UK-CTAP meeting, 13 April 2021.
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, noting this the first meeting as an observer for [redacted, General Data Protection Regulation].
Chair outlined that the agenda included some decision making but also a forward look at how UK-CTAP might operate as case numbers decline and the understanding of COVID-19 increases.
No new conflicts were recorded.
The record of decisions from the last meeting (10 March 2021) were agreed with an amendment proposed by Frederick Hayden.
2. Drugs discussed and decision
2.1 Higher dose corticosteroid
Chair invited the secretariat due diligence team to introduce higher dose corticosteroids.
The panel heard that higher doses result in increased glucocorticoid receptor (GCR) occupancy, and that GCR occupancy inversely correlates with interleukin 6 levels.
Chair invited the views of the RECOVERY principal investigators in relation to international trials.
The panel noted that in some international settings clinicians are unable to augment 6mg dexamethasone with expensive immunotherapy. There is a question remaining over whether dose augmentation of dexamethasone could deliver a similar benefit.
A patient stratification of “all hypoxic patients” for RECOVERY was accepted by the panel, noting that dexamethasone could have a positive effect on progression to mechanical ventilation of those on even low flow oxygen.
The panel noted concerns that very high dose steroids could cause harm. Safety concerns included delirium and dysregulation of glucose metabolism.
The panel heard that doubling of GCR occupancy might not result in doubling of effect, and 24mg would be an optimised dose over 10 days.
The panel recommended up to 24mg dose of dexamethasone for 10 days into RECOVERY (in hypoxic patients) and REMAP-CAP (where the combination of dexamethasone 6mg and tocilizumab is not effective).
Chair invited the secretariat due diligence team to present an update on nitazoxanide, which the panel had previously considered.
[Redacted for commercial sensitivity]
The panel considered this new information noting the prophylaxis sub-group would review nitazoxanide 14 April 2021.
The panel decided there was insufficient evidence to review their position on nitazoxanide for the treatment of hospitalised patients.
3. Subgroup advice
3.1 Early phase trials
Subgroup chair noted that this was the first early phase trials subgroup to sit and thanked the due diligence team for the high quality of briefing papers.
3.2 Dihydroorotate dehydrogenase (DHODH) inhibitors
The panel noted considerable interest in DODH inhibitors particularly [redacted for commercial sensitivity], but ideally in combination with RNA-dependent RNA polymerase (RDRP) inhibitors, including suggestion of favipriavir or molnupiravir. The subgroup would like to see further in vivo data.
The panel heard that the antiviral subgroup also saw a role in early stage disease.
The panel were advised that plans to extend funding to high-throughput assays to establish effective combinations were still moving forward.
3.3 Neutrophil inhibitors
The panel heard advice that there was conceptual plausibility of efficacy in addition to dexamethasone.
The panel noted that none of the named drugs were considered suitable for phase 1 or 2a trials for a variety of reasons.
The subgroup asked that novel compounds in the class should be sought, advising there was no necessity for pre-clinical in vivo work as the dissimilarities between animal and human response would likely negate any benefit.
The subgroup’s advice would be to take promising candidates to phase 1 or 2a trial and that short-term efficacy markers would need careful consideration.
UK-CTAP secretariat to identify novel neutrophil inhibitors.
The panel considered the pre-print of the PHOSP-C study to inform a decision on dapagliflozin. They further noted the AstraZeneca press release for the DARE-19 phase 3 trial for farxiga in COVID-19.
It was highlighted that the subgroup was advised that there was a likely profound catabolic effect in severe COVID-19 but that this should not stop a recommendation for dapagliflozin in HEAL.
The panel noted that PHOSP findings suggested that large sample sizes would be required outcomes of interest such as renal disease or significant heart failure.
The panel were advised that dapagliflozin was already licensed for some groups in whom it might be trialled but not for others.
The panel agreed that there was insufficient in-patient data to confirm the conditional recommendation of dapagliflozin.
UK-CTAP secretariat to monitor for new data that might expand support for a definitive decision on dapagliflozin.
4. Any other business
4.1 World Health Organization (WHO) update
The UK-CTAP secretariat updated that initial meetings with WHO had been positive and progress had been made in establishing non-disclosure agreements to facilitate information sharing.
The next steps would be to establish a mutually acceptable sharing platform, after which an initial list of available briefs would be made available.
Chair updated a similar process was underway with the European Clinical Research Infrastructure Network.
The panel also heard that WHO were commencing with a new 4-armed trial.
Frederick Hayden highlighted the WHO and International Society for Influenza and other Respiratory Virus Diseases (ISIRV) virtual conference.
The panel agreed that these were positive developments and encouraged the widest possible sharing to facilitate finding therapeutics for COVID-19.
4.2 Future UK-CTAP operations
Chair introduced the item noting that UK-CTAP was established with funding for 2 years and had achieved a healthy pipeline for the platforms to which it recommended.
Noting that the understanding of the pathogenesis of COVID-19 was better understood, the panel and observers were asked to reflect on how the modus operandi could change to reflect this.
The panels reflections were:
- investigators highlighted that UK-CTAP had added value to the UK’s clinical trials infrastructure, specifically:
- protecting triallists from lobbyists, allowing them to concentrate on trial delivery
- reassuring triallists of plausibility in their thoughts and choices
- filtering of large catalogues of anti-viral and auto-immune drugs to plausible and evidenced recommendations
- investigators expressed a view that there was a continuing role for UK-CTAP in drug filtering, great importance was attached to the effort and intellectual capital engaged in establishing and that in losing such a capability the UK would not easily restore it
- a note of caution was expressed about such a proposal, noting that rather than it being a role for all interventional trials there was stronger case for addressing acute respiratory infection over 2 or 3 years
- other suggestions included diversifying UK-CTAP’s role to act as an ongoing reference panel for experimental therapeutics for seldomly seen diseases such as Ebola
- the panel felt focus has been on hospitalised patients, UK-CTAP could look to identify any underserved strata in the patient population
- the panel felt there may be a rational for a ‘swap in or swap out’ approach to optimise combinations of treatment, it was noted that the auto-immune subgroup was looking at C5 inhibitors and anti GM-CSF drugs for additionality to dexamethasone
- the panel identified that subgroup attendance was becoming an issue as other research agendas reopened and COVID-19 cases fell – this raised questions about the sustainability and viability of UK-CTAP
- it was suggested that the secretariat should continue to draw from secondment and could tap in career development pathways, including through the National Institute for Health and Care Research academy:
- it was acknowledged that this approach would need to be supported by a full-time professional backbone
- the professional backbone should have a role in surveillance, identifying what might be needed and when and could explore new models of doing this including the use of genomic information and artificial intelligence
- the panel agreed it was time to restructure the UK-CTAP and that merging groups or enlarging the pool of those involved might allow the panel to call on wider expertise and remain independent and quorate without putting undue pressure of commitments on panel members – it was noted that the turnover of the subgroups would also help to ensure an inclusive membership.
4.3 Low priority list
The panel were asked to raise any objections to the deprioritisation of the low priority list. No objections were raised.
Chair thanked the group and closed the meeting.
- Patrick Chinnery (Chair)
- Michael Jacobs
- Frederick Hayden
- Charlotte Summers
- Ian Hall
- Duncan Richards
- Moira Whyte
- Munir Pirmohamed
- 5 trial investigators
- 1 Department of Health and Social Care representative
- 4 secretariat members