Anti-inflammatory Action of Oral Clarithromycin in Community-acquired Pneumonia

NCT04724044 | Completed Phase 3

• 2 other identifiers: ACCESS2020-004452-15
• Study Type: interventional
• Target: 278
• Locations: 1 country
• Sites: 18

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.

Conditions

Community-acquired Pneumonia; Sepsis; Inflammatory Response; Mortality; Biomarkers; SIRS

Keywords

Macrolides; Clarithromycin

Outcome Measures

Primary Outcomes (2)

• Change of baseline respiratory symptoms score

  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

  4 days

• Change of baseline total sequential organ failure assessment (SOFA) score and/or change of baseline serum PCT

  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

  4 days

Secondary Outcomes (23)

• Change of baseline respiratory symptoms score in the subgroup of patients infected or colonized by clarithromycin-susceptible S.pneumoniae

  4 days

• Change of baseline respiratory symptoms score in the subgroup of patients infected or colonized by clarithromycin-resistant S.pneumoniae

  4 days

• 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

  4 days

• 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

  4 days

• Mortality rate at 28 days

  28 days

Study Arms (2)

Placebo

PLACEBO COMPARATOR

These patients will be treated with 1 placebo tablet every 12 hours and intravenously with ceftriaxone or one β-lactam/β-lactamase combination 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.The dose regimen of ceftriaxone will be 2g once daily. The β-lactam/β-lactamase combination can be either amoxycilln/clavulanate or ampicillin/sulbactam or piperacillin/tazobactam. These may be administered three or four times daily and the dose is adjusted according to renal clearance. In case urinary antigen for Legionella spp is positive and/or Mycoplasma pneumoniae spp is isolated in sputum culture and/or in BioFire Respiratory FilmArray, patients will receive intravenously 400mg of moxifloxacin instead of ceftriaxone as part of standard of care therapy according to bibliographic references.

Drug: Tablets

Clarithromycin

ACTIVE COMPARATOR

These patients will be treated with 1 tablet of 500 mg of clarithromycin every 12 hours and intravenously with ceftriaxone or one β-lactam/β-lactamase combination 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.The dose regimen of ceftriaxone will be 2g once daily. The β-lactam/β-lactamase combination can be either amoxycilln/clavulanate or ampicillin/sulbactam or piperacillin/tazobactam. These may be administered three or four times daily and the dose is adjusted according to renal clearance. In case urinary antigen for Legionella spp is positive and/or Mycoplasma pneumoniae spp is isolated in sputum culture and/or in BioFire Respiratory FilmArray, patients will receive intravenously 400mg of moxifloxacin instead of ceftriaxone as part of standard of care therapy according to bibliographic references.

Drug: Clarithromycin 500mg

Interventions

Tablets DRUG

Oral tablets of similar appearance to active study drug

Also known as: 2g of intravenous ceftriaxone or one β-lactam/β-lactamase combination(dose adjusted according to renal clearance) or 400mg of intravenous moxifloxacin

Placebo

Clarithromycin 500mg DRUG

Oral tablets of 500mg of clarithromycin

Also known as: 2g of intravenous ceftriaxone or one β-lactam/β-lactamase combination(dose adjusted according to renal clearance) or 400mg of intravenous moxifloxacin

Clarithromycin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (≥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
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Hellenic Institute for the Study of Sepsis: lead

Study Sites (18)

4th Department of Internal Medicine, Attikon University Hospital

Athens, 12462, Greece

Location

1st Department of Internal Medicine, Amalia Fleming General Hospital

Athens, Greece

Location

1st Department of Internal Medicine, Gennimatas General Hospital

Athens, Greece

Location

1st Department of Internal Medicine, Konstantopouleio-Patission General Hospital

Athens, Greece

Location

1st Department of Internal Medicine, THRIASIO Eleusis General Hospital

Athens, Greece

Location

1st Department of Internal Medicine,Korgialeneio-Benakeio General Hospital

Athens, Greece

Location

2nd Department of Internal Medicine, Attikon University Hospital

Athens, Greece

Location

2nd Department of Internal Medicine, Thriasio General Hospital

Athens, Greece

Location

3rd Department of Internal Medicine, KORGIALENEION-BENAKEION Athens General Hospital

Athens, Greece

Location

3rd Department of Internal Medicine, Sotiria General Hospital

Athens, Greece

Location

5th Department of Internal Medicine, Evangelismos General Hospital

Athens, Greece

Location

Department of Chest Medicine, EVANGELISMOS Athens General Hospital

Athens, Greece

Location

Department of Pulmonary Medicine, General Hospital of Kerkyra

Corfu, Greece

Location

1st Department of Internal Medicine, Ioannina University General Hospital

Ioannina, Greece

Location

Department of Internal Medicine, Larissa University General Hospital

Larissa, Greece

Location

Department of Internal Medicine, Patras University General Hospital

Pátrai, Greece

Location

2nd Department of Internal Medicine, Tzaneion General Hospital

Piraeus, Greece

Location

Department of Emergency Medicine, Tzanneion General Hospital

Piraeus, Greece

Location

Related Publications (1)

• Giamarellos-Bourboulis EJ, Siampanos A, Bolanou A, Doulou S, Kakavoulis N, Tsiakos K, Katopodis S, Schinas G, Skorda L, Alexiou Z, Armenis K, Katsaounou P, Chrysos G, Masgala A, Poulakou G, Antonakos N, Safarika A, Kyprianou M, Dakou K, Gerakari S, Papanikolaou IC, Milionis H, Marangos M, Dalekos GN, Tzavara V, Akinosoglou K, Hatziaggelaki E, Sympardi S, Kontopoulou T, Mouktaroudi M, Papadopoulos A, Niederman MS. Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2024 Apr;12(4):294-304. doi: 10.1016/S2213-2600(23)00412-5. Epub 2024 Jan 3.

  PMID: 38184008 DERIVED

MeSH Terms

Conditions

Community-Acquired Pneumonia; Sepsis

Interventions

Tablets; Clarithromycin

Condition Hierarchy (Ancestors)

Community-Acquired Infections; Infections; Pneumonia; Respiratory Tract Infections; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Evangelos J Giamarellos-Bourboulis, MD, PhD

  Hellenic Sepsis Study Group

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a prospective, 1:1 randomized, double-blind, placebo-controlled trial

Study Record Dates

• First Submitted: January 20, 2021
• First Posted: January 26, 2021
• Study Start: January 25, 2021
• Primary Completion: April 11, 2023
• Study Completion: April 11, 2023
• Last Updated: December 12, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

GR (18)