Clarithromycin Treatment to Prevent Sepsis Progression in CAP (REACT)
NCT ID: NCT06294600
Last Updated: 2025-12-16
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
330 participants
INTERVENTIONAL
2024-02-12
2026-07-30
Brief Summary
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Detailed Description
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Numerous attempts have been done the last decades to decrease the substantial mortality of sepsis. Standard-of-care (SoC) therapy for sepsis is framed by the Surviving Sepsis Campaign (SSC) guidelines which are published every four years since 2004 (last publication 2021). The backbone of these guidelines is the early administration of intravenous antibiotics and fluids. In all editions of the SSC guidelines "early" means less than one hour from sepsis recognition. The experts recognize that the secret to decrease mortality is to intervene early before the dysregulated host response to the infection becomes exaggerated and impossible to withhold. The experts state that for every hour of delay in intervention the odds for survival decrease by relative 7.6%. Then the real ambiguity moves on how the initiation of the sepsis process can be recognized earlier than clinical deterioration appears.
The only way to achieve our current strategy is to implement a strategy linking the increase of a biomarker to an early intervention. This biomarker can be either a measured circulating protein or a bioscore. An example of how this strategy works is the biomarker-guided treatment of early COVID-19 (coronavirus disease 2019) recently approved by the European Medicines Agency (EMA). The biomarker suPAR (soluble urokinase plasminogen activator receptor) was used as a tool to recognize the patient at risk for severe respiratory failure and guided the start of the drug anakinra. This led to an overall 64% clinical benefit so as to become the first early precision intervention approved for infections by the EMA. The registered cut-off of suPAR which guides early intervention is 6 ng/ml or more.
The suPAR assay is not commercially available in the United States. However, all enrolled patients in SAVE-MORE trial were required to have a plasma soluble urokinase plasminogen activator receptor (suPAR) level ≥ 6 ng/mL. SAVE-MORE was double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. In order to identify a comparable population as was studied in the SAVE-MORE trial, an alternative patient identification method was developed by the Food and Drug Administration (FDA) of the United States to select patients most likely to have suPAR ≥ 6 ng/mL based on commonly measured patient characteristics (Appendix I). This score contains eight clinical variable and patients meeting at least 3 of the variables should receive early anakinra treatment. Patients meeting at least three of the following eight criteria are considered likely to have suPAR ≥ 6 ng/mL at baseline: i) age 75 years or more; ii) need for oxygen supplementation; iii) current/previous smoking status; iv) Sequential Organ Failure Assessment (SOFA) score 3 or more; v) neutrophil-to-lymphocyte ratio (NLR) 7 or more; vi) blood hemoglobin 10.5 g/dL or less; vii) medical history of ischemic stroke; and viii) blood urea 50 mg/dL or more and/or medical history of renal disease. According to the SmPC, suPAR is a biomarker is used at the Emergency Department (ED) for the triage of patients for early discharge home or not; levels exceeding 6ng/ml advise for hosptialization.
With this precision-embedded approach adjunctive treatments may attenuate the exaggerated response of the host and improve outcomes. Macrolides are a unique class of drugs that combine both antibiotic and anti-inflammatory properties. Several meta-analyses have proven that addition of a macrolide to treatment decreases mortality by community-acquired pneumonia (CAP). However, the mortality benefit from macrolides treatment is coming from meta-analyses and no randomized clinical trial (RCT) has been published so far to demonstrate such a benefit. This is also heavily criticized in the recently published guidelines by the European Society of Intensive Care with the European Society of Clinical Microbiology and Infections Diseases (ESCMID) for the management of severe CAP where the recommendation for the co-administration of macrolides to β-lactams is characterized as low-quality evidence.
The only available RCT testing the value of early intervention with macrolides in patients with community-acquired pneumonia (CAP) is ACCESS (A randomized clinical trial of oral Clarithromycin in Community-acquired pneumonia to attenuatE inflammatory responseS and improve outcomeS) (EudraCT number 2020-004452-15; ClinicalTrials.gov NCT04724044). The inclusion criteria of the ACCESS trial have the characteristics of precision therapy i.e. participants were adults with CAP, meeting at least two of the criteria of the systemic inflammatory response syndrome, with SOFA (sequential organ failure assessment) score 2 or more and circulating procalcitonin 0.25 ng/ml or more. ACCESS had a composite primary endpoint pointing towards an early anti-inflammatory clinical benefit of clarithromycin. Patients achieving the endpoint should meet both two conditions A and B by day 4 since start of the study drug: condition A defined as at least 50% decrease of the respiratory symptoms score (RSS); and condition B defined as at least 30% decrease of the baseline SOFA score and/or favorable PCT kinetics (defined as at least 80% decrease of the baseline PCT or PCT less than 0.25 ng/ml). The study succeeded in the primary endpoint since this was met in 38.3% of patients randomized to the SoC + placebo group and in 67.9% of patients randomized to the SoC + clarithromycin group (p\<0.0001). The ACCESS study also showed remarkable efficacy in all secondary endpoints and mainly to those endpoints pointing towards prevention of sepsis progression:
11.30% of patients treated with SoC and placebo progressed into sepsis during the 28-day follow-up compared to only 2.25% of patients treated with oral clarithromycin and placebo (hazard ratio 0.19; p: 0.009) 27.8% of patients treated with SoC and placebo developed a new sepsis episode during the 28-day follow-up compared to only 14.8% of patients treated with oral clarithromycin and placebo (hazard ratio 0.48; p: 0.009); and 65.4% of patients treated with SoC and placebo were discharged from hospital alive compared to 78.4% of patients treated with oral clarithromycin and placebo (hazard ratio 1.38; p: 0.027) Post-hoc analysis showed that 87.4% of study participants were meeting at least 3 of the FDA clinical score making the participants at high likelihood for suPAR 6 ng/ml or more. This means that use of suPAR can discriminate early patients with CAP who are at high likelihood to receive benefit towards prevention of progression into sepsis and organ dysfunction through early start of clarithromycin treatment.
Data from the ACCESS study also showed a significant effect of clarithromycin treatment on modulation of immune dysregulation taking place in CAP by day 4 when the primary endpoint was met. These data points towards improvement of the function of circulating monocytes towards better production of TNFα (tumour necrosis factor-alpha) after stimulation, decrease of circulating interleukin (IL)-10 and improvement of the IL-8/IL-10 ratio.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Placebo
These patients will be treated with 1 placebo tablet every 12 hours and it is suggested that all patients receive at least one of antibiotics based on the current ESCMID guidelines for severe CAP13 (Ampicillin/sulbactam, Amoxicillin/clavulanate, Piperacillin/tazobactam, Ceftriaxone, Cefotaxime, Ceftaroline, Moxifloxacin). The total duration of treatment will be seven days.Τhe dosage, the dosage regime, the route and mode of administration, and the treatment period for the aforementioned antibiotics can be found in the relevant SmPCs (available in References). However, the attending physician may modify the antimicrobial treatment based on risk factors for multidrug-resistance pathogens, microbiology results and local epidemiology. All SoC treatment products and clarithromycin are authorised for use in Greece, where the trial will be conducted.
Tablets
Oral tablets of similar appearance to active study drug
Clarithromycin
These patients will be treated with oral clarithromycin 500 mg twice daily for seven days and it is suggested that all patients receive at least one of antibiotics based on the current ESCMID guidelines for severe CAP13 (Ampicillin/sulbactam, Amoxicillin/clavulanate, Piperacillin/tazobactam, Ceftriaxone, Cefotaxime, Ceftaroline, Moxifloxacin). The total duration of treatment will be seven days.Τhe dosage, the dosage regime, the route and mode of administration, and the treatment period for the aforementioned antibiotics can be found in the relevant SmPCs (available in References). However, the attending physician may modify the antimicrobial treatment based on risk factors for multidrug-resistance pathogens, microbiology results and local epidemiology. All SoC treatment products and clarithromycin are authorised for use in Greece, where the trial will be conducted.
Clarithromycin 500mg
Oral tablets of 500mg of clarithromycin
Interventions
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Clarithromycin 500mg
Oral tablets of 500mg of clarithromycin
Tablets
Oral tablets of similar appearance to active study drug
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Male or female gender
* In case of women of reproductive age, willingness to use dual contraceptive method during the study period
* Written informed consent provided by the patient. For subjects without decision-making capacity, informed consent must be obtained from a legally designated representative following the national legislation
* Community-acquired pneumonia (CAP)
* Presence of at least two of the following signs: i) cough; ii) purulent sputum expectoration; iii) dyspnea; and/or iv) pleuritic chest pain
* PCT ≥0.25 ng/ml
* suPAR ≥6 ng/ml
Exclusion Criteria
* Denial of written informed consent
* Any stage IV malignancy
* Any do not resuscitate decision
* Patients necessitating non-invasive ventilation or mechanical ventilation
* Hospitalization in Intensive Care Unit
* Infection by SARS-CoV-2
* Oral or IV intake of corticosteroids at a daily dose equal to or greater than 0.4 mg/kg prednisone for a period greater than the last 15 days
* Intake of any macrolide for the current episode of CAP under study
* Known infection by the human immunodeficiency virus
* Any chronic anti-cytokine treatment for more than two months
* QTc interval at rest in the ECG ≥500 msec or history of know long QT syndrome
* Medical history of allergy to macrolides
* Concomitant oral intake of astemizole, cizapride, doperidone, pimozide, terfenadine, midazolam, ranolazine, ergot alkaloids (e.g. ergotamine and dihydroergotamine), lomitapide and colchicine; patients may be enrolled in the trial if they stop these drugs during trial participation.
* Medical history of torsades de pointes arrhythmia
* Concomitant intake of lovostatin or simvastatin; patients may be enrolled in the trial if they stop these drugs during trial participation.
* Concomitant presence of end-stage liver failure and end-stage renal failure.
* Severe hypokalemia or severe hypomagnesemia; a patient may be enrolled one any of these electrolyte disturbances are restored.
* Any contradictions for macrolide uptake
* Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
* Participation in any other interventional trial within the last 30 days
18 Years
ALL
No
Sponsors
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Hellenic Institute for the Study of Sepsis
OTHER
Responsible Party
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Principal Investigators
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Evangelos J Giamarellos-Bourboulis, MD, Phd
Role: STUDY_CHAIR
Hellenic Sepsis Study Group
Locations
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5th Pulmonary Department, SOTIRIA Athens General Hospital of Chest Diseases
Athens, Athens, Greece
1st Department of Internal Medicine - General Hospital of Athens "Sismanogleio-Amalia Fleming"
Athens, Greece, Greece
1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
Athens, Greece, Greece
1st Department of Internal Medicine, EVANGELISMOS Athens General Hospital
Athens, Greece, Greece
1st Department of Internal Medicine, G. GENNIMATAS Athens General Hospital
Athens, Greece, Greece
1st Department of Internal Medicine, General University Hospital of Ioannina
Athens, Greece, Greece
1st Department of Internal Medicine, KORGIALENEIO-BENAKEIO E.E.S. Athens General Hospital
Athens, Greece, Greece
1st Department of Internal Medicine, THRIASIO General Hospital of Elefsis
Athens, Greece, Greece
1st University Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens, Greece, Greece
2nd Department of Internal Medicine, Attikon University Hospital
Athens, Greece, Greece
2nd Department of Internal Medicine, THRIASIO General Hospital of Elefsis
Athens, Greece, Greece
2nd Department of Internal Medicine, TZANEIO Piraeus General Hospital
Athens, Greece, Greece
2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
Athens, Greece, Greece
3rd Department of Internal Medicine - General State Hospital of Nikaia "Saint Panteleimon" - West Attica General Hospital
Athens, Greece, Greece
3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO- BENAKEIO E.E.S.
Athens, Greece, Greece
3rd University Department of Internal Medicine, SOTIRIA Athens General Hospital of Chest Diseases
Athens, Greece, Greece
4th Department of Internal Medicine, Attikon University Hospital
Athens, Greece, Greece
6th Pulmonary Medicine Department, SOTIRIA General Hospital of Chest Diseases of Athens
Athens, Greece, Greece
Department of Chest Medicine, EVANGELISMOS Athens General Hospital
Athens, Greece, Greece
Department of Internal Medicine, Larissa University General Hospital
Athens, Greece, Greece
Department of Internal Medicine, Patras University General Hospital
Athens, Greece, Greece
Department of Pulmonary Medicine, General Hospital of Kerkira
Athens, Greece, Greece
Emergency Department, TZANEIO Piraeus General Hospital
Athens, Greece, Greece
3rd Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
Thessaloniki, Thessaloniki, Greece
Countries
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Central Contacts
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Facility Contacts
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Other Identifiers
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2023-507295-40
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
REACT
Identifier Type: -
Identifier Source: org_study_id