Clinical trial NCT04398004: Anti-inflammatory Clarithromycin for Improving COVID-19 Infection Early
Official title: Anti-inflammatory Clarithromycin to Improve SARS-CoV-2 (COVID-19) Infection Early: The ACHIEVE Open-label Non-randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Virus Diseases
Corona Virus Infection
Keywords: COVID-19
SARS-CoV-2
Clarithromycin
Hydroxychloroquine
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2020-05-21
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Treatment with clarithromycin
Primary purpose: PREVENTION

Brief summary: Recent information appearing from different countries suggest that treatment of Coronavirus disease 2019 (COVID-19) with hydroxychloroquine or with a combination of hydroxychloroquine and azithromycin has either an indifferent effect on viral replication or substantial cardiotoxicity. This is a clinical trial aiming to prove that addition of oral clarithromycin to treatment regimen of COVID-19 is associated with early clinical improvement and attenuation of the high inflammatory burden of the host. The study will not comprise a placebo-comparator group since this is considered inappropriate in an era of a pandemic with substantial global mortality.

Detailed description: Humanity is experiencing since December 2019 a new pandemic by the novel SARS Coronavirus-19 (SARS-CoV-2). As of March 25 2020 418,099 documented case were reported worldwide; 18,608 patients died. The analysis of the clinical characteristics of these patients showed that the natural course of this disease, known with the acronym COVID-19, is several times unpredictable. Most patients who develop pneumonia do not have worrying symptoms although their chest X-ray or chest computed tomography may be positive for diffuse infiltrates. Suddenly a certain proportion of these patients deteriorate into severe respiratory failure; this usually takes place between the 5th and the 10th day of illness and arrives without any preceding symptom. Published evidence suggests that this is due to the sudden arrival of an acute pro-inflammatory reaction of the host. With this in mind, it is reasonable to make the assumption than the early treatment with an agent that can efficiently modulate the host response and prevent sudden hyper-inflammatory reaction may prevent the development of severe respiratory failure (SRF).

The new guidelines published by the American Thoracic Society in 2019 clearly suggest that the management of community-acquired pneumonia (CAP) should rely on the combination of β-lactam antibiotics with macrolides. This position statement is pretty much influenced by the retrospective analyses of observational studies and of their meta-analyses in showing that the addition of a macrolide improves survival from severe CAP. Since patients leave in an era of antimicrobial resistance, it is profound that survival benefit is linked to the anti-inflammatory properties of the macrolide class of antibiotics. These properties are not only limited to the attenuation of the production of pro-inflammatory mediators but they involve the enhancement of pathogen clearance.

With this in mind, a small open-label trial among patients with COVID-19 showed better viral containment as assessed by the persistence of the virus in respiratory secretions, when patients were treated with a combination of azithromycin and hydroxychloroquine. However, the clinical benefit coming from this study has not yet been published. Contrary to azithromycin, clinical evidence suggests that clarithromycin is associated with substantial clinical benefit among critically ill patients. Two randomized clinical studies in a total of 800 patients with sepsis have shown 28-day survival benefit among the most severe cases. One of these studies enrolled patients with sepsis and ventilator-associated pneumonia; among 100 patients allocated to placebo treatment 40% survived until day 90; this was 57% among clarithromycin-treated patients.

In recent publication coming from the research network of the Hellenic Sepsis Study Group (HSSG) 130 patients with CAP were treated with a combination of β-lactam and clarithromycin. These patients were compared with 130 patients treated with a combination of β-lactam and azithromycin. Groups were well-matched for severity and comorbidities; 28-day mortality was 20.8% and 33.8% respectively.

Based on the above analysis, it seems likely that treatment of patients with COVID-19 with oral clarithromycin will substantially increase their anti-inflammatory properties and decrease the chances for development of severe respiratory failure.

As stated above, the efficacy of the treatment combination of hydroxychloroquine with azithromycin is based on results coming from only six patients. Since the publication of these data other, yet unpublished, reports have appeared in the internet challenging the treatment efficacy of this combination. These results show that treatment with hydroxychloroquine either single or in combination with azithromycin have either an indifferent effect on viral replication or even a deleterious effect on the patient due to cardiotoxicity. With this in mind it is obvious that macrolide treatment in COVID-19 patients many of which have coronary heart disease and chronic heart failure as comorbidities should be administered without hydroxychloroquine.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* Male of female gender
* Written informed consent provided by the patients or by a first-degree relative in case of patients unable to consent
* In case of women, unwillingness to remain pregnant during the study period achieved either by their partner using condom or by themselves using oral contraceptives.
* Confirmed infection by SARS-CoV-2 virus
* Infection of the upper respiratory tract or of the lower respiratory tract

Exclusion Criteria:

* Age below 18 years
* Denial of written informed consent
* Intake of any macrolide for the current episode of infection under study
* Intake of hydroxychloroquine or chloroquine phosphate.
* Presence of severe respiratory failure
* Oral or intravenous intake of corticosteroids defined as any more than 0.4mg/kg daily intake of equivalent prednisone for the last 15 days
* Neutropenia defined as an absolute neutrophil count below 1,000/mm3
* Presence of any contraindications for the study drugs as stated in local label information
* QTc interval at rest electrocardiogram ≥500 msec or history of known congenital long QT syndrome
* Pregnancy or lactation

Primary outcomes:
measure: Clinical outcome negative for two parameters(hospital admission/disease progression)
timeFrame: Day 1 to Day 8
measure: At least 50% change of the score of respiratory symptoms from the baseline
timeFrame: Day 1 to Day 8
Secondary outcomes:
measure: Comparison of two parameters with historical comparators from Hellenic Sepsis Study Group Database
timeFrame: Day 1 to Day 8
measure: Comparison of the score of respiratory symptoms with historical comparators from Hellenic Sepsis Study Group Database
timeFrame: Day 1 to Day 8
measure: Clinical outcome negative for two parameters(hospital admission/disease progression) on day 4
timeFrame: Day 4
measure: At least 50% change of the score of respiratory symptoms from the baseline on day 4
timeFrame: Day 4
measure: Range of development of severe respiratory failure
timeFrame: Day 1 to Day 14
measure: Range of hospital readmission until day 14
timeFrame: Day 1 to Day 14
measure: Change of viral load in respiratory secretions from baseline on day 8
timeFrame: Day 1 to Day 8
measure: Change of function of monocytes at days 1 and 8
timeFrame: Day 1 to Day 8
measure: Change of function of Th1 cells at days 1 and 8
timeFrame: Day 1 to Day 8
measure: Change of function of Th2 cells at days 1 and 8
timeFrame: Day 1 to Day 8
measure: Change of serum interleukin-6 (IL-6) cytokine levels between days 1 and 8
timeFrame: Day 1 to day 8
measure: Change of serum interleukin-8 (IL-8) cytokine levels between days 1 and 8
timeFrame: Day 1 to day 8
measure: Change of serum human beta defensin-2 (hBD-2) between days 1 and 8
timeFrame: Day 1 to day 8
measure: Change of cytokine levels interleukin-6 (IL-6) at the rhinopharynx between days 1,4 and 8
timeFrame: Day 1 to day 8
measure: Change of interleukin-1 (IL-1) cytokine levels at the rhinopharynx between days 1,4 and 8
timeFrame: Day 1 to day 8
measure: Change of the IL-10/TNFα ratio between days 1 and 8
timeFrame: Day 1 to Day 8
Other outcomes:
Locations:
city: Marousi
country: Greece
facility: COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING
state: Athens
city: Piraeus
country: Greece
facility: 2nd Department of Internal Medicine, General Hospital of Nikaia
state: Attica
city: Alexandroupolis
country: Greece
facility: 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
city: Athens
country: Greece
facility: 1st University Department of Internal Medicine, LAIKO General Hospital of Athens
city: Athens
country: Greece
facility: 2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
city: Athens
country: Greece
facility: 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA
city: Ioánnina
country: Greece
facility: 1st Department of Internal Medicine, General University Hospital of Ioannina
city: Piraeus
country: Greece
facility: 2nd Department of Internal Medicine, General Hospital of Piraeus "Tzaneio"
city: Thessaloníki
country: Greece
facility: 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
Study officials:
affiliation: National Kapodistrian University of Athens, Medical School
name: Garyfallia Poulakou, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tsiakos K, Tsakiris A, Tsibris G, Voutsinas PM, Panagopoulos P, Kosmidou M, Petrakis V, Gravvani A, Gkavogianni T, Klouras E, Katrini K, Koufargyris P, Rapti I, Karageorgos A, Vrentzos E, Damoulari C, Zarkada V, Sidiropoulou C, Artemi S, Ioannidis A, Papapostolou A, Michelakis E, Georgiopoulou M, Myrodia DM, Tsiamalos P, Syrigos K, Chrysos G, Nitsotolis T, Milionis H, Poulakou G, Giamarellos-Bourboulis EJ. Early Start of Oral Clarithromycin Is Associated with Better Outcome in COVID-19 of Moderate Severity: The ACHIEVE Open-Label Single-Arm Trial. Infect Dis Ther. 2021 Dec;10(4):2333-2351. doi: 10.1007/s40121-021-00505-8. Epub 2021 Aug 6.