A Phase 3 interventional study of Placebo and clarithromycin in Sepsis, sponsored by Hellenic Institute for the Study of Sepsis. Recruiting at 19 sites in Greece. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-11-03.
Sponsored by Hellenic Institute for the Study of Sepsis · Phase 3, Interventional, and Treatment
The goal of this clinical trial is to assess whether clarithromycin, given as an adjunct to standard-of-care antibiotic therapy, can reduce the risk of new infections and secondary sepsis in adult patients hospitalized with community-acquired pneumonia (CAP), sepsis, and sepsis-induced immunoparalysis (SII). The primary objective is to evaluate the effect of clarithromycin on the incidence of new infection, including worsening or recurrence of the initial CAP episode, new infections at other sites, and secondary sepsis during the 28-day follow-up period. Secondary objectives are to investigate the impact of clarithromycin on mortality, sepsis response, type of secondary infection, time to antimicrobial escalation, hospital readmission, quality of life, cost-effectiveness, and biomarkers of sepsis-induced immunoparalysis.
Researchers will compare clarithromycin plus standard-of-care antibiotic therapy to placebo plus standard-of-care antibiotic therapy.
Participants will:
Pneumonia remains the leading cause of sepsis-related deaths worldwide and is one of the primary causes for antimicrobial resistance development. Despite advances in antimicrobial therapy and supportive care, community-acquired pneumonia (CAP) frequently progresses into sepsis and septic shock, resulting in high mortality and prolonged hospitalization.
Sepsis is a heterogeneous syndrome, and patients may present different patterns of immune dysfunction. Sepsis-induced immunoparalysis (SII) is characterized by profound downregulation of both innate and adaptive immune responses, with features including decreased monocyte human leukocyte antigen-DR (HLA-DR) expression, lymphopenia, and impaired production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Patients with SII are at increased risk of secondary infections and late mortality.
There is currently no universally accepted bedside method for identifying SII. Most publications suggest one of the following: exhaustion of peripheral blood mononuclear cells (PBMCs) for the ex vivo production of TNFα, absolute number of HLA-DR receptors on CD14-monocytes less than 8,000/cell, and blood levels of IFNγ less than 3pg/ml. These methods may be complex and are not widely available in routine clinical practice. Absolute lymphocyte count (ALC) has therefore been proposed as a readily available bedside marker of immune dysfunction. Previous analyses have shown an association between low ALC and SII and adverse outcomes. In particular, an ALC below 800/mm³ has demonstrated high specificity for SII, while an ALC below 1,000/mm³ has been associated with increased mortality in hospitalized patients. Other studies have suggested different thresholds, reflecting the lack of an established diagnostic cutoff for SII.
Clarithromycin is a macrolide antibiotic with established antimicrobial activity and additional immunomodulatory properties. Previous randomized controlled trials in patients with sepsis have shown that adjunctive clarithromycin may improve laboratory markers of immune dysfunction. These effects have included increased cytokine production by PBMCs and increased expression of HLA-DR on circulating monocytes, consistent with partial reversal of SII. In the randomized controlled trials INCLASS and ACCESS, adjunctive clarithromycin was also associated with a reduction in secondary infections among sepsis survivors. However, SII was not used as an inclusion criterion in these previous studies, and improvement in clinical outcomes was not the primary objective. These findings provide a rationale for evaluating clarithromycin specifically in patients with sepsis and evidence of SII.
The CLASSIFY trial is designed to determine whether adjunctive treatment with clarithromycin, administered IV or orally, can reduce the incidence of new infection episodes, including secondary sepsis, within 28 days in patients with CAP-RELATED sepsis, and evidence of SII. By focusing on an immunologically defined population, this study aims to validate the immunomodulatory benefit of clarithromycin, clarify its role as an adjunctive therapy for reversing SII, and contribute to precision immunotherapy strategies in sepsis management. The CLASSIFY trial is distinguished by the fact that it introduces the ALC as a beside tool to identify SII and for sensitivity analyses allowing validation of the ALC for diagnosis of SII.
The primary objective of the CLASSIFY trial is to determine whether clarithromycin added to standard-of-care antibiotic therapy reduces the 28-day incidence of new infections compared with placebo plus standard-of-care antibiotic therapy in patients with CAP-related sepsis and SII. The primary outcome is a composite endpoint including worsening or recurrence of the initial CAP episode, development of a new infection at a non-pulmonary site, and secondary sepsis.
