Clarithromycin as Immunomodulator for the Management of Sepsis

NCT ID: NCT01223690

Last Updated: 2011-08-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-07-31
• Study Completion Date: 2011-04-30

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.

Conditions

Sepsis; Severe Sepsis; Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days

Group Type: PLACEBO_COMPARATOR

Dextrose 5%

Intervention Type: DRUG

1000 mg diluted into 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days

Clarithromycin

1000 mg of clarithromycin diluted in 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days

Group Type: ACTIVE_COMPARATOR

Clarithromycin

Intervention Type: DRUG

1000 mg diluted into 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days

Interventions

Clarithromycin

1000 mg diluted into 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days

Intervention Type: DRUG

Dextrose 5%

1000 mg diluted into 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days

Intervention Type: DRUG

Other Intervention Names

Klaricid IV; Dextrose solution

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Athens

OTHER

Sponsor Role: lead

Responsible Party

Evangelos Giamarellos-Bourboulis, Assistant Professor of Medicine

Principal Investigators

Evangelos Giamarellos-Bourboulis, MD, PhD

Role: STUDY_CHAIR

National and Kapodistrian University of Athens

Helen Giamarellou, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

National and Kapodistrian University of Athens

Apostolos Armaganidis, MD

Role: PRINCIPAL_INVESTIGATOR

National and Kapodistrian University of Athens

George Koratzanis, MD

Role: PRINCIPAL_INVESTIGATOR

Sismanogleion Athens General Hospital

Charalambos Gogos, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Patras

Konstantinos Atmatzidis, MD

Role: PRINCIPAL_INVESTIGATOR

University of Thessaloniki

Emmanouel Douzinas, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

National and Kapodistrian University of Athens

Locations

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

Athens, , Greece

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

Athens, , Greece

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

Athens, , Greece

2nd Department of Medicine, Sismanogleion General Hospital

Athens, , Greece

1st Department of Medicine, University of Patras

Pátrai, , Greece

2nd Department of Surgery, University of Thessaloniki

Thessaloniki, , Greece

Countries

Greece

References

Giamarellos-Bourboulis EJ. Macrocycle molecules for the management of systemic infections: the clarithromycin paradigm. Curr Top Med Chem. 2010;10(14):1470-5. doi: 10.2174/156802610792232033.

Reference Type: BACKGROUND

PMID: 20536418 (View on PubMed)

Giamarellos-Bourboulis EJ, Pechere 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.

Reference Type: BACKGROUND

PMID: 18444850 (View on PubMed)

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. doi: 10.1093/jac/dkl084. Epub 2006 Mar 20.

Reference Type: BACKGROUND

PMID: 16549515 (View on PubMed)

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. doi: 10.1128/AAC.48.1.93-99.2004.

Reference Type: BACKGROUND

PMID: 14693524 (View on PubMed)

Vittoros V, Kyriazopoulou E, Lada M, Tsangaris I, Koutelidakis IM, Giamarellos-Bourboulis EJ. Soluble fms-like tyrosine kinase 1, placental growth factor and procalcitonin as biomarkers of gram-negative sepsis: Analysis through a derivation and a validation cohort. Medicine (Baltimore). 2021 Nov 5;100(44):e27662. doi: 10.1097/MD.0000000000027662.

Reference Type: DERIVED

PMID: 34871241 (View on PubMed)

Karakike E, Kyriazopoulou E, Tsangaris I, Routsi C, Vincent JL, Giamarellos-Bourboulis EJ. The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: analysis through a derivation and a validation cohort. Crit Care. 2019 Nov 29;23(1):387. doi: 10.1186/s13054-019-2665-5.

Reference Type: DERIVED

PMID: 31783881 (View on PubMed)

Gainaru G, Papadopoulos A, Tsangaris I, Lada M, Giamarellos-Bourboulis EJ, Pistiki A. Increases in inflammatory and CD14dim/CD16pos/CD45pos patrolling monocytes in sepsis: correlation with final outcome. Crit Care. 2018 Mar 3;22(1):56. doi: 10.1186/s13054-018-1977-1.

Reference Type: DERIVED

PMID: 29499723 (View on PubMed)

Antonakos N, Tsaganos T, Oberle V, Tsangaris I, Lada M, Pistiki A, Machairas N, Souli M, Bauer M, Giamarellos-Bourboulis EJ. Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome. Crit Care. 2017 Mar 9;21(1):48. doi: 10.1186/s13054-017-1625-1.

Reference Type: DERIVED

PMID: 28274246 (View on PubMed)

Other Identifiers

A06-269

Identifier Type: -

Identifier Source: org_study_id