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    Summary
    EudraCT Number:2020-001736-95
    Sponsor's Protocol Code Number:ACCORD-2-001,Sub2,3,4,6,5,8
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-04-23
    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 ConcernedUK - MHRA
    A.2EudraCT number2020-001736-95
    A.3Full title of the trial
    ACCORD 2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID 19 in Hospitalised Patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study for the Treatment of COVID 19 in Hospitalised Patients
    A.3.2Name or abbreviated title of the trial where available
    ACCORD 2-Treatment of COVID 19 in Hospitalised Patients
    A.4.1Sponsor's protocol code numberACCORD-2-001,Sub2,3,4,6,5,8
    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 SponsorUniversity Hospital Southampton NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsor
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Southampton NHS Foundation Trust
    B.5.2Functional name of contact pointEmma Perry
    B.5.3 Address:
    B.5.3.1Street AddressSouthampton General Hospital, Level E, Laboratory & Pathology Block, SCBR - MP138
    B.5.3.2Town/ cityTremona Road, Southampton
    B.5.3.3Post codeSO16 6YD
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailsponsor@uhs.nhs.uk
    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 nameBemcentinib
    D.3.2Product code BGB324
    D.3.4Pharmaceutical form Capsule, hard
    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 INNbemcentinib
    D.3.9.1CAS number 1037624-75-1
    D.3.9.2Current sponsor codeBGB324
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 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 nameMEDI3506
    D.3.2Product code MEDI3506
    D.3.4Pharmaceutical form Solution for injection
    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.3.9.1CAS number 2376858-66-9
    D.3.9.2Current sponsor codeMEDI3506
    D.3.9.3Other descriptive namehuman immunoglobulin (Ig) G1 monoclonal antibody (mAb)
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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: 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 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 nameacalabrutinib
    D.3.2Product code ACP-196
    D.3.4Pharmaceutical form Capsule, hard
    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 INNacalabrutinib
    D.3.9.1CAS number 1420477-60-6
    D.3.9.2Current sponsor codeACP-196
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 nameZilucoplan
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZilucoplan
    D.3.9.1CAS number 1841136-73-9
    D.3.9.2Current sponsor codeRA101495
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Yes
    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: 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 Heparin
    D.2.1.1.2Name of the Marketing Authorisation holderWockhardt UK Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameHeparin
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHeparin
    D.3.9.4EV Substance CodeAS7
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25000
    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 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 nameTD139
    D.3.4Pharmaceutical form Inhalation powder
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRefer to IMPD
    D.3.9.4EV Substance CodeAS8
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    COVID 19
    E.1.1.1Medical condition in easily understood language
    COVID 19
    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 23.0
    E.1.2Level PT
    E.1.2Classification code 10051905
    E.1.2Term Coronavirus infection
    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
    •Stage 1: To evaluate the efficacy of candidate agents as add on therapies to Standard of Care (SoC) in patients hospitalised with COVID 19 in a screening stage.

    •Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID 19 in an expansion stage.
    E.2.2Secondary objectives of the trial
    Secondary
    • To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points
    • To evaluate the number of oxygen free days.
    • To evaluate ventilator-free days and incidence and duration of any form of new ventilation use.
    • To evaluate SARS CoV 2 viral load.
    • To evaluate response rate. (see primary endpoint for definition of responder).
    • To evaluate time to discharge.
    • To evaluate overall mortality.
    • Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2),
    • To evaluate the safety of candidate agents as add on therapy to SoC in patients with COVID-19.
    • To evaluate intensive care unit (ICU) and hospitalisation length.
    • To evaluate National Early Warning Score 2 (NEWS2).
    ***********
    Additional sub protocol(ACCORD-2-002) secondary objectives
    To evaluate the pharmacokinetic exposure to bemcentinib in Covid-19
    To evaluate pharmacodynamic response to bemcentinib by circulating biomarkers (GAS6, soluble AXL
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Sub protocol(ACCORD-2-002)

    Title: ACCORD 2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID 19 in Hospitalised Patients

    Sub Protocol (ACCORD-2-003), Date: 29Apr2020, Version: Protocol Amendment 01 Final) The objectives and endpoints are as for the master protocol.

    This form is for a sub-protocol. (Title: None, Sub-protocol Number: ACCORD 2-004, Date: 1 May 2020, Version: Final) The objectives and endpoints are as for the master protocol:

    Sub-protocol ACCORD 2-006

    Sub-protocol ACCORD 2-005

    Sub-protocol ACCORD 2-008

    E.3Principal inclusion criteria
    Patients are eligible to be included in the study only if all of the following criteria apply (as well as all criteria from the appropriate sub-protocol):
    1. Adults (≥18 years) with SARS-CoV-2 infection confirmed by laboratory tests and/or point of care tests (which may include results from a test that was performed prior to hospital admission if, in the opinion of the Investigator, it is relevant to ongoing COVID-19).
    2. Patients with symptoms and/or signs consistent with COVID-19, requiring treatment.
    3. A score of Grade 3 to 5 on the 9-point ordinal scale.
    4. a) Male patients:
    • A male patient must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period.
    b) Female patients:
    • A female patient is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least 1 of the following conditions applies:
    i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
    OR
    ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 90 days after the last dose of study treatment.
    5. Women who are lactating who agree not to breastfeed their child during the study and for a fixed period of time (following guidance that will be given by the investigator as appropriate
    CONFIDENTIAL ACCORD-2-001 – Master Protocol (Amendment 02)
    Final, 02 June 2020 32
    for any candidate agent administered) after termination of study therapy (they may continue to express milk away from the child during this period, but this milk must be discarded).
    6. Ability to provide informed consent signed by the study patient or legally authorized representative.

    In addition for the sub-protocol ACCORD-2-003:
    a) Male subjects
    A male subject must agree to use contraception as detailed in Appendix 2 of this protocol during the treatment period and for at least 12 weeks after the last dose of study treatment and refrain from donating sperm during this period.
    b) Female subjects
    A female subject is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least 1 of the following conditions applies:
    i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR
    ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the treatment period and for at least 12 weeks after the last dose of study treatment

    In addition for the sub-protocol ACCORD-2-004:
    Male subjects:
    A male subject must agree to use contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 12 weeks after the last dose of study treatment and refrain from donating sperm during this period.

    A female subject is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least 1 of the following conditions applies:
    i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3.
    OR
    ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 12 weeks after the last dose of study treatment.

    In addition for the sub-protocol ACCORD-2-006:
    Antibiotic prophylaxis: PLEASE NOTE that, according to Section 4.1.1.1, all patients must take antibiotic prophylaxis concomitantly, starting with the first dose of zilucoplan.

    For Sub study ACCORD 2-005, please refer to the Master protocol.

    For Sub study ACCORD 2-008, please refer to the Master protocol.


    E.4Principal exclusion criteria
    Patients are excluded from the study if any of the following criteria apply (or any of the criteria from the appropriate sub-protocol):
    1. Patients who have previously had a score of 6 or 7 on the 9-point ordinal scale.
    2. Any patient whose interests are not best served by study participation, as determined by a senior attending clinician.
    3. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >5 × the upper limit of normal (ULN).
    4. Known active infection with HIV or hepatitis B or C.
    5. Stage 4 severe chronic kidney disease.
    6. Anticipated transfer to another hospital that is not a study centre within 72 hours.
    7. Allergy to any study medication.
    8. Experimental off-label usage of medicinal products as treatments for COVID-19 (except where the product has either been given a positive opinion under the Early Access to Medicines Scheme [EAMS] or is a SARS-CoV-2 vaccine) at the time of enrolment.
    9. Patients participating in another clinical study of an investigational medicinal product, unless co-enrolment in the other study has been pre-approved by the Steering Committee.
    10. Active tuberculosis defined as requiring current treatment for tuberculosis.

    Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-002:
    11. Inability to swallow capsules (administration via nasogastric tube is permitted in patients who become unable to swallow after starting the study drug)
    12. Patients with a permanent cardiac pacemaker implanted.
    13. History of the following cardiac conditions:
    a) Myocardial infarction within 3 months prior to the first dose
    b) Unstable angina
    c) History of clinically significant dysrhythmias (long QT features on ECG, sustained bradycardia [≤55 bpm]), left bundle branch block, or ventricular arrhythmia) or history of familial long QT.
    Patients with an implantable cardioverter defibrillator device in place, will be allowed to enrol. Atrial fibrillation will not be a reason for exclusion.
    14. Screening 12-lead ECG with a measurable QTc interval according to Fridericia correction (QTcF) >470 msec
    In the presence of a temporary cardiac pacemaker, QTcF will need to be calculated from an ECG which has been recorded during a period where ventricular (QRS) complexes without pacing are present. If no unpaced ventricular complexes are present to allow calculation of QTcF, the patient should not be enrolled in this sub-protocol.
    15. Clinically significant hypokalaemia. Individuals who do not meet this criterion may be rescreened once, after correction of electrolyte abnormality
    16. Therapeutic anticoagulation with vitamin K antagonists. Note: Patients receiving low doses prescribed to maintain
    the patency of venous access devices may be included.
    17. Previous bowel resection that would interfere with drug absorption


    Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-003:
    18. Active tuberculosis defined as requiring current treatment for tuberculosis
    Active tuberculosis defined as requiring current treatment for tuberculosis
    19. A known family history of heart failure defined as either of the following:
    a) ≥2 first degree relatives with clinically significant heart failure, or
    b) ≥1 first degree relative with heart failure known to be heritable (eg, hypertrophic cardiomyopathy), unless inheritance was previously excluded by genetic testing
    Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-004:
    • Unable to take acalabrutinib by mouth
    • Profound neutropenia and/or profound thrombocytopenia as defined as an absolute neutrophil count < 500/µL and platelet count < 50,000/µL respectively at screening per local laboratory

    Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-006:

    20.Participants with unresolved or suspected infection with Neisseria meningitidis, or a past history of Neisseria meningitidis (eg, in a complement deficient patient), should not receive treatment with zilucoplan.

    For Sub study ACCORD 2-005, please refer to the Master protocol.

    For Sub study ACCORD 2-008, please refer to the Master protocol.
    E.5 End points
    E.5.1Primary end point(s)
    •Time to sustained clinical improvement of at least 2 points (from randomisation) on a 9 point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses).

    9-point category ordinal scale:
    0. Uninfected, no clinical or virological evidence of infection
    1. Ambulatory, no limitation of activities
    2. Ambulatory, limitation of activities
    3. Hospitalised – mild disease, no oxygen therapy
    4. Hospitalised – mild disease, oxygen by mask or nasal prongs
    5. Hospitalised – severe disease, noninvasive ventilation or high flow oxygen
    6. Hospitalised – severe disease, intubation and mechanical ventilation
    7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO)
    8. Death
    ***************
    Sub-protocol-ACCORD-2-002: As defined in Master Protocol.
    E.5.1.1Timepoint(s) of evaluation of this end point
    As defined in Main protocol

    Sub-protocol-ACCORD-2-003:
    Day 29
    E.5.2Secondary end point(s)
    Secondary Endpoints
    • The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, and 29.
    • Duration (days) of oxygen use and oxygen free days.
    • Duration (days) of ventilation and ventilation-free days.
    • Incidence of any form of new ventilation use and duration (days) of new ventilation use.
    • Duration (days) of organ support.
    • Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) in oropharyngeal/nasal swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and 29
    •Response rate (number and %) by treatment arm at Days 2, 8, 15, 22, and 29.
    • Time to live discharge from the hospital.
    • Mortality at Days 15, 29, and 60.
    • Time from treatment start date to death.
    •SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death
    • Physical examination.
    • Clinical laboratory examinations.
    • Vital signs (blood pressure/heart rate/temperature/respiratory rate).
    • Adverse events.
    •Duration (days) of ICU and hospitalisation.
    •NEWS2 assessed daily while hospitalised and on Days 15 and 29.
    •Time to a NEWS2 of ≤2, maintained for at least 24 hours.
    • Ranked trajectory over 29 days, with trajectory ranked as defined in the protocol.
    *************
    Secondary endpoints in the Master Protocol, will be considered as key secondary endpoints for the purposes of this sub-protocol.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Master protocol ACCORD-2-001:
    As defined in Main Protocol

    Sub-protocol ACCORD-2-002:
    PK/PD: blood samples will be analysed for plasma bemcentinib and metabolites and soluble AXL, GAS6 and other blood proteins at pre-dose (Day 1); pre-dose and 6 hours postdose (Day 4), and predose on Days 8 and 15.

    Sub-protocol ACCORD-2-003:
    As described 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 Yes
    E.6.11Pharmacogenomic Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    SOC control arm
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    SOC control arm
    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 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 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

    For each sub protocol, the end of the study for that candidate agent will be defined as the date on which the last patient completes the last visit for that sub protocol.
    For the overall study, the end of the study will be defined as the date on which the last patient completes the last visit for the final sub protocol to be concluded.
    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
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months0
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    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 No
    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 state825
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 825
    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)
    Treatment after the End of the Study

    Please refer to Master Protocol.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-24
    P. End of Trial
    P.End of Trial StatusOngoing
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