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

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 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.

Study Overview

• Status: Recruiting
• Conditions: Community-acquired Pneumonia
• Intervention / Treatment: Drug: Trimodulin; Drug: Placebo (human albumin 1%)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 590
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Claudia Schulte; Phone Number: +4915222801491; Email: claudia.schulte@biotest.com
• Study Contact Backup: Name: Iris Bobenhausen, PhD; Phone Number: +4915222801073; Email: iris.bobenhausen@biotest.com

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aire, Argentina, C1039AAO
    • Recruiting
    • Sanatorio de la Trinidad Mitre
  • Ciudad Autonoma de Buenos Aire, Argentina, C1181ACH
    • Recruiting
    • Hospital Italiano de Buenos Aires
  • Ciudad Autonoma de Buenos Aire, Argentina, C1430EGF
    • Recruiting
    • Clinica Adventista Belgrano
  • Ciudad Autonoma de Buenos Aire, Argentina, C1430BKC
    • Recruiting
    • Hospital General de Agudos Dr. Ignacio Pirovano
  • Córdoba, Argentina, 5000
    • Recruiting
    • Hospital San Roque
  • Córdoba, Argentina, 5000
    • Recruiting
    • Clinica Chutro
  • Córdoba, Argentina, X5000BSQ
    • Recruiting
    • Sanatorio Privado de la Canada - Cordoba
  • Rosario, Argentina, S2001SBK
    • Recruiting
    • Centro Medico IPAM
  • San Nicolas, Argentina, 2900
    • Recruiting
    • Estudios Clinicos de los Arroyos
  • Villa María, Argentina, 5900
    • Recruiting
    • Sanatorio de la Canada
• Australia
  • Footscray, Australia, 3011
    • Recruiting
    • Footscray Hospital
  • Heidelberg, Australia, 3084
    • Recruiting
    • Austin Health
  • Saint Albans, Australia, 3021
    • Recruiting
    • Sunshine Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
• Austria
  • Klagenfurt, Austria, 9020
    • Recruiting
    • KABEG-Klinikum Klagenfurt
  • Vienna, Austria, 1090
    • Recruiting
    • AKH - Medizinische Universität Wien
• Belgium
  • Brugge, Belgium, 8000
    • Recruiting
    • AZ Sint-Jan
  • Brussel, Belgium, 1200
    • Recruiting
    • Cliniques Universitaires Saint-Luc
  • Bruxelles, Belgium, 1070
    • Recruiting
    • Hopital Erasme
  • Edegem, Belgium, 2650
    • Recruiting
    • Antwerp University Hospital (UZA)
  • Gent, Belgium, 9000
    • Recruiting
    • AZ Maria Middelares
  • Liège, Belgium, 4000
    • Recruiting
    • C. H. R. de la Citadelle
  • Ottignies, Belgium, 1340
    • Recruiting
    • Clinique Saint-Pierre
• Brazil
  • Botucatu, Brazil, 18618-686
    • Recruiting
    • UPECLIN - Unidade de Pesquisa Clínica
  • Campinas, Brazil, 13060-904
    • Recruiting
    • HMCP - Hospital e Maternidade Celso Pierro - PUC-Campinas
  • Caxias Do Sul, Brazil, 95070-560
    • Recruiting
    • Universidade de Caxias do Sul, IPCEM - Instituto de Pesquisa Clínica para Estudos Multicêntricos
  • Porto Alegre, Brazil, 90160-093
    • Recruiting
    • Hospital Ernesto Dornelles
  • Porto Alegre, Brazil, 90020-090
    • Recruiting
    • Irmandade da Santa Casa de Misericórdia de Porto Alegre
  • Porto Alegre, Brazil, 90035-903
    • Recruiting
    • Hospital de Clínicas de Porto Alegre
  • São José Do Rio Preto, Brazil, 15090-000
    • Recruiting
    • CIP - Centro Integrado de Pesquisa
  • São Paulo, Brazil, 09530-700
    • Recruiting
    • Universidade Municipal de Sao Caetano do Sul (USCS)
• Czechia
  • Brno, Czechia, 65691
    • Recruiting
    • Fakultni nemocnice u sv. Anny v Brne
  • Kolín, Czechia, 28002
    • Recruiting
    • Oblastni nemocnice Kolin a.s.
  • Kyjov, Czechia, 69701
    • Recruiting
    • Hospital Kyjov
  • Prague, Czechia, 10034
    • Recruiting
    • Fakultni nemocnice Kralovske Vinohrady
• France
  • Argenteuil, France, 95107
    • Recruiting
    • Centre Hospitalier Victor Dupouy
  • Colombes, France, 92700
    • Recruiting
    • Hôpital Louis Mourier
  • Grenoble, France, 38043
    • Recruiting
    • CHU de Grenoble - Hôpital Albert Michallon
  • Lille, France, 59037
    • Recruiting
    • CHRU Lille - Hôpital Salengro
  • Limoges, France, 87000
    • Recruiting
    • CHU de Limoges - Hôpital Dupuytren
  • Melun, France, 77000
    • Recruiting
    • Centre Hospitalier de Melun
  • Nice, France, 06202
    • Recruiting
    • CHU Nice-Hopital de l' Archet
  • Paris, France, 75679
    • Recruiting
    • Hôpital Cochin
  • Paris, France, 75018
    • Recruiting
    • Hôpital Bichat - Claude Bernard
  • Paris, France, 75020
    • Recruiting
    • Hopital Tenon
  • Paris, France, 75020
    • Recruiting
    • Groupe Hospitalier Diaconesses - Hopital De La Croix Saint Simon
  • Saint-Étienne, France, 42055
    • Recruiting
    • CHU Saint-Etienne
  • Strasbourg, France, 67098
