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Anti-inflammatory Clarithromycin for Improving COVID-19 Infection Early (ACHIEVE)

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ClinicalTrials.gov Identifier: NCT04398004
Recruitment Status : Recruiting
First Posted : May 21, 2020
Last Update Posted : May 26, 2020
Sponsor:
Information provided by (Responsible Party):
Hellenic Institute for the Study of Sepsis

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.

Condition or disease Intervention/treatment Phase
COVID-19 Virus Diseases Corona Virus Infection Drug: Clarithromycin Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Treatment with clarithromycin
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Anti-inflammatory Clarithromycin to Improve SARS-CoV-2 (COVID-19) Infection Early: The ACHIEVE Open-label Non-randomized Clinical Trial
Actual Study Start Date : May 6, 2020
Estimated Primary Completion Date : May 6, 2022
Estimated Study Completion Date : May 6, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Clarithromycin arm
Treatment will last for seven days. Every patient will receive one tablet of 500 mg of clarithromycin every 12 hours. It is explicitly stated that all other treatment is allowed with the only exclusion the parallel intake of a) any other drug of the macrolide class of antibiotics; and/or b) hydroxychloroquine or chloroquine phosphate. Drugs contraindicated with the intake of clarithromycin are also not allowed, as they are described in the local label information.
Drug: Clarithromycin
Treatment with 500 mg Clarithromycin orally twice daily for seven days
Other Name: Klaricid




Primary Outcome Measures :
  1. Clinical outcome negative for two parameters(hospital admission/disease progression) [ Time Frame: Day 1 to Day 8 ]

    This is defined on day 8 (End of Treatment - EOT). Patients with upper respiratory tract infection by SARS-CoV-2 meet the study primary endpoint if they were not admitted to hospital or their symptoms did not progress to lower respiratory tract infection.

    Patients who develop by day 8 severe respiratory failure do not meet the study primary endpoint.


  2. At least 50% change of the score of respiratory symptoms from the baseline [ Time Frame: Day 1 to Day 8 ]

    This is defined on day 8 (EOT visit). Patients with lower respiratory tract infection by SARS-CoV-2 meet the primary endpoint if they present at least 50% decrease of the score of respiratory symptoms from the baseline. This score is the sum of scoring for the symptoms of cough, dyspnea, purulent sputum expectoration and pleuritic chest pain.

    Patients who develop by day 8 severe respiratory failure do not meet the study primary endpoint. Score ranges from 0 (no symptoms) to 9 (worst for all symptoms).



Secondary Outcome Measures :
  1. Comparison of two parameters with historical comparators from Hellenic Sepsis Study Group Database [ Time Frame: Day 1 to Day 8 ]
    Evaluation of need of hospitalization, SARS-CoV-2 infection progression from upper to lower respiratory tract infection, between baseline and study visit day 8 will be compared with historical comparators from Hellenic Sepsis Study Group Database

  2. Comparison of the score of respiratory symptoms with historical comparators from Hellenic Sepsis Study Group Database [ Time Frame: Day 1 to Day 8 ]

    Respiratory score between baseline and study visit day 8 will be compared with historical comparators from Hellenic Sepsis Study Group Database.

    This score is the sum of scoring for the symptoms of cough, dyspnea, purulent sputum expectoration and pleuritic chest pain.Score ranges from 0 (no symptoms) to 9 (worst for all symptoms).


  3. Clinical outcome negative for two parameters(hospital admission/disease progression) on day 4 [ Time Frame: Day 4 ]
    Comparison of clinical data (need of hospitalization, the infection progression of SARS-CoV-2 from upper to lower respiratory tract infections) in enrolled patients between baseline and study visit day 4 Patients who develop by day 4 severe respiratory failure do not meet the study secondary endpoint.

  4. At least 50% change of the score of respiratory symptoms from the baseline on day 4 [ Time Frame: Day 4 ]

    This is defined on day 4 (5th visit). Patients with lower respiratory tract infection by SARS-CoV-2 meet the secondary endpoint if they present at least 50% decrease of the score of respiratory symptoms from the baseline. This score is the sum of scoring for the symptoms of cough, dyspnea, purulent sputum expectoration and pleuritic chest pain.

    Patients who develop by day 4 severe respiratory failure do not meet the study secondary endpoint. Score ranges from 0 (no symptoms) to 9 (worst for all symptoms).


  5. Range of development of severe respiratory failure [ Time Frame: Day 1 to Day 14 ]

    Evaluation of range of enrolled patients who develop severe respiratory failure between baseline and day 14 (TOC VISIT). Severe respiratory failure is defined by presence of all of the following

    • pO2/FiO2 less than 150
    • Need for mechanical or non-mechanical ventilation (CPAP)

  6. Range of hospital readmission until day 14 [ Time Frame: Day 1 to Day 14 ]
    Evaluation of hospital readmission until day 14 (TOC VISIT) from enrollment defined as either need of re-hospitalization for discharged patients or any need for hospitalization of out-patients.

  7. Change of viral load in respiratory secretions from baseline on day 8 [ Time Frame: Day 1 to Day 8 ]
    Comparison of Real Time - Polymerase Chain Reaction (RT-PCR) results for SARS-CoV-2 viral load in rhinopharyngeal samples of enrolled patients at days 1, 4 and 8

  8. Change of function of monocytes at days 1 and 8 [ Time Frame: Day 1 to Day 8 ]
    Change of cytokine production of monocytes in enrolled patients with upper/lower respiratory tract infection at days 1 and 8 (EOT) visit; monocytes will be stimulated for 24 hours with SARS-CoV-2 purified antigens for the production of TNFα. This will be analyzed separately for patients with upper and with lower respiratory tract infection

  9. Change of function of Th1 cells at days 1 and 8 [ Time Frame: Day 1 to Day 8 ]
    Change of cytokine production of Th1 cells in enrolled patients with upper/lower respiratory tract infection at days 1 and 8 (EOT) visit; Th1 cells will be stimulated for 24 hours with SARS-CoV-2 purified antigens for the production of IFNγ. This will be analyzed separately for patients with upper and with lower respiratory tract infection.

  10. Change of function of Th2 cells at days 1 and 8 [ Time Frame: Day 1 to Day 8 ]
    Change of cytokine production of Th2 cells in enrolled patients with lower respiratory tract infection at days 1 and 8 (EOT) visit; Th2 cells will be stimulated for 24 hours with SARS-CoV-2 purified antigens for the production of IL6. This will be analyzed separately for patients with upper and with lower respiratory tract infection.

  11. Change of serum interleukin-6 (IL-6) cytokine levels between days 1 and 8 [ Time Frame: Day 1 to day 8 ]
    Change of the serum levels of interleukin-6 (IL-6) of enrolled patients between day 1 and day 8 (EOT VISIT); this is also analyzed separately for patients with upper and with lower respiratory tract infection

  12. Change of serum interleukin-8 (IL-8) cytokine levels between days 1 and 8 [ Time Frame: Day 1 to day 8 ]
    Change of the serum levels of interleukin-8 (IL-8) of enrolled patients between day 1 and day 8 (EOT VISIT); this is also analyzed separately for patients with upper and with lower respiratory tract infection

  13. Change of serum human beta defensin-2 (hBD-2) between days 1 and 8 [ Time Frame: Day 1 to day 8 ]
    Change of the serum levels of human beta defensin-2 (hBD-2) of enrolled patients between day 1 and day 8 (EOT VISIT); this is also analyzed separately for patients with upper and with lower respiratory tract infection

  14. Change of cytokine levels interleukin-6 (IL-6) at the rhinopharynx between days 1,4 and 8 [ Time Frame: Day 1 to day 8 ]
    Change of rhinopharynx levels of interleukin-6 (IL-6) of enrolled patients between day 1, day 4 and day8 (EOT visit); this is also analyzed separately for patients with upper and with lower respiratory tract infection

  15. Change of interleukin-1 (IL-1) cytokine levels at the rhinopharynx between days 1,4 and 8 [ Time Frame: Day 1 to day 8 ]
    Change of rhinopharynx levels of interleukin-1 (IL-1) of enrolled patients between day 1, day 4 and day8 (EOT visit); this is also analyzed separately for patients with upper and with lower respiratory tract infection

  16. Change of the IL-10/TNFα ratio between days 1 and 8 [ Time Frame: Day 1 to Day 8 ]
    Comparison of the Interleukin-10/Tumor Necrosis Factor α (IL-10/TNFα) ratio in enrolled patients at days 1 and 8; this is also analyzed separately for patients with upper and with lower respiratory tract infection



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04398004


Contacts
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Contact: Evangelos Giamarellos-Bourboulis, MD, PhD +302107480662 egiamarel@med.uoa.gr
Contact: Antigoni Kotsaki, MD, PhD +306946637164 antigonebut@yahoo.com

Locations
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Greece
COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING Recruiting
Marousi, Athens, Greece, 15126
Contact: Malvina Lada, MD    +30 2132058360    malvinalada@gmail.com   
2nd Department of Internal Medicine, General Hospital of Nikaia Recruiting
Piraeus, Attica, Greece, 18454
Contact: Elias Skopelitis, MD    +306944688196    iskopelitis@hotmail.com   
2nd Department of Internal Medicine, University General Hospital of Alexandroupolis Recruiting
Alexandroupolis, Greece, 68100
Contact: Periklis Panagopoulos, MD, PhD    +30 2551351592    ppanago@med.duth.gr   
1st University Department of Internal Medicine, LAIKO General Hospital of Athens Recruiting
Athens, Greece, 11527
Contact: Mina Psychogiou, MD, PhD    +306932475847    mpsichog@yahoo.gr   
2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens Recruiting
Athens, Greece, 11527
Contact: Helen Sambatakou    +30 6977476385    helensambatakou@msn.com   
3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA Recruiting
Athens, Greece, 11527
Contact: Garyfallia Poulakou, MD, PhD    +30 2107719975    gpoulakou@gmail.com   
1st Department of Internal Medicine, General University Hospital of Ioannina Recruiting
Ioánnina, Greece, 45500
Contact: Charalambos Milionis, MD, PhD    +30 2651362736    hmilioni@uoi.gr   
2nd Department of Internal Medicine, General Hospital of Piraeus "Tzaneio" Recruiting
Piraeus, Greece, 18536
Contact: Georgios Chrysos, MD, PhD    00302104592561    gchrysos@gmail.com   
1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki Recruiting
Thessaloníki, Greece, 54621
Contact: Simeon Metallidis, MD, PhD    +30 2313303214    metallidissimeon@yahoo.gr   
Sponsors and Collaborators
Hellenic Institute for the Study of Sepsis
Investigators
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Principal Investigator: Garyfallia Poulakou, MD, PhD National Kapodistrian University of Athens, Medical School
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Responsible Party: Hellenic Institute for the Study of Sepsis
ClinicalTrials.gov Identifier: NCT04398004    
Other Study ID Numbers: ACHIEVE
2020-001882-36 ( EudraCT Number )
First Posted: May 21, 2020    Key Record Dates
Last Update Posted: May 26, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hellenic Institute for the Study of Sepsis:
COVID-19
SARS-CoV-2
Clarithromycin
Hydroxychloroquine
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Coronavirus Infections
Severe Acute Respiratory Syndrome
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Infections
Respiratory Tract Diseases
Clarithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors