Condition category
Respiratory
Date applied
15/07/2019
Date assigned
05/08/2019
Last edited
16/08/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Severely ill hospital patients often develop lung and respiratory infections such as pneumonia. Such infections are life-threatening and must be treated as soon as possible with antibiotics.
It is well known that not all antibiotics are working as well as they used to, this is largely due to resistance of the bacteria that cause the infections and has been listed as a major public health concern by the UK Department of Health and many other countries around the world.
Current practice in hospitals, when a patient is suspected of having a lung infection, is to send a sample of their sputum (spit and phlegm mixture collected from their airways) to the microbiology lab for analysis. This takes 2-3 days, during that time the suspected infection is treated with a broad range of antibiotics. It has been found that this approach means around 67% of people with pneumonia receive antibiotics that they do not need, thus creating resistance risk and can cause unnecessary and unpleasant side effects to the patients themselves.
The INHALE trial tests a rapid diagnostic machine (the Biofire "FilmArray") to see if sample results can be provided quicker than lab sample testing and if this leads to the best and most appropriate antibiotics being prescribed sooner. All participants will have their sample sent to the lab regardless of whether it is also tested on the new machine, so all standard care options are also available to their doctor. Half of participants will have a portion of their standard care sample tested on the machine straight away. Machine results should be available and reviewed within 8 hours of collection. To guide doctors in prescribing the most appropriate antibiotic according to resistance 'stewardship' guidelines, trial specific guidance will also be provided.

Who can participate?
In-patients in a participating ICU/CCU with suspected Lower Respiratory Tract Infections (LRTIs) including Hospital Acquired Pneumonia (HAP) or Ventilator Acquired Pneumonia (VAP) will be potentially eligible to participate.

What does the study involve?
As part of usual care participants will provide samples of sputum for analysis. Participants will either have their samples tested in the usual way or in the usual way and with a new test which is being trialled in this study. Treatment will proceed as usual for all participants.

What are the possible benefits and risks of participating?
There are no direct benefits to patients in hospital today but they will be playing an important part in helping the NHS to treat adults and children with pneumonia in the next few years.
The risk is considered to be no higher than the normal care that they would receive if they do not take part in this study. No new drug is being tested and their doctor can prescribe all of the same medicines regardless of how their sample has been tested.
The antibiotics given to help fight the participant’s lung infection can be changed if the results show this might help them get better quicker or that they don’t need the antibiotics. While the machine can identify the most common causes of pneumonia, there are some rare bacteria it cannot find. Therefore there is a small risk that participants might have one of these rare bacteria, in which case treatment may have to be changed again after 2-3 days, once the bacteria from their phlegm have been grown in the lab.

Where is the study run from?
University College London Hospital, UK

When is the study starting and how long is it expected to run for?
July 2019 to June 2021

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

Who is the main contact?
Dr Vicky Enne
inhale.study@uea.ac.uk

Trial website

http://www.ucl.ac.uk/inhale-project

Contact information

Type

Scientific

Primary contact

Dr Vicky Enne

ORCID ID

Contact details

University College London
Gower Street
London
WC1E 6BT
United Kingdom
+442076792000
inhale.study@uea.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

41211

Study information

Scientific title

The impact of using film array pneumonia panel molecular diagnostics for hospital-acquired and ventilator-associated pneumonia on antimicrobial stewardship and patient outcomes in UK critical care: a multicentre randomised controlled trial

Acronym

INHALE

Study hypothesis

Rapid diagnostics will be at least equivalent to standard care for clinical and safety outcomes in this trial and show improvement in antimicrobial stewardship

Ethics approval

Approved 20/03/2019, NHS REC London-Brighton & Sussex (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT; 0207 104 8241; NRESCommittee.SECoast-BrightonandSussex@nhs.net), ref: 19/LO/0400

Study design

Randomised; Interventional; Design type: Treatment, Complex Intervention

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

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

Condition

Pneumonia

Intervention

Patients in intensive care presenting with suspected Lower Respiratory Tract Infections (LRTIs) including HospitalAcquired Pneumonia (HAP) or Ventilator Acquired Pneumonia (VAP) will be potentially eligible to participate.

Intensive Care Unit (ICU) staff will be responsible for identifying potentially eligible patients. The trial has been designed as a trial of emergency medicine and as such participants samples will be tested and where relevant results acted upon before they have been approached for consent.
The sample itself will be an airway specimen (sputum), collected routinely as recommended for all patients who have a suspected LRTI. 200 microlitres of spare sample would be retained and, depending on which group the participant has been randomised to, will either be tested straight away on a new machine, or frozen.

When an eligible patient is identified, the site staff will need to add some basic details to the trial database (in order that it can generate a participant ID number and avoid adding the same person twice) they will then be able to press a button which randomly selects which group that participant will be in. Those in group A will have their sample tested on the new machine straight away, whilst also receiving all other treatment as usual and those in group B will have only treatment as usual. There is a 50:50 chance of being in either group. A total of 466 participants will be included, 233 in each group.

The machine under test is a Biofire "FilmArray" molecular diagnostic machine. This works by identifying the genetic material of the bacteria (DNA) present in a sample and thereby identifying what is causing the infection, within 1-2 hours. In this trial this will be in addition to treatment as usual (microbiology culture preparation) which will also return a result to the treating doctor within 2-3 days. To enable the treating doctor and trial team to agree that the most appropriate antibiotic have been given according to stewardship guidelines, an "algorithm" document has been produced. This has been prepared for the trial but is intended to be adapted to individual site requirements. When data are analysed, it will be against the agreed algorithm for that site that stewardship will be determined.
The treating doctor has all the usual antibiotics available to them and can choose to disregard the algorithm if appropriate. All treatments given will be recorded in the trial database.

If a sample is tested on the new machine straight away and results acted upon, it will be possible to tailor treatment with antibiotics much sooner (within 1-2 hours, although the study allows up to 8 hours) than when using standard microbiology techniques (2-3 days). It is not known whether this will lead to improvements in antibiotic stewardship - for example whether doctors will feel confident with the machine result and change the treatment sooner and if so choose a single appropriate antibiotic rather than continue to treat with a broader ranging dose of different antibiotics. The trial also aims to confirm that there is at least equivalence in cure rates of pneumonia when using the machine. Other outcomes will compare safety signals such as adverse events, septic shock and mortality rates and two other key aspects of the programme of research include a cost/benefit analysis and a behavioural study, to look at the likely success of introducing such a change to routine practice in future. To understand this it is necessary to include a control group which receives only treatment as usual. No participants in either group will have any standard treatment options withheld, those in the machine group will have the trial test in addition to standard care microbiology and their treating doctor will have all of the usual treatment options available to them.

All participants will have sample sent to the local microbiology lab as usual for standard care, but their sample will have been split at collection to retain a portion of spare sample. Those in group A will have their spare sample run on the new machine, located in or near to ICU as soon as possible. Those in group B will have their spare sample frozen for future shipping and centralised analysis. (The results of the central testing will never be reported to site and are not intended to influence local treatment in any way). From that point forwards group B participants will follow only standard care.

As soon as a machine result is available for group A participants, the treating doctor should review and together with the trial specific treatment algorithm (which may be agreed and adapted to take into account local variations) will decide whether antibiotic treatment should be modified. Further modification may be required when the lab results are known and these will be reviewed and acted upon regardless of which group the participant is in.

As soon as appropriate (recommended within 48 hours) the local research staff should approach the patient or their relatives or representatives (parent for children in specialist paediatric hospitals) to explain about the trial and seek their consent. They will be given as long as they need to decide and the participant will continue to be treated according to the protocol during this time, as long as they assent. This whole process will be undertaken by specially trained staff with agreement from the local treating clinician. We have undertaken extensive pre-trial consultation on this process, including with our patient and public involvement team (PPI) and clinicians from a range of hospitals, including GOSH, who have a lot of experience with such trial designs. We have their support and the consensus is that such a trial would not produce representative results if we were to include only participants who were able to give consent at time of randomisation.

For all participants, demographic, clinical and cost data will be collected and scores of disease progression and severity will be measured for up to 14 days following recruitment. This will be collected from medical records by site staff at no inconvenience to the participant.

For participants discharged home within 21 days following recruitment, a brief telephone interview will be conducted on day 21 (window of day 20-24), providing consent has been given to this. This will include the EQ-5D-5L questionnaire and some simple questions about their current condition. Other than consent, this is the only information collected directly with the participant.
There will also be a review of mortality at 28 days, a simple yes/no collected from medical records and again at no inconvenience to the participant.

Information collected from clinical records will be:
• Reasons for ICU admission, including dates of ICU and hospital admission and discharge (this may pre and post date the trial period)
• Type of LRTI/pneumonia (HAP, VAP)
• Demographics (including age, gender)
• Hospital and ICU/CCU stays in the 3 months prior to the current admission
• Patient functional measures (Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Paediatric Index of Mortality 3 (PIM3), which are recorded on admission) and Sequential Organ Failure Assessment (SOFA) score, paediatric SOFA score and Paediatric Logistic Organ Dysfunction (PELOD-2) score which are recorded daily while in ICU/CCU),
• Ventilation status (daily)
• Need for and type of ventilation (if relevant)
• Septic shock
• Mortality (all cause, up to 28 days after randomisation)
• Details of pathogens identified by routine microbiology from all body sites, from 7 days prior to randomisation to 21 days after
• Antimicrobial prescriptions (including antibiotics administration in the 7 days prior to the study enrolment and antibiotics used to treat HAP/VAP) and reasons for stopping the antibiotic, where the course is not completed, and including number of doses of empirical treatment given
• Presence or absence of any significant co-morbidities
• Time of specimen collection and time that results were reviewed in ICU/CCU
• Results from routine microbiology (all participants) and machine (for intervention group)
• Whether a routine x-ray and/or CT scan was carried out and if so the dates closest to screening, day 14 and day 21and whether it showed evidence of pneumonia
• Clostridium difficile infections and any other adverse events potentially related to antibiotic use
• Health service resource use data relating to cost of the ICU/hospital stay
• On day 14 (all participants) the database will ask for the clinician's view on whether the pneumonia is cured
• For the second primary outcome (anti-microbial stewardship) this will be calculated by a dedicated panel of staff based on doses prescribed given and when and compared to the local version of the prescribing algorithm.

Intervention type

Device

Phase

Not Applicable

Drug names

Biofire "FilmArray" molecular diagnostic machine

Primary outcome measure

1. Non-inferiority in clinical cure of pneumonia at 14 days post randomisation. Cure of pneumonia defined as: absence of (i) death where the pneumonia was considered causative or at least contributory, (ii) septic shock (except when associated with a documented non-respiratory infection), or (iii) relapse of pneumonia. Relapse is defined as an infectious pulmonary event, associated with clinical and radiological signs of HAP or VAP, or a worsening of 2 points of the baseline multiple organ dysfunction score (SOFA or PELOD-2).
2. Improvement in antimicrobial stewardship at 24 h post-randomisation. Defined as: Participants on active and proportionate antimicrobial therapy within 24 h of clinical diagnosis, where active therapy is defined as receiving an antimicrobial active against the organism(s) in vitro and proportionate as defined in the prescribing algorithm specific to that site.; Timepoint(s): .

