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# Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older
(COVERAGE trial)

Alexandre Duvignaud, Edouard Lhomme, Thierry Pistone, Racha Onaisi, Rémi Sitta, Valérie Journot, Duc Nguyen, Nathan Peiffer-Smadja, Antoine Crémer, Stéphane Bouchet, et al.

HAL Id: hal-03142773

https://inria.hal.science/hal-03142773

Submitted on 15 Jan 2024

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Distributed under a Creative Commons Attribution 4.0 International License
# Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older
(COVERAGE trial)

Alexandre Duvignaud, Edouard Lhomme, Thierry Pistone, Racha Onaisi, Rémi Sitta, Valérie Journot, Duc Nguyen, Nathan Peiffer-Smadja, Antoine Crémer, Stéphane Bouchet, et al.

HAL Id: hal-03142773

https://inria.hal.science/hal-03142773v1

Submitted on 15 Jan 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
► To cite this version:

Alexandre Duvignaud, Edouard Lhomme, Thierry Pistone, Racha Onaisi, Rémi Sitta, et al.. Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial). Trials, 2020, 21 (1), 10.1186/s13063-020-04619-1. doi: 10.1186/s13063-020-04619-1
<figure><img src="image_2.png" /></figure>
LETTER

Open Access

<figure><img src="image_3.png" /></figure>

Check for
updates

# Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial)

Alexandre Duvignaud<sup>1,2*†</sup>, Edouard Lhomme<sup>3,4,5†</sup>, Thierry Pistone<sup>1,2</sup>, Racha Onaisi<sup>6</sup>, Rémi Sitta<sup>3,5</sup>, Valérie Journot<sup>2</sup>, Duc Nguyen<sup>1,2</sup>, Nathan Peiffer-Smadja<sup>7,8,9</sup>, Antoine Crémer<sup>10,11</sup>, Stéphane Bouchet<sup>11,12</sup>, Thomas Darnaud<sup>13</sup>, Delphine Poitrenaud<sup>14</sup>, Lionel Piroth<sup>15,16</sup>, Christine Binquet<sup>17</sup>, Jean-François Michel<sup>18,19</sup>, Benjamin Lefèvre<sup>20</sup>, David Lebeaux<sup>21</sup>, Josselin Lebel<sup>22,23</sup>, Julie Dupouy<sup>24,25,26,27</sup>, Caroline Roussillon<sup>28</sup>, Anne Gimbert<sup>29</sup>, Linda Wittkop<sup>5,30</sup>, Rodolphe Thiébaut<sup>3,4,5</sup>, Joanna Orne-Gliemann<sup>2</sup>, Jean-Philippe Joseph<sup>31</sup>, Laura Richert<sup>3,4,5†</sup>, Xavier Anglaret<sup>2†</sup>, Denis Malvy<sup>1,2†</sup> and the COVERAGE study group

**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:

(Continued on next page)

<footnote>* Correspondence: alexandre.duvignaud@chu-bordeaux.fr</footnote>

<footnote>The entire COVERAGE study group is listed in the Additional file 3.</footnote>

<footnote>†Alexandre Duvignaud, Edouard Lhomme, Laura Richert, Xavier Anglaret and Denis Malvy contributed equally to this work.</footnote>

<footnote n="1">¹CHU Bordeaux, Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, F-33000 Bordeaux, France</footnote>

<footnote n="2">²Inserm U1219, Univ. Bordeaux, IRD, F-33000 Bordeaux, France
Full list of author information is available at the end of the article</footnote>
LETTER

Open Access

<figure><img src="image_3.png" /></figure>

Check for
updates

# Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial)

Alexandre Duvignaud<sup>1,2*†</sup>, Edouard Lhomme<sup>3,4,5†</sup>, Thierry Pistone<sup>1,2</sup>, Racha Onaisi<sup>6</sup>, Rémi Sitta<sup>3,5</sup>, Valérie Journot<sup>2</sup>, Duc Nguyen<sup>1,2</sup>, Nathan Peiffer-Smadja<sup>7,8,9</sup>, Antoine Crémer<sup>10,11</sup>, Stéphane Bouchet<sup>11,12</sup>, Thomas Darnaud<sup>13</sup>, Delphine Poitrenaud<sup>14</sup>, Lionel Piroth<sup>15,16</sup>, Christine Binquet<sup>17</sup>, Jean-François Michel<sup>18,19</sup>, Benjamin Lefèvre<sup>20</sup>, David Lebeaux<sup>21</sup>, Josselin Lebel<sup>22,23</sup>, Julie Dupouy<sup>24,25,26,27</sup>, Caroline Roussillon<sup>28</sup>, Anne Gimbert<sup>29</sup>, Linda Wittkop<sup>5,30</sup>, Rodolphe Thiébaut<sup>3,4,5</sup>, Joanna Orne-Gliemann<sup>2</sup>, Jean-Philippe Joseph<sup>31</sup>, Laura Richert<sup>3,4,5†</sup>, Xavier Anglaret<sup>2†</sup>, Denis Malvy<sup>1,2†</sup> and the COVERAGE study group

**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:

(Continued on next page)

<footnote>* Correspondence: alexandre.duvignaud@chu-bordeaux.fr</footnote>

<footnote>The entire COVERAGE study group is listed in the Additional file 3.</footnote>

<footnote>†Alexandre Duvignaud, Edouard Lhomme, Laura Richert, Xavier Anglaret and Denis Malvy contributed equally to this work.</footnote>

<footnote n="1">¹CHU Bordeaux, Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, F-33000 Bordeaux, France</footnote>

<footnote n="2">²Inserm U1219, Univ. Bordeaux, IRD, F-33000 Bordeaux, France
Full list of author information is available at the end of the article</footnote>
(Continued from previous page)

* 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 piperacrine, 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, flicafenine, 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; Hypersensitivity 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.

(Continued on next page)
(Continued from previous page)

* 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 piperacrine, 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, flicafenine, 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; Hypersensitivity 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.

(Continued on next page)
(Continued from previous page)

**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 ClinicalTrials.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).

# Supplementary information

Supplementary information accompanies this paper at https://doi.org/10.1186/s13063-020-04619-1.

**Additional file 1.** COVERAGE trial protocol version 1.2 (April 8th 2020).

**Additional file 2.** SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.

**Additional file 3.** List of members of the COVERAGE study group.

## Authors' contributions

AD, EL, TP, RO, DN, JP, NP, VJ, RS, LR, XA and DM designed the study and wrote the protocol. AD, EL, TP, RO, RS, VJ, DN, NP, TD, DP, LP, CB, JFM, BL, DL, JL, JD, CR, AG, LW, RT, JO, JJ, LR, XA and DM are involved in the collection, analysis and interpretation of the data. AD, EL, XA and DM wrote the manuscript. LR reviewed the manuscript for important intellectual content. All authors approved the final version before submission.

## Funding

The COVERAGE trial received funding from the following sources: University of Bordeaux, Research and Action Targeting Emerging Infectious Diseases (REACTing) / Institut de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche (ANR) and the French Ministry of Health (DGOS). The immunological substudy received funding from EIT HEALTH. The funding sources had a role neither in the design of the study nor in the collection, analysis, and interpretation of data and in writing the manuscript.

## Availability of data and materials

Not applicable.

## Ethics approval and consent to participate

The study was approved by the "Comité de Protection des Personnes Ile de France 1" ethics committee (reference CPPIDF1-2020-ND45 cat.1) on April 7th 2020, and by the French regulatory Agency, "ANSM" (reference MEDAECNAT-2020-03-00065) on April 10th 2020, as required by national regulations regarding the evaluation of experimental drugs in humans. Eligible individuals may only be included in the study after receiving full explanation, having received sufficient time to consider the trial, asking questions and receiving satisfying responses to all questions, and after providing written Ethics Committee-approved informed consent. Individuals who are not able to understand the study and to provide informed consent by themselves are not eligible to participate.

## Consent for publication

Not applicable.

## Competing interests

The authors declare that they have no competing interests.

## Author details

¹CHU Bordeaux, Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, F-33000 Bordeaux, France.

²Inserm U1219, Univ. Bordeaux, IRD, F-33000 Bordeaux, France. ³Univ. Bordeaux, Inserm, CHU Bordeaux, CIC 1401, EUCLID/F-CRIN Clinical Trials Platform, F-33000 Bordeaux, France. ⁴Univ. Bordeaux, Department of Public Health, Inserm Bordeaux Population Health Research Centre, Inria SISTM, F-33000 Bordeaux, France. ⁵CHU Bordeaux, Pôle de Santé Publique, F-33000 Bordeaux, France. ⁶Department of General Practice, Univ. Bordeaux, F-33000 Bordeaux, France. ⁷CHU Bichat Claude Bernard, Department of Infectious Diseases and Tropical Medicine, APHP, F-75000 Paris, France. ⁸Université de Paris, IAME, INSERM, F-75018 Paris, France. ⁹National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London, London, UK. ¹⁰Department of Cardiology - Hypertension, CHU Bordeaux, F-33000 Bordeaux, France. ¹¹Inserm U1219, Univ. Bordeaux, F-33000 Bordeaux, France.

¹²Department of Pharmacology and Toxicology, CHU Bordeaux, F-33000 Bordeaux, France. ¹³Centre Hospitalier de Bastia, Service de Chirurgie Spécialisée & Unité de Recherche Clinique, F-20200 Bastia, France. ¹⁴Department of Infectious Diseases and Tropical Medicine, Centre Hospitalier d'Ajaccio, F-20090 Ajaccio, France.

¹⁵Department of Infectious Diseases and Tropical Medicine, CHU Dijon, F-21079 Dijon, France. ¹⁶Inserm U1432, Univ. Bourgogne, F-21000 Dijon, France. ¹⁷Inserm, CHU Dijon, CIC-EC 1432, F-21000 Dijon, France. ¹⁸Centre Medical de Steinsel, Steinsel, Luxembourg. ¹⁹Formation Spécialisée en Medecine Generale (FSMG), Université de Luxembourg, Luxembourg City, Luxembourg. ²⁰Department of Infectious Diseases and Tropical Medicine, CHU Nancy, F-54000 Nancy, France.

²¹Department of Infectious Diseases and Tropical Medicine, Hôpital Européen Georges Pompidou, APHP, F-75000 Paris, France. ²²Department of General Practice, Université de Paris, F-75018 Paris, France. ²³UMR 1137, INSERM, IAME, F-75018 Paris, France. ²⁴MSPU Pins Justaret, F-31860 Pins Justaret, France. ²⁵Department of General Practice, Univ. Paul Sabatier, F-31000 Toulouse, France. ²⁶UMR 1027 Inserm Univ. Paul Sabatier, F-31000 Toulouse, France. ²⁷CHU Toulouse, CIC, F-31000 Toulouse, France. ²⁸Clinical Research and Innovation Department, Safety and vigilance, CHU Bordeaux, F-33000 Bordeaux, France. ²⁹Clinical Research and Innovation Department, CHU Bordeaux, F-33000 Bordeaux, France. ³⁰Univ. Bordeaux, Department of Public Health, Inserm Bordeaux Population Health Research Centre, MORPH3EUS, F-33000 Bordeaux, France. ³¹Department of General Practice, CIC 1401, Univ. Bordeaux, F-33000 Bordeaux, France.

Received: 13 July 2020 Accepted: 15 July 2020

Published online: 13 October 2020

## Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
(Continued from previous page)

**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 ClinicalTrials.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).

**Supplementary information**

Supplementary information accompanies this paper at https://doi.org/10.1186/s13063-020-04619-1.

**Additional file 1.** COVERAGE trial protocol version 1.2 (April 8th 2020).

**Additional file 2.** SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.

**Additional file 3.** List of members of the COVERAGE study group.

**Authors' contributions**

AD, EL, TP, RO, DN, JP, NP, VJ, RS, LR, XA and DM designed the study and wrote the protocol. AD, EL, TP, RO, RS, VJ, DN, NP, TD, DP, LP, CB, JFM, BL, DL, JL, JD, CR, AG, LW, RT, JO, JJ, LR, XA and DM are involved in the collection, analysis and interpretation of the data. AD, EL, XA and DM wrote the manuscript. LR reviewed the manuscript for important intellectual content. All authors approved the final version before submission.

**Funding**

The COVERAGE trial received funding from the following sources: University of Bordeaux, Research and Action Targeting Emerging Infectious Diseases (REACTing) / Institut de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche (ANR) and the French Ministry of Health (DGOS). The immunological substudy received funding from EIT HEALTH. The funding sources had a role neither in the design of the study nor in the collection, analysis, and interpretation of data and in writing the manuscript.

**Availability of data and materials**

Not applicable.

**Ethics approval and consent to participate**

The study was approved by the "Comité de Protection des Personnes Ile de France 1" ethics committee (reference CPPIDF1-2020-ND45 cat.1) on April 7th 2020, and by the French regulatory Agency, "ANSM" (reference MEDAECNAT-2020-03-00065) on April 10th 2020, as required by national regulations regarding the evaluation of experimental drugs in humans. Eligible individuals may only be included in the study after receiving full explanation, having received sufficient time to consider the trial, asking questions and receiving satisfying responses to all questions, and after providing written Ethics Committee-approved informed consent. Individuals who are not able to understand the study and to provide informed consent by themselves are not eligible to participate.

**Consent for publication**

Not applicable.

**Competing interests**

The authors declare that they have no competing interests.

**Author details**

¹CHU Bordeaux, Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, F-33000 Bordeaux, France.

²Inserm U1219, Univ. Bordeaux, IRD, F-33000 Bordeaux, France. ³Univ. Bordeaux, Inserm, CHU Bordeaux, CIC 1401, EUCLID/F-CRIN Clinical Trials Platform, F-33000 Bordeaux, France. ⁴Univ. Bordeaux, Department of Public Health, Inserm Bordeaux Population Health Research Centre, Inria SISTM, F-33000 Bordeaux, France. ⁵CHU Bordeaux, Pôle de Santé Publique, F-33000 Bordeaux, France. ⁶Department of General Practice, Univ. Bordeaux, F-33000 Bordeaux, France. ⁷CHU Bichat Claude Bernard, Department of Infectious Diseases and Tropical Medicine, APHP, F-75000 Paris, France. ⁸Université de Paris, IAME, INSERM, F-75018 Paris, France. ⁹National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London, London, UK. ¹⁰Department of Cardiology - Hypertension, CHU Bordeaux, F-33000 Bordeaux, France. ¹¹Inserm U1219, Univ. Bordeaux, F-33000 Bordeaux, France.

¹²Department of Pharmacology and Toxicology, CHU Bordeaux, F-33000 Bordeaux, France. ¹³Centre Hospitalier de Bastia, Service de Chirurgie Spécialisée & Unité de Recherche Clinique, F-20200 Bastia, France. ¹⁴Department of Infectious Diseases and Tropical Medicine, Centre Hospitalier d'Ajaccio, F-20090 Ajaccio, France.

¹⁵Department of Infectious Diseases and Tropical Medicine, CHU Dijon, F-21079 Dijon, France. ¹⁶Inserm U1432, Univ. Bourgogne, F-21000 Dijon, France. ¹⁷Inserm, CHU Dijon, CIC-EC 1432, F-21000 Dijon, France. ¹⁸Centre Medical de Steinsel, Steinsel, Luxembourg. ¹⁹Formation Spécialisée en Medecine Generale (FSMG), Université de Luxembourg, Luxembourg City, Luxembourg. ²⁰Department of Infectious Diseases and Tropical Medicine, CHU Nancy, F-54000 Nancy, France.

²¹Department of Infectious Diseases and Tropical Medicine, Hôpital Européen Georges Pompidou, APHP, F-75000 Paris, France. ²²Department of General Practice, Université de Paris, F-75018 Paris, France. ²³UMR 1137, INSERM, IAME, F-75018 Paris, France. ²⁴MSPU Pins Justaret, F-31860 Pins Justaret, France. ²⁵Department of General Practice, Univ. Paul Sabatier, F-31000 Toulouse, France. ²⁶UMR 1027 Inserm Univ. Paul Sabatier, F-31000 Toulouse, France. ²⁷CHU Toulouse, CIC, F-31000 Toulouse, France. ²⁸Clinical Research and Innovation Department, Safety and vigilance, CHU Bordeaux, F-33000 Bordeaux, France. ²⁹Clinical Research and Innovation Department, CHU Bordeaux, F-33000 Bordeaux, France. ³⁰Univ. Bordeaux, Department of Public Health, Inserm Bordeaux Population Health Research Centre, MORPH3EUS, F-33000 Bordeaux, France. ³¹Department of General Practice, CIC 1401, Univ. Bordeaux, F-33000 Bordeaux, France.

Received: 13 July 2020 Accepted: 15 July 2020

Published online: 13 October 2020

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