Rapid diagnostic tests and treatment opportunities for fungal infection in critically ill patients
| ISRCTN | ISRCTN43895480 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN43895480 |
| Secondary identifying numbers | B17/23 |
- Submission date
- 04/10/2017
- Registration date
- 09/10/2017
- Last edited
- 26/07/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Current plain English summary as of 11/04/2019:
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 or been prescribed 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 May 2023
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
Mary Guiney, ASTOP@nictu.hscni.net
Previous 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
Contact information
Scientific
Kelvin Laboratory Building
The Royal Hospitals
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
Public
7 Lennoxvale
Belfast
BT9 5BY
United Kingdom
| Phone | +44 (0)28 961 51447 |
|---|---|
| ASTOP@nictu.hscni.net |
Study information
| Study design | A multi-centre prospective diagnostic test accuracy study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Cohort study |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet’ |
| Scientific title | Antifungal stewardship opportunities with rapid tests for fungal infection in critically ill patients |
| Study acronym | A-STOP |
| Study hypothesis | The rapid tests under study have high diagnostic accuracy for ruling out Candida infection in critically ill adults and children. |
| Ethics approval(s) | Approved 03/01/2018, South Central - Hampshire A Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT; 0207 104 8049), ref: 17/SC/0613 |
| Condition | Critically ill patients with suspected fungal infection or proven 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 |
| Primary outcome measure | 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 study start date | 01/04/2017 |
| Overall study end date | 15/05/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 4 Weeks |
| Sex | Both |
| Target number of participants | 1,250 |
| Total final enrolment | 1251 |
| Participant inclusion criteria | Current participant inclusion criteria as of 11/04/2019: 1. Adults and children >4 weeks old 2. Admitted to a UK ICU (level 2 or 3) 3. Prescribed systemic antifungal therapy, for suspected or confirmed Candida infection, during the preceding 24 hours Previous 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 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 Added 26/10/2021: 7. Proven or suspected active infection with COVID-19 |
| Recruitment start date | 01/01/2018 |
| Recruitment end date | 01/01/2022 |
Locations
Countries of recruitment
- England
- Northern Ireland
- United Kingdom
- Wales
Study participating centres
BT12 6BA
United Kingdom
SS16 5NL
United Kingdom
WF1 4DG
United Kingdom
B9 5SS
United Kingdom
TR1 3LJ
United Kingdom
DE22 3NE
United Kingdom
TS4 3BW
United Kingdom
L7 8XP
United Kingdom
CH49 5PE
United Kingdom
BT41 2RL
United Kingdom
BT47 6SB
United Kingdom
RH1 5RH
United Kingdom
BT16 1RH
United Kingdom
MK6 5LD
United Kingdom
B15 2GW
United Kingdom
BT63 5QQ
United Kingdom
BL4 0JR
United Kingdom
OX3 9DU
United Kingdom
B4 6NH
United Kingdom
RG1 5AN
United Kingdom
M23 9LT
United Kingdom
BS10 5NB
United Kingdom
SE5 9RS
United Kingdom
NG17 4JL
United Kingdom
NE1 4LP
United Kingdom
SA6 6NL
United Kingdom
NR4 7UY
United Kingdom
TS19 8PE
United Kingdom
S60 2UD
United Kingdom
EX2 5DW
United Kingdom
CF72 8XR
United Kingdom
BA1 2NG
United Kingdom
TA1 5DA
United Kingdom
TQ2 7AA
United Kingdom
WR5 1HN
United Kingdom
WR5 1DD
United Kingdom
ME7 5NY
United Kingdom
HA1 3UJ
United Kingdom
LS9 7TF
United Kingdom
DH1 5TW
United Kingdom
CF14 4XW
United Kingdom
S75 2EP
United Kingdom
NE29 8NH
United Kingdom
OL1 2JH
United Kingdom
Sponsor information
University/education
63 University Road
Belfast
BT7 1NN
Northern Ireland
United Kingdom
"ROR" |
https://ror.org/00hswnk62 |
|---|
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| 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 plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 7.0 | 25/03/2021 | 28/09/2021 | No | No |
| Protocol file | version 8.0 | 27/05/2021 | 07/12/2021 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
26/07/2024: The total final enrolment was changed from 1250 to 1251.
19/12/2023: The overall study end date was changed from 31/12/2023 to 15/05/2023.
18/05/2023: The total final enrolment was added.
13/06/2022: The following changes have been made:
1. The overall trial end date has been changed from 01/06/2022 to 31/12/2023 and the plain English summary updated accordingly.
2. The intention to publish date has been changed from 01/06/2023 to 31/12/2024.
07/12/2021: Uploaded protocol (not peer reviewed).
26/10/2021: The following changes were made to the trial record:
1. The contact details and exclusion criteria were updated.
2. The following trial participating centres were added: Worcestershire Royal Hospital, Medway Maritime Hospital, Northwick Park Hospital, St James’s University Hospital, University Hospital of North Durham, University Hospital of Wales, Barnsley Hospital, Northumbria Specialist Emergency Hospital, The Royal Oldham Hospital.
28/09/2021: Uploaded protocol (not peer reviewed).
08/03/2021: The following changes have been made:
1. The recruitment end date has been changed from 30/09/2020 to 01/01/2022.
2. The overall trial end date has been changed from 31/03/2021 to 01/06/2022 and the plain English summary updated accordingly.
3. The target enrolment has been changed from 1720 to 1250.
4. The intention to publish date has been changed from 31/03/2022 to 01/06/2023.
5. The public contact has been changed and the plain English summary updated accordingly.
03/09/2020: IPD sharing statement added.
27/08/2020: Recruitment to this study is no longer paused.
23/04/2020: Due to current public health guidance, recruitment for this study has been paused.
11/04/2019: The following changes were made:
1. The condition is updated from "Critically ill patients with suspected fungal infection" to "Critically ill patients with suspected fungal infection or proven fungal infection".
2. The plain English summary was updated.
3. The participant inclusion criteria were updated.
4. The trial participating centres were updated.
5. The ethics approval was updated.
6. The contact details were updated.
