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Journal Pre-proof

Hydroxychloroquine in mild-to-moderate COVID-19: a placebo-controlled double blind

trial

Vincent Dubée, M.D., Ph.D., Pierre-Marie Roy, M.D., Ph.D., Bruno Vielle, M.D.,
Ph.D., Elsa Parot-Schinkel, M.D., Ph.D., Odile Blanchet, M.D., Astrid Darsonval,
Pharm.D., Caroline Lefeuvre, Pharm.D., Ph.D., Chadi Abbara, Pharm.D., Ph.D.,
Sophie Boucher, M.D., Ph.D., Edouard Devaud, M.D., Olivier Robineau, M.D., Patrick
Rispal, M.D., Thomas Guimard, M.D., Emma d’Anglejean, M.D., Sylvain Diamantis,
M.D., Marc-Antoine Custaud, M.D., Ph.D., Isabelle Pellier, M.D., Ph.D., Alain Mercat,
M.D., Ph.D., for the HYCOVID study group

PII: S1198-743X(21)00140-3
DOI: https://doi.org/10.1016/j.cmi.2021.03.005
Reference: CMI 2452

To appear in: Clinical Microbiology and Infection

Received Date: 10 January 2021

Revised Date: 19 March 2021
Accepted Date: 21 March 2021

Please cite this article as: Dubée V, Roy P-M, Vielle B, Parot-Schinkel E, Blanchet O, Darsonval
A, Lefeuvre C, Abbara C, Boucher S, Devaud E, Robineau O, Rispal P, Guimard T, d’Anglejean E,
Diamantis S, Custaud M-A, Pellier I, Mercat A, for the HYCOVID study group, Hydroxychloroquine in
mild-to-moderate COVID-19: a placebo-controlled double blind trial, Clinical Microbiology and Infection,
https://doi.org/10.1016/j.cmi.2021.03.005.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
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© 2021 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious
Diseases.
 1 Hydroxychloroquine in mild-to-moderate COVID-19: a placebo-

2 controlled double blind trial

3 Vincent Dubée, M.D., Ph.D., Pierre-Marie Roy, M.D., Ph.D., Bruno Vielle, M.D., Ph.D., Elsa Parot-

4 Schinkel, M.D., Ph.D., Odile Blanchet, M.D., Astrid Darsonval, Pharm.D., Caroline Lefeuvre, Pharm.D.,

5 Ph.D., Chadi Abbara, Pharm.D., Ph.D., Sophie Boucher, M.D., Ph.D., Edouard Devaud, M.D., Olivier

6 Robineau, M.D., Patrick Rispal, M.D., Thomas Guimard, M.D., Emma d’Anglejean, M.D., Sylvain

7 Diamantis, M.D., Marc-Antoine Custaud, M.D., Ph.D., Isabelle Pellier, M.D., Ph.D., Alain Mercat,

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8 M.D., Ph.D., for the HYCOVID study group.

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9 Vincent Dubée and Pierre-Marie Roy contributed equally to the study.
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10 Author affiliations
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11 Vincent Dubée: Service des Maladies Infectieuses et Tropicales, CHU d’Angers, Angers, France;

12 CRCINA, Inserm, Université de Nantes, Université d’Angers, Angers, 44200 Nantes, France
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13 Pierre-Marie Roy: Emergency Department, CHU d’Angers, Angers, France; Institut MitoVasc, UMR
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14 CNRS 6215 INSERM 1083, Université d’Angers, Angers, France

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15 Bruno Vielle: Biostatistics and Methodology Department, Maison de la recherche, CHU d’Angers,

16 Angers, France

17 Elsa Parot-Schinkel: Biostatistics and Methodology Department, Maison de la recherche, CHU

18 d’Angers, Angers, France

19 Odile Blanchet: Centre de Ressources Biologiques, BB-0033-00038, CHU d’Angers, Angers, France

20 Astrid Darsonval: Service Pharmacie, CHU d’Angers, Angers, France

21 Caroline Lefeuvre: Département des Agents Infectieux, Laboratoire de virologie, CHU Angers,

22 Angers, France

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23 Chadi Abbara: Laboratoire de Pharmacologie - toxicologie, CHU d’Angers, Angers, France

24 Sophie Boucher: Service d’ORL et Chirurgie Cervico-faciale, CHU d’Angers, Angers, France; Institut

25 MitoVasc, UMR CNRS 6215 INSERM 1083, Université d’Angers, Angers, France

26 Edouard Devaud: Service de médecine interne et maladies infectieuses, CH R. Dubos, Pontoise,

27 France

28 Olivier Robineau: Service Universitaire des Maladies Infectieuses et du Voyageur, CH de Tourcoing,

29 Tourcoing, France

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30 Patrick Rispal: Service de médecine interne, CH Agen, Agen, France

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31 Thomas Guimard: Service de médecine Post-urgence, CH Départemental de Vendée, La Roche sur

32 Yon, France
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33 Emma d’Anglejean: Service de médecine interne et maladies infectieuses, CH Versailles - Hôpital
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34 André Mignot, Le Chesnay, France

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35 Sylvain Diamantis: Service de médecine polyvalente et maladies infectieuses, Groupe Hospitalier

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36 Sud Ile de France, Melun, France

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37 Marc-Antoine Custaud: Centre de Recherche Clinique, CHU d’Angers, Angers, France; MITOVASC

38 Institute, UMR CNRS 6015, UMR INSERM 1083, Angers, France

39 Isabelle Pellier: Unité d’hématologie et d’oncologie pédiatrique, CHU d’Angers, Inserm U1232-

40 CRCINA, Université d’Angers, Angers, France.

41 Alain Mercat: Département de Médecine Intensive-Réanimation, CHU d’Angers, Université d’Angers,

42 Angers, France.

43 A complete list of investigators (HYCOVID study group) is available in the Supplementary appendix.

44

45 Corresponding author
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46 Professor Vincent Dubée

47 Service des Maladies Infectieuses et Tropicales

48 CHU d’Angers

49 4, rue Larrey

50 49933 Angers Cedex 9, France

51 Phone: 0033241353872

52 Fax: 0033241353455

53 vincent.dubee@chu-angers.fr

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54

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55 Keywords: COVID-19; hydroxychloroquine; randomized controlled trial; SARS-CoV-2.

56 Running title: Hydroxychloroquine for COVID-19

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58 Conflict of interest statement: All author: none in relation to this work.

59 Authors’ contribution statement: All authors contributed significantly to the study and agree to be
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60 accountable for all aspects of the work. VD, PMR, IP and AM take responsibility for the publication.
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61
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62 Word count: 2,493

63 Total number of Tables and Figures: 4

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64 Abstract

65 Objectives

66 To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with

67 mild-to-moderate COVID-19 at high risk of worsening.

68 Methods

69 We conducted a multicentre randomized double-blind placebo-controlled trial evaluating

70 hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for

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71 worsening: need for supplemental oxygen, age ≥75 years, age between 60 - 74 years and presence

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72 of at least one comorbidity. Severely ill patients requiring oxygen therapy > 3L/min or intensive care

73
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were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800mg
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74 hydroxychloroquine on Day 0 followed by 400mg per day for 8 days or a placebo. The primary
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75 endpoint was a composite of death or start of invasive mechanical ventilation within 14 days

76 following randomization. Secondary endpoints included mortality and clinical evolution at Day 14
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77 and 28, viral shedding at Day 5 and 10.

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78 Results
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79 The trial was stopped after 250 patients were included due to a slowdown of the pandemic in

80 France. The intention-to-treat population comprised 123 and 124 patients in the placebo and

81 hydroxychloroquine groups, respectively. The median age was 77 (interquartile range 58 – 86) years

82 and 151/250 (60.4%) patients required oxygen therapy. The primary endpoint occurred in 9/124

83 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group

84 (relative risk 1.12; 95% confidence interval 0.45– 2.80). The rate of positive SARS-CoV-2 RT-PCR at

85 day 5 and 10 was 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0%

86 (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between

87 the two groups in any of the other secondary endpoints.

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88 Conclusion

89 In this underpowered trial involving mainly older patients with mild-to-moderate COVID-19, patients

90 treated with hydroxychloroquine did not experience better clinical or virological outcomes than

91 those receiving the placebo.

92 Trial registration: ClinicalTrials.gov Identifier: NCT04325893

93 (https://clinicaltrials.gov/ct2/show/NCT04325893)

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 94 In t r o d u c t io n
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96 Hydroxychloroquine, a derivative of chloroquine that is commonly used in certain autoimmune

97 diseases, has been proposed as a possible treatment of coronavirus-2 (SARS-CoV-2) disease (COVID-

98 19). Preliminary studies suggested that this drug inhibits SARS-CoV-2 replication in vitro [1] and

99 could play a role in shortening viral shedding [2]. However, clinical trials evaluating the efficacy of

100 hydroxychloroquine in COVID-19 subsequently reported controversial and often disappointing

101 results [3–11].

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102 The aim of HYCOVID trial was to evaluate the efficacy and safety of hydroxychloroquine in adult

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103 patients with mild-to-moderate COVID-19 at risk of worsening.
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105 Patients and Methods

106 Trial design

107 HYCOVID was a double-blind, placebo-controlled, randomized trial conducted from April 2 to May

108 21, 2020 in 48 hospitals in France and the Principality of Monaco. Eligible patients were randomly

109 assigned in a 1:1 ratio to receive either hydroxychloroquine (200 mg tablets, orally) or its matching

110 placebo at a dose of two tablets twice daily on the first day followed by one tablet twice daily for

111 8 days (total hydroxychloroquine dose of 4 g) plus standard care as needed.

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112 Patients were randomized immediately after their inclusion into the study using an online

113 application on the study website. Treatment assignment was performed according to a 1:1 ratio by

114
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means of dynamic randomization (randomization by minimization), considering the following eight
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115 criteria: age ≥75 years, need for supplemental oxygen therapy, diagnostic criteria for COVID-19
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116 (positive SARS-CoV-2 RT-PCR or chest CT-scan), initial symptoms of COVID-19 for less than 7 days,
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117 hospitalization, concomitant treatment with azithromycin, concomitant treatment with

118 lopinavir/ritonavir, treatment with corticosteroids, and centre. The allocation arm was concealed for
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119 the patient and for all medical and paramedical staff.
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120 Patients

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121 Men and non-pregnant women aged ≥18 years with a diagnosis of COVID-19 confirmed by positive

122 SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) on a nasopharyngeal swab

123 within 2 days were assessed for eligibility. In centres where RT-PCR could not be performed due to a

124 shortage of swabs or RT-PCR material, the diagnosis could be made based on a chest computed

125 tomography (CT) scan showing typical features of COVID-19. Patients were eligible if they had at

126 least one of the following risk factors for worsening: (i) need for supplemental oxygen to reach a

127 peripheral capillary oxygen saturation of more than 94% (SpO2 >94%) or a ratio of oxygen partial

128 pressure to fractional inspired oxygen less than or equal to 300 mmHg (PaO2/FiO2 ≤300 mmHg); (ii)

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129 age ≥75 years; (iii) age between 60 and 74 years and presence of at least one of the following

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130 comorbidities: obesity (body mass index ≥30 kg/m²), arterial hypertension requiring treatment, or

131 diabetes mellitus requiring treatment. -p

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132 Patients requiring more than 3 L/min of oxygen to reach an SpO2 of 94% were excluded, as were
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133 those with a clinical condition necessitating admission to intensive care unit, a negative SARS-CoV-2

134 RT-PCR, a short-term life-threatening comorbidity (life expectancy <3 months), any condition
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135 contraindicating hydroxychloroquine treatment (known hypersensitivity or allergy, retinopathy,

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136 concomitant treatment associated with a risk of ventricular arrhythmias, use of medications that are
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137 contraindicated with hydroxychloroquine and cannot be replaced or stopped during the trial), or

138 conditions associated with an increased risk of adverse event (see Supplementary Appendix for

139 details). Of note, concomitant treatment with azithromycin was allowed.

140 Clinical and laboratory monitoring

141 For patients with an initial positive SARS-CoV-2 RT-PCR, nasopharyngeal swabs were sampled on Day

142 5 and 10 after randomization, and SARS-CoV-2 RT-PCR was performed using the same local

143 technique as the initial RT-PCR.

144 All adverse events that occurred during a patient’s participation were declared to the sponsor, with

145 the exception of adverse events linked to the COVID-19 itself (for details, see the protocol, available

146 in the Supplementary Materials).

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147 Outcome measures

148 The primary endpoint was a composite of death and the need for invasive mechanical ventilation

149 within 14 days following randomization. Secondary efficacy outcomes included the rate of mortality

150 or invasive ventilation within 28 days following treatment initiation, clinical evolution using the

151 World Health Organization nine-point Ordinal Scale for Clinical Improvement for COVID-19 (with

152 scores ranging from 0 [patients at home without any clinical or biological sign of infection] to 8

153 [death] [12]) at Day 14 and 28, all-cause mortality at Day 14 and 28, the rate of RT-PCR tests positive

154 for SARS-CoV-2 on nasopharyngeal swab samples at Day 5 and Day 10. Three criteria were used for

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155 clinical evolution: the absence of deterioration (stability or decrease of at least one point on the

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156 ordinal scale), clinical improvement (decrease of at least one point on the ordinal scale), and

157
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recovery (score of 0, 1, or 2 on the ordinal scale). The secondary safety outcome consisted in the
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158 rate of serious adverse events at Day 28. Clinical events were adjudicated by an independent event
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159 adjudication committee, whose members were unaware of group assignments.

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160 Trial oversight

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161 The protocol was approved by an independent protection committee and by the French National
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162 Agency for Medicines and Health Products Safety (ANSM), according to French regulations. Written

163 informed consent was obtained prior to any study procedure from each patient or from the patient’s

164 legal representative if the patient was unable to provide consent.

165 Statistical analysis

166 Based on the first available epidemiological data on COVID-19 [13, 14], we estimated the rate of the

167 primary outcome to be 20%. A headcount of 615 patients per group allows demonstrating, under a

168 bilateral hypothesis, an absolute difference of 6% between the two groups (relative difference of

169 30%), with an alpha risk of 5% and a power of 80%. To allow for up to 5% non-evaluable or lost-to-

170 follow-up patients, we set the sample size at 1,300 patients in total.

