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    Clinical Trial Results:
    A multi-centre, open-label, single therapy, dose ranging study to characterise the pharmacokinetics and tolerability of BTDS 5-20 μg/h in children who require opioid analgesia for moderate to severe mouth pain secondary to chemotherapy induced mucositis

    Summary
    EudraCT number
    2008-002428-27
    Trial protocol
    GB   DK  
    Global end of trial date
    21 Oct 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Dec 2016
    First version publication date
    30 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BUP1501
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00947466
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Mundipharma Research Ltd.
    Sponsor organisation address
    194-198 Cambridge Science Park, Cambridge, United Kingdom, CB4 0GW
    Public contact
    Mundipharma Research Ltd., European Medical Operations, +44 1223424900, info@contact-clinical-trials.com
    Scientific contact
    Mundipharma Research Ltd., European Medical Operations, +44 1223424900, info@contact-clinical-trials.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Oct 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To characterise the pharmacokinetics of BTDS 5-20 μg/h in children.
    Protection of trial subjects
    Approximately 15 subjects weighing ≥25kg were to be recruited in the first phase of the study. The data obtained from these subjects were reviewed by an IDSMC. If the IDSMC was satisfied that there are no significant safety concerns then approximately 15 further subjects were to be recruited weighing ≥25kg and approximately 30 further subjects were to be recruited weighing ≥15kg and <25kg. Changed To: Approximately 15 subjects weighing ≥10kg will be recruited in the first phase of the study. The data obtained from these subjects will be reviewed by an IDSMC. If the IDSMC is satisfied that there are no significant safety concerns then recruitment will continue. [Protocol amendment number 4, 12 Apr 2010, (UK) and number 2, 05 May 2010, (DK)]. Addition: The IDSMC will also review the data after approximately 15 further subjects weighing ≥12kg have been recruited. [Protocol amendment number 5, 04 Jul 2011, (UK) and number 3, 27 Jul 2011, (DK)].
    Background therapy
    On Day 1 subjects were allowed rescue doses of morphine to treat any breakthrough pain. Each rescue dose should not have exceeded 1/6th of the total daily morphine dose. On Days 2-3 it was recommended that any rescue dose was 1/12th of the total daily morphine dose. If this failed to control the pain and further rescue doses were required they could be increased to 1/6th of the total daily morphine dose. From Day 4 onwards when the maximum effect of buprenorphine was likely to be established, a continuous infusion of morphine should have been commenced for any subjects who required more than 3 rescue doses in the previous 24 hours. The total continuous infusion over 24 hours should have been equivalent to the total dose of morphine received as rescue analgesia in the previous 24 hour period. For subsequent days (including post patch removal), the continuous infusion may have been adjusted according to the clinical impression of the mucositis, pain scores, opioid side effects and the requirements for additional rescue doses. On Day 8 when the patch was removed, if required, a continuous morphine infusion could have been commenced at 0.01mg/kg/hour and reduced by 50% on Day 8. Rescue doses of PO or IV morphine could have been used throughout the follow up period to treat any breakthrough pain at 1/6th of the total daily morphine dose. All doses of supplementary medication (date, time, and dose) were recorded in the CRF. Any changes in concomitant medication were recorded throughout the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    1
    Children (2-11 years)
    15
    Adolescents (12-17 years)
    9
    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
    All 25 subjects were enrolled in one site in the UK between 25 Feb 2010 and 10 Oct 2012.

    Pre-assignment
    Screening details
    A total of 28 subjects provided written informed consent and were screened. 3 subjects failed screening and so 25 subjects were entered the study. Of these, 18 subjects completed and 7 discontinued. The primary reasons for discontinuation were adverse events (1 subject), subject's choice (4 subjects) and lack of therapeutic effect (2 subjects).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Weight <25kg
    Arm description
    Subjects weighing ≥10kg and <25kg
    Arm type
    Experimental

    Investigational medicinal product name
    Buprenorphine patches (BTDS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    The study used buprenorphine patches (BTDS) 5mg (5 μg/h), 10mg (10 μg/h) and 20mg (20 μg/h). The dose was determined by subject weight. The nearest available patch size/combination of patches was used. The patch was applied to the upper back region (shoulder blade area) and subjects wore the same patch continuously for 7 days. Subject weight: ≥10kg to <20kg - 5 μg/h ≥20kg to <30kg - 10 μg/h ≥30kg to <40kg - 10 μg/h + 5 μg/h ≥40kg - 20 μg/h

    Arm title
    Weight ≥25kg
    Arm description
    Subjects weighing ≥25kg
    Arm type
    Experimental

    Investigational medicinal product name
    Buprenorphine patches (BTDS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    The study used buprenorphine patches (BTDS) 5mg (5 μg/h), 10mg (10 μg/h) and 20mg (20 μg/h). The dose was determined by subject weight. The nearest available patch size/combination of patches was used. The patch was applied to the upper back region (shoulder blade area) and subjects wore the same patch continuously for 7 days. Subject weight: ≥10kg to <20kg - 5 μg/h ≥20kg to <30kg - 10 μg/h ≥30kg to <40kg - 10 μg/h + 5 μg/h ≥40kg - 20 μg/h

    Number of subjects in period 1
    Weight <25kg Weight ≥25kg
    Started
    7
    18
    Completed
    6
    12
    Not completed
    1
    6
         Lack of efficacy
    -
    2
         Adverse event, non-fatal
    -
    1
         Consent withdrawn by subject
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Weight <25kg
    Reporting group description
    Subjects weighing ≥10kg and <25kg

    Reporting group title
    Weight ≥25kg
    Reporting group description
    Subjects weighing ≥25kg

    Reporting group values
    Weight <25kg Weight ≥25kg Total
    Number of subjects
    7 18 25
    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)
    1 0 1
        Children (2-11 years)
    6 9 15
        Adolescents (12-17 years)
    0 9 9
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    4 ± 2 11.1 ± 3.03 -
    Gender categorical
    Units: Subjects
        Female
    3 7 10
        Male
    4 11 15
    Race
    Units: Subjects
        Caucasian
    4 17 21
        Black
    2 1 3
        Asian
    1 0 1
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    16.5 ± 4.79 39.4 ± 11.19 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    97.5 ± 14.39 149.6 ± 15.62 -

    End points

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    End points reporting groups
    Reporting group title
    Weight <25kg
    Reporting group description
    Subjects weighing ≥10kg and <25kg

    Reporting group title
    Weight ≥25kg
    Reporting group description
    Subjects weighing ≥25kg

    Primary: Buprenorphine AUCt

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    End point title
    Buprenorphine AUCt
    End point description
    Buprenorphine AUCt values were determined from plasma buprenorphine concentrations measured from the time of dosing to the last measurable concentration.
    End point type
    Primary
    End point timeframe
    Blood samples (2 mL each sample) for pharmacokinetic assessments were drawn at the following times 0h (before patch application), 24h, 48h, 72h, 96h, 120h, 144h, 168h (before patch removal), 192h, 216h, 240h, 264h.
    End point values
    Weight <25kg Weight ≥25kg
    Number of subjects analysed
    7
    18
    Units: pg.h/mL
        geometric mean (geometric coefficient of variation)
    21100.52 ± 95
    34475.01 ± 56
    Statistical analysis title
    Weight <25kg versus Weight ≥ 25kg
    Statistical analysis description
    Dose adjusted area under the plasma concentration-time curve (AUCt/D) values were compared between weight groups (test versus reference, where the reference dose was Weight≥ 25 kg) using an analysis of variance (ANOVA) with fixed terms for weight group (if applicable) on the logarithmic-transformed values.
    Comparison groups
    Weight <25kg v Weight ≥25kg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Ratio (%) (Test/Reference)
    Point estimate
    172.7
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    103.69
         upper limit
    287.65

    Primary: Buprenorphine Cmax

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    End point title
    Buprenorphine Cmax
    End point description
    Buprenorphine Cmax values were determined from plasma buprenorphine concentrations measured from the time of dosing to the last measurable concentration.
    End point type
    Primary
    End point timeframe
    Blood samples (2 mL each sample) for pharmacokinetic assessments were drawn at the following times 0h (before patch application), 24h, 48h, 72h, 96h, 120h, 144h, 168h (before patch removal), 192h, 216h, 240h, 264h.
    End point values
    Weight <25kg Weight ≥25kg
    Number of subjects analysed
    7
    18
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    175.5 ± 70
    325.4 ± 40
    Statistical analysis title
    Weight <25kg versus Weight ≥25kg
    Statistical analysis description
    Dose adjusted maximum observed concentration (Cmax/D) values were compared between weight groups (test versus reference, where the reference dose was Weight ≥25 kg) using an analysis of variance (ANOVA) with fixed terms for weight group (if applicable) on the logarithmic-transformed values.
    Comparison groups
    Weight <25kg v Weight ≥25kg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Ratio (%) (Test/Reference)
    Point estimate
    152.19
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    104.24
         upper limit
    222.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded from the time a subject provided their informed consent at screening until 14 days after the subject's completion/discontinuation visit.
    Adverse event reporting additional description
    Any AE that was still ongoing 14 days after the completion/discontinuation visit had an end date of ‘ongoing’ in the CRF, however the Investigator continued to follow up ongoing AEs and record information in the source documents.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Weight <25kg
    Reporting group description
    Subjects weighing ≥10kg and <25kg

    Reporting group title
    Weight ≥25kg
    Reporting group description
    Subjects weighing ≥25kg

    Serious adverse events
    Weight <25kg Weight ≥25kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 18 (22.22%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutrophenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Miosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Therapeutic response decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Aspergillosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Weight <25kg Weight ≥25kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    18 / 18 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Hypotension
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 18 (27.78%)
         occurrences all number
    1
    8
    Pallor
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Immune system disorders
    Aspergillosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    5
    General disorders and administration site conditions
    Application site discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Application site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Application site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Application site pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Crepitations
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Device occlusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    3
    Face oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gait disturbance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 18 (16.67%)
         occurrences all number
    2
    4
    Therapeutic response decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Personality Change
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Excoriation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Blood phosphorus increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    Blood potassium increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood sodium decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Drug level increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Fungal test positive
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 18 (22.22%)
         occurrences all number
    2
    5
    International normalised ratio increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 18 (16.67%)
         occurrences all number
    3
    4
    PcO2 increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ph urine decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Platelet Count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 18 (16.67%)
         occurrences all number
    2
    3
    Stool analysis normal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Weight increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Epistaxis
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory distress
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Coagulopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Febrile neutropenia
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 18 (16.67%)
         occurrences all number
    4
    3
    Neutropenia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Balance disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dyskinesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Encephalopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Incoherent
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Eye disorders
    Eye oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Eye pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Eye pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Miosis
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Ocular hyperaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Tympanic membrane disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 18 (27.78%)
         occurrences all number
    2
    6
    Abdominal pain upper
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 18 (16.67%)
         occurrences all number
    4
    3
    Diarrhoea
         subjects affected / exposed
    4 / 7 (57.14%)
    5 / 18 (27.78%)
         occurrences all number
    8
    8
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Haematemesis
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 18 (11.11%)
         occurrences all number
    1
    4
    Haematochezia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ileus paralytic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Lip dry
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Lip swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Loose tooth
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 18 (27.78%)
         occurrences all number
    1
    5
    Oesophagitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pancreatitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Proctalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Retching
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Tongue Coated
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 7 (42.86%)
    6 / 18 (33.33%)
         occurrences all number
    5
    7
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Renal impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    3
    Excessive granulation tissue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Livedo reticularis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Pain of skin
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 18 (22.22%)
         occurrences all number
    1
    5
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rash generalised
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rash macular
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Skin depigmentation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin discolouration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Limb discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    4
    Upper extremity mass
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    5 / 18 (27.78%)
         occurrences all number
    4
    7
    Hypophagia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Catheter site infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Device related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oral Candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pneumonia influenzal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Varicella
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Vulvovaginal Candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2008
    Provides guidance with respect to the number of days the subjects need to remain as inpatients. All subjects need to remain as inpatients until patch removal (Day 8). From Day 8 to Day 12, subjects do not need to be inpatients as long as they return daily for assessments. PCO2 and oxygen saturation monitoring will be continuous up until Day 8. Provides further guidance that blood samples can now be taken from a central line as well as an indwelling cannula. Clarifies that hospitals can use their own internal protocol with respect to the use of Naloxone Hydrochloride.
    20 Feb 2009
    Addresses the fact that after discussions with the Medicines for Children Research Network (MCRN), it was decided that recruitment would only be open to subjects weighing ≥15kg. The study will now be conducted in two phases with subjects weighing ≥25kg being recruited in the first phase of the study. The data obtained from these subjects will then be reviewed by an Independent Data and Safety Monitoring Committee (IDSMC). If the IDSMC is satisfied that there are no significant safety concerns, subjects weighing ≥15kg and <25kg will then be included in the second phase of the study. This approach also leads to slight changes in dose being administered for safety purposes. As this study will now be only conducted in children weighing ≥15kg, this leads to a change in study title. The study title now is: BUP1501: A multi-centre, open-label, single therapy, dose ranging study to characterise the pharmacokinetics and tolerability of BTDS 5-20 μg/h in children who require opioid analgesia for severe mouth pain secondary to chemotherapy induced mucositis Also addresses the fact that the original protocol was not clear that the capnography was mandatory and continuous for the whole time that the subject had the patch applied, so this has been re-worded. Recommends that the patch is positioned on/near the subject’s shoulder blade and that the patch can be removed if it is felt the subject has achieved adequate pain control
    21 Apr 2009
    Addresses the fact that 7-day buprenorphine transdermal system has a changed therapeutic indication in adults and is now indicated for the treatment of non-malignant pain of moderate intensity when an opioid is necessary for obtaining adequate analgesia. After extensive discussions with Dr Richard Hain (Principal Investigator) and the Danish Regulatory Authorities (DKMA) who act as the reference Member State for BuTrans, it was felt that this study would benefit from assessing whether any children entering the study had moderate to severe pain. There would be no change in the study design; the FLACC or FPS (R) pain scales will be utilised in the same manner and the pain score on entry will be used as a baseline pain score. These pain scores would be reviewed to see if some children classified their pain as moderate rather than severe. Although we expect the majority of children suffering oral mucositis to experience severe pain we know that pain is very subjective and some may report moderate pain and this would give us the opportunity to characterise the pharmacokinetics in moderate to severe pain. As this study will now be conducted in children with moderate to severe pain, this leads to a change in study title. The study title now is: BUP1501: A multi-centre, open-label, single therapy, dose ranging study to characterise the pharmacokinetics and tolerability of BTDS 5-20 μg/h in children who require opioid analgesia for moderate to severe mouth pain secondary to chemotherapy induced mucositis Also addresses some omissions from amendment number 2. In amendment number 2, all references to “age group” should have been changed to “weight group”, however some of these were omitted erroneously.
    12 Apr 2010
    Instigated after a meeting with Dr Richard Hain (Chief Investigator), Dr Richard Howard (Principal Investigator, Great Ormond Street Hospital, UK) and representatives from the Medicines for Children Research Network, UK. It was discussed and agreed that subjects weighing ≥10kg could safely be recruited into the study (current weight limit ≥15kg) and that subjects of any weight could be recruited initially (currently recruiting only subjects weighing ≥25kg). It was felt by all of the clinicians present that neither of these two changes would compromise subject safety. It was also decided that the measurement of PCO2 andoxygen saturation levels during the study would be discretionary as this intervention was not normally part of clinical practice in these subjects.
    04 Jul 2011
    Instigated following the meeting of the Independent Data Monitoring Committee (IDSMC) on 01 July 2011. Following an interim whole statistics analysis, 2 out of 15 patients were identified as having buprenorphine AUCt values of 87.5 and 85.3 ng.h/mL, which are above the guideline limits set out in the protocol. Guidelines for the IDMC are to recommend stopping the study if any subject has an AUCt measure of buprenorphine greater than 82 ng.h/mL. It was therefore decided by the sponsor on the 20 April 2011 to put recruitment on hold until the IDSMC had convened to review the interim safety data and pharmacokinetic exposure profile and make a recommendation on whether the study should continue in its current design. The IDSMC suggested the following modifications to the protocol, which form the basis of this amendment: • Increase the lower age limit to 2 years • Increase the lower weight limit to 12 kg • Increase the AUCt safety threshold recommendation for the IDMC, based on data from more recent healthy volunteer studies (increased to greater than 156 ng.h/mL). • Recommend that when a patient is immobile such as in a high dependency unit or PICU that an alternative patch site (above the abdomen) could be considered • If the Investigator feels it is appropriate to use a different strength of patch from the recommended dose, then this is allowable (especially if the subject has a weight close to the lower limits of the dose) • A further meeting of the IDSMC to be convened after the next 15 patients have been recruited with the revised protocol The risk benefit document has been updated with the above information and there is considered to be no change to the risk benefit profile for the IMP.
    06 Sep 2011
    Instigated following a recommendation from the UK Ethics Committee (letter dated 15 August 2011). Further guidance has been included in the protocol regarding how close to the lower weight limit a child should be in order to allow the clinician to exercise their discretion to change to a lower dose.

    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.
    This trial was prematurely discontinued after only 25 of the 60 planned subjects were enrolled due to recruitment issues. However, it was agreed that further recruitment into this study would not have added any meaningful information.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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