Individualisation of Voriconazole Antifungal Therapy Antifungal Therapy (PIVOTAL)

PIVOTAL: Pharmacological Individualisation of VOriconazole Therapy for AntifungaL Treatment

This is a trial to determine whether giving a patient a tailored dose of voriconazole is safe and effective.

Study Overview

• Status: Suspended
• Conditions: Aspergillosis; Immunocompromised Patient; Fusarium
• Intervention / Treatment: Drug: VFEND

Detailed Description

Invasive fungal infections are a major cause of morbidity and mortality in patients with haematological malignancy and haematopoietic stem cell transplantation.

Voriconazole is routinely used as a first-line agent for the treatment of invasive aspergillosis, invasive fusariosis and scedosporiosis. Voriconazole has extreme pharmacokinetic variability. Adult patients with a trough concentration of < 1 mg/L have a lower probability of clinical response whereas patients with trough concentrations > 6 mg/L a higher probability of toxicity.

Therapeutic drug monitoring for dose adjustment is advocated but there are no algorithms that enable voriconazole dosage to be reliably adjusted to achieve desired trough concentrations in a timely and optimally precise manner.

Novel ways to deliver optimised antifungal therapy are urgently required and this trial will evaluate whether giving a patients a tailored dose of voriconazole is safe and effective.

Plasma concentrations will be taken in real time and inputted in dose software that will calculate an optimum dose for the required trough concentration of 1-3 mg/L.

The software has been developed using data from phase I and III trials of voriconazole.

• Study Type: Interventional
• Enrollment (Anticipated): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust

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:

• Any adult ≥18 years old
• Patients where a new course of voriconazole is indicated for suspected or confirmed invasive aspergillosis or other serious fungal infections that is deemed by the treating physician to be susceptible to voriconazole
• Patients must have venous access to permit the administration of voriconazole and enable the procurement of multiple plasma samples to measure voriconazole concentrations.
• Estimated creatinine clearance ≥ 50 mL/min
• Able to give written informed consent
• Considered fit to receive the trial treatment
• Able to remain in the hospital for at least 5 days or until they complete their trial treatment
• Female patients must satisfy the investigator that they are not pregnant, or are not of childbearing potential, or are using adequate contraception
• Men must also use adequate contraception

Exclusion Criteria:

• Patients with an estimated creatinine clearance < 50 mL/minute (this precludes the use of intravenous voriconazole)
• Patients receiving any form of renal replacement therapy i.e. haemodialysis or haemofiltration
• Patients with hepatic insufficiency
• Female patients that are pregnant, breast feeding or planning pregnancy during the study
• Past history of intolerance to voriconazole
• Age <18
• Evidence of a clinically relevant fungal isolate that is resistant to voriconazole
• QT prolongation on ECG
• Use of other medications that contraindicate the use of voriconazole
• Patients receiving any other medications that are contraindicated with the use of voriconazole i.e. terfenadine, long acting barbiturates, ergot alkaloids, etc. (Refer to SMPC). Only patients on rifampicin, rifabutin, phenytoin, and carbamazepine would have voriconazole precluded. Voriconazole influences with the pharmacokinetics of many additional agents- (see SMPC)- most importantly anti-rejection compounds- cyclosporine, tacrolimus]
• Uncontrolled cardiac, respiratory or other disease or any serious medical or psychiatric disorder that would preclude trial therapy or informed consent.
• Hypersensitivity to Voriconazole, its excipients or other triazoles

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Voriconazole; Standard adult Voriconazole (VFEND) Loading (1 hr infusion): 6mg/kg at 1 hour and 12 hours on day 1. Followed by standard maintenance dose 4mg/kg at 1 hour and 12 hours on day 2 (1 hour infusion). Day 3 follows the same schedule, expect the dose is adjusted, this dose is used on Day 4 and a further dose adjustment is made that is administered as above on Day 5.	Drug: VFEND; voriconazole will be administered in iv form; Other Names: voriconazole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose adjustment success	Dose adjustment success will be evaluated by plasma trough concentration on day 5, successful dose adjustment is defined as a trough concentration of 1-3 mg/L of voriconazole.	Day 5 of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality of patients	To examine the mortality of patients receiving individualised voriconazole dosing	35 Day after starting treatment
Toxicity	To evaluate the adverse events that are attributable to voriconazole as assessed by CTCAE v4.	Day 5 of treatment and 35 day follow-up

Collaborators and Investigators

• Sponsor: Brynn Chappell
• Collaborators: The Christie NHS Foundation Trust
• Investigators: Study Chair: William Hope, University of Liverpool

Publications and helpful links

Helpful Links

• Christie NHS website

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Anticipated): November 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: June 7, 2013
• First Submitted That Met QC Criteria: June 24, 2013
• First Posted (Estimate): June 26, 2013

Study Record Updates

• Last Update Posted (Estimate): October 7, 2015
• Last Update Submitted That Met QC Criteria: October 6, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: voriconazole; VFEND; individualised; personalised
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Aspergillosis; 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: 13_DOG06_172; 2013-002578-34 (EudraCT Number)