Azithromycin+Amoxicillin/Clavulanate vs Amoxicillin/Clavulanate in COVID19 Patients With Pneumonia in Non-intensive Unit

Study Overview
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Brief Summary
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The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, in December 2019, and has since spread worldwide.1 As of April 14, 2020, there have been more than 1.5 million reported cases and 124 000 deaths in more than 200 countries. A recent open-label nonrandomized French study reporte that addition of azithromycin to hydroxychloroquine in 6 patients resulted in numerically superior viral clearance (6/6, 100%) compared with hydroxychloroquine monotherapy (8/14, 57%) or control (2/16, 12.5%). Azithromycin alone has never been tested, whereas azithromycin has immunomodulating and anti-inflammatory properties that could theoretically prevent or limit secondary worsening. Our hypothesis is that azithromycin combined with amoxicillin/clavulanate will be superior to amoxicillin/clavulanate alone to obtain viral clearance at Day 6 in COVID-19 patients with pneumonia and hospitalized in a non-intensive care unit ward.

Official Title
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Azithromycin With Amoxicillin/Clavulanate Versus Amoxicillin/Clavulanate Alone in COVID-19 Patients With Pneumonia and Hospitalized in a Non-intensive Care Unit Ward (AziA): a Superiority Open-label Randomized Controlled Trial

Conditions
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COVID-19 Pneumonia

Intervention / Treatment
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* Combination Product: Azithromycin with amoxicillin/clavulanate
* Drug: amoxicillin/clavulanate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult ≥ 18 ans, Patient with positive SARS-CoV-2 RT-PCR on nasopharyngeal sample at randomization or within the previous 48 hours, Patient with pneumonia diagnosed by thorax CT-scan or echography, Patient able to take per os medication, Written and signed consent of the patient, Patients affiliated with or benefitting from a social security scheme. Exclusion Criteria: Patient hospitalized in intensive care unit, Patient who received more than 24 hours of antibiotic treatment for the ongoing episode, Chronic renal failure with a Glomerular Filtration Rate < 20ml/min, Severe hepatic failure, Severe chronic cardiac insufficiency, Allergy to macrolides, Electrocardiogram showing corrected QT prolongation greater than 470 ms in men and 480 ms in women. Life-threatening presentation expected to lead to possible imminent death (based on provider assessment)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin with amoxicillin/clavulanate<br>Combination of azithromycin during 4 days with amoxicillin/clavulanate during 7 days. | Combination Product: Azithromycin with amoxicillin/clavulanate<br>* Patients will receive azithromycin 500 mg on day 1 followed by 250mg per day for the next four days with amoxicillin/clavulanate 1 gr 3 times per day during 7 days. In case of allergy, amoxicillin/clavulanate can be replaced by a third-generation cephalosporin<br>|
| Active Comparator: Amoxicillin/clavulanate<br>Amoxicillin/clavulanate every day during 7 days. | Drug: amoxicillin/clavulanate<br>* Patients will receive amoxicillin/clavulanate 1 gr 3 times per day during 7 days. In case of allergy, amoxicillin/clavulanate can be replaced by a third-generation cephalosporin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of positive SARS-CoV-2 RT-PCR | Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal sample | Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of positive SARS-CoV-2 RT-PCR | Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal sample | Day 10 | 
| Clinical evolution on the World Health Organization Ordinal Scale for Clinical Improvement for COVID-19 | Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 score. Scale ranging from 0 to 8 (0:unifected; 8:dead) | day 6, day 10, and day 30 | 
| Total duration of antibiotic treatment during the 30 days following inclusion | Total duration of antibiotic treatment during the 30 days following inclusion | 30 days | 
| Number of all-cause mortality during the 30 days following inclusion | Number of all-cause mortality during the 30 days following inclusion | 30 days | 
| Number of in-hospital mortality during the 30 days following inclusion | Number of in-hospital mortality during the 30 days following inclusion | 30 days | 
| Number of patients transferred to intensive care unit during the 30-day follow-up | Number of patients transferred to intensive care unit during the 30-day follow-up | 30 days | 
| Number of days without mechanical ventilation during the 30 days following inclusion | Number of days without mechanical ventilation during the 30 days following inclusion | 30 days | 
| adverse events attributable to antibiotic treatment during the 30 days following inclusion | adverse events attributable to antibiotic treatment during the 30 days following inclusion | 30 days | 
| Hospital length of stay during the 30 days following inclusion | Hospital length of stay during the 30 days following inclusion | 30 days |