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171 Our main analysis was performed in the intention-to-treat population. Interim analyses were

172 performed by conducting the triangle test on every 50 patients and were submitted to the

173 Independent Data and Safety Monitoring Board that was formed for this study. A sensitivity analysis

174 was performed in the per-protocol population, i.e., patients with no major deviation from the study

175 protocol. For the safety analysis, all patients who received at least one dose of hydroxychloroquine

176 were included in the intervention group.

177 The rates of the primary outcome were compared between the two groups using the Chi-squared

178 test. The relative risks for each clinical event at Day 14 and 28 and their 95% confidence interval (CI)

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179 were calculated with an adjustment taking into account the baseline status using a Mantel-Haenszel

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180 estimation.
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181 A sequential analysis based on the triangle test was performed using R software, version 3.6.3. Stata
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182 software (version 13) was used for other analyses. Further details regarding the statistical analysis
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183 are provided in the statistical analysis plan, available in the Supplementary Appendix.
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184
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185
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186 Results

187 Patients

188 The trial started on April 1, 2020 and was suspended on May 26, 2020 by the French regulatory

189 authority because of reports of hydroxychloroquine toxicity in pharmacovigilance databases [15] and

190 observational studies [16]. It was definitively stopped by the sponsor on June 9, 2020 because of a

191 low inclusion rate in the context of the slowdown of the pandemic in France (Figure S1).

192 In the 33 centers that completed the screening survey, 11% (202 patients out of 1,822 patients) of

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193 the patients assessed for eligibility were included in the study. In total, 250 patients were

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194 randomized, of which 125 were assigned to receive hydroxychloroquine and 125 the placebo (Figure

195
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1). Among them, one and two patients withdrew consent in the hydroxychloroquine and placebo
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196 groups, respectively. The per-protocol population comprised 226 patients: 116 in the placebo group
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197 and 110 in the hydroxychloroquine group. A summary of the major violations that led to exclusion

198 from the per-protocol population is provided in the Supplementary appendix.

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199 The median age was 77 (interquartile range [IQR]: 58–86) years (Figure S2), and 60% of the patients
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200 required supplemental oxygen at baseline (Table 1). The median time from symptom onset to
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201 randomization was 5 days (IQR: 3–9). The treatment groups were well balanced for baseline

202 demographic and clinical characteristics, as well as for the treatments of interest received at

203 randomization.

204 Primary outcome

205 There was no significant difference in the rate of the primary endpoint, which occurred within

206 14 days following randomization in 8 of 123 patients assigned to the placebo group (6.5%) and 9 of

207 124 patients assigned to the hydroxychloroquine group (7.3%) (relative risk 1.12; 95% CI: 0.45 to

208 2.80; P=0.82) (Table 2 and Figure S3). At 28 days after randomization, 9.8% (12/123) of the patients

209 in the placebo group had died or had been intubated compared to 7.3% (9/124) in the

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210 hydroxychloroquine group (relative risk 0.74; 95% CI: 0.33 to 1.70; Table 2). Details about the cause

211 of death can be found in the supplementary material (Table S3).

212 In the per-protocol population, death or requirement for invasive mechanical ventilation within 14

213 days was observed in 6 of the 116 patients (5.2%) who received the placebo and in 7 of the 110

214 patients treated with hydroxychloroquine (6.4%). The relative risk for death or invasive mechanical

215 ventilation was 1.23 (95% CI: 0.43–3.55) (Table S2). No significant difference between the treatment

216 groups was observed at Day 28.

217

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218 Secondary outcomes

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The clinical evolution assessed by the change in ordinal scale score between Day 0 and Day 14 and
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220 between Day 0 and 28 did not differ between the two groups (Table 2 and Figure 2). At Day 14, 68 of
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221 the 123 patients assigned to the placebo had returned home (55.3%) compared to 71 of the

222 124 patients assigned to hydroxychloroquine (57.3%). The rate of clinical improvement was 65.9%
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223 (81/123) in the placebo group and 67.7% (84/124) in the hydroxychloroquine group. At Day 28,
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224 68.3% (84/123) and 73.4% (91/124) of patients had been discharged from hospital in the placebo
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225 and hydroxychloroquine groups (Table 2), and the rate of clinical improvement was 75.6% (93/123)

226 and 79.0% (98/124), respectively.

227 Viral shedding could be assessed by RT-PCR in 203 and 174 patients at Day 5 and Day 10,

228 respectively (Table 2). The rate of SARS-CoV-2-positive RT-PCR did not differ significantly between

229 the two groups.

230 Analysis of the different outcomes in predefined subgroups can be found in the Supplementary

231 material (Figure S4).

232 Adverse events

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233 Adverse events occurred in 70 of the 124 patients treated with hydroxychloroquine (56.5%)

234 compared to 61 of the 120 patients who received the placebo (50.8%) (Table S4). Serious adverse

235 events were infrequent and occurred at the same frequency in both groups (3 patients in the

236 hydroxychloroquine group [2.4%], and 4 patients in the placebo group [3.3%]; Table S4).

237

238 Discussion

239 In this trial involving patients with mild-to-moderate COVID-19 at higher risk of worsening, we did

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240 not observe a significant difference in the rate of death or start of mechanical ventilation at 14 days

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241 following inclusion between patients treated with hydroxychloroquine and those who received the

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placebo. The rate of serious adverse events was also similar in the two groups.
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243 This is in line with the results observed in randomized open-label studies involving hospitalized
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244 patients [3, 7], as well as with a double-blind, placebo-controlled trial evaluating early

245 hydroxychloroquine treatment in ambulatory [4] and hospitalized patients [17]. All these trials
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246 involved younger patients with a median age of 40 to 58 years. In our trial, the median time from
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247 symptom onset to treatment initiation was 5 days; in the other aforementioned studies, it ranged
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248 from 2 to 7 days.

249 Similarly, we observed no benefit of hydroxychloroquine therapy on the duration of RT-PCR

250 positivity. Previous data concerning the impact of hydroxychloroquine on the duration of viral

251 shedding were conflicting. While an uncontrolled study found that the drug alone or combined with

252 azithromycin induced a rapid decrease in the rate of RT-PCR positivity [2], another found a

253 decreased speed of viral clearance [18], and two randomized open-label studies showed no effect [7,

254 19]. Of note, the decrease in the rate of positive RT-PCR tests observed in our study is in agreement

255 with previous works, which reported a median duration of detectable viral shedding of 14 days after

256 symptom onset in mild COVID-19 and 21 days in severe cases [20-22].

257
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258 The lack of power is the main limitation of our trial. The study was prematurely stopped after the

259 inclusion of 19% of the planned number of patients due to the slowdown of the epidemic and

260 following the publication of a subsequently retracted study raising concerns over

261 hydroxychloroquine cardiovascular toxicity [16]. Severe cardiovascular adverse events with

262 hydroxychloroquine were also reported by the French Network of Pharmacovigilance Centers [15].

263 Finally, an open labelled and a retrospective studies provided negative results on the clinical efficacy

264 of hydroxychloroquine in mild-to-moderate COVID-19 patients [5, 7]. All have contributed to an

265 important decrease of inclusions, questioning study feasibility and justifying an early termination of

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266 the trial. Indeed, the daily number of new covid-19 cases had dramatically decreased in France

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267 (Figure S1) and lead to consider impossible to achieve the planned number of inclusions.

268
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We did not identify any safety concerns related to hydroxychloroquine use. However, we excluded
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269 patients with conditions that put them at risk of increased hydroxychloroquine toxicity, such as
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270 hypokalemia, prolonged corrected QT interval, or concomitant treatment with an increased risk of

271 torsade de pointes, with the exception of azithromycin. Of note, hypokalemia has been identified as
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272 a frequent complication of COVID-19 [23], and its presence is associated with disease severity. The
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273 exclusion of hypokalemic patients may have contributed to the low rate of adverse course that we
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274 observed.

275 The frequency of the primary endpoint, a composite of death or the need for invasive mechanical

276 ventilation at Day 14, was much lower than expected (6.9% versus 20%). This result, in addition with

277 the prematurely stop of the inclusions, impairs the statistical power of our trial. This discrepancy

278 may arise from several factors. First, recent data have demonstrated mortality rates lower than

279 those observed in the early phases of the epidemic in Wuhan, on which we based the estimate of

280 the number of needed patients [13, 14]. Second, 15% of the patients included in this study have

281 been treated with corticosteroids during the disease course, and it has been recently demonstrated

282 that dexamethasone decreases mortality in severe COVID-19 [24]. Finally, we excluded patients with

283 an organ failure requiring intensive care or needing more than 3 L/min of oxygen during the initial

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284 evaluation. This was based on the hypothesis that antiviral agents are more likely to be effective if

285 they are prescribed early in the course of the disease. On the basis of epidemiological studies, we

286 suspected that COVID-19 patients with advanced age and/or with serious comorbidity would

287 frequently worsen, even if they had no sign of severity at baseline. Our results show that most of

288 them had an uncomplicated course with or without hydroxychloroquine.

289

290 In conclusion, due a prematurely stop of the inclusions and a rate of primary outcome lower than

291 expected, this study did not achieve enough power to state on the efficacy of hydroxychloroquine in

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292 patients with mild-to-moderate COVID-19. Nevertheless, no effect of hydroxychloroquine on clinical

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293 evolution or on the kinetics of viral shedding was observed. In line with other recent studies on this

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topic, these results do not support the use of hydroxychloroquine alone in this population.
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296 Conflict of interest: Dr. Mercat reports personal fees from Faron Pharmaceuticals, Air Liquide
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297 Medical Systems, Löwenstein Medical, Fisher Paykel, Medtronic, and Drager Medical, outside the
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298 submitted work. In addition, Dr. Mercat has a patent General Electric licensed.

299 Dr. Robineau reports personal fees and non-financial support from Viiv Healthcare, Gilead, and MSD,
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300 outside the submitted work.

301 Dr. Guimard reports other support from Pfizer Vaccine France, Gilead science, ViiV Healthcare, MSD

302 France, Sanofi aventis France, and Novartis Pharma, outside the submitted work.

303 Dr. Dubee reports other support from Pfizer France and Gilead, outside the submitted work.

304 Dr. Roy reports personal fees and non-financial support from Bayer Health care, Boehringer

305 Ingelheim France, Bristol Myers Squibb, Pfizer, Apsen, Daiichi Sankyo, and Sanofi Aventis France,

306 outside the submitted work.

307 Disclosure forms provided by the authors are available as supplementary material.

308 Funding: This work was supported by a grant from the French Ministry of Health through a national

309 call for proposals for therapeutic trials on COVID-19. The trial also received an exceptional donation
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310 from the Pays de la Loire region and from the Angers Loire Métropole conurbation. None of the

311 funding organizations played any role in the trial design, data collection, analysis of results, or

312 writing of the manuscript.

313 Access to data: anonymized individual data are available upon reasonable request to

314 DataManagement.DRCI@chu-angers.fr

315 Acknowledgments: The authors would like to thank all patients who participated to the study, and

316 all people who contributed to the trial. A complete list of investigators and other people implicated

317 in the study is provided in the supplementary appendix.

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318 Authors' contributions: VD, PMR, HP, EPS, and AM conceptualized the study and its methodology,

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319 VD and PMR supervised the conduct of the study and wrote the original draft of the manuscript. BV

320
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was in charge of data curation and formal analysis. SB, ED, OR, PR, TG, EA, SD, and MAC participated
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321 in data collection. AD was responsible for preparation and shipping of study drugs. CL and OB were
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322 in charge of biological samples. CA was responsible for drug safety. All authors reviewed and edited

323 the manuscript and approved its final version.

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324
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325

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326 References

327 1. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively

328 inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30: 269–71.

329 2. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and

330 azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical

331 trial. Int J Antimicro Agents 2020; 56: 105949.

332 3. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, et al. Hydroxychloroquine with or

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333 without Azithromycin in Mild-to-Moderate Covid-19. New Eng J Med 2020; NEJMoa2019014.

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334 4. Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al.

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340 6. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of

341 Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients

342 With COVID-19 in New York State. JAMA 2020; 323: 2493–502.

343 7. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with

344 mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.

345 BMJ 2020; 369: m1849.

346 8. Mitjà O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias A, et al. Hydroxychloroquine

347 for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clin Infect Dis

348 2020; ciaa1009.

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350 Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020; 382: 2411–8.

351 10. Fiolet T, Guihur A, Rebeaud M, Mulot M, Peiffer-Smadja N, Mahamat-Saleh Y. Effect of

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353 systematic review and meta-analysis. Clin Microbiol Infect 2020; S1198-743X(20)30505-X.

354 11. RECOVERY Collaborative Group. Effect of Hydroxychloroquine in Hospitalized Patients with

355 Covid-19. [Published 8 October 2020]. New Eng J Med. doi: 10.1056/NEJMoa2022926

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19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf. Date last
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361 Diseases (COVID-19) — China, 2020. CCDCW 2020;2(8):113‑22.

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362 14. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir–Ritonavir in Adults
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364 15. Gérard A, Romani S, Fresse A, Viard D, Parassol N, Granvuillemin A, et al. "Off-label" use of

365 hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey

366 of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers.

367 Therapie 2020;75:371-9

368 16. Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine

369 with or without a macrolide for treatment of COVID-19: a multinational registry analysis.

370 Lancet 2020; S0140-6736(20)31180-6.

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371 17. Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of

372 Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A

373 Randomized Clinical Trial. JAMA 2020; 324:2165-76

374 18. Mallat J, Hamed F, Balkis M, Mohamed MA, Mooty M, Malik A, et al. Hydroxychloroquine is

375 associated with slower viral clearance in clinical COVID-19 patients with mild to moderate

376 disease: A retrospective study. MedRxiv [Preprint]. Available at:

377 https://www.medrxiv.org/content/10.1101/2020.04.27.20082180v1. Date last accessed: 8

378 October 2020.

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384 transmissibility of COVID-19. Nat Med 2020; 26: 672–5.

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385 21. Widders A, Broom A, Broom J. SARS-CoV-2: The viral shedding vs infectivity dilemma. Infect Dis
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386 Health 2020; 25: 210–5.

387 22. Zheng S, Fan J, Yu F, Feng B, Lou B, Zou Q, et al. Viral load dynamics and disease severity in

388 patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020:

389 retrospective cohort study. BMJ 2020; 369: m1443.