    • Recruiting
    • CHU Strasbourg - Hôpital Hautepierre
  • Strasbourg, France, 67091
    • Recruiting
    • CHU Strasbourg - Nouvel Hôpital Civil
  • Toulon, France, 83056
    • Recruiting
    • Hôpital Sainte Musse
  • Tours, France, 37000
    • Recruiting
    • CHU Tours - Hôpital Bretonneau
  • Trévenans, France, 90400
    • Recruiting
    • Hôpital Nord Franche-Comté
• Germany
  • Berlin, Germany, 10117
    • Recruiting
    • Charité Universitätsmedizin Berlin - Campus Charité Mitte
  • Hamburg, Germany, 20246
    • Recruiting
    • Universitätsklinikum Hamburg-Eppendorf
  • Hanover, Germany, 30625
    • Recruiting
    • Medizinische Hochschule Hannover
• Hungary
  • Gyöngyös, Hungary, 3200
    • Recruiting
    • Bugat Pal Korhaz
  • Pécs, Hungary, 7624
    • Recruiting
    • Aneszteziologiai es Intenziv Terapias Intezet
  • Szeged, Hungary, 6725
    • Recruiting
    • Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
• Israel
  • Haifa, Israel, 31096
    • Recruiting
    • Rambam Medical Center
  • Petach Tikva, Israel, 4941492
    • Recruiting
    • Rabin Medical Center
• New Zealand
  • Otahuhu, New Zealand, 2025
    • Recruiting
    • Middlemore Hospital
• Philippines
  • Baguio City, Philippines, 2600
    • Recruiting
    • Baguio General Hospital and Medical Center
  • Caloocan, Philippines, 1427
    • Recruiting
    • Dr. Jose N. Rodriguez Memorial Hospital
  • Davao City, Philippines, 8000
    • Recruiting
    • Southern Philippines Medical Center
  • Iloilo City, Philippines, 5000
    • Recruiting
    • West Visayas State University Medical Center
  • Iloilo City, Philippines, 5000
    • Recruiting
    • St.Paul's Hospital
  • Quezon City, Philippines, 1100
    • Recruiting
    • Lung Center of the Philippines
• Romania
  • Bucharest, Romania, 022328
    • Recruiting
    • Institutul Clinic Fundeni
  • Bucharest, Romania, 050098
    • Recruiting
    • Spitalul Universitar de Urgenta Bucuresti
  • Timişoara, Romania, 300723
    • Recruiting
    • Spitalul Clinic Judetean de Urgenta "Pius Brinzeu"
• South Africa
  • Johannesburg, South Africa, 1500
    • Recruiting
    • Worthwhile Clinical Trials
  • Pretoria, South Africa, 0002
    • Recruiting
    • RYEXO Clinical Research Zuid Afrikaans Hospital
  • Pretoria, South Africa, 0184
    • Recruiting
    • RYEXO Clinical Research
  • Somerset West, South Africa, 7130
    • Recruiting
    • Dr JM Engelbrecht Trial Site
• Spain
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clínic de Barcelona
  • Barcelona, Spain, 8035
    • Recruiting
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08041
    • Recruiting
    • Hospital de la Santa Creu i de Sant Pau
  • Córdoba, Spain, 14004
    • Recruiting
    • Hospital Universitario Reina Sofia
  • Girona, Spain, 17007
    • Recruiting
    • Hospital Universitari de Girona Dr Josep Trueta
  • Madrid, Spain, 28046
    • Recruiting
    • Hospital Universitario La Paz
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Universitario Clinico San Carlos
  • Majadahonda, Spain, 28222
    • Recruiting
    • Hospital Universitario Puerta de Hierro Majadahonda
  • Tarragona, Spain, 43007
    • Recruiting
    • Hospital Universitari de Tarragona Joan XXIII
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitari I Politecnic La Fe
• United Kingdom
  • Guildford, United Kingdom, GU2 7XX
    • Recruiting
    • Royal Surrey County Hospital
  • Plymouth, United Kingdom, PL6 8DH
    • Recruiting
    • Derriford Hospital
• United States
  • California
    • Fresno, California, United States, 93701
      • Recruiting
      • University of California San Francisco-Fresno
  • Michigan
    • Lansing, Michigan, United States, 48912
      • Recruiting
      • Sparrow Clinical Research Institute
    • Royal Oak, Michigan, United States, 48073
      • Recruiting
      • William Beaumont Hospital
  • Missouri
    • Hannibal, Missouri, United States, 63401
      • Recruiting
      • Hannibal Clinic
  • Montana
    • Butte, Montana, United States, 59701
      • Recruiting
      • Mercury Street Medical Group
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • Recruiting
      • St. Michael's Medical Center
  • New York
    • Buffalo, New York, United States, 14215
      • Recruiting
      • Buffalo VA Medical Center
    • New York, New York, United States, 10075-1850
      • Recruiting
      • Lenox Hill Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Wake Forest Baptist
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Jefferson University Hospitals
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Recruiting
      • Medical City Fort Worth
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Recruiting
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

1. Written informed consent.
2. Hospitalized, adult (≥ 18 years of age) subject.
3. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) negative status.
4. Signs of inflammation based on C-reactive protein threshold level.
5. Diagnosis of active pneumonia.
6. Radiological (or other imaging technology) evidence consistent with active pneumonia.
7. Acute respiratory failure requiring IMV.

Main Exclusion Criteria:

1. For an incapacitated subject: any indication that the subject's presumed will would be against inclusion in the trial.
2. Pregnant or lactating women.
3. Subjects not willing to use reliable contraceptive measures during the trial and for 15 weeks after the last IMP treatment.
4. Suspected hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP).
5. Diagnosis of COVID-19 during the last 4 weeks.
6. Subjects that required oxygen therapy due to COVID-19 in the last 6 months.
7. Defined neutrophil counts within 24 hours prior to start of IMP treatment.
8. Defined platelet counts within 24 hours prior to start of IMP treatment.
9. Defined hemoglobin within 24 hours prior to start of IMP treatment.
10. Known hemolytic disease.
11. Known thrombosis or thromboembolic events (TEEs) or known medical history of TEEs or subjects particularly at risk for TEEs.
12. Subject on dialysis or with severe renal impairment within 24 hours prior to start of IMP treatment.
13. Subject with end-stage renal disease (ESRD) or known primary focal segmental glomerulosclerosis (FSGS).
14. 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).
15. Known decompensated heart failure.
16. Known pre-existing hepatic cirrhosis, severe hepatic impairment (Child Pugh score ≥ 9 points), or hepatocellular carcinoma.
17. Known intolerance to proteins of human origin or known allergic reactions to components of trimodulin / placebo.
18. Selective immunoglobulin A (IgA) deficiency with known antibodies to IgA.
19. Known treatment for thorax/head/neck/hematologic malignancies in the last 12 months before screening.
20. 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.
21. Morbid obesity with high body mass index (BMI) ≥ 40 kg/m2, or malnutrition with low BMI < 16 kg/m2.
22. Known treatment with polyvalent immunoglobulin preparations, plasma, or albumin preparations during the last 21 days before screening.
23. Known treatment with predefined medications, during the last 5 days before screening.
24. Any type of interferon during the last 21 days before screening.
25. Ongoing treatment with immunosuppressants other than guideline recommended immunosuppressants for treatment of active pneumonia.
26. Participation in another interventional clinical trial within 30 days before screening or previous participation in this clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum concentration of immunoglobulins	Changes of serum concentration of IgM, IgA, and IgG from baseline, during and after treatment	Day 1, 5, 14
Pharmacokinetic assessment of immunoglobulins	Assessment of changes in serum concentrations (g/L) of IgM, IgA, and IgG before, during and after treatment	Day 1, 2, 3, 4, 5, 6, 7, 9, 14, 21, 29
Pharmacodynamic assessment of disease related serum proteins	Assessment of relative changes in serum concentrations from baseline, during and after treatment of factors and markers of coagulation (e.g. % change in D-dimer), markers of inflammation (e.g. % change in CRP), complement factors (e.g. % change in C3, C4), specific antibody titers against sCAP-related pathogens (e.g. % change in Streptococcus pneumoniae antibody titers)	Day 1, 2, 3, 4, 5, 7, 14, 21, 29

Collaborators and Investigators

• Sponsor: Biotest
• Investigators: Principal Investigator: Tobias Welte, Prof., Hannover Medical School

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2023
• Primary Completion (Estimated): February 28, 2025
• Study Completion (Estimated): April 30, 2025

Study Registration Dates

• First Submitted: January 11, 2023
• First Submitted That Met QC Criteria: January 31, 2023
• First Posted (Actual): February 10, 2023

Study Record Updates

• Last Update Posted (Estimated): April 26, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Severe Community-acquired Pneumonia
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia
• Other Study ID Numbers: 996

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No