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Anticholium® Per Se

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ClinicalTrials.gov Identifier: NCT03013322
Recruitment Status : Completed
First Posted : January 6, 2017
Last Update Posted : January 29, 2018
Sponsor:
Information provided by (Responsible Party):
Johannes Zimmermann, University Hospital Heidelberg

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Shock, Septic Sepsis Perioperative Period Drug: Physostigmine Drug: Isotonic Saline Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : January 28, 2015
Actual Primary Completion Date : February 18, 2017
Actual Study Completion Date : February 18, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis Shock

Arm Intervention/treatment
Active Comparator: Treatment Group
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).
Drug: Physostigmine
Other Name: Anticholium

Placebo Comparator: Placebo Group
The placebo group is treated with 0.9% sodium chloride.
Drug: Isotonic Saline



Primary Outcome Measures :
  1. 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 ]
    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.


Secondary Outcome Measures :
  1. duration of artificial ventilation [ Time Frame: up to 90 d ]
  2. duration of intensive care [ Time Frame: up to 90 d ]
  3. length of stay [ Time Frame: up to 90 d ]
  4. 30-day mortality [ Time Frame: 30 d ]
  5. 90-day mortality [ Time Frame: 90 d ]
  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. 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 ]
  16. 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 ]
  17. 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 ]
  18. 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 ]
  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. frequency of vasopressors [ Time Frame: up to 90 days ]
  23. duration of vasopressors [ Time Frame: up to 90 days ]
  24. frequency of renal replacement therapy [ Time Frame: up to 90 days ]
  25. duration of renal replacement therapy [ Time Frame: up to 90 days ]
  26. 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 ]
  27. 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 ]
  28. 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 ]
  29. 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 ]
    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)


Other Outcome Measures:
  1. microbiological analyses of potential pathogens including susceptibility tests [ Time Frame: up to 90 days ]
  2. 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 ]
    determined with a validated high-performance liquid chromatography (HPLC) method

  3. 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 ]
    determined with a validated high-performance liquid chromatography (HPLC) method

  4. 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 ]
    determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)

  5. 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 ]
    determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Age 18-85 years
  • APACHE II score <34
  • Intra-abdominal infection

    • findings of diffuse peritonitis or a circumscribed abscess
  • Perioperative sepsis

    • and secure evidence of infection, clinically backed up or secured microbiologically
    • ≥2 of the following four criteria:

      • fever ≥38.0° C or hypothermia ≤36.0° C secured by rectal intravesical or intravascular measurement
      • tachycardia ≥90/min
      • tachypnea ≥20/min or hyperventilation secured by arterial blood gas analysis with PaCO2 ≤4.3 kPa or 33 mmHg or mechanical artificial respiration
      • leukocytosis ≥12,000/mm³ or leukopenia ≤4000/mm³ or ≥10% immature neutrophils in the differential count
  • Shock (<24 h duration): necessary use of vasopressors despite adequate fluid resuscitation to keep systolic blood pressure ≥90 mmHg or mean blood pressure ≥70 mmHg
  • No more than one planned and/or one emergency basis/as an emergency procedure performed since admission (no repeated revisions)
  • No infaust prognosis of a primary or concomitant illness, expecting the death within the follow-up phase
  • No do-not-resuscitate order
  • Written informed consent of full-age patients/their legal guardian to participate [written consent (according to AMG § 40 (1) 3b)] and unable to consent adults [§ 41 (1) 2 AMG)]

Exclusion criteria

  • Known hypersensitivity to physostigmine salicylate, sodium metabisulfite, sodium EDTA, or any of the other ingredients of Anticholium®
  • Known contraindications against Anticholium®: gangrene, coronary artery disease
  • Known absolute contraindications against Anticholium®: myotonic dystrophy; depolarization block by depolarizing muscle relaxants; intoxication by "irreversibly acting" cholinesterase inhibitors; closed craniocerebral trauma; obstruction in the gastrointestinal tract (mechanical constipation); obstruction in the urinary tract (mechanical urinary retention)
  • Known relative contraindications against Anticholium®: bronchial asthma; bradycardia; AV-conduction disturbances
  • Having undergone splenectomy
  • Having undergone solid organ transplantation
  • Positive pregnancy test, pregnancy, and lactation
  • Participation in another clinical trial, according to AMG or the follow-up phase of another study, according to AMG

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03013322


Locations
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Germany
University Hospital Heidelberg
Heidelberg, Baden-Württemberg, Germany, 69120
Sponsors and Collaborators
University Hospital Heidelberg
Investigators
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Principal Investigator: Johannes B Zimmermann, MD, MSc University Hospital Heidelberg
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Johannes Zimmermann, Dr. med. Johannes B. Zimmermann, MSc, University Hospital Heidelberg
ClinicalTrials.gov Identifier: NCT03013322    
Other Study ID Numbers: D.10060224
First Posted: January 6, 2017    Key Record Dates
Last Update Posted: January 29, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Sepsis
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock
Physostigmine
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Miotics
Autonomic Agents
Peripheral Nervous System Agents