Condition category
Infections and Infestations
Date applied
04/10/2017
Date assigned
09/10/2017
Last edited
09/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Treatment with ‘antifungal’ drugs is started when patients are thought to be at risk of fungal infection, even though the large majority turn out not to have this infection. This leads to the clinical problem that is over-prescription of drugs used to treat Candida fungal infection in adults and children in intensive care units (ICU). The majority of ICU patients who are treated with an antifungal drug receive treatment on an empirical basis. Typically, 7% of patients in ICU receive treatment for fungal infection and the majority of patients are started on a presumptive, basis. Of these, only 1 in 20 have fungal infection confirmed. Up to 11000 patients receive potentially unnecessary antifungal treatment each year, at a cost of up to £12 million to the NHS. Most patients treated fail to benefit and are disadvantaged by the risk of side effects. Over-treatment can also lead to resistance to these drugs in the wider population. This study evaluates how accurately three different rapid tests can diagnose fungal infection in adults and children, started presumptively on antifungal treatment. Blood samples from patients who are being started on antifungal treatment are collected and the results of the tests will not be made available to their doctors in this study and their treatment will not be affected by participating. The clinical and economic impact of implementing these rapid tests, based on how accurately they diagnose fungal infection is determined. The main aim of this study is to establish the ability of these tests, to rule out fungal infection in this patient group. We will use these results to develop a guideline that could be used by ICU staff to reduce unnecessary antifungal drug use.

Who can participate?
Adults and children over the age of 4 weeks old who are admitted to the ICU and are started on systemic antifungal therapy.

What does the study involve?
A blood sample is taken from each participant and tested with three new diagnostic tests. If there is any blood sample left after completing these tests the study team would like to store this, with permission, for potential use in future ethically approved research studies. In addition, adult participants are asked to complete a short questionnaire about health-related quality of life approximately one month after entry into the study.

What are the possible benefits and risks of participating?
Participants in this research will not benefit as the results obtained from the new tests will not be used to guide doctors or alter current patient care. The main benefit of this study will be to help future patients with fungal infection by reducing unnecessary treatment which may result in fewer side effects and drug resistance. Patients taking part in this research may experience discomfort from the blood sampling required.

Where is the study run from?
This study is being run by The Queen's University of Belfast (UK) and takes place in UK hospitals.

When is the study starting and how long is it expected to run for?
April 2017 to March 2021

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
1. Dr Ronan McMullan
2. Dr Nicole Goodfellow

Trial website

Contact information

Type

Scientific

Primary contact

Dr Ronan McMullan

ORCID ID

Contact details

Kelvin Laboratory Building
The Royal Hospitals
Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Type

Public

Additional contact

Dr Nicola Goodfellow

ORCID ID

Contact details

Northern Ireland Clinical Trials Unit
1st Floor
Elliott Dynes Building
Royal Hospital Site
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
+44 2890635794
ASTOP@nictu.hscni.net

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

B17/23

Study information

Scientific title

Antifungal stewardship opportunities with rapid tests for fungal infection in critically ill patients

Acronym

The A-STOP Study

Study hypothesis

The rapid tests under study have high diagnostic accuracy for ruling out Candida infection in critically ill adults and children.

Ethics approval

Not provided at time of registration

Study design

A multi-centre prospective diagnostic test accuracy study

Primary study design

Observational

Secondary study design

Cohort study

Trial setting

Hospitals

Trial type

Diagnostic

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet’

Condition

Critically ill patients with suspected fungal infection

Intervention

The A-STOP Study is a multi-centre, prospective, diagnostic test accuracy study. The purpose of this project is to assess the performance of three rapid tests for fungal infection. The accuracy of these tests are compared and the optimal test (or combination) identified. The emphasis is on their ability to rule-out infection so that a test-based protocol for early discontinuation of antifungal therapy can be developed.

This test-based protocol is modelled for clinical and cost effectiveness, accounting for expected beneficial and adverse outcomes. This modelling, together with a value of information analysis, will inform the design of a future clinical & cost effectiveness RCT.

In order to see if these new tests could be used to make decisions in the future, it is necessary to see how they compare to conventional tests currently used in the NHS. Blood samples for Candida infection are tested with three new tests (beta-D-glucan and two PCR-based tests) and the results are compared with those obtained from cultures that have been sent to the laboratory as part of the patient's normal care. This is to work out how accurate and useful the new tests might be. An exploratory sub-analysis of the main diagnostic accuracy analysis is undertaken to evaluate variation in accuracy measures in the following sub-groups; children; patients with end organ dysfunction, assessed using SOFA and PELOD score (for adults and children respectively); prior antifungal exposure; patients with infection due to different Candida species; and patients with candidaemia.

At least 35 paediatric and adult intensive care units (ICUs) across the UK participate. Adult and paediatric patients admitted to the ICU who are started on presumptive antifungal treatment will be screened for inclusion into the study.

This research collects 1720 blood samples (one per person) over a 36-month period, with the result of each being compared to its paired culture result to estimate conventional diagnostic metrics (sensitivity, specificity, positive/negative predictive values (at specified prevalence), and positive/negative likelihood ratios) in the main analysis. The standard care blood samples are taken in the usual manner, for the participating study site. At the time a blood culture is taken, a ‘research’ sample of blood are also collected for testing. For adults, this is approximately 12mL and for children approximately 4mL.

Health related quality of life (for adults only) is measured using the EQ-5D-5L questionnaire at day 28 (up to day 35 if required). Patient survival after discharge from hospital will be determined either from hospital information systems, using the Health and Social Care Information Centre (if available) or by contacting their GP.

There is no change to standard care treatment of recruited patients.

Intervention type

Other

Phase

Drug names

Primary outcome measures

Accuracy is measured using the negative predictive value for each index test

Secondary outcome measures

1. Measures of diagnostic test accuracy, for each test alone and in combination, based on an international consensus reference standard for proven invasive fungal disease, applied for Candida infection. These will comprise sensitivity, specificity, positive/negative predictive values and positive/negative likelihood ratios.
2. Measures of diagnostic test accuracy, for each test alone and in combination, based on an international consensus reference standard for proven and probable invasive fungal disease, applied for Candida infection.
3. Estimated proportion of patients receiving systemic antifungal therapy in this cohort for whom treatment is unnecessary, derived from the reference standards used. Estimated number of days’ avoidable antifungal treatment if negative index test results were used to stop treatment.
4. Development of a test-based protocol using the index tests (alone or in combination), as a strategy for early cessation of empirical antifungal treatment, with assessment of its expected cost-effectiveness modelled on test accuracy, disease prevalence and clinical/economic outcomes in this patient group.

Overall trial start date

01/04/2017

Overall trial end date

31/03/2021

Reason abandoned

Eligibility

Participant inclusion criteria

1. Adults and children >4 weeks old
2. Admitted to a UK ICU (level 2 or 3)
3. Started systemic antifungal therapy, for presumed Candida infection, during the preceding 24 hours

Participant type

Patient

Age group

Mixed

Gender

Both

Target number of participants

1720

Participant exclusion criteria

1. More than 24 hours systemic antifungal therapy in the preceding 7-days
2. Treatment with antifungal therapy for proven or suspected mould infection (eg.e.g. aspergillosis)
3. Neutropenia (absolute neutrophil count <0.5x109/L) during preceding 28 days
4. Acute leukaemia or within 12 months of bone-marrow transplantation
5. Hospitalised prisoners
6. Previously enrolled in this study

Recruitment start date

01/01/2018

Recruitment end date

30/09/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Belfast City Hospital
BT9 7AB
United Kingdom

Trial participating centre

Leicester Royal Infirmary
LE2 7LX
United Kingdom

Trial participating centre

Basildon University Hospital
SS16 5NL
United Kingdom

Trial participating centre

Pinderfields Hospital
WF1 4DG
United Kingdom

Trial participating centre

Birmingham Heartlands Hospital
B9 5SS
United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh
EH16 4SA
United Kingdom

Trial participating centre

Royal Cornwall Hospital
TR1 3LJ
United Kingdom

Trial participating centre

Royal Derby Hospital
DE22 3NE
United Kingdom

Trial participating centre

James Cook University Hospital
TS4 3BW
United Kingdom

Trial participating centre

Royal Liverpool University Hospital
L7 8XP
United Kingdom

Trial participating centre

Arrowe Park Hospital
CH49 5PE
United Kingdom

Trial participating centre

Antrim Area Hospital
BT41 2RL
United Kingdom

Trial participating centre

Altnagelvin Hospital
BT47 6SB
United Kingdom

Trial participating centre

The Great Western Hospital
SN3 6BB
United Kingdom

Trial participating centre

East Surrey Hospital
RH1 5RH
United Kingdom

Trial participating centre

Ulster Hospital
BT16 1RH
United Kingdom

Trial participating centre

Milton Keynes University Hospital
MK6 5LD
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
B15 2GW
United Kingdom

Trial participating centre

Craigavon Area Hospital
BT63 5QQ
United Kingdom

Trial participating centre

Royal Bolton Hospital
BL4 0JR
United Kingdom

Trial participating centre

Royal Victoria Hospital
Belfast
BT12 6BA
United Kingdom

Trial participating centre

Royal Hospital for Sick Children
NHS Lothian
EH9 1LF
United Kingdom

Trial participating centre

Southampton General Hospital
SO16 6YD
United Kingdom

Trial participating centre

John Radcliffe Hospital
OX3 9DU
United Kingdom

Trial participating centre

Birmingham Chidren's Hospital
B4 6NH
United Kingdom

Trial participating centre

Alder Hey Children's Hospital
L12 2AP
United Kingdom

Trial participating centre

Royal Berkshire Hospital
RG1 5AN
United Kingdom

Trial participating centre

University Hospital of South Manchester
M23 9LT
United Kingdom

Trial participating centre

Southmead Hospital
BS10 5NB
United Kingdom

Sponsor information

Organisation

The Queen's University of Belfast

Sponsor details

63 University Road
Belfast
BT7 1NN
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in high-impact peer reviewed journals and presentation of findings at national/international meetings and appropriate patient groups.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/03/2022

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes