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CLARITHROMYCIN TO PREVENT SECONDARY INFECTIONS IN PATIENTS WITH SEPSIS FOLLOWING LOWER RESPIRATORY TRACT INFECTIONS: THE CLASSIFY TRIAL (CLASSIFY)

2026年11月2日 更新者：Hellenic Institute for the Study of Sepsis

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.

調査の概要

状態

募集

条件

介入・治療

詳細な説明

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.

研究の種類

介入

入学 (推定)

252

段階

  • フェーズ 3

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究連絡先

  • 名前：Evangelos J Giamarellos-Bourboulis, Professor
  • 電話番号：0030 2105831994
  • メール：egiamarel@med.uoa.gr

研究場所

  • ギリシャ
    • Achaea
      • Pátrai、Achaea、ギリシャ、265 04
        • 募集
        • General University Hospital of Patras, Department of Internal Medicine
        • コンタクト：
          • Karolina Akinosoglou, Professor
          • 電話番号：+306977762897
          • メール：akin@upatras.gr
        • 主任研究者：
          • Karolina Anthoula Akinosoglou, Professor
    • Attica
      • Athens、Attica、ギリシャ、106 76
        • 募集
        • Evaggelismos Hospital, 1st Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Theano Kontopoulou
      • Athens、Attica、ギリシャ、115 26
        • 募集
        • General Hospital of Athens Korgialenio Benakio H.R.C, Intensive Care Unit
        • 主任研究者：
          • Maria Patrani
        • コンタクト：
      • Athens、Attica、ギリシャ、115 26
        • 募集
        • General Hospital of Athens Korgialenio Benakio H.R.C., 1st Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Vasiliki Tzavara
      • Athens、Attica、ギリシャ、115 27
        • 募集
        • General Hospital of Athens G.Gennimatas, 1st Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Georgios Adamis
      • Athens、Attica、ギリシャ、115 27
        • 募集
        • Thoracic General Hospital of Athens I Sotiria, 3rd University Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Garyfallia Poulakou, Associate Professor
      • Athens、Attica、ギリシャ、115 27
        • 募集
        • Thoracic General Hospital of Athens I Sotiria, 6th Department of Pulmonary Medicine
        • コンタクト：
        • 主任研究者：
          • Ioannis A Ioannis
      • Athens、Attica、ギリシャ、115 28
        • 募集
        • General Hospital of Athens Alexandra, Ηigh Dependency Unit of Department of Clinical Therapeutics
        • コンタクト：
          • Georgios Dimopoulos, Professor
          • 電話番号：+306944756565
          • メール：gdimop@med.uoa.gr
        • 主任研究者：
          • Georgios Dimopoulos, Professor
      • Athens、Attica、ギリシャ、124 61
        • 募集
        • University General Hospital Attikon-General Hospital of West Attica H Agia Varvara, 2nd Department of Propaedeutic Medicine
        • コンタクト：
        • 主任研究者：
          • Eleni Boutati, Professor
      • Athens、Attica、ギリシャ、124 61
        • 募集
        • University General Hospital Attikon-General Hospital of West Attica H Agia Varvara, 4th Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Antonios Papadopoulos, Professor
      • Athens、Attica、ギリシャ、145 64
        • 募集
        • General Oncological Hospital of Kifisia Agioi Anargyroi, Intensive Care Unit
        • コンタクト：
        • 主任研究者：
          • Pavlos Myrianthefs, Professor
    • Ioannina
      • Ioannina、Ioannina、ギリシャ、455 00
        • 募集
        • University General Hospital of Ioannina, 1st Department of Internal Medicine
        • コンタクト：
          • Charalampos Milionis, Professor
          • 電話番号：+30 6944521512
          • メール：hmilioni@uoi.gr
        • 主任研究者：
          • Charalampos Milionis, Professor
    • Thessaloniki
      • Thessaloniki、Thessaloniki、ギリシャ、546 36
        • 募集
        • University General Hospital of Thessaloniki Ahepa, Intensive Care Unit
        • コンタクト：
        • 主任研究者：
          • Eleni Argyriadou, Professor
      • Thessaloniki、Thessaloniki、ギリシャ、546 42
        • 募集
        • Ippokratio General Hospital of Thessaloniki, 2nd Propaedeutic Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Michael Doumas, Professor
      • Thessaloniki、Thessaloniki、ギリシャ、564 29
        • 募集
        • General Hospital of Thessaloniki Papageorgiou, Department of Internal Medicine
        • コンタクト：
          • Vasileios Kotsis, Professor
          • 電話番号：6974748860
          • メール：vkotsis@auth.gr
        • 主任研究者：
          • Vasileios Kotsis, Professor
      • Thessaloniki、Thessaloniki、ギリシャ、570 10
        • 募集
        • Geniko Nosokomeio Thessalonikis George Papanikolaou, Intensive Care Unit
        • 主任研究者：
          • Athina Lavrentieva
        • コンタクト：
    • Thrace
      • Alexandroupoli、Thrace、ギリシャ、681 00
        • 募集
        • University General Hospital of Alexandroupolis, 2nd Department of Internal Medicine
        • コンタクト：
          • Periklis Panagopoulos, Professor
          • 電話番号：+30 6944410495
          • メール：ppanago@med.duth.gr
        • 主任研究者：
          • Periklis Panagopoulos, Professor
    • West Attica
      • Elefsina、West Attica、ギリシャ、190 18
        • 募集
        • General Hospital of Eleusina Thriasio, 1st Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Styliani Sympardi, MD
      • Elefsina、West Attica、ギリシャ、190 18
        • 募集
        • General Hospital of Eleusina Thriasio, 2nd Department of Internal Medicine
        • コンタクト：
        • 主任研究者：
          • Konstantina Iliopoulou, MD

