CLARITHROMYCIN TO PREVENT SECONDARY INFECTIONS IN PATIENTS WITH SEPSIS FOLLOWING LOWER RESPIRATORY TRACT INFECTIONS: THE CLASSIFY TRIAL
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 252
- 试验地点
- 19
- 主要终点
- Incidence of new infection
研究概览
简要总结
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:
- Receive clarithromycin or placebo, administered orally or intravenously, in addition to standard-of-care antibiotic therapy for up to 7 days.
- Be evaluated during treatment and follow-up through Day 28, with additional assessment of mortality, hospital readmission, and health status through Day 90.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 highly effective contraception during and seven days after the administration of the IMP.
- •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.
排除标准
- •Age below 18 years
- •Denial of written informed consent
- •Pregnancy (confirmed by blood or urinary pregnancy test) or lactation for female patients
- •Unwillingness to receive contraception during and seven days after the administration of the IMPstudy 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 0.4mg/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 less than 6 months
- •Neutropenia < 500/mm³
- •Intake of any macrolide for the current episode of CAP under study
- •QTc 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
- •Severe hypokalemia or hypomagnesemia; patients may be enrolled once these electrolyte abnormalities are corrected.
- •Any contradictions for macrolide uptake
- •Previous participation in the CLASSIFY study
- •Participation in any other interventional trial within the last 30 days
- •Severe hepatic failure in combination with renal impairment
研究组 & 干预措施
Standard-of-care (SoC) and placebo
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.
干预措施: Placebo (Drug)
Standard-of-care (SoC) and clarithromycin
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.
干预措施: clarithromycin (Drug)
结局指标
主要结局
Incidence of new infection
时间窗: Day 1 through Day 28.
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.
次要结局
- All-cause mortality at Day 28(Day 28.)
- All-cause mortality at Day 90(Day 90.)
- Sepsis response at Day 7(Day 7.)
- Type of new sepsis episode(Through Day 28.)
- Each of the elements of the composite primary endpoint separately(Through Day 28.)
- Time to antimicrobial escalation(Through Day 28.)
- Need for hospital readmission up to day 90(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.(According to the corresponding secondary endpoint.)
- Comparison of outcomes between patients who receive intravenous clarithromycin and patients who receive oral clarithromycin.(Through Day 90.)
- Patient status self-report documented by the EQ-5D questionnaire or a bespoke visual-analog scale.(During follow-up through Day 90.)
- Incremental cost-effectiveness ratio(From day 1 through day 90.)
- Biomarkers of sepsis-induced immunoparalysis(Study days 1, 4 and 8)