390 23. Chen D, Li X, Song Q, Hu C, Su F, Dai J, Ye Y, et al. Assessment of Hypokalemia and Clinical

391 Characteristics in Patients With Coronavirus Disease 2019 in Wenzhou, China. JAMA Netw

392 Open 2020; 3: e2011122.

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393 24. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al.

394 Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med

395 2020; NEJMoa2021436.

396

397

398

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399 Tables
400 Table 1: Baseline demographic, biological, and clinical characteristics of the patients

Characteristic

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 Lopinavir – ritonavir 1 (0.8) 2 (1.6)

Corticosteroids 13 (10.4) 11 (8.8)

Angiotensin-converting enzyme inhibitors or

43 (34.4) 39 (32.2)
angiotensin receptor blockers

Symptoms – no. (%)

Body temperature >38°C 28 (22.4) 25 (20.2)

Diarrhea 22 (17.6) 12 (9.6)

Rhinitis 9 (7.2) 7 (5.6)

Anosmia or hyposmia 19 (15.2) 17 (13.7)

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Confusion 16 (12.8) 17 (13.6)

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Median time (IQR) from onset of symptoms to inclusion

– days -p5 (3-9) 5 (3-8)

*One patient may have several severity risk criteria.

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402

403 Table 2: Outcomes in the intention-to-treat population

Hydroxychloroquine Placebo
Relative risk (95% CI)
Outcomes (N = 124) (N = 123)

Primary outcome

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405 Figure Legends
406

407 Figure 1. Patient selection, treatment allocation, and follow-up.

408 Assessment of eligibility criteria in all consecutive patients admitted for COVID-19 was reported in 33

409 of the 48 participating centers. Among the 1822 patients assessed for eligibility in these 33 centers,

410 202 patients were included leading to an inclusion rate of COVID-19 patients in the HYCOVID trial of

411 11%.

412

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416 Figure 2. Clinical status at inclusion, Day 14, and Day 28 according to treatment group.
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417 The figure shows the clinical status of patients allocated to the placebo (n = 123) or
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418 hydroxychloroquine (HCQ) at inclusion, Day 14, and Day 28. Data are missing at Day 14 and 28 for
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419 two patients in each group. No patient had a score of 5 (non-invasive ventilation or high-flow

420 oxygen) at Day 14 or 28.

421 The Ordinal Scale for Clinical Improvement is proposed by the World Health Organization as an

422 outcome measure. The score reads as follows: 0: patient uninfected, no clinical or virological signs of

423 infection; 1: patient at home, without limitation of activities; 2: patient at home, with limitation of

424 activities; 3: patient hospitalized without oxygen therapy; 4: patient with oxygen therapy by mask or

425 nasal prongs; 5: patient under non-invasive ventilation or high-flow oxygen; 6: patient under invasive

426 mechanical ventilation; 7; patient under invasive mechanical ventilation and additional organ

427 support, including vasopressors, renal replacement therapy, and extracorporeal membrane

428 oxygenation; 8: death.

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Members of the HYCOVID study group and people

to be acknowledged

HYCOVID investigators .............................................................................................................................. 2

Composition of the HYCOVID management team .................................................................................... 8
Acknowledgments ..................................................................................................................................... 9

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Dubee V et al. Hydroxychloroquine for COVID-19

HYCOVID investigators
(last names in bold characters)

Angers University Hospital

Antoine Brangier, M.D., Service de gériatrie, CHU d’Angers, Angers, France
Philippe Codron, M.D., Service de neurologie, CHU d’Angers, Angers, France
Jean Michel Lemée, M.D., Service de neurochirurgie, CHU d’Angers, Angers, France
Virginie Pichon, M.D., Service de neurologie, CHU d’Angers, Angers, France
Robin Dhersin, Service de maladies infectieuses et tropicales, CHU d’Angers, Angers, France
Geoffrey Urbanski, Service de médecine interne, CHU d’Angers, Angers, France
Christian Lavigne, Service de médecine interne, CHU d’Angers, Angers, France

Cholet Hospital
Roxane Courtois, M.D., Service de Médecine post-urgences – Maladies infectieuses, CH Cholet, Cholet,

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France

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Laval Hospital
Hélène Danielou, M.D., Service de Médecine interne, hématologie, maladies infectieuses, CH Laval, Laval,
France -p
Jonathan Lebreton, M.D., Service de Médecine interne, hématologie, maladies infectieuses, CH Laval, Laval,
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France
Rémi Vatan, M.D., Service de Médecine interne, hématologie, maladies infectieuses, CH Laval, Laval, France
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Le Mans Hospital
Nicolas Crochette, M.D., Service de maladies infectieuses et tropicales, CH Le Mans, Le Mans, France
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Jean-Baptiste Lainé, M.D., Service de maladies infectieuses et tropicales, CH Le Mans, Le Mans, France
Lucia Perez, M.D., Service de maladies infectieuses et tropicales, CH Le Mans, Le Mans, France
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Sophie Blanchi, M.D., Service de maladies infectieuses et tropicales, CH Le Mans, Le Mans, France
Hikombo Hitoto, M.D., Service de maladies infectieuses et tropicales, CH Le Mans, Le Mans, France
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Tours University Hospital

Louis Bernard, M.D., Ph.D., Service de maladies infectieuses et tropicales, CHU Tours, Tours, France
François Maillot, M.D., Ph.D., Service de médecine interne, CHU Tours, Tours, France
Sylvain Marchand Adam, M.D., Service de médecine interne, CHU Tours, Tours, France

Quimper Hospital
Jean-Philippe Talarmin, M.D., Service de médecine interne, maladies du sang et infectiologie, CH de
Quimper, Quimper, France

La Roche sur Yon Hospital

Emeline Gaigneux, M.D., Service de Rhumatologie, Centre Hospitalier Départemental Vendée, La Roche sur
Yon, France
Pauline Motte-Vincent, M.D., Service de Médecine Post-urgence, Centre Hospitalier Départemental
Vendée, La Roche sur Yon, France
Marine Morrier, M.D., Service de Médecine Post-urgence, Centre Hospitalier Départemental Vendée, La
Roche sur Yon, France
Dominique Merrien, M.D., Service de Médecine Post-urgence, Centre Hospitalier Départemental Vendée,
La Roche sur Yon, France

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Dubee V et al. Hydroxychloroquine for COVID-19

Yves Bleher, M.D., Service de Médecine Post-urgence, Centre Hospitalier Départemental Vendée, La Roche
sur Yon, France
Maxime Flori, M.D., Service de Cardiologie, Centre Hospitalier Départemental Vendée, La Roche sur Yon,
France
Amélie Ducet-Boiffard, M.D., Service d’endocrinologie - diabétologie, Centre Hospitalier Départemental
Vendée, La Roche sur Yon, France
Orane Colin, M.D., Service de Médecine Post-urgence, Centre Hospitalier Départemental Vendée, La Roche
sur Yon, France
Ronan Février, M.D., Service de Médecine Gériatrique, Centre Hospitalier Départemental Vendée, La Roche
sur Yon, France

Tourcoing Hospital
Pauline Thill, MD, Service Universitaire des Maladies Infectieuses et du Voyageur, CH de Tourcoing,
Tourcoing, France

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Macha Tetart, MD, Service Universitaire des Maladies Infectieuses et du Voyageur, CH de Tourcoing,
Tourcoing, France

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François Demaeght, MD, Service Universitaire des Maladies Infectieuses et du Voyageur, CH de Tourcoing,
Tourcoing, France
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Barthelemy Lafond-Desmurs, MD, Service Universitaire des Maladies Infectieuses et du Voyageur, CH de
Tourcoing, Tourcoing, France
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Maxime Pradier, MD, Service Universitaire des Maladies Infectieuses et du Voyageur, CH de Tourcoing,
Tourcoing, France
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Agnes Meybeck, MD, Service Universitaire des Maladies Infectieuses et du Voyageur, CH de Tourcoing,
Tourcoing, France
Marjorie Picaud, MD, Service de pneumologie, CH de Tourcoing, Tourcoing, France
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Orléans Hospital
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Thierry Prazuck, M.D., Service de maladies infectieuses et tropicales, CH régional d’Orléans, Orléans, France
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Nantes University Hospital

Guillaume Chapelet, M.D., Service de médecine aiguë gériatrique, CHU de Nantes, Nantes, France
Agnès Rouaud, M.D., Service de médecine aiguë gériatrique, CHU de Nantes, Nantes, France
Paul Le Turnier, M.D., Service de maladies infectieuses et tropicales, CHU de Nantes, Nantes, France

Niort Hospital
Simon Sunder, M.D., Service de maladies infectieuses et tropicales, CH de Niort, Niort, France

Lorient Hospital
Aurélien Lorleac'h, M.D., Service de médecine interne - maladies infectieuses, Hôpital du Scorff, Groupe
Hospitalier Bretagne Sud, Lorient, France
Christophe Dollon, M.D., Service de médecine polyvalente, Hôpital du Scorff, Groupe Hospitalier Bretagne
Sud, Lorient, France
Antoine Jacquet, M.D., Service de médecine polyvalente, Hôpital du Scorff, Groupe Hospitalier Bretagne
Sud, Lorient, France
Francois Le Vely, M.D., Service de médecine polyvalente, Hôpital du Scorff, Groupe Hospitalier Bretagne
Sud, Lorient, France

Brest University Hospital

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Dubee V et al. Hydroxychloroquine for COVID-19

Pierre Gazeau, M.D., Service de maladies infectieuses et tropicales, CHU de Brest, Brest, France
Séverine Ansart, M.D., Ph.D., Service de maladies infectieuses et tropicales, CHU de Brest, Brest, France

Cherbourg Hospital
Hélène Roger, M.D., Service de médecine interne et maladies infectieuses, CH du Cotentin, Cherbourg,
France
François Laterza, M.D., Service de médecine interne et maladies infectieuses, CH du Cotentin, Cherbourg,
France

Saint-Brieuc Hospital
Rodolphe Buzelé, M.D., Service de médecine interne et maladies infectieuses, CH Yves Le Foll, Saint-Brieuc,
France

Créteil – APHP University Hospital

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Fella Tahmi, M.D., Service de Gériatrie, CHU Henri Mondor – APHP, Créteil, France.
Raphael Lepeule, M.D., Unité Transversale de Traitement des Infections, CHU Henri Mondor – APHP,

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Créteil, France.

Saint-Antoine – APHP University Hospital -p

Karine Lacombe, M.D., Ph.D., Service de maladies infectieuses et tropicales, CHU Saint Antoine – APHP,
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Paris, France
Bénédicte Lefebvre, M.D., Service de maladies infectieuses et tropicales, CHU Saint Antoine – APHP, Paris,
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France

Saint-Etienne University Hospital

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Thomas Célarier, M.D., Service de gérontologie clinique, CHU Saint-Etienne, Saint-Etienne, France
Amandine Gagneux-Brunon, M.D., PhD., Service d’Infectiologie, CHU Saint-Etienne, Saint-Etienne, France
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Elisabeth Botelho-Nevers, M.D., Ph.D., Service d’infectiologie, CHU Saint-Etienne, Saint-Etienne, France
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Toulouse University Hospital

Marc Bernard, M.D., Post-Urgences Médicale, CHU Toulouse, Toulouse, France
Camille Garnier, M.D., Service de maladies infectieuses et tropicales, CHU Toulouse, Toulouse, France
Morgane Mourguet, M.D., Service de maladies infectieuses et tropicales, CHU Toulouse, Toulouse, France
Gregory Pugnet, M.D., Ph.D, Service de Médecine interne, CHU Toulouse, Toulouse, France
Sara Vienne-Noyes, M.D., Post-Urgences Gériatrique, CHU Toulouse, Toulouse, France
Guillaume Martin-Blondel, M.D., Ph.D., Service de maladies infectieuses et tropicales, CHU Toulouse,
Toulouse, France
Pierre Delobel, M.D., Ph.D., Service de maladies infectieuses et tropicales, CHU Toulouse, Toulouse, France
Gaspard Grouteau, M.D., Service de maladies infectieuses et tropicales, CHU Toulouse, Toulouse, France
Alexa Debard, M.D., Service de maladies infectieuses et tropicales, CHU Toulouse, Toulouse, France
Laurent Guilleminault, M.D., Ph.D., Service de Pneumologie, CHU Toulouse, Toulouse, France

Melun Hospital
Pauline Arias, M.D., Service de médecine polyvalente et maladies infectieuses, Groupe Hospitalier Sud Ile
de France, Melun, France
Catherine Chakvetadze, Service de médecine polyvalente et maladies infectieuses, Groupe Hospitalier Sud
Ile de France, Melun, France

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Dubee V et al. Hydroxychloroquine for COVID-19

Clara Flateau, Service de médecine polyvalente et maladies infectieuses, Groupe Hospitalier Sud Ile de
France, Melun, France
Aude Kopp, Service de médecine polyvalente et maladies infectieuses, Groupe Hospitalier Sud Ile de
France, Melun, France

Dijon University Hospital

Alain Putot, ervice de médecine interne gériatrie, CHU Dijon Bourgogne, Dijon, France
Jeremy Barben, Service de médecine interne gériatrie, CHU Dijon Bourgogne, Dijon, France
Suzanne Mouries Martin, Service de médecine interne et maladies systémiques, CHU Dijon Bourgogne,
Dijon, France
Valentine Nuss, Service de médecine interne gériatrie, CHU Dijon Bourgogne, Dijon, France
Lionel Piroth, M.D., Ph.D., Département d’infectiologie, CHU Dijon Bourgogne, Dijon, France

Princesse Grace – Monaco Hospital

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Yann-Erick Claessens, M.D., Ph.D., Service des urgences, Centre Hospitalier Princesse Grace, Monaco,
Principauté de Monaco

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Versailles Hospital
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Veronique Hentgen, M.D., Service de pédiatrie, CH Versailles - Hôpital André Mignot, Le Chesnay, France
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Colmar Hospital
Martin Martinot, M.D., Service de Maladies Infectieuses et Tropicales, Hôpital Pasteur Colmar, Colmar,
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France
Maxime Bach-Bunner, M.D., Service de médecine interne, Hôpital Pasteur Colmar, Colmar, France
Thomas Bonijoly, M.D., Service de Maladies Infectieuses et Tropicales, Hôpital Pasteur Colmar, Colmar,
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France
Simon Gravier, M.D., Service de Maladies Infectieuses et Tropicales, Hôpital Pasteur Colmar, Colmar,
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France
Jean-Marc Michel, M.D., Service de gériatrie, Hôpital Pasteur Colmar, Colmar, France
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Agen-Nerac Hospital
Mathilde Andreu, M.D., Service de pneumologie, CH Agen, Agen, France
Mélanie Roriz, M.D., Service de médecine interne, CH Agen, Agen, France

Caen University Hospital

Aurélie Baldolli, M.D., Service de Maladies Infectieuses et Tropicales, CHU Caen, Caen, France

Saint-Nazaire Hospital
Julia Brochard, M.D., Service de médecine polyvalente – infectiologie, CH Saint Nazaire, St Nazaire, France

Nantes – Confluent Hospital

Olivier Grossi, M.D., Service de médecine interne et maladies infectieuses, Hôpital privé du Confluent,
Nantes, France
Samuel Pineau, M.D., Service de médecine interne et maladies infectieuses, Hôpital privé du Confluent,
Nantes, France

Limoges University Hospital

Josselin Brisset, M.D., Service de maladies infectieuses et tropicales, CHU de Limoges, Limoges, France

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Dubee V et al. Hydroxychloroquine for COVID-19

Edouard Desvaux, M.D., Service de médecine interne et gériatrique, CHU de Limoges, Limoges, France
Guillaume Gondran, M.D., Service de médecine interne A, CHU de Limoges, Limoges, France
Jean-François Faucher, M.D., Ph.D., Service de maladies infectieuses et tropicales, CHU de Limoges,
Limoges, France
Paul-Antoine Quesnel, M.D., Service d’accompagnement et soins palliatifs, CHU de Limoges, France
Holy Bezanahary, M.D., Service de médecine interne A, CHU de Limoges, Limoges, France
Clément Danthu, M.D., Service de néphrologie, CHU de Limoges, Limoges, France
Blandine Gutierrez, M.D., Service de médecine interne A, CHU de Limoges, Limoges, France
Kim Ly, M.D.,Ph.D., Service de médecine interne A, CHU de Limoges, Limoges, France
Yannick Simonneau, Service de pathologie respiratoire, CHU de Limoges, Limoges, France
Anne Cypierre, M.D., Service de maladies infectieuses et tropicales, CHU de Limoges, Limoges, France
Pauline Pinet, M.D., Service de maladies infectieuses et tropicales, CHU de Limoges, Limoges, France
Hélène Durox, M.D., Service de maladies infectieuses et tropicales, CHU de Limoges, Limoges, France
Sophie Ducroix-Roubertou, M.D., Service de maladies infectieuses et tropicales, CHU de Limoges, Limoges,

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France
Claire Genet, M.D., Service de maladies infectieuses et tropicales, CHU de Limoges, Limoges, France

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Poitiers University Hospital
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Guillaume Beraud, M.D., Service de maladies infectieuses et tropicales, CHU de Poitiers, Poitiers, France
Gwenael Le Moal, M.D., Service de maladies infectieuses et tropicales, CHU de Poitiers, Poitiers, France
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Blandine Rammaert, M.D., Ph.D., Service de maladies infectieuses et tropicales, CHU de Poitiers, Poitiers,
France
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Amiens University Hospital

Jean-Philippe Lanoix, M.D., Ph.D., Service de Service de maladies infectieuses et tropicales, CHU d’Amiens,
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Amiens, France
Claire Andrejak, M.D., Ph.D., Service de pneumologie, CHU Amiens, Amiens, France
ur

Cédric Joseph, M.D., Service de Service de maladies infectieuses et tropicales, CHU d’Amiens, Amiens,
France
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Sandrine Soriot-Thomas, M.D., Centre de recherche clinique, CHU d’Amiens, Amiens, France

Bobigny – APHP University Hospital

Robin Dhote, M.D., Ph.D., Service de médecine interne, CHU Avicennes – APHP, Bobigny, France
Sébastien Abad, M.D., Service de médecine interne, CHU Avicennes – APHP, Bobigny, France
Ruben Benainous, M.D., Service de médecine interne, CHU Avicennes – APHP, Bobigny, France

Cergy-Pontoise Hospital
Jean-François Boitiaux, M.D., Service de pneumologie, CH René-Dubos, Cergy-Pontoise, France
Guillaume Briend, M.D., Service de pneumologie, CH René-Dubos, Cergy-Pontoise, France
Celine Gonfroy, M.D., Service d’endocrinologie, CH René-Dubos, Cergy-Pontoise, France
Stanislas Harent, M.D., Service de médecine interne et maladies infectieuses, CH René-Dubos, Cergy-
Pontoise, France
Aurore Lagrange, M.D., M.D., Service de pneumologie, CH René-Dubos, Cergy-Pontoise, France

Valencienne Hospital
Alina Tone, M.D., Service d’infectiologie, CH de Valenciennes, Valenciennes, France
Laura Wayenberg, M.D., Service d’infectiologie, CH de Valenciennes, Valenciennes, France
Sophie Desoutter, M.D., Service d’infectiologie, CH de Valenciennes, Valenciennes, France

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Dubee V et al. Hydroxychloroquine for COVID-19

Nicolas Ettahar, M.D., Service d’infectiologie, CH de Valenciennes, Valenciennes, France

Valencienne – Clinique Tessier Hospital

Thomas Gey, M.D., M.D., Service de pneumologie, Clinique Teissier, Valencienne, France
Vincent Leroy, M.D., Service de pneumologie, Clinique Teissier, Valenciennes, France
Sacha Gaillard, M.D., Service de pneumologie, Clinique Teissier, Valenciennes, France

Henri-Mondor – APHP University Hospital

Andrea Toma, M.D., Ph.D., Service A1, Hôpital Dupuytren, CHU Henri Mondor-APHP, Draveil, France
Amaury Broussier, M.D., Service de Gériatrie Ambulatoire, Hôpital Emile Roux – GHU-APHP Henri Mondor,
Limeil Brévannes, France
Sandrine Etienne, M.D., Service de Gérontologie 1, Hôpital Emile Roux – GHU-APHP Henri Mondor, Limeil
Brévannes, France
Yann Spivac, M.D., Service de Gérontologie 1, Hôpital Emile Roux – GHU-APHP Henri Mondor, Limeil

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Brévannes, France

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Chalon-sur-Saône Hospital
Benoit Martha, M.D., Service de maladies infectieuses, CH de Chalon-sur-Saône, Chalon-sur-Saône, France
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Nathalie Roch, M.D., Service de maladies infectieuses, CH de Chalon-sur-Saône, Chalon-sur-Saône, France
Pierre Diaz, M.D., Service de pneumologie, CH de Chalon-sur-Saône, Chalon-sur-Saône, France
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Danièle N’guyen Baranoff, M.D., Service de pneumologie, CH de Chalon-sur-Saône, Chalon-sur-Saône,
France
lP

Marseille European Hospital

Stanislas Rebaudet, M.D., Ph.D., Hôpital Européen, Marseille, France
na

Auxerre Hospital
ur

François Jourda, M.D., Service de Cardiologie, CH d’Auxerre, Auxerre, France

Jo

Diaconnesses Croix-Saint-Simon Hospital

Valérie Zeller, M.D., Service de Médecine interne et infectiologie, Groupe Hospitalier Diaconesses – Croix
Saint Simon, Paris, France

Marseille – Saint Joseph Hospital

Boris Bienvenu, M.D., Ph.D., Service de médecine interne, Hôpital Saint Joseph, Marseille, France
Arnaud Boyer, M.D., Service de pneumologie, Hôpital Saint Joseph, Marseille, France

7
Dubee V et al. Hydroxychloroquine for COVID-19

Composition of the HYCOVID management team

Steering committee (authors)
Isabelle Pellier
Alain Mercat
Astrid Darsonval
Odile Blanchet
Marc-Antoine Custaud
Caroline Lefeuvre
Elsa Parot-Schinkel
Bruno Vielle
Marie Briet
Pierre-Marie Roy (Chair)
Vincent Dubée

of
Independant data safety and monitoring board

ro
Bertrand Guidet (Chair)
Patrick Mismetti
Eric Vicaut -p
re
Independent adjudication of clinical events committee
Olivier Sanchez
Philippe Girard
lP

Antoine Elias
Francis Couturaud
na

Study management
Coordination
ur

Béatrice Gable
Sybille Lazareff
Jo

Loïc Carballido
Catherine Hue

Data management
Jean-Marie Chrétien
Adrien Goraguer
Lucie van Eeckhoutte

8
Dubee V et al. Hydroxychloroquine for COVID-19

Acknowledgments
Other people who contributed to the study but do not fulfill the criteria for auhtorship
Center First Name

of
ro
-p
re
lP
na
ur
Jo

9
Dubee V et al. Hydroxychloroquine for COVID-19

Chalon/Saône Jérôme Poirot Research management assistant

Chalon/Saône Jérôme Coutet Doctor of Pharmacy
Cherbourg Aude Grébert-Manuardi Clinical Study Coordinator
Cherbourg Bertrand Sauneuf Doctor of Medicine
Cherbourg Bleuenn Dreves Doctor of Medicine
Cherbourg Caroline Viron Doctor of Medicine
Cherbourg Cécilia Deac Doctor of Medicine
Cherbourg Cindy Beche Doctor of Medicine
Cherbourg Eleonore Deck Doctor of Medicine
Cherbourg Thierry Colin Doctor of Medicine
Cholet Caroline Francois Research management assistant
Cholet Laetitia Seguin Research management assistant
Cholet Laura Vallee Research management assistant
Cholet Marie Gaume Doctor of Pharmacy

of
Colmar Anne Pachart Research management assistant
Colmar Sabine Camara Research management assistant

ro
Dupuytren Patrick Leglise Doctor of Pharmacy
Dupuytren Zafy Ralantonisainana Doctor of Medicine
Emile Roux
GH Croix Saint Simon
Veronique
Youbes
-p
Vianefe
Kerroumi
Research management assistant
Clinical Research Assistant
re
Hôpital Européen Marseille Amélie Rognon Doctor of Pharmacy
Hôpital Européen Marseille Christina Psomas Doctor of Medicine
lP

Hôpital Européen Marseille Corine Madjarian Clinical Research Assistant

Hopital Privé du Confluent Claire Hussenet Doctor of Medicine
Hopital Privé du Confluent Delphine Egret Research management assistant
na

La Roche sur Yon Hélène Pélerin Research management assistant

La Roche sur Yon Catherine Albrecht Research management assistant
ur

La Roche sur Yon Edwige Migne Clinical Research Nurse

La Roche sur Yon Hélène Durand Clinical Research Nurse
Jo

La Roche sur Yon Peguy Chupeau Clinical Research Nurse

Le Chesnay Beulaygue Anais Research management assistant
Le Chesnay Greder Belan Alix Doctor of Medicine
Le Chesnay Kaoudji Salima Research management assistant
Limoges Eloïse Dobbels Research management assistant
Limoges Françoise Renon-Carron Doctor of Pharmacy
Limoges Hugues Caly Doctor of Medicine
Limoges Laurent Fourcade Doctor of Medicine
Limoges Lynda Pervieux Research management assistant
Lorient Mariella Le Saux Research management assistant
Melun Tracy Youbong Doctor of Medicine
Mondor Amel Gouja Research management assistant
nantes Albane Soria Clinical Research Assistant
Nantes Benjamin Gaborit Doctor of Medicine
Nantes Ernesto Paredes Clinical Research Assistant
Nantes Jérémie Orain Clinical Research Assistant
Nantes Morane Cavellec Clinical Research Assistant
Nantes Morgane Le Bras Clinical Research Assistant
Niort Anabele Dos Santos Doctor of Medicine

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Dubee V et al. Hydroxychloroquine for COVID-19

Niort Diane Chuillet Moreau Clinical Research Assistant

Niort Jeanne Oddoz Clinical Research Assistant
Niort Kinda Schepers Doctor of Medicine
Niort Veronique Goudet Doctor of Medicine
Pontoise Celeste Lambert Doctor of Medicine
Pontoise Marine Gosset Doctor of Medicine
Pontoise Sixtine Decaux Resident
Quimper Clémence Arrivé Clinical Research Assistant
Quimper Lydie Khatchatourian Doctor of Medicine
Quimper Marie-Sarah Fangous Doctor of Pharmacy
Quimper Nadia Saïdani Doctor of Medicine
Quimper Nicolas Cassou Doctor of Pharmacy
Quimper Pascaline Rameau Clinical Research Assistant
Saint Brieuc Marie Cécile Hervé Research management assistant

of
Saint-Antoine Paris Christian Tran Clinical Research Assistant
Saint-Antoine Paris Cyrielle Le Taillandier Clinical Research Assistant

ro
Saint-Antoine Paris Jean-Luc Lagneau Clinical Research Assistant
Saint-Antoine Paris Julie Lamarque Clinical Research Assistant
Saint-Antoine Paris
Saint-Antoine Paris
Juliette
Manuela
-p
Blondy
Le Cam
Clinical Research Assistant
Clinical Research Assistant
re
Saint-Etienne Anne Pouvaret Doctor of Medicine
Saint-Etienne Anne Fresard Doctor of Medicine
lP

Saint-Etienne Céline Cazorla Doctor of Medicine

Saint-Etienne Cyrille Renaud Clinical Research Assistant
Saint-Etienne Maelle Detoc Clinical Research Assistant
na

Saint-Etienne Marie France Lutz Doctor of Medicine

Saint-Etienne Veronique Ronat Clinical Research Assistant
ur

St Nazaire Aurore Deininger Doctor of Pharmacy

St Nazaire Pauline Le Floch Clinical Research Assistant
Jo

St Nazaire Servane Vastral Clinical Research Assistant

Tourcoing Marie-Caroline Marien Clinical Research Assistant
Tourcoing Pauline Cornavin Clinical Research Assistant
Tourcoing Solange Trehoux Clinical Research Assistant
Tourcoing Sylvie Devlieger Clinical Research Assistant
Tourcoing Vincent Derdour Clinical Research Assistant
Valencienne Marielle Fery Clinical Research Assistant
Valencienne Stéphanie Legrand Clinical Research Assistant
Valencienne Aurore Dehon Clinical Research Assistant
Valencienne Dominique Dautel Doctor of Pharmacy
Valencienne Nathalie Leone Medical Doctor

11