MRC Clinical Trials Unit at UCL
90 High Holborn
Information on COVID-19
As of 17:00 on 9th April 2020, randomisation to STAMPEDE has been paused.
Please review this page for updates on COVID-19; we are continuously updating information as the situation develops.
There have been recent updates on the following sections:
- Guidance for management of patients on abiraterone, enzalutamide, metformin and progynova.
- New section on SAE reporting
- New section on recording protocol deviations
KEY POINTS REGARDING FOLLOW UP
- At the present time we do not recommend that patients stop their trial treatment but we will continue to monitor the situation closely. If treatment is interrupted, please document any treatment breaks on the appropriate follow-up CRF and deviation log.
- Please also continue to send in SAE CRFs and the team will acknowledge receipt in the normal way.
- Active consideration should be given to patients obtaining local blood tests and the results sent in to the treating centre. All trial consultations can be carried out by phone and this should be encouraged to minimise the need for patients to travel to hospital.
- Drug supply can be sent out by post/courier depending on the IMP or consideration given to “fly by” medication pick up whereby patients wait in the car and drug is taken out to them to minimise exposure in at risk individuals. Patients may wait in their car and receive a text from pharmacy when their prescription is ready.
- Unfortunately, there is currently no funding available for couriers to take IMPs to the patient’s home. We are looking at the potential for funding and will update if more information becomes available. In the meantime, if you do courier trial medication to patients, can you please keep a list of the deliveries and estimate the costs to us as we are actively looking into ways to fund this.
- We recognize that the usual recommendation to consider upfront Docetaxel in metastatic patients may not be appropriate in light of the ongoing situation. Similarly, the timelines for any radical radiotherapy may also shift. We support clinical teams in making these decisions as per local guidelines and advice.
- Upfront Abiraterone is permitted for men with metastatic disease entering the trial. At present this is not funded by the NHS apart from men with high risk disease in Scotland. We have written to NHS England (and similar letters sent to NHS Wales, Scotland and Northern Ireland) urgently requesting that upfront Abiraterone is funded for all men with metastatic disease. We are hopeful that this will lead to a rapid change in policy and will inform you if this occurs. Potentially eligible men, for whom Docetaxel was not considered due to COVID-19 may need therefore to be identified.
- We appreciate that some visits will need to be postponed (and will fall outside the stipulated visit windows). Please document where this occurs and let us know.
- Please add any protocol deviations to CRFs and your site deviation log labelled as COVID-19 where this is the underlying cause.
MORE DETAILED ADVICE ON EACH POINT
- STAMPEDE will be paused to recruitment from 17:00 April 9th 2020.
- If you have a patient who has already been approached to participate in the study and the clinician and patient feel it is in the best interest of the patient to be randomised then they can still be entered. In these situations please ensure that sufficient protocol safety monitoring can be maintained.
- If you have such patients please let the STAMPEDE team know by the 17:00 ( April 8th 2020) Please email the mailbox (email@example.com) and state “Randomisation Request” in the subject line. A Trial Manager will contact you, therefore in the email please provide the name, a contact phone number and the time to call. Please do not ring the normal randomisation line as all staff are now working from home.
- There is currently no evidence that any of the treatments used in STAMPEDE either increase the risk of infection with COVID-19 or are dangerous to continue if a patient has COVID-19 symptoms but remains well enough to stay at home.
- If any patient becomes unwell with suspected COVID-19 infection, it is at the discretion of the treating clinician to decide whether to continue or with-hold any STAMEPEDE medication. We will continue to monitor the situation closely.
- If treatment is interrupted, please document any treatment breaks on the appropriate follow-up CRF.
Abiraterone, Prednisolone and Enzalutamide:
Abiraterone and Enzalutimide have no known interaction with COVID-19, sites have however raised concerns about Prednisolone and immune-suppression and the view of the Trial Management Group is detailed below.
- Prednisolone should continue at the standard 5mg dose. The steroid is a glucocorticoid replacement therapy and as such is unlikely to cause immunosuppression. Any risk from continuing Prednisolone is likely to be much smaller than the risks of stopping it. The steroid dose is necessary to inhibit overactivity in the mineralocorticoid axis leading to hypertension and hypokalaemia. If the dose has had to be increased to 10mg daily then this may lead to a mild degree of immunosuppression and patients should be advised of this. As we know that the combination of Abiraterone and Prednisolone 5mg daily leads to large gains in prostate cancer related outcomes, this risk is likely to be outweighed by the effect on prostate cancer. Clearly this risk benefit needs to be assessed on a patient by patient basis.
1. Supply for pharmacy:
- Arm G: Please request 6 months supply for pharmacy for all patients – this is shipped from Belgium so it is important to ensure you have sufficient stock
- Arm J: Please review your stock levels of Abiraterone and Enzalutamide, the distributor is located in Wales so there are no immediate issues but we will monitor this closely.
- Please remember that both Enzalutamide and Abiraterone have handling warnings. Women who are or who may become pregnant should not handle Abiraterone acetate or AEzalutamide without gloves. The Enzalutamide trial stock does not currently have this warning on the label so please make sure this is communicated.
2. Safety checks and treatment administration:
- Treating physicians can consider 3 monthly safety tests (K+, LFTs and BP) during this time if the benefit of reduced visits outweighs the risks of less frequent follow-up. However, if patients are unable to perform safety blood tests when the physician considers these necessary, treatment should be discontinued until the necessary safety investigations are available.
- Physicians can consider extending prescriptions to give a 4-month supply as allowed by their pharmacy in order to reduce patient visits.
- Patients on Abiraterone or Abiraterone and Enzalutamide can be encouraged to buy home blood pressure monitoring equipment (available from all major pharmacies or from online outlets) and record their blood pressure on a regular basis; this should be shared with the research team for review.
- Local teams should consider and discuss with the patient the risks and benefits of attending for safety blood tests versus pausing treatment.
- If the patient is unable to complete safety blood tests they should pause treatment.
- If the patient has been stable on treatment there is unlikely to be significant impact from pausing treatment for 1-2 months, we know the medications continue to act in the body for a period after treatment has stopped.
- If the patient requires a pause in treatment, and has been on Abiraterone and Prednisolone (with or without Enzalutamide) they should continue Prednisolone. This is because their body will be reliant on the steroid tablets, and they could experience an Addisonian crisis if these are stopped suddenly. Prednisolone can be posted to the patient and does not require safety tests.
- If a patient pauses treatment due to being unable to complete safety tests during the Covid-19 crisis, then once they are able to complete the safety tests they can restart treatment, provided the local clinician feels it remains in the patients best interests. Thereafter normal rules would apply as to when the patient should stop (i.e.: once meeting all three categories of progression, see protocol for further guidance).
- This drug has no known interactions with COVID-19. The drug is supplied through hospital stock and sufficient supplies should be available locally. However, please check this with your local pharmacy team.
- If patients develop diarrhoea (5-10% of COVID-19 patients appear to have GI symptoms) they should stop taking Metformin until any clinical uncertainty has resolved.
- For patients who have been on trial Metformin for 12 months and tolerated the treatment well, a 6 month prescription of Metformin could be dispensed to work alongside the blood testing timelines.
- If a patient is unable to complete their 6 monthly safety tests (renal function) they should stop taking Metformin until they have had the opportunity for medical review. For most patients, blood tests for cancer monitoring will remain essential and hence we do not anticipate this should be a problem. For additional guidance on treatment breaks whilst taking Metformin please refer to section 6.2.6 of the STAMPEDE protocol v19.0 June 2018.
- Patients who have stopped Metformin do not need to attend for metabolic blood profile tests during this period.
- As noted above, consideration should be given to obtaining blood tests as close as possible to the patient’s home and all follow up switched to telephone based.
- This drug has no known interaction with COVID-19
- It is important that patients with locally advanced and metastatic prostate cancer remain on ADT with effectively suppressed testosterone levels and as such the regular blood tests for patients on tE2 remain important.
- It may be that sites are able to dispense longer prescriptions or utilise alternative delivery services to supply patients with their medication - see general comments above.
- If it becomes impossible to monitor patients’ estradiol and testosterone levels, it may on occasion be necessary to switch patients to LHRHa treatment to ensure androgen suppression is maintained. However, we appreciate that this may also be challenging given the pressures and reconfiguration of primary care at this time. For patients on patches with good disease control (low, stable PSA readings for example or those whose oestradiol has remained below 2000), the safest course of action may be to continue the patches with regular monitoring being resumed as soon as possible, rather than switching to ADT. This removes the need for patients to visit either GPs or hospitals to change therapy. Regular monitoring should be resumed as soon as the current emergency situation abates. Any deviations from regular monitoring should be documented.Clearly this risk benefit needs to be assessed on a patient by patient basis.
- We recognise that the usual recommendation to consider upfront Docetaxel in metastatic patients may not be appropriate in light of the ongoing situation.
Accessing Trial Treatment and Prescriptions
There is no funding presently available for Medical Couriers to take IMPs to patients home. We are looking at the potential for funding and will update once more information becomes available.
- Strategies suggested by sites that are permissible in STAMPEDE for accessing Trial treatment:
- Patients may wait in their car and receive a text from pharmacy when their prescription is ready
- It is permissible to post Progynova and Metformin by Royal Mail or other postage services. At the present time, we don’t recommend posting Abiraterone or Enzalutamide.
- If NHS staff are willing and able to take IMP to the patient’s home address this is acceptable, suitable precautions should be applied to avoid transmission.
- Sites may use their clinical judgement to assure regular therapy continues as per the protocol and the patients’ needs.
- Where a courier or postal delivery is to be used, verbal consent from the patient to provide their address to the courier must be obtained and documented. Drug can be sent by any method deemed suitable by the site, provided mechanisms are in place to confirm receipt by the patient (a follow up telephone call would be appropriate if the patient cannot sign for the delivery). The nominated address for the delivery should be recorded in the patient’s notes. Temperature monitoring is not required.
- All of these processes should be documented at site and sent to the STAMPEDE team for review.
- The handling warnings for all drugs should be observed during all of these methods of delivery.
The STAMPEDE team understand the difficulty of reporting SAEs at this unprecedented time. The current MHRA guidance is now that sites should report events within 24 hours of awareness of the event to the sponsor. They do also state “Particular attention should be paid to timely reporting of suspected unexpected serious adverse reactions (SUSARs) which put participant safety at risk on a trial or have the potential to impact participants of other trials. Every effort should be made to notify MHRA in this case”. We understand sites may not be aware of the events to be able to report within the 24 hour required timeline and therefore please can sites ensure that a systematic review occurs when there is capacity and the research team is in place to ensure any unreported SAEs are reported.
PATIENT MANAGEMENT AND FOLLOW-UP ASSESSMENTS
- Follow-up visits can be conducted via phone to reduce patient exposure wherever necessary and this is preferable to postponing these assessments. Please use the STAMPEDE Telephone Follow-Up Checklist for guidance.
- For telephone follow-up, sites should annotate next to any missed assessments (e.g. blood tests, scans, BP) to confirm the reason they have been missed and these will not be queried as missing data. It is acceptable for patients to self-measure blood pressure using home equipment. If there is concern that readings are unacceptably high then this needs to be checked either via the GP or a hospital visit.
- Patients in the Quality of life sub study can be sent blank CRFs for patient for completion by post or e-mail.
We understand there will be some necessary changes on how patients are followed up during this period, we will work closely with you to try and aid where we can.
The MHRA have given clear guidance about recording deviations, as there is a high probability of these occurring while research teams deal with the challenges of the COVID-19 pandemic. To aid in the identification and tracking of these please follow the below guidance:
Ensure all deviations are recorded using the Site Deviation Log
Site Deviation Log Guidance
There is a high probability of deviations occurring while research teams deal with the challenges of the COVID-19 pandemic. Ensure all deviations that occur are recorded using the Site deviation log.
When using the log first ensure the tab “Deviations” is selected at the bottom of the spreadsheet, and ensure your site name and site number is entered into the appropriate cells. Fill in a row for each single deviation, such as missed safety bloods, a missed blood pressure measurement or if the follow up has been missed entirely. Some cells are free text fields whilst others have drop down menus for you to select the most appropriate answer, such as the below.
- Deviation category
- Current status
Select which category you believe best describes the issue in the “Deviation category”. The “Current Status” column should be considered open or closed depending on status of resolution. The “Severity” category is intended as a guide on whether a deviation needs to be reported to the STAMDPEDE team immediately.
Critical Deviation - Any change, divergence, or departure from study protocol that significantly impacts patients’ rights, safety and/or well-being or significantly impacts the integrity and/or reliability of study results.
Major Deviation - Any change, divergence, or departure from study protocol that may impact the patients’ rights, safety and/or well-being or significantly impact the completeness, accuracy and/or reliability of study data
Other Deviation - Any deviation that will not adversely affect patients’/data but should be dealt with appropriately.
If you believe any of the issues identified to be a Critical or Major Deviation, please contact the STAMPEDE team as soon as possible. If you are unsure if the deviation meets either category, do contact the STAMPEDE team who will be happy to review the issue with you.
The tab “PI Sign Off” is intended for PI review of closed deviations, this can be completed post Covid-19 pandemic.
Examples of deviations that will need to be logged include:
- Follow up visits not completed
- Missed safety tests
These deviations should also be captured on CRFs by indicating when data points have been missed due to the current COVID-19 pandemic, by clearly writing “COVID-19” next to the field with the missing data. Deviation logs where possible should be sent to the STAMPEDE team on a periodic basis. This will enable the study team to assess the impact of this challenging period on the study results at the time of analysis. If you have any questions about how to use the log or a query about how to classify a deviation, please do not hesitate to get in touch with the team.
- Please continue to send saliva and plasma samples to the laboratories as normal.
- Please note, as the STAMPEDE team is currently working remotely, we are unable to send out any new kits. When this situation changes we will let you know. Please check the website for updates.
- Please document on the relevant CRF where samples have been missed for this reason or if visit has been conducted by telephone.
- You can continue to send tumour blocks, though we accept that this will not be a high priority activity for Trusts. If you have no kits to do this, blocks can be held locally and will be requested at a later date .
CONTACT WITH THE CTU TEAM/RETURNING DATA
- The CTU team are now all working remotely but can still be contacted on the normal numbers and via the trial mailbox.
- Wherever possible, please scan CRFs and consent forms and send them to us via fax (+44 (0)20 7670 4818) or via Galaxkey (if you do not already have an account please let us know and we can set you up with one) or other secure mechanisms until further notice. If this is not possible, please let the STAMPEDE Team know and an alternative mechanism will be sought. Until this is possible, please store all completed CRFs securely at your site. Please DO NOT SEND to the MRC CTU at UCL.
- Please also continue to send in SAE CRFs via fax or securely via email and the team will acknowledge receipt in the normal way.
- Please add any protocol deviations to CRFs and the site deviation log labelled as COVID-19 where this is the underlying cause.
MRC Clinical Trials Unit at UCL