Secondary objectives are to evaluate the effect of clarithromycin on 28-day and 90-day survival, duration of hospitalization, improvement in organ dysfunction after seven days, the relationship between changes in ALC and the development of specific secondary infections, restoration of immunological function, and the cost-effectiveness of treatment. The study will also evaluate biomarkers associated with SII, including IFN-γ, HLA-DR expression, TNF-α production following ex vivo stimulation, serum lipids, ferritin, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble TNF receptor-1 (sTNFR-1), interleukin-6 (IL-6), interleukin-8 (IL-8), protein C, and plasminogen activator inhibitor-1 (PAI-1).
CLASSIFY is a prospective, multicenter, double-blind, randomized, placebo-controlled Phase III clinical trial that will be conducted at 19 investigator sites in Greece.
Adult patients of either sex hospitalized with CAP and sepsis will be screened for eligibility. CAP will be defined by the presence of a new consolidation on chest imaging in a patient with a compatible clinical presentation, such as fever, dyspnea, cough, or sputum production, without a history of contact with a hospital or healthcare facility for two or more days during the preceding 90 days. Sepsis will be defined according to the Sepsis-3 classification criteria as an increase of at least 2 points in the total Sequential Organ Failure Assessment (SOFA-1) score compared with the patient's baseline score. The CLASSIFY protocol uses SOFA-1 for the definition of sepsis; data required for both SOFA-1 and SOFA-2 will be collected during the study.
Eligible participants must have an ALC below 1,000/mm³. The baseline ALC will be determined from a complete blood count obtained within 48 hours before enrolment. Investigators will make every reasonable effort to determine the patient's pre-existing baseline SOFA-1 score using available medical records and relevant clinical information.
Patients will be excluded if they are younger than 18 years, do not provide informed consent, are pregnant or lactating, or are unwilling to use highly effective contraception during treatment and for seven days following administration of the investigational medicinal product when applicable. Other exclusion criteria include known HIV infection with a CD4 count of 200/mm³ or less, solid-organ or bone marrow transplantation, significant recent immunosuppressive treatment, recent biological therapy, active malignancy or another condition associated with an expected survival of less than six months, severe neutropenia, treatment with a macrolide for the CAP episode under study, significant QT prolongation or known long QT syndrome, history of macrolide allergy or torsades de pointes, and concomitant use of medications contraindicated with clarithromycin. Patients with severe hypokalemia or hypomagnesemia may become eligible after correction of the electrolyte abnormality. Patients with severe hepatic failure combined with renal impairment, contraindications to macrolide treatment, previous participation in CLASSIFY, or participation in another interventional clinical trial within the preceding 30 days will also be excluded. Finally, patients receiving oral or intravenous corticosteroids 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.
Following informed consent and confirmation of eligibility, patients will be randomized in a 1:1 ratio to receive either standard-of-care antibiotic therapy plus clarithromycin or standard-of-care antibiotic therapy plus placebo.
2,416 studies on the registry are indexed under Sepsis; 541 are open to participants now.
This study's planned enrollment of 252 is above the median of 102 across 1,165 interventional studies indexed under Sepsis.
Browse Sepsis studies →Hellenic Institute for the Study of Sepsis is the lead sponsor of 32 studies on the registry; 7 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CD4 count
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CYP3A (CYP3A4) inhibitors and inducers
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Washout period
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
In the case of IV placebo medication, patients receive water for injection at a volume of 10ml diluted to a final volume of 250 ml dextrose in water 5%. The duration of the infusion is 1 hour and treatment is given every 12 hours daily for 7 days. In the case of oral placebo medication, this is given as oral tablets every 12 hours once for 7 days. Step-down from IV to oral medication, respectively, is permitted.
Drug: Placebo
In the case of IV medication, patients receive 500 mg of clarithromycin diluted with water for injection at a volume of 10ml and further diluted to a final volume of 250 ml dextrose in water 5%. The duration of the infusion is 1 hour and treatment is given every 12 hours daily for 7 days. In the case of oral medication, this is given as clarithromycin IR 500mg every 12 hours for 7 days. Step-down from IV to oral medication, respectively, is permitted.
Drug: clarithromycin
There is no other intervention in this clinical study and participation in another clinical study is an exclusion criterion.
There is no other intervention in this clinical study and participation in another clinical study is an exclusion criterion.
