UK-CTAP meeting, 2 November 2020.
Held via Video Teleconference.
Some information has been redacted for the reasons listed in ‘details’ for UK COVID-19 Therapeutics Advisory Panel: records of decisions.
1. Welcome and introductions
Chair welcomed the group and invited any new members or observers to introduce themselves.
Chair thanked the panel for their consideration via correspondence of, and subsequent agreement to, support the advice of the thrombostasis subgroup of recommending aspirin into the RECOVERY trial.
This recommendation has now been signed off by the Chief Medical Officer (CMO), who acknowledged the two caveats raised around 150mg versus 75mg dose and the associated side effects, and whether there should be a loading dose.
The briefing document and the formal readout of this meeting would be shared with the CMO in due course. The minutes of the previous UK-CTAP (7 October 2020) were signed off as an accurate record of discussions.
2. Governance: conflicts of interest
Chair introduced the governance paper which was formally agreed by the UK-CTAP and that the document should be shared with subgroup members.
It was noted that conflicts should be raised throughout the meeting in relation to specific proposed compounds.
Declarations
Michael Jacobs declared that he was on the trial management group for AGILE. No action required.
Munir Pirmohamed declared that he was on the trial management group for AGILE. No action required.
Frederick Hayden [declaration redacted, GDPR]. No action required.
No other conflicts were recorded.
3. Early phase work
Chair introduced an item on the early clinical trial landscape and highlighted that the AGILE platform had been approved for funding by the Department for Health and Social Care (DHSC) and that funding would be implemented through UKRI.
The Chair advised that there is a strong appetite from the AGILE investigators to work more closely with UK-CTAP to help identify compounds or combinations of compounds that require early phase work before they can later move into phase 2 or 3 trials.
The additional UKRI funding would allow expansion to other CRF’s that have the capacity to deliver early phase studies. Linking that capacity into this process would see an integrated national approach to the development of the best therapeutics.
It was suggested that the prioritisation panel of the AGILE platform could transition into a subgroup of the UK-CTAP – an early phase trials subgroup to provide a consistency of approach to candidate prioritisation and enable clear link up with the other UK-CTAP panels.
The chair highlighted that the Therapeutics Task Force (TTF) had similarly proposed that the prioritisation panel for the prophylaxis trials could transition into an advisory subgroup of the UK-CTAP.
The panel supported this approach in principle and felt that bringing these groups on board would fit well with the UK-CTAP operational structure and add expertise to the group that may be applicable to other settings. However, engagement and involvement of devolved nations must be considered. The panel do not wish to prevent any studies from taking place but are aware that there can be a mismatch between UKRI funding (UK-wide) and National Institute for Health and Care Research (NIHR) funding (England only) that can inhibit centres in Wales, Scotland and Northern Ireland taking part.
The chair advised that the TTF have confirmed they are content for the UK-CTAP to make compound recommendations to the PRINCIPLE community study for which funding has been confirmed for the next 18 months.
The panel concluded this section of the meeting by agreeing that it would be advantageous to have a better understanding of when the existing phase 2 platforms (ACCORD, TACTIC, CATALYST and DEFINE) would read out in order to inform decision-making on progression of any compounds into a phase 3 trial.
It was reported that CATALYST trial lost ‘urgent public health’ (UPH) status amid post-hoc changes to the clinical trial protocol regarding its primary endpoint. It was noted by the panel that alongside these phase 2 studies there would be a granulocyte-macrophage colony-stimulating factor (GM-CSF) phase 3 study result from the GSK otilimab study which was due to readout by the end of November.
4. Antivirals subgroup advice
Subgroup chair fed back on the experience of the 3 sub group meetings as detailed below.
4.1 Niclosamide
Was recommended and approved for a placebo-controlled phase 2a study by the CMO as part of the RECOVERY+ platform.
[Comment redacted for commercial sensitivity].
Recommendation
Niclosamide trial is paused and awaiting readouts on further phase 1 studies [redacted for commercial sensitivity].
Action
Chair to follow up for progress with the TTF.
4.2 Favipiravir (FVP)
Recent trial data suggest antivirals may not have important benefits in the overall population of patients hospitalised with COVID-19, and trials in the community (such as PRINCIPLE) and possibly in milder groups of hospitalised patients may be more likely to demonstrate any treatment benefit.
Agreement that based on the evidence to date there is a high degree of uncertainty regarding the optimal dosing of FVP to achieve sufficient antiviral efficacy against SARS-CoV-2.
Ethnicity may influence drug exposure. FPV has been most commonly tested in the Japanese population. A previous trial in healthy adult US population reported plasma prodrug exposure around 50% of that of the Japanese population under the same dosing regimen.
More detailed study of pharmacokinetics needed, possibly suited to AGILE study.
[Redacted comment, unpublished academic data].
FPV has well studied safety issues. Concern about its teratogenicity especially for use in the community setting or at high doses. Inclusion criteria need to be established to safeguard patients in the prophylaxis setting.
Recommendation
UK-CTAP would not recommend favipiravir to RECOVERY at this time.
UK-CTAP proposes favipiravir be progressed to the AGILE platform in order to identify an adequate dosing regimen shown to be safe in representative UK patients.
It was noted that favipiravir when taken orally struggles to get adequate drug exposure in seriously ill patients and it may be worth considering the intravenous formulation of favipiravir as part of an early phase study. [Redacted, commercial sensitivity] are planning a phase 1 study possibly as early as January 2021.
In order to increase potency, it may be appropriate to consider this in combination, perhaps with remdesivir.
Action
Chair to update the TTF and discuss with AGILE principal investigator
5. Anti-inflammatory and immune subgroup advice
Subgroup chair fed back on the experience of his subgroup meetings as detailed below.
5.1 CXCL10 inhibitors and CCR2 inhibitors
It was agreed that further data was required before a decision could be taken on these compounds.
Recommendation
If these were to be prioritised it would be appropriate for them to be considered as part of an early phase study.
5.2 Inflammasome inhibitors
New drugs in this category have been proposed through the Podio platform and these will be considered at the next subgroup meeting.
5.3 Anti GM-CSF antibodies and infliximab
Readouts of phase 2 trials were being awaited before further consideration would be given to these compounds.
5.4 Interferon beta
Subcutaneous interferon beta was being studied as part of the Solidarity trial, initial results showed a lack of effect on mortality.
Intravenous interferon beta was being explored as part of REMAP–CAP and the subgroup concluded that any decision on a possible recommendation to a bigger trial such as RECOVERY would await the readout of [existing] trials.
The ACTT-3 study led by the NIH testing interferon beta in combination with remdesivir had recently announced they were stopping enrolment of patients requiring high flow oxygen due to safety concerns but were continuing enrolment of less severely ill patients.
[Redacted comment, commercial sensitivity].
It is possible that the antiviral effects of interferon beta treatment are largely relevant for early-stage disease. Timing of administration of interferon would be critical (MERS viral load peaks between 7 to 10 days into illness, while SARS-CoV-2 viral load peaks at the onset of symptoms).
A small (100 person) trial in MERS had shown a substantial mortality benefit of using subcutaneous interferon beta in combination with other compounds (lopinavir- ritonavir) early in the disease onset (within 7 days).
Animal studies with SARS-CoV-1 and MERS-CoV has shown that it is possible to worsen outcomes if intervention with interferon beta is made later in the disease course.
Recommendation
Given [redacted] had received UPH badging for UK participation in an international phase 3 study of inhaled interferon beta, it was agreed that it would not be appropriate to recommend that RECOVERY should attempt to align with this trial based on the data available at the present time.
The group did not recommend either subcutaneous or intravenous interferon beta for entry into RECOVERY+.
The group did acknowledge that failure in other trials may be due to an inability for antiviral treatments to influence disease progression in hospitalised patients who are largely admitted needing oxygen therapy.
6. Thrombostasis subgroup advice
Subgroup chair fed back on the work of her sub-group, highlighting that they looked at several types of antiplatelet therapies.
6.1 Antiplatelet therapies including aspirin
The subgroup looked at several types of antiplatelet therapies including combinations and recommended aspirin at 150mg daily dose (without loading dose) to UK-CTAP for inclusion as a phase 3 arm in RECOVERY+.
It was confirmed that the subgroup did not intend to revisit alternative antiplatelet therapies in the near future.
Recommendation
ASPIRIN at 150mg daily (without loading dose) should be considered for inclusion as a phase 3 arm in RECOVERY+.
It was agreed that an anti-platelet expert from the subgroup would be nominated at the request of RECOVERY to join the steering group of the aspirin arm of the trial.
6.2 Low molecular weight heparin
The next meeting of the subgroup would focus on low molecular weight heparin.
As part of this discussion consideration would be given as to how to manage the differing standard of care for anticoagulation across the NHS, which already includes the use of low molecular weight heparin. It was highlighted that a National Institute for Health and Care Excellence (NICE) guideline is about to be published, which will provide guidance and should lead to more homogenous clinical practice.
7. Renin-angiotensin-aldosterone system (RAAS) subgroup advice
Subgroup chair highlighted that the RAAS subgroup previously considered spironolactone and angiotensin 1-7 and had reported back on this at the previous meeting.
The subgroup chair advised that as there were no candidates in this space at this time that the subgroup could look at compounds that didn’t have a natural home in other subgroups and would triage a list of potential compounds with the UK-CTAP secretariat.
8. Cell therapy subgroup advice
Subgroup chair highlighted that the subgroup had yet to meet and were due to convene on 26 November 2020.
A member of the subgroup had shared a document that outlined approximately 20 trials currently ongoing in the UK. These were mainly split between mesenchymal stem cells and umbilical derived mononuclear stem cells. Scalability is likely to be a challenge in this space.
9. Any other business
Due diligence team member outlined the work programme for the recently launched Innovative Medicines Initiative ‘Corona Accelerated R&D in Europe’ (CARE) and informed the group that CARE had invited a member of the UK-CTAP to join their Scientific Advisory board in order to facilitate a closer working relationship between the two projects.
Chair invited UK-CTAP members to express an interest in this opportunity offline.
Chair appealed to the panel for assistance in helping to expand the due diligence team of the scientific secretariat in order to ensure the secretariat was not a limiting factor in identifying potential compounds for trial.
[Redacted comment, commercial sensitivity].
10. Close
Chair thanked the group and closed the meeting.
Attendees
Scientific experts
- Patrick Chinnery, Chair (Medical Research Council)
- Munir Pirmohamed
- Moira Whyte
- Duncan Richards
- Ian Hall
- Charlotte Summers
- Frederick Hayden
- Michael Jacobs
Observers
- 2 trial investigators
- 6 secretariat members