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Anticholium® Per Se

Primary Purpose

Shock, Septic, Sepsis, Perioperative Period

Status
Completed
Phase
Not Applicable
Locations
Germany
Study Type
Interventional
Intervention
Physostigmine
Isotonic Saline
Sponsored by
University Hospital Heidelberg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Shock, Septic

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University Hospital Heidelberg

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Treatment Group

Placebo Group

Arm 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).

The placebo group is treated with 0.9% sodium chloride.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Full Information

First Posted
January 1, 2017
Last Updated
January 25, 2018
Sponsor
University Hospital Heidelberg
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1. Study Identification

Unique Protocol Identification Number
NCT03013322
Brief Title
Anticholium® Per Se
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
January 28, 2015 (Actual)
Primary Completion Date
February 18, 2017 (Actual)
Study Completion Date
February 18, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital Heidelberg

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Shock, Septic, Sepsis, Perioperative Period

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment Group
Arm Type
Active Comparator
Arm 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 Title
Placebo Group
Arm Type
Placebo Comparator
Arm Description
The placebo group is treated with 0.9% sodium chloride.
Intervention Type
Drug
Intervention Name(s)
Physostigmine
Other Intervention Name(s)
Anticholium
Intervention Type
Drug
Intervention Name(s)
Isotonic Saline
Primary Outcome Measure Information:
Title
mean Sequential Organ Failure Assessment (SOFA) score
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.
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
Secondary Outcome Measure Information:
Title
duration of artificial ventilation
Time Frame
up to 90 d
Title
duration of intensive care
Time Frame
up to 90 d
Title
length of stay
Time Frame
up to 90 d
Title
30-day mortality
Time Frame
30 d
Title
90-day mortality
Time Frame
90 d
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
frequency of vasopressors
Time Frame
up to 90 days
Title
duration of vasopressors
Time Frame
up to 90 days
Title
frequency of renal replacement therapy
Time Frame
up to 90 days
Title
duration of renal replacement therapy
Time Frame
up to 90 days
Title
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
Title
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
Title
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
Title
occurrence of side effects
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)
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
Other Pre-specified Outcome Measures:
Title
microbiological analyses of potential pathogens including susceptibility tests
Time Frame
up to 90 days
Title
plasma concentrations of physostigmine
Description
determined with a validated high-performance liquid chromatography (HPLC) method
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
Title
plasma concentrations of eseroline
Description
determined with a validated high-performance liquid chromatography (HPLC) method
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
Title
acetylcholinesterase activity
Description
determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)
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
Title
butyrylcholinesterase activity
Description
determined with ChE check mobile (Securetec, Neubiberg, Germany) from remaining material drawn for routine blood gas analyses (arterial samples)
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Johannes B Zimmermann, MD, MSc
Organizational Affiliation
University Hospital Heidelberg
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Heidelberg
City
Heidelberg
State/Province
Baden-Württemberg
ZIP/Postal Code
69120
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
31398669
Citation
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.
Results Reference
derived
PubMed Identifier
31035187
Citation
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.
Results Reference
derived
PubMed Identifier
29126416
Citation
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.
Results Reference
derived

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Anticholium® Per Se

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