A Trial Comparing Efficacy and Safety of Voriconazole Administered With Therapeutic Drug Monitoring vs. Standard Dosing (VoriTDM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Johns Hopkins University
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Kieren Marr, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01416025
First received: August 11, 2011
Last updated: March 18, 2014
Last verified: March 2014
  Purpose

This is a prospective, multicenter, randomized trial to study therapeutic drug monitoring (TDM) of voriconazole among patients with an invasive mould infection (IMI). The primary objective of this study will be to assess the effect of prospective voriconazole TDM on the composite of adverse events (AE) and clinical response.


Condition Intervention Phase
Fungal Infection
Drug: Prospective TDM Arm
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective, Randomized Trial Comparing the Efficacy and Safety of Voriconazole Administered With Therapeutic Drug Monitoring vs. Standard Dosing

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • Treatment failure [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]

    The primary endpoint of the study will be a binary outcome, called Failure, defined as one of the following: measured at 42 days from initiation of drug administration:

    1. Progression of underlying infection (clinical failure)
    2. Death
    3. Development of a voriconazole-associated SAE: LFTs, Rash, Visual disturbance, Neurologic abnormality (e.g: hallucinations)


Secondary Outcome Measures:
  • The frequency and timing of voriconazole-related AEs [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
    Composite endpoint of liver impairment, skin rash, visual changes, and mental status changes.

  • Clinical response rate [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
  • All cause mortality [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
    post initiation of voriconazole in subjects with possible, probable or proven IMI

  • All cause mortality [ Time Frame: 4 weeks post completion of voriconazole ] [ Designated as safety issue: Yes ]
    in subjects with possible, probable, or proven IMI

  • The time to death [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
    The time to death (all cause mortality) and relapse-free death

  • Number of dose adjustments [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
    The number of dose adjustments to 42 days post initiation of voriconazole

  • The number of switch to and addition of other antifungals [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 146
Study Start Date: January 2012
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prospective TDM Arm
Voriconazole dose will be adjusted based on per protocol obtained TDM levels
Drug: Prospective TDM Arm
Voriconazole dose will be adjusted based on per protocol obtained TDM levels
Other Name: VFEND
No Intervention: Standard dosing
Standard doses of voriconazole will be used

Detailed Description:

This is a prospective study of patients who receive voriconazole as treatment for an IMI (proven, probable, and possible by the EORTC/MSG definitions), other than zygomycosis. Patients will be randomized to receive either standard dosing or dosing based on TDM, stratified by whether initial voriconazole therapy is PO or IV. Assessment of outcomes will be made 42 days after start of voriconazole. An additional follow up for safety reporting will be performed 4weeks after completion of voriconazole

The patients will be randomized to:

  • Prospective TDM: voriconazole dose will be adjusted based on per protocol obtained TDM levels, and
  • Standard dosing: standard doses of voriconazole will be used.

In the prospective TDM arm, voriconazole TDM will be performed in real time at each site and results will be reported to treating physicians for dose adjustment. All efforts will be taken to obtain results within 24 hours of blood sample collection. In the standard dosing arm, blood samples will be collected, stored, and batched for voriconazole levels to be tested retrospectively. Voriconazole plasma levels will be measured by validated high performance liquid chromatography (HPLC) assays as detailed. Voriconazole trough levels will be performed on Day Baseline/Screening, 5, 14, 28, and 42.

Voriconazole peak level will be measured on Day 5. Trough voriconazole levels will be obtained in case of an event, defined as suspected drug-associated toxicity and/or clinical failure.

Assessment of AEs for all patients will be monitored during the study and response to treatment will be assessed. The composite of overall AE/clinical failure will be assessed on day 42.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Indication for voriconazole administration: proven, probable, or possible IMI, excluding zygomycosis (based on the revised EORTC/MSG consensus definitions) [De Pauw, Clin Infect Dis. 2008; 46:1813].
  • Male or female ≥12 years of age.
  • Evidence of a personally signed and dated informed consent document in accordance with local regulatory and legal requirements indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
  • Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

  • Known history of allergy, hypersensitivity or serious reaction to azole antifungals.
  • Patients with aspergilloma or allergic bronchopulmonary aspergillosis (ABPA).
  • Patients with chronic invasive aspergillosis with duration of symptoms or radiological finding for more than 4 weeks prior to study entry.
  • Patients who are receiving and cannot discontinue the following drugs at least 24 hours prior to randomization: terfenadine, pimozide or quinidine (because of the possibility of QT prolongation), St John's wort preparation.
  • Patients receiving any of the following medications: sirolimus, rifampin, rifabutin, carbamazepine, long acting barbiturates (e.g., phenobarbital, mephobarbital), ritonavir, efavirenz, or ergot alkaloids (e.g., ergotamine, dihydroergotamine).
  • Receipt of more than 5 days of voriconazole as treatment prior to enrollment.
  • Receipt of 7 days or more of systemic antifungal treatment for the current episode of IMI.
  • Severe liver dysfunction (defined as total bilirubin, AST, ALT, or alkaline phosphatase >5x upper limit of normal). Local laboratory results may be used to qualify individuals for enrollment.
  • Patients with any condition which, in the opinion of the investigator, could affect patient safety, preclude evaluation of response, or make it unlikely that the proposed course of therapy can be completed.
  • Patients who have already participated in this trial within the last 30 days.
  • Patients with a high likelihood of death due to factors unrelated to IA (e.g., due to relapsed malignancy, severe GVHD, other underlying diseases, etc.) within 30 days following planned enrollment (investigator's discretion).
  • Patients that weigh <45 and >120 kg, respectively, upon enrollment. If patients' weight is beyond those limits upon serial assessments during the study period, the study monitor should be contacted and decisions to keep or withdraw subject from the study will be made.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01416025

Contacts
Contact: Kieren Marr, MD (443) 287-6217 kmarr4@jhmi.edu
Contact: Darin Ostrander, PhD 410-614-1824 dostrander@jhu.edu

Locations
United States, Maryland
Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21205
Contact: Kieren Marr, MD    443-287-6217    kmarr4@jhmi.edu   
Contact: Darin Ostrander, PhD    (410) 614-6702    dostran1@jhmi.edu   
Principal Investigator: Kieren Marr, MD         
Sponsors and Collaborators
Johns Hopkins University
Pfizer
Investigators
Principal Investigator: Kieren Marr, MD Johns Hopkins University
  More Information

No publications provided

Responsible Party: Kieren Marr, Professor of Medicine and Oncology, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01416025     History of Changes
Other Study ID Numbers: NA_00041916
Study First Received: August 11, 2011
Last Updated: March 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Johns Hopkins University:
Voriconazole
Therapeutic drug monitoring
Hematopoietic stem cell transplant
Hematologic malignancy
Invasive mould infection

Additional relevant MeSH terms:
Mycoses
Voriconazole
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 19, 2014