Frequently Asked Questions
General
We would like sites to participate in all three arms. If they cannot, there is an option to participate in trials 1 and 2 together, or trial 3 alone. Please discuss with the SepTiC trial team first.
Yes, the patient is still eligible, antibiotics that are pre- existing and used to chronic problems / infections should not be recorded on the antibiotic CRF
No, sepsis must be a major part of the reason for ICU admission. If a patient is admitted to ICU for another reason (e.g.: after elective surgery), is then discharged to the ward and readmitted with sepsis, yes they would be eligible.
Yes, if the patient does not enrol in arms 1&2 they can still enrol in the GM-CSF intervention however they must be eligible for this part of the study i.e. within 120h from ICU admission and extra inclusion and exclusion criteria.
SepTiC can co-enrol with:
All observational trials
REMAP-CAP (not Antibiotics, Macrolide, Immune Modulation)
MARCH
VITALIZE
T4P
GUARDS
UKROX
GENOMICC
RASECAL
INFINITE – Sites can co-enrol with the diagnostic and
fluid interventions not the GM-CSF intervention.
SHORTER – Sites can run both trials. If a patient is
recruited early then they should be recruited to SepTIC (within 24h of ICU admission), if this inclusion criteria for SepTiC is not met and it has been longer than 24h since ICU admission then the patient can be recruited to SHORTER. This has been agreed with the SHORTER trial team. If a patient is in the SHORTER trial, they can be randomised to the GM-CSF intervention only in SepTiC.
- UKROX
- SOS – Patients who have a severe TBI and are eligible for SOS are not eligible for inclusion in SepTiC as the major cause of their admission to ICU is TBI (not sepsis). But if a patient who has been in SOS before then gets readmitted to ICU due to sepsis, then they can be enrolled in SepTiC at that time.
- RECOVERY
- COBRA Study
- FRECycl-D
SepTiC cannot co-enrol with:
TRAITS
MOSAICC (may conflict with conservative fluid trial due to use of bicarbonate) however patients recruited to MOSAICC could be randomised to the GM-CSF trial
GREAT-2
EVIS
- TILIA
Yes, non-research/clinical staff can conduct the MOCA- blind and EQ-5D if they are on the delegation log and have completed appropriate training on how to conduct the questionnaires.
SepTiC can co-enrol with the influenza, antiviral and corticosteroid domains and the COVID-19 immunoglobulin domains of REMAP. SepTiC cannot co-enrol with antibiotics or macrolide domains.
No, there is no SepTiC specific GP letter. Information on the patient’s involvement in the trial should be included in the hospital discharge letter.
Enrolment into studies after SepTiC should be discussed with the study team on a case-by-case basis.
As per the study protocol the ProLR must be a doctor (who is independent of the study – not listed on the delegation log.
Yes, we have a telephone agreement form for personal legal representative (England/Wales/NI) or nearest relative/guardian/welfare attorney (Scotland). This form can also be used to obtain retrospective consent if the patient is discharged with capacity and written consent was not obtained prior to discharge.
We would want sites to participate in all three of the interventions however, if the site is not familiar with running a double blind CTIMP then they can run only the fluid and diagnostic arms of the study. Please discuss with the SepTiC study team first.
We have not stipulated an age in our protocol or IRAS application. If you believe the patient has the potential to be pregnant please conduct a pregnancy test. Usually, a test is conducted as standard practice at most hospitals depending on the local policy.
Yes, although we have a streamlined training for clinicians only assessing eligibility.
Eligibility must be assessed by a clinician (defined by the MHRA as a medical doctor).
Yes, questionnaires will be on the online database, however sites will have to fill in a paper version and follow the guidance when speaking with the patient. This will be used as source data.
If a patient has to follow a specific fluid strategy due to an underlying (e.g. DKA or SAH) condition and the fluid cannot be restricted, then they would be excluded from the trial.
No, previously enrolled participants are not eligible to be re-enrolled in the study again for the fluid or diagnostic intervention. Any readmissions to hospital/ICU will be captured on the Day 95 follow-up form.
If the participant was initially recruited for the fluid and/or diagnostic intervention, they potentially may be eligible for the GM-CSF intervention if they meet the eligibility criteria and are readmitted within 5 days.
Due to the critical nature of the study, patients can be enrolled in the study without consent.
Yes, prisoners can be randomised to SepTiC.
If you have not obtained retrospective consent before the patient is discharged please try telephone and postal, if you have exhausted those avenues then please generate a NtF and explain that you have exhausted those avenues.
Yes you can also follow-up at 6 months and try again (and explain this in the NtF) and update the NtF at the time.
Yes, antibiotic data on the daily data form needs to be captured until Day 28 even if patient is discharged to ward, as this is one of the secondary outcomes of the study as outlined in the protocol.
We would ask the site to contact the patient three times, at different times of day, if possible. Please ensure attempts to contact the patient are documented in the notes.
You have 14 days (2 weeks) from day 180 to contact the patient, these dates are automatically calculated from the day of randomisation and can be found on the randomisation log.
If a dose is accidentally missed then sites should enter the antibiotic regimen that has been prescribed for the patient.
If an antibiotic has been stopped then record the doses given on that day up until the stop.
The database was designed for sites to reduce data entry burden. Therefore, if there is no change to the antibiotic prescription or all antibiotics have stopped this is easier to enter than recording which antibiotics a patient has taken on a daily basis as there can be great variation with this.
If the patient is suspected to have endocarditis and planned to be treated with a prolonged course of antibiotics on that suspicion, then the patient is ineligible. If the patient is suspected to have endocarditis and is not treated based on that suspicion, then they may be eligible for the study. Please contact the SepTiC trial team in this instance.
Unless it is confirmed on the outset that patients are going to have 3 weeks of antibiotics, we would recommend enrolling such patients if eligible.
If the deterioration is felt to be related to the indication to which they are receiving long term antibiotics (e.g. after splenectomy or for TB) and then they deteriorate with a second new infection and end up on pneumococcal pneumonia – these patients would be eligible as the expectation is that they will be deescalated to their usual care which would be long-term antibiotics or prophylactic antibiotics. They would not be automatically excluded. The long-term/prophylactic antibiotics do not need to be recorded in the eCRF.
The exclusion criteria ‘not expected to survive 90 days’ is due to their pre-existing chronic disease only and is different to their acute illness and acute severity. Unless the patient is though to be receiving “end-of-life” care then are likely still eligible.
Baseline us up-to Randomisation and Day 1 is from Randomisation until the end of the chart day.
Different sites have different “end of the day”. Any time is acceptable as long as your unit uses the same timeframe to classify a day throughout the trial.
Currently, the trial does not offer e-consent as an option.
Currently the trial does not offer translated documents, but we are working towards this. in the interim, we recommend sites to use their hospital translation services.
No, if a summary PIs-ICF was completed during the time of consent, then a full PIS-ICF does not need to be completed at a later stage.
We have an array of PIS-ICFs available to cover all situations. The summary PIS-ICF should be used for situations when the patient/family are unable to go through the full PIS-ICF. If a summary PIs-ICF is completed, a copy of the full PIS-ICF should still be provided to the patient/family.
Record that the dose has changed from 3 doses to 2 doses a day. The next day if the antibiotic has stopped, sites should record that all antibiotics have stopped.
Yes, for the 2-organ support, one support can be High flow/NIV/CPAP.
Diagnostic
Procalcitonin (PCT) – is costed as a treatment cost in our SoECAT and therefore there is no additional fee.
Yes please. If a PCT test is not sent at or before inclusion, we would ask that one is sent as soon as possible afterwards. And then a second one sent the day after.
We strongly encourage sites to follow the advice given and discuss positive results with your local microbiology team to try to optimise antibiotic therapy. If the PCR and PCT are negative and there are no other objective signs of infection, we encourage sites to stop antibiotics as the patient is unlikely to have sepsis. We are evaluating the role of the rapid PCR test; if sites do not follow the advice from the rapid results then the evaluation will not be meaningful.
Yes, non-research nurses/bedside nurses can collect samples, these are similar to samples that would usually be collected but they will not be processed at the site.