Secondary outcome measures

1. ICU length of stay – time from randomisation to discharge from ICU
2. Number of ventilator-free days over 21 days post randomisation (VAP participants only surviving 21 days post randomisation)
3. Mortality - death from any cause within 28 days of randomisation
4. Incidence of septic shock – within 21 days of randomisation.
5. Change in SOFA (ΔSOFA) score from randomisation to 7 days post-randomisation (adults)
6. Change in PELOD-2 (ΔPELOD-2) score from randomisation to 7 days post-randomisation (children)
7. Change in pSOFA (ΔpSOFA) score from randomisation to 7 days post-randomisation (children)
8. % of participants on antibiotics active/inactive against the pathogen(s) found at 24 and 72h from randomisation
9. % of participants on proportionate/disproportionate antibiotics in relation to pathogen(s) found at 24 and 72h from randomisation
10. % of participants on narrow-spectrum antimicrobials at 24 and 72 h from randomisation
11. % of participants with specific adverse events associated with antibiotics within 21 day from randomisation
12. % of participants that contract a secondary pneumonia within 21 days from randomisation
13. Total antibiotic usage in Defined Daily Dose (DDDs) at 21 days post randomisation (all conditions)
14. In patient stay related costs

Overall trial start date

01/10/2018

Overall trial end date

30/06/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. About to receive an antimicrobial to treat a suspected lower respiratory infection (LRTI – including suspected HAP/VAP) for the first time, or a change in existing antimicrobial for LRTI because of deteriorating clinical condition. This relates both to spontaneously breathing patients and those who are intubated for any reason
2. In-patients in a participating ICU/CCU
3. Hospitalised for > 48 hours
4. Sufficient volume of airway specimen obtained for routine testing at site plus 200 microlitres for the FilmArray test

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 466; UK Sample Size: 466

Participant exclusion criteria

1. Previous inclusion in work programme 3
2. Concurrent participation in the active phase (defined as within 30 days of primary end point) of an interventional trial not agreed as acceptable for co-enrolment by the local PIs of both trials. Participants will be permitted to co-enrol in studies that do not involve an intervention (e.g. observational studies).
3. Moribund and/or not expected to live more than 48 h
4. Presence of an existing directive to withhold life-sustaining treatment
5. Prisoners or young offenders currently in custody of HM Prison Service or supervised by the probation service

Recruitment start date

01/07/2019

Recruitment end date

31/03/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University College London Hospitals NHS Foundation Trust
235 Euston Road
London
NW1 2BU
United Kingdom

Trial participating centre

Fazakerley Hospital
Lower Lane
Liverpool
L9 7AL
United Kingdom

Trial participating centre

Chelsea and Westminster Hospital NHS Foundation Trust
Chelsea and Westminster Hospital 369 Fulham Road
London
SW10 9NH
United Kingdom

Trial participating centre

Russells Hall Hospital
Pensnett Road
Dudley
DY1 2HQ
United Kingdom

Trial participating centre

Great Ormond Street Hospital
Great Ormond Street
London
WC1N 3JH
United Kingdom

Trial participating centre

Guy’s Hospital
Guy’s & St Thomas’ NHS Foundation Trust Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

James Paget University Hospitals Nhs Foundation Trust
Lowestoft Road Gorleston
Great Yarmouth
NR31 6LA
United Kingdom

Trial participating centre

Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom

Trial participating centre

Royal Liverpool University Hospital
Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

Staffordshire and Stoke on Trent Partnership NHS Trust
Haywood Hospital High Lane Burslem
Stoke on Trent
ST6 7AG
United Kingdom

Trial participating centre

BUPA Cromwell Hospital
164-178 Cromwell Road
London
SW5 0TU
United Kingdom

Sponsor information

Organisation

University College London

Sponsor details

Gower Street
London
WC1E 6BT
United Kingdom
+442034475274
uclh.randd@nhs.net

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

NIHR Central Commissioning Facility (CCF); Grant Codes: RP-PG-0514-20018

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal

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

Intention to publish date

30/06/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

16/08/2019: the protocol file was uploaded (not peer-reviewed). 15/07/2019: Trial’s existence confirmed by NIHR.