<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/NCT03013322</url>
  </required_header>
  <id_info>
    <org_study_id>D.10060224</org_study_id>
    <nct_id>NCT03013322</nct_id>
  </id_info>
  <brief_title>Anticholium® Per Se</brief_title>
  <official_title>Anticholium® Per Se a Randomized, Double-blind, Placebo-controlled, Monocentric Trial on the Adjunctive Use of Physostigmine Salicylate (Anticholium®) in Perioperative Sepsis and Septic Shock</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Heidelberg</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital Heidelberg</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to&#xD;
      assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20&#xD;
      patients with perioperative sepsis and septic shock as a result of intra-abdominal infection&#xD;
      are enrolled. According to randomization, participants are treated with physostigmine&#xD;
      salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean&#xD;
      Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive&#xD;
      care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome&#xD;
      measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics&#xD;
      study investigates plasma concentrations of physostigmine and its metabolite eseroline.&#xD;
      Further analyses will contribute to the understanding of the role of various cytokines in the&#xD;
      pathophysiology of human sepsis. A computer-generated list is used for blocked randomization.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 28, 2015</start_date>
  <completion_date type="Actual">February 18, 2017</completion_date>
  <primary_completion_date type="Actual">February 18, 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>mean Sequential Organ Failure Assessment (SOFA) score</measure>
    <time_frame>up to 14 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h after continuous infusion is commenced</time_frame>
    <description>The mean SOFA score (at least two individual values) during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome in critically ill patients with perioperative sepsis and septic shock due to intra-abdominal infection.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>duration of artificial ventilation</measure>
    <time_frame>up to 90 d</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of intensive care</measure>
    <time_frame>up to 90 d</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>length of stay</measure>
    <time_frame>up to 90 d</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>30-day mortality</measure>
    <time_frame>30 d</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>90-day mortality</measure>
    <time_frame>90 d</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>arterial blood gas analyses</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>central venous blood gas analyses</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>partial pressure of arterial oxygen (PaO2)</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>fraction of inspired oxygen (FiO2)</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>platelet count</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>leukocyte count</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>creatinine</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>urea</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>total bilirubin</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-reactive protein</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>prothrombin time</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>D-dimer</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>procalcitonin</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL-6</measure>
    <time_frame>up to 30 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 14 d±8 h, 28 d±8 h, 30 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>thrombin-antithrombin complex</measure>
    <time_frame>up to 30 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 14 d±8 h, 28 d±8 h, 30 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mean blood pressure</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>frequency of vasopressors</measure>
    <time_frame>up to 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of vasopressors</measure>
    <time_frame>up to 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>frequency of renal replacement therapy</measure>
    <time_frame>up to 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of renal replacement therapy</measure>
    <time_frame>up to 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glasgow Coma Scale (GCS) score</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute Physiology And Chronic Health Evaluation (APACHE) II score</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Simplified Acute Physiology Score (SAPS) II score</measure>
    <time_frame>up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>occurrence of side effects</measure>
    <time_frame>up to 6 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h after continuous infusion is commenced</time_frame>
    <description>nausea or vomiting, clinically relevant changes in heart rate or blood pressure (mainly hypotension), and clinically relevant changes in airway resistance (mainly bronchiospasms as a result of hypersensitivity reactions to the sodium metabisulfite contained in the investigational medicinal product spontaneous breathing: acute dyspnea or artificial ventilation: clinically relevant decline in respiratory volume at constant pressure settings, or clinically relevant incline in peak or inspiratory pressures at constant respiratory volumes)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>microbiological analyses of potential pathogens including susceptibility tests</measure>
    <time_frame>up to 90 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>plasma concentrations of physostigmine</measure>
    <time_frame>up to 6 d, assessed 3±2 min after study med, end of initial ±2 min, 10, 20, 30±2 min, 1 h±10 min, 2 h±30 min, 24, 48, 72, 96, 120±2 h after continuous (end of study med), 10, 20, 30±2 min, 1, 2 h±10 min after end of study med, 6 d ± 4 h after continuous</time_frame>
    <description>determined with a validated high-performance liquid chromatography (HPLC) method</description>
  </other_outcome>
  <other_outcome>
    <measure>plasma concentrations of eseroline</measure>
    <time_frame>up to 6 d, assessed 3±2 min after study med, end of initial ±2 min, 10, 20, 30±2 min, 1 h±10 min, 2 h±30 min, 24, 48, 72, 96, 120±2 h after continuous (end of study med), 10, 20, 30±2 min, 1, 2 h±10 min after end of study med, 6 d ± 4 h after continuous</time_frame>
    <description>determined with a validated high-performance liquid chromatography (HPLC) method</description>
  </other_outcome>
  <other_outcome>
    <measure>acetylcholinesterase activity</measure>
    <time_frame>up to 6 d, assessed 1 h±10 min, 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h after continuous infusion is commenced</time_frame>
    <description>determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)</description>
  </other_outcome>
  <other_outcome>
    <measure>butyrylcholinesterase activity</measure>
    <time_frame>up to 6 d, assessed 1 h±10 min, 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h after continuous infusion is commenced</time_frame>
    <description>determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Shock, Septic</condition>
  <condition>Sepsis</condition>
  <condition>Perioperative Period</condition>
  <arm_group>
    <arm_group_label>Treatment Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The treatment group receives an infusion of 0.04 mg/kg physostigmine salicylate with a maximum dose of 4 mg. The infusion is administered at 0.4 mg/min (= 1 mL/min = 60 mL/h). The initial dose is followed by a continuous infusion of 0.017 mg/min, i.e. 1 mg/h (= 0.042 mL/min = 2.5 mL/h) for 2-5 days, i.e. 48-120 hours (treatment phase).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The placebo group is treated with 0.9% sodium chloride.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Physostigmine</intervention_name>
    <arm_group_label>Treatment Group</arm_group_label>
    <other_name>Anticholium</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isotonic Saline</intervention_name>
    <arm_group_label>Placebo Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria&#xD;
&#xD;
          -  Age 18-85 years&#xD;
&#xD;
          -  APACHE II score &lt;34&#xD;
&#xD;
          -  Intra-abdominal infection&#xD;
&#xD;
               -  findings of diffuse peritonitis or a circumscribed abscess&#xD;
&#xD;
          -  Perioperative sepsis&#xD;
&#xD;
               -  and secure evidence of infection, clinically backed up or secured&#xD;
                  microbiologically&#xD;
&#xD;
               -  ≥2 of the following four criteria:&#xD;
&#xD;
                    -  fever ≥38.0° C or hypothermia ≤36.0° C secured by rectal intravesical or&#xD;
                       intravascular measurement&#xD;
&#xD;
                    -  tachycardia ≥90/min&#xD;
&#xD;
                    -  tachypnea ≥20/min or hyperventilation secured by arterial blood gas analysis&#xD;
                       with PaCO2 ≤4.3 kPa or 33 mmHg or mechanical artificial respiration&#xD;
&#xD;
