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

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

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.

Study Overview

• Status: Unknown
• Conditions: COVID-19 Pneumonia
• Intervention / Treatment: Combination product: Azithromycin with amoxicillin/clavulanate; Drug: amoxicillin/clavulanate

• Study Type: Interventional
• Enrollment (Anticipated): 104
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Emmanuel MONTASSIER; Phone Number: +33 (0)2 53 48 20 38; Email: Emmanuel.montassier@chu-nantes.fr

Study Locations

• France
  • Angers, France
    • CHU Angers
    • Contact: Vincent DUBEE, MD, PhD
  • La Roche-sur-Yon, France
    • CHD Vendee
    • Contact: Romain DECOURS, MD, PhD
  • Poitiers, France
    • CHU Poitiers
    • Contact: Blandine RAMMAERT, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azithromycin with amoxicillin/clavulanate; Combination of azithromycin during 4 days with amoxicillin/clavulanate during 7 days.	Combination product: Azithromycin with amoxicillin/clavulanate; 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
Active Comparator: Amoxicillin/clavulanate; Amoxicillin/clavulanate every day during 7 days.	Drug: amoxicillin/clavulanate; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nantes University Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): April 30, 2020
• Primary Completion (Anticipated): July 30, 2020
• Study Completion (Anticipated): July 30, 2020

Study Registration Dates

• First Submitted: April 23, 2020
• First Submitted That Met QC Criteria: April 23, 2020
• First Posted (Actual): April 27, 2020

Study Record Updates

• Last Update Posted (Actual): April 29, 2020
• Last Update Submitted That Met QC Criteria: April 27, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin; Azithromycin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: RC20_0168

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No