E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
E.1.1.1 | Medical condition in easily understood language |
invasion of the bloodstream by virulent microorganisms and is characterized by decreased blood flow, hypotension, organ dysfunction, impaired mental state, multiple organ failure |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The present randomised, placebo-controlled, double-blind, monocentre study on the application of physostigminsalicylate (Anticholium®) as adjunctive measure in perioperative sepsis/septic shock is expected to bring forward a proof of efficacy in man and to show that the cholinergic anti-inflammatory pathway may be transferred into clinical use. |
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E.2.2 | Secondary objectives of the trial |
The tests conducted in the scientific framework programme will shed more light on the complex interaction of interleukin-2, of interleukin-2-receptor, of TNF-alpha, of RAGE, of HMGB1, of AGEs, of NF-kappa-B in human sepsis and at the same time clarify whether RAGe may be considered for diagnostic marker. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Up for inclusion are all patients who fulfil all of the following criteria
1. Age at least 18 and not more than 85 years
2. APACHE II-Score < 34
3. intraabdominal infection (less than 24 hours existing)
finding of a diffuse peritonitis or
of a localised abscess
4. perioperative sepsis and
verified evidence of an infection
clinically verified or
microbiologically verified
and at least two of the following four criteria
- fever ≥ 38,0 °C or
hypothermia ≤ 36,0 °C verified through rectal or intravesical or intravasal measurement
- tachycardia ≥ 90/min
- tachypnoea ≥ 20/min or
hyperventilation verified through taking of an arterial blood gas analysis with PaCO2 ≤ 4,3 kPa or 33 mmHg or
mechanical/artificial ventilation
- leukocytosis ≥ 12.000/mm3 or
leukopenia ≤ 4.000/mm3 or
≥ 10 % immature neutrophils in the differential blood count
5. shock (less than 24 hours existing)
necessary use of vasopressors* despite sufficient fluid administration** to keep (the systolic arterial pressure ≥ 90 mmHg or) the mean arterial pressure ≥ 70 mmHg
6. no more than one scheduled and/or one emergency procedure since admission (no repeated revisions)
7. no infaust prognosis of a underlying or concomitant disease that gives reason to expect the death within the follow-up period
8. no do-not-resuscitate order
9. written consent of the full aged patient/her/his legal representative to participation (written consent (according to AMG [German drug law] §40 (1) 3B))
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E.4 | Principal exclusion criteria |
Up for exclusion are all patients who fulfil at least one of the following criteria:
1. known oversensitivity towards physostigminsalicylate, sodiummetabisulphite, sodiumethylenediaminetetraacetic acid or one of the remaining ingridients of Anticholium®
2. known contraindications* against Anticholium®
- gangrene
- coronary heart disease
3. known absolute contraindications* against Anticholium®
- myotonic dytrophy
- depolarization block after depolarising muscle relaxants
- intoxications through “irreversible acting” cholinesterase inhibitors
- closed traumatic brain injuries
- obstructions in the gastrointestinal tract (mechanic constipation)
- obstructions in the urinary tract (mechanic urinary retention)
4. known relative contraindications* against Anticholium®
- bronchial asthma
- bradycardia
- AV-conduction disorders
5. status post splenectomy
6.status post organ transplantation
7. positive pregnancy test, pregnancy and breastfeeding
8. participation in another clinical trial according to AMG or the follow-up period of another trial according to the AMG
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome measure / efficacy endpoint is the mean SOFA-Score (Sequential Organ Failure Assessment Score)
of seriously ill patients with perioperative sepsis/septic shock due to an intraabdominal infection during the treatment and in the subsequent time under intensive care.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Visits 0, 2 to 7, 8 to 16, 17, 18, 19, 20 and end of study visit (within 24 hours before treatment start, 2 hours ± 30 minutes, 24 hours ± 2 hours, 48 hours ± 2 hours, 72 hours ± 2 hours, 96 hours ± 2 hours after treatment start, 6 days ± 4 hours, 7 days ± 4 hours, 8 days ± 8 hours, 9 days ± 8 hours, 10 days ± 8 hours, 11 days ± 8 hours, 12 days ± 8 hours, 13 days ± 8 hours, 14 days ± 8 hours after treatment start, 28 days ± 8 hours after treatment start, 30 days ± 8 hours after treatment start, 84 days ± 8 hours after treatment start, 90 days ± 8 hours after treatment start and day of discharge/transferral from intensive care unit; end of study visit is not done in case of death) |
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E.5.2 | Secondary end point(s) |
Secondary outcome measure(s) / efficacy endpoint(s) are direct patienztrelevant
- the duration of artificial ventilation
- the duration of stay under intensive care and in hospital
- the 30- and 90-day mortality
on surrogate and scores ( indirect patientrelevant)
- arterial blood gas( analys)es
- central venous blood gas( analys)es
- PaO2/FiO2
- platelet count
- leukocyte count
- creatinine
- urea
- total bilirubin
- C-reactive protein
- Quick's test (prothrombin time)
- D-dimer
- procalcitonin
- interleukin-6
- thrombin-antithrombin-complex
- mean arterial pressure and use of vasopressors (frequency and duration)
- the use of renal replacement therapy (frequency and duration)
- GCS-score
- APACHE II-score
- SAPS II
and on
the occurrence of side effects as
- nausea, vomiting
- changes in heart rate:
clinically relevant decrease in heart rate or
clinically relevant increase in heart rate
- changes in arterial pressure:
clinically relevant decrease in arterial pressure
- changes in airway resistance
spontaneous breathing:
acute shortness of breath
artificial ventilation:
clinically relevant decrease in ventilation volume at steady ventilation pressure or
clinically relevant increase in ventilation pressure at steady ventilation volume (Δpressure = peak pressure - end-expiratory pressure)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Visits 0, 2 to 7, 8 to 16, 17, 18, 19, 20 and end of study visit (within 24 hours before treatment start, 2 hours ± 30 minutes, 24 hours ± 2 hours, 48 hours ± 2 hours, 72 hours ± 2 hours, 96 hours ± 2 hours after treatment start, 6 days ± 4 hours, 7 days ± 4 hours, 8 days ± 8 hours, 9 days ± 8 hours, 10 days ± 8 hours, 11 days ± 8 hours, 12 days ± 8 hours, 13 days ± 8 hours, 14 days ± 8 hours after treatment start, 28 days ± 8 hours after treatment start, 30 days ± 8 hours after treatment start, 84 days ± 8 hours after treatment start, 90 days ± 8 hours after treatment start and day of discharge/transferral from intensive care unit; end of study visit is not done in case of death)
interleukin-6 and thrombin-antithrombin-complex only at visits 0, 2 to 7, 8, 9 and 16, 17, 18
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS (the last visit of the last subject) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |