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Clarithromycin as Immunomodulator for the Management of Sepsis

Information source: University of Athens
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Sepsis; Severe Sepsis; Septic Shock

Intervention: Clarithromycin (Drug); Dextrose 5% (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: University of Athens

Official(s) and/or principal investigator(s):
Evangelos Giamarellos-Bourboulis, MD, PhD, Study Chair, Affiliation: National and Kapodistrian University of Athens
Helen Giamarellou, MD, PhD, Principal Investigator, Affiliation: National and Kapodistrian University of Athens
Apostolos Armaganidis, MD, Principal Investigator, Affiliation: National and Kapodistrian University of Athens
George Koratzanis, MD, Principal Investigator, Affiliation: Sismanogleion Athens General Hospital
Charalambos Gogos, MD, PhD, Principal Investigator, Affiliation: University of Patras
Konstantinos Atmatzidis, MD, Principal Investigator, Affiliation: University of Thessaloniki
Emmanouel Douzinas, MD, PhD, Principal Investigator, Affiliation: National and Kapodistrian University of Athens

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Effect of clarithromycin in mortality and risk for death by severe sepsis/shock and multiple organ dysfunction compared with placebo

Secondary outcome:

Effect of clarithromycin compared with placebo in time to resolution of infection

Effect of clarithromycin compared with placebo in time to resolution of sepsis

Effect of clarithromycin compared with placebo in time to progression to severe sepsis or septic shock and multiple organ failure

Influence of administration of clarithromycin compared with placebo on systemic inflammatory response

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens, Athens 12462, Greece

2nd Department of Medicine, Sismanogleion General Hospital, Athens 15126, Greece

3rd Department of Critical Care Medicine, National and Kapodistrian University of Athens, Athens 11528, Greece

4th Department of Internal Medicine, National and Kapodistrian University of Athens, Athens 12462, Greece

1st Department of Medicine, University of Patras, Patras 24100, Greece

2nd Department of Surgery, University of Thessaloniki, Thessaloniki 54635, Greece

Additional Information

Related publications:

Giamarellos-Bourboulis EJ. Macrocycle molecules for the management of systemic infections: the clarithromycin paradigm. Curr Top Med Chem. 2010;10(14):1470-5. Review.

Giamarellos-Bourboulis EJ, Pechère JC, Routsi C, Plachouras D, Kollias S, Raftogiannis M, Zervakis D, Baziaka F, Koronaios A, Antonopoulou A, Markaki V, Koutoukas P, Papadomichelakis E, Tsaganos T, Armaganidis A, Koussoulas V, Kotanidou A, Roussos C, Giamarellou H. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis. 2008 Apr 15;46(8):1157-64. doi: 10.1086/529439.

Giamarellos-Bourboulis EJ, Tziortzioti V, Koutoukas P, Baziaka F, Raftogiannis M, Antonopoulou A, Adamis T, Sabracos L, Giamarellou H. Clarithromycin is an effective immunomodulator in experimental pyelonephritis caused by pan-resistant Klebsiella pneumoniae. J Antimicrob Chemother. 2006 May;57(5):937-44. Epub 2006 Mar 20.

Giamarellos-Bourboulis EJ, Adamis T, Laoutaris G, Sabracos L, Koussoulas V, Mouktaroudi M, Perrea D, Karayannacos PE, Giamarellou H. Immunomodulatory clarithromycin treatment of experimental sepsis and acute pyelonephritis caused by multidrug-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2004 Jan;48(1):93-9.

Starting date: July 2007
Last updated: August 3, 2011

Page last updated: August 23, 2015

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