DAWN-antivirals: The DAWN antivirals trial for ambulatory

Summary (French or Dutch)

With this study, we aim to find out whether antiviral drugs are effective in treating symptomatic COVID-19 patients. Two antiviral drugs will be tested: camostat, a drug that has been on the market for over 30 years in Japan and other Asian countries, and molnupiravir, an oral antiviral treatment that was initially developed for treatment of influenza, and has a good safety profile.

Patients who are 40 or older, presenting to their GP or local primary care triage point with recent COVID-19 symptoms (for a maximum of 5 days) are eligible for the trial if SARS-CoV-2 infection is confirmed using a rapid antigen or PCR test and if they do not need hospital admission at that time. If patients consent to be included in the trial, they will be randomly assigned to either camostat, molnupiravir or placebo, randomised 1:1:1 between the 3 arms. For up to 30 days after inclusion, patients are asked to fill in a symptom diary every day. This can be done either by using a smartphone app, on the computer or on paper, whatever is most convenient for the patient.
Patients will be phoned on day 2, 4 and day 30 by a study nurse, to ask about symptoms, side effects and any other queries the patients may have. Patients will also be visited by a study nurse on day 8.

The primary target for evaluating the antivirals are whether they can reduce the time to self-reported recovery. 474 patients will be included in the trial. Other outcomes include their effect on hospitalisation, death, symptom recovery, severity of COVID-19 and quality of life.

Summary of results
The DAWN antivirals trial aimed to evaluate two types of antiviral medication in the primary care setting but failed to recruit the target sample size and was therefore stopped prematurely. 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. A process evaluation was performed which aimed to capture lessons learnt and improve future national trial set-ups in general practice. The process evaluation found that 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; and 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. The process evaluation concluded that although many barriers were related to the pandemic itself, hurdles such as a 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 standardisation of processes.

Summary of results

The DAWN antivirals trial aimed to evaluate two types of antiviral medication in the primary care setting but failed to recruit the target sample size and was therefore stopped prematurely.
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.

A process evaluation was performed which aimed to capture lessons learnt and improve future national trial set-ups in general practice.
The process evaluation found that 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; and 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.

The process evaluation concluded that although many barriers were related to the pandemic itself, hurdles such as a 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 standardisation of processes.

TRIAL DESCRIPTION

Title	The DAWN antivirals trial: the efficacy of antivirals for COVID-19 infections presenting to ambulatory care: a randomized controlled trial.
Participants (P)	• Aged 40 years or older; • At least 2 Covid-19 suggestive symptoms with onset of a maximum of 5 days prior to enrolment, and which cannot be explained by an alternative cause, and defined by the current Sciensano case definition; • Positive result on a PCR test or rapid Antigen in the 7 days before inclusion or at the time of inclusion in the study; Patient is community dwelling;
Intervention (I)	Camostat, 200 mg four times a day, for 7 days, oral tablets (total daily dose of 800 mg) Molnupiravir, 800 mg (4 capsules of 200 mg) two times a day, for 5 days, oral capsule (total daily dose of 1600 mg)
Control (C)	Placebo, four times a day, for 7 days, oral tablets
Outcome (O)	primary endpoint: time to first self-reported recovery within 30 days after randomisation.
Trial Design	Prospective, individually randomised (1:1:1), placebo controlled phase III trial
Sample Size	474 (150 in each arm in addition to the 24 patients already included)
Trial duration	11 months from FPI to CSR primary endpoint, 23 months for 12m FU CSR
Budget	€2,590,000

TRIAL TEAM

Sponsor	UZ Leuven – KU Leuven
Chief Investigator	Prof Ann Van den Bruel, MD
External Partners	KU Leuven - Academic Centre of General Practice UZ Leuven - lung diseases and internal medicine U Liege - Dept. medicine, research group general practice and health UGent - Primary Care and internal medicine UA - Primary Care VUB - Family Medicine and Chronic Care ZOL CTC (data management)
Number of participating sites	Approximately 125 GPs working in 5-10 triage points - 50 GP practices
Academic centre collaborating investigators	KU Leuven - Nicolas Delvaux, Jan Verbakel, Birgitte Schoenmakers U Liege – Laetitia Buret UGent - An De Sutter, Stefan Heytens UA - Samuel Coenen VUB - Dirk Devroey

DOCUMENTS

Protocol

Results

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REFERENCES

Clinicaltrials.gov: NCT04730206

Webpage: DAWN-antivirals study webpage

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DAWN-antivirals: The DAWN antivirals trial for ambulatory COVID-19 patients (COV201279)