Clarithromycin as Immunomodulator for the Management of Sepsis

This study has been completed.
Sponsor:
Information provided by:
University of Athens
ClinicalTrials.gov Identifier:
NCT01223690
First received: October 18, 2010
Last updated: August 3, 2011
Last verified: October 2010
  Purpose

The herein protocol is based on the results of one former clinical trial conducted by our study group showing the considerable efficacy of intravenously administered clarithromycin as an adjuvant to antimicrobial chemotherapy for patients with sepsis, septic shock and respiratory failure in the field of ventilator-associated pneumonia. The proposed clinical trial is based on the need to generalize the application of intravenous clarithromycin in the total of admitted septic patients irrespective of the underlying cause of sepsis.


Condition Intervention Phase
Sepsis
Severe Sepsis
Septic Shock
Drug: Clarithromycin
Drug: Dextrose 5%
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind Randomized Placebo-controlled Clinical Trial of the Safety and Efficacy of Intravenous Clarithromycin as Immunomodulatory Therapy for the Management of Sepsis

Resource links provided by NLM:


Further study details as provided by University of Athens:

Primary Outcome Measures:
  • Effect of clarithromycin in mortality and risk for death by severe sepsis/shock and multiple organ dysfunction compared with placebo [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    Survival analysis for 28 days will be done between placebo-treated patients and clarithromycin-treated patients separately for patients with sepsis; for patients with severe sepsis; and for patients with septic shock. Odds ratios for death by septic shock and/or multiple organ dysfunction will be assessed separately for each arm. Comparison of odds ratios will be done.


Secondary Outcome Measures:
  • Effect of clarithromycin compared with placebo in time to resolution of infection [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    Time analysis between placebo-treated patients and clarithromycin-treated patients will be done

  • Effect of clarithromycin compared with placebo in time to resolution of sepsis [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    Time analysis between placebo-treated patients and clarithromycin-treated patients will be done

  • Effect of clarithromycin compared with placebo in time to progression to severe sepsis or septic shock and multiple organ failure [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    Time analysis between placebo-treated patients and clarithromycin-treated patients will be done

  • Influence of administration of clarithromycin compared with placebo on systemic inflammatory response [ Time Frame: 10 days ] [ Designated as safety issue: No ]
    Comparative analysis of serum markers estimated at consecutive time intervals over the first 10 days of follow-up


Enrollment: 600
Study Start Date: July 2007
Study Completion Date: April 2011
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days
Drug: Dextrose 5%
1000 mg diluted into 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days
Other Name: Dextrose solution
Active Comparator: Clarithromycin
1000 mg of clarithromycin diluted in 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days
Drug: Clarithromycin
1000 mg diluted into 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days
Other Name: Klaricid IV

Detailed Description:

The idea for the application of intravenous clarithromycin as immunomodulatory therapy for the management of sepsis has been evolved on in vitro results showing that concentrations close to 10μg/ml may refrain biosynthesis of pro-inflammatory cytokines by inhibiting the activation of the translation factor NF-κB. Intravenously administered clarithromycin has been widely applied in experimental sepsis by one susceptible isolate of Escherichia coli, one multidrug-resistant isolate of Pseudomonas aeruginosa and one pan-resistant isolate of Klebsiella pneumoniae after induction of pyelonephritis by the test isolates. Results of these animal studies revealed that clarithromycin inhibited the evolution of the systemic inflammatory response syndrome (SIRS) acting at the cellular level of blood monocytes and that its effect was expressed when administered after induction of sepsis.

Based on the latter experimental data, one double-blind randomized clinical trail was conducted over the period June 2004-December 2005 in the 4th Department of Internal Medicine, in the 1st Department of Critical Care and in the 2nd Department of Critical Care of the University of Athens. The study enrolled 200 subjects with ventilator-associated pneumonia (VAP) and sepsis, severe sepsis or septic shock; 100 received placebo and 100 clarithromycin. Statistical analysis of results revealed that clarithromycin effected earlier resolution of signs of sepsis and of VAP accompanied by a) prolongation of survival of the total of patients over the first 16 days of follow-up, b) prolongation of survival of patients with septic shock for 28 days of follow-up, and c) 2.75-fold reduction of the relative risk of death over the first 28 days of follow-up in patients with multiple organ failure.

The proposed clinical trial is based on the extremely beneficial results of clarithromycin in the septic population of patients with VAP creating the following needs: a) to generalize the application of intravenous clarithromycin in the total of admitted septic patients irrespective of the underlying cause of sepsis, and b) to expand the effect of clarithromycin over a greater time period than the first 19 days post start of administration.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • One or more of the following infections: a) primary or secondary bacteremia by Gram-negative bacteria, b) acute pyelonephritis, or c) intrabdominal infection. Only one episode of infection per patient will be enrolled. Both patients with community-acquired and nosocomial infections are eligible for the study.
  • The presence of at least two of the following criteria of sepsis according to ACCP/SCCM (8) a) body temperature >38 degreesC or <36 degreesC; b) pulse rate >90/min; c) breath rate >20/min or Pco2<32mmHg; and/or d) leukocytosis (white blood cell count >12,000/μl) or leukopenia (white blood cell count <4,000/μl) or >10% band forms

Exclusion Criteria:

  • Presence of HIV infection
  • Intake of corticosteroids at a dose more than or equal to 1mg/kg of equivalent prednisone for more than one month
  • Neutropenia as <500 neutrophils/μl
  • Selection by the attending physician of a macrolide as empiric antimicrobial therapy for the infection making the patient eligible for the study
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01223690

Locations
Greece
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Athens, Greece, 12462
2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens
Athens, Greece, 12462
3rd Department of Critical Care Medicine, National and Kapodistrian University of Athens
Athens, Greece, 11528
2nd Department of Medicine, Sismanogleion General Hospital
Athens, Greece, 15126
1st Department of Medicine, University of Patras
Patras, Greece, 24100
2nd Department of Surgery, University of Thessaloniki
Thessaloniki, Greece, 54635
Sponsors and Collaborators
University of Athens
Investigators
Study Chair: Evangelos Giamarellos-Bourboulis, MD, PhD National and Kapodistrian University of Athens
Principal Investigator: Helen Giamarellou, MD, PhD National and Kapodistrian University of Athens
Principal Investigator: Apostolos Armaganidis, MD National and Kapodistrian University of Athens
Principal Investigator: George Koratzanis, MD Sismanogleion Athens General Hospital
Principal Investigator: Charalambos Gogos, MD, PhD University of Patras
Principal Investigator: Konstantinos Atmatzidis, MD University of Thessaloniki
Principal Investigator: Emmanouel Douzinas, MD, PhD National and Kapodistrian University of Athens
  More Information

Publications:
Responsible Party: Evangelos Giamarellos-Bourboulis, Assistant Professor of Medicine
ClinicalTrials.gov Identifier: NCT01223690     History of Changes
Other Study ID Numbers: A06-269
Study First Received: October 18, 2010
Last Updated: August 3, 2011
Health Authority: Greece: National Organization of Medicines

Keywords provided by University of Athens:
sepsis
infection
bacteremia
clarithromycin

Additional relevant MeSH terms:
Sepsis
Toxemia
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock
Clarithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014