INCLASS: Benefit of Clarithromycin in Patients With Severe Infections Through Modulation of the Immune System

Sponsor

Hellenic Institute for the Study of Sepsis (Other)

Overall Status

Completed

CT.gov ID

NCT03345992

Collaborator

European Commission (Other)

110

Enrollment

Locations

Arms

36.1

Actual Duration (Months)

9.2

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

High mortality associated with sepsis and Multiple Organ Dysfunction Syndrome (MODS) calls for alternative, individualized therapies in selected patients that might benefit form specific interventions. Role of macrolides as potential immunomodulatory treatment in sepsis is promising, but unclear. Subgroup analysis of previous large-scale clinical trials on patients with ventilator-associated pneumonia or gram-negative sepsis, showed that addition of clarithromycin to standard antibiotic therapy conferred a significant survival benefit in the subgroup of patients with respiratory dysfunction and MODS. The INCLASS study is aiming to assess the efficacy of intravenous treatment of clarithromycin in the reduction of 28-day mortality among patients suffering from these entities.

Condition or Disease	Intervention/Treatment	Phase
Sepsis Pneumonia Gram-Negative Bacteria Infection Multiple Organ Failure Respiratory Distress Syndrome Mortality Biomarkers	Drug: Clarithromycin Drug: Water for injection	Phase 3

Detailed Description

Sepsis is a condition with actually rising incidence, estimated around 19 cases per 1000 hospitalizations per year in academic hospitals in USA and similar trends in Europe. It is associated with unacceptably high early (in-hospital) mortality of 40- 50%. Current guidelines promote best practice by early recognition and management with timely antibiotic administration, fluids, vasopressors and early identification/ control of infection source. However, in spite of adherence to more intensive and costly protocols of early goal-directed therapy, no further decrease in mortality is achieved. Syndromic approaches on sepsis and therapies targeting immune modulation are under evaluation and failures may partly be due to incomplete understanding of underlying pathophysiological mechanisms and immunological phases (pro and anti-inflammatory) of sepsis.

Macrolides, such as clarithromycin or azithromycin have been shown beneficial in reducing Chronic Obstructive Pulmonary Disease exacerbations (OR 0.55; 95% Confidence Intervals [CI] 0.39-0.77; p<0.001) partly through anti-inflammatory properties. Besides, when added to a beta-lactam regimen in community-acquired pneumonia, macrolide therapy was associated with reduced mortality risk (OR 0.67; 95% CI 0.61-0.73; p<0.001) in a recent meta- analysis of observational studies including 42942 patients. An immunomodulatory effect of macrolides, beyond their antimicrobial action may explain these findings.

Clarithromycin as adjunctive treatment to standard antibiotic therapy has been used by our group in two previous large-scale multi-center Randomised Controlled Trials (RCTs) conducted in Greece after approval from the Greek regulatory authorities. The first RCT studied 200 patients with sepsis due to Ventilator Associated Pneumonia (VAP) ( www.clinicaltrials.gov NCT00297674). Identified pathogens mainly included gram- negative bacteria i.e. Acinetobacter baumannii and Pseudomonas aeruginosa that do not belong to the usual antimicrobial spectrum of macrolides. Although 28-day mortality in both arms was similar, patients assigned to the clarithromycin arm experienced earlier weaning from mechanical ventilation and more rapid resolution of VAP, compared to the placebo arm. In the subgroup of patients with septic shock and multiple organ dysfunction syndrome (MODS), probability of sepsis-related death was significantly lower (OR 3.78 vs 19; p = 0.043). Serious adverse events (SAEs) occurred in 3 (3%) clarithromycin-treated patients, with no clear causative link with the study drug in 2 out of 3 cases. Furthermore, hospitalization costs associated clarithromycin use were significantly reduced (by 7000 euros/ patient) compared to the placebo arm.

The second multi-center RCT compared the efficacy of clarithromycin versus placebo added to standard antibiotic therapy in patients with gram-negative sepsis caused by acute pyelonephritis, intra-abdominal infections and primary gram- negative bacteremia; 600 patients were included (www.clinicaltrials.gov NCT01223690). Overall mortality at 28 days in both arms did not differ, but probability of death due to septic shock and MODS was shown once more lower in the clarithromycin-treated group (OR 3.58 vs 6.21; p = 0.036). Interestingly, survival benefit from clarithromycin was even greater in those patients suffering from adult respiratory distress syndrome (ARDS). SAEs were described in 2 (0.7%) patients treated with clarithromycin, while its use was associated with saving of a median of 1000 euros/ hospitalized patient.

Immunomodulatory effects of clarithromycin in sepsis are not yet elucidated. The analysis of circulating monocytes and of circulating cytokines of patients participating in the first RCT showed that treatment with clarithromycin was associated with a decline in Interleukin-10 (IL-10)/ Tumor Necrosis Factor-α (TNF-α) ratio, greater apoptosis of monocytes, enhanced antigen presentation capacity of monocytes, as well as improved capacity of monocytes for cytokine production suggesting an effect consistent with reversal of sepsis-induced immunosuppression. These findings in conjunction with evidence generated from in vitro and animal experiments suggest modulation of the immune response as the mechanism of action of clarithromycin.

In both RCTs, clarithromycin was administered intravenously at a dose of 1g as continuous one-hour intravenous infusion for three or four days. The drug was safe, well tolerated and cost-effective. However, benefit from treatment in both RCTs was shown only after sub-group analysis of the sub-group of patients with respiratory dysfunction and not when analysis comprised the entire study population. As a consequence, in order to consolidate the benefit of clarithromycin among patients with sepsis and respiratory dysfunction, the INCLASS study is a RCT designed to target a patient population with sepsis and respiratory dysfunction. It also targets a population with infections likely to be caused by Gram-negative bacteria that do not belong to the antimicrobial spectrum of clarithromycin. The study's aims are to assess the effect on mortality associated with the use of clarithromycin as adjunctive treatment in the above setting, as well as to provide insight on different biomarkers modification during treatment, to propose a mechanism of action of this treatment and to perform a cost analysis.

Study Design

Study Type:

Interventional

Actual Enrollment :

110 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients assigned to either intravenous clarithromycin or placeboPatients assigned to either intravenous clarithromycin or placebo

Masking:

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

Primary Purpose:

Treatment

Official Title:

A Double-Blind, Randomized, Placebo-Controlled Clinical Study of the Efficacy of Intravenous Clarithromycin as Adjunctive Treatment in Patients With Sepsis and Respiratory and Multiple Organ Dysfunction Syndrome

Actual Study Start Date :

Dec 15, 2017

Actual Primary Completion Date :

Sep 22, 2019

Actual Study Completion Date :

Dec 19, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo After enrollment, the placebo arm will receive water for injection at a volume of 20ml diluted to a final volume of 250 ml dextrose in water 5%, infused once daily through intravenous route, within 1 hour, for a duration of four consecutive days.	Drug: Water for injection Water for injection 20 ml will be administered, diluted in D/W 5%, IV, once daily for four consecutive days Other Names: Sterile Water For Injection
Active Comparator: Clarithromycin After enrollment, the active drug arm will receive 1g of clarithromycin (500 mg powder for concentrate for solution for infusion per vial), dissolved into 20 ml water for injection and then diluted to a final volume of 250 ml dextrose in water 5%. This will be infused through intravenous route, once daily within 1 hour, for a duration of four consecutive days.	Drug: Clarithromycin Clarithromycin two vials of lyophilised powder for reconstitution as solution for IV administration per patient, once daily, for four consecutive days. Other Names: Klaricid Biclar

Arm

Intervention/Treatment

Placebo Comparator: Placebo

After enrollment, the placebo arm will receive water for injection at a volume of 20ml diluted to a final volume of 250 ml dextrose in water 5%, infused once daily through intravenous route, within 1 hour, for a duration of four consecutive days.

Drug: Water for injection

Water for injection 20 ml will be administered, diluted in D/W 5%, IV, once daily for four consecutive days

Other Names:

Sterile Water For Injection

Active Comparator: Clarithromycin

After enrollment, the active drug arm will receive 1g of clarithromycin (500 mg powder for concentrate for solution for infusion per vial), dissolved into 20 ml water for injection and then diluted to a final volume of 250 ml dextrose in water 5%. This will be infused through intravenous route, once daily within 1 hour, for a duration of four consecutive days.

Drug: Clarithromycin

Clarithromycin two vials of lyophilised powder for reconstitution as solution for IV administration per patient, once daily, for four consecutive days.

Other Names:

Klaricid

Biclar

Outcome Measures

Primary Outcome Measures

Mortality rate at 28 days [28 days]
Differences in early (28-day) all-cause mortality rate between clarithromycin and placebo-treated arms

Secondary Outcome Measures

Mortality rate at 90 days [90 days]
Differences in middle term (90-day) all-cause mortality rate between clarithromycin and placebo-treated arms
Mortality rate at 28 days for patients with septic shock [28 days]
Differences in early (28-day) all-cause mortality rate between clarithromycin and placebo-treated arms in the subgroup of patients with septic shock
Rate of early sepsis response at 3 days [3 days]
The number of patients who present at least 25% decrease of day 1 SOFA score on day 3 will be compared between clarithromycin and placebo-treated groups
Rate of sepsis resolution at 7 days [7 days]
The number of patients who present at least 25% decrease of day 1 SOFA score on day 7 will be compared between clarithromycin and placebo-treated groups
New sepsis episode until 28 days [28 days]
The number of patients who present a new increase of SOFA score by at least 2 points, consequent to infection, after having previously experienced sepsis resolution, will be compared between clarithromycin and placebo-treated groups
Time to new sepsis episode until 28 days [28 days]
The time to new sepsis episode, defined as a new increase of SOFA score by at least 2 points, consequent to infection, in patients who have previously experienced sepsis resolution, will be compared between clarithromycin and placebo-treated groups
Cell population analysis [10 days]
Flow cytometry will be compared between clarithromycin and placebo-treated arms
Transcriptome analysis [10 days]
Expression of messenger Ribonucleic Acid (mRNA) will be compared between clarithromycin and placebo-treated arms
Metabolome analysis [10 days]
Metabolites will be compared between clarithromycin and placebo-treated arms
Microbiome analysis [10 days]
Gut microbiome composition will be compared between clarithromycin and placebo-treated arms
Cost of hospitalization [28 days]
Real cost of hospitalization, i.e. medication administered and interventions performed, in euros (€), will be compared between clarithromycin and placebo-treated groups

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patients (≥18 years)
Patients of both genders
Informed consent form signed by patient or by first-degree relative in case of patient unable to consent
Negative (blood or urinary) pregnancy test for female patients of reproductive age
Willingness to receive contraception during and seven days after the administration of the study drug.
Presence of one or more of the following infections: hospital-acquired pneumonia (HAP), health-care associated pneumonia (HCAP), ventilator-associated pneumonia (VAP), primary Gram-negative bacteremia and intra-abdominal infections.
Presence of sepsis as defined by: Sequential Organ Failure Assessment (SOFA) score of 2 or more points for patients who are admitted with infection at the emergency department or increase of admission SOFA score by 2 or more points consequent to infection, for patients already hospitalized
Respiratory dysfunction defined as one Partial Arterial Oxygen Pressure to Fraction of Inspired Oxygen (PaO2/FiO2) ratio inferior to 200, independently of the Positive End Expiratory Pressure (PEEP) level.
Total SOFA points for organ dysfunctions other than the respiratory function more than 3

Exclusion Criteria:

Denial for informed consent
Age inferior to 18 years
Pregnancy (confirmed by blood or urinary pregnancy test) or lactation for female patients of reproductive age.
Unwillingness to receive contraception during and seven days after the administration of the study drug.
HIV infection (with known Cluster of Differentiation 4-positive [CD4] cell count ≤ 200/mm3)
Solid organ, or bone marrow transplantation
Corticosteroid oral or intravenous intake greater than 0.4 mg/kg of equivalent prednisone daily over the last 15 days
Known active neoplasms compromising short-term survival (1 month)
Neutropenia <1000/mm3
Known allergy to macrolides
Previous participation in the study
Administration of a macrolide for the current infection

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Intensive Care Unit, Saint-Pierre University Hospital	Brussels	Belgium	1000
2	Intensive Care Unit, Brugmann University Hospital	Brussels	Belgium	1020
3	Intensive Care Unit, Erasme University Hospital	Brussels	Belgium	1070
4	Intensive Care Unit, Korgialeneio-Benakeio General Hospital	Athens	Greece	11526
5	Intensive Care Unit, Laikon General Hospital	Athens	Greece	11527
6	2nd Department of Intensive Care Medicine, Attikon University Hospital	Athens	Greece	12462
7	4th Department of Internal Medicine, Attikon University Hospital	Athens	Greece	12462
8	2nd Department of Internal Medicine, Sismanogleio General Hospital	Athens	Greece	15126
9	Intensive Care Unit, Agios Dimitrios General Hospital	Thessaloniki	Greece	54 634
10	Intensive Care Unit, G. Gennimatas General Hospital	Thessaloniki	Greece	546 35
11	Intensive Care Unit, Theageneio Oncological Hospital	Thessaloniki	Greece	546 39
12	Intensive Care Unit, Ippokrateion General Hospital	Thessaloniki	Greece	546 42