Efficacy and Safety of Trimodulin (BT588) in Hospitalized Adults with Non-Severe CAP or Moderate/Severe COVID-19: A Randomized, Placebo-Controlled Phase III Trial

The primary objective of this study is to assess the **efficacy** and **safety** of trimodulin as an adjunctive treatment to standard of care (SoC) compared to placebo plus SoC in adult hospitalized subjects with non-severe community-acquired pneumonia (CAP) or moderate/severe Coronavirus Disease 2019 (COVID-19) pneumonia. This evaluation is clinically relevant as it aims to determine whether trimodulin can improve patient outcomes in these conditions, potentially offering a new therapeutic option for managing CAP and COVID-19 pneumonia.

Secondary objectives include:

• To determine the **pharmacokinetic** (PK) and **pharmacodynamic** (PD) properties of trimodulin.

The clinical trial involves a total of **192 participants** who are hospitalized adults aged 18 years and older, encompassing both **male and female** subjects. The study population includes individuals diagnosed with **non-severe community-acquired pneumonia (CAP)** or moderate to severe **Coronavirus Disease 2019 (COVID-19)** pneumonia. Participants were selected based on their hospitalization status and diagnosis, with the requirement of receiving oxygen therapy via low-flow oxygen, non-invasive ventilation, or high-flow oxygen at the start of treatment. The trial population is characterized by a vulnerable group, as it includes individuals with significant respiratory conditions requiring hospitalization. Participants must have radiologic evidence of new pulmonary infiltrates consistent with CAP or COVID-19 pneumonia and must be receiving standard care treatment. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the study focuses on assessing the efficacy and safety of trimodulin as an adjunctive treatment in a well-defined patient group.

The clinical trial is a **randomized**, **placebo-controlled**, **double-blind**, multi-center, phase III study designed to evaluate the efficacy and safety of **trimodulin** as an adjunctive treatment to standard of care (SoC) in adult hospitalized subjects with non-severe community-acquired pneumonia (CAP) or moderate to severe **COVID-19** pneumonia. The trial will compare trimodulin plus SoC to placebo plus SoC. The study is expected to run from December 2022 to April 2026, with participant involvement lasting up to 29 days, plus an additional 3 days for safety follow-up.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), hospitalization status, and diagnosis of CAP or COVID-19 pneumonia. The investigational medicinal product (IMP) must be initiated within 7 days of hospital admission. Subsequent visits will monitor clinical parameters, adverse events, and treatment efficacy. The primary endpoint is a composite of deterioration and mortality rates, while secondary endpoints include clinical deterioration rates, all-cause mortality rates, and various pharmacokinetic and pharmacodynamic measures.

Study visits will include baseline assessments, treatment administration, and follow-up evaluations to assess clinical outcomes and safety. The end-of-study visit will occur on day 29, with additional safety assessments extending to day 32. Participants may be withdrawn from the study early due to severe adverse events, non-compliance, or withdrawal of consent. The trial aims to provide comprehensive data on the potential benefits and risks of trimodulin in the specified patient population.

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

The trial also includes a **placebo** control, which is a **solution for infusion** of human albumin at a concentration of 1%. This placebo is prepared by diluting Albiomin 20% and is administered via **intravenous infusion**. The placebo serves as a comparator to evaluate the efficacy and safety of Trimodulin when used as an adjunctive treatment to the standard of care in adult hospitalized subjects with non-severe community-acquired pneumonia or moderate to severe COVID-19 pneumonia. The placebo is designed to mimic the administration characteristics of the investigational product to maintain the double-blind nature of the study.

The efficacy of trimodulin as an adjunctive treatment to standard of care in adult hospitalized subjects with non-severe community-acquired pneumonia (CAP) or moderate/severe **Coronavirus Disease 2019 (COVID-19)** pneumonia will be assessed through a randomized, placebo-controlled, double-blind, multi-center, phase III trial. The primary endpoint for evaluating efficacy is a composite measure of deterioration/mortality rate. Secondary efficacy endpoints include clinical deterioration rates from day 6 to 29 and day 1 to 29, 28-day and 90-day all-cause mortality rates, time to recovery to a score of ≤ 2 until day 29, and the proportion of subjects with a score of ≤ 2 on day 29. Additionally, the proportion of subjects who have improved, remained unchanged, or deteriorated/died compared to baseline at several time points will be evaluated.

Secondary pharmacokinetic (PK) endpoints will involve changes in serum concentrations of IgM, IgA, and IgG from baseline during and after treatment. Secondary pharmacodynamic (PD) endpoints will assess changes in factors and markers of coagulation, markers of inflammation, complement factors, biomarkers, and titers against SARS-CoV-2 and S. pneumoniae. These parameters will be measured and analyzed at specified time points throughout the trial to determine the efficacy of the investigational medicinal product.