Hydroxychloroquine, a derivative of chloroquine (an antimalarial drug) with a weak immunosuppressive effect, is prescribed by some teams alone or in combination with azithromycin. No randomized controlled trials have demonstrated its efficacy, particularly in primary care in the early stages of the disease. However, currently available data suggest better efficacy if treatment is given early in the disease, before symptoms worsen. To date, the majority of COVID-19 patients treated in outpatient care, particularly in general practice, represent the majority of COVID-19 patients. It is essential to evaluate, in primary care, the efficacy and safety of hydroxychloroquine combined with azithromycin in Covid-19 patients in order to be able to implement this therapeutic strategy as soon as the first symptoms appear. We realize a randomized, controlled, open superiority trial, in 2 parallel groups (ratio 1:1).The main objective is to assess the efficacy of Hydroxychloroquine combined with azithromycin in COVID-19 patients in primary care, in add-on to standard of care, on unfavorable outcome defined by the onset of at least one of the following between D0 and D14: hospitalization, death or percutaneous O² saturation ≤ 92% in ambient air.
Randomized, controlled, open superiority trial, in 2 parallel groups (ratio 1:1).
Eligible consecutive patient will be offered to take part in the trial during a visit to
thier GP for COVID symptoms. After verification of eligibility criteria and written informed
consent, a nasopharyngeal swab, an ECG and a blood sampled (kalaemia, magnesemia and
calcemia) will be performed.
Patient with SARS-CoV-2 PCR positive result and still fulfilling eligibility criteria will be
randomized on day2 (D2) through a web-based allocation system, following a computer generated
allocation list, stratified on center and existence of any comorbidity, to experimental or
control group. Patients without confirmation of SARS-CoV-2 infection on PCR will not continue
the trial. Both groups patients will have a paper-based diary to record their daily symptoms
and drug intake. A clinical follow-up will be done by the GP at D5, D8, D14 and D28.The main
analysis population will be in intention to treat. An intermediate efficacy analysis is
planned when 50% of patients have reached D14.
Two hundred consecutive patients (from pre-identified centers) will be included in an
ancillary virological study to assess evolution of viral load at D8 and D14. For these
patients all nasopharyngeal swab will be sent to a centralised lab at Pitié-Salpêtrière
Hospital.
Drug: Hydroxychloroquine and Azithromycin
Hydroxychloroquine sulfate (PLAQUENIL®), 200mg x 3 /d, for 10 days AND Azithromycin (ZITHROMAX®), 500mg on D1 and then 250mg/d for the next 4 days, in addition to standard of care
Dietary Supplement: Azinc
Dietetary supplement, Azinc form and vitality®, 2 capsules per day, for 10 days, in addition to standard of care
Inclusion Criteria:
- Inclusion criteria :
- Adult aged 18 to 75 years old
- Taken into primary health care for suspicion of early-stage COVID-19 infection
(maximum 5 days of evolution). The patient must have presented within the previous 5
days at least one of the following criteria: fever (≥38°C), cough, anosmia, agueusia,
diarrhea, headache, myalgia.
Criteria for randomization at D2 :
- Positive PCR on deep nasopharyngeal swab.
- Kalemia ≥ 3.5 mmol/L
- Normal magnesium and calcium levels (according to laboratory standards)
- QTc ≤ 460ms for women or QTc ≤ 450ms for men
- Beta-hCG negative
Exclusion criteria :
- Comorbidity(ies) or clinical condition of the patient requiring immediate oxygen
therapy, hospitalization and/or ventilatory assistance
- Concomitant treatment contraindicated, not recommended, or with precautions for use in
combination with hydroxychloroquine or azithromycin:
- drug likely to induce torsades de pointe or at increased risk of ventricular
arrhythmia, and in particular citalopram, escitalopram, hydroxyzine, domperidone,
piperazine, class IA and III antiarrhythmics, tricyclic antidepressants,
antipsychotics and certain anti-infectives (macrolides, fluoroquinolones).
- Alkaloids of ergot of rye, colchicine, cisapride
- proconvulsant or epileptogenic threshold lowering drugs: imipraminic
antidepressants, selective serotonin reuptake inhibitors, neuroleptics
(phenothiazines and butyrophenones) and tramadol.
- Known history of contraindications or increased risk of treatment with
hydroxychloroquine or azithromycin (retinopathy,renal failure, significant liver
failure, severe cholestasis, porphyria, known G6PD deficit, hypomagnesemia and
hypokalemia, diabetes, myasthenia gravis, Heart diseases (heart failure, infarction,
arrhythmia, congenital QTc prolongation, abnormalities that interfere with QTc
measurement such as Left Bundle Branch Block, Right Bundle Branch Block, Pace maker
with ventricular pacing), epilepsy, allergy to hydroxychloroquine, chloroquine,
azithromycin, erythromycin, any other macrolide, ketolide or any of the excipients of
Plaquenil® or Zithromax® or any of the components of Azinc form and vitality®.
- Ongoing treatment with hydroxychloroquine or azithromycin, regardless of the
indication.
- Taking other antiviral targeted therapy used in COVID-19 disease
- Women who are pregnant or breastfeeding or planning to become pregnant within 8 months
of discontinuing hydroxychloroquine therapy.
- No National Health Insurrance (sécurité sociale, CMU or AME) coverage.
- Major under guardianship or curatorship
- Participation in another therapeutic clinical trial for COVID-19
- Refusal to participate in the study and/or lack of signature of a consent
Julie CHASTANG, Dr, Principal Investigator
Department of General Medicine