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    Clinical Trial Results:
    “TRANSARTERIAL EMBOLIZATION ALONE VERSUS DRUG-ELUTING BEADS CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA. A RANDOMIZED CONTROLLED TRIAL”

    Summary
    EudraCT number
    		 2018-000740-25
    Trial protocol
    		 IT  
    Global end of trial date
    19 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Nov 2024
    First version publication date
    20 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RAD-18-TAcE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 RAD-18-TAcE: RAD-18-TAcE
    Sponsors
    Sponsor organisation name
    IRCCS Azienda Ospedaliero-Universitaria di Bologna
    Sponsor organisation address
    Via Albertoni 15, Bologna, Italy, 40138
    Public contact
    U.O. Radiologia , IRCCS Azienda Ospedaliero-Universitaria di Bologna, +39 051212958, matteo.renzulli@aosp.bo.it
    Scientific contact
    U.O. Radiologia, IRCCS Azienda Ospedaliero-Universitaria di Bologna, +39 0512142958, matteo.renzulli@aosp.bo.it
    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
    29 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare TTP since randomization, as recommended from expert panel opinion [26] after TAE and DEB-TACE in a homogeneous HCC patients population and using small size beads in both arms.
    Protection of trial subjects
    Yes, by specific insurance
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2019
    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
    Italy: 111
    Worldwide total number of subjects
    111
    EEA total number of subjects
    111
    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)
    43
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study involves the enrollment of patients with a HCC diagnosis, according to the guidelines of the American Association for the Study of the Liver Disease (AASLD), as in clinical practice. The enrolled patients will have to meet the inclusion criteria and sign the informed consent for the participation in this study.

    Pre-assignment
    Screening details
    		 Inclusion and exclusion criteria are assessed at the time of screening before treatment.

    Period 1
    Period 1 title
    Tratment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DEB-TACE
    Arm description
    		 The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM (Boston Scientific) microspheres. TANDEM™ embozene microspheres are made of non-resorbable, biocompatible, hydrogel microspheres, subjected to precision calibration and coated with an inorganic perfluorate polymer (Polyzene®-F). Thanks to their design, the microspheres can be loaded with drugs, such as doxorubicin, in order to administer a local, controlled and constant dose of the drug to the tumor sites affected after embolization.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxorubicin + TANDEM™ embozene microspheres
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Dispersion for injection in pre-filled syringe
    Routes of administration
    Intraarterial use
    Dosage and administration details
    TANDEM™ embozene microspheres are available in three different sizes, in 2 ml and 3 ml volumes of product and are supplied in preloaded vials and syringes.The maximum loadable amount on the hydrospheres 50 mg of Doxorubicina for ml. The maximum injectable dose of Doxorubicin for each treatment is 150 mg and therefore the maximum amount of microspheres that can be used for each treatment is 3 ml. The size of microspheres that will be used in this study is up to 100 ± 25 μm.

    Arm title
    		 TAE-arm
    Arm description
    		 The TAE will be performed with Embozene microspheres (Boston Scientific). Embozene microspheres are spherical particles of hydrogel, precisely calibrated, biocompatible, non-absorbable and coated with a perfluorinated inorganic polymer (Polyzene®-F). To this product it is necessary to add an appropriate amount of non-ionic contrast medium in order to obtain a homogeneous suspension and with good visibility during the injection under fluoroscopy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TANDEM™ embozene microspheres
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    Embozene microspheres are offered in vials containing 1 ml of suspended product in physiological saline solution for apyrogenic sterile transport. The total volume of the Embozene microspheres, including the transport solution, is about 7 ml.

    Number of subjects in period 1
    		DEB-TACE TAE-arm
    Started
    55
    56
    Completed
    13
    12
    Not completed
    42
    44
         Consent withdrawn by subject
    1
    -
         Physician decision
    10
    5
         Death
    7
    11
         Excluded from the inclusion criteria
    15
    16
         Lost to follow-up
    9
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DEB-TACE
    Reporting group description
    		 The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM (Boston Scientific) microspheres. TANDEM™ embozene microspheres are made of non-resorbable, biocompatible, hydrogel microspheres, subjected to precision calibration and coated with an inorganic perfluorate polymer (Polyzene®-F). Thanks to their design, the microspheres can be loaded with drugs, such as doxorubicin, in order to administer a local, controlled and constant dose of the drug to the tumor sites affected after embolization.

    Reporting group title
    TAE-arm
    Reporting group description
    		 The TAE will be performed with Embozene microspheres (Boston Scientific). Embozene microspheres are spherical particles of hydrogel, precisely calibrated, biocompatible, non-absorbable and coated with a perfluorinated inorganic polymer (Polyzene®-F). To this product it is necessary to add an appropriate amount of non-ionic contrast medium in order to obtain a homogeneous suspension and with good visibility during the injection under fluoroscopy.

    Reporting group values
    		 DEB-TACE TAE-arm Total
    Number of subjects
    		 55 56 111
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 18 25 43
        From 65-84 years
    		 37 31 68
        85 years and over
    		 0 0 0
        From 18 - 64 years
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.7 ( 9.7 ) 67.4 ( 10.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 9 15
        Male
    		 49 47 96
    Child-Pugh
    Units: Subjects
        5A
    		 26 27 53
        6A
    		 19 13 32
        7B
    		 10 16 26
    MELD
    Units: Subjects
        6-9
    		 31 21 52
        10-13
    		 21 28 49
        14+
    		 3 7 10
    Number of lesions
    Units: Subjects
        Single
    		 29 27 56
        Oligonodular
    		 11 13 24
        Multiple
    		 15 16 31
    Bilirubin
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 1.21 ( 0.66 ) 1.45 ( 0.66 ) -
    Albumin
    Units: g/dL
        arithmetic mean (standard deviation)
    		 3.78 ( 0.49 ) 3.67 ( 0.43 ) -
    Creatinine
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 0.85 ( 0.24 ) 0.83 ( 0.25 ) -
    Max dimension
    Units: mm
        arithmetic mean (standard deviation)
    		 24.7 ( 11.2 ) 24.4 ( 9.5 ) -
    Days of hospitalization
    Units: Days
        arithmetic mean (standard deviation)
    		 4.62 ( 2.24 ) 5.20 ( 2.92 ) -

