Adjunctive Clarithromycin to Prevent Secondary Infections in Patients with Community‑Acquired Pneumonia‑Related Sepsis and Sepsis‑Induced Immunoparalysis (CLASSIFY)

The primary objective is to evaluate whether adjunctive sepsis prevention with clarithromycin, given intravenously or orally, decreases the incidence of secondary infection episodes—including recurrent sepsis—within 28 days in patients experiencing community‑acquired pneumonia‑related sepsis with documented sepsis‑induced immunoparalysis. Demonstrating a reduction in secondary infections would have direct therapeutic relevance by potentially lowering morbidity, mortality, and healthcare utilization in this high‑risk population.

The trial enrolled adult patients of both sexes, with eligibility limited to individuals aged 18 years or older who were diagnosed with Community‑acquired pneumonia and met the Sepsis‑3 definition of sepsis, demonstrated by a ≥2‑point increase in the SOFA‑1 score, and exhibited an absolute lymphocyte count below 1000 cells/mm³. Participants were selected through screening of hospitalized patients presenting with CAP‑related sepsis and evidence of sepsis‑induced immunoparalysis, and enrollment required written informed consent from the patient or a legally authorized representative for those lacking decision‑making capacity; female participants of reproductive potential also needed a negative pregnancy test and agreement to use contraception. The sponsor did not provide information on the total number of participants. Both male and female subjects, including vulnerable individuals, were included, and no specific dietary, physical activity, or habit restrictions were stipulated beyond standard clinical care. Key inclusion criteria comprised age ≥18 years, confirmed CAP, sepsis per Sepsis‑3 criteria, and lymphopenia, while exclusion criteria were not detailed in the provided data.

The CLASSIFY trial is a randomized, double‑blind, placebo‑controlled Phase III study evaluating adjunctive clarithromycin administered intravenously or orally in adults with community‑acquired pneumonia‑related sepsis and evidence of sepsis‑induced immunoparalysis. Participants are screened (visit 1) to confirm eligibility, including age ≥18 years, CAP, Sepsis‑3 criteria, and absolute lymphocyte count <1000 /mm³. Eligible subjects are randomized 1:1 to clarithromycin (1000 mg daily IV bolus or oral tablet) or matching placebo for 7 days, in addition to standard‑of‑care antibiotics. Follow‑up visits occur on day 7 (assessment of treatment response and safety), day 28 (primary endpoint evaluation for new infections or secondary sepsis), and day 90 (mortality, rehospitalization, and health‑status questionnaires). The end‑of‑study visit coincides with the day 90 assessment. Total participant involvement spans approximately 90 days from the screening visit. Early termination may occur if a participant withdraws consent, experiences a serious adverse event, violates protocol requirements, or dies before study completion.

The investigational product KLARICID® 500 mg/vial is supplied as a sterile solution for infusion intended for preparation of an intravenous bolus or infusion. Each dose contains 1000 mg of clarithromycin and is administered via the intravenous route. The specified pharmaceutical form is a concentrated solution for infusion, and the dosing regimen calls for a single 1000 mg dose administered once daily in accordance with the study protocol.

The oral investigational product KLARICID® 500 mg comprises film‑coated tablets containing 1000 mg of clarithromycin per dose. The tablets are taken by mouth, with the recommended frequency of one tablet daily as defined in the protocol. This formulation provides an oral route of administration for adjunctive therapy.

For the intravenous placebo comparator, a sterile water for injection is provided as a 20 ml solution for infusion. The solution contains no active drug substance and is administered by the same intravenous route and schedule as the active infusion to maintain blinding.

A second intravenous placebo consists of a 160 ml 5 % glucose solution (glucose monohydrate) formulated as a solution for infusion. This diluent is administered in an identical manner to the active intravenous product, matching volume and infusion parameters.

The oral placebo is a matched tablet formulated to resemble the clarithromycin film‑coated tablet in appearance, weight, and packaging. It contains no active pharmaceutical ingredient and is taken orally once daily, parallel to the active oral regimen.

All study medications and placebos are administered according to a predefined schedule, with dosing times recorded in the case report form. Compliance is monitored through direct observation of administration for intravenous infusions and by tablet count and patient diary for oral dosing. Adherence data are reviewed regularly to ensure protocol fidelity.

Efficacy assessment is based on a composite primary endpoint that captures the incidence of new infection episodes within 28 days. The component events include: (1) worsening of the index community‑acquired pneumonia (CAP) requiring a change in standard‑of‑care (SoC) antibiotics within the first 7 days (excluding a switch to moxifloxacin for atypical pathogens); (2) recurrence of CAP symptoms after the initial 7‑day improvement, judged by the attending physician and prompting new or altered therapy; (3) any new infection at a non‑pulmonary site occurring during the first 28 days; and (4) secondary sepsis between day 8 (cessation of study drug) and day 28, defined by either a new infection or CAP recrudescence accompanied by a ≥2‑point increase in the total SOFA-1 score relative to the pre‑infection baseline. Clinical evaluation, documentation of treatment changes, and serial SOFA‑1 scoring are performed at screening, daily during the first 7 days, and at follow‑up visits on day 28.

Secondary efficacy measures include all‑cause mortality at 28 days and 90 days, a sepsis response defined as a ≥25 % reduction in the day‑1 SOFA‑1 score by day 7, time to antimicrobial escalation, hospital re‑admission by day 90, and detailed characterization of any new sepsis episode (pathogen and site). Patient‑reported health status is captured using the EQ-5D questionnaire and a bespoke visual‑analog scale. Economic evaluation involves calculation of incremental cost‑effectiveness ratios. Serial biomarkers of sepsis‑induced immunosuppression (including IFNγ, HLA‑DR expression, TNFα, serum lipids, ferritin, sTREM‑1, sTNFR‑1, IL‑6, IL‑8, protein C, and PAI‑1) are measured at baseline, day 7, and day 28 to support mechanistic analyses. All endpoints are analyzed according to the predefined statistical analysis plan, with primary comparisons between adjunctive clarithromycin (intravenous or oral) and placebo groups.