Biomarker-Guided Early Clarithromycin Administration to Prevent Sepsis Progression in Community-Acquired Pneumonia: A Randomized Controlled Trial

The primary objective of the REACT Randomized Clinical Trial is to optimize the clinical benefit of adjunctive **clarithromycin** treatment, as demonstrated in the ACCESS trial, by providing evidence for the clinical benefit of an early start of adjunctive oral clarithromycin guided by suPAR. This approach aims to prevent the progression into sepsis in patients with community-acquired pneumonia (CAP) who are at risk. The clinical relevance of this objective lies in its potential to improve patient outcomes by reducing the incidence of sepsis, a severe and life-threatening condition, in individuals with CAP.

The secondary objectives of the REACT trial are to investigate the impact of early adjunctive treatment with clarithromycin on the resolution of CAP at the test-of-cure (TOC) visit. This evaluation is crucial for understanding the broader effects of clarithromycin on CAP recovery and its potential role in enhancing treatment protocols.

The clinical trial focuses on patients diagnosed with **community-acquired pneumonia** (CAP). The study population includes both male and female participants aged 18 years and older. Participants are required to provide written informed consent, or consent must be obtained from a legally designated representative if the participant lacks decision-making capacity. The trial includes individuals who exhibit at least two specific symptoms such as cough, purulent sputum expectoration, dyspnea, or pleuritic chest pain. The trial population is selected based on specific biomarkers, including a procalcitonin (PCT) level of 0.25 ng/ml or higher and a soluble urokinase plasminogen activator receptor (suPAR) level of 6 ng/ml or higher. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that special considerations are in place to protect these participants. The sponsor has not disclosed further details about the selection process or additional demographic characteristics of the participants.

The clinical trial is designed to evaluate the efficacy of **clarithromycin** in preventing the progression of sepsis in patients with community-acquired pneumonia. This is a randomized, double-blind, controlled trial, with participants receiving either clarithromycin or a placebo. The trial is expected to last until November 2025, with recruitment starting in November 2023. Participants will be involved for a maximum of 7 days, corresponding to the treatment period with clarithromycin, which is administered orally in the form of film-coated tablets.

The study includes several key visits: an initial screening visit, follow-up visits, and an end-of-study visit. During the screening visit, eligibility is assessed based on criteria such as age, gender, and specific clinical signs of pneumonia. Participants must provide written informed consent, and women of reproductive age must agree to use dual contraceptive methods. Follow-up visits are scheduled to monitor the primary endpoint, which is assessed on day 4. This endpoint is a composite of symptom reduction, SOFA score improvement, and specific biomarker changes. The end-of-study visit evaluates secondary endpoints, including organ dysfunction development, sepsis progression, and clinical success.

Participants may be terminated early from the study if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial aims to provide evidence for the clinical benefit of early adjunctive clarithromycin treatment guided by suPAR levels, optimizing outcomes for patients at risk of sepsis progression. The trial's primary objective is to demonstrate the clinical benefit of this approach, building on findings from previous studies.

The clinical trial involves the administration of **clarithromycin**, marketed under the name KLARICID® 500 mg, as the experimental medication. This pharmaceutical product is presented in the form of a **film-coated tablet**. The active substance, clarithromycin, is a chemical compound classified under the ATC code J01FA09. The medication is administered orally, with a maximum daily dose of 1000 mg and a total maximum dose of 7000 mg over a treatment period of up to 7 days. The trial aims to evaluate the efficacy of early adjunctive clarithromycin treatment in preventing the progression of community-acquired pneumonia into sepsis. Participant compliance with the dosing schedule is monitored throughout the study.

A **placebo** is used as a comparator treatment in this trial. The placebo is designed to mimic the appearance of the clarithromycin film-coated tablets, ensuring blinding of the study participants and investigators. The placebo does not contain any active pharmaceutical ingredients and is administered in the same manner as the experimental medication, following the same oral route and dosing schedule. The use of a placebo allows for the assessment of the true efficacy of clarithromycin by providing a control group for comparison.

Efficacy in the clinical trial titled "Biomarker-Guided Early Clarithromycin Treatment To Prevent Sepsis Progression In Community-Acquired Pneumonia: The REACT Randomized Clinical Trial" will be assessed using a composite primary endpoint evaluated on day 4. This endpoint consists of three conditions that must all be met for a patient to be considered as having succeeded. Condition A requires a reduction of at least 50% in the Respiratory Symptom Score (RSS) from the baseline score on day 1, without the development of any new symptoms. Condition B involves a decrease of at least 30% in the Sequential Organ Failure Assessment (SOFA) score from the baseline on day 1. Condition C is a combination of biomarker assessments: plasma Procalcitonin (PCT) must decrease by at least 80% from baseline or be below 0.25 ng/ml, and either plasma Interleukin-10 (IL-10) must decrease by at least 25% from baseline or be below the lower limit of detection, or the IL-8 to IL-10 ratio must decrease by less than 15% from baseline. Patients who die before day 4 are considered to have failed the primary endpoint.

Secondary endpoints include the development of new organ dysfunctions until day 28, progression into **sepsis**, clinical success at the Test of Cure (TOC) visit, and the need for escalation of standard-of-care antibiotics. Additional secondary measures involve the achievement of more than a 50% decrease in the baseline SOFA score at the end-of-treatment (EOT) visit, improvement in CAP-associated immune dysregulation, changes in cytokine production by peripheral blood mononuclear cells (PBMCs) on day 4, and associations of 28-day and 90-day mortality with immune dysregulation scores. The cost of hospital stay is also evaluated. These endpoints will be measured and analyzed at specified timepoints, including day 4, the TOC visit, and the EOT visit, using validated scales and laboratory tests.