PIVOTAL: Individualisation of Voriconazole Antifungal Therapy Antifungal Therapy

Sponsor

Brynn Chappell (Other)

Overall Status

Suspended

CT.gov ID

NCT01887457

Collaborator

The Christie NHS Foundation Trust (Other)

Enrollment

Location

Arm

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Immunocompromised Patient Aspergillosis Fusarium	Drug: VFEND	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

33 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

PIVOTAL: Pharmacological Individualisation of VOriconazole Therapy for AntifungaL Treatment

Study Start Date :

Sep 1, 2014

Anticipated Primary Completion Date :

Nov 1, 2016

Anticipated Study Completion Date :

Dec 1, 2016

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Dose adjustment success [Day 5 of treatment]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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