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

• 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)
  
  

• 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 ]
  

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.