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

NCT03345992 | Completed Phase 3

• 1 other identifier: INCLASS
• Study Type: interventional
• Target: 110
• Locations: 2 countries
• Sites: 12

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.

Conditions

Sepsis; Pneumonia; Gram-Negative Bacteria Infection; Multiple Organ Failure; Respiratory Distress Syndrome; Mortality; Biomarkers

Keywords

Macrolides

Outcome Measures

Primary Outcomes (1)

• Mortality rate at 28 days

  Differences in early (28-day) all-cause mortality rate between clarithromycin and placebo-treated arms

  28 days

Secondary Outcomes (11)

• Mortality rate at 90 days

  90 days

• Mortality rate at 28 days for patients with septic shock

  28 days

• Rate of early sepsis response at 3 days

  3 days

• Rate of sepsis resolution at 7 days

  7 days

• New sepsis episode until 28 days

  28 days

Study Arms (2)

Placebo

PLACEBO COMPARATOR

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

Clarithromycin

ACTIVE COMPARATOR

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

Interventions

Clarithromycin DRUG

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

Also known as: Klaricid, Biclar

Clarithromycin

Water for injection DRUG

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

Also known as: Sterile Water For Injection

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hellenic Institute for the Study of Sepsis: lead
• European Commission: collaborator

Study Sites (12)

Intensive Care Unit, Saint-Pierre University Hospital

Brussels, 1000, Belgium

Location

Intensive Care Unit, Brugmann University Hospital

Brussels, 1020, Belgium

Location

Intensive Care Unit, Erasme University Hospital

Brussels, 1070, Belgium

Location

Intensive Care Unit, Korgialeneio-Benakeio General Hospital

Athens, 11526, Greece

Location

Intensive Care Unit, Laikon General Hospital

Athens, 11527, Greece

Location

2nd Department of Intensive Care Medicine, Attikon University Hospital

Athens, 12462, Greece

Location

4th Department of Internal Medicine, Attikon University Hospital

Athens, 12462, Greece

Location

2nd Department of Internal Medicine, Sismanogleio General Hospital

Athens, 15126, Greece

Location

Intensive Care Unit, Agios Dimitrios General Hospital

Thessaloniki, 54 634, Greece

Location

Intensive Care Unit, G. Gennimatas General Hospital

Thessaloniki, 546 35, Greece

Location

Intensive Care Unit, Theageneio Oncological Hospital

Thessaloniki, 546 39, Greece

Location

Intensive Care Unit, Ippokrateion General Hospital

Thessaloniki, 546 42, Greece

Location

Related Publications (7)

• Giamarellos-Bourboulis EJ, Mylona V, Antonopoulou A, Tsangaris I, Koutelidakis I, Marioli A, Raftogiannis M, Kopterides P, Lymberopoulou K, Mouktaroudi M, Papageorgiou C, Papaziogas B, Georgopoulou AP, Tsaganos T, Papadomichelakis E, Gogos C, Ladas M, Savva A, Pelekanou A, Baziaka F, Koutoukas P, Kanni T, Spyridaki A, Maniatis N, Pelekanos N, Kotsaki A, Vaki I, Douzinas EE, Koratzanis G, Armaganidis A. Effect of clarithromycin in patients with suspected Gram-negative sepsis: results of a randomized controlled trial. J Antimicrob Chemother. 2014 Apr;69(4):1111-8. doi: 10.1093/jac/dkt475. Epub 2013 Nov 28.

  PMID: 24292991 RESULT

• Spyridaki A, Raftogiannis M, Antonopoulou A, Tsaganos T, Routsi C, Baziaka F, Karagianni V, Mouktaroudi M, Koutoukas P, Pelekanou A, Kotanidou A, Orfanos SE, van der Meer JW, Netea MG, Giamarellos-Bourboulis EJ. Effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by Gram-negative bacteria: results from a randomized clinical study. Antimicrob Agents Chemother. 2012 Jul;56(7):3819-25. doi: 10.1128/AAC.05798-11. Epub 2012 May 7.

  PMID: 22564837 RESULT

• 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.

  PMID: 18444850 RESULT

• Tsaganos T, Raftogiannis M, Pratikaki M, Christodoulou S, Kotanidou A, Papadomichelakis E, Armaganidis A, Routsi C, Giamarellos-Bourboulis EJ. Clarithromycin Leads to Long-Term Survival and Cost Benefit in Ventilator-Associated Pneumonia and Sepsis. Antimicrob Agents Chemother. 2016 May 23;60(6):3640-6. doi: 10.1128/AAC.02974-15. Print 2016 Jun.

  PMID: 27044546 RESULT

• Schultz MJ, Speelman P, Hack CE, Buurman WA, van Deventer SJ, van Der Poll T. Intravenous infusion of erythromycin inhibits CXC chemokine production, but augments neutrophil degranulation in whole blood stimulated with Streptococcus pneumoniae. J Antimicrob Chemother. 2000 Aug;46(2):235-40. doi: 10.1093/jac/46.2.235.

  PMID: 10933646 RESULT

• Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010 Jul;23(3):590-615. doi: 10.1128/CMR.00078-09.

  PMID: 20610825 RESULT

• Karakike E, Scicluna BP, Roumpoutsou M, Mitrou I, Karampela N, Karageorgos A, Psaroulis K, Massa E, Pitsoulis A, Chaloulis P, Pappa E, Schrijver IT, Frantzeskaki F, Lada M, Dauby N, De Bels D, Floros I, Anisoglou S, Antoniadou E, Patrani M, Vlachogianni G, Mouloudi E, Antoniadou A, Grimaldi D, Roger T, Wiersinga WJ, Tsangaris I, Giamarellos-Bourboulis EJ. Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial. Crit Care. 2022 Jun 18;26(1):183. doi: 10.1186/s13054-022-04055-4.

  PMID: 35717241 DERIVED

MeSH Terms

Conditions

Sepsis; Pneumonia; Gram-Negative Bacterial Infections; Multiple Organ Failure; Respiratory Distress Syndrome

Interventions

Clarithromycin; Water; Injections

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Shock; Respiration Disorders

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Hydroxides; Alkalies; Inorganic Chemicals; Anions; Ions; Electrolytes; Oxides; Oxygen Compounds; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Apostolos Armaganidis, MD, PhD

  National Kapodistrian University of Athens, Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients assigned to either intravenous clarithromycin or placebo

Study Record Dates

• First Submitted: November 9, 2017
• First Posted: November 17, 2017
• Study Start: December 15, 2017
• Primary Completion: September 22, 2019
• Study Completion: December 19, 2020
• Last Updated: December 22, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

BE (3); GR (9)