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Anti-inflammatory Action of Oral Clarithromycin in Community-acquired Pneumonia (ACCESS)

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ClinicalTrials.gov Identifier: NCT04724044
Recruitment Status : Recruiting
First Posted : January 26, 2021
Last Update Posted : June 22, 2021
Sponsor:
Information provided by (Responsible Party):
Hellenic Institute for the Study of Sepsis

Brief Summary:
Traditional management of community-acquired pneumonia (CAP) relies on the prompt administration of antimicrobials that target the most common causative pathogens. Retrospective analysis of observational clinical studies in CAP showed that the addition of macrolides to standard antibiotic therapy conferred a significant survival benefit. The proposed benefit of macrolides is coming from their anti-inflammatory mode of action. An RCT that proves the attenuation of the high inflammatory burden of the host with CAP after addition of clarithromycin in the treatment regimen is missing. This RCT is aiming to prove that addition of oral clarithromycin to a β-lactam rapidly attenuates the high inflammatory burden of the host in CAP.

Condition or disease Intervention/treatment Phase
Community-acquired Pneumonia Sepsis Inflammatory Response Mortality Biomarkers SIRS Drug: Tablets Drug: Clarithromycin 500mg Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 278 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a prospective, 1:1 randomized, double-blind, placebo-controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Clinical Trial of Oral Clarithromycin in Community-acquired Pneumonia to Attenuate Inflammatory Responses and Improve Outcomes: the ACCESS Clinical Trial
Actual Study Start Date : January 25, 2021
Estimated Primary Completion Date : January 24, 2023
Estimated Study Completion Date : April 20, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

Arm Intervention/treatment
Placebo Comparator: Placebo
These patients will be treated with 1 placebo tablet every 12 hours and intravenously with ceftriaxone 2g once daily as part of standard of care therapy indicated by the summary of product characteristics and according to bibliographic references. The total duration of treatment will be seven days.
Drug: Tablets
Oral tablets of similar appearance to active study drug
Other Name: 2g of intravenous ceftriaxone or 400mg of intravenous moxifloxacin(in case of positive urinary antigen for Legionella spp)

Active Comparator: Clarithromycin
These patients will be treated with 1 tablet of 500 mg of clarithromycin every 12 hours intravenously and with ceftriaxone 2g once daily as part of standard of care therapy indicated by the summary of product characteristics and according to bibliographic references. The total duration of treatment will be seven days.
Drug: Clarithromycin 500mg
Oral tablets of 500mg of clarithromycin
Other Name: 2g of intravenous ceftriaxone or 400mg of intravenous moxifloxacin(in case of positive urinary antigen for Legionella spp)




Primary Outcome Measures :
  1. Change of baseline respiratory symptoms score [ Time Frame: 4 days ]
    At least 50 percent (%) decrease of the sum of scoring (0-12) for the symptoms of cough (0-3), dyspnea (0-3), purulent sputum expectoration (0-3) and pleuritic chest pain (0-3) between baseline and Study Day 4

  2. Change of baseline total sequential organ failure assessment (SOFA) score and/or change of baseline serum PCT [ Time Frame: 4 days ]
    At least 30 percent (%) decrease between baseline sequential organ failure assessment (SOFA) score and measured sequential organ failure assessment (SOFA) score at Study Day 4 and/or at least 80 percent (%) decrease of serum PCT from baseline PCT at Study Day 4 and/or serum PCT below 0.25 ng/ml at Study Day 4


Secondary Outcome Measures :
  1. Change of baseline respiratory symptoms score in the subgroup of patients infected or colonized by clarithromycin-susceptible S.pneumoniae [ Time Frame: 4 days ]
    Comparison of the number of patients reaching at least 50 percent (%) decrease of the sum of scoring (0-12) for the symptoms of cough (0-3), dyspnea (0-3), purulent sputum expectoration (0-3) and pleuritic chest pain (0-3) between baseline and Study Day 4, among clarithromycin and placebo-treated patients, infected or colonized by clarithromycin-susceptible S.pneumoniae

  2. Change of baseline respiratory symptoms score in the subgroup of patients infected or colonized by clarithromycin-resistant S.pneumoniae [ Time Frame: 4 days ]
    Comparison of the number of patients reaching at least 50 percent (%) decrease of the sum of scoring (0-12) for the symptoms of cough (0-3), dyspnea (0-3), purulent sputum expectoration (0-3) and pleuritic chest pain (0-3) between baseline and Study Day 4, among clarithromycin and placebo-treated patients, infected or colonized by clarithromycin-susceptible S.pneumoniae

  3. Change of baseline total sequential organ failure assessment (SOFA) score and/or change of baseline serum PCT in the subgroup of patients infected or colonized by clarithromycin-susceptible S.pneumoniae [ Time Frame: 4 days ]
    Comparison of the number of patients reaching at least 30 percent (%) decrease between baseline sequential organ failure assessment (SOFA) score and measured sequential organ failure assessment (SOFA) score at Study Day 4 and/or at least 80 percent (%) decrease of serum PCT from baseline at Study Day 4 and/or serum PCT below 0.25 ng/ml at Study Day 4, among clarithromycin and placebo-treated patients infected or colonized by clarithromycin-susceptible S.pneumoniae

  4. Change of baseline total sequential organ failure assessment (SOFA) score and/or change of baseline serum PCT in the subgroup of patients infected or colonized by clarithromycin-resistant S.pneumoniae [ Time Frame: 4 days ]
    Comparison of the number of patients reaching at least 30 percent (%) decrease between baseline sequential organ failure assessment (SOFA) score and measured sequential organ failure assessment (SOFA) score at Study Day 4 and/or at least 80 percent (%) decrease of serum PCT from baseline at Study Day 4 and/or serum PCT below 0.25 ng/ml at Study Day 4, among clarithromycin and placebo-treated patients infected or colonized by clarithromycin-resistant S.pneumoniae

  5. Mortality rate at 28 days [ Time Frame: 28 days ]
    Differences in 28-day all-cause mortality rate between clarithromycin and placebo-treated arms

  6. Mortality rate at 90 days [ Time Frame: 90 days ]
    Differences in 90-day all-cause mortality rate between clarithromycin and placebo-treated arms

  7. Clinical success at the end of treatment Visit (day 8) [ Time Frame: 8 days ]
    Difference in clinical success rate at day 8, as defined by at least 50 percent (%) decrease of the baseline sum of scoring (0-12) for the symptoms of cough (0-3), dyspnea (0-3), purulent sputum expectoration (0-3) and pleuritic chest pain (0-3)

  8. Hospital discharge until day 90 [ Time Frame: 90 days ]
    Comparison of length of hospital stay (days) until day 90 between clarithromycin and placebo-treated arms

  9. Hospital readmission until day 90 [ Time Frame: 90 days ]
    Comparison of hospital readmission rate until day 90 between clarithromycin and placebo-treated arms

  10. Change of baseline total sequential organ failure assessment (SOFA) score at the end of treatment Visit (day 8) [ Time Frame: 8 days ]
    Comparison of number of patients reaching more than 50 percent (%) decrease between baseline sequential organ failure assessment (SOFA) score and measured sequential organ failure assessment (SOFA) score at Study Day 8 between clarithromycin and placebo-treated arms

  11. Development of new organ dysfunctions until day 90 [ Time Frame: 90 days ]
    Comparison of the rate of development of new organ dysfunctions between clarithromycin and placebo-treated arms

  12. Change of function of monocytes, Th1, Th2 and T17 cells at Study Visit 4 [ Time Frame: 4 days ]
    Comparison of cytokine production by stimulation of monocytes, Th1,Th2 and T17 cells between clarithromycin and placebo-treated arms

  13. Change of gene expression of anti-inflammatory genes at Study Visit 4 [ Time Frame: 4 days ]
    Comparison of the expressions of four genes (FGL-2, IL7R, HLA-DPA1, CPVL), that are down-regulated upon development of severe infections, between clarithromycin and placebo-treated arms

  14. Anti-inflammatory PCT change at study Visit 6 [ Time Frame: 6 days ]
    Comparison of number of patients reaching at least 80 percent (%) decrease of serum PCT from baseline on day 6 or any value of PCT below 0.25 ng/ml on day 6 between clarithromycin and placebo-treated arms

  15. Anti-inflammatory PCT change at the end of treatment Visit (day 8) [ Time Frame: 8 days ]
    Comparison of number of patients reaching at least 80 percent (%) decrease of serum PCT from baseline on day 8 or any value of PCT below 0.25 ng/ml on day 8 between clarithromycin and placebo-treated arms

  16. Change of the IL-10/TNFα ratio at study Visit 6 [ Time Frame: 6 days ]
    Comparison of the change of the IL-10/TNFα ratio between baseline and day 6 among clarithromycin and placebo-treated arms

  17. Change of the IL-10/TNFα ratio at the end of treatment Visit (day 8) [ Time Frame: 8 days ]
    Comparison of the of the change of the IL-10/TNFα ratio between baseline and day 8 among clarithromycin and placebo-treated arms



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:

  • Adult patients (≥18 years)
  • Male of female gender
  • In case of non-menopausal women, unwillingness to become pregnant during the study period. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study.
  • Written informed consent provided by the patients or by a first-degree relative in case of patients unable to consent
  • Presence of at least two signs of SIRS (see below for definition)
  • SOFA score ≥2 (see Appendix I)
  • PCT ≥0.25 ng/ml
  • Presence of at least two of the following signs: i) cough; ii) purulent sputum expectoration; iii) dyspnea; and/or iv) pleuritic chest pain
  • Presence of CAP (see below for definition)

SIRS is defined by the presence of at least two of the following criteria:

  • Core temperature >38 Celsius degrees or <36 Celsius degrees
  • Heart rate >90 beats/minute
  • Breath rate >20 breaths/minute or pco2<32 mmHg
  • Total white blood cell count >12,000/mm3 or <4,000/mm3 or >15% bands

CAP is defined as the presence of auscultatory findings compatible with CAP and new consolidation in chest X-ray in a patient without any history of contact with the hospital environment or with health-care facilities the last 90 days.

