No abstract

Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. Intervention and comparator The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. Main outcome The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. Randomisation Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). Blinding (masking) This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. Numbers to be randomised (sample size) A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. Trial Status This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. Trial registration The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background The emergency set-up and implementation of outpatient clinical trials on epidemic emerging infectious diseases such as COVID-19 raise many issues in terms of research structuration, regulations, and health systems organization. We aimed to describe the experience and points of view of different stakeholders involved in a French home-based outpatient trial on COVID-19 and to identify the early barriers and facilitators to the trial implementation. Methods We conducted a mixed-methods study in July 2020. A self-administered questionnaire was emailed to 213 clinical, operational and research stakeholders involved in the Coverage trial; individual semi-directed interviews were conducted among 14 stakeholders. Questionnaire data and written interview notes are presented together by key theme. Results One hundred fifty six stakeholders responded to the questionnaire. 53.4% did not have prior experience in clinical research. The motivation of most stakeholders to participate in the Coverage trial was to feel useful during the pandemic. 87.9% agreed that the trial had an unusual set-up timeframe, and many regretted a certain lack of regulatory flexibility. Mobile medical teams and specific professional skills were perceived as instrumental for outpatient research. Conclusions The implementation of a home-based outpatient clinical trial on COVID-19 was perceived as relevant and innovative although requiring important adaptations of usual professional responsibilities and standard research procedures. Lessons learned from the Coverage trial underline the need for improved networks between hospital and community medicine, and call for a dedicated and reactive outpatient research platform on emerging or threatening infectious diseases.

Contexte : La réflexivité est considérée par de nombreux auteurs comme une composante essentielle du professionnalisme, tout en étant au cœur du développement de ce dernier et de l’identité professionnelle. Le portfolio, outil de soutien de l’apprentissage et d’évaluation en médecine générale, comporte des traces écrites d’apprentissage à visée réflexive. Il n’existe pas d’outil validé en langue française permettant d’évaluer la réflexivité au travers des traces écrites d’apprentissage. But : L’objectif de cette étude est donc d’adapter la grille REFLECT, validée en anglais, pour un usage en langue française. Méthode : Un processus de double traduction puis double rétro-traduction a été mené afin de garantir une adaptation interculturelle respectant le sens de la version originale. Des tests pilotes ont été menés sur la version française préliminaire avec évaluation de la validité de contenu. Résultats : L’évaluation de la clarté de la version française a conduit à une version finale comportant 5 critères ayant chacun 4 niveaux d’évaluation possibles. La version française de la grille REFLECT présente une validité de contenu élevée. Conclusion : L’utilisation de la grille REFLECT en français permettra vraisemblablement d’optimiser le développement de la réflexivité chez les internes en médecine générale et de faciliter la rétroaction par les superviseurs.