Efficacy and Safety of Trimodulin (BT588) in Subjects With CAP Including COVID-19 Pneumonia

Study Overview
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Brief Summary
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The main objectives of the trial are to assess the efficacy and safety of trimodulin as 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. Other objectives are to determine pharmacokinetic (PK) and pharmacodynamic (PD) properties of trimodulin.

Detailed Description
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This is a randomized, placebo-controlled, double-blind, multi-center, phase III trial to assess the efficacy and safety of trimodulin compared to placebo treatment, adjunctive to SoC in adult hospitalized subjects with non-severe community-acquired pneumonia (CAP) or moderate / severe Coronavirus Disease 2019 (COVID-19) pneumonia. Patients requiring low-flow oxygen, non-invasive ventilation or high-flow oxygen and with signs of early systemic inflammation (defined by C reactive protein (CRP), D-dimer and platelet levels) will be enrolled. Subjects will be randomized to receive either trimodulin or placebo on a 1:1 basis, stratified by type of oxygen supply before randomization and by region. Investigational Medicinal Product (IMP) treatments will be blinded. Subjects will be administered IMP once daily on five consecutive days (day 1 through day 5) adjunctive to SoC. The subsequent follow-up phase comprises maximally 23 days (day 6 through day 28) followed by an end-of-follow-up visit/telephone call on day 29 [+3]. For all subjects still in the hospital after day 29, an extended follow-up visit is conducted until day 90 or until discharge. For all subjects a closing visit/telephone call on day 91 [+10] will be done. For the evaluation of the primary and several secondary endpoints of the trial, a 9-category ordinal scale will be used. The primary objective is to assess efficacy of trimodulin based on clinical deterioration and mortality to demonstrate superiority to treatment with placebo. Secondary objectives are to assess efficacy and safety and to determine PK and PD properties of trimodulin compared to placebo.

Official Title
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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 CAP Including COVID-19 Pneumonia.

Conditions
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COVID-19, Respiratory Infection, Pneumonia, Community-acquired Pneumonia, Acute Respiratory Distress Syndrome, Viral Pneumonia, Bacterial Pneumonia, Fungal Pneumonia

Intervention / Treatment
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* Drug: Trimodulin
* Drug: Placebo (human albumin 1%)


