COVID-19 - Coronavirus disease 2019

Home treatment of people infected with SARS-CoV-2 without signs of severity but at risk of complications: a randomized multi-arm, multi-stage trial (MAMS) to evaluate the efficacy of several antivirals – COVERAGE

Submission summary

Optimizing home treatment for patients with COVID-19 and risk factors for aggravation could reduce hospitals' workload and improve individual outcomes. This is one of the biggest challenges to be met in the coming weeks.
We propose a trial to compare possible drugs for this indication to the current standard of care. The trial will start with available drug candidates (darunavir/cobicistat, hydroxychloroquine, favipiravir, imatinib). It will allow new candidates to be considered at any stage, and ineffective treatments to be discontinued on the basis of futility criteria. It will include a feasibility and acceptability evaluation component and an efficacy evaluation component. It will be implemented in partnership with general practitioners, other healthcare workers in the community and patients.
We have designed the project as a multi-centre open-label Phase IIb and Phase III ("Multi-arm multi-stage, MAMS") randomized controlled superiority trial. This design fits the rapidly changing situation and allows not to lose time between Phase II and Phase III.
To adapt to the emergency, phase II will be implemented in Bordeaux as soon as sufficient funding has been secured. Phase III will then take place either entirely in Bordeaux if the epidemic is still active, or in one or more African partner countries if the epidemic is no longer active in France but still active in these countries. Data from phase II will enable to maximise phase III feasibility and encourage preparedness for large scale home testing.
The inclusion criteria will be: (i) Positive nasopharyngeal SARS-CoV-2 RT-PCR; (ii) Onset of symptoms <72 hours; (iii) Age > 65 years, or stage III-IV heart failure or chronic obstructive respiratory insufficiency; (iv) No hospitalization criteria as per current recommendations; (v) Signed informed consent.
Individuals will be identified by their general practitioner or by the outpatient screening centre team. Pre-inclusion and inclusion will take place on site if the person is already in the ambulatory testing centre; or at home by one of the 15 mobile teams set up for the trial. The nasopharyngeal swab will be tested immediately. If the test is positive, patients will be randomly allocated to one of the treatment strategies or to the standard of care. Telephone calls will then be made at Day 1 (D1), D3, D5, D9, D12, with a standardized questionnaire on clinical condition, treatment intake and mental state. Home visits by the mobile team will take place at D7 and D14, with clinical examination, blood oximetry, blood tests and nasopharyngeal swab.
The primary outcome will be hospitalization or death. Secondary outcomes will be RT-PCR negativation, biological markers progression; adverse events and acceptability of treatment.
The number of people to be included is 169 per arm. The total number of participants can be reached in 70 days. Three interim analyses are planned, when the number of participants in the standard arm reaches 30, 60 and 102 participants. If for any of these arms the analysis concludes futility, that arm will be discontinued. An interim efficacy analysis will be conducted at the third interim analysis. Final analyses will take place when all patients complete follow-up. Each arm remaining in phase III will be separately compared to arm 1.
A Data & Safety Monitoring Board will meet every two weeks. It will be informed daily in the interim of the number of hospitalizations and deaths.
The project will contribute to public health response to the current outbreak in France and worldwide, including low and middle income countries. It will provide high level evidence that treating outpatients individuals with COVID-19 and risk factors for aggravation can decrease the risk of hospitalizations or deaths and accelerate virological test negativity. It will increase knowledge on COVID-19 natural history, factors associated with poor outcomes, and provide evidence for home-based care guidelines.

Project coordination

Denis Malvy (ADERA)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

ADERA

Help of the ANR 199,917 euros
Beginning and duration of the scientific project: March 2020 - 12 Months

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