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    Clinical Trial Results:
    An Open Label Evaluation of the Safety and Clinical Utility of the Active, Separated System with Enhanced Controller (SSEC) Fentanyl 40 mcg for the Management of Acute Postoperative Pain in Pediatric Patients 12 to Less Than 18 Years of Age

    Summary
    EudraCT number
    2014-002405-37
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    12 Sep 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Nov 2018
    First version publication date
    14 Jul 2017
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Clarification of the timeframe for the primary end point (assessment of participant's ability to use the SSEC).

    Trial information

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    Trial identification
    Sponsor protocol code
    PD2013-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02395653
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Incline Therapeutics Inc., a wholly owned subsidiary of The Medicines Company
    Sponsor organisation address
    900 Saginaw Drive, Suite 200, Redwood City, United States, 94063
    Public contact
    Incline Therapeutics Inc., a wholly owned subsidiary of The Medicines Company, Global Health Science Center, +1 650-241-6800, medical.information@themedco.com
    Scientific contact
    Incline Therapeutics Inc., a wholly owned subsidiary of The Medicines Company, Global Health Science Center, +1 650-241-6800, medical.information@themedco.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001509-PIP01-13
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and clinical utility of the active, separated system with enhanced controller (SSEC) fentanyl 40 micrograms (mcg) for the management of acute, postoperative pain in pediatric participants, 12 to less than 18 years of age.
    Protection of trial subjects
    This study was conducted under the supervision of medical personnel experienced with conducting studies of opioids in children, in accordance with International Conference on Harmonisation Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jun 2015
    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
    United States: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    0
    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)
    71
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Pediatric participants from 12 to less than 18 years of age who had undergone general or regional anesthesia for elective abdominal, pelvic/genitourinary, orthopedic, or thoracic surgery.

    Pre-assignment
    Screening details
    Screening was to take place within 3 weeks of the start of the study. Screening assessments included review of inclusion/exclusion criteria, signature of informed consent, medical history, height, weight, vital signs, and American Society of Anesthesiologists physical status. Participants were also instructed on the use of the SSEC.

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

    Arms
    Arm title
    SSEC
    Arm description
    Post-surgery, participants received IONSYS, (fentanyl hydrochloride), an SSEC fentanyl transdermal system (hereafter referred to as SSEC), that provided on-demand systemic delivery of 40 mcg fentanyl per dose for up to 24 hours, or a maximum of 80 doses, whichever came first, for up to 3 consecutive days (up to 72 hours).
    Arm type
    Experimental

    Investigational medicinal product name
    IONSYS (fentanyl hydrochloride)
    Investigational medicinal product code
    Other name
    SSEC fentanyl
    Pharmaceutical forms
    Transdermal system
    Routes of administration
    Transdermal use
    Dosage and administration details
    IONSYS® is a participant-controlled fentanyl transdermal system that provides on demand systemic delivery of 40 mcg fentanyl per dose for up to 24 hours, or a maximum of 80 doses, whichever comes first. The start of the treatment period (that is to say, Hour 0) began at the time the SSEC system was first assembled and applied to the participant's intact non-irritated skin on the chest or upper outer arm. As needed, the participant could continue to use SSEC for up to 72 hours. Each SSEC system was to be removed at the completion of every 24-hour SSEC treatment period or when 80 doses had been administered from the system, whichever occurred first, and a new SSEC system applied to a new location. Each on-demand dose delivered a nominal 40 mcg fentanyl dose over a 10-minute period, with a maximum of 6 doses delivered each hour.

    Number of subjects in period 1
    SSEC
    Started
    71
    Received at least 1 dose of study drug
    61
    Completed
    59
    Not completed
    12
         Screen failure - exclusion criteria met
    4
         Screen failure-consent withdrawn by participant
    1
         Participant had SSEC application but with 0 dose
    1
         Consent withdrawn by subject
    1
         Screen failure - Investigator decision
    1
         Screen failure - inclusion criteria not met
    3
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SSEC
    Reporting group description
    Post-surgery, participants received IONSYS, (fentanyl hydrochloride), an SSEC fentanyl transdermal system (hereafter referred to as SSEC), that provided on-demand systemic delivery of 40 mcg fentanyl per dose for up to 24 hours, or a maximum of 80 doses, whichever came first, for up to 3 consecutive days (up to 72 hours).

    Reporting group values
    SSEC Total
    Number of subjects
    71 71
    Age categorical
    Participants aged 12 years to less than 18 years
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    71 71
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.7 ± 1.51 -
    Gender categorical
    Units: Subjects
        Female
    50 50
        Male
    21 21

    End points

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    End points reporting groups
    Reporting group title
    SSEC
    Reporting group description
    Post-surgery, participants received IONSYS, (fentanyl hydrochloride), an SSEC fentanyl transdermal system (hereafter referred to as SSEC), that provided on-demand systemic delivery of 40 mcg fentanyl per dose for up to 24 hours, or a maximum of 80 doses, whichever came first, for up to 3 consecutive days (up to 72 hours).

    Subject analysis set title
    Evaluable Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The evaluable population consists of all participants who received fentanyl from the SSEC for at least 3 hours. The evaluable population was used for the primary analysis on clinical utility, pain intensity, and global assessments.

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population consists of all participants who received at least 1 dose of fentanyl from the SSEC. The safety population was used for safety analysis.

    Primary: Assessment Of Participant's Ability To Use The SSEC

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    End point title
    Assessment Of Participant's Ability To Use The SSEC [1]
    End point description
    Investigator's assessment of participant's ability to use the SSEC system safely and effectively. The assessment consisted of a 4-level categorical evaluation (poor, fair, good, and excellent).
    End point type
    Primary
    End point timeframe
    Completed at the time of the participant’s termination of study treatment (up to 72 hours after study drug administration).
    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: Because of the descriptive nature of this study, no formal statistical hypothesis testing was performed.
    End point values
    SSEC
    Number of subjects analysed
    61
    Units: participants
        Poor
    1
        Fair
    2
        Good
    10
        Excellent
    48
        Missing
    0
    No statistical analyses for this end point

    Primary: Assessment Of Adherence Of The SSEC System To Skin

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    End point title
    Assessment Of Adherence Of The SSEC System To Skin [2]
    End point description
    The adhesion of each SSEC was evaluated immediately prior to removal at each 24-hour time point, or at early withdrawal. Adhesion was recorded using the following classification: System adhered to at least 90% of the application area with no edges unattached; System adhered between 75% and 89%; System was <75% adhered and not taped; System was secured with tape. The number of SSEC systems for all time points in each category is presented.
    End point type
    Primary
    End point timeframe
    Immediately prior to removal at each 24-hour time point, or at early withdrawal, for up to 3 consecutive days (up to 72 hours).
    Notes
    [2] - 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: Because of the descriptive nature of this study, no formal statistical hypothesis testing was performed.
    End point values
    SSEC
    Number of subjects analysed
    61 [3]
    Units: SSEC systems
        ≥90% of area with no edges unattached, N=107
    97
        75% to 89%, N=107
    6
        <75% adhered and not taped, N=107
    3
        System was secured with tape, N=107
    1
        Not assessed, N=107
    0
    Notes
    [3] - 107 SSEC systems used by 61 participants were evaluated for this end point.
    No statistical analyses for this end point

    Secondary: Change From Baseline To 1 Hour And 24 Hours In Skin Irritation Score After SSEC Removal

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    End point title
    Change From Baseline To 1 Hour And 24 Hours In Skin Irritation Score After SSEC Removal
    End point description
    Skin irritation at the SSEC application site was to be assessed immediately prior to placement of the study system and at 1 and 24 hours after removal of each study system. The application site was to be scored using the following scale: 0=No evidence of irritation; 1=Minimal erythema, barely perceptible; 2=Definite erythema, readily visible, minimal oedma, or minimal papular response; 3=Erythema and papules; 4=Definite oedma; 5=Erythema, oedma, and papules; 6=Vesicular eruption; 7=Strong reaction spreading beyond the application site.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 hour and 24 hours after SSEC removal.
    End point values
    SSEC
    Number of subjects analysed
    61
    Units: units on a scale
    arithmetic mean (standard deviation)
        System 1, Hour 1, N=61
    1.1 ± 0.94
        System 1, Hour 24, N=48
    1.8 ± 1.43
        System 2, Hour 1, N=39
    1 ± 0.61
        System 2, Hour 24, N=34
    1.6 ± 1.33
        System 3, Hour 1, N=5
    1 ± 1.22
        System 3, Hour 24, N=4
    0.8 ± 1.26
    No statistical analyses for this end point

    Secondary: Number Of Participants To Experience Clinically Relevant Respiratory Depression (CRRD)

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    End point title
    Number Of Participants To Experience Clinically Relevant Respiratory Depression (CRRD)
    End point description
    Respiratory function and occurrence of CRRD was defined as simultaneous occurrence of bradypnoea (respiratory rate <10 breaths per minute for participants 9-15 years of age and sustained for 1 minute, or <8 breaths per minute for participants 16-17 years of age), with excessive sedation (that is, the participant is not easily aroused).
    End point type
    Secondary
    End point timeframe
    From the time of application of the first system through 7 days following end of study drug administration.
    End point values
    SSEC
    Number of subjects analysed
    61
    Units: Number of Participants
        Bradypnoea
    0
        Excessive Sedation
    0
        Simultaneous Bradypnoea and Excessive Sedation
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of application of the first system through 7 days following the end of study drug administration.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    SSEC
    Reporting group description
    Post-surgery, participants received an SSEC fentanyl iontophoretic transdermal system that provided on-demand systemic delivery of 40 mcg fentanyl per dose for up to 24 hours, or a maximum of 80 doses, whichever came first, for up to 3 consecutive days (up to 72 hours).

    Serious adverse events
    SSEC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 61 (1.64%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SSEC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 61 (72.13%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    9
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    10 / 61 (16.39%)
         occurrences all number
    10
    Application site papules
         subjects affected / exposed
    10 / 61 (16.39%)
         occurrences all number
    10
    Pyrexia
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    19 / 61 (31.15%)
         occurrences all number
    23
    Nausea
         subjects affected / exposed
    18 / 61 (29.51%)
         occurrences all number
    19
    Constipation
         subjects affected / exposed
    11 / 61 (18.03%)
         occurrences all number
    11
    Skin and subcutaneous tissue disorders
    Pruritus generalised
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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