Clinical trial NCT01223690: Clarithromycin as Immunomodulator for the Management of Sepsis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sepsis
Severe Sepsis
Septic Shock
Keywords: sepsis
infection
bacteremia
clarithromycin
Lead sponsor: University of Athens
Sponsor class: OTHER
First posted: 2010-10-19
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Effect of clarithromycin in mortality and risk for death by severe sepsis/shock and multiple organ dysfunction compared with placebo
timeFrame: 28 days
Secondary outcomes:
measure: Effect of clarithromycin compared with placebo in time to resolution of infection
timeFrame: 28 days
measure: Effect of clarithromycin compared with placebo in time to resolution of sepsis
timeFrame: 28 days
measure: Effect of clarithromycin compared with placebo in time to progression to severe sepsis or septic shock and multiple organ failure
timeFrame: 28 days
measure: Influence of administration of clarithromycin compared with placebo on systemic inflammatory response
timeFrame: 10 days
Other outcomes:
Locations:
city: Athens
country: Greece
facility: 3rd Department of Critical Care Medicine, National and Kapodistrian University of Athens
city: Athens
country: Greece
facility: 2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens
city: Athens
country: Greece
facility: 4th Department of Internal Medicine, National and Kapodistrian University of Athens
city: Athens
country: Greece
facility: 2nd Department of Medicine, Sismanogleion General Hospital
city: Patras
country: Greece
facility: 1st Department of Medicine, University of Patras
city: Thessaloniki
country: Greece
facility: 2nd Department of Surgery, University of Thessaloniki
Study officials:
affiliation: National and Kapodistrian University of Athens
name: Evangelos Giamarellos-Bourboulis, MD, PhD
role: STUDY_CHAIR
affiliation: National and Kapodistrian University of Athens
name: Helen Giamarellou, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National and Kapodistrian University of Athens
name: Apostolos Armaganidis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sismanogleion Athens General Hospital
name: George Koratzanis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Patras
name: Charalambos Gogos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Thessaloniki
name: Konstantinos Atmatzidis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National and Kapodistrian University of Athens
name: Emmanouel Douzinas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.