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

Community-acquired Pneumonia Clinical Trial

— ESsCAPE  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05722938
• Other study ID #: 996
• Status: Recruiting
• Phase: Phase 3
• Start date: September 9, 2023
• Est. completion date: April 30, 2025

Study information

• Verified date: March 2024
• Source: Biotest
• Contact: Iris Bobenhausen, PhD
• Phone: +4915222801073
• Email: iris.bobenhausen[@]biotest.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 590
• Est. completion date: April 30, 2025
• Est. primary completion date: February 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Community-acquired Pneumonia
• Pneumonia

Intervention

Drug:
• Trimodulin
IMP will be administered via IV infusion on 5 consecutive days
• Placebo (human albumin 1%)
IMP will be administered via IV infusion on 5 consecutive days

Locations

Country	Name	City	State
Argentina	Clinica Adventista Belgrano	Ciudad Autonoma de Buenos Aire
Argentina	Hospital General de Agudos Dr. Ignacio Pirovano	Ciudad Autonoma de Buenos Aire
Argentina	Hospital Italiano de Buenos Aires	Ciudad Autonoma de Buenos Aire
Argentina	Sanatorio de la Trinidad Mitre	Ciudad Autonoma de Buenos Aire
Argentina	Clinica Chutro	Córdoba
Argentina	Hospital San Roque	Córdoba
Argentina	Sanatorio Privado de la Canada - Cordoba	Córdoba
Argentina	Centro Medico IPAM	Rosario
Argentina	Estudios Clinicos de los Arroyos	San Nicolas
Argentina	Sanatorio de la Canada	Villa María
Australia	Footscray Hospital	Footscray
Australia	Austin Health	Heidelberg
Australia	Sunshine Hospital	Saint Albans
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	KABEG-Klinikum Klagenfurt	Klagenfurt
Austria	AKH - Medizinische Universität Wien	Vienna
Belgium	AZ Sint-Jan	Brugge
Belgium	Cliniques Universitaires Saint-Luc	Brussel
Belgium	Hopital Erasme	Bruxelles
Belgium	Antwerp University Hospital (UZA)	Edegem
Belgium	AZ Maria Middelares	Gent
Belgium	C. H. R. de la Citadelle	Liège
Belgium	Clinique Saint-Pierre	Ottignies
Brazil	UPECLIN - Unidade de Pesquisa Clínica	Botucatu
Brazil	HMCP - Hospital e Maternidade Celso Pierro - PUC-Campinas	Campinas
Brazil	Universidade de Caxias do Sul, IPCEM - Instituto de Pesquisa Clínica para Estudos Multicêntricos	Caxias Do Sul
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre
Brazil	Hospital Ernesto Dornelles	Porto Alegre
Brazil	Irmandade da Santa Casa de Misericórdia de Porto Alegre	Porto Alegre
Brazil	CIP - Centro Integrado de Pesquisa	São José Do Rio Preto
Brazil	Universidade Municipal de Sao Caetano do Sul (USCS)	São Paulo
Czechia	Fakultni nemocnice u sv. Anny v Brne	Brno
Czechia	Oblastni nemocnice Kolin a.s.	Kolín
Czechia	Hospital Kyjov	Kyjov
Czechia	Fakultni nemocnice Kralovske Vinohrady	Prague
France	Centre Hospitalier Victor Dupouy	Argenteuil
France	Hôpital Louis Mourier	Colombes
France	CHU de Grenoble - Hôpital Albert Michallon	Grenoble
France	CHRU Lille - Hôpital Salengro	Lille
France	CHU de Limoges - Hôpital Dupuytren	Limoges
France	Centre Hospitalier de Melun	Melun
France	CHU Nice-Hopital de l' Archet	Nice
France	Groupe Hospitalier Diaconesses - Hopital De La Croix Saint Simon	Paris
France	Hôpital Bichat - Claude Bernard	Paris
France	Hôpital Cochin	Paris
France	Hôpital Tenon	Paris
France	CHU Saint-Etienne	Saint-Étienne
France	CHU Strasbourg - Hôpital Hautepierre	Strasbourg
France	CHU Strasbourg - Nouvel Hôpital Civil	Strasbourg
France	Hôpital Sainte Musse	Toulon
France	CHU Tours - Hôpital Bretonneau	Tours
France	Hôpital Nord Franche-Comté	Trévenans
Germany	Charité Universitätsmedizin Berlin - Campus Charité Mitte	Berlin
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hanover
Hungary	Bugat Pal Korhaz	Gyöngyös
Hungary	Aneszteziologiai es Intenziv Terapias Intezet	Pécs
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged
Israel	Rambam Medical Center	Haifa
Israel	Rabin Medical Center	Petach Tikva
New Zealand	Middlemore Hospital	Otahuhu
Philippines	Baguio General Hospital and Medical Center	Baguio City
Philippines	Dr. Jose N. Rodriguez Memorial Hospital	Caloocan
Philippines	Southern Philippines Medical Center	Davao City
Philippines	St.Paul's Hospital	Iloilo City
Philippines	West Visayas State University Medical Center	Iloilo City
Philippines	Lung Center of the Philippines	Quezon City
Romania	Institutul Clinic Fundeni	Bucharest
Romania	Spitalul Universitar de Urgenta Bucuresti	Bucharest
Romania	Spitalul Clinic Judetean de Urgenta "Pius Brinzeu"	Timisoara
South Africa	Worthwhile Clinical Trials	Johannesburg
South Africa	RYEXO Clinical Research	Pretoria
South Africa	RYEXO Clinical Research Zuid Afrikaans Hospital	Pretoria
South Africa	Dr JM Engelbrecht Trial Site	Somerset West
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i de Sant Pau	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Hospital Universitari de Girona Dr Josep Trueta	Girona
Spain	Hospital Universitario Clinico San Carlos	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda
Spain	Hospital Universitari de Tarragona Joan XXIII	Tarragona
Spain	Hospital Universitari i Politecnic La Fe	Valencia
United Kingdom	Royal Surrey County Hospital	Guildford
United Kingdom	Derriford Hospital	Plymouth
United States	Buffalo VA Medical Center	Buffalo	New York
United States	Mercury Street Medical Group	Butte	Montana
United States	Medical City Fort Worth	Fort Worth	Texas
United States	University of California San Francisco-Fresno	Fresno	California
United States	Hannibal Clinic	Hannibal	Missouri
United States	Sparrow Clinical Research Institute	Lansing	Michigan
United States	Lenox Hill Hospital	New York	New York
United States	St. Michael's Medical Center	Newark	New Jersey
United States	Jefferson University Hospitals	Philadelphia	Pennsylvania
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	University of Utah	Salt Lake City	Utah
United States	Wake Forest Baptist	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Biotest

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Czechia,  France,  Germany,  Hungary,  Israel,  New Zealand,  Philippines,  Romania,  South Africa,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serum concentration of immunoglobulins	Changes of serum concentration of IgM, IgA, and IgG from baseline, during and after treatment	Day 1, 5, 14
Other	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
Other	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
Primary	28-day all-cause mortality rate	Percentage of subjects that died until day 29 regardless of cause of death	Between days 1-29
Secondary	90-day all-cause mortality rate	Percentage of subjects that died until day 91 regardless of cause of death	Between days 1-91
Secondary	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
Secondary	Deterioration rate (day 6-29)	Percentage of subjects with at least one deterioration event between day 6 and day 29	Between days 6-29
Secondary	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
Secondary	Deterioration rate (day 1-29)	Percentage of subjects with at least one deterioration event between day 1 and day 29	Between days 1-29
Secondary	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
Secondary	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
Secondary	Days of invasive mechanical ventilation (IMV) until day 29	Days of invasive mechanical ventilation (IMV) until day 29	Until day 29
Secondary	Ventilator-free days (VFD) until day 29	Ventilator-free days (VFD)	Until day 29
Secondary	Days with oxygen supply until day 29	Days with oxygen supply	Until day 29
Secondary	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
Secondary	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
Secondary	Vasopressor-free days until day 29	Vasopressor-free days until day 29	Until day 29
Secondary	Days in intensive care unit (ICU) until day 29	Days in intensive care unit (ICU) until day 29	Until day 29
Secondary	Time to discharge from ICU	Time to discharge from ICU	Until day 91
Secondary	Proportion of subjects in ICU on days 7, 14, 21 and 29	Percentage of subjects in ICU	On days 7, 14, 21, 29
Secondary	Days of hospitalization until day 29	Days of hospitalization	Until day 29
Secondary	Time to discharge from hospital	Time to discharge from hospital	Until day 91
Secondary	Proportion of subjects in hospital on days 7, 14, 21 and 29	Percentage of subjects in hospital	On days 7, 14, 21, 29
Secondary	28-day readmission rate	Percentage of subjects readmitted to the hospital	Day 29
Secondary	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
Secondary	Time to return to normal activities until day 91	Time to return to normal activities	Until day 91
Secondary	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
Secondary	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
Secondary	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
Secondary	Infusion-related TEAEs	Number of all infusion-related TEAEs	Until day 29
Secondary	Serious adverse events (SAEs)	Number, severity, causality, and outcome of all SAEs	Until day 29
Secondary	Dose modifications	Dose modifications (including reductions and changes in infusion rate)	Day 1-5
Secondary	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
Secondary	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
Secondary	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