Pharmacologic Optimization of Voriconazole

Phase 3

Completed

• Conditions: Invasive Fungal Infection; Hematological Malignancy
• Interventions: Drug: voriconazole (dosing according to the SPC); Drug: voriconazole

• Registration Number: NCT00893555
• Lead Sponsor: Jan-Willem C Alffenaar

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.

Study Timeline

• Study Start: 2009-04
• Study First Submitted: 2009-05-04
• Study First Submitted QC: 2009-05-05
• Study First Posted: 2009-05-06
• Primary Completion: 2016-11
• Status Verified: 2017-01
• Study Completion: 2017-01
• Last Update Submitted: 2017-01-11
• Last Update Posted: 2017-01-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 189

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

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Exclusion Criteria

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
control	voriconazole (dosing according to the SPC)	Voriconazole dosing based on SPC
TDM	voriconazole	Voriconazole serum concentration based dosing

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Overall mortality	7 and 28 days; 12 weeks
% 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
Side effects	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

Trial Locations

Locations (1)

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands