Pharmacologic Optimization of Voriconazole

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Invasive Fungal Infection, Hematological Malignancy

Intervention / Treatment
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* Drug: voriconazole
* Drug: voriconazole (dosing according to the SPC)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: control<br>Voriconazole dosing based on SPC | Drug: voriconazole (dosing according to the SPC)<br>* No serum concentrations are determined<br>* Other names: Vfend;|
| Experimental: TDM<br>Voriconazole serum concentration based dosing | Drug: voriconazole<br>* TDM (through level of 2-5mg/L).<br>* Other names: Vfend;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Invasive fungal infection, hematological malignancy, voriconazole, therapeutic drug monitoring