E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Infection with the novel coronavirus, designated SARS-CoV-2 |
Infektion mit dem neuartigen Coronavirus SARS-CoV-2 |
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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 primary objective of the AGNES-19 trial is to evaluate if improvement of vascular integrity with Adrecizumab on top of standard of care (SOC) is superior to placebo/ control substance (NaCl 0.9%) on top of SOC in reduction of the endpoint ”time to clinical improvement” until day 28 in patients with moderate to severe COVID-19.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the AGNES-19 trial intend to evaluate the effect of Adrecizumab in com-parison to placebo, with respect to safety and tolerability of Adrecizumab on top of SOC in patients with moderate to severe COVID-19, clinical status at day 28, all-cause mortality, rate of new invasive mechanical ventilation, length of invasive mechanical ventilation, length of initial stay at ICU, rate of renal replacement therapy, change in SOFA score, clinical status according to ordinal WHO scale for COVID-19, and life quality as assessed by EQ5D. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Hospitalization with moderate to severe COVID-19, defined as fulfilling at a minimum the following clinical status category on the WHO 8-point ordinal scale (corresponds to RKI score “severe” and “critical”): (i) “score 4” [oxygen via mask or nasal] • Laboratory-confirmed SARS-CoV-2 infection at index hospitalisation as determined by PCR or other validated commercial or public health assay • Bio-ADM ≥50 pg/mL or ≥30% increase until the end of the next day (with a minimum of 35 pg/mL at all) • DPP3 ≤ 30 ng/mL • Age above 18 years at time of screening • Body weight below 150 kg at time of screening • Informed consent
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E.4 | Principal exclusion criteria |
• Life expectancy less than 3 months before COVID-19 at the discretion of the investigator • Invasive mechanical ventilation ≥72 hours at time-point of randomization • Resuscitation > 45 minutes • Known or assumed hypersensitivity to the active substance, to Adrecizumab or any of its excipients, or known serious hypersensitivity to other monoclonal antibodies • Uncontrolled haematological/ oncological malignancies • Absolute neutropenia <500 per µL • Pre-existing severe chronic liver disease (i.e. Child-Pugh C) before COVID-19 hospitalization • Participation in a clinical trial or use of an IMP within 30 days or five times the half-life of the IMP - whichever is longer - prior to receiving the first dose within this study • History of relevant physical or psychiatric illness, any medical disorder that may require treatment or make the patient unlikely to fully complete the clinical trial • Positive pregnancy test before the first treatment or if patient is breast feeding • Patient is not willing to use adequate contraceptive precautions during the study and for up to 3 months after the scheduled dose of IMP
Note: ECMO (initiated during current COVID-19 hospitalization) is not an exclusion criteria
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on the WHO 8-point ordinal scale or live discharge from the hospital, whichever came first. Failure of clinical improvement and deaths will be censored at 28 days for this endpoint.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary efficacy objectives are to compare the active treatment and placebo/ control sub-stance (NaCl 0.9%) groups with respect to:
• Clinical status at day 28, as measured on the WHO 8-point ordinal scale • Survival (time-to-event) until day 28, and until end of follow-up (90 days) • Rate and length of invasive mechanical ventilation until day 28 and day 90, defined as use of endotracheal or tracheostomy tube assisted ventilation • Rate and length of ECMO therapy until day 28 and day 90 • Length of stay at ICU after application of IMP up to a total of 90 days • Length of hospital stay after application of IMP up to a total of 90 days • All-cause rehospitalisation within 90 days • Rate of renal replacement therapy until day 28 and day 90 • Change in clinical status on the WHO 8-point ordinal scale for COVID-19 at days 7, 28, 90 • Change in SOFA score sum (only during hospitalisation on ICU) within 24 hours of IMP administration (start of infusion), 48h, day 7 post-infusion • Between-group difference in life quality as assessed by EQ5D at discharge, day 28, day 90
Primary safety endpoint • Frequency and severity of SAEs/ AEs/SUSARs in both arms within 28 days • Mortality related to Adrecizumab • Interruption of infusion due to intolerability to Adrecizumab • New treatment-emergent adverse events (and changes in severity and frequency in these) related to Adrecizumab
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- day 28 and / or day 90 - days 7, 28, and 90 for change in clinical status on the WHO 8-point ordinal scale for COVID-19 - within 24 hours of IMP administration (start of infusion), 48h, day 7 post-infusion for change in SOFA score sum |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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 | 20 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 16 |
E.8.9.1 | In the Member State concerned days | |