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Individualisation of Voriconazole Antifungal Therapy Antifungal Therapy (PIVOTAL)

Primary Purpose

Immunocompromised Patient, Aspergillosis, Fusarium

Status

Suspended

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

VFEND

About this trial

This is an interventional treatment trial for Immunocompromised Patient focused on measuring voriconazole, VFEND, individualised, personalised

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

The Christie NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Voriconazole

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Mortality of patients

To examine the mortality of patients receiving individualised voriconazole dosing

Toxicity

To evaluate the adverse events that are attributable to voriconazole as assessed by CTCAE v4.

Full Information

NCT ID

NCT01887457

First Posted

June 7, 2013

Last Updated

October 6, 2015

Sponsor

Brynn Chappell

Collaborators

The Christie NHS Foundation Trust

1. Study Identification

Unique Protocol Identification Number

NCT01887457

Brief Title

Individualisation of Voriconazole Antifungal Therapy Antifungal Therapy

Acronym

PIVOTAL

Official Title

PIVOTAL: Pharmacological Individualisation of VOriconazole Therapy for AntifungaL Treatment

Study Type

Interventional

2. Study Status

Record Verification Date

October 2015

Overall Recruitment Status

Suspended

Why Stopped

Transfer of management of study

Study Start Date

September 2014 (undefined)

Primary Completion Date

November 2016 (Anticipated)

Study Completion Date

December 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Brynn Chappell

Collaborators

The Christie NHS Foundation Trust

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Immunocompromised Patient, Aspergillosis, Fusarium

Keywords

voriconazole, VFEND, individualised, personalised

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

33 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Voriconazole

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

VFEND

Other Intervention Name(s)

voriconazole

Intervention Description

voriconazole will be administered in iv form

Primary Outcome Measure Information:

Title

Dose adjustment success

Description

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.

Time Frame

Day 5 of treatment

Secondary Outcome Measure Information:

Title

Mortality of patients

Description

To examine the mortality of patients receiving individualised voriconazole dosing

Time Frame

35 Day after starting treatment

Title

Toxicity

Description

To evaluate the adverse events that are attributable to voriconazole as assessed by CTCAE v4.

Time Frame

Day 5 of treatment and 35 day follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

William Hope

Organizational Affiliation

University of Liverpool

Official's Role

Study Chair

Facility Information:

Facility Name

The Christie NHS Foundation Trust

City

Manchester

ZIP/Postal Code

M20 4BX

Country

United Kingdom

12. IPD Sharing Statement

Links:

URL

http://www.christie.nhs.uk/

Description

Christie NHS website

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Individualisation of Voriconazole Antifungal Therapy Antifungal Therapy

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