Pharmacologic Optimization of Voriconazole (VORI911)

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

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.

Study Overview

• Status: Completed
• Conditions: Invasive Fungal Infection; Hematological Malignancy
• Intervention / Treatment: Drug: voriconazole (dosing according to the SPC); Drug: voriconazole

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 Type: Interventional
• Enrollment (Actual): 189
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713GZ
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Jan-Willem C Alffenaar
• Collaborators: UMC Utrecht; Erasmus Medical Center; Amsterdam UMC, location VUmc; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); St. Antonius Hospital; Leiden University Medical Center; Haga Hospital; University Medical Center Nijmegen; Meander Medical Center; Klinikum Oldenburg gGmbH
• Investigators: Study Chair: J GW Kosterink, PharmD, PhD, University Medical Center Groningen; Principal Investigator: J WC Alffenaar, PharmD PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: May 4, 2009
• First Submitted That Met QC Criteria: May 5, 2009
• First Posted (Estimate): May 6, 2009

Study Record Updates

• Last Update Posted (Estimate): January 12, 2017
• Last Update Submitted That Met QC Criteria: January 11, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: voriconazole; hematological malignancy; therapeutic drug monitoring; Invasive fungal infection
• Additional Relevant MeSH Terms: Infections; Neoplasms by Site; Hematologic Diseases; Bacterial Infections and Mycoses; Neoplasms; Hematologic Neoplasms; Mycoses; Invasive Fungal Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Voriconazole
• Other Study ID Numbers: VORI911