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Frequently Asked Questions

Key FAQ's

Contracting

Site set up

Screening

Eligibility

Consent

Randomisation

Co-enrolment

Data Collection

IMP management

Blood samples

Safety Reporting

COVID-19


Key FAQ's

What is the need for the trial?

Septic shock is a life-threatening condition caused by severe infection. For reasons still poorly understood, in some patients, the inflammation in their system doesn’t reduce after an infection. Instead of fighting the infection, an ongoing inflammatory state results in widespread injury to the body and failure of normal functioning of the body’s vital organs, such as the lungs, heart, brain and kidneys. A common indicator of septic shock is a very low blood pressure that does not improve. In 2013, a doctor called Morelli showed that when patients were being treated with a very high dose of noradrenaline, were also given a beta blocker (a type of drug that reduces the heart rate), patients on average got better more often, more quickly. We propose to repeat their study in multiple (approx. 45) intensive care units throughout the UK to see if we can confirm the safety and benefits of using beta blockers. By targeting patients with spontaneous persisting tachycardia and vasopressor requirement, the study group is a particular at-risk cohort. It is crucial to discover if the safety and efficacy Morelli described can be reproduced in a prospective randomised multicentre study in which mechanisms of action can also be explored.

Site activation process?

The following is required to activate a site:

  • R&D Capacity and Capability confirmation
  • Site Agreement signed by all parties
  • Attendance at SIV training
  • CV and GCP training for PI as a minimum
  • Signed Delegation Log and Training Log
  • Pharmacy confirmation of IMP storage and oversight
  • Lab Accreditation Certificate and letter confirmation from UKAS

After receiving these documents Warwick CTU will:

  • Order 80 IMP vials for delivery to pharmacy site
  • Once IMP delivery confirmed by pharmacy site, SIV and greenlight activation letter will be issued to site to open them to recruitment
  • Issue database log in and IVR PIN number for randomisation to site

Site recruitment target?

1 patient every 3 months.

Can we participate in the trial if we have concerns regarding capacity due to COVID-19?

Yes. We understand the current ongoing capacity challenges due to COVID-19 and will we assess this with you on an ongoing basis as and when required if this affects your regular ability to screen and recruit to STRESS-L.

Equipoise?

The clinical team must be willing to manage atrial fibrillation with correction of potassium, magnesium and amiodarone in the control group as the use of beta-blockers in these patients would risk making the trial results uninterpretable.

IMP training?

Landiolol is supplied as a power in vials with a nominal filling volume of 50ml containing 300mg landiolol hydrochloride and inactive ingredients Mannitol E421 and Sodium Hydroxide (for pH adjustment). It can be reconstituted using solution as per normal local practice

The trial is pragmatic and allows for bedside nurses and clinicians trained on the IMP infusion protocol to reconstitute and administer the IMP without GCP training or being listed on the trial delegation log. The research team should always have oversight and ensure local training where required is carried out.

Is IMP temperature monitoring required?

Yes, the IMP must be stored between 2-4 °C using a calibrated thermometer as per MHRA requirements. IMP must be stored on ICU and pharmacy. If a dedicated IMP fridge on ICU is not available the IMP can be stored in a general ICU fridge as long as it is stored on a dedicated shelf and clearly labelled for IMP use only within a restricted access area.

How is IMP supplied?

Warwick CTU trial team are responsible for ordering IMP stock to be delivered to site pharmacy departments to reduce the burden on sites and help monitor stock levels. IMP is delivered to sites by Mawdsleys.

Are blood samples required?

Yes, blood samples are taken for every patient on Days 0, 1, 2, 4, 6 and End of Noradrenaline Treatment Visit (when noradrenaline has stopped for more than 12 hours). Blood samples are not required once a patient has stopped Landiolol treatment and noradrenaline. Mandatory blood samples must be processed immediately after being taken therefore, some weekend work will be required although this will be minimal due to the low recruitment target of 1 patient every 3 months.

Are COVID-19 patients included?

Yes, but blood samples should not be taken for these patients.


Contracting

Do you require wet ink signature?

The site must wet ink sign the agreement however, a scanned signed PDF copy is acceptable to sponsor and a copy does not need to be posted.

What funding is provided to sites?

Payments to sites are as follows;

  • £800 pharmacy set up, maintenance and close down fee issued upon greenlight
  • £500 per patient recruitment and follow up fee
  • £7.53 per participant – drug accountability per patient
  • £12.54 per participant – drug dispensing per patient

Site set up

What is the site activation process?

The following is required to activate a site:

  • R&D Capacity and Capability confirmation
  • Site Agreement signed by all parties
  • Attendance at SIV training
  • CV and GCP training for PI as a minimum
  • Signed Delegation Log and Training Log
  • Pharmacy confirmation of IMP storage and oversight
  • Lab Accreditation Certificate and letter confirmation from UKAS

After receiving these documents Warwick CTU will:

  • Order 80 IMP vials for delivery to pharmacy site
  • Once IMP delivery confirmed by pharmacy site, SIV and greenlight activation letter will be issued to site to open them to recruitment
  • Issue database log in and IVR PIN number for randomisation to site

Is a dedicated IMP fridge required to store Landiolol?

IMP must be stored at 2-8°C on ICU and pharmacy. If a dedicated IMP fridge on ICU is not available the IMP can be stored in a general ICU fridge as long as it is stored on a dedicated shelf and clearly labelled for IMP use only within a restricted access area.

What are the training requirements?

The site team must undergo SIV training with the Warwick CTU trial team prior to being provided the greenlight to recruitment. Any new members of staff joining the site team whilst the site is open can be locally trained by site staff on the protocol and database. Warwick CTU trial team can facilitate further training if required.

As a minimum a copy of the PI’s CV and GCP will be required prior to issuing the greenlight to open a site to recruitment. All site trial staff must be listed on the delegation log and investigator training log and will be required to have a CV and GCP certificate on file. An exemption to this is any medically qualified physician who is responsible for only overseeing the clinical care of a trial patient, prescribing the IMP or confirming eligibility who is not required to have GCP training.

What training materials and aide memoirs are available?

Click here to see our full list.

Are electronic signatures acceptable on delegation logs?

Yes. Electronic signatures of site staff and the PI is acceptable as long as the PI sends email confirmation to confirm the site staff member added has been delegated the relevant responsibility codes alongside the date the site staff member joined the trial.

Can we participate in the trial if we have concerns regarding capacity due to COVID-19?

Yes. We understand the current ongoing capacity challenges due to COVID-19 and will we assess this with you on an ongoing basis as and when required if this affects your regular ability to screen and recruit to STRESS-L.

How are SIV’s being conducted?

SIV’s are being conducted by the Warwick CTU trial team and Chief Investigator remotely via online video conferencing.

Are extra consumables being provided?

All blood sampling consumables are provided alongside IMP supply.


Screening

What screening information is required for the trial?

Only septic shock patients receiving noradrenaline for >24hours will be screened and added to a screening log for the trial.

Septic Shock diagnosis (as per Sepsis-3 criteria): SEPSIS + Noradr (for Mean BP=65) + Lactate >=2
Sepsis diagnosis: Infection (known or suspected) + antibiotics + SOFA score change >=2 – do not add to screening log.

Is there a specific timescale from identification of patient/meeting eligibility criteria to randomisation?

Once the patient has met the 24 hour vasopressor therapy eligibility window for randomisation, there is a 48 hour window for randomisation as the patient must not exceed 72 hours of vasopressor therapy. Due to this short window, informed consent may be sought during the first 24 hours of vasopressor therapy. It will be made clear to the patient or their legal representative that if they no longer meet the eligibility criteria after the 24 hour mark the participant will not be randomised into the trial.


Eligibility

Are COVID-19 patients eligible for STRESS-L?

Yes. COVID-19 patients are eligible for the trial but blood samples should not be taken for these patients to reduce risk of viral transmission.

Does the 24 hour vasoporessor therapy inclusion criteria refer to any vasopressor?

Yes. This includes any vasoporessor therapy (including metaraminol) and is not just limited to noradrenaline. However, the patient must be received noradrenaline at a rate of >0.1mcg/kg/min at the time of randomisation.

If the patient starts and restarts noradrenaline or another vasopressor therapy, when does the 24 hour window clock begin?

If vasopressor therapy:

  • Stops and restarts for less than 12 hours – 24 hour window begins at start of initial vasopressor treatment
  • Stops and restarts after 72 hours – 24 hour window begins at start of second vasopressor treatment
  • Stops and restarts after 12 hours but before 72 hours – contact trial team to confirm eligibility
  • Vasopressor does not stop and is continuous for >72 hours – Patient is not eligible

Does the patient need to be tachycardic for the whole of the 24 hours?

  1. It is only necessary that the patient is tachycardic at the time of randomisation and it the cause of the tachycardia must be sepsis driven.

Is a patient eligible if they have already been receiving a beta blocker?

Yes, if a patient is on a beta blocker for a pre-existing condition they can still be eligible for the trial, and the beta blocker can be continued (as per clinician discretion), unless the beta blocker has been prescribed for Atrial Fibrillation, in which case the beta blocker would need to be switched to Amiodarone, Magnesium or potassium as per the protocol.

Can we recruit patients from level 2 and level 3 care?

Yes ITU and HDU patients can be recruited.

Who can sign the eligibility form?

The eligibility form must be signed by a medically qualified physician listed on the delegation log as per MHRA guidance for CTIMPs. A research nurse should not sign the eligibility form.

Can patients with Atrial Fibrillation be included?

Yes. Although we believe Landiolol therapy may prevent Atrial Fibrillation (AF), there is nothing in the protocol to exclude patients already in AF. This also includes AF from all sources whether Acute (as a result of the present Septic Shock episode) or chronically (as a result of old age, ischaemic heart disease or any other co-morbidity).


Consent

Is there a timeframe for receiving consent after patient is identified?

Yes. Due to the short eligibility timeframe window, informed consent may be sought during the first 24 hours of vasopressor therapy. It will be made clear to the patient or their legal representative that if they no longer meet the eligibility criteria after the 24 hour mark the participant will not be randomised into the trial.

Are research nurses able to consent or does it have to be a doctor?

As long as your NHS trust allows research nurses to take consent for CTIMPs we have no objection.

If a patient has COVID-19 should written informed consent be obtained?

No. If there are concerns regarding the risk of viral transmission due to COVID-19 verbal informed consent can be obtained from the relative. An impartial witness must be present alongside the investigator obtaining verbal consent. The impartial witness and investigator will both sign the consent form and a copy will be given to the patient. The patient will not be required to sign. This process will be clearly documented in the patient’s medical records.

If a patient lacks capacity, can a personal legal representative provide verbal consent over telephone?

Yes. Due to current COVID-19 visitation restrictions, the personal legal representative will be contacted by telephone or videoconference facilities and provided with information about the trial. An impartial witness must be present alongside the investigator obtaining verbal consent during the telephone call. The impartial witness and investigator will both sign the consent form and a copy will be posted to the personal legal representative. The personal legal representative will not be required to return a signed copy. This process will be clearly documented in the patient’s medical records.

Who should act as a Professional Legal Representative?

A Professional Legal Presentative must be a registered medical qualified physician, independent to the trial (not listed on delegation log) and is willing to be consulted.

What is the definition of an impartial witness?

An impartial witness is a person, who is independent of the study and who cannot be unfairly influenced by people involved with the study. Therefore, they must not be listed on the trial delegation or investigator training log. Examples of an impartial witness include non-research bedside nurses and clinicians.

If an impartial witness is not available when consent is required from a Personal Legal Representative, can consent be initially sought from a Professional Legal Representative?

If an impartial witness cannot be identified at the time of consent you can initially obtain consent using a Professional Legal Representative instead and ensure this is communicated to the relative. Thereafter, when an impartial witness is available, you should seek verbal consent from the Personal Legal Representative. This consent process and justification for this must be clearly documented in the patient’s medical records

To reduce risk of viral transmission due to COVID-19 we are using an app to upload a photo of the signed consent form that we print off and place a copy of in the Investigator Site File. Is this acceptable for STRESS-L?

Yes, as long as the NHS Trust are happy this information is secure in transmission and storage to the app, the trial team do not object to printed copies of the consent forms in site files.


Randomisation

How are patients randomised in to the study?

A 24/7 automated telephone interactive voice response (IVR) line is dialled to randomise a patient to the trial. Each site staff member will be provided with an individual IVR pin number to input prior to randomising a patient. Following randomisation, the patient will automatically appear in the trial database.


Co-enrolment

Can patients be enrolled into other COVID-19 trials?

Yes. The STRESS-L trial team are currently reviewing the possibility of co-enrolment with other COVID-19 trials. Currently approval is in place for the RECOVERY-RS trial.

A full list of all co-enrolment trials can be found on the trial website, which is regularly updated: https://warwick.ac.uk/fac/sci/med/research/ctu/trials/stressl/health/coenrolment/


Data Collection

Should data for all daily data forms be collected until day 14?

Daily data forms should be completed until day 14 unless the patient is discharged from ICU or the patient dies. Only cardiovascular data (Heart Rate, MAP, AF, Inotrope doses) is collected hourly until day 2 and then 6 hourly up until day 14. Data can be entered retrospectively.

When does Day 0 and Day 1 begin?

Day 0 refers to 24 hours prior to randomisation up until the point of randomisation. Day 1 starts at the time of randomisation up until 24 hours after randomisation. All subsequent days following this pattern. Please do not use calendar days.

What should be captured in the Fluids in and out CRF?

Total Fluids IN:
ORAL (ml): Includes anything the patient receives via the mouth and/or has a calorific value. This includes enteral feeding, NG feed, water etc.
CRYSTALLOID: Includes all IV drugs whether or not diluted with crystalloid, TPN etc.
COLLOID: Includes all colloids and blood products

Total Fluids OUT:
URINE: Includes urine, drains, NG aspirates, blood loss during surgery etc.
CVVHF Balance: Balances from the 24 hour CVVH

What is the definition of the End of Noradrenaline Treatment visit (EONT)?

Once the patient has been off Noradrenaline for 12 hours the EONT is completed on the e-CRF and a blood sample is taken. If EONT falls on a blood sample day i.e. day 0, 1, 2, 4 or 6, an additional sample is NOT required.


IMP Management

Can you clarify the 1 week rule in regards to temperature excursions up to 25°C?

Temperature excursions that do not exceed 25.4°C for a maximum duration of 1 week are NOT reportable to AOP. The 1 week clock starts when the temperature exceeds 8.4°C and stops when the temperature returns to 2-8.4°C. Therefore, if multiple temperature excursions occur within a 1 week period but individually each temperature excursion does not exceed 1 week these are NOT reportable to AOP and you can continue using the IMP stock.

Stability data has confirmed temperature excursions up to 25.4°C for less than 1 week do not pose any negative impact on the project quality or safety; therefore, the IMP can continue to be used.

PLEASE NOTE: Although Appendix 1 states up to 25°C, rounding rules apply; therefore, temperature excursions between 25.1 – 25.4 are rounded down to 25°C.

If the patient’s heart rate fall is <80 bpm but the patient is receiving noradrenaline, should the Landiolol Infusion continue?

  1. If the patient’s heart rate falls below 80 bpm, the Landiolol Infusion should be reduced in a step wise fashion by 1.0 mcg/kg/min to achieve the target heart rate or weaned off if the target heart rate cannot be achieved regardless of if the patient’s noadrenaline treatment is ongoing.

When should the Landiolol be weaned and stopped?

Once all vasopressor agents have been stopped for 12 hours, and the patient is consistently within the target heart rate range, the Landiolol should be weaned.

What happens to the Landiolol if the noadrenaline has been discontinued for <12 hours?

The Landiolol dose should continue and be adjusted accordingly to maintain the target heart rate of 80-94bpm as per the Landiolol Infusion Protocol.

What happens to the Landiolol if the noradrenaline has been discontinued for >12 hours?

If the patient is no longer tachycardic and is persistently within the target heart rate range of 80-94bpm, Landilol should begin to be weaned down by 1.0mcg/kg/min. If the patient remains tachycardic (>94bpm) the Landiolol infusion should continue to be increased as per protocol. The Landiolol infusion can be stopped and restarted at any time if EONT has occurred and the Landiolol has only been stopped for <12 hours.

Once EONT has occurred AND landiolol has been stopped for >12hours, Landiolol should not be restarted.

If the patient is still on Landiolol at Day 14 when should it be stopped?

The Landiolol should be begin to be weaned at the end of Day 14 and eventually stopped.

Can bedside ICU staff administer IMP?

Yes. The trial is pragmatic and allows for bedside nurses and clinicians trained on the IMP infusion protocol to reconstitute and administer the IMP without GCP training or being listed on the trial delegation log. The research team should always have oversight and ensure local training where required is carried out. A clear handover before the weekend and night shifts should take place between the research team and bedside staff to prevent protocol non-compliances and protect patient safety.

Who supplies the IMP?

Pharmacy will be responsible for letting Warwick CTU trial team know when you require re-supply, as they will be holding the 2 back up boxes. Each time a box is released, please keep us updated by emailing: stress-l@warwick.ac.uk . The research nurses will also take responsibility for this by informing us if a patient is on max dose as they are a heavy patient however, pharmacy will also be responsible for informing us if your stock levels are running low.


Blood samples

Can bloods be taken by staff nurses at weekend and left for processing on Monday?

No - these blood samples are mandatory and it is expected that a member of the research team or a co-investigator will have to come in on the weekend to process the samples. Only minimal weekend work will be required over the duration of the trial.

Are you providing consumables for taking blood samples?

Yes – please see ‘site activation process’ section.

What are the timelines for the bloods – how long plus or minus the infusion time do we have to take the bloods?

Day 0 bloods must be taken as close as possible to the time of randomisation and prior to the administration of Landiolol. Day 1 starts as soon as you randomise. We haven’t specified when the bloods have to be taken on each sampling day, as long as they are taken on days 0, 1, 2, 4, 6 and end of noradrenaline treatment. If a patient is randomised in the evening or the middle of the night you can take bloods the following day.


Safety Reporting

What events are exempt from reporting?

The following events are exempt from adverse event reporting AND serious adverse events as well as SUSAR’s and SAR’s UNLESS the investigator deems the event to be related to the administration of the study drug:

  • Death Related to sepsis
  • Cardiovascular failure, including the need for vasopressors / inotropes
  • Respiratory failure, including mechanical ventilation and acute lung injury
  • Hepatic impairment as measured by Transaminases <1000 IU/L
  • Renal failure, including the need for renal replacement therapy
  • Haematological / Coagulation failure, including thrombocytopaenia and disseminated intravascular coagulopathy
  • Delirium / confusion

COVID-19

Are COVID-19 patients eligible for STRESS-L?

Yes. COVID-19 patients are eligible for the trial but blood samples should not be taken for these patients to reduce risk of viral transmission.

If there is a delay in receiving a test result to confirm the patient is COVID-19 positive, should the patient be randomised?

Yes. This patient should be randomised to the trial however; blood samples should not be taken as they have suspected COVID-19. We do not expect this to occur often, as by the time the patient is eligible for randomisation in to the STRESS-L the clinical status of the patient should be known. If the patient is not suspected or has received a negative test result for COVID-19, blood samples must be taken for these patients.

Will evidence of a COVID-19 test be required for the trial?

A: Confirmation of a COVID-19 –ve (negative) test will be required when shipping blood samples from site to sponsor. A column has been added to the Blood Sample Transport Form that you must initial to confirm a –ve swab was received. Written evidence of the COVID-19 test result is not required. Please note: This is not required for any blood samples taken pre COVID.