                    -  leukocytosis ≥12,000/mm³ or leukopenia ≤4000/mm³ or ≥10% immature&#xD;
                       neutrophils in the differential count&#xD;
&#xD;
          -  Shock (&lt;24 h duration): necessary use of vasopressors despite adequate fluid&#xD;
             resuscitation to keep systolic blood pressure ≥90 mmHg or mean blood pressure ≥70 mmHg&#xD;
&#xD;
          -  No more than one planned and/or one emergency basis/as an emergency procedure&#xD;
             performed since admission (no repeated revisions)&#xD;
&#xD;
          -  No infaust prognosis of a primary or concomitant illness, expecting the death within&#xD;
             the follow-up phase&#xD;
&#xD;
          -  No do-not-resuscitate order&#xD;
&#xD;
          -  Written informed consent of full-age patients/their legal guardian to participate&#xD;
             [written consent (according to AMG § 40 (1) 3b)] and unable to consent adults [§ 41&#xD;
             (1) 2 AMG)]&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
          -  Known hypersensitivity to physostigmine salicylate, sodium metabisulfite, sodium EDTA,&#xD;
             or any of the other ingredients of Anticholium®&#xD;
&#xD;
          -  Known contraindications against Anticholium®: gangrene, coronary artery disease&#xD;
&#xD;
          -  Known absolute contraindications against Anticholium®: myotonic dystrophy;&#xD;
             depolarization block by depolarizing muscle relaxants; intoxication by &quot;irreversibly&#xD;
             acting&quot; cholinesterase inhibitors; closed craniocerebral trauma; obstruction in the&#xD;
             gastrointestinal tract (mechanical constipation); obstruction in the urinary tract&#xD;
             (mechanical urinary retention)&#xD;
&#xD;
          -  Known relative contraindications against Anticholium®: bronchial asthma; bradycardia;&#xD;
             AV-conduction disturbances&#xD;
&#xD;
          -  Having undergone splenectomy&#xD;
&#xD;
          -  Having undergone solid organ transplantation&#xD;
&#xD;
          -  Positive pregnancy test, pregnancy, and lactation&#xD;
&#xD;
          -  Participation in another clinical trial, according to AMG or the follow-up phase of&#xD;
             another study, according to AMG&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Johannes B Zimmermann, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital Heidelberg</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Heidelberg</name>
      <address>
        <city>Heidelberg</city>
        <state>Baden-Württemberg</state>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>January 1, 2017</study_first_submitted>
  <study_first_submitted_qc>January 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 6, 2017</study_first_posted>
  <last_update_submitted>January 25, 2018</last_update_submitted>
  <last_update_submitted_qc>January 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 29, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Heidelberg</investigator_affiliation>
    <investigator_full_name>Johannes Zimmermann</investigator_full_name>
    <investigator_title>Dr. med. Johannes B. Zimmermann, MSc</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Shock, Septic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Physostigmine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03013322
org study id: D.10060224
nct id: NCT03013322
lead sponsor: 
has dmc: No
Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to
      assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20
      patients with perioperative sepsis and septic shock as a result of intra-abdominal infection
      are enrolled. According to randomization, participants are treated with physostigmine
      salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean
      Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive
      care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome
      measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics
      study investigates plasma concentrations of physostigmine and its metabolite eseroline.
      Further analyses will contribute to the understanding of the role of various cytokines in the
      pathophysiology of human sepsis. A computer-generated list is used for blocked randomization.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: mean Sequential Organ Failure Assessment (SOFA) score
time frame: up to 14 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h after continuous infusion is commenced
description: The mean SOFA score (at least two individual values) during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome in critically ill patients with perioperative sepsis and septic shock due to intra-abdominal infection.
measure: duration of artificial ventilation
time frame: up to 90 d
measure: duration of intensive care
time frame: up to 90 d
measure: length of stay
time frame: up to 90 d
measure: 30-day mortality
time frame: 30 d
measure: 90-day mortality
time frame: 90 d
measure: arterial blood gas analyses
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: central venous blood gas analyses
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: partial pressure of arterial oxygen (PaO2)
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: fraction of inspired oxygen (FiO2)
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: platelet count
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: leukocyte count
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: creatinine
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: urea
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: total bilirubin
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: C-reactive protein
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: prothrombin time
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: D-dimer
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: procalcitonin
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: IL-6
time frame: up to 30 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 14 d±8 h, 28 d±8 h, 30 d±8 h after continuous infusion is commenced
measure: thrombin-antithrombin complex
time frame: up to 30 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 14 d±8 h, 28 d±8 h, 30 d±8 h after continuous infusion is commenced
measure: mean blood pressure
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: frequency of vasopressors
time frame: up to 90 days
measure: duration of vasopressors
time frame: up to 90 days
measure: frequency of renal replacement therapy
time frame: up to 90 days
measure: duration of renal replacement therapy
time frame: up to 90 days
measure: Glasgow Coma Scale (GCS) score
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: Acute Physiology And Chronic Health Evaluation (APACHE) II score
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: Simplified Acute Physiology Score (SAPS) II score
time frame: up to 90 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h, 7 d±4 h, 8 d±8 h, 9 d±8 h, 10 d±8 h, 11 d±8 h, 12 d±8 h, 13 d±8 h, 14 d±8 h, 28 d±8 h, 30 d±8 h, 84 d±8 h, 90 d±8 h after continuous infusion is commenced
measure: occurrence of side effects
time frame: up to 6 d, assessed 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h after continuous infusion is commenced
description: nausea or vomiting, clinically relevant changes in heart rate or blood pressure (mainly hypotension), and clinically relevant changes in airway resistance (mainly bronchiospasms as a result of hypersensitivity reactions to the sodium metabisulfite contained in the investigational medicinal product spontaneous breathing: acute dyspnea or artificial ventilation: clinically relevant decline in respiratory volume at constant pressure settings, or clinically relevant incline in peak or inspiratory pressures at constant respiratory volumes)
measure: microbiological analyses of potential pathogens including susceptibility tests
time frame: up to 90 days
measure: plasma concentrations of physostigmine
time frame: up to 6 d, assessed 3±2 min after study med, end of initial ±2 min, 10, 20, 30±2 min, 1 h±10 min, 2 h±30 min, 24, 48, 72, 96, 120±2 h after continuous (end of study med), 10, 20, 30±2 min, 1, 2 h±10 min after end of study med, 6 d ± 4 h after continuous
description: determined with a validated high-performance liquid chromatography (HPLC) method
measure: plasma concentrations of eseroline
time frame: up to 6 d, assessed 3±2 min after study med, end of initial ±2 min, 10, 20, 30±2 min, 1 h±10 min, 2 h±30 min, 24, 48, 72, 96, 120±2 h after continuous (end of study med), 10, 20, 30±2 min, 1, 2 h±10 min after end of study med, 6 d ± 4 h after continuous
description: determined with a validated high-performance liquid chromatography (HPLC) method
measure: acetylcholinesterase activity
time frame: up to 6 d, assessed 1 h±10 min, 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h after continuous infusion is commenced
description: determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)
measure: butyrylcholinesterase activity
time frame: up to 6 d, assessed 1 h±10 min, 2 h±30 min, 24±2 h, 48±2 h, 72±2 h, 96±2 h, 120±2 h, 6 d±4 h after continuous infusion is commenced
description: determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)
arm group label: Treatment Group
arm group type: Active Comparator
description: The treatment group receives an infusion of 0.04 mg/kg physostigmine salicylate with a maximum dose of 4 mg. The infusion is administered at 0.4 mg/min (= 1 mL/min = 60 mL/h). The initial dose is followed by a continuous infusion of 0.017 mg/min, i.e. 1 mg/h (= 0.042 mL/min = 2.5 mL/h) for 2-5 days, i.e. 48-120 hours (treatment phase).
arm group label: Placebo Group
arm group type: Placebo Comparator
description: The placebo group is treated with 0.9% sodium chloride.
intervention type: Drug
intervention name: Physostigmine
arm group label: Treatment Group
other name: Anticholium
intervention type: Drug
intervention name: Isotonic Saline
arm group label: Placebo Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Johannes B Zimmermann, MD, MSc
role: Principal Investigator
affiliation: University Hospital Heidelberg
facility: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: University Hospital Heidelberg
investigator full name: Johannes Zimmermann
investigator title: Dr. med. Johannes B. Zimmermann, MSc
mesh term: Sepsis
mesh term: Shock, Septic
mesh term: Physostigmine
sharing ipd: Undecided