Samples should be collected on all patients recruited into the fluid and diagnostic trials as soon as they are enrolled and posted as soon as possible.
Patients in the GM-CSF trial need 3 additional RNA samples to be collected. These should be taken
after randomisation but before the first dose of the drug is given,
and on days 3
and on day 5
These should also be posted as soon as possible.
Samples can be posted over the weekend.
The lab will send the results of the PCR to the email on the sample shipping form. This will include whether the PCR was positive or negative and if an organism was detected.
The site staff will then liaise with their local microbiology department and inform them of the results of the PCR. After sequencing the lab will send a further result which will contain information about the organism that was detected. The full, detailed sequence of the organism will not be sent to sites. If the microbiology department would like to know what organisms could potentially be detected, please contact the study team and they will send over the whole list.
If collecting blood from an indwelling line (arterial or central line) draw 5ml of blood and discard prior to collecting research samples.
The study team does not require any quality control documentation for PCT tests.
The control group can have PCT tests if that is your normal clinical practice. The novel intervention is the PCR diagnostic and we think it will work best coupled with PCT, so that is why we mandate PCT in the intervention arm. The control group should follow normal site procedure, which might include PCT. All routine clinical microbiology tests are allowed.
Yes, if sites routinely conduct PCT tests, this can be entered in eCRF.
The safety of patients takes precedence over the science of the protocol. We have designed the trial in conjunction with patients to ensure safety. All patients in SepTiC are treated with antibiotics for at least 24-48 hours. If the PCR and both PCTs are negative without any other objective sign of infection then it is highly likely that the patient doesn’t have sepsis or it has already been adequately treated, so then the antibiotics should be stopped. This is the basis for the study.
Yes, there is an option on the microbiology form to capture antibiotics for a new infection
Yes, these patients are still eligible for the trial. The aim of the diagnostic arm is to improve antibiotic stewardship. The study might help to improve targeting of antibiotics using the additional information provided by the PCR results as other pathogens may be detected.
Yes, at baseline we collect information on any positive blood cultures collected in the previous 72hrs of randomisation.
Yes the PCR test used, Molzym Sepsitest, is available for purchase in the UK and has a CE marking. |
Yes, a PCT result prior to admission can be used, this must have been done up to 48h before admission.
Yes. Please collect samples as outlined in the SepTiC Sample Manual.
Fluid
Protocol says: Intravenous drugs will be given in the smallest acceptable volumes. The following is suggested:
Using 10% or 20% glucose rather than 5% to halve / quarter the volume.
Only need about 50g of glucose a day to prevent ketosis, which works out at 250mL of 20% dextrose in 24h, assuming no other calorie intake.
Bottom line: 15-20ml/h of 20% dextrose will work well (or even 30ml/hr of 10% dextrose which is more suitable for peripheral infusion if no central line present).
Yes, please use your standard crystalloid solution for fluid boluses. Only give the boluses according to the criteria that suggest hypovolaemia.
We would suggest you review how close your usual practice matches the intervention arm. Do you only give fluid boluses based on the criteria listed?
Do you start de-resuscitation on day 2 or is it usually later?
Even if you follow a more conservative fluid strategy than in the past, if it is different to the protocol then you can still take part. We can discuss individually, as needed.
We are not centrally monitoring deviations for fluids. Sites should monitor themselves and (re)educate local clinicians as needed.
We are monitoring the difference between two groups on average. The study team will be monitoring adherence by looking at diuretic use if fluid balance is positive on days 2- 5, while noradrenaline is <0.2.
There are a range of cardiac output monitors on the market, giving a range of information. Absolute measures of stroke volume, cardiac output, stroke volume variation (SVV), and pulse pressure variation (PPV), central venous pressure or pulmonary capillary wedge pressure are not very helpful to guide fluid in a critically ill population. Uncalibrated devices, in particular, do not provide useful information in the setting of vasoactive support, and even less so when patients have arrhythmias, are making spontaneous breathing efforts, or are undergoing lung-protective ventilation. Most importantly, even if the device is accurate and gives hints as to fluid responsiveness, none are indicators of fluid need.
If a cardiac output monitor is used, the indications for fluid boluses remain unchanged. If desired, a change in stroke volume >10% in response to a fluid bolus may be used to predict further fluid responsiveness. However, the defined indications for fluid boluses remain the same i.e. skin mottling beyond the area of the kneecap, BP not maintained despite up-titration of vasoactive drugs, lactate>=3mmol/L, or UO<0.25ml/kg/h (on day 1). To put it a different way, the goal is to ensure adequate perfusion, not to eliminate fluid responsiveness. |
If the patient is showing signs of hypovolemia, i.e. noradrenaline is going up or any of the other signs of objective hypovolemia listed on the fluid flow chart, they should receive a bolus of 250mls, if this resolves the hypovolemia partially they should be given a second dose, if the next day the patient is stable you may want to take that fluid off, we don’t want people to be hypovolemic |
All objective signs of hypovolemia should be treated. The conservative fluid arm should be followed if the patient is cardiovascularly stable, if there are showing signs that they are unstable (ie noradrenaline dose going up) then fluid should be given until they are stable.
The flowchart summarises the protocol so should be followed to allow a proper evaluation of this intervention. If the treating clinician does not wish to follow the plan, please record the decision and the reason why in the patient notes and on a protocol deviation form (on OpenClinica) so this is clear for monitoring purposes.
There is no evidence to suggest conservative fluid administration or diuretics, worsen cardiovascular stability or kidney function once hypovolaemia is corrected. This protocol does not require clinicians to give diuretics if there is hypovolaemia – if there is objective evidence of hypovolaemia, fluid bolus should be given.
It is still unknown what is the best way to manage fluid requirements in sepsis. As well as specifying a conservative fluid regimen we are also evaluating an early derususcitation regimen. Therefore, even if you use a relatively conservative fluid management plan this can still be followed in the control arm and we encourage sites to randomised if the patient is eligible.
GM-CSF
A persistent low lymphocyte count identifies an immune- supressed phenotype which is associated with a higher risk of mortality. A low HLA-DR is probably the best- characterised example of sepsis-associated immune cell dysfunction, but it is not available for routine clinical testing. Lymphocyte count is a suitable alternative and persistent lymphopaenia has been shown to be correlated with other measures of immunosuppression such as low monocyte HLA-DR values and transcriptomic signatures. As lymphocyte count is routinely measured within the NHS, it is therefore an appropriate biomarker to identify an immune supressed phenotype and enrich the study population in a clinical trial of GM-CSF.
No, although there are guidelines which state neutrophils may increase with GM-CSF, we do not require neutrophil count collection. If the total white blood cell count rises to about 50 x109 /L then GM-CSF should be stopped and a protocol deviation form completed.
Yes, the IMP can be administered by staff authorised to provide drugs to patients – this includes bedside nurses.
No, the nurses do not need to be on the delegation log, they will have to be given brief training on administering the drug and will be asked to sign a training log after. The nurse does not need to be GCP trained.
IMP should be administered once a day for 8 days, if a dose is missed this will be captured in the ‘Daily Data’ Form in the ECRF and a “reason why” should be given. If the patient is discharged from the ICU before the 8th day, then the study drug should be given on the ward until 8 doses in total have been, if logistics allow. It will not be a protocol deviation if this is not possible. If the patient is discharged from hospital before the 8th day, then the study drug will stop.
Yes, the study team will provide the site with an accountability log to track the movement of the IMP between the ICU and the ward.
The protocol states that the IMP will be given “once a day for 8 days in the ICU” it does not specifically state that this must be at the same time every day. The time when the IMP is given is not captured however the suggestion would be to administer the IMP at roughly the same time every day. Ensure 12 hours minimum between doses.
All vials including empty and unused vials can be destroyed at site and do not require reconciliation or approval from the study. If the IMP is recalled/damaged/expired the pharmacist should inform the study team and approval will be provided for destruction and a destruction log provided.
