E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
moderate or severe Coronavirus Disease 2019 (COVID-19) |
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E.1.1.1 | Medical condition in easily understood language |
moderate or severe Coronavirus Disease 2019 (COVID-19) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10084268 |
E.1.2 | Term | COVID-19 |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objectives of the trial are 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 moderate or severe COVID-19.
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E.2.2 | Secondary objectives of the trial |
Other objectives are to determine pharmacokinetic (PK) and pharmacodynamic (PD) properties of trimodulin. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent obtained from the subject or legally acceptable/authorized representative (LAR) or informed verbal consent in case of pandemic restrictions, in compliance with all local legal requirements. 2. Hospitalized, adult (≥ 18 years of age) subject (any gender). 3. Laboratory-confirmed acute SARS-CoV-2 infection within 5 days prior to screening. 4. Receiving oxygen supply via low-flow oxygen (LFO, by mask or nasal prongs) or on non-invasive ventilation (NIV) or high-flow oxygen (HFO) at start of treatment. 5. Fulfilling at least one of the following clinical respiratory parameters within 24 hours prior to start of treatment: - SpO2 ≤ 94% (on room air, and without preceding chronic lung disease); - 100 mm Hg < PaO2/FiO2 ≤ 300 mm Hg under HFO or NIV; - Radiologic evidence of COVID-19 pneumonia. 6. C-reactive protein ≥ 50 mg/L and ≤ 150 mg/L within 24 hours prior to start of treatment. 7. D-dimer ≤ 3 mg/L and platelets ≥ 130 x109/L within 24 hours prior to start of treatment. 8. Treatment with investigational medicinal product (IMP) has to be started within 7 days after first hospital-admission for COVID-19. 9. Subject must receive SoC treatment for COVID-19 according to Section 6.9 in the protocol. |
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating women. 2. Subject on invasive mechanical ventilation (IMV) and/or extracorporeal membrane oxygenation (ECMO) or predicted to be on IMV and/or ECMO at start of treatment. 3. Subject with sustained improvement in any form of oxygen supply (e.g. change from IMV to NIV/HFO/LFO, or change from HFO to LFO) during the last 7 days or with predicted cessation of oxygen supply at start of treatment. 4. Severe neutropenia (neutrophil count < 0.5 x109/L) assessed within 24 hours prior to start of treatment. 5. Hemoglobin < 7g/dL assessed within 24 hours prior to start of treatment. 6. Known hemolytic disease. 7. Known thrombosis or acute 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 3 months before entering the trial. Subjects particularly at risk for TEEs caused by other reasons than the current COVID-19 infection (e.g. history of thrombophilia). 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. COPD (GOLD stage III-IV / Group D), 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. Morbid obesity with high body mass index ≥ 40 kg/m², or malnutrition with low body mass index < 16 kg/m². 19. Known treatment with polyvalent immunoglobulin preparations, plasma, or albumin preparations during the last 21 days before entering the trial. 20. Known treatment with exploratory selective immune suppressors (cytokine inhibitors, cytokine receptor inhibitors, kinase inhibitors) during the last 10 days before entering the trial. 21. Known treatment with fluoroquinolone preparations, during the last 5 days before entering the trial. 22. Known treatment with any type of interferon during the last 21 days before entering the trial. 23. Known treatment with immunosuppressants other than guideline recommended immunosuppressants for treatment of acute COVID-19. 24. Participation in another interventional clinical trial within 30 days before entering, or previous participation in this clinical trial. 25. Employee or direct relative of an employee of the contract research organization, the trial site, or Biotest. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Composite primary endpoint: Deterioration / mortality rate |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Clinical deterioration (increment of at least 1 category on the 9-category ordinal-scale from baseline) between day 6 and day 29 - 28-day all-cause mortality between day 1 and day 29 |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints: - Clinical deterioration rate (day 6-29) - Clinical deterioration rate (day 1-29) - 28-days all-cause mortality rate on day 29 - 90-days all-cause mortality rate on day 91 - Time to recovery to score ≤ 2 until day 29 - Proportion of subjects with score ≤ 2 on day 29 - Proportion of subjects improved, unchanged, and deteriorated/died compared to baseline at several days - Proportion of subjects with PaO2/FiO2 ratio < 100, 100 to < 200, 200 to < 300 or ≥ 300 on days 7, 14, 21, 29 - Days of IMV/ECMO until day 29 - Proportion of subjects on IMV/ECMO until day 29 - Days with oxygen supply until day 29 - Proportion of subjects with oxygen supply on days 7, 14, 21, 29 - Days in intensive care unit (ICU) until day 29 - Proportion of subjects in ICU until day 29 - Days of hospitalization until day 29
Secondary safety endpoints: - Number, severity, causality, outcome, and seriousness of all adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest (AESIs), infusional TEAEs, TEAEs that led to permanent withdrawal of IMP, and TEAEs that led to discontinuation of the trial through day 29 [+3] - Number of all infusion-related TEAEs through day 29 [+3] - Number, severity, causality, and outcome of all serious adverse events (SAEs) through day 29 [+3] - Dose modifications (incl. reductions and changes in infusion rate) - Distribution and changes over time for safety, laboratory, vital signs parameters, and ECG
Secondary PK endpoints: Changes from baseline, during and after treatment: - Serum concentration of IgM, IgA, and IgG
Secondary PD endpoints: Changes from baseline, during and after treatment: - Factors and markers of coagulation - Markers of inflammation - Complement factors - Biomarkers - Anti-SARS-CoV-2 titers
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 79 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Chile |
Colombia |
Israel |
Mexico |
Peru |
South Africa |
Austria |
Estonia |
France |
Latvia |
Lithuania |
Poland |
Germany |
Italy |
Belgium |
Denmark |
Hungary |
Portugal |
Slovakia |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of this clinical trial (Study 1001) is defined as the Last Visit of the Last Subject. The Last Visit is the closing visit done on day 91 [+10], or a telephone interview on day 91 [+10] in case the Last Subject is discharged before day 91, or has been transferred to another hospital. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |