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    Clinical Trial Results:
    Neuroprotection with Dexmedetomidine in patients undergoing elective cardiac or abdominal surgery

    Summary
    EudraCT number
    2013-000823-15
    Trial protocol
    DE  
    Global end of trial date
    30 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Oct 2020
    First version publication date
    29 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NEUPRODEX
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02096068
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Charité - Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Univ.-Prof. Dr. C. Spies, Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), +49 30450 551001 , claudia.spies@charite.de
    Scientific contact
    Univ.-Prof. Dr. C. Spies, Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), +49 30450 551001 , claudia.spies@charite.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Incidence of postoperative delirium measured with the Confusion Assessment Method for the ICU (CAM-ICU)“or the „Confusion Assessment Method (CAM) and/or Chart Review and/or DSM V/ICD-10 “
    Protection of trial subjects
    During anesthesia changes of hemodynamic parameters in the intraoperative transoseophageal echocardiography and in the processive electroencephalography and eletromyography were measured. Incidence of adverse events which start after the application of the study drug were evaluated for five postoperative days.
    Background therapy
    Surgical patients received standard of care in the university hospital.
    Evidence for comparator
    not applicable, Placebo use
    Actual start date of recruitment
    13 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Scientific research
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 75
    Worldwide total number of subjects
    75
    EEA total number of subjects
    75
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    17
    From 65 to 84 years
    57
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Study group: 13.07.2014 - 08.03.2016 (Last study patient in) POCD control group: 17.10.2015 - 20.04.2018 (Last control subject in)

    Pre-assignment
    Screening details
    n= 484 patients were screened, n= 421 screening failure (1. n= 49 refused participation; n= 119 did not meet inclusion criteria; 3. other) n= 63 were included. n=3 patients drop-out criteria occurred after inclusion, reasons: 1. one patient refused study participation; 2. received no heart lung machine surgery, 3. emergency operation

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All role members were unblinded after database closure on May 15, 2019.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Verum
    Arm description
    Experimental: Study group Application of Dexmedetomidine (Dexdor®) perioperatively for a maximum of 48 hours Dosing Scheme: during operation and mechanical ventilation: 0,7μg/kgABW/h; recovery time until extubation: 0,4μg/kgABW/h; after extubation: 0,2-1,4μg/kgABW/h Dexmedetomidine was supplied in a 2 ml ampoule containing 200 μg (100 μg/ml) dexmedetomidine (as a base) for dilution with 48 ml 0.9% sodium chloride injection (giving a solution containing 4 μg/ml) in 50 ml syringe.
    Arm type
    Experimental

    Investigational medicinal product name
    Dexdor 100 Mikrogramm/ml
    Investigational medicinal product code
    ATC code N05CM18
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Dexmedetomidine was supplied in a 2 ml ampoule containing 200 μg (100 μg/ml) dexmedetomidine (as a base) for dilution with 48 ml 0.9% sodium chloride injection (giving a solution containing 4 μg/ml) in 50 ml syringe. During operation and mechnical ventilation: 0,7μg/kgABW/h recovery time until extubation: 0,4μg/kgABW/h after extubation: 0,2-1,4μg/kgABW/h

    Arm title
    Placebo
    Arm description
    Placebo Comparator: Control group Application of placebo for a maximum of 48 hours Placebo for dexmedetomidine was a 50 ml syringe containing 0.9% sodium chloride isotonic infusion solution/0.9 % sodium chloride injection solution
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% sodium chloride isotonic physiological solution
    Investigational medicinal product code
    ATC code: B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo for dexmedetomidine was a 50 ml syringe containing 0.9% sodium chloride isotonic infusion solution/0.9 % sodium chloride injection solution During operation and mechnical ventilation: 0,7μg/kgABW/h recovery time until extubation: 0,4μg/kgABW/h after extubation: 0,2-1,4μg/kgABW/h

    Arm title
    Control POCD
    Arm description
    No Intervention: POCD (postoperative cognitive deficit) control group A non-surgical control group of 15 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. The participants are matched on age, education, and gender to the study patients.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Verum Placebo Control POCD
    Started
    28
    32
    15
    Completed
    28
    32
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    The intention-to-treat population includes 28 patients in the dexmedetomidine group and 32 patients in the placebo group. A non-surgical control group of 15 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings.

    Reporting group values
    overall trial Total
    Number of subjects
    75 75
    Age categorical
    Units: Subjects
        60-64 years
    17 17
        65-84 years
    57 57
        85 years and over
    1 1
        not recorded
    0 0
    Gender categorical
    Units: Subjects
        Female
    28 28
        Male
    47 47
    ASA-Status
    The ASA physical status classification system is a system for assessing the fitness of patients before surgery. In 1963 the American Society of Anesthesiologists (ASA) adopted the five-category physical status classification system; a sixth category was later added. These are: Healthy person. Mild systemic disease. Severe systemic disease. Severe systemic disease that is a constant threat to life. A moribund person who is not expected to survive without the operation. A declared brain-dead person whose organs are being removed for donor purposes.
    Units: Subjects
        ASA 1
    1 1
        ASA 2
    38 38
        ASA 3
    36 36
        not recorded
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Verum
    Reporting group description
    Experimental: Study group Application of Dexmedetomidine (Dexdor®) perioperatively for a maximum of 48 hours Dosing Scheme: during operation and mechanical ventilation: 0,7μg/kgABW/h; recovery time until extubation: 0,4μg/kgABW/h; after extubation: 0,2-1,4μg/kgABW/h Dexmedetomidine was supplied in a 2 ml ampoule containing 200 μg (100 μg/ml) dexmedetomidine (as a base) for dilution with 48 ml 0.9% sodium chloride injection (giving a solution containing 4 μg/ml) in 50 ml syringe.

    Reporting group title
    Placebo
    Reporting group description
    Placebo Comparator: Control group Application of placebo for a maximum of 48 hours Placebo for dexmedetomidine was a 50 ml syringe containing 0.9% sodium chloride isotonic infusion solution/0.9 % sodium chloride injection solution

    Reporting group title
    Control POCD
    Reporting group description
    No Intervention: POCD (postoperative cognitive deficit) control group A non-surgical control group of 15 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. The participants are matched on age, education, and gender to the study patients.

    Primary: Delirium

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    End point title
    Delirium [1]
    End point description
    Incidence of postoperative delirium measured with the Confusion Assessment Method for the ICU (CAM-ICU) or the Confusion Assessment Method (CAM)
    End point type
    Primary
    End point timeframe
    Unitil the fifth postoperative day
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary end point is reporting statistics for all the study arms e.g. verum arm and placebo arm in the baseline period. In the POCD control group no delirium (primary endpoint) was measured.
    End point values
    Verum Placebo
    Number of subjects analysed
    28
    32
    Units: yes/no
        yes
    5
    14
        no
    23
    18
    Statistical analysis title
    Primary endpoint
    Statistical analysis description
    Fisher-Boschloo-Test
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Post-hoc
    Analysis type
    equivalence [2]
    P-value
    < 0.05
    Method
    Fisher-Boschloo-Test
    Confidence interval
    Notes
    [2] - For the primary endpoint we found a reduction of delirium incidence measured by CAM-ICU / CAM within the first five postoperative days from 43.8% (n=14) in the placebo group to 17.9% (n=5) in the verum group. According to the Fisher-Boschloo-Test this difference is significant with p=0.038. The Fisher-Boschloo test was used because it constitutes an alternative to the Fisher's Exact Test with larger statistical power, while ensuring the same level of type-I-error.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Incidence of adverse events which start after the application of the study medication within 5 postoperative days.
    Adverse event reporting additional description
    Every adverse event that started within 5 postoperative days has to be followed up until decrease of the symptoms or stabilisation. Patients were evaluated regarding their safety profil during ech study visit twice per day.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Verum
    Reporting group description
    This group received study medication Dexdor.

    Reporting group title
    Placebo
    Reporting group description
    This group received 0.9% NaCl

    Serious adverse events
    Verum Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 28 (25.00%)
    9 / 32 (28.13%)
         number of deaths (all causes)
    0
    5
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hematoma
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative bleeding
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enhanced secretion production
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Oversedation
    Additional description: In this study one serious adverse drug reaction was reported.
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Expired study medication
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anesthesia overhang
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delayed awakening
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asystolia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation with tachyarrhythmia absoluta
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhtyhmia absoluta
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Necrotic pancreatitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal occlusion
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Increased liver values
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Verum Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 28 (100.00%)
    32 / 32 (100.00%)
    Vascular disorders
    Hypertonia
         subjects affected / exposed
    3 / 28 (10.71%)
    10 / 32 (31.25%)
         occurrences all number
    3
    10
    Hypotension
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 32 (12.50%)
         occurrences all number
    3
    4
    Injury, poisoning and procedural complications
    Hypothermia
         subjects affected / exposed
    4 / 28 (14.29%)
    2 / 32 (6.25%)
         occurrences all number
    4
    2
    Delayed awakening
         subjects affected / exposed
    2 / 28 (7.14%)
    5 / 32 (15.63%)
         occurrences all number
    2
    5
    Inadequate awakening
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 32 (12.50%)
         occurrences all number
    1
    4
    Investigations
    Hyperglycemia
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 32 (12.50%)
         occurrences all number
    1
    4
    Pateint state index decreased
         subjects affected / exposed
    8 / 28 (28.57%)
    8 / 32 (25.00%)
         occurrences all number
    8
    8
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    20 / 28 (71.43%)
    21 / 32 (65.63%)
         occurrences all number
    20
    21
    Tachyarrhythmia absoluta
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 32 (9.38%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Dystelectasis
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 32 (12.50%)
         occurrences all number
    1
    4
    Pleural effusion
         subjects affected / exposed
    9 / 28 (32.14%)
    10 / 32 (31.25%)
         occurrences all number
    9
    10
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    Hypovolaemia
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Oedema
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 32 (6.25%)
         occurrences all number
    3
    2
    Pain
         subjects affected / exposed
    2 / 28 (7.14%)
    6 / 32 (18.75%)
         occurrences all number
    2
    6
    Psychiatric disorders
    Subsyndromal delirium
         subjects affected / exposed
    20 / 28 (71.43%)
    21 / 32 (65.63%)
         occurrences all number
    20
    21
    Gastrointestinal disorders
    PONV
         subjects affected / exposed
    5 / 28 (17.86%)
    7 / 32 (21.88%)
         occurrences all number
    5
    7
    Obstipation
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 32 (9.38%)
         occurrences all number
    1
    3
    Diarrhoea
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 32 (12.50%)
         occurrences all number
    3
    4
    Infections and infestations
    SIRS
         subjects affected / exposed
    10 / 28 (35.71%)
    5 / 32 (15.63%)
         occurrences all number
    10
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2014
    Amendment 01: changes of the protocol 1.0 to 1.1 within the ethical applications, submitted to BfArM again as substantial Amendment 01.
    14 Aug 2015
    Amendment 02: Substantial Amendment changes of the protocol 1.1 to 1.2: Primary reason for amendment were changes in study design: a POCD-control group of 15 patients was requested and three inclusion and exclusion criteria were specified. Three secondary endpoints were added. The time schedule of the study was adapted.and changes of the summary of product characteristics Dexdor 11/2014, sodium chloride Fresenius (07/2013), sodiume chloride BBraun (06/2014) were included in the new protocol version and patient information sheets. Safety documentation was set for 5 postoperative days. Fulfilling conditions of the ethical committee: Changes of the protocol 1.2 to 1.4: Including to the safety documentation that every adverse event that started within 5 postoperative days has to be followed up until decrease of the symptoms or stabilisation.
    02 Mar 2016
    Amendment 03 changes of the protocol 1.4 to 1.5 Primary reason for amendment were changes in study design: the study title was changed. The inclusion criterion was expanded to abdominal surgery. Specific protocol exceptions to expected SAE Reporting were added. Measurement of Cortisol is collected from blood samples and salivary juice.
    27 May 2016
    Amendment 04 changes of the protocol 1.5 to 1.6 to fulfill the conditions of the BfArM: The benefit risk evaluation regarding the inclusion of study patients undergoing hepatic, gastric and intestinal surgery was added. The safety documentation and annual reporting was specified in the study protocol according to ICH Topic E2F and the importance of the reporting of SUSARS after unblinding of adverse events which fulfil the criteria causal relationship and unexspectedness was emphasized.
    29 Dec 2016
    Amendment 05 changes of the protocol 1.6 to 1.7 Primary endpoint time measurement is reduced from 7 to 5 postoperative days. POCD measurements are specified to baseline, 5 (+/-2) postoperative days and between 90 postoperative days. Changes of the summary of product characteristics Dexdor 05/2016 were updated. The study drug could patient develops delirium within 2 hours of pausing be restarted up to 48 hours postoperatively if the patient develops delirium within 2 hours of pausing.
    05 Jan 2018
    Amendment 06 changes of the protocol 1.7 to 1.8 Following Changes in study design: Primary and secondary endpoints Delirium measurement are expanded by validated Delirium scores. The enrollment rates are adapted by a current lower Drop-Out rate. The SUMMARY OF PRODUCT CHARACTERISTICS of NaCl (Placebo) is updated. The biometric institute, that has to perform the statistical analysis, was changed
    15 May 2018
    Amendment 07 to fulfill the conditions of the ethical committee: changes of the protocol 1.8 to 1.9 Primary and secondary endpoints Delirium measurement are reduced to validated Delirium scores according to protocol V1.7.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    not applicable
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