A randomized, placebo-controlled, double-blind, multi-center, phase III trial to assess the efficacy and safety of trimodulin (BT588) in adult hospitalized subjects with severe community-acquired pneumonia (sCAP)

The primary objective of this study is to evaluate the **efficacy** of trimodulin in reducing 28-day all-cause mortality in adult patients hospitalized with severe community-acquired pneumonia (sCAP), aiming to demonstrate its superiority over placebo. This is clinically relevant as it addresses a critical outcome in a population with high mortality risk, potentially offering a new therapeutic option for managing sCAP.

Secondary objectives include assessing the efficacy and safety of trimodulin, as well as determining its pharmacokinetic (PK) and pharmacodynamic (PD) properties compared to placebo. These objectives are essential for understanding the overall therapeutic profile of trimodulin, ensuring its safe and effective use in clinical practice.

The clinical trial involves a total of **340 participants** diagnosed with **severe community-acquired pneumonia (sCAP)**. The study population comprises hospitalized adults aged 18 years and older, including both male and female subjects. Participants were selected based on specific criteria, including a **C-reactive protein (CRP)** level of at least 70 mg/L within 24 hours prior to the start of treatment and a diagnosis of active community-acquired pneumonia either before or shortly after hospital admission. The trial includes individuals experiencing acute respiratory failure requiring invasive mechanical ventilation, which defines the severity of their condition. Participants must have received standard care treatment for sCAP according to applicable guidelines. The trial population is considered vulnerable, and written informed consent was obtained from each subject or their legally authorized representative. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

The clinical trial is a **randomized**, **placebo-controlled**, **double-blind**, multi-center, phase III study designed to evaluate the efficacy and safety of trimodulin in adult hospitalized subjects with severe community-acquired pneumonia (sCAP). The primary objective is to assess the efficacy of trimodulin based on the 28-day all-cause mortality rate, aiming to demonstrate superiority over placebo treatment. The trial is expected to commence recruitment on May 1, 2023, and conclude by November 2, 2026.

Participants will be randomly assigned to receive either trimodulin or a placebo, both administered via **intravenous infusion**. The maximum treatment period is five days, with a maximum daily dose of 191.2 mg/kg and a total dose not exceeding 956 mg/kg. The study will include several visits: an initial screening visit to confirm eligibility, followed by treatment visits, and multiple follow-up visits to monitor outcomes and safety. The end-of-study visit will occur after the final follow-up assessments.

Inclusion criteria require participants to be hospitalized adults aged 18 or older, with a confirmed diagnosis of active community-acquired pneumonia and acute respiratory failure necessitating invasive mechanical ventilation. Treatment with the investigational medicinal product (IMP) must begin within 24 hours of initiating mechanical ventilation. Participants must also receive standard-of-care treatment for sCAP according to applicable guidelines. The study will exclude individuals who do not meet these criteria.

The expected duration of participant involvement is approximately 91 days, encompassing the treatment phase and follow-up period. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or any situation where continued participation is deemed unsafe by the investigator. The trial will measure both primary and secondary endpoints, including various mortality rates, clinical cure rates, and changes in health status, to comprehensively evaluate the treatment's impact.

The clinical trial involves the administration of **Trimodulin**, a **solution for infusion** containing human IgM, IgA, and IgG. This investigational medication is administered via **intravenous infusion**. The dosing regimen for Trimodulin is based on body weight, with a maximum daily dose of 191.2 mg/kg and a total maximum dose of 956 mg/kg over a treatment period of up to 5 days. Trimodulin is derived from human blood, ensuring a structurally diverse composition. The product is manufactured by Biotest and is identified by the sponsor product code BT588. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** control, which is a **solution for infusion** of 1% human albumin. The placebo is administered via **intravenous infusion** to maintain the double-blind nature of the trial. The placebo serves as a comparator to evaluate the efficacy and safety of Trimodulin in the treatment of severe community-acquired pneumonia (sCAP) in adult hospitalized subjects. The use of a placebo control is essential to demonstrate the superiority of Trimodulin over standard treatment without active therapeutic agents.

The efficacy of trimodulin in the treatment of severe community-acquired pneumonia (sCAP) will be assessed in a randomized, placebo-controlled, double-blind, multi-center, phase III clinical trial. The primary efficacy endpoint is the **28-day all-cause mortality rate**, which will be used to demonstrate the superiority of trimodulin over placebo. Secondary efficacy endpoints include the 90-day all-cause mortality rate, deterioration rates from day 6 to 29 and day 1 to 29, and changes in the Sequential Organ Failure Assessment (SOFA) score from baseline to various timepoints including days 3, 5, 7, 14, 21, 29, and discharge.

Additional secondary endpoints involve the proportion of subjects achieving clinical cure of pneumonia on days 7, 14, 21, 29, and discharge, as well as various measures of respiratory support and hospitalization, such as days of invasive mechanical ventilation (IMV), ventilator-free days, and days in the intensive care unit (ICU) until day 29. The trial will also evaluate the time to discharge from ICU and hospital, the proportion of subjects in ICU and hospital on specified days, and the 28-day readmission rate. Furthermore, the trial will assess health status using the Clinical Frailty Scale (CFS) on day 91 and quality of life using the Nottingham Health Profile (NHP) on days 29 and 91.

Data collection will include serum concentrations of immunoglobulins (IgM, IgA, IgG) and pharmacokinetic parameters for subjects in the pharmacokinetic substudy. Changes in markers of inflammation, coagulation, complement factors, biomarkers, and anti-pathogen titers will also be monitored. The trial is designed to provide comprehensive data on the efficacy of trimodulin in improving clinical outcomes for patients with sCAP.