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年歳以上 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

説明

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 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-1.
  • Absolute lymphocyte count (ALC) less than 1000/mm³.

Exclusion Criteria:

  • 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

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：4倍

武器と介入

参加者グループ / アーム
介入・治療
プラセボコンパレーター：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.
薬：Placebo

There is no other intervention in this clinical study and participation in another clinical study is an exclusion criterion.
アクティブコンパレータ：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.
薬：clarithromycin

There is no other intervention in this clinical study and participation in another clinical study is an exclusion criterion.

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
Incidence of new infection
時間枠：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.
Day 1 through Day 28.

二次結果の測定

結果測定
メジャーの説明
時間枠
All-cause mortality at Day 28
時間枠：Day 28.

Proportion of participants who die from any cause within 28 days after randomization.
Day 28.
All-cause mortality at Day 90
時間枠：Day 90.

Proportion of participants who die from any cause within 90 days after randomization.
Day 90.
Sepsis response at Day 7
時間枠：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.
Day 7.
Type of new sepsis episode
時間枠：Through Day 28.

Characterization of new sepsis episodes according to the predominant pathogen and site of infection.
Through Day 28.
Each of the elements of the composite primary endpoint separately
時間枠：Through Day 28.

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.
Through Day 28.
Time to antimicrobial escalation
時間枠：Through Day 28.

Time from randomization to escalation or change of antimicrobial treatment, measured in days.
Through Day 28.
Need for hospital readmission up to day 90
時間枠：up to day 90 from enrollment

Proportion of participants requiring hospital readmission for any reason following hospital discharge after randomization 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.
時間枠：According to the corresponding secondary endpoint.

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
According to the corresponding secondary endpoint.
Comparison of outcomes between patients who receive intravenous clarithromycin and patients who receive oral clarithromycin.
時間枠：Through Day 90.

Comparison of clinical outcomes (primary and secondary endpoints) between participants receiving intravenous clarithromycin and participants receiving oral clarithromycin.
Through Day 90.
Patient status self-report documented by the EQ-5D questionnaire or a bespoke visual-analog scale.
時間枠：During follow-up through Day 90.

Use of standardized questionnaires to measure health-related quality of life
During follow-up through Day 90.
Incremental cost-effectiveness ratio
時間枠：From day 1 through day 90.

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.
From day 1 through day 90.
Biomarkers of sepsis-induced immunoparalysis
時間枠：Study days 1, 4 and 8

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.
Study days 1, 4 and 8

その他の成果指標

結果測定
メジャーの説明
時間枠
Sepsis response by SOFA-2
時間枠：Day 7.

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.
Day 7.
Primary endpoint according to baseline IL-6 and IFN-γ levels
時間枠：Through Day 28.

Analysis of the primary composite endpoint according to patient subgroups defined by baseline levels of IL-6 and IFN-γ.
Through Day 28.

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Hellenic Institute for the Study of Sepsis

捜査官

  • スタディチェア：Evangelos J Giamarellos-Bourboulis, Professor、Hellenic Institute for the Study of Sepsis

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (実際)

2026年9月16日

一次修了 (推定)

2029年10月1日

研究の完了 (推定)

2029年12月1日

試験登録日

最初に提出

2026年8月26日

QC基準を満たした最初の提出物

2026年9月16日

最初の投稿 (実際)

2026年9月22日

学習記録の更新

投稿された最後の更新 (実際)

2026年11月3日

QC基準を満たした最後の更新が送信されました

2026年11月2日

最終確認日

2026年9月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • CLASSIFY
  • 2025 (米国 NIH グラント/契約)
  • 2025-525058-20-00 (Ctis)

医薬品およびデバイス情報、研究文書

米国FDA規制医薬品の研究

いいえ

米国FDA規制機器製品の研究

いいえ

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