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    Summary
    EudraCT Number:2020-001302-30
    Sponsor's Protocol Code Number:ACOVACT
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-04-09
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2020-001302-30
    A.3Full title of the trial
    A multicenter, randomized, active controlled, open label, platform trial on the efficacy and safety of experimental therapeutics for patients with COVID-19 (caused by infection with severe acute respiratory syndrome coronavirus-2)

    ACOVACT (Austrian CoronaVirus Adaptive Clinical Trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter, randomized, active controlled, open label, platform trial on the efficacy and safety of experimental therapeutics for patients with a lung disease caused by coronavirus infection

    ACOVACT (Austrian CoronaVirus Adaptive Clinical Trial)
    A.4.1Sponsor's protocol code numberACOVACT
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMedical University of Vienna
    B.1.3.4CountryAustria
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedical University of Vienna
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical University of Vienna, Department of Clinical Pharmacology
    B.5.2Functional name of contact pointSponsor
    B.5.3 Address:
    B.5.3.1Street AddressWähringer Gürtel 18-20
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1090
    B.5.3.4CountryAustria
    B.5.6E-mailklin-pharmakologie@meduniwien.ac.at
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Kaletra
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Deutschland GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLOPINAVIR
    D.3.9.1CAS number 192725-17-0
    D.3.9.4EV Substance CodeSUB02970MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITONAVIR
    D.3.9.1CAS number 155213-67-5
    D.3.9.4EV Substance CodeSUB10342MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Xarelto
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRIVAROXABAN
    D.3.9.1CAS number 366789-02-8
    D.3.9.4EV Substance CodeSUB29263
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCandesartan
    D.3.9.3Other descriptive nameCANDESARTAN CILEXETIL
    D.3.9.4EV Substance CodeSUB13222MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAsunercept
    D.3.2Product code APG101
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNASUNERCEPT
    D.3.9.2Current sponsor codeAPG101
    D.3.9.4EV Substance CodeSUB189861
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Veklury
    D.2.1.1.2Name of the Marketing Authorisation holderGilead Sciences Ireland UC
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNREMDESIVIR
    D.3.9.3Other descriptive nameREMDESIVIR
    D.3.9.4EV Substance CodeSUB195655
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Pentaglobin
    D.2.1.1.2Name of the Marketing Authorisation holderBiotest Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePentaglobin
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNImmunglobulin
    D.3.9.3Other descriptive nameHUMAN NORMAL IMMUNOGLOBULIN
    D.3.9.4EV Substance CodeSUB14196MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Infection with SARS-COV-2 (=COVID-19)
    E.1.1.1Medical condition in easily understood language
    respiratory infection ranging from mild symptoms to severe pneumonia and acute respiratory distress syndrome (failure of lungs)
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10035737
    E.1.2Term Pneumonia viral
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10003083
    E.1.2Term ARDS
    E.1.2System Organ Class 100000004855
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10038700
    E.1.2Term Respiratory infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10084268
    E.1.2Term COVID-19
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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 three times a week
     Duration of hospitalization, ICU treatments & admissions
    • 15-, 29- & 60-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
    • 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 will be investigated
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.3Principal 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).
    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.4Principal 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.5.1Primary end point(s)
    Time to sustained improvement of one category from admission in the 7-point clinical performance scale
    E.5.1.1Timepoint(s) of evaluation of this end point
    measured daily until day 29
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other 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.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 250
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state500
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-15
    P. End of Trial
    P.End of Trial StatusOngoing
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