Anticholium® Per Se

NCT03013322 | Completed

• 1 other identifier: D.10060224
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Shock, Septic; Sepsis; Perioperative Period

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (29)

• 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

Other Outcomes (5)

• microbiological analyses of potential pathogens including susceptibility tests

  up to 90 days

• plasma concentrations of physostigmine

  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

  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

Study Arms (2)

Treatment Group

ACTIVE COMPARATOR

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

Placebo Group

PLACEBO COMPARATOR

The placebo group is treated with 0.9% sodium chloride.

Drug: Isotonic Saline

Interventions

Physostigmine DRUG

Also known as: Anticholium

Treatment Group

Isotonic Saline DRUG

Placebo Group

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital Heidelberg: lead

Study Sites (1)

University Hospital Heidelberg

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Related Publications (3)

• 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.

  PMID: 31398669 DERIVED

• 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.

  PMID: 31035187 DERIVED

• 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.

  PMID: 29126416 DERIVED

MeSH Terms

Conditions

Shock, Septic; Sepsis

Interventions

Physostigmine; Sodium Chloride

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Phenylcarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Johannes B Zimmermann, MD, MSc

  University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. med. Johannes B. Zimmermann, MSc

Study Record Dates

• First Submitted: January 1, 2017
• First Posted: January 6, 2017
• Study Start: January 28, 2015
• Primary Completion: February 18, 2017
• Study Completion: February 18, 2017
• Last Updated: January 29, 2018

Record last verified: 2018-01

Locations

DE (1)