Has the study received HRA/REC approval?

Yes.  T4P has received a favourable outcome from the HRA and REC (ref. 22/SC/0186).  The IRAS project ID is 312405.

When is the recruitment end date?

31^st December 2025

What is the planned trial period?

60 months

What is the target sample size?

2,550 patients from 66 sites

What are the primary outcomes of the study?

90-day all-cause mortality

What are the secondary outcomes of the study?

• Mortality at discharge from critical care unit, hospital and at one year
• Survival to longest available follow-up
• Rates of major and fatal bleeds classified according to the HEME bleeding score
• Venous and arterial thromboses in hospital and to one year
• Duration of renal, advanced cardiovascular and advanced respiratory support according to UK Critical Care Minimum Data Set (CCMDS) criteria
• Length of critical care unit and acute hospital stay
• Health-related quality of life (EQ-5D-5L questionnaire at 90 days and one year)

Economic outcomes of the study

Primary cost-effectiveness outcome:

• Net monetary benefit (NMB) at 90 days

Secondary cost-effectiveness outcomes:

• NMB at one year
• Resource use and costs at 90 days and one year

What funding is available for participating sites?

The study is adopted onto the CRN Portfolio – CPMS ID 53274

Sites may be funded locally by their CRN.

Sites will also be reimbursed the following via ICNARC:

• £250 start up and first patient
• £175 per patient thereafter
• £250 close down

Will T4P be part of the NIHR Associate PI Scheme?

Yes – the T4P trial is registered with the Associate PI Scheme.

What is the required involvement of haematologists/transfusion lab managers at site?

A haematologist and/or transfusion lab manager with responsibility for transfusion should be available at each site. S/he should be aware of T4P, have an understanding of the trial design and in agreement for site participation. Once patients are recruited into the study, the haematologist/transfusion lab manager should also be made aware of the randomisation and allocated threshold. If possible, transfusion teams are then able to monitor non-adherence to the assigned platelet threshold. Haematologists and/or transfusion lab managers are encouraged to attend Site Initiation Visits to provide them with an understanding of the T4P trial.

Eligibility Criteria

What are the inclusion criteria?

1. Adult (aged ≥18 years)
2. Accepted for admission or admitted to a participating critical care unit
3. Platelet count <50x109/L
4. Planned to undergo a specified* low bleeding risk invasive procedure OR platelet transfusion being considered for an ‘other’ procedure

*Specified low bleeding risk invasive procedures include the following:

• Central venous vascular catheter insertion (including vascular access for renal replacement therapy)
• Paracentesis/superficial abdominal fluid collection drainage
• Pleural aspiration

 

‘Other’ procedures may be included if the clinician deems these to be a low bleeding risk invasive procedure and a platelet transfusion is being considered for the procedure. These include, but are not limited to, the following:

• Arterial catheter insertion
• Arterial or central venous catheter removal
• Pleural drain
• Interventional radiology (as defined by Society of Interventional Radiology guidelines)
• Bronchoscopy with or without lavage
• Wound dressing changes
• Surgical procedures where the clinical team agree risk of bleeding is low, e.g. re-look laparotomy, or wound closure

 

 What are the exclusion criteria?

1. Ongoing major haemorrhage requiring blood products and/or surgical/radiological intervention†
2. Intracranial haemorrhage within prior 72 hours†
3. Contra-indication to platelet transfusion (such as thrombotic microangiopathies; heparin-induced thrombocytopaenia; immune thrombocytopaenia; congenital platelet function defects)
4. Acute promyelocytic leukaemia (APML)
5. Advance decision refusing blood/blood component transfusions (e.g., Jehovah’s Witnesses)
6. Death perceived as imminent or admission for palliation.
7. Previously randomised into T4P
8. Fulfilled all the inclusion criteria and none of the other exclusion criteria ≥ 72 hours

†Exclusion criteria no. 1 and 2 are dynamic, and if resolved, the patient may be reconsidered for the trial.

Patients undergoing procedures not eligible for randomisation will remain available for inclusion where subsequent eligible procedures occur, provided it is not more than 72 hours after they initially fulfilled all eligibility criteria.

What exactly does exclusion criterion no. 8 “fulfilled all the inclusion criteria and none of the exclusion criteria ≥ 72 hour” mean?

Patients are no longer eligible for T4P if they initially became eligible more than 72 hours prior to randomisation.

For example, a patient may have a platelet transfusion for a low bleeding risk procedure whilst their platelet count was 50x10⁹/L, but they were not randomised before this procedure despite meeting ALL eligibility criteria.

However, although the patient was not randomised prior to this procedure, they can still be randomised within the next 72 hours, providing they still meet the eligibility criteria again (which includes needing another low bleeding risk invasive procedure) and that they are randomised immediately prior to that low bleeding risk invasive procedure.

If the patient does not require another low bleeding risk invasive procedure in the 72-hour timeframe from initially meeting eligibility, they now meet exclusion criterion no. 8 and are no longer eligible for T4P.

What if a patient initially meets an exclusion criterion but then the situation changes and they no longer meet the exclusion?

A patient can be recruited at any time during critical care admission provided they are within 72hrs of meeting all inclusion and none of the exclusion criteria and are randomised prior to the low bleeding risk invasive procedure that deemed them eligible for inclusion. 

Exclusion criteria no. 1 and 2 are dynamic (i.e. (1) Ongoing major haemorrhage requiring blood products or surgical/radiological intervention. (2) Intracranial haemorrhage within prior 72 hours). If resolved, the patient may be reconsidered for the trial.

For example, a patient may be admitted to critical care following major haemorrhage requiring interventional radiology. However, on day 2 they have stabilised, with no active bleeding, and now require a central venous catheter. Their platelet count is 45x109/L. This patient would potentially be eligible for T4P.

Eligibility / Screening / Randomisation

Who can screen and randomise patients?

• Doctors, nurses and AHPs (including research nurses/practitioners) who are appropriately trained and delegated by the PI. These staff will be listed on the Delegation and Training Logs and have GCP training.
• However, other appropriate clinical staff may be involved solely in the screening and randomisation of patients. These staff members should be provided with trial-specific training to carry out these tasks and recorded on the Training Log. These staff do not need to be on the Delegation Log or have GCP training.

In all cases there must be overall oversight by a medically qualified doctor who should confirm eligibility.

Who can confirm eligibility?

• Who can confirm eligibility - A doctor, nurse, or clinical practitioner, as long as they are appropriately qualified, and have undergone study training as documented on the training log. Must still be overall oversight by a medically qualified doctor.  
  • i.e., if the person confirming eligibility is not a doctor, they must receive agreement from the doctor responsible for the patient’s care that the patient is suitable to be entered into the trial. Document this in the medical notes. The doctor responsible for the patient’s care does not necessarily need to be trial trained.
• Note: If the doctor, nurse or clinical practitioner, is performing the eligibility/randomisation tasks ONLY, then they do not need to go on the delegation log. They can complete the training log once they have received trial training.  
• The new randomisation form contains an extra field to enter the name of the person with medical oversight. Overall, the randomisation form now captures the following information:  
  • The person who confirmed eligibility (trial trained doctor, nurse or clinical practitioner)
  • The doctor with medical oversight (doctor responsible for the patients care, does not need to be trial trained)
  • The person who randomised the patient (any trial trained staff member)
• Note: This may be all the same person, or 3 different people. If the same person is doing all 3 steps as they are a trial trained doctor, then they only need to document their name in the ‘randomised by’ and ‘signature (person randomising)’ boxes (as instructed on the randomisation form)

How long is a patient screened for?

All patients should be screened at the point of the decision to admit to a critical care unit and then for the duration of their critical care admission until recruitment, refusal, or critical care discharge. A patient can be recruited at any time during critical care admission provided they are within 72hrs of meeting all inclusion criteria and none of the exclusion criteria.

When should the patient be randomised?

Ideally, patients are randomised as soon as they become eligible for T4P (i.e they first meet all inclusion criteria and none of the exclusion criteria) as they need to be randomised prior to the low bleeding risk invasive procedure that deemed them eligible for inclusion (inclusion criterion no. 4, see eligibility section).

If a patient is not randomised prior to the initial procedure that first deemed them eligible for T4P, there is 72 hours remaining to randomise them IF they meet the eligibility criteria again within this timeframe, i.e., require another low bleeding risk invasive procedure. They should be randomised prior to the procedure.

If the patient does not meet the eligibility criteria again within the 72-hour timeframe, i.e., they don’t need another low bleeding risk invasive procedure, then they meet exclusion criterion no. 8 and are no longer eligible for T4P.

Out of hours randomisation?

Patients can be randomised out of hours by any staff who have been trained to screen and randomise and are named on the training log.  They do not need to be on the delegation log or be GCP trained.  Training materials will be provided by ICNARC on eligibility/screening and randomisation to give to staff providing out of hours cover. 

Note that, prior to randomisation, eligibility must be confirmed by a medically qualified doctor with responsibility for the care of the patient in the Critical Care Unit.

Are patients who have received antiplatelet agents prior to critical care admission included (even if these had since been discontinued)?

Yes. This is an important group to recruit since there is some evidence that giving platelets to this group of patients may be harmful. We will record antiplatelet agents prior to randomisation on the CRF.

Are patients who have received platelets prior to critical care admission included (even if these had since been discontinued)?

Yes. We will record transfusion of platelets prior to randomisation on the CRF.

Can patients be enrolled for T4P at any point during their critical care unit admission?

Once a patient is admitted to a critical care unit, they could become eligible for T4P at any point during their stay until they are discharged from critical care. 

 

Intervention

When does the intervention/allocated threshold allocation start?

This starts at the point of randomisation. The platelet transfusion should be given/not given (according to allocated threshold) for the invasive procedure that is due (i.e. the procedure that was used for assessment of eligibility).

Once a patient is recruited and then they have another procedure, do we have to strictly adhere to allocated thresholds?

For eligibility / randomising into the trial the patient does need to be having a procedure that is considered low bleeding risk and for which platelets are being considered.  For this first procedure the randomised threshold allocation must be adhered to. Once randomised (and after this first procedure) each procedure is considered individually. It should be documented in the patient’s records whether the procedure is considered low risk of bleeding or not – this will also be documented in the CRF. If it is considered to be of low bleeding risk, then the randomised threshold allocation must be adhered to.

What if a patient is having multiple procedures on critical care?

The patient would stay in their allocated threshold for the entire duration of their critical care unit stay, not just for the first procedure which made them eligible. The randomised threshold must be adhered to for subsequent invasive procedures deemed low bleeding risk for the remainder of the critical care unit stay. It should be documented in the patient’s records whether a procedure (initial and subsequent) is considered low risk of bleeding or not. Procedures deemed low bleeding risk will be documented in the CRF as well.

Use of TEG (thromboelastographic machines)

We recognise that some units routinely use TEG/ROTEM measurements to guide transfusion in stable critically ill patients, although this is not evidence-based. For the purposes of T4P, the most recent platelet count should be used, and the randomised allocated platelet threshold adhered to, as per protocol. If TEG is used to guide a platelet transfusion when the platelet count is above the allocated threshold, then this would be classed as a protocol deviation.

Consent

Who can take informed consent / opinion?

Consent (and opinion) must be sought by a GCP-trained staff member who has been delegated this duty on the trial delegation log.

Who can act as a Nominated Consultee?

A Nominated Consultee will be an appropriately qualified clinician who is independent of the trial, i.e., they are not on the T4P delegation log or training log.

Does the witness for the telephone call consent/opinion need to be GCP trained or on the delegation log?

No.

Which consent forms need to be used and when?

Scenario 1: Before randomisation if the patient has capacity to consent:

• Use the Prospective Patient Information Sheet & Prospective Informed Consent Form.

Note that the patient may not have full mental capacity for the purpose of fully informed consent for research (including reading the information sheet and completing the consent form). There also may not be time for this full procedure. A verbal conversation with the patient may be adequate at this stage to gauge verbal agreement or objection. Such conversation should be documented in the medical notes. Consent can then be followed up later (after randomisation if the patient has not objected) at a more appropriate time.

Scenario 2: Before randomisation if the patient does not have capacity to consent, and a personal consultee is present and it is appropriate to approach (i.e., it has been a few days on ICU and the situation is no longer an emergency):

• Use the Patient information leaflet - this can be used to get an immediate indication of objection. Written opinion/consent can be followed up later (after randomisation) to avoid delays in treatment.

Scenario 3: After randomisation, once the situation is no longer an emergency and the patient still does not have capacity to consent, approach a consultee for opinion:

        1) Personal Consultee:

• In-person: use the deferred Patient Information Sheet, Personal Consultee Patient Information Sheet cover sheet and the Personal Consultee opinion form
• Postal: use the deferred Patient Information Sheet, Personal Consultee Patient Information Sheet cover sheet, the Personal Consultee enrolment covering letter, and the personal consultee postal opinion form
• Telephone: use the deferred Patient Information Sheet, personal consultee Patient Information Sheet cover sheet and the personal consultee remote opinion form (Please note this method needs to be witnessed by another member of staff)

        2) Nominated Consultee:

• In-person: use the deferred Patient Information Sheet, the nominated consultee Patient information Sheet cover sheet, and the nominated consultee opinion form

Scenario 4: After randomisation, once the patient regains capacity, approach for consent:

• In-person: use the deferred Patient Information Sheet and Deferred Informed Consent Form
• Postal: use the deferred Patient Information Sheet, Patient enrolment covering letter, patient postal Informed Consent Form
• Telephone: use the deferred Patient Information Sheet, patient remote Informed Consent Form

 Consent Training Resources

• Slides can be found here
• A recording can be accessed here
• Trial Consent Guide here

Data Collection

What are the data entry requirements?

Data will be entered into an eCRF ‘MACRO’.  A CRF guidance document is provided. Optional paper worksheets may also be used, but all date will need to be transferred to MACRO.

The eCRF includes the following:

1. Randomisation
2. Baseline data
3. Daily data*
4. Platelet administration deviation form
5. Consent
6. Withdrawal of consent form
7. Outcomes
8. Survival status – 90 days and 12 months

*There are 3 pages of daily data which will be competed each day from randomisation until critical care discharge

Patient transfers

What if the patient is transferred to a Critical Care Unit in another hospital?

Treatment allocation:

Please inform the receiving clinical and research teams (at the receiving site) that the patient has been recruited into the T4P trial and to which platelet threshold they were allocated.

If the receiving hospital is another T4P site:

Treatment:
The aim is for the allocated treatment to be continued if possible, however this is not mandated.

Consent:
The research team at the initial site & receiving site should communicate the progress of the consent process – which may be continued by research staff at the receiving site with the consultee/patient. This should be documented in the patient’s medical records and communicated to the randomising site for eCRF completion. It is the responsibility of the randomising site to ensure the consent process is completed.

Data collection: 
The eCRF (MACRO) can be transferred to the receiving site as they are participating in T4P. The randomising site must ensure data collection is up to date on the eCRF to enable the transfer.  

If the receiving site is not a T4P site:

Treatment:
The site can consider whether they will continue the allocated treatment: treatment & adherence data will not be collected.

Consent:
The initial, randomising, site is responsible for continuing the consent process.

Data collection:
The eCRF (macro) will not be transferred to another site.

It is the responsibility of the randomising site to complete data collection – however, daily data while the patient is at the new (receiving) site will not be required. Consent and Outcome data CRFs will be required.

This will require communication between sites for information (e.g., dates of transfer / discharge).

If the patient is transferred back to the original critical care unit (i.e., the randomising site):

Continue with the allocated treatment threshold, provided:

• this is within the same hospital admission period (i.e., the patient has not been discharged home and then re-admitted)
• within 90 days of randomisation

If the patient is transferred to a ward and then readmitted to critical care (at the randomising site):

Continue with the allocated treatment threshold, provided:

• this is within the same hospital admission period (i.e., the patient has not been discharged home and then re-admitted)
• within 90 days of randomisation