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Written informed consent. Hospitalized, adult (≥ 18 years of age) subjects. Diagnosis of CAP or COVID- 19 pneumonia (e.g. according to local guidelines) and with radiologic evidence showing new pulmonary lobar or multilobar infiltrates consistent with CAP or COVID-19 pneumonia. Receiving oxygen supply via low-flow oxygen, high-flow oxygen or on non-invasive ventilation. Fulfilling at least one clinical respiratory parameter (SpO2 ≤ 94% and/or 100 mm Hg < PaO2/FiO2 ≤ 300 mm Hg). Signs of early systemic inflammation based on CRP and coagulation parameter threshold levels. Main Exclusion Criteria: Pregnant or lactating women. Subject on invasive mechanical ventilation and/or extracorporeal membrane oxygenation. Subject with septic shock and in need for vasopressors. Severe neutropenia prior to start of treatment. Hemoglobin >7 g/dL prior to start of treatment. Pre-existing hemolytic disease. Pre-existing thromboembolic events (TEEs). Subject on dialysis or with severe renal impairment prior to start of treatment. Subject with end stage renal disease, or known primary focal segmental glomerulosclerosis. Pre-existing severe lung diseases to current pneumonia. Pre-existing decompensated heart failure. Pre-existing hepatic cirrhosis, severe hepatic impairment , or hepatocellular carcinoma. Known intolerance to proteins of human origin or known allergic reactions to components of trimodulin/placebo. Selective, absolute immunoglobulin A (IgA) deficiency with known antibodies to IgA. Known human immunodeficiency virus infection. Life expectancy of less than 90 days. Morbid obesity or malnutrition. Treatment with predefined medications (certain immune modulators or immunosuppressants) before entering the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized to receive either trimodulin or placebo on a 1:1 basis, stratified by type of oxygen supply before randomization and by region
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trimodulin<br>Trimodulin (human IgM, IgA, IgG solution) for intravenous (IV) administration. | Drug: Trimodulin<br>* IMP will be administered via IV infusion on 5 consecutive days<br>* Other names: BT588;|
| Placebo Comparator: Placebo<br>Human albumin 1% | Drug: Placebo (human albumin 1%)<br>* IMP will be administered via IV infusion on 5 consecutive days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Endpoint | Composite of percentage of subjects with a change of at least 1 category on the 9-category ordinal scale from baseline (between days 6-29) and 28-day all-cause mortality rate (between days 1-29) | Until day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical deterioration rate | Percentage of subjects with a change of at least 1 category on the category ordinal-scale | Between days 6-29 and days 1-29 | 
| 28-days all-cause mortality rate | Percentage of subjects with a change to 8 on 9-category ordinal scale. | Day 29 | 
| 90-days all-cause mortality rate | Percentage of subjects with a change to 8 on 9-category ordinal scale. | Day 91 | 
| Time to recovery | Number of days to score ≤ 2 until day 29 | Between days 1-29 | 
| Proportion of subjects with score ≤ 2 | Proportion of subjects that improved to score ≤ 2 | Day 29 | 
| Proportion of subjects improved, unchanged, and deteriorated/died | Proportion of subjects improved, unchanged, and deteriorated/died compared to baseline at several days | Between days 1-29 | 
| Proportion of subjects with different partial pressure of oxygen (PaO2)/ fraction of inspired oxygen (FiO2) ratios | Proportion of subjects with PaO2/FiO2 ratio < 100, 100 to < 200, 200 to < 300 or ≥ 300 | Days 7, 14, 21, 29 | 
| Days of invasive mechanical ventilation (IMV)/ extracorporeal membrane oxygenation (ECMO) | Days of IMV/ECMO | Day 29 | 
| Proportion of subjects on IMV/ECMO | Proportion of subjects on IMV/ECMO | Day 29 | 
| Days with oxygen supply | Days with oxygen supply | Day 29 | 
| Proportion of subjects with oxygen supply | Proportion of subjects with oxygen supply | Days 7, 14, 21, 29 | 
| Days in intensive care unit (ICU) | Days in intensive care unit | Day 29 | 
| Proportion of subjects in ICU | Proportion of subjects in ICU | Day 29 | 
| Days of hospitalization | Days of hospitalization | Day 29 | 
| All adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest (AESIs), infusional TEAEs, TEAEs that led to permanent withdrawal of IMP and/or discontinuation of trial | Number, severity, causality, outcome, and seriousness of all adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest (AESIs), infusional TEAEs, TEAEs that led to permanent withdrawal of IMP, and TEAEs that led to discontinuation of the trial | Until day 29 | 
| TEAEs | Number of all related TEAEs | Until day 29 | 
| SAEs | Number, severity, causality, and outcome of all serious adverse events (SAEs) | Until day 29 | 
| Dose modifications | Dose modifications (incl. reductions and changes in infusion rate) | Day 1-5 | 
| Change over time in ECG parameters | ECG recordings, (including heart rate, QT-interval, QTcF) showing abnormal, clinically relevant findings will be reported as adverse event | Days -1, 1, 3, 5 and once between days 8-13 | 
| Changes over time in vital signs | Changes in recordings of vital sign parameters showing clinically significant measurements outside the normal range will be reported as adverse event. | Days -1,1-3, 5, 7 ,14, 21, 29 | 
| Changes over time in clinical laboratory parameters | Changes in recordings for clinical laboratory values (including chemistry, hematology and coagulation) showing clinically significant measurements outside the normal range will be reported as adverse event. | Days -1, 1-5, 7,14, 21, 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAP, Non severe community acquired pneumonia, COVID-19, SARS-CoV-2