Anticholium® Per Se

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

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Shock, Septic; Perioperative Period
• Intervention / Treatment: Drug: Physostigmine; Drug: Isotonic Saline

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • University Hospital Heidelberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Anticholium
Placebo Comparator: Placebo Group; The placebo group is treated with 0.9% sodium chloride.	Drug: Isotonic Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean Sequential Organ Failure Assessment (SOFA) score	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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
duration of artificial ventilation		up to 90 d
duration of intensive care		up to 90 d
length of stay		up to 90 d
30-day mortality		30 d
90-day mortality		90 d
arterial blood gas analyses		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
central venous blood gas analyses		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
partial pressure of arterial oxygen (PaO2)		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
fraction of inspired oxygen (FiO2)		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
platelet count		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
leukocyte count		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
creatinine		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
urea		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
total bilirubin		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
C-reactive protein		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
prothrombin time		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
D-dimer		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
procalcitonin		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
IL-6		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
thrombin-antithrombin complex		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
mean blood pressure		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
frequency of vasopressors		up to 90 days
duration of vasopressors		up to 90 days
frequency of renal replacement therapy		up to 90 days
duration of renal replacement therapy		up to 90 days
Glasgow Coma Scale (GCS) score		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
Acute Physiology And Chronic Health Evaluation (APACHE) II score		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
Simplified Acute Physiology Score (SAPS) II score		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
occurrence of side effects	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)	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
microbiological analyses of potential pathogens including susceptibility tests		up to 90 days
plasma concentrations of physostigmine	determined with a validated high-performance liquid chromatography (HPLC) method	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
plasma concentrations of eseroline	determined with a validated high-performance liquid chromatography (HPLC) method	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
acetylcholinesterase activity	determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)	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
butyrylcholinesterase activity	determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)	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

Collaborators and Investigators

• Sponsor: University Hospital Heidelberg
• Investigators: Principal Investigator: Johannes B Zimmermann, MD, MSc, University Hospital Heidelberg

Publications and helpful links

General Publications

• Pinder N, Zimmermann JB, Gastine S, Wurthwein G, Hempel G, Bruckner T, Hoppe-Tichy T, Weigand MA, Swoboda S. Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling. Biomed Pharmacother. 2019 Oct;118:109318. doi: 10.1016/j.biopha.2019.109318. Epub 2019 Aug 6.
• Pinder N, Bruckner T, Lehmann M, Motsch J, Brenner T, Larmann J, Knebel P, Hoppe-Tichy T, Swoboda S, Weigand MA, Hofer S, Zimmermann JB. Effect of physostigmine on recovery from septic shock following intra-abdominal infection - Results from a randomized, double-blind, placebo-controlled, monocentric pilot trial (Anticholium(R) per Se). J Crit Care. 2019 Aug;52:126-135. doi: 10.1016/j.jcrc.2019.04.012. Epub 2019 Apr 9.
• Zimmermann JB, Pinder N, Bruckner T, Lehmann M, Motsch J, Brenner T, Hoppe-Tichy T, Swoboda S, Weigand MA, Hofer S. Adjunctive use of physostigmine salicylate (Anticholium(R)) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium(R) per Se). Trials. 2017 Nov 10;18(1):530. doi: 10.1186/s13063-017-2231-x.

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2015
• Primary Completion (Actual): February 18, 2017
• Study Completion (Actual): February 18, 2017

Study Registration Dates

• First Submitted: January 1, 2017
• First Submitted That Met QC Criteria: January 4, 2017
• First Posted (Estimate): January 6, 2017

Study Record Updates

• Last Update Posted (Actual): January 29, 2018
• Last Update Submitted That Met QC Criteria: January 25, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Cholinesterase Inhibitors; Miotics; Physostigmine
• Other Study ID Numbers: D.10060224

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided