UK-CTAP meeting, 3 December 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 asked members to declare if any new conflicts of interest had arisen.
Declarations
Frederick Hayden [declaration redacted, General Data Protection Regulation]. No action required.
No other conflicts were recorded.
2. Trials update
Chair invited RECOVERY+ trial investigators to update the panel on the progress of colchicine into trial.
RECOVERY+ trial investigators outlined the rapid turnaround from recommendation to trial commencement and shared that circa 100 patients had been already randomised into the colchicine arms of the RECOVERY trial.
3. Drugs discussed and decisions
3.1 PIMSTIC (anakinra, infliximab, tocilizumab, intravenous immunoglobulin, methyl prednisolone)
Chair asked how the proposal for a complex trial in paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) should be handled.
The panel explored whether this paediatric condition that is related with COVID-19 represented a distinct clinical entity.
The panel agreed that this condition is distinct from COVID-19 and therefore would also merit a dedicated trial arms to investigate compounds for its treatment.
The panel noted 62 children were enrolled in the RECOVERY paediatric arm.
Patients with PIMS-TS are already eligible for inclusion in RECOVERY.
The panel noted two agents from the proposal (tociluzumab and steroids) were already available in the RECOVERY paediatric sub-protocol.
Recommendation
The panel recommended UK-CTAP due diligence should review single agents not already in a RECOVERY arm for suitability.
Action
RECOVERY and PIMSTIC to be connected to discuss PIMS-TS treatment.
3.2 Vitamin D
The panel noted that low vitamin D levels are associated with poor outcomes in COVID, and a diverse range of other illnesses. However, there is currently insufficient evidence that an intervention with vitamin D in COVID-19 will improve clinical outcomes.
The panel agreed that a higher dose than the recently promulgated government advice would be needed to drive prompt vitamin D repletion, in the order of 2,000 to 4,000 international units.
Whilst vitamin D is safe, very high dose vitamin D can lead to toxicity side effects including bone loss and hypercalcaemia.
The panel also discussed the importance of understanding the natural history of COVID-19 in terms of vitamin D levels but also vitamin D binding protein levels.
The panel agreed that whilst the importance of vitamin D in public health outcomes is well established, the evidence for its therapeutic value in COVID-19 (and other conditions) is less clear.
Recommendation
The panel considered that a large-scale public health trial with a cohort more than 40,000 would likely be required to demonstrate prophylactic effect.
The panel did not believe that current evidence supports a role for the use of vitamin D (in either standard of high doses) in acute COVID-19.
3.3 Dimethyl fumarate
The panel agreed this is an interesting compound with potential as a treatment for COVID.
There is significant clinical experience in multiple sclerosis (MS) and psoriasis.
The panel discussed uncertainties regarding the dose that would be required for treatment of COVID-19 given that the primary direct pharmaceutical target might not be the inflammasome.
Some additional pharmacokinetics and pharmacodynamics modelling is warranted before it could enter a phase 3 trial in COVID-19.
The panel noted that long-term use in MS had led to lymphopenia, but this was unlikely to be a concern in short-term use for COVID-19.
The panel agreed the compound should be trialled independent of other agents in the first instance to demonstrate a potential treatment effect.
Recommendation
Dimethyl fumarate should be tested in either a phase 1, 2a or 2b trial.
Action
RECOVERY, UK-CTAP due diligence and UK-CTAP panel members with expertise should meet to consider dose regimen and trial endpoints with a view to recommending a phase1, 2a or 2b trial at the 11 January UK-CTAP meeting.
4. Subgroup advice
4.1 Immune subgroup
Subgroup chair outlined the rationale for deprioritising [comment redacted for commercial sensitivity].
No other observations were raised with the record of advice.
Recommendation
The panel agreed the advice of the subgroup on recommendations and prioritisation.
4.2 Thrombostasis subgroup
Chair outlined the rationale for deprioritising low molecular weight heparin.
No other observations were raised with the record of advice.
Recommendation
The panel agreed the advice of the subgroup on recommendations and prioritisation.
4.3 Cell therapy subgroup
Subgroup chair outlined the rationale for deprioritising two proposed cell therapies containing allogeneic regulatory T-cells and allogenic gamma delta T-cells respectively.
The panel noted the subgroups views on the merit of mesenchymal stromal cell therapy in COVID-19, although it questioned scalability.
The subgroup advised that the immune subgroup should review compounds that could have the capability to stimulate proliferation of endogenous T-cell populations, for example human recombinant IL-2 and, or, IL-7 and rapamycin.
No other observations were raised with the record of advice.
Recommendation
The panel agreed the advice of the subgroup, including to monitor the readout of the REALIST trial for mesenchymal stromal cells therapy.
Action
Moira Whyte to attend immune subgroup when compounds for endogenous T-cell proliferation are reviewed.
4.4 Renin-angiotensin-aldosterone system/other subgroup
Subgroup chair outlined the rationale for deprioritizing oxytocin, dutasteride and enoximone.
Recommendation
The panel agreed the advice of the subgroup on recommendations and prioritisation.
4.5 Antiviral subgroup
Chair led a discussion on the current status of antiviral therapy in COVID-19.
The panel discussed that the list of repurposed antivirals is nearly exhausted and that there remains a need for (potentially less potent) antiviral medicines in the pre- and post-exposure prophylaxis of COVID-19 and more potent antivirals for COVID-19 therapy.
The panel noted that additional pharmacokinetics and pharmacodynamics on favipiravir is ongoing for reconsideration of its repurposing in COVID-19.
The panel agreed that combination therapies of different antiviral medicines could be a suitable strategy in COVID-19. However, evidence to support combinations is currently lacking.
Potential new candidates were highlighted based on emerging evidence, which may be considered in future sub-group meetings: selective serotonin reuptake inhibitors (for example fluvoxamine) as well as [comment redacted for commercial sensitivity].
5. Any other business
Chair updated the group on the expanded remit to be announced for UK-CTAP, recommending into RECOVERY, AGILE, PROTECT, PRINCIPLE and REMAP CAP.
The panel was interested to understand if medicines for IV administration (for example neutralising antibodies) could be recommended into trials in the pre- and post-exposure setting as this would require specific infrastructure that might not be currently available in the UK. [Comment redacted due to government policy exemption (section 35)].
Mike Jacobs offered to update the panel on the two recommendations from the Prophylaxis Oversight Group at the next meeting.
6. Close
Chair thanked the group and closed the meeting.
Attendees
Scientific experts
- Patrick Chinnery (Chair)
- Munir Pirmohamed
- Michael Jacobs
- Frederick Hayden
- Duncan Richards
- Moira Whyte
Observers
- 4 trial investigators
- 1 Department of Health and Social Care representative
- 8 secretariat members
Apologies
- Charlotte Summers
- Ian Hall