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    Clinical Trial Results:
    Pilot study to optimise the use and to evaluate the diagnostic value of intraoperative contrast-enhanced 3D-ultrasound with SonoVue® for imaging of intracranial tumors

    Summary
    EudraCT number
    		 2010-022057-42
    Trial protocol
    		 DE  
    Global end of trial date
    23 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2020
    First version publication date
    12 Aug 2020
    Other versions
    Summary report(s)
    		 Trial Synopsis of the 3D-iUS-NCH Study

    Trial information

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    Trial identification
    Sponsor protocol code
    3D-iUS-NCH
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    university of Leipzig
    Sponsor organisation address
    Ritterstr. 26, Leipzig, Germany, 04109
    Public contact
    Dr. Dirk Lindner, University of Leipzig Neurochirurgie, 0049 3419717500,
    Scientific contact
    Dr. Dirk Lindner, University of Leipzig Neurochirurgie, 0049 3419717500,
    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
    26 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Comparison of intraoperative, 3D reconstructed and contrast enhanced, transdural ultrasound with the preoperative 3D- MRi as Gold Standard. Comparison of intraoperative, 3D reconstructed and contrast enhanced ultrasound after tumor resection to verify the extent of resection as well as accuracy of navigation with the early post operative3D- MRi as Gold Standard
    Protection of trial subjects
    patients with planned surgery were included in this methodological study; in all of them an OP indication was stated due to intracranial tumor; the contrast-enhacing substance applied should allow a more precise identification of the margins of the tumor for surgery and the brain shift during surgery. SonoVue/Schwefelhexafluorid was already approved for application in cerebral arteries. (S)AE were systematically collected an analysed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    65
    From 65 to 84 years
    34
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 inclusion of a consecutive sample of patients with intracranial tumors a who fulfil the in/exclusion criteria in a single centre and into a single-armed study

    Pre-assignment
    Screening details
    		 consecutive sample of patients with intracranial tumors a who fulfil the in/exclusion criteria with planned surgery in a single centre

    Period 1
    Period 1 title
    application
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 all patients
    Arm description
    		 This study aimed at a methodological comparison of imaging methods and analysed the precision of 3D-US imaging with/ without application of contrast- enhacing application of SonoVue compared to pre/post MRI for intra-operative navigation and resection control in the surgery of intracranial tumors.
    Arm type
    		 all Patients

    Investigational medicinal product name
    SonoVue (Schwefelhexafluorid)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intracavernous use
    Dosage and administration details
    4.8 mL (216 µgram) two times during surgery

    Number of subjects in period 1
    		all patients
    Started
    100
    Completed
    100
    Period 2
    Period 2 title
    post-surgery short-term FUP
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 all patients
    Arm description
    		 -
    Arm type
    		 Safety analysis population

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		all patients
    Started
    100
    Completed
    100

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    application
    Reporting group description
    		 all patients in whom an intracranial surgey was indicated/ planned

    Reporting group values
    		 application Total
    Number of subjects
    		 100 100
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 60 (50.3 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 38 38
        Male
    		 62 62
    tumor class
    Units: Subjects
        Glioblastoma multiforme
    		 48 48
        Meningeom
    		 5 5
        astrocytome
    		 11 11
        oligodendrogliom
    		 2 2
        metastasis in primum
    		 32 32
        no rest identifyable
    		 1 1
        not reported
    		 1 1
    smoker
    Units: Subjects
        yes
    		 15 15
        no
    		 85 85
    complete resection planned
    Units: Subjects
        no
    		 26 26
        yes
    		 70 70
        not reported
    		 4 4
    serious AE reported
    without SAE reporting requirements according to trail protocol
    Units: Subjects
        yes
    		 12 12
        no
    		 88 88
    Subject analysis sets

    Subject analysis set title
    all patients
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Since the study aimed at methodological comparison of different imaging method in intracranial surgery, the primary analysis reported here is the safety of patients regarding the contrast enhancing IMP applied

    Subject analysis sets values
    		 all patients
    Number of subjects
    100
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
    38
        Male
    62
    tumor class
    Units: Subjects
        Glioblastoma multiforme
    48
        Meningeom
    5
        astrocytome
    11
        oligodendrogliom
    2
        metastasis in primum
    32
        no rest identifyable
    1
        not reported
    1
    smoker
    Units: Subjects
        yes
    15
        no
    85
    complete resection planned
    Units: Subjects
        no
    26
        yes
    70
        not reported
    4
    serious AE reported
    without SAE reporting requirements according to trail protocol
    Units: Subjects
        yes
    12
        no
    88

    End points

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    End points reporting groups
    Reporting group title
    all patients
    Reporting group description
    		 This study aimed at a methodological comparison of imaging methods and analysed the precision of 3D-US imaging with/ without application of contrast- enhacing application of SonoVue compared to pre/post MRI for intra-operative navigation and resection control in the surgery of intracranial tumors.
    Reporting group title
    all patients
    Reporting group description
    		 -

    Subject analysis set title
    all patients
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Since the study aimed at methodological comparison of different imaging method in intracranial surgery, the primary analysis reported here is the safety of patients regarding the contrast enhancing IMP applied

    Primary: size of tumor (3D-US / MRT)

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    End point title
    		 size of tumor (3D-US / MRT) [1]
    End point description
    within the most frequently class of tumors met (glioblastoma, metastases) in the study sample; and using all images which were segmented/ analysed estimates with 95% confidence limits were calculated and compared between the different imagin procedures
    End point type
    Primary
    End point timeframe
    before surgical tumor resection via 3D-US / MR imaging
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was a single armed study to compare different imaging methods in intracranial surgery. The 95% confidence intervals for the tumor size before surgery (according to the imaging method) resulted in : • MRI: 30,2 [17,9; 42,5] ml, • 3D-US with SonoVue: 25,2 [14,2; 36,8] ml, • 3D-US without SonoVue: 24,2 [15,0; 33,4] ml. Therefore, the contrast-enhanced US provided 15.6% smaller values in tumor size.
    End point values
    		 all patients all patients
    Number of subjects analysed
    21 [2]
    21 [3]
    Units: ml
        median (inter-quartile range (Q1-Q3))
    39.3 (1.2 to 242.9)
    39.3 (1.2 to 242.9)
    Notes
    [2] - with glioblastoma
    [3] - in patients with glioblastoma
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from time of SonoVue-application until MRT investigation post surgery (SAE) resp. discharge of the hospital (AE)
    Adverse event reporting additional description
    No SAE was reported during the course of study. A single AE (pneumonia) with fatal outcome occurred duringe the hospitalisation of the patient. A causality to SonoVue is not possible since death occurred on 21 Sept. 2011 (surgery/ application of SonoVue on 6 Sept. 2011)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    SAE reporting period
    Reporting group description
    		 from first application until <=48h post surgery/ 2nd MRT imaging; exception: events during surgery and without relationship to SonoVue were only to be documented as AE acc. to protocol.

    Reporting group title
    all patients until discharge from hospital
    Reporting group description
    		 The death reported after pneumonia (as serious AE) during hospitalisation occurred later than the end of SAE reporting period.

    Serious adverse events
    		 SAE reporting period all patients until discharge from hospital
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 100 (0.00%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 SAE reporting period all patients until discharge from hospital
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 100 (0.00%)
    13 / 100 (13.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 100 (0.00%)
    4 / 100 (4.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 100 (0.00%)
    4 / 100 (4.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
    Additional description: since this AE with fatal outcome occured after the SAE reporting period (acc. to trial protocol) but within the observation of patients no SAE report was necessary
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    8 / 100 (8.00%)
         occurrences all number
    0
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Feb 2013
    1) Administration of 2.4 mL of (108 micro gram) SonoVue® (sulfurhexafluoride) was changed to 4,8 mL SonoVue® (216 µg Schwefelhexafluorid). 2) The study was prolonged

    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.
    At the end of the study the data on segmented/analysed images was not complete yet but the safety data were completely available. Therefore the study report was finalized.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26883549
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