Efficacy and Safety of Trimodulin in Subjects With Severe COVID-19 (ESsCOVID)

A Randomized, Placebo-controlled, Double-blind, Multi-center, Phase II Trial Investigating the Efficacy and Safety of Trimodulin (BT588) as add-on Therapy to Standard of Care in Adult Subjects With Severe COVID-19

The objectives of the trial are to evaluate the efficacy and safety of trimodulin as add-on therapy to standard of care (SoC) compared to placebo treatment in adult hospitalized subjects with severe COVID-19.

Additionally, pharmacodynamic (PD) and pharmacokinetic (PK) properties of trimodulin will be evaluated in all subjects.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Trimodulin; Other: Placebo (human albumin 1%)

Detailed Description

This is a randomized, placebo-controlled, double-blind, multi-center, phase II trial investigating the efficacy and safety of trimodulin compared to placebo treatment, as add-on therapy to SoC in adult subjects with severe COVID-19. Severe COVID-19 patients with need for non-invasive ventilation or high flow oxygen and with dysregulated inflammatory responses demonstrated by an elevated CRP level, will be enrolled.

Subjects will be randomized to receive either trimodulin or placebo on a 1:1 basis, stratified by center. Investigational Medicinal Product (IMP) treatments will be blinded. Subjects will be administered IMP once daily on five consecutive days (day 1 through day 5) as add-on therapy to SoC. The subsequent follow-up phase comprises 23 [+3] days (day 6 through day 28) followed by an end-of-trial visit/ telephone call on day 29 [+3]. For evaluation of this trial, a 9-category ordinal scale will be used. The primary aim of trimodulin treatment in the enrolled severely ill patients with a score of 5, is to prevent their clinical deterioration to a critical disease stage (score 6-7, e.g. requiring invasive mechanical ventilation or ECMO) and death (score 8). Accordingly, a composite primary efficacy endpoint reflecting the deterioration / mortality rate is used.

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil, 90020-090
    • Investigational site # 5503
  • Santo André, Brazil, 09030-010
    • Investigational site # 5502
  • Santo André, Brazil, 09080-110
    • Investigational site # 5505
  • São Paulo, Brazil, 05403-000
    • Investigational site # 5501
• France
  • Paris, France, 75020
    • Investigational site # 3304
  • Paris, France, 75877
    • Investigational site # 3301
  • Saint-Étienne, France, 42 055
    • Investigational site # 3305
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • Investigational site # 0707
  • Krasnoyarsk, Russian Federation, 660062
    • Investigational site # 0709
  • Moscow, Russian Federation, 111539
    • Investigational site # 0702
  • Moscow, Russian Federation, 119048
    • Investigational site # 0706
  • Moscow, Russian Federation, 125015
    • Investigational site # 0711
  • Moscow, Russian Federation, 125367
    • Investigational site # 0704
  • Moscow, Russian Federation, 129301
    • Investigational site # 0708
  • Saint Petersburg, Russian Federation, 197706
    • Investigational site # 0701
• Spain
  • Barcelona, Spain
    • Investigational Site # 3401
  • Madrid, Spain
    • Investigational Site # 3402

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Written informed consent obtained from the subject or legally authorized representative or informed verbal or administration consent due to pandemic situation, in compliance with all local legal requirements.
2. Male or female subject ≥18 years of age.
3. Laboratory-confirmed SARS-CoV-2 infection from a test done in a respiratory tract sample within the last 5 days at screening.

4. Diagnosis of community-acquired severe COVID-19 within 10 days after hospital-admission, with severe defined as:

   Need for non-invasive ventilation (NIV), or high-flow oxygen therapy (score =5 on the 9-category ordinal scale).

   At least one of the following clinical respiratory parameters is fulfilled: dyspnea, respiratory frequency ≥30/min, SpO2 ≤93%, 100 mmHg < PaO2/FiO2 ≤300 mmHg, and/or lung infiltrates >50% within 24 to 48 hours.

   At least one measurement of C-reactive protein ≥50 mg/L within 36 hours prior to start of treatment.

5. Subject must receive SoC treatment for COVID-19.

Exclusion Criteria:

1. Pregnant or lactating women.
2. Subjects that deteriorated to score >5 on the 9-category ordinal scale (e.g. receiving invasive mechanical ventilation (IMV), and/or extracorporeal membrane oxygenation (ECMO)) or subjects that improved to score <5 prior to randomization.
3. Severe neutropenia (neutrophil count <500/mm³) assessed within 24 hours prior to start of treatment.
4. Thrombocytopenia (platelet count <30,000/mm³) assessed within 24 hours prior to start of treatment.
5. Hemoglobin <7g/dL assessed within 24 hours prior to start of treatment.
6. Known hemolysis.
7. Known thrombosis or thromboembolic events (TEEs) or known medical history of TEEs (e.g. cerebrovascular accidents, transient ischemic attack, myocardial infarction, pulmonary embolism, and deep vein thrombosis) within the previous 3 months or those subjects particularly at risk for TEEs (e.g. history of thrombophilia, permanent immobilization, or permanent paralysis of the lower extremities) caused by other reasons than COVID-19.
8. Subject on dialysis or with severe renal impairment, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² assessed within 24 hours prior to start of treatment (details in Appendix 3: Estimated Glomerular Filtration Rate).
9. Subject with end stage renal disease (ESRD), or known primary focal segmental glomerulosclerosis (FSGS).
10. Known severe lung diseases interfering with COVID-19 therapy (e.g. severe interstitial lung disease, cystic fibrosis, idiopathic pulmonary fibrosis, active tuberculosis, chronically infected bronchiectasis, or active lung cancer).
11. Known decompensated heart failure (New York Heart Association class III-IV).
12. Known pre-existing hepatic cirrhosis, severe hepatic impairment (Child Pugh C score ≥9 points), or hepatocellular carcinoma.
13. Known intolerance to proteins of human origin or known allergic reactions to components of trimodulin.
14. Selective, absolute immunoglobulin A (IgA) deficiency with known antibodies to IgA.
15. Known treatment for thorax/head/neck/hematologic malignancies in the last 12 months.
16. Known human immunodeficiency virus infection.
17. Life expectancy of less than 90 days, according to the Investigator's clinical judgment, because of medical conditions neither related to COVID-19 nor to associated medical complications.
18. Obesity (body mass index ≥40 kg/m²), a body weight of more than 123 kg, or anorexia (body mass index <16 kg/m²).
19. Known immunosuppressive treatment other than acute treatment for COVID-19 (e.g. transplant recipient, subject with autoimmune disease).
20. Known treatment with polyvalent immunoglobulin preparations, any type of blood product, or any type of interferon during the last 21 days before entering the trial.
21. Participation in another interventional clinical trial within 30 days before entering, or during the trial, or previous participation in this clinical trial.
22. Employee or direct relative of an employee of the contract research organization, the trial site, or Biotest.

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%	Other: 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
Clinical detoriation rate	Percentage of subjects with a change of clinical status to score 6 or 7 on the 9-category ordinal scale	Between day 6 and day 29
28-day all-cause mortality rate	Percentage of subjects with a change to score 8 on the 9-category ordinal scale	Between day 1 and day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose modifications	Dose modifications (incl. reductions and changes in infusion rate)	Day 1-5
Clinical deterioration rate	Percentage of subjects with a change to score 6-7	Days 1-29 and days 6-29
28-days all-cause mortality rate on day 29	Percentage of subjects with score=8, assessed at the end-of-trial visit on day 29 [+3].	Day 29
Time to clinical deterioration	Number of days to first change from score 5 (enrollment) to score 6-7	Time Frame: between Days 1-29 and days 6-29
Time to Mortality	Number of days to change to score =8	Time Frame: between Day 1 and day 29
Proportion of subjects in each of the 9-categories of the ordinal scale	Number of patients by score on specific study days	Days 7, 14, 21, 29
Time to clinical improvement	Number of days to change to score 4 (mild disease, with supplemental oxygen) or score 3 (mild disease, no supplemental oxygen)	Day 29
Proportion of subjects with score ≤2	Proporation of subjects that improved to score ≤2	Day 29
Days on IMV	Number of calendar days on IMV until day 29	Until day 29
Days without oxygen supply	Number of calendar days without any form of oxygen support until day 29	Until day 29
Time to discontinuation from any form of oxygen supply	Time to definite stop of any form of additional oxygenation, irrespective of short interruptions	Until day 29
Proportion of subjects without any form of oxygen supply	Proportion of subjects that improved to not requiring supplemental oxygen.	Day 29
Hospital-free-days	Calendar days between hospital discharge and day 29	Until day 29
SARS-CoV-2 status	Time to SARS-CoV-2 negative status	Until day 29
Adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest, infusional TEAEs	Number, severity, causality, outcome, and seriousness of all. AE, TEAEs that led to permanent withdrawal of IMP, and TEAEs that led to discontinuation of the trial.	Until day 29
TEAEs	Number of all infusion related TEAEs	Until day 29
SAEs	Number, severity, causality, and outcome of all SAEs	Until day 29
Time to recovery	Number of days to change to score ≤2 (hospital discharged or meets discharge criteria)	Day 29
Change over time in ECG parameters	ECG recordings, (including heart rate, PR interval, RR interval, QRS interval, QT-interval, QTcF) showing abnormal, clinically relevant findings will be reported as adverse event.	Until day 29
Change over time in vital signs	Changes in recordings of vital sign parameters (including systolic and diastolic blood pressure, Arterial oxygen saturation, heart rate, respiratory rate and body temperature) showing clinically significant measurements outside the normal range will be reported as adverse event.	Until day 29

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic assessment of immunoglobulins	Assessment of changes in serum concentrations (g/L) of IgM, IgA, and IgG before, during and after treatment.	Day 1(baseline) to day 29
Pharmacodynamic assessment of disease related serum proteins	Assessment of relative changes in serum concentrations from baseline before, during and after treatment including inflammation markers (e.g. % change in CRP, PCT, Ferritin, TNF-alpha, IL-6, IL-8 and IL-10), biomarkers (e.g. % change in p-selectin) and complement factors (e.g. % change in C3, C4).	Day 1(baseline) to day 29

Collaborators and Investigators

• Sponsor: Biotest
• Investigators: Principal Investigator: Antoni Torres, MD, University of Barcelona Hospital Clinic of Barcelona Spain

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2020
• Primary Completion (Actual): June 29, 2021
• Study Completion (Actual): June 29, 2021

Study Registration Dates

• First Submitted: September 24, 2020
• First Submitted That Met QC Criteria: October 5, 2020
• First Posted (Actual): October 6, 2020

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: January 9, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Covid19; Acute Respiratory Distress Syndrome; Severe community acquired pneumonia; Severe Corona Virus Disease
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 998

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