Agenda or minutes

23 March 2021 UK-CTAP: record of decisions

From:
UK-CTAP
Published:

UK-CTAP meeting, 23 March 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, thanking them for their continued hard work.

Chair noted the apologies but confirmed the panel was quorate. Item two, prophylaxis update, was held in abeyance.

Declarations

Chair asked members if any new conflicts of interest had arisen, noting the ongoing conflict of Charlotte Summers and Duncan Richards and their role as co-investigator of HEAL COVID.

No other new conflicts were recorded.

The record of decisions from the last meeting (10 March 2021) were agreed without amendment.

2. Actions

Chair confirmed and noted:

  • UK-CTAP secretariat to develop a full brief on [redacted for commercial sensitivity] for the other therapeutics subgroup review alongside metformin, with the support of an expert diabetologist – Complete
  • The antiviral subgroup will review the readout from LifeArc DEFEAT-COVID and IONIC on leflunomide and IMU-838, respectively – Ongoing, pending read out
  • UK-CTAP Secretariat Expand report [redacted for commercial sensitivity] – Complete
  • UK-CTAP Secretariat Expand report [redacted for commercial sensitivity] – Complete
  • UK-CTAP Secretariat [redacted for commercial sensitivity] – Complete
  • antiviral subgroup review daclatasvir when the full clinical trial readout of Iranian trial is published – Ongoing, pending read out.

3. Subgroup advice

3.1 Antivirals ([redacted for commercial sensitivity], pegylated interferons) subgroup

Subgroup chair introduced [redacted for commercial sensitivity] noting cautious enthusiasm by the subgroup for phase 2 trials.

The panel endorsed the view that pre-clinical animal tests and supply chain information was needed from the company before recommendation could be made.

Sub-group chair introduced pegylated interferons, noting that clinical trials in advanced disease with non-pegylated interferons had not shown benefit, to date, whereas early use in mild illness was associated with significant antiviral effects.

[Redacted for commercial sensitivity]. The panel considered the timing of administration of pegylated interferons and the issue of pegylation delaying the effect to later disease. Concluded there was an argument for the use of interferons in early disease, with early symptomatic populations.

The panel endorsed the view that there was more evidence for the use of interferon beta in a nosocomial or care home setting.

[Redacted for commercial sensitivity]

Recommendation

Pegylated interferon beta for early treatment (trial platform not indicated).

[Redacted for commercial sensitivity]

Action

UK-CTAP Secretariat to obtain preclinical and supply chain information for [redacted for commercial sensitivity].

Pegylated interferon beta to be reviewed by prophylaxis sub-group.

3.2 Immune ([redacted for commercial sensitivity] , inhaled steroids, oral steroids) subgroup

Charlotte Summers and Duncan Richards recused.

Chair presented the consideration of the auto-immune subgroup in the absence of the subgroup chair.

The panel noted further consideration of [redacted for commercial sensitivity] had been deferred, as while data is encouraging, it is still preliminary and needs to be considered alongside other potential compounds for phase 2, for example CSF-1 inhibitors.

The panel heard advice on inhaled steroids (ICS), for use in hospital and post-hospital setting, noting current trials in pre-hospital populations with budesonide in PRINCIPLE and ciclesonide in PROTECT-CH.

The panel agreed that ICS are unlikely to provide significant additive benefit for patients already on dexamethasone. Although, there is a good rationale for using ICS early in the disease to modulate the inflammatory reaction in lungs before dexamethasone is initiated.

The panel explored the possibility of the use of ICS on hospital admission in patients not on dexamethasone or patients on a virtual ward without needing hospital admission. The panel noted that there may not be a suitable trial platform for this setting.

The panel agreed that systemic steroids rather than ICS might be more useful (to treat ongoing pneumonitis) in the post-discharge setting.

The panel heard advice on oral steroids for HEAL in the post hospital setting noting the longstanding controversy regarding the role of steroids in ARDS.

The panel noted the advice of the subgroup that in the COVID-19 post-discharge setting, patient stratification would be key for the use of oral steroids. The panel discussed that CT scan is more useful than chest X-ray to identify patients with organising pneumonia.

The panel considered the existing potential backlog of CT scanning requirements that could impact availability for trial use and that chest radiography could be a suitable alternative.

The panel discussed dosing options for oral steroids.

The panel discussed the potential use of high dose steroids in international settings. The RECOVERY platform highlighted their international activity and noted some medications were not appropriate in less resourced treatment settings.

The panel agreed that there was a rationale for trialling dexamethasone internationally at higher doses than the UK 6mg standard of care.

Recommendation

Inhaled steroids were not currently prioritised for acute treatment.

Prednisolone (oral administration) was recommended for HEAL, with strong suggestion for patients with organising pneumonia. Suggested dose 20 to 30mg, with a duration of 2 to 3 weeks.

3.3 Other therapeutics (oestrogen, [redacted for commercial sensitivity]) subgroup

The panel noted the subgroup was not quorate in its consideration.

Chair clarified that UK-CTAP had been provided the same briefs available to the subgroup and that a UK-CTAP decision would be quorate.

Subgroup chair outlined discussion regarding oestrogen.

The panel noted it had been proposed on the basis of observational data showing that female COVID-19 patients have better clinical outcomes compared to male COVID-19 patients

The panel agreed with the subgroup’s observation that there is currently no evidence to support that intervention with oestrogen could reverse the poorer clinical outcomes observed in the male COVID-19 patient population.

The panel shared the subgroup’s concern over safety of intervention with oestrogen in the male patient population and concern about use of unopposed oestrogen in the female population.

Alternate subgroup chair outlined discussion regarding [redacted for commercial sensitivity], with reference to a comparison to metformin as previously discussed by UK-CTAP.

The panel heard that while molecular mechanisms are not yet fully understood, trials have demonstrated that SGLT2 inhibitors have significant clinical benefits in chronic heart failure and chronic and acute kidney disease in patients with and without type 2 diabetes. The principal benefit is prevention of heart failure and is likely to be related to natriuresis. [Redacted for commercial sensitivity].

The panel noted the limited evidence on the reason for hospital readmission post COVID, but preliminary evidence suggests that some patients are showing signs and symptoms of heart failure after hospital discharge.

The panel agreed there is a need for a clinical study in patients who might benefit from SGLT-2 intervention but would not receive SGLT2 inhibitors as standard of care (according to authorised indications). Noting that patient selection would be required to identify patients with clinical signs of heart failure and, or, kidney disease and exclude patients with malnutrition and, or, muscle wastage after COVID-19 hospitalisation.

Recommendation

Oestrogen was not currently prioritised.

The panel made a conditional recommendation for [redacted for commercial sensitivity] into HEAL subject to the outcomes of longitudinal studies such as PHOSP in relations to cardiac and renal events.

Metformin is not currently prioritised.

The panel agreed that [redacted for commercial sensitivity] were not currently prioritised for evaluation in acute COVID-19. This is due to potential negative consequences associated with glucose lowering, volume depletion and occurrence of diabetic keto-acidosis in this particular patient population.

4. Publications arising from the work of UK-CTAP

Chair asked the opinion of UK-CTAP on the publication of work arising from UK-CTAP’s due diligence team, noting the hard work and commitment of the due diligence team.

The panel expressed their gratitude for the quality and thoroughness of the briefs prepared by the due diligence team. They noted that they offered an unbiased summary of evidence which was unusual in the norms of academia.

The panel agreed that the sharing of information was desirable for both interest and transparency. The panel warned that any publication should be clear on the date of use, as the scientific landscape was rapidly evolving. There should also be a clarity around the purpose of such briefings, identifying that these were not academic papers nor were they the sole information used in decision making.

The panel urged that any publications arising from the work of UK-CTAP should be open access.

Chair highlighted ongoing efforts to share information with National Institutes of Health (USA), World Health Organization and European Clinical Research Infrastructure Network to both make best use of the material produced by the due diligence team and to ensure wider global collaboration and coordination.

5. Close

Chair thanked the group and closed the meeting.

Attendees

Scientific experts

  • Patrick Chinnery (Chair)
  • Frederick Hayden
  • Charlotte Summers
  • Ian Hall
  • Duncan Richards

Observers

  • 5 trial investigators
  • 1 Department of Health and Social Care representative
  • 7 secretariat members

Apologies

  • Michael Jacobs
  • Moira Whyte
  • Munir Pirmohamed

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