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    Clinical Trial Results:
    An Open-Label Study of XOMA 358, with Optional Dose Escalation, in Patients with Congenital Hyperinsulinism

    Summary
    EudraCT number
    2016-001275-80
    Trial protocol
    DE  
    Global end of trial date
    20 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    04 May 2018
    First version publication date
    04 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    X358605
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Xoma (US) LLC
    Sponsor organisation address
    2200 Powell Street, Suite 310, Emeryville, United States, CA 94608
    Public contact
    Kirk Jonhson, Xoma (US) LLC, +1 501 204 7439, Kirk.Johnson@xoma.com
    Scientific contact
    Kirk Jonhson, Xoma (US) LLC, +1 501 204 7439, Kirk.Johnson@xoma.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this Phase 2 study was to evaluate the safety, pharmacokinetics and pharmacodynamics of XOMA 358 in patients aged 12 years and older with hypoglycemia associated with congenital hyperinsulinism (CHI).
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable local regulatory requirements. Patients were assured that they could withdraw from the study at any time without jeopardizing their medical care. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Sep 2016
    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
    Germany: 4
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    2
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects with blood glucose < 60 mg/dL or with clinically meaningful decrease in blood glucose in conjunction with symptoms during monitored fasts, who could be safely washed out of background medications used to treat CHI and who met all inclusion/exclusion criteria were enrolled. No subjects failed screening.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Cohort 1
    Arm description
    All patients were enrolled in Cohort 1 and received a first dose of 3 mg/kg X358 on Day 1 followed by a second dose of 6 mg/kg X358 on Day 4 or 5
    Arm type
    Experimental

    Investigational medicinal product name
    X358
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single 3 mg/kg dose of X358 followed by a single 6 mg/kg dose. Both doses administered as an IV infusion over 30 minutes.

    Number of subjects in period 1
    Cohort 1
    Started
    4
    Completed
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Reporting group values
    overall trial Total
    Number of subjects
    4 4
    Age categorical
    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)
    2 2
        Adults (18-64 years)
    2 2
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.5 ± 13.87 -
    Gender categorical
    Units: Subjects
        Female
    1 1
        Male
    3 3
    K(ATP) mutation
    Units: Subjects
        Yes
    2 2
        no
    2 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    All patients were enrolled in Cohort 1 and received a first dose of 3 mg/kg X358 on Day 1 followed by a second dose of 6 mg/kg X358 on Day 4 or 5

    Primary: Cumulative time blood glucose < 70 mg/dL (< 3.89 mM)

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    End point title
    Cumulative time blood glucose < 70 mg/dL (< 3.89 mM) [1]
    End point description
    Duration of hypoglycaemia (blood glucose < 70 mg/dL) is presented for Baseline values collected during the Screening period (where 24-hour CGM was recorded) and Days 1 to D12 post 3 mg/kg X358 and 6 mg/kg X358 administration. Duration of hypoglycaemia is calculated as the sum of the total time in the specified threshold; number of data points < threshold multiplied by 5 minutes.
    End point type
    Primary
    End point timeframe
    Glucose was followed via the continuous glucose monitor from check in (5 days prior to dosing) until Day 29 post dose.
    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: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: minutes
    arithmetic mean (standard deviation)
        Baseline; 3 mg/kg Dose
    558.44 ± 307.699
        Day 1 to 12; 3 mg/kg Dose
    703.85 ± 520.096
        Baseline; 6 mg/kg Dose
    558.44 ± 307.699
        Day 1 to 12; 6 mg/kg Dose
    483.65 ± 323.573
    No statistical analyses for this end point

    Primary: Frequency of hypoglycaemic events (< 60 mg/dL)

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    End point title
    Frequency of hypoglycaemic events (< 60 mg/dL) [2]
    End point description
    The number of hypoglycemic episodes (< 60 mg/dL) over each 24-hour day was reported, and summarised herein for Baseline (taken as average number of episodes for non-fast days during checkin and Screening where 24-hour CGM was recorded, combined) and post-treatment (average number of episodes for all Days D1 to D12 combined). An instance of hypoglycemia was defined as 3 consecutive measurements within a 15 minute window that are < 60 mg/dL.
    End point type
    Primary
    End point timeframe
    Glucose was followed via the continuous glucose monitor from check in (5 days prior to dosing) until Day 29 post dose.
    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: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: Events
    arithmetic mean (standard deviation)
        Baseline; 3 mg/kg Dose
    2.81 ± 2.569
        Day 1 to 12, 3 mg/kg Dose
    4.21 ± 3.148
        Baseline; 6 mg/kg
    2.81 ± 2.569
        Day 1 to 12; 6 mg/kg Dose
    3.65 ± 2.461
    No statistical analyses for this end point

    Primary: Concomitant treatment/medications used during rescue

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    End point title
    Concomitant treatment/medications used during rescue [3]
    End point description
    Rescue medication taken by subjects for hypoglycaemia during the study is presented.
    End point type
    Primary
    End point timeframe
    Concomitant treatment used during rescue were reported from Baseline until the end of the study.
    Notes
    [3] - 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: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: Rescue medication required
        Glucose infusion
    1
        Paracetamol
    1
    No statistical analyses for this end point

    Primary: Glucose area under the curve (AUC24)

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    End point title
    Glucose area under the curve (AUC24) [4]
    End point description
    Glucose (mg/dL) AUC(0-24) via CGMS is presented for Baseline #1 (average of AUC on non-fast days (during checkin and Screening period where 24 hr CGM was recorded), Baseline #2 (average of AUC on all days (checkin and Screening period where 24hr CGM was recorded) and Days 1 to 11 post-dose, checkout [Day 16) and follow-up visits [Day 29 and 33])
    End point type
    Primary
    End point timeframe
    Glucose was followed via the continuous glucose monitor from check in (5 days prior to dosing) until Day 29 post dose.
    Notes
    [4] - 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: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline #1; 3 mg/kg Dose
    2023.875 ± 283.2190
        Baseline #2; 3 mg/kg Dose
    1972.454 ± 285.0928
        Day 1; 3 mg/kg Dose
    1898.10 ± 778.72
        Day 2; 3 mg/kg Dose
    1911.73 ± 577.06
        Day 3; 3 mg/kg Dose
    1876.89 ± 450.43
        Day 4; 3 mg/kg Dose
    2600.35 ± 149.46
        Baseline #1; 6 mg/kg Dose
    2023.875 ± 283.2190
        Baseline #2; 6 mg/kg Dose
    1972.454 ± 285.0928
        Day 1; 6 mg/kg Dose
    2286.32 ± 758.49
        Day 2; 6 mg/kg Dose
    2288.27 ± 691.35
        Day 3; 6 mg/kg Dose
    2123.73 ± 710.25
        Day 4; 6 mg/kg Dose
    2219.66 ± 785.31
        Day 5; 6 mg/kg Dose
    2196.83 ± 621.43
        Day 6; 6 mg/kg Dose
    2210.13 ± 517.73
        Day 7; 6 mg/kg Dose
    2110.61 ± 568.05
        Day 8; 6 mg/kg Dose
    2184.74 ± 495.83
        Day 9; 6 mg/kg Dose
    2270.03 ± 976.55
        Day 10; 6 mg/kg Dose
    2209.28 ± 538.09
        Day 11; 6 mg/kg Dose
    2412.12 ± 492.44
        Check Out; 6 mg/kg Dose
    2311.46 ± 461.112
        Follow-up; 6 mg/kg Dose
    1546.44 ± 538.014
    No statistical analyses for this end point

    Primary: Fasting and postprandial glucose, insulin, C-peptide

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    End point title
    Fasting and postprandial glucose, insulin, C-peptide [5]
    End point description
    Glucose measurements via a bedside glucometer, serum insulin and C-peptide measurements are presented for fasting days (0-hour, pre-breakfast) for both Baseline and post-treatment days. Post-prandial measurements are presented for both Baseline (average of 0-hour, pre-breakfast measurements) and post-treatment (average of 2-hour post-breakfast measurements).
    End point type
    Primary
    End point timeframe
    AM fasting: Baseline (Screening period, and prior to dosing on Day 1) and post-treatment (Days 2, 4, 5, 6, 7, 8, and 9) Post-prandial: Baseline (Screening period) and post-treatment (Days 2, 4, 5, 6, 7, 8 and 9)
    Notes
    [5] - 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: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: mg/dL; mIU/L; (ng/mL
    arithmetic mean (standard deviation)
        Glucose; AM Fasting; Baseline; 3 mg/kg Dose
    66.52 ± 16.282
        Glucose; AM Fasting; Post-Treatment; 3 mg/kg Dose
    66.22 ± 29.243
        Glucose; AM Fasting; Baseline; 6 mg/kg Dose
    69.07 ± 18.923
        Glucose; AM Fasting; Post-Treatment; 6 mg/kg Dose
    73.20 ± 25.810
        Glucose; Post-prandial; Baseline; 3 mg/kg Dose
    68.24 ± 17.382
        Glucose; Post-prandial; Post-Treatment; 3 mg/kg Do
    122.75 ± 70.025
        Glucose; Post-prandial; Baseline; 6 mg/kg Dose
    68.24 ± 17.382
        Glucose; Post-prandial; Post-Treatment; 6 mg/kg Do
    146.40 ± 39.863
        Insulin; AM Fasting; Baseline; 3 mg/kg Dose
    12.383 ± 4.4984
        Insulin; AM Fasting; Post-Treatment; 3 mg/kg Dose
    57.225 ± 43.6895
        Insulin; AM Fasting; Baseline; 6 mg/kg Dose
    41.800 ± 45.5670
        Insulin; AM Fasting; Post-Treatment; 6 mg/kg Dose
    114.604 ± 52.2824
        Insulin; Post-prandial; Baseline; 3 mg/kg Dose
    12.938 ± 5.7387
        Insulin; Post-prandial; Post-Treatment; 3 mg/kg Do
    296.200 ± 210.6859
        Insulin; Post-prandial; Baseline; 6 mg/kg Dose
    12.938 ± 5.7387
        Insulin; Post-prandial; Post-Treatment; 6 mg/kg Do
    559.481 ± 164.0734
        C-peptide; AM Fasting; Baseline; 3 mg/kg Dose
    1.8458 ± 0.43435
        C-peptide; AM Fasting; Post-Treatment; 3 mg/kg Dos
    1.3800 ± 0.63038
        C-peptide; AM Fasting; Baseline; 6 mg/kg Dose
    2.1296 ± 0.77543
        C-peptide; AM Fasting; Post-Treatment; 6 mg/kg Dos
    2.0569 ± 0.56838
        C-peptide; Post-prandial; Baseline; 3 mg/kg Dose
    1.8725 ± 0.52122
        C-peptide; Post-prandial; Post-Treatment; 3 mg/kg
    7.4588 ± 4.75957
        C-peptide; Post-prandial; Baseline; 6 mg/kg Dose
    1.8725 ± 0.52122
        C-peptide; Post-prandial; Post-Treatment; 6 mg/kg
    9.7088 ± 2.11836
    No statistical analyses for this end point

    Primary: Time to hypoglycemia during provocation (< 60 mg/dL [< 3.33 mM])

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    End point title
    Time to hypoglycemia during provocation (< 60 mg/dL [< 3.33 mM]) [6]
    End point description
    First occurrence of glucose < 60 mg/dL (3.33 mM) from the start of fasting challenge post-dosing of 3 and 6 mg/kg X358 on Day 3 (provocation day) is presented.
    End point type
    Primary
    End point timeframe
    Day 3 post dose (Provocation)
    Notes
    [6] - 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: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: minutes
    arithmetic mean (standard deviation)
        3 mg/kg Dose
    2920.0 ± 3704.70
        6 mg/kg Dose
    5797.5 ± 943.99
    No statistical analyses for this end point

    Post-hoc: Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (non-fast)

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    End point title
    Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (non-fast)
    End point description
    Percentage change in glucose measurements (mg/dL) via CGM over 24 hours on non-fast Days 1-7 and 8-12 post 6 mg/kg X358 dose versus Baseline glucose values for non-fast days (S-1 to S4 where 24hr CGM is recorded) is presented.
    End point type
    Post-hoc
    End point timeframe
    Glucose was followed via the continuous glucose monitor from check in (5 days prior to dosing) until Day 29 post dose.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: Percent change from baseline
    median (full range (min-max))
        Days 1-7 (non-fast)
    10.226 (-15.70 to 23.81)
        Days 8-12 post 6 mg/kg X358 (non-fast)
    12.738 (-5.82 to 24.22)
    No statistical analyses for this end point

    Post-hoc: Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)

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    End point title
    Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)
    End point description
    Percentage change in glucose measurements (mg/dL) via CGMS over 24 hours on Days 1-8 post 6 mg/kg X358 dose versus Baseline (4-5 days) is presented.
    End point type
    Post-hoc
    End point timeframe
    Glucose was followed via the continuous glucose monitor from check in (5 days prior to dosing) until Day 29 post dose.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: Percent change from baseline
    median (full range (min-max))
        Days 1-8 post 6 mng/kg X358
    12.216 (-10.36 to 24.19)
    No statistical analyses for this end point

    Post-hoc: Subgroup Analysis: Fasting Blood Glucose -Days 4 and 5 vs. Baseline (2-days)

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    End point title
    Subgroup Analysis: Fasting Blood Glucose -Days 4 and 5 vs. Baseline (2-days)
    End point description
    The change in fasting blood glucose (mg/dL) on Days 4 and 5 versus Baseline ( 2-days) is presented.
    End point type
    Post-hoc
    End point timeframe
    Baseline (S3 or S4) to Day 5 post 2nd dose.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: Change from baseline
    median (full range (min-max))
        Days 4 and 5 post 2nd dose
    -1.351 (-4.50 to 37.84)
    No statistical analyses for this end point

    Post-hoc: Subgroup Analysis: Fasting Blood Glucose- Days 4 and 5 vs. Baseline (3-days)

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    End point title
    Subgroup Analysis: Fasting Blood Glucose- Days 4 and 5 vs. Baseline (3-days)
    End point description
    The change in fasting blood glucose (mg/dL) on Days 4 and 5 post 6 mg/kg X358 dose versus Baseline (average of blood glucose on S3, S4 and Day 1 pre-dose) is presented
    End point type
    Post-hoc
    End point timeframe
    Baseline (S3 or S4 and Day pre-dose where fasting blood glucose is recorded) to Day 5 post 2nd dose.
    End point values
    Cohort 1
    Number of subjects analysed
    4
    Units: Change from baseline(3-days)
    median (full range (min-max))
        Days 4 and 5 post 2nd dose
    2.252 (-2.10 to 36.04)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from date of informed consent until end of study.
    Adverse event reporting additional description
    Pre-treatment adverse events were not related to protocol procedures and were related to underlying disease. All Treatment-Emergent Adverse Events were considered unrelated to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    X358
    Reporting group description
    -

    Serious adverse events
    X358
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    X358
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    Investigations
    Eosinophil count increased
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1

    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.
    Due to the small number of patients enrolled into this study, definitive conclusions cannot be drawn
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