UK-CTAP meeting, 25 May 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 was the first meeting as an observer for:
- [redacted, General Data Protection Regulation (GDPR)] (due diligence lead UK-CTAP secretariat)
- [redacted, GDPR] (programme manager, UK-CTAP secretariat).
No new conflicts were recorded.
The record of decisions from the last meeting (14 April 2021) were agreed without amendment.
Chair noted that the pegylated interferon beta recommendation had not been allocated to a suitable trial in the last record of decisions and as such had not yet been formally recommended to the Chief Medical Officer (CMO).
Chair to inform CMO of pegylated interferon beta recommendation for early phase of disease.
Chair invited an update on the use of high dose dexamethasone in REMAP-CAP.
The panel heard that REMAP-CAP would look to utilise 48 to 96mg dose based on pharmacokinetic/target engagement modelling and that this would be administered to those stuck on ventilation after two weeks. This would allow for utilising more than one inhibitor in combination with low dose steroids.
RECOVERY trial team updated that the trials were live internationally for 20mg per day dexamethasone, in Vietnam and Indonesia.
The panel noted the wide media coverage of fungal infection and the proposed link between the immune suppression of dexamethasone, especially in higher doses than used in the domestic RECOVERY trial.
They heard that RECOVERY was not currently trialling dexamethasone in India so could offer no insight on the validity of this link.
2. Pending decision
A number of drugs had pending decisions which needed formal resolution by UK-CTAP.
2.1 [Redacted for commercial sensitivity]
These anti-fibrotics had been awaiting a decision due to the perceived need for stratification.
The panel noted that there was no clear biomarker to identify patients at risk of developing progressive fibrosis, nor a view of how many patients develop progressive fibrosis.
The panel heard that the safety profile of [redacted for commercial sensitivity] caused some concern with up to 30% of patients taking the drug for idiopathic pulmonary fibrosis discontinuing treatment, and that it may cause liver injury [at the suggested dose].
The panel considered that in SARS fibrosis develops in 3 to 6 months but often resolves completely within 12 months and that consequently the risk versus benefit did not warrant a trial in COVID-19.
[Redacted for commercial sensitivity] were not prioritised for trial.
2.2 Metformin and dapagliflozin
Metformin and dapagliflozin had been brought to UK-CTAP separately in respect of use in long COVID.
The panel agreed that metformin was a well understood and widely used drug and suitable for use in an unstratified trial.
In respect of dapagliflozin, an SGLT2 inhibitor, the panel heard that since their last consideration the data from the DARE study had been made available and showed signals of efficacy.
The panel noted safety considerations around the use of SGLT2 inhibitors in those with type 1 diabetes.
The panel agreed that in the post hospital setting it was preferable that patients should receive a SGLT2 inhibitor as treatment, in line with current licensing, rather than as part of a trial.
The panel also agreed that the new data from DARE supported the rationale for inclusion in severe patients in hospital.
Metformin was recommended to HEAL
SGLT2 inhibitors (including dapagliflozin) were recommended to RECOVERY, with the final decision on which inhibitor to be made when an arm becomes available.
3. [Redacted for commercial sensitivity]
3.1 [Redacted for commercial sensitivity]
Chair invited [redacted for commercial sensitivity].
The panel inquired about mutagenic potential, hearing that contraception to 100 days post-treatment was advised to minimise the mutagenic impact.
The panel agreed that there was low likelihood of efficacy with [redacted for commercial sensitivity] monotherapy in hospitalised patients.
UK-CTAP due diligence team to monitor [redacted for commercial sensitivity] for use in combination.
4. Subgroup advice
Subgroup chair updated the panel that the pipeline for prophylaxis was lacking.
The panel noted that the 3 interventions to date had been intranasal topical agents and that the subgroup was yet to be convinced of systemic prophylaxis candidates.
The UK-CTAP chair noted that the due diligence secretariat was monitoring developments with camostat and nitazoxanide.
Subgroup chair introduced the antifolates methotrexate and [redacted for commercial sensitivity]. The panel did not support use of anti-folate drugs as potential antivirals in clinical trials based on current evidence.
The panel heard the sub-group were keen to set-up preclinical testing of combinations with antiviral candidates to identify additive and synergistic effects.
The panel heard funding will be made available for testing combinations in vitro at Queens University Belfast in collaboration with University of Liverpool.
Subgroup chair updated the panel that the therapeutic taskforce showed interest to get an updated view of UK-CTAP on evaluation of convalescent plasma or hyperimmune immunoglobulin in immunosuppressed patients without further treatment options, such as haematology patients.
Chair expressed an intention to explore this outside of the panel structure before bringing it back to an antiviral sub-panel meeting.
Subgroup chair enquired about the necessary alignment with Antivirals Taskforce (ATF).
UK-CTAP chair reflected an understanding that this is an initiative to enhance commercial trials on oral antiviral candidates, for deployment in the autumn of 2021.
The antivirals subgroup chair accepted the offer of meeting with ATF leadership.
UK-CTAP secretariat to liaise with Queens University Belfast to identify the possibility of appropriate combination assays with antifolate and RNA-dependent RNA polymerase inhibitors
Ian Hall to explore hyperimmune immunoglobulin use case in immunosuppressed population with NHS Blood and Transplant and bring back to antivirals subgroup.
4.3 Early phase
The early phase subgroup representative noted that the majority of submitted candidates did not lead to [advice to recommend].
The panel heard that [redacted for commercial sensitivity], a dihydroorotate dehydrogenase (DHODH) inhibitor that has been previously discussed in antiviral and early phase subgroup was of interest.
The panel noted in vitro data of [redacted for commercial sensitivity] in combination with remdesivir suggest synergistic effects. It highlights [redacted for commercial sensitivity] as a potential candidate to test in combination with another oral antiviral medicine in order to enhance its mechanism of action, such as [redacted for commercial sensitivity].
The panel noted animal testing models were inappropriate as the compound was unique to human DODH.
The panel heard advice that both [redacted for commercial sensitivity] and [redacted for commercial sensitivity] must be assessed singly before being considered in combinations. It was noted that this would be suitable for a first in human challenge study.
[Redacted for commercial sensitivity] in combination was recommended as an opportunity for first in human challenge study.
5. Nosocomial trials
The panel noted that whilst the reduction in cases lessened the burden on hospitals, it did not eliminate considerations of hospital-based transmission, but that currently there was no further information on the possibility of nosocomial trials.
6. Any other business
The panel heard that the readout for the aspirin arm of RECOVERY was imminent.
The panel heard that UK-CTAP had webpages on the UKRI website and that transparency on the scientific decision making was being balanced with the commercial sensitivities of contributing parties.
6.1 Low priority list
The panel were asked to raise any objections to the reprioritisation 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
- 8 secretariat members