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

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ClinicalTrials.gov Identifier: NCT03345992
Recruitment Status : Completed
First Posted : November 17, 2017
Last Update Posted : December 22, 2020
Sponsor:
Collaborator:
European Commission
Information provided by (Responsible Party):
Hellenic Institute for the Study of Sepsis

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients 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 : December 15, 2017
Actual Primary Completion Date : September 22, 2019
Actual Study Completion Date : December 19, 2020


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 Name: 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




Primary Outcome Measures :
  1. Mortality rate at 28 days [ Time Frame: 28 days ]
    Differences in early (28-day) all-cause mortality rate between clarithromycin and placebo-treated arms


Secondary Outcome Measures :
  1. Mortality rate at 90 days [ Time Frame: 90 days ]
    Differences in middle term (90-day) all-cause mortality rate between clarithromycin and placebo-treated arms

  2. Mortality rate at 28 days for patients with septic shock [ Time Frame: 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

  3. Rate of early sepsis response at 3 days [ Time Frame: 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

  4. Rate of sepsis resolution at 7 days [ Time Frame: 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

  5. New sepsis episode until 28 days [ Time Frame: 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

  6. Time to new sepsis episode until 28 days [ Time Frame: 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

  7. Cell population analysis [ Time Frame: 10 days ]
    Flow cytometry will be compared between clarithromycin and placebo-treated arms

  8. Transcriptome analysis [ Time Frame: 10 days ]
    Expression of messenger Ribonucleic Acid (mRNA) will be compared between clarithromycin and placebo-treated arms

  9. Metabolome analysis [ Time Frame: 10 days ]
    Metabolites will be compared between clarithromycin and placebo-treated arms

  10. Microbiome analysis [ Time Frame: 10 days ]
    Gut microbiome composition will be compared between clarithromycin and placebo-treated arms

  11. Cost of hospitalization [ Time Frame: 28 days ]
    Real cost of hospitalization, i.e. medication administered and interventions performed, in euros (€), will be compared between clarithromycin and placebo-treated groups



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03345992


Locations
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Belgium
Intensive Care Unit, Saint-Pierre University Hospital
Brussels, Belgium, 1000
Intensive Care Unit, Brugmann University Hospital
Brussels, Belgium, 1020
Intensive Care Unit, Erasme University Hospital
Brussels, Belgium, 1070
Greece
Intensive Care Unit, Korgialeneio-Benakeio General Hospital
Athens, Greece, 11526
Intensive Care Unit, Laikon General Hospital
Athens, Greece, 11527
2nd Department of Intensive Care Medicine, Attikon University Hospital
Athens, Greece, 12462
4th Department of Internal Medicine, Attikon University Hospital
Athens, Greece, 12462
2nd Department of Internal Medicine, Sismanogleio General Hospital
Athens, Greece, 15126
Intensive Care Unit, Agios Dimitrios General Hospital
Thessaloniki, Greece, 54 634
Intensive Care Unit, G. Gennimatas General Hospital
Thessaloniki, Greece, 546 35
Intensive Care Unit, Theageneio Oncological Hospital
Thessaloniki, Greece, 546 39
Intensive Care Unit, Ippokrateion General Hospital
Thessaloniki, Greece, 546 42
Sponsors and Collaborators
Hellenic Institute for the Study of Sepsis
European Commission
Investigators
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Principal Investigator: Apostolos Armaganidis, MD, PhD National Kapodistrian University of Athens, Medical School
Publications of Results:

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Responsible Party: Hellenic Institute for the Study of Sepsis
ClinicalTrials.gov Identifier: NCT03345992    
Other Study ID Numbers: INCLASS
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: December 22, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Hellenic Institute for the Study of Sepsis:
Macrolides
Additional relevant MeSH terms:
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Infections
Sepsis
Gram-Negative Bacterial Infections
Respiratory Distress Syndrome
Respiratory Distress Syndrome, Newborn
Syndrome
Multiple Organ Failure
Disease
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Systemic Inflammatory Response Syndrome
Inflammation
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Shock
Bacterial Infections
Bacterial Infections and Mycoses
Clarithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors