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Clarithromycin as Immunomodulator for the Management of Sepsis

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ClinicalTrials.gov Identifier: NCT01223690
Recruitment Status : Completed
First Posted : October 19, 2010
Last Update Posted : August 4, 2011
Sponsor:
Information provided by:
University of Athens

Tracking Information
First Submitted Date  ICMJE October 18, 2010
First Posted Date  ICMJE October 19, 2010
Last Update Posted Date August 4, 2011
Study Start Date  ICMJE July 2007
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 18, 2010)
Effect of clarithromycin in mortality and risk for death by severe sepsis/shock and multiple organ dysfunction compared with placebo [ Time Frame: 28 days ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01223690 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 18, 2010)
  • Effect of clarithromycin compared with placebo in time to resolution of infection [ Time Frame: 28 days ]
    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 ]
    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 ]
    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 ]
    Comparative analysis of serum markers estimated at consecutive time intervals over the first 10 days of follow-up
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clarithromycin as Immunomodulator for the Management of Sepsis
Official Title  ICMJE A Double-blind Randomized Placebo-controlled Clinical Trial of the Safety and Efficacy of Intravenous Clarithromycin as Immunomodulatory Therapy for the Management of Sepsis
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Sepsis
  • Severe Sepsis
  • Septic Shock
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days
    Intervention: Drug: Dextrose 5%
  • 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
    Intervention: Drug: Clarithromycin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 18, 2010)
600
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 2011
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Greece
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01223690
Other Study ID Numbers  ICMJE A06-269
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Evangelos Giamarellos-Bourboulis, Assistant Professor of Medicine
Study Sponsor  ICMJE University of Athens
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account University of Athens
Verification Date October 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP