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    Summary
    EudraCT Number:2018-000246-19
    Sponsor's Protocol Code Number:3-3002
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-06-14
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-000246-19
    A.3Full title of the trial
    SCARLET-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of ART-123 in Subjects with Sepsis and Coagulopathy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of ART-123 in patients with coagulopathy due to sepsis and a concurrent diagnosis of shock and/or respiratory dysfunction that requires mechanical ventilation to treat hypoxemia.
    A.4.1Sponsor's protocol code number3-3002
    A.5.4Other Identifiers
    Name:INDNumber:100334
    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 SponsorAsahi Kasei Pharma America Corporation
    B.1.3.4CountryUnited States
    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 supportAsahi Kasei Pharma America Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAsahi Kasei Pharma America Corporation
    B.5.2Functional name of contact pointMedical Monitor
    B.5.3 Address:
    B.5.3.1Street Address200 Fifth Avenue
    B.5.3.2Town/ cityWaltham, MA
    B.5.3.3Post code02451
    B.5.3.4CountryUnited States
    B.5.6E-maildfineberg@akpamerica.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 nameART-123
    D.3.2Product code ART-123
    D.3.4Pharmaceutical form Lyophilisate and solvent for 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.3.8INN - Proposed INNART-123
    D.3.9.1CAS number 120313-91-9
    D.3.9.2Current sponsor codeART-123
    D.3.9.3Other descriptive nameTHROMBOMODULIN ALFA
    D.3.9.4EV Substance CodeSUB32083
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7.2
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate and solvent for solution for injection
    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
    Sepsis, defined by the presence of infection and host inflammation, is a lethal clinical syndrome. In severe disease, the coagulation system becomes diffusely activated, with consumption of multiple clotting factors resulting in Disseminated Intravascular Coagulation (DIC).
    E.1.1.1Medical condition in easily understood language
    Sepsis has been defined as infection complicated by a systemic inflammatory response syndrome.Coagulopathy is associated with increased mortality in sepsis
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10053840
    E.1.2Term Bacterial sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10009802
    E.1.2Term Coagulopathy
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •To evaluate whether ART-123, when administered to subjects with bacterial infection complicated by at least one organ dysfunction (cardiac or respiratory)and coagulopathy, can reduce mortality.
    •To evaluate the safety of ART-123 in this population.
    E.2.2Secondary objectives of the trial
    •Assessment of the efficacy of ART-123 in resolution of organ dysfunction(ventilator, dialysis, shock) in this population.
    •Assessment of anti-drug antibody development in subjects with coagulopathy due to bacterial infection treated with ART-123.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Subjects must be receiving treatment in an ICU or in an acute care setting (e.g.,Emergency Room, Recovery Room).
    2.Subjects with either compelling evidence of infection OR clinical syndromes highly likely to be bacterial in origin, as follows:
    a.Compelling objective evidence of bacterial infection and a known site of infection. Objective evidence would be met with a grossly purulent site of infection, Gram stain evidence, culture, rapid immunoassay or genomic based rapid diagnostic assays confirming a bacterial pathogen from normally sterile fluids (blood, urine, cerebrospinal fluid (CSF), peritoneal fluid, etc.), having either:
    •White Blood Cell (WBC) count greater > 12,000/mm3 or <4,000/mm3 or > 10% bands within 36 hours of randomization
    OR
    •Temperature <36°C or fever >38°C
    b.Clinical syndromes highly likely to be bacterial in origin but not compelling
    •White Blood Cell (WBC) count greater > 12,000/mm3 or <4,000/mm3 or > 10% bands within 36 hours of randomization
    AND
    •Temperature <36°C or fever >38°C
    3.Current treatment with intravenous antibiotics for the acute bacterial infection(i.e. not prophylactic antibiotics)
    4.Subjects with sepsis associated organ dysfunction defined by at least one ofthe following:
    a.Cardiovascular Dysfunction defined as requiring both adequate fluid resuscitation and vasopressors* to maintain Mean Arterial Pressure(MAP) greater than or equal to (≥) 65 mmHg (implies fluidresuscitation alone does not raise MAP to ≥ 65 mmHg), with onset time being the time vasopressors are initiated (end of surgery if initiated in surgery), with adequate fluid resuscitation defined as:
    •Intravenous administration of at least 20 mL/kg crystalloid or 10 mL/kg colloid infusion within 6 hours.
    OR
    •Central Venous Pressure (CVP) of greater than (>) 8 mmHg or Pulmonary Artery Wedge Pressure (PAWP) of greater than ( >) 12 mmHg.
    *If dopamine is the only vasopressor used, the infusion ratemust be greater than (>) 5 μg/kg/min (i.e., must be prescribedto support cardio-pulmonary perfusion). If vasopressin is used,it must be given in conjunction with another vasopressor.
    b.Respiratory Dysfunction defined as the acute need for mechanical ventilation and PaO2/FiO2 ratio of <250 (or < 200 when lung is the site of infection), with onset time being time of intubation prior to the first qualifying PaO2:FiO2 (if intubated for surgery and unable to extubate the qualifying time is the end of surgery), with mechanical ventilation defined as any type of ventilation administered via anendotracheal or nasotracheal tube.
    5.Subjects with coagulopathy characterized by an INR >1.40 without other known etiology (e.g., anticoagulant therapy, chronic liver disease), and having an onset at the time of the first local laboratory blood draw yielding a qualifying result (point of care device INR results must be confirmed by local laboratory).
    6.Subjects with coagulopathy characterized by platelet count that meets any of the below criteria, and having an onset at the time of the first blood draw yielding a qualifying result.
    a.≥ 20,000/mm3 and < 30,000/mm3 that upon retesting after platelet transfusion is > 30,000/mm3 (qualifying at the time of the first blood draw yielding a result ≥ 20,000/mm3 and ≤ 30,000/mm3).
    b.> 30,000/mm3 to < 150,000/mm3
    c.> 30% decrease in platelet count within 24 hours
    7.First and last qualifying criteria of sepsis associated organ dysfunction, platelet count, and INR (results from local or transferring hospital) occurring in ≤ 24hours
    E.4Principal exclusion criteria
    1.Subject or Authorized Representative is unable or unwilling to provide informed consent (as applicable per local and country regulations)
    2.Subject is pregnant (positive serum or urine human Chorionic Gonadotropin(hCG)) or breastfeeding or intends to get pregnant within 28 days of enrollinginto the study
    3.Subject is < 18 years of age
    4.Body weight ≥ 175 kg
    5.Subject is unwilling to allow transfusion of blood or blood products
    6.Presence of an advance directive to withhold life-sustaining treatment except Cardiopulmonary Resuscitation, or likely to have life support withdrawn within 24 hours of consent
    7.Subject has had previous treatment with ART-123
    8.Platelet count < 20,000/ mm3 for any reason, or for platelet count ≥ 20,000/mm3and ≤ 30,000/mm3 that upon retesting after platelet transfusion does not increase > 30,000/mm3
    9.Elevated INR, leukopenia, or thrombocytopenia that is not due to sepsis, (e.g. patients treated by chemotherapy agent). Please refer to Appendix C of the protocol as an example of agents known to cause myelosuppression that should be evaluated as the potential cause of leukopenia or thrombocytopenia
    10.Inability to randomize patients in ≤ 12 hours after meeting Inclusion # 7 (onset time requirements for sepsis associated organ dysfunction, INR, and platelet count)
    11.≤ 8 hours remaining from the end of a major surgery having a high risk of post-operative bleeding and randomization (e.g. extensive intraabdominal orintrathoracic dissection, debridement of a large surface area of tissue, complications arising during surgery, problems with hemostasis during surgery, surgeries of long duration, surgeries with large estimated blood loss).
    a.Ensures all randomized surgical subjects with a high risk of post-operative bleeding can be dosed no earlier than 12 hours post-operatively, as described in Section 2.6.3. (minimum 8 hour delay before randomization and 4 hour maximum time to dose after randomization)
    12.Stroke within 3 months prior to consent, trauma or major surgery within 3 months prior to consent that may increase the risk of bleeding
    13.Known bleeding diatheses or anatomical anomaly that predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia, esophageal varices, arteriovenous malformation)
    14.Gastrointestinal bleeding (e.g. melena, hematemesis) or genitourinary bleeding within 6 weeks prior to consent unless a corrective interventional procedure has been performed (i.e. therapeutic endoscopy), or there is evidence of complete resolution
    15.Known thrombophilia or a history of deep-vein thrombosis or pulmonary embolism within 3 months prior to consent
    16.Need for full dose anticoagulation therapy other than IV unfractionated heparin discontinued > 12 hours prior to randomization, full dose or catheter directed thrombolysis, aspirin at a daily dose > 325 mg, long-acting antiplatelet drugs (e.g. clopidogrel, prasugrel, or ticagrelor), dual antiplatelet therapy, and doses of anticoagulants exceeding thromboprophylaxis doses within 72 hours prior to the first dose of study drug
    17.Acute liver failure not due to sepsis, sepsis associated acute liver failure in any patient with a history of cirrhosis, Class C Chronic liver disease (Child-Pughscore of 10-15)
    18.Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture or Gram stain consistent with bacterial infection. Also, in the opinion of the treating physician the subject is at increased risk for developing hemorrhagic pancreatitis over the duration of the study
    19.Acute renal failure not due to sepsis or chronic renal failure requiring chronic RRT (Renal Replacement Therapy)
    20.Imminent death or anticipated life expectancy < 90 days for any reason other than the acute sepsis
    21.Participation in another research study involving an investigational agent within 30 days prior to consent, or projected study participation before the Day 29 assessment post randomization
    22.Confirmed or suspected endocarditis, malaria, Pneumocystis jiroveci pneumonia, or viral infections associated with hemorrhage (e.g. dengue fever, lassa, ebola, Bolivian) during the current admission
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint:
    • 28 day (Day 29) all-cause mortality

    Primary Safety Endpoints:
    •Serious Adverse Events
    •Major Bleeding Events
    •Adverse Events
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please refer to the Schedule of Activities (SOA): Table 1: Visit Schedule and Assessments
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    •Follow-up of all-cause mortality at 3 months
    •Resolution of Organ Dysfunction through 28 days (Day 29) as measured by:
    oShock free and alive days
    oVentilator free and alive days
    oDialysis free and alive days

    Secondary Safety Endpoint:
    •Anti-drug antibodies (ADA) to ART-123
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to the Schedule of Activities (SOA): Table 1: Visit Schedule and Assessments
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA53
    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
    Australia
    Belgium
    Brazil
    Canada
    Czech Republic
    Finland
    France
    Germany
    Israel
    Netherlands
    Spain
    United Kingdom
    United States
    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
    LSLV
    The Data Monitoring Committee (DMC) will use the stopping rules regarding stopping the study early for safety or efficacy. Please refer to "10.3 Study Stopping Rules / Interim Analyses" of the protocol.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days14
    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: 640
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 160
    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 No
    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
    It is anticipated, by the very nature of the study that many subjects who will be eligible for this protocol will not be able to give fully informed consent themselves due to various reasons including sedation, unconscious state, etc.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state166
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 354
    F.4.2.2In the whole clinical trial 800
    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)
    Subjects will be contacted to obtain their survival status at 3 months (90 ± 3 Days), 6 months (180 ± 3 Days) and 12 months (360 ± 3 days) after the first dose of study drug.
    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 Decision2018-09-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-05-16
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