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    Summary
    EudraCT Number:2013-001496-21
    Sponsor's Protocol Code Number:LOC-2013
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFinland - Fimea
    A.2EudraCT number2013-001496-21
    A.3Full title of the trial
    The Neural Mechanisms of Anesthesia and Human Consciousness
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Neural Mechanisms of Anesthesia and Human Consciousness
    A.3.2Name or abbreviated title of the trial where available
    The Neural Mechanisms of Anesthesia and Human Consciousness
    A.4.1Sponsor's protocol code numberLOC-2013
    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 SponsorHarry Scheinin
    B.1.3.4CountryFinland
    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 supportUniversity of Turku
    B.4.2CountryFinland
    B.4.1Name of organisation providing supportHospital District of Southwest Finland
    B.4.2CountryFinland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Turku
    B.5.2Functional name of contact pointTurku PET Centre
    B.5.3 Address:
    B.5.3.1Street AddressKiinamyllynkatu 4-8
    B.5.3.2Town/ cityTurku
    B.5.3.3Post codeFIN-20520
    B.5.3.4CountryFinland
    B.5.5Fax number35822318191
    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.2.1.1.1Trade name Dexdor
    D.2.1.1.2Name of the Marketing Authorisation holderOrion Corporation
    D.2.1.2Country which granted the Marketing AuthorisationFinland
    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 Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDEXMEDETOMIDINE
    D.3.9.1CAS number 113775-47-6
    D.3.9.4EV Substance CodeSUB07037MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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.IMP: 2
    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.2.1.1.1Trade name Propofol-Lipuro 10 mg/ml
    D.2.1.1.2Name of the Marketing Authorisation holderB. Braun Melsungen AG
    D.2.1.2Country which granted the Marketing AuthorisationFinland
    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 Concentrate for emulsion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpropofol
    D.3.9.3Other descriptive namePROPOFOL
    D.3.9.4EV Substance CodeSUB10116MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    No medical condition or disease involved. The study subjects are healthy volunteers.
    E.1.1.1Medical condition in easily understood language
    Not applicable. Healthy volunteers will be studied.
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this study is to reveal what happens in the brain when consciousness is impaired during sleep and during anesthetic-induced sedation, which brain structures are responsible for the most primitive conscious state and what makes our rich conscious experiences possible. Finding tools for the distinction of consciousness, connectedness and responsiveness would be groundbreaking and would represent a major leap forward in the study of human consciousness.
    E.2.2Secondary objectives of the trial
    Not applicable.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Healthy male volunteers will be considered eligible for the study.
    The subjects must meet all of the following criteria:
    1. Male
    2. Age 20–30 years
    3. Good general health i.e. American Society of Anesthesiologists (ASA) physical status I
    4. Fluent in Finnish language
    5. Right handedness
    6. Written informed consent
    7. Good sleep quality
    E.4Principal exclusion criteria
    The subject must be excluded if any of the following criteria are met:
    1. Chronic medication
    2. History of alcohol and/or drug abuse
    3. Strong susceptibility for allergic reactions
    4. Serious nausea in connection with previous anesthesia
    5. Strong susceptibility for nausea
    6. Any use of drugs or alcohol during the 48 hours preceding anesthesia
    7. Use of caffeine products 10–12 hours prior the study, 24 hours before sleep studies
    8. Smoking
    9. Clinically significant previous cardiac arrhythmia / cardiac conduction impairment
    10. Clinically significant abnormality in prestudy laboratory tests
    11. Positive result in the drug screening test
    12. Blood donation within 90 days prior to the study
    13. Participation in any medical study with an experimental drug or device during the preceding 60
    days
    14. The study subject has undergone a prior PET or SPECT study
    15. Any contraindication to magnetic resonance imaging (MRI)
    16. Hearing impairment
    17. Detected unsuitability based on initial electrophysiological measurements (Parts 2–5)
    18. Detected unsuitability based on MRI scanning results (Parts 3–6)
    19. Sleep disorder or severe sleep problem
    E.5 End points
    E.5.1Primary end point(s)
    Due to the exploratory nature of the study no primary variables are defined. This is explained and justified in the study protocol. Analysis of PET and other data is described in detail in section 11.
    During the study, a series of Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and electroencephalography (EEG) studies will be carried out on 200–240 healthy male subjects to reveal the neural correlates of consciousness. Consciousness of the subjects will be manipulated with normal sleep and anesthetic agents dexmedetomidine acting through α2-agonism, with propofol and sevoflurane both mainly acting through the enhancement of gamma-aminobutyric acid (GABA) system, and with S-ketamine acting through N-methyl-D-aspartate (NMDA) receptor antagonism.
    The study consists of six (6) parts. First, various neurophysiological tools to separate consciousness, connectedness and responsiveness during normal sleep will be tested in Part 1. The most suitable methods and subjects will be selected and then tested during anesthetic-induced sedation and loss of responsiveness (LOR) in Part 2. The anesthetics (dexmedetomidine or propofol) will be administered as target-controlled infusions (TCI) with step-wise concentration-increments at 10–20
    min intervals until LOR is detected in 40 (20 for dexmedetomidine and 20 for propofol) subjects. In Part 3, the TCIs are repeated in the same 40 subjects but adjusted according to the individual drug
    target concentrations sufficient for LOR, and a series of PET perfusion imaging measurements will be performed to obtain the brain activity information in various states of consciousness. Based on the experiences from Part 1 and 2, the most promising neurophysiological tools will be applied during the imaging session. In Part 4, the same 40 subjects who participated in Parts 2 and 3 will be imaged with PET for brain activity after sleep deprivation (awake), after falling asleep (sleep onset NREM stage 1), during light (NREM stage 2) sleep, during deep (slow-wave, NREM stage 3) sleep and immediately after awakening. In Part 5, 10 dexmedetomidine subjects who participated in Parts 2–4
    will be given the drug once more, and functional MRI (fMRI) data will be collected at various states of consciousness before and during verbal and nonverbal vocalizations. In Part 6, a separate set of
    160 subjects will be recruited to receive EC50 concentration of dexmedetomidine or propofol (40 subjects/drug) while being imaged for cerebral metabolic rate of
    glucose (CMRglu). EEG will be continuously collected in all sessions (Parts 1–6). The depth of anesthesia will be measured using quantitative EEG and bispectral index (BIS) monitoring.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Multiple time points. See E.5.1.
    E.5.2Secondary end point(s)
    Not applicable. See E.5.1.
    E.5.2.1Timepoint(s) of evaluation of this end point
    not applicable. See E.5.1.
    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 No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    The explanation of consciousness poses one of the greatest challenges to science and philosophy in the 21st century. It remains unclear what consciousness is and how it emerges from brain activity. By studying anesthesia and sleep, we aim to reveal what happens in the brain when consciousness is lost and when it returns.
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    The study is partly randomized.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Anesthesia will be compared to natural sleep.
    E.8.2.4Number of treatment arms in the trial4
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    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: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state240
    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)
    None.
    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 Decision2013-06-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-01-08
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