<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03803007</url>
  </required_header>
  <id_info>
    <org_study_id>ACT-CS-002</org_study_id>
    <secondary_id>2018-002855-13</secondary_id>
    <nct_id>NCT03803007</nct_id>
  </id_info>
  <brief_title>Acute Ischemic Stroke Interventional Study</brief_title>
  <acronym>ACTIMIS</acronym>
  <official_title>Randomized, Double Blind, Multi Center, Multinational, Placebo Controlled, Single Parallel Escalating Dose Safety and Efficacy Study of ACT017 Used as an Add on Therapy on Top of Standard of Care of Acute Ischemic Stroke</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Acticor Biotech</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Acticor Biotech</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To assess safety of single IV (bolus + infusion) doses of ACT017 in patients with an acute&#xD;
      ischemic stroke in addition to best emergency standard of care (including fibrinolysis by&#xD;
      rtPA with or without added thrombectomy), with a specific focus on hemorrhage, whether&#xD;
      clinically symptomatic (NIHSS score + 4 points or death, without other explanation), or seen&#xD;
      (excluding other diagnoses) on 24-hour (hr) CT scan, serious adverse events (SAEs), suspected&#xD;
      unexpected serious adverse reactions (SUSARs), and medically important events and other&#xD;
      safety items including biological and immunological tolerability.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This first in-patient randomized, double blind, multicenter, multinational,&#xD;
      placebo-controlled, parallel-dose 2-phase study combines a dose-escalation phase (1b) and a&#xD;
      consolidation phase (2a).&#xD;
&#xD;
      Dose Escalation (Phase 1b):&#xD;
&#xD;
      Phase 1b was designed to (I) assess the dose- related safety and potential efficacy of&#xD;
      glenzocimab administered as soon as possible and no later than 3 hours after the start of&#xD;
      thrombolysis with tPA (itself administered within 4.5 hrs of the onset of acute ischemic&#xD;
      stroke symptoms), and (II) identify the recommended phase 2 dose (RP2D).&#xD;
&#xD;
      During this phase, patients were unevenly randomized between groups, to obtain a total of 60&#xD;
      patients, 12 at each dose level. At the starting level, 8 patients received either&#xD;
      glenzocimab at the lowest pharmacologically active dose of 125 mg (n=4) or the matching&#xD;
      placebo(n=4). After real-time review by the DSMB of clinical safety and a CT scan (and where&#xD;
      available MRI) and giving a favorable opinion, the next patients were randomized in the&#xD;
      second cohort (n=8) with 4 patients under a higher dose of 250 mg, 2 patients remaining at&#xD;
      the initial starting dose (125 mg), and 2 patients under placebo. Following the same process,&#xD;
      and after favorable opinion from the DSMB, patients were randomized in the third cohort&#xD;
      (n=10) and received glenzocimab 500 mg (n=4), randomized versus 250 mg (n=2), 125 mg (n=2) or&#xD;
      placebo (n=2). Similarly, the fourth cohort (n=12) randomized patients between ahigher dose&#xD;
      of 1000 mg (n=4), versus 500 mg (n=2), 250 mg (n=2), 125 mg (n=2), or placebo (n=2). Once&#xD;
      this fourth cohort completed, the DSMB issued a further positive opinion and the fifth cohort&#xD;
      (n=22) randomized patients to 1000 mg (n=8), versus 500 mg (n=6), 250 mg (n=4), 125 mg (n=2),&#xD;
      or placebo (n=2).&#xD;
&#xD;
      Consolidation Phase with Final Dose (Phase 2a):&#xD;
&#xD;
      After having reviewed patient's safety data included in the first part of the study, the DSMB&#xD;
      confirmed that the study can continue with the glenzocimab recommended dose of 1000 mg.&#xD;
      During this phase, a group of 100 patients will be treated, 50 with glenzocimab and 50 with&#xD;
      matching placebo to complete the group of 160 patients planned to participate in this study.&#xD;
&#xD;
      In addition, patients in each treatment arm will be stratified by type of Standard of Care&#xD;
      (SOC) administered:&#xD;
&#xD;
        -  Thrombolysis with tPA only;&#xD;
&#xD;
        -  Thrombolysis with tPA AND mechanical thrombectomy Each treatment arm will contain 25&#xD;
           patients with one SOC, and 25 with the other SOC. The active glenzocimab dose will be&#xD;
           that recommended after the last safety analysis has been performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 6, 2019</start_date>
  <completion_date type="Actual">September 27, 2021</completion_date>
  <primary_completion_date type="Actual">September 27, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>The phase Ib of the study with a sequential design has been achieved (5 arms). The second phase IIa is ongoing. The selected dose (1000mg) for this second part will be compared to placebo (2 arms) with a parallel design.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Symptomatic intracranial haemorrhages</measure>
    <time_frame>24 hours</time_frame>
    <description>Number of participants experiencing a symptomatic haemorrhage defined by a secondary increase in National Institute Health Stroke Scale score by 4 points or greater, or death</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of non-symptomatic intracranial haemorrhages</measure>
    <time_frame>24 hours</time_frame>
    <description>Non-symptomatic haemorrhages are those detected by Computerized Tomography scan</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline of National Institute Health Stroke Scale score (7 minimum, 42 maximum), brain lesions and vessel recanalization</measure>
    <time_frame>24 hours</time_frame>
    <description>Absolute change from baseline of National Institute Health Stroke Scale score, change from baseline on brain lesions as assessed by Computerized Tomography scan or Magnetic Resonance Imaging or Magnetic Resonance Angiography, change from baseline on Recanalization as measured by the modified Thrombolysis In Cerebral Infarction score (0 minimum, 3 maximum) on Magnetic Resonance Angiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline of National Institute Health Stroke Scale score (7 minimum, 42 maximum), brain lesions and vessel recanalization</measure>
    <time_frame>24 hours</time_frame>
    <description>Relative (%) change from baseline of National Institute Health Stroke Scale score, change from baseline on brain lesions as assessed by Computerized Tomography scan or Magnetic Resonance Imaging or Magnetic Resonance Angiography, change from baseline on Recanalization as measured by the modified Thrombolysis In Cerebral Infarction score (0 minimum, 3 maximum) on Magnetic Resonance Angiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline of modified Ranking Scale score assessment</measure>
    <time_frame>Day 90</time_frame>
    <description>modified Ranking Scale score (0 minimum and 6 maximum): number of patients with favorable outcome (score 0-2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline of modified Ranking Scale score assessment</measure>
    <time_frame>Day 90</time_frame>
    <description>modified Ranking Scale score (0 minimum and 6 maximum): percentage of patients with favorable outcome (score 0-2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on size of infarct zone</measure>
    <time_frame>Day 7</time_frame>
    <description>Change from baseline on size of infarct zone assessed by a central Magnetic Resonance Imaging review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on vital signs</measure>
    <time_frame>6 hours, 24 hours, Day 7, Day 30 and Day 90</time_frame>
    <description>Change from baseline on systolic and diastolic blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on vital signs</measure>
    <time_frame>6 hours, 24 hours, Day 7, Day 30 and Day 90</time_frame>
    <description>Change from baseline on heart rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on clinical laboratory assessments</measure>
    <time_frame>Day 90</time_frame>
    <description>Change from baseline on plasma haemoglobin level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on clinical laboratory assessments</measure>
    <time_frame>Day 90</time_frame>
    <description>Change from baseline on platelet count</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on clinical laboratory assessments</measure>
    <time_frame>Day 90</time_frame>
    <description>Change from baseline on serum glucose concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on clinical laboratory assessments</measure>
    <time_frame>Day 90</time_frame>
    <description>Change from baseline on serum creatinine concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline on ElectroCardioGram (ECG)</measure>
    <time_frame>24 hours and Day 90</time_frame>
    <description>Change from baseline on 12-lead ElectroCardioGram (ECG)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evidence of anti-ACT017 antibodies (ADA)</measure>
    <time_frame>Day 30 and Day 90</time_frame>
    <description>To assess evidence of anti-ACT017 antibodies (ADA) as a possible to ACT017 administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics on ACT017 plasma concentration</measure>
    <time_frame>30 minutes, 9 hours and 24 hours</time_frame>
    <description>Change from baseline on ACT017 plasma concentration</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">160</enrollment>
  <condition>Acute Ischemic Stroke</condition>
  <arm_group>
    <arm_group_label>Intravenous glenzocimab (ACT017) 1000 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intravenous glenzocimab (ACT017) 1000 mg to be added to a tissue plasminogen activator +/- mechanical thrombectomy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intravenous Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Intravenous Placebo to be added to a tissue plasminogen activator +/- mechanical thrombectomy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intravenous ACT017 1000 mg</intervention_name>
    <description>Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms</description>
    <arm_group_label>Intravenous glenzocimab (ACT017) 1000 mg</arm_group_label>
    <other_name>Thrombolysis by rtPA +/- thrombectomy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Intravenous Placebo</intervention_name>
    <description>Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms</description>
    <arm_group_label>Intravenous Placebo</arm_group_label>
    <other_name>Thrombolysis by rtPA +/- thrombectomy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult male or female patients ≥ 18 years (i.e., at least 18 years old at time of&#xD;
             randomization). Extreme caution should be exercised in patients over 80 years of age&#xD;
             with regards their general health, neurological status and any concomitant diseases&#xD;
             and treatments that are likely to be more common;&#xD;
&#xD;
          2. Patients who have given written consent, legal representative consent or emergency&#xD;
             consent (including e-consent) in accordance with local legal and IECs/IRBs&#xD;
             requirements;&#xD;
&#xD;
          3. Patients presenting with an acute disabling ischemic stroke in either the anterior or&#xD;
             posterior circulation.The time of onset is known or if unknown, the last time the&#xD;
             patient was seen well, was at most 4.5 hrs before confirmation of the diagnosis&#xD;
             enabling the initiation of alteplase administration within this time-frame;&#xD;
&#xD;
          4. Patients presenting at least a NIHSS ≥ 6 prior to thrombolysis with tPA;&#xD;
&#xD;
          5. Patients eligible for, or administered thrombolysis treatment with tPA;&#xD;
&#xD;
          6. Patients who can undergo mechanical thrombectomy if eligible;&#xD;
&#xD;
          7. Patients affiliated to social security insurance (if applicable, in accordance to&#xD;
             local regulations);&#xD;
&#xD;
          8. Effective birth control method should be used for at least the next 2 months by women,&#xD;
             and 4 months by men after IMP administration; birth control methods considered to be&#xD;
             highly effective include:&#xD;
&#xD;
               -  intrauterine device&#xD;
&#xD;
               -  intrauterine hormone-releasing system&#xD;
&#xD;
               -  bilateral tubal occlusion&#xD;
&#xD;
               -  vasectomized partner&#xD;
&#xD;
               -  sexual abstinence (if applicable in accordance to local regulations)&#xD;
&#xD;
          9. Women of child-bearing potential must undergo a urinary or plasma pregnancy test with&#xD;
             negative results;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Coma, and/or NIHSS &gt;25;&#xD;
&#xD;
          2. Patients &lt; 18 years of age;&#xD;
&#xD;
          3. Prior ischemic stroke within the past 3 months with pre-stroke mRS known to be &gt; 2;&#xD;
&#xD;
          4. Baseline CT-scan evaluation: more than 1/3 of the middle cerebral artery) regions of&#xD;
             clear hypodensity on the baseline imaging;&#xD;
&#xD;
          5. Significant mass effect with midline shift;&#xD;
&#xD;
          6. Stroke of hemorrhagic origin;&#xD;
&#xD;
          7. Contra-indications to thrombolysis with tPA:&#xD;
&#xD;
               1. Patients with known hypersensitivity to the active substance alteplase or to any&#xD;
                  of its excipients;&#xD;
&#xD;
               2. Patients with a high risk of hemorrhages:&#xD;
&#xD;
                    -  significant bleeding disorder at present or within the past 6 months;&#xD;
&#xD;
                    -  known haemorrhagic diathesis (episodes within past 6 months);&#xD;
&#xD;
                    -  patients receiving effective oral anticoagulant treatment, e.g. warfarin&#xD;
                       sodium;&#xD;
&#xD;
                    -  manifest or recent severe or dangerous bleeding;&#xD;
&#xD;
                    -  known history of or suspected intra-cranial haemorrhage;&#xD;
&#xD;
                    -  any history of central nervous system lesion (i.e. trauma, intra-parenchymal&#xD;
                       neoplasm, unsecured aneurysm, intracranial or spinal surgery, vascular&#xD;
                       malformation etc..);&#xD;
&#xD;
                    -  recent (&lt; 10 days) traumatic external heart massage, obstetrical delivery,&#xD;
                       or puncture of a non-compressible blood-vessel (e.g. subclavian or jugular&#xD;
                       vein puncture);&#xD;
&#xD;
                    -  bacterial endocarditis, pericarditis;&#xD;
&#xD;
                    -  acute pancreatitis;&#xD;
&#xD;
                    -  documented ulcerative gastrointestinal disease during the past 3 months,&#xD;
                       oesophageal varices, arterial-aneurysm, arterial/venous malformations;&#xD;
&#xD;
                    -  neoplasm involving an increased risk of bleeding;&#xD;
&#xD;
                    -  severe liver disease, including hepatic failure, cirrhosis, portal&#xD;
                       hypertension (esophageal varices) and active hepatitis;&#xD;
&#xD;
                    -  major surgery or significant trauma during the past 3 months;&#xD;
&#xD;
                    -  patients receiving anti-coagulants prior to study: the inclusion may however&#xD;
                       be considered when the dose or time since the last intake of anticoagulant&#xD;
                       treatment makes residual efficacy unlikely. This should be confirmed by the&#xD;
                       appropriate tests of anticoagulant activity for the product(s) concerned to&#xD;
                       show no clinically relevant activity on the coagulation system defined as&#xD;
                       follows :&#xD;
&#xD;
                         -  INR ≤ 1.5 for vitamin K antagonists; .&#xD;
&#xD;
                         -  Low Molecular Weight Heparin (LMWH) and Unfractionated Heparin (UFH):&#xD;
                            aPPT/ACT/KCT ≤ 39 sec or their patient/witness ratio ≤ 1.2 and/or PT ≤&#xD;
                            16 sec (heparin at sub-therapeutic doses (≤ 50 IU/kg) during the&#xD;
                            mechanical thrombectomy procedure is authorized);&#xD;
&#xD;
                         -  Non-Vitamin-K or Direct Oral Anti-Coagulants (NOACs- DOACs) ≤ 50 ng/mL&#xD;
                            in patients with normal renal function;&#xD;
&#xD;
                    -  need for carotid stenting together with a dual anti-platelet treatment (on&#xD;
                       top of glenzocimab); this can be carried out 24 hrs after the initiation of&#xD;
                       treatment with glenzocimab;&#xD;
&#xD;
                    -  platelets count &lt;100 × 103/μL (&lt;100 000/ mm3)&#xD;
&#xD;
                    -  prior hemorrhagic stroke.&#xD;
&#xD;
               3. Systolic blood pressure ≥ 185 mm Hg despite appropriate acute therapy to lower&#xD;
                  blood pressure therapy;&#xD;
&#xD;
               4. Diastolic blood pressure ≥ 110 mm Hg; despite appropriate acute therapy to lower&#xD;
                  blood pressure therapy;&#xD;
&#xD;
               5. Glucose &gt;400 mg/dL (&gt;4 g/L) despite treatment;&#xD;
&#xD;
               6. Glycemia &lt;50 mg/dL (&lt;0,5 g/L);&#xD;
&#xD;
          8. Patients receiving a dual antiplatelet treatment;&#xD;
&#xD;
          9. Cardiopulmonary resuscitation within the past 10 days;&#xD;
&#xD;
         10. Childbirth within the past 10 days,&#xD;
&#xD;
         11. Epileptic seizure at the onset of symptoms;&#xD;
&#xD;
         12. Life expectancy &lt; 3 months&#xD;
&#xD;
         13. Pregnant or breastfeeding;&#xD;
&#xD;
         14. Females of childbearing potential not using effective birth control methods;&#xD;
&#xD;
         15. Known severe (grade 3 and above) renal impairment or Glomerular Filtration Rate &lt; 30&#xD;
             ml/min/1.73 m2 or Serum Creatinine &gt; 2X ULN (1.2 mg/dL for men and 1.0 mg/dL for&#xD;
             women) at screening;&#xD;
&#xD;
         16. Known current participation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrea Comenducci, MD</last_name>
    <role>Study Director</role>
    <affiliation>Acticor Biotech</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Bordeaux,</name>
      <address>
        <city>Bordeau</city>
        <zip>33404</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Voors-Pette C, Lebozec K, Dogterom P, Jullien L, Billiald P, Ferlan P, Renaud L, Favre-Bulle O, Avenard G, Machacek M, Pletan Y, Jandrot-Perrus M. Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol. 2019 May;39(5):956-964. doi: 10.1161/ATVBAHA.118.312314.</citation>
    <PMID>31017822</PMID>
  </reference>
  <reference>
    <citation>Renaud L, Lebozec K, Voors-Pette C, Dogterom P, Billiald P, Jandrot Perrus M, Pletan Y, Machacek M. Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen-Induced Platelet Aggregation. J Clin Pharmacol. 2020 Sep;60(9):1198-1208. doi: 10.1002/jcph.1616. Epub 2020 Jun 4.</citation>
    <PMID>32500636</PMID>
  </reference>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>January 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>October 5, 2021</last_update_submitted>
  <last_update_submitted_qc>October 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Haemorrhages</keyword>
  <keyword>Thrombolysis</keyword>
  <keyword>Thrombectomy</keyword>
  <keyword>Anti-platelet</keyword>
  <keyword>glenzocimab</keyword>
  <keyword>ACT017</keyword>
  <keyword>stroke</keyword>
  <keyword>GPVI</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
    <mesh_term>Ischemic Stroke</mesh_term>
    <mesh_term>Cerebral Infarction</mesh_term>
    <mesh_term>Ischemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glenzocimab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03803007
org study id: ACT-CS-002
secondary id: 2018-002855-13
nct id: NCT03803007
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To assess safety of single IV (bolus + infusion) doses of ACT017 in patients with an acute
      ischemic stroke in addition to best emergency standard of care (including fibrinolysis by
      rtPA with or without added thrombectomy), with a specific focus on hemorrhage, whether
      clinically symptomatic (NIHSS score + 4 points or death, without other explanation), or seen
      (excluding other diagnoses) on 24-hour (hr) CT scan, serious adverse events (SAEs), suspected
      unexpected serious adverse reactions (SUSARs), and medically important events and other
      safety items including biological and immunological tolerability.
This first in-patient randomized, double blind, multicenter, multinational,
      placebo-controlled, parallel-dose 2-phase study combines a dose-escalation phase (1b) and a
      consolidation phase (2a).

      Dose Escalation (Phase 1b):

      Phase 1b was designed to (I) assess the dose- related safety and potential efficacy of
      glenzocimab administered as soon as possible and no later than 3 hours after the start of
      thrombolysis with tPA (itself administered within 4.5 hrs of the onset of acute ischemic
      stroke symptoms), and (II) identify the recommended phase 2 dose (RP2D).

      During this phase, patients were unevenly randomized between groups, to obtain a total of 60
      patients, 12 at each dose level. At the starting level, 8 patients received either
      glenzocimab at the lowest pharmacologically active dose of 125 mg (n=4) or the matching
      placebo(n=4). After real-time review by the DSMB of clinical safety and a CT scan (and where
      available MRI) and giving a favorable opinion, the next patients were randomized in the
      second cohort (n=8) with 4 patients under a higher dose of 250 mg, 2 patients remaining at
      the initial starting dose (125 mg), and 2 patients under placebo. Following the same process,
      and after favorable opinion from the DSMB, patients were randomized in the third cohort
      (n=10) and received glenzocimab 500 mg (n=4), randomized versus 250 mg (n=2), 125 mg (n=2) or
      placebo (n=2). Similarly, the fourth cohort (n=12) randomized patients between ahigher dose
      of 1000 mg (n=4), versus 500 mg (n=2), 250 mg (n=2), 125 mg (n=2), or placebo (n=2). Once
      this fourth cohort completed, the DSMB issued a further positive opinion and the fifth cohort
      (n=22) randomized patients to 1000 mg (n=8), versus 500 mg (n=6), 250 mg (n=4), 125 mg (n=2),
      or placebo (n=2).

      Consolidation Phase with Final Dose (Phase 2a):

      After having reviewed patient's safety data included in the first part of the study, the DSMB
      confirmed that the study can continue with the glenzocimab recommended dose of 1000 mg.
      During this phase, a group of 100 patients will be treated, 50 with glenzocimab and 50 with
      matching placebo to complete the group of 160 patients planned to participate in this study.

      In addition, patients in each treatment arm will be stratified by type of Standard of Care
      (SOC) administered:

        -  Thrombolysis with tPA only;

        -  Thrombolysis with tPA AND mechanical thrombectomy Each treatment arm will contain 25
           patients with one SOC, and 25 with the other SOC. The active glenzocimab dose will be
           that recommended after the last safety analysis has been performed.
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: The phase Ib of the study with a sequential design has been achieved (5 arms). The second phase IIa is ongoing. The selected dose (1000mg) for this second part will be compared to placebo (2 arms) with a parallel design.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Symptomatic intracranial haemorrhages
time frame: 24 hours
description: Number of participants experiencing a symptomatic haemorrhage defined by a secondary increase in National Institute Health Stroke Scale score by 4 points or greater, or death
measure: Incidence of non-symptomatic intracranial haemorrhages
time frame: 24 hours
description: Non-symptomatic haemorrhages are those detected by Computerized Tomography scan
measure: Change from baseline of National Institute Health Stroke Scale score (7 minimum, 42 maximum), brain lesions and vessel recanalization
time frame: 24 hours
description: Absolute change from baseline of National Institute Health Stroke Scale score, change from baseline on brain lesions as assessed by Computerized Tomography scan or Magnetic Resonance Imaging or Magnetic Resonance Angiography, change from baseline on Recanalization as measured by the modified Thrombolysis In Cerebral Infarction score (0 minimum, 3 maximum) on Magnetic Resonance Angiography
measure: Change from baseline of National Institute Health Stroke Scale score (7 minimum, 42 maximum), brain lesions and vessel recanalization
time frame: 24 hours
description: Relative (%) change from baseline of National Institute Health Stroke Scale score, change from baseline on brain lesions as assessed by Computerized Tomography scan or Magnetic Resonance Imaging or Magnetic Resonance Angiography, change from baseline on Recanalization as measured by the modified Thrombolysis In Cerebral Infarction score (0 minimum, 3 maximum) on Magnetic Resonance Angiography
measure: Change from baseline of modified Ranking Scale score assessment
time frame: Day 90
description: modified Ranking Scale score (0 minimum and 6 maximum): number of patients with favorable outcome (score 0-2)
measure: Change from baseline of modified Ranking Scale score assessment
time frame: Day 90
description: modified Ranking Scale score (0 minimum and 6 maximum): percentage of patients with favorable outcome (score 0-2)
measure: Change from baseline on size of infarct zone
time frame: Day 7
description: Change from baseline on size of infarct zone assessed by a central Magnetic Resonance Imaging review
measure: Change from baseline on vital signs
time frame: 6 hours, 24 hours, Day 7, Day 30 and Day 90
description: Change from baseline on systolic and diastolic blood pressure
measure: Change from baseline on vital signs
time frame: 6 hours, 24 hours, Day 7, Day 30 and Day 90
description: Change from baseline on heart rate
measure: Change from baseline on clinical laboratory assessments
time frame: Day 90
description: Change from baseline on plasma haemoglobin level
measure: Change from baseline on clinical laboratory assessments
time frame: Day 90
description: Change from baseline on platelet count
measure: Change from baseline on clinical laboratory assessments
time frame: Day 90
description: Change from baseline on serum glucose concentration
measure: Change from baseline on clinical laboratory assessments
time frame: Day 90
description: Change from baseline on serum creatinine concentration
measure: Change from baseline on ElectroCardioGram (ECG)
time frame: 24 hours and Day 90
description: Change from baseline on 12-lead ElectroCardioGram (ECG)
measure: Evidence of anti-ACT017 antibodies (ADA)
time frame: Day 30 and Day 90
description: To assess evidence of anti-ACT017 antibodies (ADA) as a possible to ACT017 administration
measure: Pharmacokinetics on ACT017 plasma concentration
time frame: 30 minutes, 9 hours and 24 hours
description: Change from baseline on ACT017 plasma concentration
arm group label: Intravenous glenzocimab (ACT017) 1000 mg
arm group type: Experimental
description: Intravenous glenzocimab (ACT017) 1000 mg to be added to a tissue plasminogen activator +/- mechanical thrombectomy
arm group label: Intravenous Placebo
arm group type: Placebo Comparator
description: Intravenous Placebo to be added to a tissue plasminogen activator +/- mechanical thrombectomy
intervention type: Drug
intervention name: Intravenous ACT017 1000 mg
description: Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms
arm group label: Intravenous glenzocimab (ACT017) 1000 mg
other name: Thrombolysis by rtPA +/- thrombectomy
intervention type: Other
intervention name: Intravenous Placebo
description: Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms
arm group label: Intravenous Placebo
other name: Thrombolysis by rtPA +/- thrombectomy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrea Comenducci, MD
role: Study Director
affiliation: Acticor Biotech
facility: 
country: France
citation: Voors-Pette C, Lebozec K, Dogterom P, Jullien L, Billiald P, Ferlan P, Renaud L, Favre-Bulle O, Avenard G, Machacek M, Pletan Y, Jandrot-Perrus M. Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol. 2019 May;39(5):956-964. doi: 10.1161/ATVBAHA.118.312314.
PMID: 31017822
citation: Renaud L, Lebozec K, Voors-Pette C, Dogterom P, Billiald P, Jandrot Perrus M, Pletan Y, Machacek M. Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen-Induced Platelet Aggregation. J Clin Pharmacol. 2020 Sep;60(9):1198-1208. doi: 10.1002/jcph.1616. Epub 2020 Jun 4.
PMID: 32500636
responsible party type: Sponsor
mesh term: Stroke
mesh term: Ischemic Stroke
mesh term: Cerebral Infarction
mesh term: Ischemia
mesh term: Glenzocimab
sharing ipd: No