ADAPT-Sepsis Trial. BiomArker-guided Duration of Antibiotic treatment in hospitalised PaTients with suspected Sepsis

The University of Manchester requires access to NHS England Data for the purpose of the following research project: BiomArker-guided Duration of Antibiotic treatment in hospitalised PaTients with suspected Sepsis: the ADAPT-Sepsis Trial.

The following is a summary of the aims of the research project provided on behalf of the University of Manchester:

A Multicentre three-arm randomised controlled trial with internal pilot, to deliver a UK-wide multi-centre randomised controlled trial to determine whether treatment protocols based on monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with suspected sepsis.

Sepsis is a condition that results from potentially serious infections. If a patient has sepsis, their body’s defence mechanisms (or ‘immune system’) may react excessively and fail. It is known that treatment using antibiotics, started as early as possible, is essential. While starting antibiotics to combat sepsis is crucial it is less clear when this treatment can safely stop. The lack of research on when to stop treatment safely may be leading to an overuse of antibiotics. Antibiotic overuse is becoming a problem because it promotes bacteria that are resistant to antibiotics (so-called antimicrobial resistance), which means that sepsis and, indeed, other infections would become difficult to treat in the future. Shorter courses of antibiotics for a patient with sepsis, may result in reducing the risk of antibiotic resistance, with fewer side effects (all medicines including antibiotics may cause side effects in some patients) and reduced costs.

Chemicals circulating in the blood can indicate the level of an infection and how effective the treatment of an infection is. These chemicals are called biomarkers. The two most well researched biomarkers in sepsis are ‘C-reactive protein’ (CRP) and ‘procalcitonin’ (PCT). They are both chemicals produced by the human body in response to infection and they can be easily measured in blood samples using NHS laboratory equipment. A number of studies around the world have shown that high levels of both CRP and PCT in the blood of patients with sepsis fall when antibiotics are given and the infection is reduced. The ADAPT-Sepsis trial hopes to determine if the duration of antibiotic treatment given to patients with sepsis can be safely reduced if these biomarkers are closely monitored every day.

The ADAPT-Sepsis trial will focus on hospitalised adults who have been commenced on intravenous antibiotics for sepsis. The inclusion criteria is:

(a) At least 18 years old;

(b) receiving intravenous antibiotics for sepsis;

(c) no more than 24 hours of systemic antibiotic treatment for present sepsis episode;

(d) likely to require intravenous antibiotics for at least 72 hours and

(e) requirement for critical care.

Main exclusions are:

(a) prolonged antimicrobial therapy mandated;

(b) severely immunocompromised;

(c) All treatment for suspected sepsis likely to be stopped within 24 hours of its initiation because of futility

(d) any patient given, or anticipated to receive an IL-6 receptor inhibitor drug (e.g. tocilizumab or sarilumab) during their acute hospital admission.

Outcomes will be assessed to 28 and 90 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; dose of antibiotics; length and level of critical care stay and length of hospital stay. 90-day all-cause mortality rates will also be collected.

Patients are expected to have been transferred and/or discharged up until the 28-day and 90-day data collection points. Informed consent has been obtained from the patient via signing the consent forms or via Personal Consultee Advice (as described below) for these data collection points (if not withdrawn before this point).

However, in many cases it is not possible to obtain prospective consent from the patient at the time of enrolment. This is due to the fact that many patients have a reduced level of consciousness due to their illness or due to sedative medications used as part of their treatment. If the patient is unable to give consent, advice will be sought from the patient’s Personal Consultee, who may be a relative, partner or close friend. This is in line with the legal requirements for obtaining consent in patients without capacity in England and Wales (Mental Capacity Act 2005). Patients, for whom an opinion is given by a Consultee, will be monitored and if they gain capacity by the time of primary hospital discharge, or by 28 days from randomisation, (whichever is earliest) they will be informed of their participation in the trial by the responsible clinician or a member of the research team and asked to provide their direct consent. If the patient does not want to continue follow-up in the study no further clinical data beyond that time-point or new samples will be collected.

The Trial team have worked with the Intensive Care Society’s Patients and Relative Committee (ICSPRC) which includes the ICU Support Teams for Ex-Patients (ICUSteps). These groups include patients and relatives who have experienced sepsis and acute hospital care, providing crucial insights for the proposed study and its acceptability for patients. Specific work includes developing a study protocol to offer participation to a wide range of hospitalised adults with sepsis across the UK; developing the Public and Patient Involvement (PPI) study plan; help with developing connectivity with relevant government advisory groups (notably the Advisory Committee on Antimicrobial Resistance & HAI). Additionally, there is public representation on the Trial Steering Committee (TSC). To ensure broader engagement, a PPI collaboration has been formed, with links to the Trial Management Group (TMG). This is a two-way process, to ensure the research team benefit from understanding public perception on sepsis and outputs are communicated effectively to the public.

Patients will be randomised to one of two intervention groups (CRP or PCT guided antibiotic duration) or a standard care (control) group. The cohort of patients in this trial will be cumulative over time as recruitment is ongoing, made up of approximately 3,000 individuals. Recruitment started in January 2018 and hopes to be completed by the end of July 2024. The trial will end when all participants have completed 90-day follow-up and the trial database is locked.

