Description

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.