Efficacy and Safety of Trimodulin (BT588) in Subjects With Severe Community-acquired Pneumonia (sCAP)

Study Overview
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Brief Summary
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The main objective of the trial is 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 sCAP on invasive mechanical ventilation (IMV). Other objectives are to determine detailed pharmacokinetic (PK) properties of trimodulin in a PK substudy and to determine its pharmacodynamic (PD) properties.

Detailed Description
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This is a randomized, placebo-controlled, double-blind, multi-center, multi-national, phase III trial, to assess the efficacy and safety of trimodulin compared to placebo treatment, as adjunctive treatment to SoC in adult hospitalized subjects with sCAP receiving IMV. Subjects will be randomized on a 1:1 basis to receive trimodulin or placebo, stratified by center. Investigational medicinal product (IMP) treatments will be blinded. Subject will be administered IMP once daily on 5 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 subjects still in the hospital (trial site) after day 29, an extended follow-up is conducted until discharge or until day 90. For all subjects alive on day 29, a closing visit/telephone call on day 91 [+10] will be done.

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 Severe Community-acquired Pneumonia (sCAP)

Conditions
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Community-acquired 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) subject. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) negative status. Signs of inflammation based on C-reactive protein threshold level. Diagnosis of active pneumonia. Radiological (or other imaging technology) evidence consistent with active pneumonia. Acute respiratory failure requiring IMV. Main Exclusion Criteria: For an incapacitated subject: any indication that the subject's presumed will would be against inclusion in the trial. Pregnant or lactating women. Subjects not willing to use reliable contraceptive measures during the trial and for 15 weeks after the last IMP treatment. Suspected hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP). Diagnosis of COVID-19 during the last 4 weeks. Subjects that required oxygen therapy due to COVID-19 in the last 6 months. Defined neutrophil counts within 24 hours prior to start of IMP treatment. Defined platelet counts within 24 hours prior to start of IMP treatment. Defined hemoglobin within 24 hours prior to start of IMP treatment. Known hemolytic disease. Known thrombosis or thromboembolic events (TEEs) or known medical history of TEEs or subjects particularly at risk for TEEs. Subject on dialysis or with severe renal impairment within 24 hours prior to start of IMP treatment. Subject with end-stage renal disease (ESRD) or known primary focal segmental glomerulosclerosis (FSGS). Known severe lung diseases interfering with sCAP therapy (e.g., subjects with chronic obstructive pulmonary disease [COPD], severe interstitial lung disease [incl. idiopathic pulmonary fibrosis], cystic fibrosis, active tuberculosis, chronically infected bronchiectasis, or active lung cancer). Known decompensated heart failure. Known pre-existing hepatic cirrhosis, severe hepatic impairment (Child Pugh score ≥ 9 points), or hepatocellular carcinoma. Known intolerance to proteins of human origin or known allergic reactions to components of trimodulin / placebo. Selective immunoglobulin A (IgA) deficiency with known antibodies to IgA. Known treatment for thorax/head/neck/hematologic malignancies in the last 12 months before screening. Life expectancy of less than 90 days, according to the investigator's clinical judgment, because of medical conditions related neither to sCAP nor to sCAP-associated septic conditions. Morbid obesity with high body mass index (BMI) ≥ 40 kg/m2, or malnutrition with low BMI < 16 kg/m2. Known treatment with polyvalent immunoglobulin preparations, plasma, or albumin preparations during the last 21 days before screening. Known treatment with predefined medications, during the last 5 days before screening. Any type of interferon during the last 21 days before screening. Ongoing treatment with immunosuppressants other than guideline recommended immunosuppressants for treatment of active pneumonia. Participation in another interventional clinical trial within 30 days before screening or previous participation in this clinical 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 on a 1:1 basis to receive trimodulin or placebo, stratified by center
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 |
| --- | --- | --- |
| 28-day all-cause mortality rate | Percentage of subjects that died until day 29 regardless of cause of death | Between days 1-29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90-day all-cause mortality rate | Percentage of subjects that died until day 91 regardless of cause of death | Between days 1-91 | 
| 28-day all-cause mortality rate plus day 6-29 deterioration rate | Percentage of subjects that died until day 29 Percentage of subjects with at least one deterioration event between day 6 and day 29 | 1. Between days 1-29; 2. Between days 6-29 | 
| Deterioration rate (day 6-29) | Percentage of subjects with at least one deterioration event between day 6 and day 29 | Between days 6-29 | 
| 28-day all-cause mortality rate plus day 1-29 deterioration rate | Percentage of subjects that died until day 29 Percentage of subjects with at least one deterioration event between day 1 and day 29 | 1.+2. Between days 1-29 | 
| Deterioration rate (day 1-29) | Percentage of subjects with at least one deterioration event between day 1 and day 29 | Between days 1-29 | 
| Change in Sequential Organ Failure Assessment (SOFA) score from baseline to days 3, 5, 7, 14, 21, 29 and discharge | Change in Sequential Organ Failure Assessment (SOFA) | Between baseline and Days 3, 5, 7, 14, 21, 29 and discharge | 
| Proportion of subjects with clinical cure of pneumonia on days 7, 14, 21, 29 and discharge | Percentage of subjects with clinical cure of pneumonia | On days 7, 14, 21, 29 or on the day of discharge | 
| Days of invasive mechanical ventilation (IMV) until day 29 | Days of invasive mechanical ventilation (IMV) until day 29 | Until day 29 | 
| Ventilator-free days (VFD) until day 29 | Ventilator-free days (VFD) | Until day 29 | 
| Days with oxygen supply until day 29 | Days with oxygen supply | Until day 29 | 
| Proportion of subjects with oxygen supply on days 7, 14, 21, 29 and discharge | Percentage of subjects with oxygen supply | On days 7, 14, 21, 29 or on the day of discharge | 
| Proportion of subjects with PaO2/FiO2 ratio < 100, 100 to < 200, 200 to < 300 or ≥ 300 on days 7, 14, 21, and 29 | Percentage of subjects with PaO2/FiO2 ratio < 100, 100 to < 200, 200 to < 300 or ≥ 300 | On days 7, 14, 21, 29 | 
| Vasopressor-free days until day 29 | Vasopressor-free days until day 29 | Until day 29 | 
| Days in intensive care unit (ICU) until day 29 | Days in intensive care unit (ICU) until day 29 | Until day 29 | 
| Time to discharge from ICU | Time to discharge from ICU | Until day 91 | 
| Proportion of subjects in ICU on days 7, 14, 21 and 29 | Percentage of subjects in ICU | On days 7, 14, 21, 29 | 
| Days of hospitalization until day 29 | Days of hospitalization | Until day 29 | 
| Time to discharge from hospital | Time to discharge from hospital | Until day 91 | 
| Proportion of subjects in hospital on days 7, 14, 21 and 29 | Percentage of subjects in hospital | On days 7, 14, 21, 29 | 
| 28-day readmission rate | Percentage of subjects readmitted to the hospital | Day 29 | 
| Rate of unscheduled return(s) to the emergency department or primary physician between day 29 and day 91 | Percentage of subjects returning to the emergency department or primary physician | Between Days 29 - 91 | 
| Time to return to normal activities until day 91 | Time to return to normal activities | Until day 91 | 
| Health status based on Clinical Frailty Scale (CFS) on day 91 | Change in Health status from Baseline assessment based on Clinical Frailty Scale (score 1 very fit to score 9 terminally ill) | Between Days 29 - 91 | 
| Quality of life based on Nottingham Health Profile (NHP) on days 29 and 91 | Change in Quality of life based on Nottingham Health Profile (NHP) | Day 29 and day 91 | 
| 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 AEs and TEAEs, AESIs, infusional TEAEs, TEAEs that led to permanent withdrawal of IMP, and TEAEs that led to discontinuation of the trial | Until day 29 | 
| Infusion-related TEAEs | Number of all infusion-related TEAEs | Until day 29 | 
| Serious adverse events (SAEs) | Number, severity, causality, and outcome of all SAEs | Until day 29 | 
| Dose modifications | Dose modifications (including reductions and changes in infusion rate) | Day 1-5 | 
| Change over time in electrocardiogram (ECG) parameters | ECG output (diagram including QT-interval and QTcF) showing abnormal, clinically relevant findings will be reported as adverse event | Days -1, 1, 3, 5 and once between days 8-13 | 
| Number and changes in observed Adverse Events in vital signs over time | Clinically significant changes in values of vital signs (including systolic and diastolic blood pressure, arterial oxygen saturation, heart rate, respiratory rate and body temperature) are rated as adverse events. The number of adverse events and changes in numbers of the adverse events over time will be reported | Days -1, 1-3, 5, 7, 14, 21, 29 | 
| Number and changes in observed Adverse Events in clinical laboratory parameters over time | Clinically significant changes in clinical laboratory values (including chemistry, hematology and coagulation) are rated as adverse events. The number of adverse events and changes in numbers of the adverse events over time will be reported | 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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Severe Community-acquired Pneumonia