| Participants |
500 participants; ≥ 18 years, female and male
Inclusion criteria:
Laboratory‐confirmed (i.e. PCR‐based assay) infection with SARS‐CoV‐2 (ideally but not necessarily 72 h before randomisation for “antiviral” treatments) OR radiological signs of COVID‐19 in chest X‐ray or CT Hospitalisation due to SARS‐CoV‐2 infection (for anti‐viral treatment arms) Requirement of oxygen support (due to oxygen saturation < 94% on ambient air or > 3% drop in case of COPD) Informed consent obtained, the patient understands and agrees to comply with the planned study procedures, except for sub‐study C: obtaining informed consent may be impossible due to the severe condition of the patient and may be waived 18 years of age For female patients with childbearing potential: willingness to perform effective measures of contraception during the study For treatment arm 4 (convalescent plasma) only immunocompromised patients (e.g. after having received chemotherapy, with inherited or acquired immunodeficiency syndromes) are eligible Sub‐study A: eGFR of > 20 mL/min Sub‐study B: outpatients with COVID‐19 may be included Sub‐study B: blood pressure =130/85 mmHg in 2 consecutive measurements or patients with established and treated hypertension Sub‐study B: control group 1: patients with suspected but negative tests for COVID‐19. This group may consist of hospitalised and non‐hospitalised patients Sub‐study B: control group 2: healthy volunteers Sub‐study C: signs of respiratory deterioration and progressing inflammation: need for oxygen supplementation, non‐invasive ventilation, high‐flow oxygen devices or mechanical ventilation and CRP levels > 5 mg/dL (for pentaglobin only), and admission to an ICU (for pentaglobin only) If for any given reason a patient does not qualify to participate in the main study, this will not preclude participation in sub‐study C In case of negative PCR but clear radiological signs of COVID‐19 patients have to be retested with serial nasopharyngeal swabs and PCR and, if possible antibody‐based assays. In any case, a laboratory‐based proof of COVID‐19 is required or else the patient may be excluded from the per protocol analysis.
Exclusion criteria:
Moribund or estimated life expectancy < 1 month (e.g. terminal cancer, etc.) Patient does not qualify for intensive care, based on local triage criteria Pregnancy or breastfeeding Severe liver dysfunction (e.g. ALT/AST > 5 times upper limit of normal) Stage 4 CKD or requiring dialysis for direct anticoagulant treatment Allergy or intolerances to any of the experimental substances ‐> exclusion for the respective treatment arm; for asunercept known hereditary fructose intolerance Anticipated discharge of hospital within 48 h (for anti‐viral treatment arms) Contraindications treatment arm 2 (lopinavir/ritonavir): severe hepatic impairment, CYP3A4/5 metabolised drugs as deemed relevant by treating physicians, HIV positive Contraindication treatment arm 3 (remdesivir): bodyweight < 40 kg Contraindications treatment arm 5 (convalescent plasma): IgA deficiency Sub‐study A contraindications: active bleeding or bleeding diathesis, lesion or condition considered as major risk factor for bleeding, recent brain or spinal injury, recent brain or spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms, major intraspinal or intracerebral vascular abnormalities Sub‐study A: ongoing therapeutic anticoagulation, which will continue, according to clinical practice Sub‐study B contraindications chronic heart failure, allergies, hypersensitivities and intolerances, severe hepatic impairment and/or cholestasis, concomitant therapy with aliskiren‐containing medications (for patients with diabetes mellitus or a GFR < 60 mL/min/1.73 m²), known significant bilateral renal artery stenosis or renal artery stenosis of a solitary kidney Sub‐study B: control group 1: with or without RAS blockers, control group 2: healthy volunteers: concomitant medication with RAS‐blockers Sub‐study C: known active HIV or viral hepatitis Asunercept: women of childbearing potential Sub‐Study C: known active TB
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| Outcomes |
Primary
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Main objective: to investigate the efficacy of various experimental therapeutics for patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2); for efficacy assessment an ordinal scale for clinical severity assessment as proposed by the WHO will be used
Primary end point(s): time to sustained improvement of 1 category from admission in the 7‐point clinical performance scale -
Secondary objective:
Time to discharge or to a NEWS of 2 and maintained for 24 h, whichever occurs first Change from baseline Oxygenation‐free days until day 29 Incidence and duration of new oxygen use during trial Ventilator‐free days until day 29 Incidence and duration of new mechanical ventilation use Viral load/viral clearance change at baseline and 3 times/week Duration of hospitalisation, ICU treatments and admissions 15‐, 29‐ & 60‐day mortality RAS‐fingerprint at baseline and at least once weekly (on days 7 ± 1, 14 ± 1, 21 ± 1, 28 ± 1, through recovery Within all participants, the impact of obesity and associated diseases on mortality will be investigated Cumulative incidence of SAEs Discontinuation or temporary suspension of therapy Changes in WBC, haemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, AST Time point(s) of evaluation of this end point: measured daily until day 29
Secondary
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Secondary end point(s): clinical status of participants according to the above‐mentioned WHO scale:
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NEWS:
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Oxygenation
Oxygenation‐free days until day 29 Incidence and duration of new oxygen use during the trial (e.g. oxygen insufflation, high‐flow oxygen, non‐invasive ventilation, mechanical ventilation, etc.)
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Mechanical ventilation
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Viral load/viral clearance
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Hospitalisation
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Mortality
Sub‐study A: number of thromboembolic events -
Within all participants, the impact of obesity and associated diseases on mortality will be investigated (e.g. mortality, inflammatory response, duration of hospitalisation, ICU admission, new oxygen use, duration of oxygen)
Exploratory assessment of transaminases (including alkaline phosphatase, GGT, AST), ALT) and liver function parameters (including bilirubin, prothrombin time, INR, albumin, fibrinogen) and their course during the disease and treatment An exploratory endpoint will encompass a comprehensive assessment of inflammatory parameters and their changes during treatment and wash‐out time, as well as exploratory genotype and RNA analysis with a focus on inflammation, coagulation, and the specific pathophysiology of the disease (if possible for centre) Sub‐study C: modified SOFA score, paO2/FiO2 ratio, or SpO2/FiO2 ratio Sub‐study B: to investigate the RAS fingerprint of patients with SARS‐CoV‐2 infection, with and without RAS‐blocking treatment, as specified above; to investigate blood pressure, dyspnoea, body temperature, fear/anxiety
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Time point(s) of evaluation of this end point:
NEWS: daily NEWS change from baseline (daily) up to day 29 Oxygenation‐free days until day 29 Incidence and duration of new oxygen use during trial Ventilator‐free days until day 29 Incidence and duration of new mechanical ventilation use Viral load/viral clearance change from baseline and 3 times/week Duration of hospitalisation 15‐day, 29‐day mortality RAS‐fingerprint at baseline and at least once weekly (on days 7 ± 1, 14 ± 1, 21 ± 1, 28 ± 1, through recovery All included scores in sub‐study B: approximately once weekly Cumulative incidence of SAEs Discontinuation or temporary suspension of therapy Changes in WBC, haemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, AST until day 29
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