The DAWN antivirals trial: process evaluation of a COVID-19 trial in general practice

Tare et al., BJGP Open, doi:10.3399/bjgpo.2023.0109, DAWN, NCT04730206

Nov 2023

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Very small early terminated RCT with 8 molnupiravir and 17 placebo patients showing worse recovery with molnupiravir, without statistical significance.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-15.

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Study covers camostat and molnupiravir.

risk of no recovery, 82.9% higher, RR 1.83, p = 0.36, treatment 4 of 7 (57.1%), control 5 of 16 (31.2%), day 30.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 6 of 8 (75.0%), control 12 of 16 (75.0%), day 8.

recovery time, 135.0% higher, relative time 2.35, treatment 8, control 17.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

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13. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

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Tare et al., 20 Nov 2023, Randomized Controlled Trial, placebo-controlled, Belgium, peer-reviewed, median age 55.0, 11 authors, study period June 2021 - July 2022, trial NCT04730206 (history) (DAWN). Contact: ann.vandenbruel@kuleuven.be.

This Paper Molnupiravir All

The DAWN antivirals trial: process evaluation of a COVID-19 trial in general practice

Dajana ; Tare, Samuel ; Coenen, An ; De Sutter, Stefan ; Heytens, Dirk ; Devroey, Laetitia ; Buret, Birgitte ; Schoenmakers, Nicolas ; Delvaux, Jan Y Verbakel, Kris ; Bogaerts, Ann Van Den Bruel

BJGP Open, doi:10.3399/bjgpo.2023.0109

Background: The DAWN Antivirals trial was a multicentric, randomised placebo-controlled trial evaluating antiviral medication for COVID-19 in general practice. The trial was prematurely terminated because of insufficient recruitment. Aim: To explore which factors contributed to the premature termination. Design and setting: General practice in Belgium. Methods: Patients were randomized to camostat or placebo (blinded) between June 2021 and July 2022); a third arm evaluating molnupiravir (open label) was opened in March 2022. We analysed available trial data and evaluated trial context, implementation and mechanisms of impact based on semi-structured interviews with trial stakeholders. Results: The trial recruited 44 participants; 19 were allocated to camostat (median age 55 years), 8 to molnupiravir (median age 60 years) and 17 to placebo (median age 56 years). There were no serious adverse events in either group. Most difficulties were related to the pandemic context: disruption to routine clinical services; multiple changes to the service model for COVID-19 patients; overwhelmed clinical staff; delays of trial medication; staff shortages in the sponsor and clinical team. In addition, regulatory approval processes were lengthy and led to additional study procedures. It was felt that the trial started too late, when vaccinations had already begun. Conclusion: The DAWN Antivirals trial was stopped prematurely. Although many barriers were related to the pandemic itself, hurdles such as small and inexperienced sponsor and clinical teams, delays in regulatory processes and research capacity in routine settings could be overcome by established research infrastructure and standardization of processes.

Author Accepted Manuscript This is an 'author accepted manuscript': a manuscript that has been accepted for publication in BJGP Open, but which has not yet undergone subediting, typesetting, or correction. Errors discovered and corrected during this process may materially alter the content of this manuscript, and the latest published version (the Version of Record) should be used in preference to any preceding versions Discussion Summary The DAWN Antivirals trial was set up when there was still an urgent need for effective treatment of COVID-19 patients in general practice. Recruitment was however insufficient and the trial was subsequently halted after 13 months. There were 12 months between trial conception and the actual start, largely due to the lengthy pre-submission advice process, delays of trial medication, and difficulties in finding staff. As a result, the trial opened when vaccination campaigns were well advanced, leading to a lower risk of serious illness and a subsequent change in endpoint, but also to decreased interest in a trial for a disease that was no longer considered a major threat. The pandemic itself had a huge impact on the trial: recruitment settings changed from testing centres to general practices to a decentralised system with remote informed consent; general practice was overwhelmed; study nurses were in short supply and charging very high rates; the number of potential participants was highly dependent on virus circulation in the population...

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