hematological malignancy
  • voriconazole
  • therapeutic drug monitoring
  • Neoplasms
  • Mycoses
  • Hematologic Neoplasms