Pharmacologic Optimization of Voriconazole (VORI911)

Jan-Willem C Alffenaar

Status and phase: Completed; Phase 3

Conditions: Invasive Fungal Infection; Hematological Malignancy

Treatments: Drug: voriconazole; Drug: voriconazole (dosing according to the SPC)

Study type: Interventional

Funder types: Other

Identifiers

NCT00893555

VORI911

Details and patient eligibility

About

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.

Full 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.

Enrollment: 189 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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189 participants in 2 patient groups

control

Active Comparator group

Description:

Voriconazole dosing based on SPC

Treatment:

Drug: voriconazole (dosing according to the SPC)

TDM

Experimental group

Description:

Voriconazole serum concentration based dosing

Treatment:

Drug: voriconazole