Efficacy and Safety of Trimodulin in 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.

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.

Eligibility Criteria:
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.