Effectiveness and Efficiency of a Voriconazole Preemptive Genotyping Strategy

Study Overview
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Brief Summary
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This is a phase IV pragmatic, multicentre, randomised, simple-blind, parallel arm, centre-stratified clinical trial. The main objective is to compare efficiency of voriconazole preemptive genotyping strategy, compared with routine practice.

Detailed Description
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Primary outcome is serum level of voriconazole on fifth day. Secondary outcome is a combined variable of therapeutic failure and adverse events, associated with voriconazole. A total of 146 patients with risk of undergoing invasive aspergillosis who potentially will receive voriconazole will be recruited, and CYP2C19 will be genotyped. If the patient receives voriconazole finally, he will be randomized (1:1 experimental/control). In the experimental arm patients receive dose according to pharmacogenetic algorithm including CYP2C19 genotype and clinical and demographic information. In the control arm patients receive dose according to clinical practice guidelines. In addition, a Spain national health system (NHS) point-of-view cost-effectiveness evaluation is going to be done. Direct costs calculation of each arm will be done.

Official Title
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Randomized and Multicenter Clinical Trial to Evaluate the Effectiveness and Efficiency of a Voriconazole Preemptive Genotyping Strategy in Patients With Risk of Aspergillosis

Conditions
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Invasive Fungal Infections

Intervention / Treatment
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* Drug: Voriconazole preemptive genotyping strategy
* Drug: Voriconazole clinical practice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient at risk of developing invasive aspergillosis, that will potentially receive treatment or prophylaxis with voriconazole: A. Pediatric population: children who are going to receive a transplant of hematopoietic precursors (HSCT) and acute myeloid leukemias, as well as relapses of it. B. Adult population: patients diagnosed with acute leukemia, and those patients with expected prolonged neutropenia, secondary to hematological process and / or after specific treatment (aplastic anemia and variants, myelodysplastic syndrome, solid organ or bone marrow transplant, etc.), and those whose responsible clinician consider individually that they could present a risk of developing a fungal infection. Those who agree to participate in the study by signing informed consent (patients equal or over 18 years old) Subjects under 18 years old whose representative / legal guardian has voluntarily signed the informed consent. In the case of mature under 18 years subjects (12-17 years of age), in addition to the consent signed by the legal guardian, the consent of the subject will be obtained. Exclusion Criteria: Patients who for any reason should not be included in the study according to the criteria of the research team. Subjects who are not capable to understand the information sheet and unable to sign the informed consent.
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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Based on the genetic study carried out and the patient's characteristics (age, weight, indication), the Pharmacogenetics Unit of the University Hospital La Paz will indicate the dose to be administered based on the therapeutic individualization protocol guided by pharmacogenetics. | Drug: Voriconazole preemptive genotyping strategy<br>* The patients who finally receives voriconazole will be randomized to receive the dose according to a pharmacogenetic algorithm including CYP2C19 genotype and clinical and demographic information.<br>|
| Active Comparator: Control group<br>No information will be provided and procedure will be carried out according to normal clinical practice, with clinical monitoring by the doctor in charge. | Drug: Voriconazole clinical practice<br>* The patients who finally receives voriconazole will be randomized to receive the dose according to clinical practice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum voriconazole concentration | Serum voriconazole concentration within the therapeutic range, in μg/mL. | Day 5 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapeutic failure | % of patients with therapeutic failure. A patient has a therapeutic failure if: In patient with suspected or confirmed invasive aspergillosis: drug change or association, because of bad clinical or radiological evolution of the disease. In patient who receive prophylactic treatment: the necessity of change because of suspected or confirmed invasive fungal disease. | Within 3 months | 
| Adverse event | % of patients with a dose-dependent drug adverse event reaction. It will be considered dose-dependent drug adverse reactions: Visual disturbances (photopsias) Skin reactions Neurotoxicity (confusion and visual hallucinations) and Corrected QT interval (QTc) lengthening | Within 3 months | 
| Costs by adverse event | Quantifying economic burden (in euros) associated with management of severe adverse events. | Day 90 of treatment | 
| Quality adjusted life years (QALY) | Measure of disease burden, including both the quality and the quantity of life lived. | Day 90 of treatment |