Exclusion Criteria:

  • Age below 18 years
  • Denial of written informed consent
  • Presence of infection by SARS-CoV-2 (COVID-19)
  • Intake of any macrolide for the current episode of CAP under study
  • 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
  • Known infection by the human immunodeficiency virus
  • Any chronic anti-cytokine treatment (e.g. antibodies against TNF for rheumatoid arthritis)
  • Hospitalization for more than 2 days the last 90 days
  • QTc interval at rest ECG ≥500 msec or history of known congenital long QT syndrome
  • Concomitant administration with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4, (lovastatin or simvastatin), and presence of any contraindications for the study drug
  • Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study.

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): NCT04724044


Contacts
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Contact: Evangelos J Giamarellos-Bourboulis, MD, Phd 00302105831994 egiamarel@med.uoa.gr
Contact: Konstantinos Tsiakos, MD 00306939031150 konstantinostsiakos@gmail.com

Locations
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Greece
4th Department of Internal Medicine, Attikon University Hospital Not yet recruiting
Athens, Greece, 12462
Contact: Antonios Papadopoulos, MD, PhD       antpapa1@otenet.gr   
1st Department of Internal Medicine, Amalia Fleming General Hospital Not yet recruiting
Athens, Greece
Contact: Aikaterini Spyridaki, MD, PhD       kspyridaki@yahoo.gr   
1st Department of Internal Medicine, Gennimatas General Hospital Not yet recruiting
Athens, Greece
Contact: George Adamis, MD, PhD       adamismd@otenet.gr   
1st Department of Internal Medicine, Konstantopouleio-Patission General Hospital Not yet recruiting
Athens, Greece
Contact: Aikaterini Masgala-Seferli, MD, PhD       katerina.masgala@gmail.com   
1st Department of Internal Medicine, Laikon General Hospital Not yet recruiting
Athens, Greece
Contact: Mina Psichogiou, MD, PhD       mpsichog@yahoo.gr   
1st Department of Internal Medicine,Korgialeneio-Benakeio General Hospital Not yet recruiting
Athens, Greece
Contact: Vasiliki Tzavara, MD, PhD       vtzavara2015@gmail.com   
1st Department of Pulmonology, Sotiria General Hospital Not yet recruiting
Athens, Greece
Contact: Antonia Koutsoukou, MD, PhD       koutsoukou@yahoo.gr   
2nd Department of Internal Medicine, Attikon University Hospital Recruiting
Athens, Greece
Contact: Erifili Hatziagelaki, MD, PhD       erihat@otenet.gr   
2nd Department of Internal Medicine, Ippokrateion General Hospital Not yet recruiting
Athens, Greece
Contact: Helen Sambatakou, MD, PhD       helensambatakou@msn.com   
2nd Department of Internal Medicine, Sismanogleio General Hospital Athens Not yet recruiting
Athens, Greece
Contact: Malvina Lada, MD, PhD       malvinalada@gmail.com   
2nd Department of Internal Medicine, Thriasio General Hospital Not yet recruiting
Athens, Greece
Contact: Zoi Alexiou, MD       z_alexiou@yahoo.gr   
3rd Department of Internal Medicine, Sotiria General Hospital Not yet recruiting
Athens, Greece
Contact: Garyphallia Poulakou, MD, PhD       gpoulakou@gmail.com   
5th Department of Internal Medicine, Evangelismos General Hospital Recruiting
Athens, Greece
Contact: Theano Kontopoulou, MD, PhD       tkontopoulou@yahoo.gr   
2nd Department of Internal Medicine, Tzanneion General Hospital Not yet recruiting
Piraeus, Greece
Contact: Georgios Chrysos, MD, PhD       gchrysos@gmail.com   
Department of Emergency Medicine, Tzanneion General Hospital Not yet recruiting
Piraeus, Greece
Contact: Styliani Gerakari, MD, PhD       sgerakari76@gmail.com   
Sponsors and Collaborators
Hellenic Institute for the Study of Sepsis
Investigators
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Study Chair: Evangelos J Giamarellos-Bourboulis, MD, PhD Hellenic Sepsis Study Group
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Responsible Party: Hellenic Institute for the Study of Sepsis
ClinicalTrials.gov Identifier: NCT04724044    
Other Study ID Numbers: ACCESS
2020-004452-15 ( EudraCT Number )
First Posted: January 26, 2021    Key Record Dates
Last Update Posted: June 22, 2021
Last Verified: June 2021
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
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Hellenic Institute for the Study of Sepsis:
Macrolides
Clarithromycin
Additional relevant MeSH terms:
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Pneumonia
Respiratory Tract Infections
Infections
Lung Diseases
Respiratory Tract Diseases
Moxifloxacin
Clarithromycin
Ceftriaxone
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptive Agents, Hormonal
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Protein Synthesis Inhibitors
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors