Outcomes of the UK COVID-19 Therapeutics Advisory Panel (UK-CTAP)

Contents

Records of decisions

These are the published records of decisions by the UK COVID-19 Therapeutics Advisory Panel (UK-CTAP).

Further records will be published later this year.

Some information has been redacted where:

  • the publication of names of pre-approval drugs could impact commercial viability
  • drugs under patent or under development that are submitted by persons who do not own the intellectual property or have commercial interest in the drug.
  • licensed drugs that are still under patent and have commercial interests
  • the information concerns novel formulations of existing drugs
  • the status of the drugs cannot be identified.

Information has been published where it:

  • is generic with no commercial sensitivity
  • relates to unbranded household foods or substances singularly or in combination
  • is in the public domain either because:
    • it has been recommended for trial
    • the manufacturer has publicly announced their view on efficacy.

Record of decisions: UK-CTAP, 11 January 2021

UK-CTAP meeting, 11 January 2021

Held via video teleconference.

1. Drug discussion

1.1 Baricitinib

The chair introduced the item referring to the committee discussion by email.
The panel discussed the use of baricitnib with remdesivir, dexamethasone and tocilizumab.

The panel discussed dosing information arising from ACTT2 and ACTT4 studies.
The group noted that many patients in RECOVERY+ would be taking remdesivir or dexamethasone as standard of care.

The group noted potential toxicity concerns of using baricitinib with tocilizumab.

Recommendation or action

Recommended for phase 3 RECOVERY trial at 4mg total daily dose, contingent on the pending read out of tocilizumab.

Baricitinib should not be used in combination with tocilizumab.

1.2 Dimethyl fumarate

The chair introduced the item referring to the phase 2 endpoint workshop of 8 January 2021, where dimethyl fumarate had been used a ‘strawman’ test case.

The panel noted that dimethyl fumarate has a well understood clinical profile in multiple sclerosis and psoriasis, and that there was a plausible case for efficacy in COVID-19.

The panel agreed a phase 2 trial to establish an efficacy signal in COVID-19 patients was required before consideration of Phase 3 trials use.

Recommendation or action

Recommended for phase 2 RECOVERY trial.

The dose regimen will be informed by pharmacokinetic (PK) modelling.

1.3 Favipiravir

A proposal for a 5-day course of treatment was presented.

The panel considered tablet burden and views on five, seven and 10-day course of treatment.

The panel noted issues arising from packaging which would impact the speed with which trials could be started.

Recommendation or action

Recommended that PRINCIPLE should use a five-day regimen.

2. Readout of immune subgroup

The subgroup chair presented baricitinib and dimethyl fumarate as noted above.

The panel considered record of decisions of 30 November 2020. The panel agreed the advice of the subgroup.

The panel considered record of decisions of 16 December 2020. The panel raised an observation on ivermectin.

Recommendation or action

The panel asked that ivermectin be revisited subsequent to meta-analysis of WHO data.
The panel agreed on all other advice of the subgroup on recommendations and prioritisation from the 16 December 2020 record of decisions.

3. Readout of cell therapy subgroup

The chair confirmed the 25 November 2020 record of decision had not changed from the draft reviewed at the last UK-CTAP.

Recommendation or action

The panel endorsed the advice of the subgroup on recommendations and prioritisation.

4. Readout of antiviral subgroup

The subgroup chair led a discussion on the dosing regimen for favipiravir in the PRINCIPLE trial as noted above.

No observations were raised with the 28 October 2020 or 10 December 2020 records of decisions.

The panel noted that there was an increasing need to explore antiviral combination to address both efficacy in treatment and potential antiviral resistance.

Recommendation or action

The panel endorsed the advice of the subgroup on recommendations and prioritisation.

UK-CTAP Secretariat to develop a proposal to explore antiviral combination therapy.

5. General discussion on approach

An update to the group on progress to date was presented.

The panel noted that the presentation did not reflect all of the progress made because the classification system did not distinguish between drugs known to be in trial from those not yet considered in detail because they were already in trial.

Panel members agreed that the work of the due diligence team had been extremely beneficial and of a very high quality leading to informed decision making by UK-CTAP.
The panel made the following recommendations to enhance the operation and outcomes of UK-CTAP:

1. Re-classify prioritisation to note submissions which are pending the outcome of existing trials before processing, to differentiate them from submissions which have not been processed at all.

2. Batch submissions which have a low probability of efficacy or do not have enough information for consideration. This would allow subgroups and panels to formally comment on them and reduce the perception of a back log.

6. HEAL-COVID platform

The HEAL-COVID platform was outlined and the panel noted US and Chinese published data highlighting 20% of patients are readmitted or die within 90 days of discharge after COVID-19. This was supported by UK Office for National Statistics (ONS) data from Scotland suggesting 1 in 10 people still have significant symptoms 12 weeks after being diagnosed with COVID-19.

The panel noted the trial had pilot funding from Department of Health and Social Care and the NIHR Cambridge Biomedical Research Centre to study post-hospital COVID-19 pending the outcome of an NIHR Health Technology Assessment panel which has been convened to evaluate the full proposal. HEAL-COVID has asked UK-CTAP to recommend therapies for inclusion in the study.

The therapies considered by the HEAL-COVID team are:

  • aspirin
  • statins
  • metformin
  • steroids
  • anti-fibrotics.

Recommendation or action

UK-CTAP to recommend first compounds by 25 January 2021.

Attendees

Scientific experts

  • Patrick Chinnery, Chair (MRC)
  • Munir Pirmohamed
  • Moira Whyte
  • Duncan Richards
  • Ian Hall
  • Charlotte Summers
  • Frederick Hayden
  • Michael Jacobs

Observers

  • six observers

Secretariat

  • nine members

Record of decisions: UK-CTAP, 10 February 2021

UK-CTAP meeting, 10 February 2021

Held via video teleconference.

1. Confirmation of agreement by email

The chair confirmed the recommendations made out of committee.

This was for colchicine into PRINCIPLE, adalimumab into PRINCIPLE, an anti-complement agent into RECOVERY+ and niclosamide (lower dose – intranasal and inhaled formulation) into AGILE. [Secretary’s note: the exact anti-complement inhibitor to be decided by triallists as the panel agreed this was a class effect.]

2. HEAL-COVID

The HEAL-COVID co-investigators presented an outline of the platform to help the panel in their consideration.

The panel noted that the trial was currently looking to identify one or two interventions likely to have an impact on morbidity and mortality. The intention of the trial was to find broadly applicable compounds that could be utilized across a range of populations and administered with GP support.

3. Drug discussion

3.1 Statins

(Charlotte Summers and Duncan Richards observed as co-investigators, in line with panel norms.)

Statins had to be brought direct to UK-CTAP as their action could be viewed as cutting across multiple mechanisms of action.

There was evidence for a class effect and the safety profile was well understood.
The panel clarified that statins could be considered for any of the UK-CTAP aligned trials, but the Co-investigators had submitted for consideration for the HEAL-COVID platform.

The panel noted that statins had a wide range of effects, but the onset of that effect made them unlikely to be effective in an acute setting.

The panel agreed the was a plausible rationale for inclusion into HEAL-COVID, with an expectation to lower hospital readmission.

The group noted that 30% of the target population may already be using statins and therefore ineligible for trial.

The panel considered water- and fat-soluble statins agreeing that atorvastatin as the optimum choice as the likelihood of drug-drug interaction was lower.

Recommendation or action

The panel recommended atorvastatin 40mg to HEAL-COVID trial.

3.2 Almitrine bismesylate

The chair introduced the item noting that almitrine bismesylate was not currently licensed in the UK but had seen short term use in France. It was highlighted as a potential for phase 2 trial.

The panel clarified that it was not within their remit to comment on any questions of UPH badging for [trial name redacted].

The panel noted there was some clinical evidence of improved oxygenation in acute respiratory distress syndrome (ARDS) and that the rationale in the proposal for COVID-19 was the shunting effect of almitrine bismesylate.

Recommendation or action

Recommendation that almitrine bismesylate is not currently prioritised for inclusion in UK publicly funded trials.

3.3 Ivermectin

The meta-analysis provided in the papers was highlighted to the panel. The panel considered whether this analysis would cause them to review their recommendation not to prioritise ivermectin.

The group noted the Merck statement on ivermectin.

The panel agreed that the meta-analysis supported the panels original recommendation not to prioritise ivermectin.

The panel expressed discomfort at any potential inclusion of ivermectin into a UK publicly funded trial, reconfirming its view there was no plausible rationale for inclusion and noting there was an opportunity cost in terms of patient numbers that could be recruited into a trial with a more plausible expectation of efficacy.

The panel noted that if a drug were taken into trial specifically to provide a definitive outcome of ‘no efficacy’ it had ethical implications.

Recommendation or action

Confirmation of the recommendation that ivermectin is not currently prioritised for inclusion in UK publicly funded trials.

4. Readout of prophylaxis subgroup

The subgroup chair noted that this was the first prophylaxis subgroup to sit (in the new CTAP structure) and thanked the Due Diligence Team for the high quality of briefing papers.

The group noted that it was likely that successful prophylactics would show some signal in a treatment setting.

The panel considered the records of decisions of 13 January 2021.

Recommendation or action

The panel asked the subgroup to explore the concept of prophylaxis driving resistance and mutation.

The panel endorsed the advice of the subgroup on recommendations and prioritisation.

5. Readout of immune subgroup

The subgroup chair presented three drugs of interest.

5.1 [Treatment redacted]

UK-CTAP discussed via email. The advice was to review after the RECOVERY+ readout on tocilizumab.

5.2 Namilumab and infliximab

The advice of the subgroup was that namilumab and/or infliximab could go into REMAP-CAP (ranking namilumab>infliximab) in a specific group of patients who are not responding to tocilizumab.

For RECOVERY+, one or both could be included in the trial pending readout from other drugs being trialled in RECOVERY+. For example, if baricitinib reduces mortality, it would be very difficult to use either of these drugs on top of baricitinib which would become standard of care.

The panel considered the records of decisions of 16 December 2020 (amended), 13 January 2021 and 2 February 2021.

Recommendation or action

The panel agreed [treatment redacted] should be reviewed after the RECOVERY+ readout on tocilizumab.

The panel recommended namilumab into trial with REMAP-CAP.

The panel agreed that considering recent immunomodulator recommendations that namilumab and infliximab should be added to a shortlist with the others, to prioritise at short notice when new arms become available, based on emerging trial data and the logistics.

The panel endorsed the advice of the subgroup on recommendations and prioritisation.

6. Readout of thrombostasis subgroup

(Charlotte Summers and Duncan Richards observed the HEAL-COVID recommendation as co-investigators, in line with panel norms.)

The subgroup chair noted that new data submitted regarding [treatment redacted] did not satisfy the subgroup and additional safety data was required if it were to be reconsidered.

The alternate subgroup chair presented direct oral anticoagulants (DOACs) noting there was a plausible case for short term thrombo-prophylaxis. The subgroup advised apixaban 2.5mg twice daily for a two-week course should be considered for HEAL–COVID.

The panel considered the record of decisions for the meeting of 20 January 2021.

Recommendation or action

The panel recommended apixaban 2.5mg twice daily for two weeks.

The panel endorsed the advice of the subgroup on recommendations and prioritisation.

7. Readout of antiviral subgroup

The subgroup chair led a discussion on the considerations for combination antivirals, noting there was no clear evidence for one combination over another.

The panel agreed there was a need for in vivo data, early clinical trials and pre-clinical trials of new compounds.

The panel heard advice from the subgroup on proposals for the use of convalescent plasma in prophylaxis and treatment settings.

The panel noted there were significant logistical challenges in deploying convalescent plasma and the potential to drive resistance.

The panel agreed that detailed feedback on RECOVERY+’s convalescent plasma trial was needed to make a definitive recommendation on the likely efficacy of plasma and blood related products.

The panel explored whether a nosocomial trial would benefit the trial of convalescent plasma and other interventions targeting early onset COVID-19.

The panel heard advice regarding [treatment redacted]. The subgroup suggested waiting for the outcome of the [redacted] study or other in vivo data, prior to any recommendation.

The panel considered the record of decisions for the meeting of 26 January 2021.

Recommendation or action

UK-CTAP Secretariat Due Diligence Team to prepare a comparison of convalescent plasma, immunoglobulin and mono-clonal antibodies.

The panel recommended the commissioning of a nosocomial trial.

The panel endorsed the advice of the subgroup on recommendations and prioritisation.

8. Any other business

8.1 Phase 2 compounds

The panel noted that UK-CTAP had a remit to recommend compounds for phase 2 trials and subgroups should ensure their considerations addressed this imperative.

The groups suggested increased proactive communications, particularly highlighting our phase 1 to 3 pipeline would be beneficial in increasing submissions to UK-CTAP. The group noted that UK-CTAP related trials represented exceptional value for money for pharmaceuticals and highlighted the benefits of drug development and trialling in the UK.

8.2 Subgroup membership

The Chair thanked the panel for its commitment, noting the efforts that panel members and subgroups had made in the period. Acknowledging the voluntary nature of panel and subgroup membership the Chair asked panel members to consider whether their subgroups needed refreshing.

Attendees

Scientific experts

  • Patrick Chinnery, Chair (MRC)
  • Munir Pirmohamed
  • Moira Whyte
  • Duncan Richards
  • Ian Hall
  • Charlotte Summers
  • Frederick Hayden
  • Michael Jacobs

Observers

  • six observers

Secretariat

  • nine members

Last updated: 23 July 2021

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