TRAITS Programme: Precision medicine trials for adults treated in critical care units

ISRCTN	ISRCTN82395639
DOI	https://doi.org/10.1186/ISRCTN82395639
IRAS number	1006975
Secondary identifying numbers	AC22166, IRAS 1006975, CPMS 58664

Submission date: 09/02/2023
Registration date: 20/09/2023
Last edited: 12/12/2024

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
The treatment of critically ill patients represents a significant healthcare burden. Outside of pandemics, almost 1 in 5 patients admitted to ICUs in Scotland die during their hospital stay, and even among survivors to hospital discharge we have shown a 5-year mortality of 23% among ICU survivors. Importantly, patients surviving critical illness have a high prevalence of multimorbidity, and more have socioeconomic deprivation compared to the general Scottish population.
Precision Medicine (PM) refers to treatments that take individual variability into account and matches treatment to individual’s illness features. PM is growing in use in cancer care, providing precise treatments for patients based on their genetics. Currently it isn’t used in ICU because patients because, unlike cancer patients, they have a rapidly changing illness state. The TRAITS programme aims to enable time-critical precision medicine (TCPM) to be used in critically ill patients.

Who can participate?
Patients aged 16 years or older, receiving organ support in a critical care setting, and resident in Scotland.

What does the study involve?
• We will use routinely collected clinical data to enable efficient design, including linking clinical data from participants to collect trial defined outcomes
• We will collect blood samples to enable identification of treatable trait, changes following treatments and to help identify novel targets for future trials.
• We will run a Scotland-wide platform Randomised Controlled Drug Trial (RCT). Patients will be allocated to usual care only or to a trait linked trial treatment plus usual care.
The RCT will run multiple protocols at the same time, called Trait Specific Protocols (TSPs), which can investigate multiple treatments against pre-defined traits. Our trial design is adaptive which means we can identify new traits, introduce new treatments, and answer questions such as benefit, futility or harm as soon as sufficient data have accrued.
In summary, our clinical trial aims to enable time-critical precision medicine for critically ill patients in Scotland and inform such approaches globally.

TRAITS has 2 stages; (1) the platform and (2) the Trait Specific Protocol (TSP)
The platform requires one blood sample to be taken which will be used to identify a trait. Some baseline data will be collected from medical notes.
In the TSP, participants will be randomised to either IMP and usual care, or usual care.

What are the possible benefits and risks of participating?
Benefits:
Not provided at time of registration
Risks:
Bloods are routinely taken from ICU patients and this is always done by experienced members of the clinical team who are trained to do this. The risk for the platform are therefore very low.
If participants are randomised to receive IMP possible side effects represent a risk to participants and these are listed within the PIL but also discussed as part of the consent discussion. The side effects have been listed as common, rare etc. to help participants interpret this information.

Where is the study run from?
University of Edinburgh and NHS Lothian (ACCORD) (UK)

When is the study starting and how long is it expected to run for?
February 2023 to May 2027

Who is funding the study?
Chief Scientist Office (UK)

Who is the main contact?
Fiona Wee, Senior trial Manager, TRAITS@ed.ac.uk
Professor Manu Shankar-Hari, manu.shankar-hari@ed.ac.uk

Study website

Contact information

Prof Manu Shankar-Hari
Scientific, Principal Investigator

Institute for Regeneration and Repair, Level 2
The University of Edinburgh
Edinburgh BioQuarter
5 Little France Drive
Edinburgh
Edinburgh
EH16 4UU
United Kingdom

Email	manu.shankar-hari@ed.ac.uk

Ms Fiona Wee
Public

Senior Trial Manager
Institute for Regeneration and Repair, Level 2
The University of Edinburgh
Edinburgh BioQuarter
5 Little France Drive
Edinburgh
EH16 4UU
United Kingdom

Email	TRAITS@ed.ac.uk

Study information

Study design	Interventional parallel group randomized controlled trial
Primary study design	Interventional
Secondary study design	Randomised parallel trial
Study setting(s)	Hospital
Study type	Treatment
Scientific title	Evaluation of interventions linked to treatable traits in acute critical illness in adults to enable precision medicine: Data enabled Bayesian adaptive platform randomised clinical trial with embedded biological characterisation (TRAITS Trial)
Study acronym	TRAITS
Study objectives	Primary objective: To evaluate the efficacy of experimental treatments in critically ill adult patients meeting eligibility criteria for a specific treatable trait, compared with usual care, on trial primary outcome of OSFD-21. Secondary objective: To evaluate the efficacy of experimental treatments in critically ill adult patients meeting eligibility criteria for a specific treatable trait, compared with usual care, on pre-specified secondary outcomes.
Ethics approval(s)	Approved 11/09/2023, Scotland A Research Ethics Committee (South East Scotland Research Ethics Service, 2nd Floor Waverley Gate, 2-4 Waterloo Place, Edinburgh, EH1 3EG, United Kingdom; +44 7814609032; sesres@nhslothian.scot.nhs.uk), ref: 23/SS/0031
Health condition(s) or problem(s) studied	Critical illness
Intervention	This is a platform trial with multiple arms running within the protocol appendices called Trait Specific Protocols (TSPs). Each TSP recruits different sub set of TRAITS participants and randomises to different interventions. 1. LYMP-RESP TSP. Participants randomised to either Budesonide (1 mg every 12 h for 7 days) and usual care, OR baricitinib (4 mg per day for up to 14 days) and usual care OR usual care 2. ENDO-SHOCK TSP. Participants randomised to either imatinib (800-mg loading dose followed by 400 mg once daily for 9 days) and usual care or usual care.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase IV
Drug / device / biological / vaccine name(s)	Budesonide, baricitinib, imatinib
Primary outcome measure	1. For the overall trial (i.e., referred to as stage-2 evaluation of interventions within each trait), the primary endpoint is number of Organ Support Free Days (OSFD) during the first 21 days from randomisation. This will apply to all treatable traits. Where the participant dies within the first 21 days, the OSFD primary endpoint will be assigned a value of minus 1. 2. For the intermediate adaptive analyses (i.e., stage-1 evaluations of interventions within each treatable trait), the intermediate endpoint will be specific for each treatable trait, and therefore highlighted in trait specific protocols.
Secondary outcome measures	Secondary endpoints are those included in the core-outcome set for mechanical ventilation measured using patient records, including: 1. Mortality at different time-points 2. Organ support free days in ICU 3. Days alive outside the hospital (hospital-free days) at 180 days of randomisation This will apply to all treatable traits. Additional secondary outcomes may be included in trait-specific protocols.
Overall study start date	06/02/2023
Completion date	01/05/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	2,000
Key inclusion criteria	Platform inclusion 1. Aged ≥18 years 2. Provision of consent (including deferred consent in accordance with Section 5.2) 3. Receiving organ support in a critical care setting 4. Organ dysfunction of at least one organ (SOFA Score>=2) 5. In clinical team’s opinion is likely to require organ support* for ≥24 h post randomisation 6. Resident in Scotland (required for ongoing data linkage) *Organ support is defined as treatments provided in the critical care units to support one or more of the organ systems, as per the critical care minimum dataset (please see link: https://www.datadictionary.nhs.uk/attributes/organ_system_supported.html). Respiratory support refers to provision of invasive or non-invasive mechanical ventilation, including high-flow nasal cannula with a flow rate ≥30 L per minute and fractional inspired oxygen concentration ≥30%). Cardiovascular support refers to infusion of vasopressor or inotropes. Renal support refers to provision of renal replacement therapy. Appendix 1: LYMP-RESP TSP inclusion 1. Provision of consent 2. Respiratory dysfunction is defined as PaO2/FiO2 ratio <40 KPa whilst receiving respiratory support with either non-invasive ventilation (including high flow nasal cannula) or invasive mechanical ventilation for 6 hours or longer. Arterial blood gas samples taken within 3 hours of trait eligibility assessment can be used to determine the PaO2/FiO2 criteria. 3. Lymphopenia defined as lymphocyte count <1.2 x 10(9)/L. The lymphocyte count measurements from blood samples done as part of routine clinical care, +/- 36 h of critical care admission could be used. The time window of +/- 36 h reflects the current routine clinical ordering of full blood counts. Appendix 2: ENDO-SHOCK TSP inclusion 1. Provision of consent 2. Presence of shock: defined as hypotension requiring vasopressor therapy to maintain mean blood pressure 65 mm Hg or greater (equates to cardiovascular SOFA score of 2 or more) and having a blood lactate level greater than 2 mmol/L after adequate initial fluid resuscitation. The term adequate is a clinical judgement. The term initial fluid resuscitation refers to the first set of fluid administration in patients presenting with shock, and acknowledges the fact that resuscitation is an ongoing process. The lactate measurement done as part of routine clinical care using either arterial or venous blood gas, around the time of resuscitation could be used. 3. Evidence of inflammation: defined as C-reactive protein (CRP) 50 mg/L or more OR neutrophil count >=12 x 10(9)/L. The CRP levels and neutrophil count measurements from blood samples done as part of routine clinical care, around the time of trait eligibility assessment (+/- 36 h window) could be used. The time window of +/- 36 h reflects the current routine clinical care.
Key exclusion criteria	Platform exclusion 1. In the Investigator’s opinion, the participant is unwilling or unable to comply with the trial intervention and/or procedures 2. Patients was admitted to ICU more than 48 h ago 3. Primary neurological ICU diagnosis 4. Neuromuscular disease and long-term home ventilation 5. Organ transplantation within 90 days 6. Patient not expected to survive 24 hours by the clinician responsible for clinical care 7. Decision to provide only palliative or end-of-life care 8. Prisoners 9. Previous randomisation on the TRAITS trial 10. Individuals with permanent incapacity 11. Known or suspected pregnancy [Note: pregnancy test result is not required for women of childbearing potential (WOCBP) when assessing platform eligibility] 12. Breast feeding Appendix 1: LYMP-RESP TSP exclusion Generic 1. Known hypersensitivity to study products or any of its excipients (excipients listed in section 6.1 of the representative SmPC) 2. More than 48 h has elapsed since ICU admission. 3. Patient is known to be pregnant. (A pregnancy test in females with childbearing potential (aged 15-55 years) will be performed prior to enrolment and patients who are pregnant will be excluded. 4. Breastfeeding Intervention-specific exclusion criteria - Budesonide 5. Patient is already receiving, or a clinical decision has been made to commence inhaled or intravenous corticosteroids Intervention-specific exclusion criteria – Baricitinib 6. Patients with active TB 7. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product. Diagnosis of sepsis is not a contraindication, given that COVID-19 patients will meet the sepsis case definition. 8. Have received any live vaccine within 4 weeks before screening 9. Alanine aminotransferase (ALT) or an aspartate aminotransferase (AST) > 5 times the upper limit of the normal range 10. Estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m², immediate need for hemodialysis or hemofiltration; 11. In the opinion of the investigator, unlikely to survive for at least 48 h after screening. 12. Have neutropenia (absolute neutrophil count <1x10(9) cells/L) 13. Have severe lymphopenia (absolute lymphocyte count <0.20x10(9) cells/L) Appendix 2: ENDO-SHOCK TSP exclusion Generic 1. Known hypersensitivity to imatinib or any of its excipients (excipients are listed in section 6.1 of the representative Summary Product of Characteristics (SmPC), 2. More than 48 h has elapsed since ICU admission. 3. Patient is known to be pregnant. (A pregnancy test in females with childbearing potential (aged 15-55 years) will be performed prior to enrolment and patients who are pregnant will be excluded. 4. Breastfeeding Intervention-specific exclusion criteria – Imatinib 5. Patient is already receiving, or a clinical decision has been made to commence imatinib or another tyrosine kinase inhibitor targeting the same pathway as imatinib (i.e. dasatinib, nilotinib, ponatinib) 6. Patient was receiving imatinib or another tyrosine kinase inhibitor targeting the same pathway as imatinib (i.e dasatinib, nilotinib, ponatinib) prior to this hospital admission 7. The treating clinician believes that participation in the domain would not be in the best interests of the patient 8. Severe liver disease or alanine aminotransferase (ALT) or an aspartate aminotransferase (AST) that is more than five times the upper limit of normal or bilirubin more than three times the upper limit of normal 9. Pancytopenia at admission defined as simultaneous presence of lower-than-normal number of red blood cells (haemoglobin less than 135 in men, 125 in women) white blood cells (total counts less than 4 and platelets counts less than 150 in the blood, assessed using a routine blood test. 10. Patients with absolute neutrophil count is less than 1.0x10(9)/l 11. Patients with platelet counts less than 50x10(9)/l 12. Active gastrointestinal bleeding at admission 13. Receiving immune suppressive therapy with a calcineurin inhibitor (e.g. cyclosporine, tacrolimus, everolimus or sirolimus) will exclude a patient from receiving enteral imatinib 14. Patients with long-standing dermatological conditions requiring systemic immunosuppressive medications such as psoriasis, and eczema 15. Patients with known hepatitis B disease 16. Patients on the following drugs: rifampicin, phenytoin, carbamazepine, and dexamethasone.
Date of first enrolment	27/11/2023
Date of final enrolment	31/03/2027

Locations

Countries of recruitment

Scotland
United Kingdom

Study participating centre

TRAITS Trial Office

Centre for Inflammation Research (CIR)
The Queen’s Medical Research Institute (QMRI)
Edinburgh BioQuarter
The University of Edinburgh
Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom

Sponsor information

Accord (United Kingdom)
University/education

University of Edinburgh and NHS Lothian (ACCORD)
Usher Building
The University of Edinburgh
5-7 Little France Road
Edinburgh BioQuarter – Gate 3
Edinburgh
EH16 4UX
Scotland
United Kingdom

Email	paul.dearie@ed.ac.uk
Website	http://www.ed.ac.uk/home
"ROR"	https://ror.org/01x6s1m65

Funders

Funder type

Government

Chief Scientist Office
Government organisation / Local government

Alternative name(s): CSO
Location: United Kingdom

Results and Publications

Intention to publish date	01/05/2026
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Peer reviewed scientific journals Conference presentation Publication on website Submission to regulatory authorities Any decision to share study data will be discussed and agreed between the study team (grant co-applicants). If sharing of data is deemed appropriate, we will share only anonymised data. The participant information leaflet (PIL) explains to patients that we would like to retain trial data after the trial has ended and so that it can be used in future research studies. Participants have to explicitly agree to this on the consent form (Yes/No) option. If participants do not agree to us retaining their data this will be recorded within the database thereby ensuring their data is removed from any future exports to external research groups.
IPD sharing plan	The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request from TRAITS@ed.ac.uk

Editorial Notes

12/12/2024: The sponsor was changed from 1. The University of Edinburgh and 2. ACCORD to the University of Edinburgh and NHS Lothian (ACCORD). The study contacts were updated.
08/11/2023: The recruitment start date was changed from 01/11/2023 to 27/11/2023.
04/10/2023: Internal review.
09/02/2023: Trial's existence confirmed by NHS HRA.