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    EudraCT Number:2012-001650-26
    Sponsor's Protocol Code Number:AnticholiumperSeIII
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-08-14
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2012-001650-26
    A.3Full title of the trial
    A randomised, placebo-controlled, double-blind, monocentre study on the application of physostigminsalicylate (Anticholium®) as adjunctive measure in perioperative sepsis/septic shock
    Eine randomisierte, placebokontrollierte, doppelblinde, monozentrische Studie zum Einsatz von Physostigminsalicylat (Anticholium®) als adjunktive Maßnahme in der perioperativen Sepsis/im septischen Schock
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study on the application of physostigminsalicylate (Anticholium®) as auxiliary measure in perioperative blood poisoning/its life-threatening form
    A.3.2Name or abbreviated title of the trial where available
    Anticholium per Se
    A.4.1Sponsor's protocol code numberAnticholiumperSeIII
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRuprecht-Karls-University Heidelberg, Med Faculty represented by Universitätsklinikum Heidelberg and its Commercial D
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDr. Franz Köhler Chemie GmbH
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Heidelberg
    B.5.2Functional name of contact pointDepartment of Anesthesiology
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 110
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.4Telephone number+4962215639407
    B.5.5Fax number+496221566988
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Anticholium
    D. of the Marketing Authorisation holderDr. Franz Köhler Chemie GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    E.1.1.1Medical 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
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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))

    E.4Principal 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
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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)
    E.5.2Secondary 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)
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS (the last visit of the last subject)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Due to the severity of the disease sepsis and especially of the diseases severe sepsis/septic shock, of the possible underlying and concomitant diseases the affected patients are put in an artificial coma and on artificial respiration.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 20
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-11-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-18
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