    End points

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    End points reporting groups
    Reporting group title
    DEB-TACE
    Reporting group description
    		 The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM (Boston Scientific) microspheres. TANDEM™ embozene microspheres are made of non-resorbable, biocompatible, hydrogel microspheres, subjected to precision calibration and coated with an inorganic perfluorate polymer (Polyzene®-F). Thanks to their design, the microspheres can be loaded with drugs, such as doxorubicin, in order to administer a local, controlled and constant dose of the drug to the tumor sites affected after embolization.

    Reporting group title
    TAE-arm
    Reporting group description
    		 The TAE will be performed with Embozene microspheres (Boston Scientific). Embozene microspheres are spherical particles of hydrogel, precisely calibrated, biocompatible, non-absorbable and coated with a perfluorinated inorganic polymer (Polyzene®-F). To this product it is necessary to add an appropriate amount of non-ionic contrast medium in order to obtain a homogeneous suspension and with good visibility during the injection under fluoroscopy.

    Primary: Time to Progression after TAE and DEB-TACE

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    End point title
    		 Time to Progression after TAE and DEB-TACE
    End point description
    Compare TTP since randomization, as recommended from expert panel opinion, after TAE and DEB-TACE in a homogeneous HCC patient population and using small size beads in both arms.
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 DEB-TACE TAE-arm
    Number of subjects analysed
    41
    33
    Units: Months
    median (standard error)
        TTP
    7.98 ( 3.24 )
    7.56 ( 3.35 )
    Statistical analysis title
    		 Time-to-event (Kaplan-Meier)
    Statistical analysis description
    Nonparametric method used to estimate the probability of survival past given time points
    Comparison groups
    DEB-TACE v TAE-arm
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [1]
    Method
    		 Kaplan-Meier curve
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.831
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.522
         upper limit
    		 1.322
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.92
    Notes
    [1] - P-value: 0.338

    Secondary: Radiologic tumor response (mRECIST)

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    End point title
    		 Radiologic tumor response (mRECIST)
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 DEB-TACE TAE-arm
    Number of subjects analysed
    54
    55
    Units: n
        Complete Response
    31
    27
        Partial Response
    15
    21
        Stable Disease
    1
    2
        Progressive Disease
    7
    5
    Statistical analysis title
    		 Best Overall Response (BOR) at 6 months
    Statistical analysis description
    Radiological response of the tumor assessed using dedicated criteria (modified Response Evaluation Criteria In Solid Tumors, mRECIST) was evaluated in terms of Best Overall Response at 6 months and compared in the two treatments
    Comparison groups
    DEB-TACE v TAE-arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [2]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [2] - P-value: 0,586

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Compare OS since randomization after TAE and DEB-TACE in a homogeneous HCC patient population and using small size beads in both arms.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 DEB-TACE TAE-arm
    Number of subjects analysed
    7
    11
    Units: Months
    arithmetic mean (standard error)
        OS
    24.40 ( 0.69 )
    22.00 ( 1.07 )
    Statistical analysis title
    		 Time-to-event (Kaplan-Meier)
    Statistical analysis description
    Nonparametric method used to estimate the probability of survival past given time points
    Comparison groups
    DEB-TACE v TAE-arm
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [3]
    Method
    		 Kaplan-Meier curve
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.697
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.657
         upper limit
    		 4.383
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.67
    Notes
    [3] - P-value: 0.270

    Secondary: Cost effectiveness

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    End point title
    		 Cost effectiveness
    End point description
    Compare cost-effectiveness of DEB-TACE vs TAE after the entire follow-up, because, if oncologic outcomes for these two procedures are equivalent, cost containment alone should be a strong reason to support a shift from TACE to TAE
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 DEB-TACE TAE-arm
    Number of subjects analysed
    50
    55
    Units: Days
    arithmetic mean (standard deviation)
        Days of hospitalization
    4.62 ( 2.24 )
    5.20 ( 2.92 )
    Statistical analysis title
    		 Comparison betweens 2 group's means
    Statistical analysis description
    The cost-effectiveness ratio of DEB-TACE vs TAE was evaluated considering that, given the same effectiveness of the two treatments highlighted by the previous points, there was no statistically significant difference in terms of hospitalization days between DEB-TACE and TAE, but a treatment price of the former significantly higher than the latter would lead to the suggestion of using TAE treatment instead of TACE as it is more advantageous in economic terms without losing effectiveness.
    Comparison groups
    DEB-TACE v TAE-arm
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.713
         upper limit
    		 0.553
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [4] - P-value: 0.638

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    DEB-TACE
    Reporting group description
    		 -

    Reporting group title
    TAE-arm
    Reporting group description
    		 -

    Serious adverse events
    		 DEB-TACE TAE-arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 56 (3.57%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Removal of common bile duct stones
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Liver abscess
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 56 (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: 0.04%
    Non-serious adverse events
    		 DEB-TACE TAE-arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 56 (0.00%)
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Biliary stenosis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 56 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2019
    Amendment of core documents at the request of the local Ethics Committee
    12 Apr 2023
    Change of Principal Investigator in the coordinating site

    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.
    None reported
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