Incidence of new infection
The incidence of new infection within 28 days following randomization, comparing intravenous or oral clarithromycin plus standard-of-care (SoC) antibiotic therapy with placebo plus SoC. The composite endpoint includes any of the following: * Worsening of the CAP episode, defined as the need to change SoC antibiotic treatment during the first 7 days. A change to moxifloxacin due to detection of atypical pathogens is not considered worsening. * Recurrence of CAP symptoms after initial improvement, requiring initiation of new treatment or a change in treatment after Day 7. * Any new infection at a non-pulmonary site during the first 28 days. * Secondary sepsis occurring between Day 8 and Day 28, defined as the onset of a new infection or recurrence of the CAP episode accompanied by an increase of at least 2 points in the total SOFA-1 score compared with the SOFA-1 score immediately before the new infection or CAP recurrence.
Time frame: Day 1 through Day 28.
All-cause mortality at Day 28
Proportion of participants who die from any cause within 28 days after randomization.
Time frame: Day 28.
All-cause mortality at Day 90
Proportion of participants who die from any cause within 90 days after randomization.
Time frame: Day 90.
Sepsis response at Day 7
Proportion of participants achieving at least a 25% decrease in the total SOFA-1 score from the pre-treatment Day 1 score by Day 7.
Time frame: Day 7.
Type of new sepsis episode
Characterization of new sepsis episodes according to the predominant pathogen and site of infection.
Time frame: Through Day 28.
Each of the elements of the composite primary endpoint separately
Incidence of each individual component of the primary composite endpoint, analyzed separately: worsening of the CAP episode, recurrence of CAP symptoms, new infection at a non-pulmonary site, and secondary sepsis.
Time frame: Through Day 28.
Time to antimicrobial escalation
Time from randomization to escalation or change of antimicrobial treatment, measured in days.
Time frame: Through Day 28.
Need for hospital readmission up to day 90
Proportion of participants requiring hospital readmission for any reason following hospital discharge after randomization up to day 90
Time frame: up to day 90 from enrollment
Analysis (comparison) of all secondary endpoints for the subgroup of patients (number of patients, %) defined by each physiological parameter that was followed for randomization per investigator site.
Analysis of all secondary endpoints for the subgroups of patients (number of patients, %) defined by each treatment parameter that was followed for randomization per investigator site. The three parameters (treatment pathways) are: 1. oral or iv administration of the investigational medical product (placebo or clarithromycin) 2. treatment or not with intravenous corticosteroids (total daily dose of at least 200mg hydrocortisone or equivalent) 3. Absolute lymphocyte count less than 800/mm³ or between 800 and 1000/mm³
Time frame: According to the corresponding secondary endpoint.
Comparison of outcomes between patients who receive intravenous clarithromycin and patients who receive oral clarithromycin.
Comparison of clinical outcomes (primary and secondary endpoints) between participants receiving intravenous clarithromycin and participants receiving oral clarithromycin.
Time frame: Through Day 90.
Patient status self-report documented by the EQ-5D questionnaire or a bespoke visual-analog scale.
Use of standardized questionnaires to measure health-related quality of life
Time frame: During follow-up through Day 90.
Incremental cost-effectiveness ratio
Incremental cost-effectiveness ratios (ICERs) comparing clarithromycin plus standard-of-care antibiotic therapy with placebo plus standard-of-care antibiotic therapy, cross-referenced with patient health status.
Time frame: From day 1 through day 90.
Biomarkers of sepsis-induced immunoparalysis
Serial assessment of biomarkers associated with sepsis-induced immunoparalysis/immunosuppression, including IFN-γ, absolute count of HLA-DR receptors on CD45/CD14-monocytes by flow cytometry. TNF-α production by ex vivo stimulation of peripheral blood monocytes (PBMCs), serum lipids, ferritin, sTREM-1, sTNFR-1, IL-6, IL-8, protein C, and PAI-1.
Time frame: Study days 1, 4 and 8
Sepsis response by SOFA-2
Proportion of participants achieving at least a 25% decrease in the total SOFA-2 score from the pre-treatment Day 1 score by Day 7.
Time frame: Day 7.
Primary endpoint according to baseline IL-6 and IFN-γ levels
Analysis of the primary composite endpoint according to patient subgroups defined by baseline levels of IL-6 and IFN-γ.
Time frame: Through Day 28.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Hellenic Institute for the Study of Sepsis