| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Infection with SARS-COV-2 (=COVID-19) |
|
| E.1.1.1 | Medical condition in easily understood language |
| respiratory infection ranging from mild symptoms to severe pneumonia and acute respiratory distress syndrome (failure of lungs) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10035737 |
| E.1.2 | Term | Pneumonia viral |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003083 |
| E.1.2 | Term | ARDS |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038700 |
| E.1.2 | Term | Respiratory infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 |
|
| 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 |
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 World Health Organization will be used:
• Time to sustained improvement of one category from admission |
|
| E.2.2 | Secondary objectives of the trial |
• Time to discharge or to a NEWS of ≤2 and maintained for 24 hours, 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 3x/w
Duration of hospitalization, ICU treatments & admissions
• 15-, 29- & 60-day mortality
• Qualitative Study: semi-structured interviews
• Renin-Angiotensin System (RAS)-fingerprint at baseline and at least once weekly
• Within all patients, the impact of obesity and associated disesaes on mortality will be investigated
• Cumulative incidence of serious adverse events
• iscontinuation or temporary suspension of therapy
• Changes in WBC,hemoglobin,platelets,creatinine,glucose,total bilirubin,ALT,AST
• Within all patients, the impact of obesity and associated diseases on mortality |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudy A Anticoagulation: Patients with eGFR of >20 mL/min will be randomized to treatment with rivaroxaban or standard of care which likely includes prophylactic doses of low molecular weight heparins.
• Sub-Study A: number of thromboembolic events
Sub-Study B: Patients with blood pressure ≥120/80mmHg (or established and treated arterial hypertension) may be included into a sub-study labelled as B. The decision whether to include patients also in sub-study B will be taken within the first 24 hours after randomization to part A. Two consecutive blood pressure measurements are a prerequisite for randomization.
Patients in the sub-study B will be randomized to two groups with different antihypertensive treatment: RAS-blocker containing treatment (candesartan) and non-RAS-blocker containing treatment (nitrendipine, doxazosin).
We expect that about 1/3 of patients in the main part might also be included in sub-study B.
Additionally, two control groups will be included: control group 1 will consist of patients with suspected COVID-19 infection, who test negatively for SARS-COV-2 infection (n=10) and healthy volunteers with negative tests for SARS-COV-2 (n=10)
Sub-Study C: we will also include a randomized sub-study for patients with signs of uni- or bilateral pneumonia, high C-reactive protein levels and oxygen demand. These patients are at increased risk to develop a severe cause or fatal disease. Thus, they may receive clazakizumab, or if not available another licensed IL-6 inhibitor (such as tocilizumab) as treatment (additionally to other antiviral treatment mentioned above). This part of the study will be randomized against standard of care, or placebo on top of SOC.
• Sub-study C: modified SOFA score, paO2/FiO2 ratio, or SpO2/FiO2 ratio |
|
| E.3 | Principal inclusion criteria |
• Laboratory confirmed (i.e. PCR-based assay) infection with SARS-CoV-2 (ideally but not necessarily ≤72 hours before randomization for “antiviral” treatments) OR radiological signs of COVID-19 in chest X-ray or computed tomography*
• 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 chronic obstructive lung disease)
• 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 ≥130/85mmHg in 2 consecutive measurements OR patients with established and treated hypertension
• Sub-study B: Control group 1: Patients with suspicion of but negative tests for COVID-19. This group may consist of hospitalized and non-hospitalized 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 >5mg/dL (for Pentaglobin only), and admission to an ICU (for Pentaglobin only).
• Qualitative Study: all participants who are fluent in German or English will be asked about participation in this study part – which is however, optional
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 subject may be excluded from the per protocol analysis.
|
|
| E.4 | Principal 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 chronic kidney disease 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 hours (for anti-viral treatment arms)
• Contraindications treatment arm 2 (lopinavir/ritonavir): severe hepatic impairment, CYP3A4/5 metabolized drugs as deemed relevant by treating physicians, HIV positive
• Contraindication treatment arm 3 (remdesivir): Bodyweight <40kg,
• 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 hemorrhage, known or suspected esophageal 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<60ml/min/1.73m2), 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: females of childbearing potential
• Sub-Study C: Known active tuberculosis.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to sustained improvement of one category from admission in the 7-point clinical performance scale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| measured daily until day 29 |
|
| E.5.2 | Secondary end point(s) |
Clinical Status of patients according to the above-mentioned WHO scale:
Time to improvement of one category from admission
Clinical status daily
Mean change in the ranking on an ordinal scale from baseline
• National Early Warning Score (NEWS):
Time to discharge or to a NEWS of ≤2 and maintained for 24 hours, whichever occurs first
Change from baseline
• 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.)
• Mechanical Ventilation
Ventilator free days until day 29
Incidence and duration of new mechanical ventilation use during the trial
• Viral load/viral clearance
Baseline, and three times a week until infection has resolved
• Hospitalization
Duration of hospitalization
• Mortality
15-day, 29-day, 60-day mortality
- Sub-Study A: number of thromboembolic events
• Within all patients, the impact of obesity and associated disesaes on mortality will be investigated (e.g. mortality, inflammatory response, duration of hospitalization, intensive care unit admission, new oxygen use, duration of oxygen)
- Exploratory assessment of transaminases (including alkaline phosphatase, gamma-glutamyltransferases (GGT), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT)) and liver function parameters (including bilirubin, prothrombin time, international normalized ratio, 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 center).
- 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, dyspnea, body temperature, fear/anxiety
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• NEW Score: 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 three times a week
• Duration of hospitalization
• 15-day, 29-day mortality
• Renin-Angiotensin System (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, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, AST until day 29
|
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Within all patients randomized to Lopinavir/Ritonavir treatment a drugdrug
interaction check will be performed in a retrospective manner.
However, if questions concerning CYP interactions or QTc prolonging
agents occur during the trial, a drug-drug-interaction check will be
possible after contact with the Department of Clinical Pharmacology. |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 10 |
| 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 | No |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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