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    Clinical Trial Results:
    A Single-Dose Open-Label Study of XOMA 358 in Patients with Congenital Hyperinsulinism (CHI)

    Summary
    EudraCT number
    2015-002847-32
    Trial protocol
    GB  
    Global end of trial date
    13 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
    X358602
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02604485
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Xoma (US) LLC
    Sponsor organisation address
    220 Powell Street, Suite 310, Emeryville, United States, CA 94608
    Public contact
    Kirk Johnson, Xoma (US) LLC, +1 510 204 7439, Kirk.Johnson@xoma.com
    Scientific contact
    Kirk Johnson, Xoma (US) LLC, +1 510 204 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
    02 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety , pharmacokinetics and pharmacodynamics of a single dose of XOMA 358 in patients with hypoglycaemia associated with congenital hyperinsulinism.
    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. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Nov 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 Kingdom: 3
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    10
    EEA total number of subjects
    3
    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)
    8
    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 ≥12 years (UK) or at ≥18 years (US) with a clinical diagnosis of CHI, who could be safely washed out of background CHI medications and met all inclusion/exclusion criteria were enrolled. There were two screen failures. The hypoglycemia inclusion criteria was modified during the study via protocol amendments (see More Information section).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    X358 1 mg/kg
    Arm description
    Single dose X358 1 mg/kg
    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 1 mg/kg IV dose of X358 as an infusion over 30 minutes on 1 occasion.

    Arm title
    X358 3 mg/kg
    Arm description
    Single dose X358 3 mg/kg
    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 IV dose of X358 as an infusion over 30 minutes on 1 occasion

    Arm title
    X358 6 mg/kg
    Arm description
    Single dose X358 6 mg/kg
    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 6 mg/kg IV dose of X358 as an infusion over 30 minutes on 1 occasion

    Arm title
    X358 9 mg/kg
    Arm description
    Single dose X358 9 mg/kg
    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 9 mg/kg IV dose of X358 as an infusion over 30 minutes on 1 occasion.

    Number of subjects in period 1
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Started
    2
    3
    4
    1
    Completed
    2
    3
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    X358 1 mg/kg
    Reporting group description
    Single dose X358 1 mg/kg

    Reporting group title
    X358 3 mg/kg
    Reporting group description
    Single dose X358 3 mg/kg

    Reporting group title
    X358 6 mg/kg
    Reporting group description
    Single dose X358 6 mg/kg

    Reporting group title
    X358 9 mg/kg
    Reporting group description
    Single dose X358 9 mg/kg

    Reporting group values
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg Total
    Number of subjects
    2 3 4 1 10
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    0 1 1 0 2
        Adults (18-64 years)
    2 2 3 1 8
    Age continuous
    Units: years
        median (standard deviation)
    22.5 ± 2.12 23.7 ± 11.50 20.8 ± 7.63 32.0 ± 0 -
    Gender categorical
    Units: Subjects
        Female
    2 0 3 0 5
        Male
    0 3 1 1 5
    K(ATP) mutation
    Units: Subjects
        Yes
    0 2 3 0 5
        No
    2 1 1 1 5

    End points

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    End points reporting groups
    Reporting group title
    X358 1 mg/kg
    Reporting group description
    Single dose X358 1 mg/kg

    Reporting group title
    X358 3 mg/kg
    Reporting group description
    Single dose X358 3 mg/kg

    Reporting group title
    X358 6 mg/kg
    Reporting group description
    Single dose X358 6 mg/kg

    Reporting group title
    X358 9 mg/kg
    Reporting group description
    Single dose X358 9 mg/kg

    Subject analysis set title
    Subgroup Analysis 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with duration of hypoglycemia < 70 mg/dL >= 120 minutes at Baseline (non-fast). Subjects in 1 mg/kg cohort are excluded

    Subject analysis set title
    Subgroup Analysis 2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with average duration of hypoglycemia of < 70 mg/dL >= 120 minutes at Baseline (4-5 days). Subjects in 1 mg/kg cohort are excluded.

    Subject analysis set title
    Subgroup Analysis 3
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All subjects excluding 1 mg/kg cohort

    Primary: Fasting glucose, insulin, C-peptide, ketones, free fatty acids

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    End point title
    Fasting glucose, insulin, C-peptide, ketones, free fatty acids [1]
    End point description
    End of fast values for glucose, insulin, C-peptide, ketones, free fatty acids are presented for Baseline (Day -5) and post dose value (Day 3, 5 or 11). The fast began after the consumption of dinner on the night before each listed day and continued for 24 hours or until blood glucose dropped to < 60 mg/dL or until other parameters were met Blood glucose and ketones were measured with a bedside glucometer, every 3 hours until blood glucose was < 70 mg/dL and every hour until blood glucose was < 60 mg/dL. The fast ended when set criteria was met: Pre-determined fasting time of 24 hours was reached, or Blood glucose was less than 60 mg/dL, or bedside ketones was > 2.5 mmol/L on 2 separate readings, or patient was symptomatic.
    End point type
    Primary
    End point timeframe
    Day -11 prior to dosing and post dose up to Day 11
    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
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Number of subjects analysed
    1
    3
    4
    1
    Units: mg/dL; mIU/L; ng/mL; mmol/L; mEq/L
    arithmetic mean (standard deviation)
        Glucose; Baseline
    74.0 ± 0
    68.3 ± 5.51
    67.8 ± 4.72
    74.0 ± 0
        Glucose; post-dose
    79.0 ± 0
    62.0 ± 0
    67.5 ± 3.42
    52.0 ± 0
        insulin; Baseline
    9.30 ± 0
    4.23 ± 3.465
    7.85 ± 1.353
    9.90 ± 0
        insulin; post-dose
    52.40 ± 0
    9.50 ± 0
    69.95 ± 26.831
    51.00 ± 0
        C-peptide; Baseline
    1.200 ± 0
    0.663 ± 0.3667
    1.203 ± 0.1841
    1.320 ± 0
        C-peptide; post-dose
    2.090 ± 0
    0.690 ± 0
    1.568 ± 0.5881
    1.360 ± 0
        ketones; Baseline
    0.540 ± 0
    0.480 ± 0.3659
    0.255 ± 0.0929
    0.090 ± 0
        ketones; post-dose
    0.100 ± 0
    1.410 ± 0
    0.625 ± 0.3516
    0.060 ± 0
        free fatty acids; Baseline
    0.90 ± 0
    1.10 ± 0.400
    0.88 ± 0.150
    0.20 ± 0
        free fatty acids; post-dose
    0.40 ± 0
    2.10 ± 0
    1.13 ± 0.538
    0.20 ± 0
    No statistical analyses for this end point

    Primary: Glucose area under the curve for each day (AUC24)

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    End point title
    Glucose area under the curve for each day (AUC24) [2]
    End point description
    Glucose area under the curve for each day (AUC24) for non-provocation days (patient did not have OGTT, protein or fasting challenges) are presented. No statistical data is included for patients in the 1 mg/kg group because both patients received diazoxide on Day 5.
    End point type
    Primary
    End point timeframe
    Glucose was followed via the continuous glucose monitor from Baseline (Day -6 to Day -1 prior to dosing) until post dose Day 29.
    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
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Number of subjects analysed
    2
    3
    4
    1
    Units: mg/dL*hr
    arithmetic mean (standard deviation)
        Day -2
    2011.95 ± 173.178
    2596.56 ± 353.453
    2400.8 ± 401.154
    1475.15 ± 0
        Day -1
    1906.97 ± 171.307
    2588.14 ± 356.522
    2234.17 ± 578.298
    1513.05 ± 0
        Day 1
    2017.87 ± 108.686
    2816.83 ± 619.072
    2708.45 ± 165.641
    1685.62 ± 0
        Day 2
    2267.18 ± 819.726
    3017.17 ± 1190.837
    3033.67 ± 234.912
    1959.78 ± 0
        Day 6
    0 ± 0
    2690.68 ± 598.16
    2819.47 ± 575.821
    1802.8 ± 0
        Day 7
    0 ± 0
    2511.89 ± 564.422
    2579.3 ± 792.292
    1869.84 ± 0
        Day 8
    0 ± 0
    2599.48 ± 469.251
    2964.46 ± 216.42
    1881.66 ± 0
        Day 9
    0 ± 0
    2633.45 ± 725.526
    2977.29 ± 336.804
    1802.72 ± 0
        Day 10
    0 ± 0
    2635.97 ± 571.989
    2954.02 ± 375.741
    2101.95 ± 0
        Day 15
    0 ± 0
    2187.55 ± 103.928
    2828.65 ± 182.06
    0 ± 0
        Day 29
    0 ± 0
    1237.89 ± 1578.544
    1185.99 ± 45.871
    0 ± 0
    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
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Number of subjects analysed
    2
    3
    4
    1
    Units: Number of subjects rescued by medication
        Number of subjects rescued by medication
    2
    1
    0
    1
    No statistical analyses for this end point

    Primary: Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL

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    End point title
    Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL [4]
    End point description
    The number of hypoglycemic episodes ( < 70 mg/dL, <60 mg/dL, and <50 mg/dL) per day was reported over each 24-hour day and summarised herein for Baseline and post-dose Day 1 to 12, grouped by day Non-Provocation Days are Days -2, -1, 1 (dosing day), 2, 6 through 10, 15 and 29. The protein challenge was performed 4 hours after the breakfast time on Day -4 and Day 4. If the patient did not demonstrate hypoglycemia during the screening fast and demonstrated hypoglycemia during the Day -4 protein challenge, then additional protein challenges occurred on Days -3, 3, 5 and 11 and the fasts were not performed. * Non-provocation days. An instance of hypoglycemia started when there were 3 consecutive measurements within a 15 minute window that were less than the threshold value. The duration was the sum of the total time the patient was in the specified threshold.
    End point type
    Primary
    End point timeframe
    Glucose was followed via the continuous glucose monitor from Baseline (Day -6 to Day -1 prior to dosing) until post dose Day 29.
    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
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Number of subjects analysed
    2 [5]
    3
    4
    1
    Units: Hypoglycemia
    geometric mean (standard deviation)
        Threshold < 50 mg/dL, Day -2 & Day -1
    0.25 ± 0.354
    0.17 ± 0.289
    0.13 ± 0.250
    4.50 ± 0
        Threshold < 50 mg/dL, Day 1
    1.00 ± 1.414
    0.00 ± 0.000
    0.00 ± 0.000
    7.00 ± 0
        Threshold < 50 mg/dL, Day 2 & Day 6*
    0.50 ± 0.707
    0.00 ± 0.000
    0.50 ± 0.408
    5.00 ± 0
        Threshold < 50 mg/dL, Day -4 & Day -1
    0.25 ± 0.354
    0.00 ± 0.000
    0.13 ± 0.250
    4.50 ± 0
        Threshold < 50 mg/dL, Day 2 to Day 12
    1.50 ± 1.650
    0.36 ± 0.315
    0.43 ± 0.155
    4.55 ± 0
        Threshold < 60 mg/dL, Day -2 & Day -1
    1.75 ± 0.354
    0.17 ± 0.289
    0.75 ± 0.500
    6.00 ± 0
        Threshold < 60 mg/dL, Day 1
    2.50 ± 2.121
    0.00 ± 0.000
    0.75 ± 0.957
    8.00 ± 0
        Threshold < 60 mg/dL, Day 2 & Day 6*
    1.50 ± 2.121
    0.33 ± 0.577
    0.63 ± 0.250
    6.50 ± 0
        Threshold < 60 mg/dL, Day -4 & Day -1
    2.50 ± 0.707
    0.00 ± 0.000
    0.88 ± 0.854
    7.50 ± 0
        Threshold < 60 mg/dL, Day 2 to Day 12
    2.50 ± 3.064
    0.61 ± 0.410
    0.84 ± 0.114
    5.64 ± 0
        Threshold < 70 mg/dL, Day -2 & Day -1
    4.50 ± 2.828
    0.50 ± 0.000
    1.75 ± 1.190
    7.50 ± 0
        Threshold < 70 mg/dL, Day 1
    4.00 ± 1.414
    1.00 ± 1.000
    1.75 ± 0.500
    4.00 ± 0
        Threshold < 70 mg/dL, Day 2 & Day 6*
    3.50 ± 4.590
    1.50 ± 1.732
    1.25 ± 0.645
    8.00 ± 0
        Threshold < 70 mg/dL, Day -4 & Day -1
    3.75 ± 2.475
    0.50 ± 0.500
    1.25 ± 0.957
    7.50 ± 0
        Threshold < 70 mg/dL, Day 2 to Day 12
    3.33 ± 2.828
    1.42 ± 0.584
    1.77 ± 0.436
    6.36 ± 0
    Notes
    [5] - Both patients received Diazoxide on Day 5. Data collected Day 5 onwards are excluded from analysis
    No statistical analyses for this end point

    Primary: Average time per day of blood glucose < 70 mg/dL

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    End point title
    Average time per day of blood glucose < 70 mg/dL [6]
    End point description
    Average time per day of blood glucose < 70 mg/dL was reported over each 24-hour day and is summarised herein for Baseline values collected during the Screening period and Days 1 to D12 post dose, grouped by day Non-Provocation Days are Days -2, -1, 1 (dosing day), 2, 6 through 10, 15 and 29. The protein challenge was performed 4 hours after the breakfast time on Day -4 and Day 4. If the patient did not demonstrate hypoglycemia during the screening fast and demonstrated hypoglycemia during the Day -4 protein challenge, then additional protein challenges occurred on Days -3, 3, 5 and 11 and the fasts were not performed. * Non-provocation days.
    End point type
    Primary
    End point timeframe
    Glucose was followed via the continuous glucose monitor from Baseline (Day -6 to Day -1 prior to dosing) until post dose Day 29.
    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
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Number of subjects analysed
    2
    3
    4
    1
    Units: minutes
    arithmetic mean (standard deviation)
        Day -2 & Day -1
    303.75 ± 132.583
    22.50 ± 18.028
    105.00 ± 47.697
    920.00 ± 0
        Day 1
    290.00 ± 134.350
    71.67 ± 67.885
    115.00 ± 41.833
    905.00 ± 0
        Day 2 & Day 6*
    375.00 ± 494.975
    109.17 ± 163.274
    80.00 ± 50.662
    652.50 ± 0
        Day -4 & Day -1
    318.75 ± 164.402
    15.00 ± 10.000
    96.88 ± 56.361
    1042.50 ± 0
        Day 2 to Day 12
    464.17 ± 555.079
    128.48 ± 119.190
    130.57 ± 43.229
    608.18 ± 0
    No statistical analyses for this end point

    Primary: Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA)

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    End point title
    Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA) [7] [8]
    End point description
    Protein challenge measurements were conducted prior to dosing (Day -4) and post dose (Day4) for glucose, insulin, C-peptide, ketones and free fatty acids. The protein challenge was performed 4 hours after the breakfast time on Day -4 and Day 4. Bedside glucose and serum PD blood draws took every 30 minutes during the protein challenge procedure, until the rescue criteria were met.Time-matched Day 4 change from Baseline (most recent, non-missing protein profile conducted during Screening period) is presented.
    End point type
    Primary
    End point timeframe
    Day -11 prior to dosing and post dose up to Day 11
    Notes
    [7] - 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.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
    End point values
    X358 3 mg/kg X358 6 mg/kg
    Number of subjects analysed
    1
    3
    Units: mg/dL; mIU/L; ng/mL; mmol/L; mEq/L
    arithmetic mean (standard deviation)
        Glucose; Day 4; 0 hr before start of provocation
    15.00 ± 0
    20.33 ± 75.182
        Glucose; Day 4; 30 minutes after provocation
    4.00 ± 0
    11.00 ± 13.115
        insulin; Day 4; 0 hr before start of provocation
    19.300 ± 0
    256.133 ± 239.5830
        insulin; Day 4; 30 minutes after provocation
    36.600 ± 0
    300.233 ± 218.3129
        C-peptide; Day 4; 0 hr before start of provocation
    0.6000 ± 0
    0.3700 ± 2.22178
        C-peptide; Day 4; 30 minutes after provocation
    0.2000 ± 0
    0.2200 ± 1.54793
        ketones; Day 4; 0 hr before start of provocation
    0.3200 ± 0
    0.0133 ± 0.02517
        ketones; Day 4; 30 minutes after provocation
    0 ± 0
    0 ± 0
        FFA; Day 4; 0 hr before start of provocation
    0.600 ± 0
    0.167 ± 0.3055
        FFA; Day 4; 30 minutes after provocation
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

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

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    End point title
    Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (nonfast)
    End point description
    Percentage change in glucose measurements (mg/dL) via CGM over 24 hours on non-fast Days 1-7 and 8-12 versus Baseline glucose values for non-fast days (Day -5 to Day -1 where 24 hour CGM is recorded) is presented. Subjects in 1 mg/kg cohort are excluded from this analysis
    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
    Subgroup Analysis 1
    Number of subjects analysed
    3
    Units: Percent Change from baseline (non-fast)
    median (full range (min-max))
        Days 1-7 (non-fast)
    14.079 (5.47 to 22.10)
        Days 8-12 (non-fast)
    10.887 (9.37 to 27.07)
    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 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
    Subgroup Analysis 2
    Number of subjects analysed
    Units: Percent Change from baseline
    median (full range (min-max))
        Days 1-8
    11.181 (5.98 to 21.74)
    No statistical analyses for this end point

    Post-hoc: Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)

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    End point title
    Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)
    End point description
    The change in fasting blood glucose (mg/dL) on Days 4 and 6 versus Baseline ( 2-days; Day -2 and Day -1) is presented.
    End point type
    Post-hoc
    End point timeframe
    Baseline (Day -2) to Day 6
    End point values
    Subgroup Analysis 3
    Number of subjects analysed
    8
    Units: Change from baseline (2-days)
    median (full range (min-max))
        Days 4 and 6
    9.255 (-7.50 to 24.50)
    No statistical analyses for this end point

    Post-hoc: Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)

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    End point title
    Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)
    End point description
    The change in fasting blood glucose (mg/dL) on Days 4 and 6 versus Baseline (average of fasting blood glucose on Day -2, Day -1 and Day 1 pre-dose) is presented
    End point type
    Post-hoc
    End point timeframe
    Baseline (Day -2) to to Day 6
    End point values
    Subgroup Analysis 3
    Number of subjects analysed
    8
    Units: Change from baseline (3-days)
    median (full range (min-max))
        Days 4 and 6
    -3.333 (-13.51 to 14.50)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were to be collected throughout the study beginning at the time the patient had signed the ICF
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    X358 1 mg/kg
    Reporting group description
    Single dose X358 1 mg/kg

    Reporting group title
    X358 3 mg/kg
    Reporting group description
    Single dose X358 3 mg/kg

    Reporting group title
    X358 6 mg/kg
    Reporting group description
    Single dose X358 6 mg/kg

    Reporting group title
    X358 9 mg/kg
    Reporting group description
    Single dose X358 9 mg/kg

    Serious adverse events
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Myoclonus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    X358 1 mg/kg X358 3 mg/kg X358 6 mg/kg X358 9 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    3 / 3 (100.00%)
    4 / 4 (100.00%)
    1 / 1 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Catheter site related reaction
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    1
    1
    Feeling hot
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Infusion site induration
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervousness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Injection site bruising
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 2 (50.00%)
    2 / 3 (66.67%)
    1 / 4 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    3
    1
    1
    Headache
         subjects affected / exposed
    2 / 2 (100.00%)
    3 / 3 (100.00%)
    3 / 4 (75.00%)
    1 / 1 (100.00%)
         occurrences all number
    5
    4
    9
    4
    Lethargy
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myoclonus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Vision blurred
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mental impairment
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    0
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 2 (100.00%)
    2 / 3 (66.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Dyspepsia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    2
    Skin irritation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jul 2015
    The amendment includes the following substantial changes:The scope of data to be reviewed by the DSRC before additional patients exposure or and changing the dose level was increased from Day 12 to all available data through Day 29.Two different Screening schedule options (Option A and Option B) were added to accommodate different availability and convenience needs of individual patients. The Schedules of Events were changed for logistic efficiency or to collect additional safety and drug characterization data.
    12 Aug 2015
    The amendment includes the following substantial changes: Protocol sections referring to pregnancy were clarified.
    08 Dec 2015
    The amendment includes the following substantial changes:A final safety follow-up visit, beyond Day 43, was added at Day 105 and collection of blood samples for hematology, chemistry, and urinalysis panels was added at Day 43. Subject inclusion criteria was modified to remove weight ≤ 90 kg at Screening to allow for the inclusion of patients who had a clinically meaningful decrease in blood glucose with symptoms during hypoglycaemia inducing procedures. If a patient did not demonstrate blood glucose values < 60 mg/dL during the Screening fast, yet demonstrated blood glucose values < 60 mg/dL during the Day -4 Protein Challenge, then a Protein Challenge was performed in lieu of a monitored fast on Days -3, 3, 5, and 11.
    22 Feb 2016
    The amendment includes the following substantial changes: The dose level for Cohort B was confirmed at 3 mg/kg, by recommendation of the DSRC and patients were permitted to participate in more than 1 cohort.
    26 May 2016
    The amendment includes the following substantial changes: The OGTT was omitted throughout the protocol. A third cohort, “Cohort C,” was added at a dose level of 6 mg/kg, and the resulting sample size was increased to up to a total of approximately 18 patients.An optional inpatient hypoglycemia provocation test (fasting procedure OR Protein Challenge procedure) was added at Day 22
    26 Aug 2016
    The amendment includes the following substantial changes: The hypoglycemia inclusion criterion was changed by replacing the required decrease in glucose levels during provocation with a required duration of decreased glucose levels as measured by CGM over a fixed period of time without provocation. The exclusion criterion “Use of any long-acting somatostatin analogs or glucose-affecting medications that require > 72-hour washout” was deleted. Screening options “A” and “B” were replaced with a single screening and Baseline schedule, and the Protein Challenge provocations have been omitted from the protocol. Cohort D with a single dose at 9 mg/kg X358 was added. Outcome measures were added for duration of hypoglycemia and number of episodes at relevant glucose levels.

    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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