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    Summary
    EudraCT Number:2020-002345-42
    Sponsor's Protocol Code Number:998
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-09-23
    Trial results View 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 ConcernedFrance - ANSM
    A.2EudraCT number2020-002345-42
    A.3Full title of the trial
    A randomized, placebo controlled, double-blind, multi-center, phase II trial investigating the efficacy and safety of trimodulin (BT588) as add-on therapy to standard of care in adult subjects with severe COVID-19
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized, placebo controlled, double-blind, multi-center, phase II trial investigating the efficacy and safety of trimodulin (BT588) as add-on therapy to standard of care in adult subjects with severe COVID-19
    A.3.2Name or abbreviated title of the trial where available
    ESsCOVID
    A.4.1Sponsor's protocol code number998
    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 SponsorBiotest AG
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBiotest AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiotest AG
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street AddressLandsteinerstrasse 5
    B.5.3.2Town/ cityDreieich
    B.5.3.3Post code63303
    B.5.3.4CountryGermany
    B.5.6E-mailpatrick.langohr@biotest.com
    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 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 nametrimodulin
    D.3.2Product code BT588
    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 INNTrimodulin (human IgM, IgA, IgG solution)
    D.3.9.2Current sponsor codeBT588
    D.3.9.3Other descriptive nameIgM Concentrate
    D.3.9.4EV Substance CodeSUB189624
    D.3.10 Strength
    D.3.10.1Concentration unit g/ml gram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.05
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe Corona Virus Disease 2019 (COVID-19)
    E.1.1.1Medical condition in easily understood language
    Severe COVID-19
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10084380
    E.1.2Term COVID-19 pneumonia
    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
    The objectives of the trial are to evaluate the efficacy and safety of trimodulin as add-on therapy to standard of care (SoC) compared to placebo treatment in adult hospitalized subjects with severe COVID-19.
    E.2.2Secondary objectives of the trial
    Pharmacodynamic (PD) and pharmacokinetic (PK) properties of trimodulin will be evaluated in all subjects.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent obtained from the subject or legally authorized representative or informed verbal or administration consent due to pandemic situation, in compliance with all local legal requirements.
    2. Male or female subject ≥18 years of age.
    3. Laboratory-confirmed SARS-CoV-2 infection.
    4. Diagnosis of community-acquired severe COVID-19 within 5 days after hospital-admission, with severe defined as:
    o Need for non-invasive ventilation (NIV), or high-flow oxygen therapy (score =5 on the 9-category ordinal scale).
    o At least one clinical respiratory parameter:
    dyspnea, respiratory frequency ≥30/min, SpO2 ≤93%, 100 mmHg < PaO2/FiO2 ≤300 mmHg, lung infiltrates >50% within 24 to 48 hours.
    o At least one measurement of C-reactive protein ≥50 mg/L within 18 hours prior to start of treatment.
    5. Subject must receive SoC treatment for COVID-19.
    E.4Principal exclusion criteria
    2. Subjects that deteriorated to score >5 on the 9-category ordinal scale (e.g. receiving invasive mechanical ventilation (IMV), and/or extracorporeal membrane oxygenation (ECMO)) or subjects that improved to score <5 prior to randomization.
    3. Severe neutropenia (neutrophil count <500/mm³) assessed within 18 hours prior to start of treatment.
    4. Thrombocytopenia (platelet count <30,000/mm³) assessed within 18 hours prior to start of treatment.
    5. Hemoglobin <7g/dL assessed within 18 hours prior to start of treatment.
    6. Known hemolysis.
    7. Known thrombosis or 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 the previous 3 months or those subjects particularly at risk for TEEs (e.g. history of thrombophilia, permanent immobilization, or permanent paralysis of the lower extremities) caused by other reasons than COVID-19.
    8. Subject on dialysis or with severe renal impairment, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² assessed within 18 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. 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.
    15. Known treatment for thorax/head/neck/hematologic malignancies in the last 12 months.
    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. Obesity (body mass index ≥40 kg/m²), a body weight of more than 123 kg, or anorexia (body mass index <16 kg/m²).
    E.5 End points
    E.5.1Primary end point(s)
    The composite endpoint is evaluated on day 29 [+3]
    E.5.1.1Timepoint(s) of evaluation of this end point
    Included in E.5.1
    Clinical deterioration rate (score =6-7) between day 6 and day 29
    28-day all-cause mortality rate (score =8) between day 1 and day 29
    E.5.2Secondary 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
    • Time to clinical deterioration (change to score 6-7, day 6-29)
    • Time to clinical deterioration (change to score 6-7, day 1-29)
    • Time to mortality (change to score =8)
    • Proportion of subjects in each of the 9-categories of the ordinal scale on days 7, 14, 21, 29
    • Time to clinical improvement to score =4 until day 29
    • Time to clinical improvement to score =3 until day 29
    • Time to recovery to score ≤2 until day 29
    • Proportion of subjects with score ≤2 on day 29
    • Days of IMV
    • Days without oxygen supply until day 29
    • Time to discontinuation from any form of oxygen supply
    • Proportion of subjects without any form of oxygen supply on day 29
    • Intensive care unit (ICU)-free days until day 29
    • Hospital-free days until day 29
    • Time to SARS-CoV-2 negative status

    Secondary safety endpoints:
    • Number, severity, causality, outcome, and seriousness of all adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest, 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 SAEs through day 29 [+3]
    • Dose modifications (incl. reductions and changes in infusion rate)
    • Distribution and changes over time for safety and vital signs parameters, and of overall evaluation of ECG and of ECG parameters

    Secondary pharmacokinetic endpoints:
    Changes from baseline, during and after treatment:
    • Serum concentration of IgM, IgA, and IgG

    Secondary pharmaodynamic endpoints:
    Changes from baseline, during and after treatment:
    • Markers for inflammation
    • Complement factors
    E.5.2.1Timepoint(s) of evaluation of this end point
    Included in E.5.2
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    France
    Russian Federation
    Spain
    Sweden
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial 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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 64
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Some subjects will be unable to give consent themselves. Consent can be given on their behalf by a legally authorized representative or in an emergency situation without prior consent, if in accordance with local requirements and approved by IEC.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 114
    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 Decision2020-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-06-29
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