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Efficacy of Azithromycin-associated Hydroxychloroquine Therapy Given in General Practice in Early-stage Disease in COVID-19 Patients (MG-COVID)

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ClinicalTrials.gov Identifier: NCT04371406
Recruitment Status : Withdrawn (Regulatory approvals have not been obtained)
First Posted : May 1, 2020
Last Update Posted : October 27, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE April 29, 2020
First Posted Date  ICMJE May 1, 2020
Last Update Posted Date October 27, 2020
Estimated Study Start Date  ICMJE April 2020
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2020)
  • Rate of patients with occurrence of an unfavorable outcome between randomization and day 14 [ Time Frame: between randomization and day14 ]
    Unfavorable outcome defined by the onset of at least one of the following between randomization and day 14: hospitalization, death or percutaneous O² saturation ≤ 92% in ambient air
  • Primary outcome of ancillary virological study : evolution of viral load between day 0 and day 14 [ Time Frame: between day 0 and day 14 ]
    Ancillary virological study : evolution of viral load between day 0 and day 14, measured by the threshold cycle,Ct, with PCR on naso-pharyngeal swab
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2020)
  • The all-cause mortality rate at day 14 [ Time Frame: day 14 ]
  • The all-cause mortality rate at day 28 [ Time Frame: day 28 ]
  • Rate of patients with occurrence of an unfavorable outcome between randomization and day 28 [ Time Frame: between randomization and day 28 ]
    Unfavorable outcome defined by the onset of at least one of the following between randomization and day 28: hospitalization, death or percutaneous O² saturation ≤ 92% in ambient air
  • The rate of use of mechanical ventilation at day 14 [ Time Frame: day 14 ]
  • The rate of use of mechanical ventilation at day 28 [ Time Frame: day 28 ]
  • The Intensive Care Unit admission rate at day 14 [ Time Frame: day 14 ]
  • The Intensive Care Unit admission rate at day 28 [ Time Frame: day 28 ]
  • Number of days of hospitalization for any cause between day 0 and day 14 [ Time Frame: between randomization and day 14 ]
  • Number of days of hospitalization for any cause between day 0 and day 28 [ Time Frame: between randomization and day 28 ]
  • The time to resolution of all COVID symptoms at day 14 [ Time Frame: day 14 ]
    Time to resolution of all COVID-19 symptoms : no COVID symptom for at least 48 hours without symptomatic treatment in previous 24 hours
  • The time to resolution of all COVID symptoms atday 28 [ Time Frame: day 28 ]
    Time to resolution of all COVID-19 symptoms : no COVID symptom for at least 48 hours without symptomatic treatment in previous 24 hours
  • The rate of use of oxygen therapy at day 14 [ Time Frame: between randomization and day 14 ]
  • The rate of use of oxygen therapy at day 28 [ Time Frame: between randomization and day 28 ]
  • The rate of use of secondary antibiotic therapy (after day 2) at day 14 [ Time Frame: between randomization and day 14 ]
  • The rate of use of secondary antibiotic therapy (after day 2) at day 28 [ Time Frame: between randomization and day 28 ]
  • Clinical status at day 14 [ Time Frame: day 14 ]
    Clinical status on a 7-point ordinal scale :
    1. Not hospitalized, no limitations on activities
    2. Not hospitalized, limitation on activities;
    3. Hospitalized, not requiring supplemental oxygen;
    4. Hospitalized, requiring supplemental oxygen;
    5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
    6. Hospitalized, on invasive mechanical ventilation or ECMO;
    7. Death.
  • Clinical status at day 28 [ Time Frame: day 28 ]
    Clinical status on a 7-point ordinal scale :
    1. Not hospitalized, no limitations on activities
    2. Not hospitalized, limitation on activities;
    3. Hospitalized, not requiring supplemental oxygen;
    4. Hospitalized, requiring supplemental oxygen;
    5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
    6. Hospitalized, on invasive mechanical ventilation or ECMO;
    7. Death.
  • number of serious adverse events at day 14 [ Time Frame: day 14 ]
  • number serious adverse events at day 28 [ Time Frame: day 28 ]
  • number of adverse events at day 14 [ Time Frame: day 14 ]
  • number of adverse events at day 28 [ Time Frame: day 28 ]
  • The rate of patients with treatment withdrawal [ Time Frame: day 14 ]
  • Ancillary virological study : rate of patients with negative viral load at day 8 [ Time Frame: day 8 ]
    Ancillary virological study : rate of patients with negative viral load at PCR on naso pharyngeal swab at day 8
  • Ancillary virological study : rate of patients with negative viral load at day 14 [ Time Frame: day 14 ]
    Ancillary virological study : rate of patients with negative viral load at PCR on naso pharyngeal swab at day 14
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Azithromycin-associated Hydroxychloroquine Therapy Given in General Practice in Early-stage Disease in COVID-19 Patients
Official Title  ICMJE Efficacy of Azithromycin-associated Hydroxychloroquine Therapy Given in General Practice in Early-stage Disease in COVID-19 Patients: Randomized Controlled Trial: MG-COVID
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Covid-19
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Experimental Arm
    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
    Intervention: Drug: Hydroxychloroquine and Azithromycin
  • Sham Comparator: Control Arm
    Dietetary supplement, Azinc form and vitality®, 2 capsules per day, for 10 days, in addition to standard of care
    Intervention: Dietary Supplement: Azinc
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: October 23, 2020)
0
Original Estimated Enrollment  ICMJE
 (submitted: April 30, 2020)
2770
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04371406
Other Study ID Numbers  ICMJE APHP200447
2020-001702-35 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Data are available upon reasonable request. The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
Access Criteria: Researchers who provide a methodological sound proposal.
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Julie CHASTANG, Dr Department of General Medicine
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP