CLARITHROMYCIN TO PREVENT SECONDARY INFECTIONS IN PATIENTS WITH SEPSIS FOLLOWING LOWER RESPIRATORY TRACT INFECTIONS: THE CLASSIFY TRIAL
Trial Snapshot
- Phase
- Phase 3
- Status
- Recruiting
- Sponsor
- Enrollment
- 252
- Locations
- 15
- Primary Endpoint
- The impact of intravenous or oral clarithromycin as adjunctive treatment to SoC antibiotic therapy compared to placebo on the incidence of new infection. This is a composite endpoint incorporating any of the following
Study Overview
Brief Summary
The CLASSIFY trial is designed to determine whether adjunctive clarithromycin, administered IV or orally, can reduce the incidence of secondary infection episodes including sepsis within 28 days among patients with CAP-related sepsis and evidence of SII.
Eligibility Criteria
- Ages
- 18 years to 65+ years (65+ Years, 18-64 Years)
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age equal to or above 18 years
- •Patients of either gender
- •Written informed consent provided by the patient. For patients without decision-making capacity, informed consent must be obtained from a legally designated representative following the national legislation.
- •Negative (blood or urinary) pregnancy test for female patients of reproductive age
- •For female patients of reproductive age, willingness to use contraception during and seven days after the administration of the study drug.
- •Presence of Community-acquired pneumonia (CAP)
- •Presence of sepsis as defined by the Sepsis-3 classification criteria (at least 2 points increase of the total SOFA-1 score from the baseline score of the specific patient). The SOFA score which will be used for the definition of sepsis has recently been renamed SOFA-
- •Absolute lymphocyte count (ALC) less than 1000/mm³.
Exclusion Criteria
- •Age below 18 years
- •Unwillingness to receive contraception during and seven days after the administration of the study drug (for Female patients)
- •Known HIV infection with known 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, or other immunosuppressive therapy. However, corticosteroids received as adjunctive treatment for the current septic/ infectious episode are allowed
- •Intake of a biological agent in the last month
- •Known active neoplasms or other conditions unrelated to sepsis that compromise short-term survival to less than 6 months.
- •Severe hypokalemia or severe hypomagnesemia; a patient may be enrolled one any of these electrolyte disturbances are restored.
- •Any contraindications for macrolide uptake
- •Participation in any other interventional trial within the last 30 days
- •Previous participation in the CLASSIFY study
- •Neutropenia defined as an absolute neutrophil count less than 500/mm³
- •Patients with severe hepatic failure or severe renal dysfunction may be excluded at the discretion of the attending physician
- •Intake of macrolide for the current episode of CAP under study
- •Corrected QT interval at rest in the ECG ≥500 msec or history of known long QT syndrome
- •Medical history of allergy to macrolides
- •Concomitant use of medicinal products contraindicated with clarithromycin, including CYP3A substrates associated with QT prolongation (e.g., astemizole, cisapride, domperidone, pimozide, terfenadine, ivabradine), ergot alkaloids (e.g., ergotamine, dihydroergotamine), oral midazolam, HMG-CoA reductase inhibitors primarily metabolised by CYP3A4 (e.g., lovastatin, simvastatin), colchicine, ticagrelor, and ranolazine. This criterion applies to all medicinal products within these classes, not only the specific examples listed, in accordance with the SmPC for clarithromycin. Patients may be enrolled provided that such medications are discontinued prior to or at the time of trial participation. Given their short half-life, no wash-out period is required
- •Medical history of torsades de pointes arrhythmia
- •Denial of written informed consent
- •Pregnancy (confirmed by blood or urinary pregnancy test) or lactation for female patients
Arms & Interventions
KLARICID® 500 mg επικαλυμμένα με λεπτό υμένιο δισκία, KLARICID® 500 mg/vial Κόνις για πυκνό σκεύασμα για παρασκευή διαλύματος προς έγχυση
Intervention: KLARICID® 500 mg επικαλυμμένα με λεπτό υμένιο δισκία (Drug)
KLARICID® 500 mg επικαλυμμένα με λεπτό υμένιο δισκία, KLARICID® 500 mg/vial Κόνις για πυκνό σκεύασμα για παρασκευή διαλύματος προς έγχυση
Intervention: KLARICID® 500 mg/vial Κόνις για πυκνό σκεύασμα για παρασκευή διαλύματος προς έγχυση (Drug)
ΔΕΞΤΡΟΖΗ ΕΝΕΣΙΜΟ ΔΙΑΛΥΜΑ / DEMO, διάλυμα για ενδοφλέβια έγχυση 5%, Placebo for Clarithromycin film coated tablets 500mg, ΥΔΩΡ ΕΝΕΣΙΜΟ/DEMO
Intervention: ΔΕΞΤΡΟΖΗ ΕΝΕΣΙΜΟ ΔΙΑΛΥΜΑ / DEMO, διάλυμα για ενδοφλέβια έγχυση 5% (Drug)
ΔΕΞΤΡΟΖΗ ΕΝΕΣΙΜΟ ΔΙΑΛΥΜΑ / DEMO, διάλυμα για ενδοφλέβια έγχυση 5%, Placebo for Clarithromycin film coated tablets 500mg, ΥΔΩΡ ΕΝΕΣΙΜΟ/DEMO
Intervention: Placebo for Clarithromycin film coated tablets 500mg (Drug)
ΔΕΞΤΡΟΖΗ ΕΝΕΣΙΜΟ ΔΙΑΛΥΜΑ / DEMO, διάλυμα για ενδοφλέβια έγχυση 5%, Placebo for Clarithromycin film coated tablets 500mg, ΥΔΩΡ ΕΝΕΣΙΜΟ/DEMO
Intervention: ΥΔΩΡ ΕΝΕΣΙΜΟ/DEMO (Drug)
Outcomes
Primary Outcomes
The impact of intravenous or oral clarithromycin as adjunctive treatment to SoC antibiotic therapy compared to placebo on the incidence of new infection. This is a composite endpoint incorporating any of the following
The impact of intravenous or oral clarithromycin as adjunctive treatment to SoC antibiotic therapy compared to placebo on the incidence of new infection. This is a composite endpoint incorporating any of the following
Worsening of the episode of CAP for which the patient is enrolled in the study. “Worsening” is defined as need to change SoC during the first 7 days of the study. Change of the SoC to moxifloxacin because of detection of atypical pathogens is not considered worsening of the episode of CAP.
Worsening of the episode of CAP for which the patient is enrolled in the study. “Worsening” is defined as need to change SoC during the first 7 days of the study. Change of the SoC to moxifloxacin because of detection of atypical pathogens is not considered worsening of the episode of CAP.
Any recurrence of the symptoms of the episode of CAP under study despite improvement after the first 7 days. “Recurrence of symptoms” is defined at the discretion of the attending physician and necessitates the start of new treatment or change of administered treatment after 7 days.
Any recurrence of the symptoms of the episode of CAP under study despite improvement after the first 7 days. “Recurrence of symptoms” is defined at the discretion of the attending physician and necessitates the start of new treatment or change of administered treatment after 7 days.
Any new infection of any other site than the lung during the first 28 days from inclusion in the study
Any new infection of any other site than the lung during the first 28 days from inclusion in the study
Any episode of secondary sepsis between day 8 (stop of the study drug) and day 28 of follow-up. This outcome is defined as either onset of any new infection or recrudescence of the episode of CAP under study accompanied by at least 2-point increase of the total SOFA-1 compared to the SOFA-1 score before the onset of the new infection or the recurrence of CAP under study.
Any episode of secondary sepsis between day 8 (stop of the study drug) and day 28 of follow-up. This outcome is defined as either onset of any new infection or recrudescence of the episode of CAP under study accompanied by at least 2-point increase of the total SOFA-1 compared to the SOFA-1 score before the onset of the new infection or the recurrence of CAP under study.
Secondary Outcomes
- All-cause 28-day mortality
- All-cause 90-day mortality
- Sepsis response: this is defined as at least 25% decrease of the day 1 (pre-treatment) SOFA-1 score by day 7
- Type of new sepsis episode (predominant pathogen and site of infection)
- Each of the elements of the composite primary endpoint separately
- Time to antimicrobial escalation (days).
- Need for hospital re-admission by day 90
- Analysis of all secondary endpoints for the subgroup of patients defined by each appropriate treatment pathway.
- Comparison of outcomes between patients who receive IV clarithromycin.
- Patient status self-report documented by the EQ-5D questionnaire or a bespoke visual-analog scale.
- Incremental cost-effectiveness ratios (ICERs) will be calculated and cross-referenced to patients’ health status for both treatment assignments.
- Biomarkers of sepsis-induced immunosuppression through serial measurement of IFNγ, absolute number of HLA-DR receptors, TNFα by ex-vivo stimulation analysis, serum lipids, ferritin, sTREM-1, sTNFR-1, IL-6, IL-8, protein C and PAI-1.
Investigators
President of the Board
Scientific
Elliniko Institouto Meletis Tis Sipsis