Hydroxychloroquine in Mild-To-Moderate COVID-19 A
Hydroxychloroquine in Mild-To-Moderate COVID-19 A
Hydroxychloroquine in Mild-To-Moderate COVID-19 A
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
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.
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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-
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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15 Bruno Vielle: Biostatistics and Methodology Department, Maison de la recherche, CHU d’Angers,
16 Angers, France
19 Odile Blanchet: Centre de Ressources Biologiques, BB-0033-00038, 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
27 France
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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37 Marc-Antoine Custaud: Centre de Recherche Clinique, CHU d’Angers, Angers, France; MITOVASC
39 Isabelle Pellier: Unité d’hématologie et d’oncologie pédiatrique, CHU d’Angers, Inserm U1232-
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
48 CHU d’Angers
49 4, rue Larrey
51 Phone: 0033241353872
52 Fax: 0033241353455
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55 Keywords: COVID-19; hydroxychloroquine; randomized controlled trial; SARS-CoV-2.
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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64 Abstract
65 Objectives
66 To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with
68 Methods
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
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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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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
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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
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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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
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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
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
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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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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
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
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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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
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
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
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
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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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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
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
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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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
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.
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
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
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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)
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
230 Analysis of the different outcomes in predefined subgroups can be found in the Supplementary
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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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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.
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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
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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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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,
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
313 Access to data: anonymized individual data are available upon reasonable request to
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
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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
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
332 3. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, et al. Hydroxychloroquine with or
of
333 without Azithromycin in Mild-to-Moderate Covid-19. New Eng J Med 2020; NEJMoa2019014.
ro
334 4. Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al.
335
-p
Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Ann
re
336 Intern Med 2020; M20–4207.
lP
337 5. Mahévas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al. Clinical efficacy of
na
338 hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational
ur
339 comparative study using routine care data. BMJ 2020; 369: m1844.
Jo
340 6. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of
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.
347 for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clin Infect Dis
17
349 9. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational Study of
350 Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020; 382: 2411–8.
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
of
356 12. COVID-19 Treatment trial design - Master Protocol [Internet]. World Health Organization;
ro
357 2020. Available at: https://www.who.int/blueprint/priority-diseases/key-action/COVID-
358 -p
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf. Date last
re
359 accessed: 8 October 2020.
lP
360 13. Team TNCPERE. The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus
na
362 14. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir–Ritonavir in Adults
Jo
363 Hospitalized with Severe Covid-19. N Engl J Med 2020; 382: 1787–99.
364 15. Gérard A, Romani S, Fresse A, Viard D, Parassol N, Granvuillemin A, et al. "Off-label" use of
366 of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers.
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.
18
371 17. Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of
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
of
379 19. Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. A pilot study of hydroxychloroquine in treatment of
ro
380 patients with moderate COVID-19. Available at:
381
-p
http://www.zjujournals.com/med/EN/10.3785/j.issn.1008-9292.2020.03.03. Date last
re
382 accessed: 8 October 2020.
lP
383 20. He X, Lau EHY, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral shedding and
na
385 21. Widders A, Broom A, Broom J. SARS-CoV-2: The viral shedding vs infectivity dilemma. Infect Dis
Jo
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:
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
19
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
396
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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)
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Confusion 16 (12.8) 17 (13.6)
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Median time (IQR) from onset of symptoms to inclusion
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Hydroxychloroquine Placebo
Relative risk (95% CI)
Outcomes (N = 124) (N = 123)
Primary outcome
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405 Figure Legends
406
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
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
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HYCOVID investigators
(last names in bold characters)
Cholet Hospital
Roxane Courtois, M.D., Service de Médecine post-urgences – Maladies infectieuses, CH Cholet, Cholet,
of
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,
re
France
Rémi Vatan, M.D., Service de Médecine interne, hématologie, maladies infectieuses, CH Laval, Laval, France
lP
Le Mans Hospital
Nicolas Crochette, M.D., Service de maladies infectieuses et tropicales, CH Le Mans, Le Mans, France
na
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
ur
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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Quimper Hospital
Jean-Philippe Talarmin, M.D., Service de médecine interne, maladies du sang et infectiologie, CH de
Quimper, Quimper, 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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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
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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
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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.
France
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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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
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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
Saint-Nazaire Hospital
Julia Brochard, M.D., Service de médecine polyvalente – infectiologie, CH Saint Nazaire, St Nazaire, 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, France
Claire Andrejak, M.D., Ph.D., Service de pneumologie, CHU Amiens, Amiens, France
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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
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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Brévannes, France
ro
Chalon-sur-Saône Hospital
Benoit Martha, M.D., Service de maladies infectieuses, CH de Chalon-sur-Saône, Chalon-sur-Saône, France
-p
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
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Auxerre Hospital
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Independant data safety and monitoring board
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Bertrand Guidet (Chair)
Patrick Mismetti
Eric Vicaut -p
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Independent adjudication of clinical events committee
Olivier Sanchez
Philippe Girard
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Antoine Elias
Francis Couturaud
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Study management
Coordination
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Béatrice Gable
Sybille Lazareff
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Loïc Carballido
Catherine Hue
Data management
Jean-Marie Chrétien
Adrien Goraguer
Lucie van Eeckhoutte
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Acknowledgments
Other people who contributed to the study but do not fulfill the criteria for auhtorship
Center First Name
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Colmar Anne Pachart Research management assistant
Colmar Sabine Camara Research management assistant
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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
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Hôpital Européen Marseille Amélie Rognon Doctor of Pharmacy
Hôpital Européen Marseille Christina Psomas Doctor of Medicine
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Saint-Antoine Paris Christian Tran Clinical Research Assistant
Saint-Antoine Paris Cyrielle Le Taillandier Clinical Research Assistant
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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
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Blondy
Le Cam
Clinical Research Assistant
Clinical Research Assistant
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Saint-Etienne Anne Pouvaret Doctor of Medicine
Saint-Etienne Anne Fresard Doctor of Medicine
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