There is one consent form used for all three interventions that allows selection of the diagnostic / fluid intervention and the GM-CSF intervention separately. The patient/PerLR cannot sign the consent form twice at different times. The aim is to seek consent for all interventions at the same time. The GM-CSF intervention box can be initialled (consented) in advance of meeting all the inclusion criteria
There are three modalities of organ support that are relevant to the GM-CSF part of the study (invasive ventilation, RRT and vasopressors), if intubated the patient is potentially eligible and if not intubated the patient would need to be receiving both RRT and vasopressors.
Yes, vials should be stored in the original carton until ready for use and protected from direct light exposure during storage.
Once taken out of the fridge, it is stable for the following times at the following temperatures (not reconstituted): Vials stored at 15°C were stable for up to 12 months.
Vials stored at 25°C were stable for up to 3 months. Once the IMP has been reconstituted with sterile or bacteriostatic water for injection, it should be used immediately.
Prior to patient allocation, IMP must be stored in the fridge.
Yes, a pharmacy technician can do this role.
The IMP is approved in the US and is considered generally safe, however we would recommend keeping an eye on the patient via their electronic records and recommend to advise the ward team to escalate any concerns to the PI/ ICU team. All safety reporting procedures should still be followed even if the patient is discharged to the ward prior to day 8 and continuing IMP.
Yes, an accountability log will have to be completed when handing the IMP over from ICU to the ward,
One of the recommended criteria for treatment discontinuation includes patients with a white blood cell count of ≥50,000/microlitre.
Please check the latest version of the Sargramostim Investigator Brochure for safety information relating to the GM-CSF and ensure safety reporting procedures are followed.
No, once the WBC is above the acceptable range IMP is permanently discontinued and cannot be re-started.
Yes, please continue to follow the protocol and collect the Day 3 and Day 5 blood samples.
It is up to the site to decide whether they would like to administer the IMP as one injection per vial (reconstitute each vial separately) or administer one injection (reconstitute two vials in one syringe).
Yes, we are classing metaraminol as an eligible vasopressor.
A standard subcutaneous needle (25G / orange) and 2ml or 5ml syringe should be used for the IMP.
Yes this is permitted as long as the site template collects the same information. Please send to the SepTiC trial team for review and approval before implementing.
IMP administration should begin as soon as possible after randomisation.
No, IMP prescriber does not need to be on the delegation log as long as they are a suitably trained prescriber and it is part of their regular duties.
A brief training log will be required to be signed to demonstrate awareness of the study.
If one of these samples falls over a weekend and no one is available to take the sample, e.g.: no research staff working, then this sample could be taken on the next day, as long as we know when the sample is collected, which is recorded onto the shipping form sent with samples. If this is not possible then the sample can be recorded as missed. The priority samples to collect is the baseline GM-CSF samples taken after randomisation.
In smaller trials of the IMP it was observed that some patients relapsed when the IMP was stopped after a few days treatment. For the SepTiC trial, the investigators have decided that the patient requires a longer treatment period to get through the immune suppression phase and receive the most potential benefit.
Yes – a patient receiving HFNO/CPAP/NIV + vasopressors or RRT is eligible for the GM-CSF trial
As per protocol inclusion criteria for GM-CSF arm requires ‘An absolute lymphocyte count < 1.2 x109 /L on two consecutive calendar days at least 12 hours apart, with no values >1.2 x109 /L in between.’
If there is a result above 1.2×109/L, then the next two results would be considered. If the subsequent two results were both below 1.2 the patient is now eligible and can enter the trial.
As per SepTiC IMP Management Plan, the IMP distributor uses an approved temperature-controlled courier. The courier will inform the distributor if there were any deviations on route and the SepTiC trial management team will inform you if any stock required quarantine.
It is a Sponsor requirement to train and document site staff to handle and administer our trial medication.
The subsequent dose should be administered at least 12 hours apart from the previous dose.
Approximately 15 minutes should be adequate.
No, this does not need to be a delegated member of staff. However, the confirmation of delivery receipt must be completed and sent to the SepTiC inbox.
In the unlikely event a vial is broken, please discard and use another vial for IMP administration. There are enough vials in the kit for 8 days of treatment. The study design does not allow for more kits to be assigned to the patient, therefore please ensure all vials are handled safely to avoid any breakage.
No, we are happy for the vials to be transferred at room temperature and placed directly into the fridge on the ICU.