The following NHS England Data will be accessed:

Civil Registrations of Deaths will be accessed for the purpose of obtaining 90-day all-cause mortality rates and data minimisation of fields selected has been applied to ensure the only data required for the above purpose has been requested.

Historic data back to February 2018 will be required to approximately October 2024 to cover the 90 day follow-up of all participants in the trial.

The University of Manchester is the research sponsor and the Controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above. The University of Manchester will have no access to record-level NHS England data.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

The funding is provided by the National Institute for Health Research (NIHR)’s Health Technology Programme. The funding is specifically for the ADAPT-Sepsis trial described. Funding is in place until July 2024. The funder will have no ability to suppress or otherwise limit the publication of findings.

The University of Warwick is a Processor acting under the instructions of the Controller. The University of Warwick's role is limited to the outcomes analysis of the trial.

An assessment of in-trial cost effectiveness will be performed by the University of Sheffield in a Health Economic Evaluation, which would include key outcomes such as: rates of mortality; costs associated with length of stay for the index hospitalisation, including escalation of care; costs associated with readmission; and costs associated with antibiotic use. However, it should be noted that the University of Sheffield will undertake this analysis on ADAPT-Sepsis study data and will not access record-level NHS England Data as described in this Data Sharing Agreement (DSA). Therefore, the University of Sheffield is not considered a Processor in this DSA.

There will be 3 cumulative cohort uploads and 3 data drops during the lifetime of this Data Sharing Agreement, following the below method:

1. The University of Warwick will extract NHS Number, Date of Birth and Date of Consent for the cohort of study participants, and then apply a pseudonymisation ID (the study ID). The University of Warwick will split the cohort into two files; One file will have directly consented individuals; one file will have individuals recruited under consultee advice. The two files will be sent securely to NHS England via NHS England’s Secure Electronic File Transfer service (SEFT).

2. NHS England will link the two cohorts to the Civil Registration of Death dataset and extract the required data fields for the 90 day period from the Date of Consent. NHS England will apply National Data Opt-Out to the cohort of individuals who were recruited to the trial under consultee consent.

3. NHS England will then return the requested record-level Data files back to University of Warwick via SEFT. a secure electronic file transfer.

The Data will be stored on servers at the University of Warwick only.

Authorised members of the ADAPT-Sepsis Trial will process the Data for the outcomes purposes described above. Access is restricted to employees or agents of the University of Warwick and are appropriately trained in data protection and confidentiality.

The trial team will link the Civil Registration of Death dataset to an existing research dataset. This database has been pseudonymised by removing all patient identifiers, leaving only the pseudonymised study ID. The identifying details will be stored in a separate database to the linked dataset used for analysis. All outcomes analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

The Data will be accessed by authorised personnel via remote access. The Data will remain on the servers at the University of Warwick at all times.

The Controller must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

- Remote access will only be from secure locations situated within the territory of use stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this agreement) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

Remote processing will be from secure locations within England. The Data will not leave England at any time.

In accordance with NIHR open access policies the trial hopes to publish the clinical findings of the trial as well as a paper describing the cost-effectiveness in the NHS setting in high quality peer-reviewed open access (via PubMed) journals. A final report hopes to also be published in the NIHR HTA journal.

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the datasets from which the information was derived.

NICE issued guidelines for PCT monitoring of sepsis in 2015 and encouraged clinicians to enter patients into future NHS trials aimed at testing biomarker-guided antibiotic discontinuation for sepsis. The trial team have planned their trial to address NICE’s recommendations so that subsequent results hope to inform their future guidance on sepsis. The Trial team aims to inform NHS managers and commissioners if the study supports a change of practice.

A lay person’s summary, led by the PPI study group, aims to be distributed to local and national patient support and liaison groups including the Critical Care Patients and Relatives Committee and the Intensive Care Unit Support Teams for Ex-Patients. Following peer reviewed publication, appropriate key findings hope to be communicated through press releases led by the NIHR in partnership with the trial host institutions to ensure dissemination to the broader public and research participants .

The results of this study would have significant impact in three main ways:

A. Patient benefit: if the trial finds that CRP or PCT-guided protocols reduce patient exposure to antibiotics, maintain patient safety and are cost-effective it would have a major impact on the way health care providers currently manage the large number of patients with sepsis in the NHS. It would also help protect the effectiveness of currently available antibiotics for the whole population and, similarly, would help develop care standards to protect future antibiotics as they are developed.

B. Change in practice: if effective it would lead to consensus on the preferred standard of care for patients with sepsis and prompt changes to NICE guidance, with resultant change to care pathways and resource use across the NHS. However, importantly if there was no benefit, the trial would provide evidence to stop the widespread use/adoption of CRP and PCT tests for monitoring sepsis care that would be expensive and ineffective or potentially harmful to patients.

C. Future trials: demonstrating clinical and cost -effectiveness alongside safety would support extending investigations of biomarker-guided antibiotic discontinuation to other populations, most notably hospitalised children and neonates with suspects sepsis.

Yielded Benefits is not a requirement for new applications.