Clarithromycin as Immunomodulator for the Management of Sepsis

Sponsor

University of Athens (Other)

Overall Status

Completed

CT.gov ID

NCT01223690

Collaborator

(none)

600

Enrollment

Locations

Arms

Duration (Months)

100

Patients Per Site

2.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis Severe Sepsis Septic Shock	Drug: Clarithromycin Drug: Dextrose 5%	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

600 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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 Start Date :

Jul 1, 2007

Actual Primary Completion Date :

Nov 1, 2010

Actual Study Completion Date :

Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days	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 Names: Dextrose solution
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	Drug: Clarithromycin 1000 mg diluted into 250 ml of dextrose 5% administered intravenously within one hour of continuous infusion for four consecutive days Other Names: Klaricid IV

Arm

Intervention/Treatment

Placebo Comparator: Placebo

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

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 Names:

Dextrose solution

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

Drug: Clarithromycin

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

Other Names:

Klaricid IV

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Effect of clarithromycin compared with placebo in time to resolution of infection [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 [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 [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 [10 days]
Comparative analysis of serum markers estimated at consecutive time intervals over the first 10 days of follow-up

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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;

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	3rd Department of Critical Care Medicine, National and Kapodistrian University of Athens	Athens	Greece	11528
2	2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens	Athens	Greece	12462
3	4th Department of Internal Medicine, National and Kapodistrian University of Athens	Athens	Greece	12462
4	2nd Department of Medicine, Sismanogleion General Hospital	Athens	Greece	15126
5	1st Department of Medicine, University of Patras	Patras	Greece	24100
6	2nd Department of Surgery, University of Thessaloniki	Thessaloniki	Greece	54635

Sponsors and Collaborators

University of Athens

Investigators

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