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 infectionEffect 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
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