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    Clinical Trial Results:
    A Placebo-Controlled, Double-Blind Randomized Withdrawal Study to Evaluate the Safety and Efficacy of CNV1014802 in Patients with Trigeminal Neuragia

    Summary
    EudraCT number
    2010-023963-16
    Trial protocol
    GB   DE   DK   IT   ES   LV   LT   EE  
    Global end of trial date
    26 Feb 2014

    Results information
    Results version number
    v3(current)
    This version publication date
    08 Jun 2016
    First version publication date
    07 Aug 2015
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    "Other name" correction required.

    Trial information

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    Trial identification
    Sponsor protocol code
    1014802/202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01540630
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Convergence Pharmaceuticals Ltd
    Sponsor organisation address
    Maia Building, Babraham Research Campus, Cambridge, United Kingdom, CB22 3AT
    Public contact
    Clinical Trials Information, Convergence Pharmaceuticals Ltd, clinicaltrials@biogen.com
    Scientific contact
    Clinical Trials Information, Convergence Pharmaceuticals Ltd, clinicaltrials@biogen.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
    26 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of repeat oral dosing of CNV1014802 on the pain experienced in trigeminal neuralgia (TG).
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason. Subjects could discontinue the study at any time due to an adverse event. Because of the severe nature of the pain associated with TN, subjects are unlikely to accept extended periods of placebo treatment. Therefore, a two-stage enriched randomized withdrawal design was selected for the study, whereby responders to CNV1014802 are identified in an initial open-label phase, and eligible responders are randomised to a second, placebo-controlled, double blind, withdrawal phase. Any subjects who were not responders in the initial open-label period were discontinued from the study and did not enter the randomized withdrawal period. Placebo was incorporated into the study as a control. However, as treatment failure was the primary outcome, subjects who received placebo and did not achieve pain relief (despite availability of rescue medication) were rapidly discontinued from the study and standard therapy re-introduced.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Apr 2012
    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
    South Africa: 8
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Estonia: 9
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Latvia: 5
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Romania: 3
    Worldwide total number of subjects
    67
    EEA total number of subjects
    56
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    43
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    125 subjects were screened, of which 67 were eligible for participation in the study.

    Period 1
    Period 1 title
    Open-label Phase
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Open-label CNV1014802
    Arm description
    Subjects received CNV1014802 150 mg three times daily (tid) for 21 days. (Any subjects who were not responders in this phase were discontinued from the study and did not enter the randomised, double-blind, placebo-controlled phase.)
    Arm type
    Experimental

    Investigational medicinal product name
    CNV1014802
    Investigational medicinal product code
    Other name
    BIIB074
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were advised to take medication in the morning, midday and in the evening approximately 8 hours apart, plus or minus 1 hour. Medication was to be taken at least 1 hour before or after food.

    Number of subjects in period 1
    Open-label CNV1014802
    Started
    67
    Completed
    44
    Not completed
    23
         Lack of efficacy
    18
         Adverse event, non-fatal
    3
         Consent withdrawn by subject
    2
    Period 2
    Period 2 title
    Double-blind Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Double-blind CNV1014802
    Arm description
    Subjects received CNV1014802 150 mg tid for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    CNV1014802
    Investigational medicinal product code
    Other name
    BIIB074
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were advised to take medication in the morning, midday and in the evening approximately eight hours apart, plus or minus 1 hour. Medication was to be taken at least 1 hour before or after food.

    Arm title
    Double-blind Placebo
    Arm description
    Subjects received placebo tid for up to 28 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were advised to take medication in the morning, midday and in the evening approximately eight hours apart, plus or minus 1 hour. Medication was to be taken at least 1 hour before or after food.

    Number of subjects in period 2 [1]
    Double-blind CNV1014802 Double-blind Placebo
    Started
    15
    14
    Completed
    10
    7
    Not completed
    5
    7
         Lack of efficacy
    4
    7
         Consent withdrawn by subject
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 44 patients who completed the open-label phase, 30 were eligible for randomisation to the double-blind phase. One subject was randomised but did not receive a dose of double-blind medication, therefore, the number of subjects in the double-blind phase that received at least 1 dose of study medication was 29 (the Intent-to-treat [ITT] population).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label Phase
    Reporting group description
    -

    Reporting group values
    Open-label Phase Total
    Number of subjects
    67 67
    Age categorical
    Age
    Units: Subjects
        Adults (18-64 years)
    44 44
        From 65-84 years
    23 23
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.7 ± 12.43 -
    Gender categorical
    Units: Subjects
        Female
    44 44
        Male
    23 23

    End points

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    End points reporting groups
    Reporting group title
    Open-label CNV1014802
    Reporting group description
    Subjects received CNV1014802 150 mg three times daily (tid) for 21 days. (Any subjects who were not responders in this phase were discontinued from the study and did not enter the randomised, double-blind, placebo-controlled phase.)
    Reporting group title
    Double-blind CNV1014802
    Reporting group description
    Subjects received CNV1014802 150 mg tid for up to 28 days.

    Reporting group title
    Double-blind Placebo
    Reporting group description
    Subjects received placebo tid for up to 28 days.

    Subject analysis set title
    Randomized Subjects ITT Population Only
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT analysis set included all subjects who were randomized into the double-blind period of the study and received at least one dose of double-blind medication.

    Subject analysis set title
    Open-label Period: Non-randomized Subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with PK assessment data in the open-label period who were not randomized in the double-blind period.

    Subject analysis set title
    Open-label Period: Placebo Randomized Subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with PK assessment data in the open-label period who were randomized to placebo in the double-blind period.

    Subject analysis set title
    Open-label Period: CNV Randomized Subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with PK assessment data in the open-label period who were randomized to CNV in the double-blind period.

    Subject analysis set title
    Double-blind Period: CNV Randomized Subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with PK assessment data in the double-blind period who were randomized to CNV in the double-blind period.

    Subject analysis set title
    CNV1014802 Overall
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of CNV1014802 at any time during the study.

    Primary: Number of Subjects Reaching Treatment Failure in the Double-blind Period

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    End point title
    Number of Subjects Reaching Treatment Failure in the Double-blind Period
    End point description
    Subjects were classified as a treatment failure if they met one of the following criteria: - 50% increase in the frequency of paroxysms compared to the final 7 days of the open-label period, to more than 3 paroxysms - When more than 3 paroxysms were reported in a 7-day period, a 50% increase in the severity of pain experienced in the paroxysms compared with the final 7 days of the open-label period - A Patient Global Improvement of Change rating of much worse/very much worse - The subject discontinued the study due to 'lack of efficacy' in the double-blind phase. (Any subject who took more than 1 dose of a prohibited oral sodium channel blocker to treat their TN was considered to be a treatment failure and was withdrawn from the study due to lack of efficacy.) - The subject discontinued due to an adverse reaction or poor tolerability. ITT population: subjects who were randomized and received a dose of double blind medication.
    End point type
    Primary
    End point timeframe
    Double-blind period: Week 4 (Day 22) through Week 7 (Day 49)
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    15
    14
    Units: subjects
    5
    9
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Treatment failure rates were compared between CNV1014802 and placebo during the double-blind treatment period.
    Comparison groups
    Double-blind Placebo v Double-blind CNV1014802
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0974 [1]
    Method
    Fisher exact
    Confidence interval
    Notes
    [1] - one-sided Fisher's exact test

    Secondary: Number of Subjects Reaching Treatment Failure, by Week

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    End point title
    Number of Subjects Reaching Treatment Failure, by Week
    End point description
    Subjects were classified as a treatment failure if they met one of the following criteria outlined in the primary endpoint (see previous endpoint). ITT population: subjects who were randomized and received a dose of double blind medication. Note: Subjects may show up in more than one category and a subject may meet different categories on different weeks if they met treatment failure criteria but were not withdrawn from the study in error.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 5, 6, and 7
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    5 [2]
    9 [3]
    Units: subjects
        Treatment failure (all categories) - Week 4
    1
    6
        Treatment failure (all categories) - Week 5
    4
    4
        Treatment failure (all categories) - Week 6
    0
    3
        Treatment failure (all categories) - Week 7
    1
    1
    Notes
    [2] - subjects in the ITT population experiencing treatment failure
    [3] - subjects in the ITT population experiencing treatment failure
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Number of Paroxysms per Day During the Open-label Phase

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    End point title
    Change From Baseline in Mean Number of Paroxysms per Day During the Open-label Phase
    End point description
    Safety population for the open-label phase: subjects who received at least one dose of open-label study medication. Observed cases; n=number of subjects with available data at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Run-in [Days -7 to -1]), Weeks 1, 2, and 3 of the open-label phase
    End point values
    Open-label CNV1014802 Randomized Subjects ITT Population Only
    Number of subjects analysed
    67
    29
    Units: paroxysms per day
    arithmetic mean (standard deviation)
        Baseline (Run-in [Days -1 to -7]); n=67, 29
    8.7 ± 8.08
    9.4 ± 8.96
        Change from Baseline at Week 1; n=66, 29
    -0.9 ± 10.1
    -4.1 ± 9.03
        Change from Baseline at Week 2; n=53, 29
    -2.7 ± 5.7
    -4.7 ± 6.42
        Change from Baseline at Week 3; n=45, 29
    -2.7 ± 4.83
    -5 ± 3.79
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Number of Paroxysms per Day During the Double-blind Phase

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    End point title
    Change From Baseline in Mean Number of Paroxysms per Day During the Double-blind Phase
    End point description
    ITT population: subjects who were randomized and received a dose of double blind medication. Observed cases; n=number of subjects with available data at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 3), Weeks 4, 5, 6, and 7 of the double-blind phase
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    15
    14
    Units: paroxysms per day
    arithmetic mean (standard deviation)
        Baseline (Mean of Week 3); n=15, 14
    5 ± 9.82
    3.8 ± 2.57
        Change from Baseline at Week 4; n=15, 14
    0.3 ± 5.8
    3.1 ± 4.86
        Change from Baseline at Week 5; n=11, 9
    0 ± 0.59
    -0.2 ± 1.83
        Change from Baseline at Week 6; n=11, 7
    -0.8 ± 1.56
    -0.8 ± 2.16
        Change from Baseline at Week 7; n=10, 5
    -1.1 ± 1.65
    -0.6 ± 3.22
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The ratio comparing the changes from baseline in the number of paroxysms for the two groups (i.e. ΔCNV/Δplacebo)
    Comparison groups
    Double-blind Placebo v Double-blind CNV1014802
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.028 [4]
    Method
    Generalized Estimating Equations
    Parameter type
    ratio of ΔCNV/Δplacebo
    Point estimate
    0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    1.02
    Notes
    [4] - one-sided test

    Secondary: Clinician Global Impression of Change (CGIC)

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    End point title
    Clinician Global Impression of Change (CGIC)
    End point description
    Changes on the CGIC were relative to Day 21 at Day 49/Premature Discontinuation. For the summary data, "Improvement" includes the following categories: much improved, very much improved, minimally improved. "No improvement" includes the following categories: no change, minimally worse, much worse, very much worse. ITT population: subjects who were randomized and received a dose of double blind medication who had available data.
    End point type
    Secondary
    End point timeframe
    Day 21, Day 49/premature discontinuation (end of double-blind period)
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    14
    13
    Units: subjects
        Day 49: Very much improved
    5
    1
        Day 49: Much improved
    4
    2
        Day 49: Minimally improved
    3
    2
        Day 49: No change
    1
    4
        Day 49: Minimally worse
    0
    1
        Day 49: Much worse
    1
    1
        Day 49: Very much worse
    0
    2
        Day 49: Improvement
    12
    5
        Day 49: No improvement
    2
    8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    CNV versus placebo: Day 21
    Comparison groups
    Double-blind CNV1014802 v Double-blind Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3674
    Method
    Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    CNV versus placebo: Day 49 (1 subject's data was missing from each arm for this time point; 27 of the 29 subjects were included in this analysis)
    Comparison groups
    Double-blind CNV1014802 v Double-blind Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0051
    Method
    Wilcoxon rank sum test
    Confidence interval

    Secondary: Patient Global Impression of Change (PGIC)

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    End point title
    Patient Global Impression of Change (PGIC)
    End point description
    Changes on the PGIC were relative to Day 21 at Day 49/Premature Discontinuation. For the summary data, "Improvement" includes the following categories: much improved, very much improved, minimally improved. "No improvement" includes the following categories: no change, minimally worse, much worse, very much worse. ITT population: subjects who were randomized and received a dose of double blind medication who had available data.
    End point type
    Secondary
    End point timeframe
    Day 21, Day 49/premature discontinuation (end of double-blind period)
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    14
    13
    Units: subjects
        Day 49: Very much improved
    4
    1
        Day 49: Much improved
    5
    3
        Day 49: Minimally improved
    2
    3
        Day 49: No change
    1
    1
        Day 49: Minimally worse
    2
    2
        Day 49: Much worse
    0
    2
        Day 49: Very much worse
    0
    1
        Day 49: Improvement
    11
    7
        Day 49: No improvement
    3
    6
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    CNV versus placebo: Day 21
    Comparison groups
    Double-blind Placebo v Double-blind CNV1014802
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1402
    Method
    Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    CNV versus placebo: Day 49 (1 subject's data was missing from each arm for this time point; 27 of the 29 subjects were included in this analysis)
    Comparison groups
    Double-blind Placebo v Double-blind CNV1014802
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0265
    Method
    Wilcoxon rank sum test
    Confidence interval

    Secondary: Change From Baseline Brief Pain Inventory - Facial (BPI-F)

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    End point title
    Change From Baseline Brief Pain Inventory - Facial (BPI-F)
    End point description
    The BPI-F is a reliable and validated multidimensional tool that consists of 18 questions. It measures 3 domains of pain: 1) pain intensity (worst and average pain intensity), 2) interference with general activities of daily living (ADL), and 3) face-specific pain interference. The BPI-F was used as an assessment measure for quality of life in TG subjects. The BPI-F uses an 11-point Likert scale, ranging from 0 (no pain/interference) to 10 (worst pain /interference imaginable). ITT population: subjects who were randomized and received a dose of double blind medication. n=number of subjects with available data at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose assessment on Day 0), Day 21 (end of open-label period), Day 49 (end of double-blind period), Follow-up (Day 56)
    End point values
    Double-blind CNV1014802 Double-blind Placebo Randomized Subjects ITT Population Only
    Number of subjects analysed
    15
    14
    29
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (Day 0); n=15, 14, 29
    84.7 ± 36.09
    90.8 ± 36.9
    87.7 ± 35.96
        Change from Baseline at Day 21; n=15, 14, 29
    -49.53 ± 29.051
    -45.29 ± 31.089
    -47.48 ± 29.587
        Change from Baseline at Day 49; n=10, 7, 17
    -71.8 ± 33.041
    -32 ± 37.251
    -55.41 ± 39.27
        Change from Baseline at Follow-up; n=14, 13, 27
    -63.36 ± 35.783
    -55.08 ± 39.267
    -59.37 ± 37.008
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Double-blind Placebo v Double-blind CNV1014802
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1278 [5]
    Method
    Generalized Estimating Equations
    Parameter type
    Mean difference (final values)
    Point estimate
    -14.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.5
         upper limit
    10.5
    Notes
    [5] - one-sided test

    Secondary: Median Time to Failure

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    End point title
    Median Time to Failure
    End point description
    Kaplan-Meier analysis of time to failure during the randomized double-blind phase. ITT population: subjects who were randomized and received a dose of double-blind medication.
    End point type
    Secondary
    End point timeframe
    Double-blind period (Day 22 to Day 49)
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    15 [6]
    14 [7]
    Units: days
        median (confidence interval 95%)
    9999 (7 to 99999)
    14 (1 to 99999)
    Notes
    [6] - 9999="Not Reached," as the 50% quartile was not reached. 99999=blank (1-sided confidence interval).
    [7] - 9999=blank (1-sided confidence interval).
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Double-blind Placebo v Double-blind CNV1014802
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0306 [8]
    Method
    Logrank
    Confidence interval
    Notes
    [8] - *The p-value from the log-rank test was 0.0611, but as the CNV group showed improvement over placebo during the double-blind phase, it was appropriate to derive the one-sided p-value of 0.0306.

    Secondary: Change From Baseline in Mean Severity of Paroxysms per Day During the Open-label Phase

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    End point title
    Change From Baseline in Mean Severity of Paroxysms per Day During the Open-label Phase
    End point description
    Subjects rated the severity of the pain during each paroxysm on an 11-point pain intensity numerical rating scale (PI-NRS) from 0 to 10, where 0 represents “no pain" and 10 represents “maximum pain imaginable.” Safety population for the open-label phase: subjects who received at least one dose of open-label study medication. Observed cases; n=number of subjects with available data at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Run-in [Days -7 to -1]), Weeks 1, 2, and 3 of the open-label phase
    End point values
    Open-label CNV1014802 Randomized Subjects ITT Population Only
    Number of subjects analysed
    67
    29
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (Run-in [Days -1 to -7]); n=67, 29
    6 ± 1.52
    5.7 ± 1.47
        Change from Baseline at Week 1; n=66, 29
    -0.4 ± 1.61
    -1 ± 1.58
        Change from Baseline at Week 2; n=53, 29
    -1.4 ± 2.02
    -2.1 ± 1.87
        Change from Baseline at Week 3; n=45, 29
    -2 ± 2.04
    -2.9 ± 1.8
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Severity of Paroxysms per Day During the Double-blind Phase

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    End point title
    Change From Baseline in Mean Severity of Paroxysms per Day During the Double-blind Phase
    End point description
    Subjects rated the severity of the pain during each paroxysm on an 11-point pain intensity numerical rating scale (PI-NRS) from 0 to 10, where 0 represents “no pain" and 10 represents “maximum pain imaginable.” Observed cases; n=number of subjects with available data at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 3), Weeks 4, 5, 6, and 7 of the double-blind phase
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    15
    14
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (Mean of Week 3); n=15, 14
    2.4 ± 2.27
    3.2 ± 2.08
        Change from Baseline at Week 4; n=15, 14
    0.5 ± 1.19
    1.3 ± 2.61
        Change from Baseline at Week 5; n=11, 9
    0.1 ± 1.65
    0 ± 1.16
        Change from Baseline at Week 6; n=11, 7
    -0.3 ± 0.45
    -0.5 ± 1.88
        Change from Baseline at Week 7; n=10, 5
    -0.3 ± 1.62
    -0.7 ± 1.71
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The ratio comparing the changes from baseline in the severity of paroxysms for the two groups (i.e. ΔCNV/Δplacebo)
    Comparison groups
    Double-blind CNV1014802 v Double-blind Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0846 [9]
    Method
    Generalized Estimating Equations
    Parameter type
    ratio of ΔCNV/Δplacebo
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.13
    Notes
    [9] - one-sided test

    Secondary: Change From Baseline in Average 24-hour Pain Intensity Numerical Rating Scale (PI-NRS) During the Open-label Phase

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    End point title
    Change From Baseline in Average 24-hour Pain Intensity Numerical Rating Scale (PI-NRS) During the Open-label Phase
    End point description
    Subjects were asked to rate their pain intensity averaged over the last 24 hours on each day, before retiring to bed. This constituted the Daily Pain Score. The 11-point PI-NRS scores ranged from 0 to 10, where 0 represents “no pain" and 10 represents “maximum pain imaginable” was used for the subject assessment of the pain. The subject's average pain was calculated for each week. Safety population for the open-label phase: subjects who received at least one dose of open-label study medication. n=number of subjects with available data at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Run-in [Days -7 to -1]), Weeks 1, 2, and 3 of the open-label phase
    End point values
    Open-label CNV1014802 Randomized Subjects ITT Population Only
    Number of subjects analysed
    67
    29
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (Run-in [Days -1 to -7]); n=67, 29
    5.9 ± 1.64
    5.7 ± 1.61
        Change from Baseline at Week 1; n=65, 29
    -0.7 ± 1.87
    -1.5 ± 1.58
        Change from Baseline at Week 2; n=52, 29
    -1.7 ± 2.03
    -2.5 ± 1.83
        Change from Baseline at Week 3; n=45, 29
    -1.9 ± 2.14
    -3.1 ± 1.67
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Average 24-hour PI-NRS During the Double-blind Phase

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    End point title
    Change From Baseline in Mean Average 24-hour PI-NRS During the Double-blind Phase
    End point description
    Subjects were asked to rate their pain intensity averaged over the last 24 hours on each day, before retiring to bed. This constituted the Daily Pain Score. The 11-point PI-NRS scores ranged from 0 to 10, where 0 represents “no pain" and 10 represents “maximum pain imaginable” was used for the subject assessment of the pain. The subject's average pain was calculated for each week. ITT population: subjects who were randomized and received a dose of double-blind medication. n=number of subjects with available data at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 3), Weeks 4, 5, 6, and 7 of the double-blind phase
    End point values
    Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    15
    14
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (Week 3); n=15, 14
    2.3 ± 2.18
    3 ± 2.19
        Change from Baseline at Week 4; n=15, 13
    0.2 ± 0.67
    2.1 ± 2.95
        Change from Baseline at Week 5; n=11, 8
    -0.1 ± 0.64
    0.3 ± 0.92
        Change from Baseline at Week 6; n=10, 6
    -0.5 ± 0.72
    0.9 ± 1.59
        Change from Baseline at Week 7; n=10, 4
    -0.9 ± 0.95
    0.2 ± 1.64
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The ratio comparing the changes from baseline in PI-NRS for the two groups (i.e. ΔCNV/Δplacebo)
    Comparison groups
    Double-blind CNV1014802 v Double-blind Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009 [10]
    Method
    Generalized Estimating Equations
    Parameter type
    ratio of ΔCNV/Δplacebo
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.77
    Notes
    [10] - one-sided test

    Secondary: Maximal Plasma Concentration at Steady State (Cmax-ss) and Minimal Plasma Concentration at Steady State (Cmin-ss)

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    End point title
    Maximal Plasma Concentration at Steady State (Cmax-ss) and Minimal Plasma Concentration at Steady State (Cmin-ss)
    End point description
    PK population: all enrolled subjects who received at least one dose of investigational medicinal product with at least one quantifiable plasma concentration after dosing and available data.
    End point type
    Secondary
    End point timeframe
    Day 0: pre-dose; Day 7: pre-dose, 2 hours post-dose; Day 21 pre-dose, 2 hours post-dose; Day 35 pre-dose, 2 hours post-dose; Day 49 pre-dose, 2 hours post-dose.
    End point values
    Open-label Period: Non-randomized Subjects Open-label Period: Placebo Randomized Subjects Open-label Period: CNV Randomized Subjects Double-blind Period: CNV Randomized Subjects
    Number of subjects analysed
    24
    13
    15
    15
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cmax-ss
    1.96 ± 19
    1.98 ± 15
    2.02 ± 17
    2.01 ± 17
        Cmin-ss
    0.87 ± 36
    0.87 ± 32
    0.99 ± 31
    0.94 ± 34
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects Experiencing Treatment-emergent Adverse Events (TEAEs)
    End point description
    Adverse event (AE): Any untoward medical occurrence in a subject, which does not necessarily have to have a causal relationship with this treatment. Serious AE: An adverse event that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is considered to be an important medical event. TEAE: an AE occurring any time after the first administration of study treatment. Safety population: subjects who received at least one dose of CNV1014802. Subjects were analysed according to the actual treatment and dose they received. Safety population for the open-label phase: subjects who received at least one dose of open-label study medication. Safety population for the double-blind phase: subjects who received at least one dose of study medication after randomization. least one dose of study medication
    End point type
    Secondary
    End point timeframe
    AEs were collected from start of Run-in (Day -7) through follow up (Day 56)
    End point values
    Open-label CNV1014802 Double-blind CNV1014802 Double-blind Placebo CNV1014802 Overall
    Number of subjects analysed
    67
    15
    14
    67
    Units: subjects
        TEAEs
    37
    4
    5
    38
        Serious TEAEs
    2
    0
    1
    2
        TEAEs leading to discontinuation
    5
    0
    0
    5
        Severe TEAEs
    6
    0
    1
    6
        Related TEAEs
    23
    2
    2
    24
        TEAEs resulting in death
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant (PCS) Vital Sign and Electrocardiogram (ECG) Abnormalities

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    End point title
    Number of Subjects With Potentially Clinically Significant (PCS) Vital Sign and Electrocardiogram (ECG) Abnormalities
    End point description
    Systolic and diastolic BP and heart rate were assessed using a digital BP monitor while sitting. Standard ten second 12-lead ECGs were obtained using ECG machines provided by an ECG core lab. Safety population: subjects who received at least one dose of CNV1014802. Subjects were analysed according to the actual treatment and dose they received. Safety population for the open-label phase: subjects who received at least one dose of open-label study medication. Safety population for the double-blind phase: subjects who received at least one dose of study medication after randomization.
    End point type
    Secondary
    End point timeframe
    Screening through Day 56
    End point values
    Open-label CNV1014802 Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    67
    15
    14
    Units: subjects
        Vital signs
    0
    0
    0
        ECGs
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Changes in Laboratory Values Reported as AEs

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    End point title
    Number of Subjects With Changes in Laboratory Values Reported as AEs
    End point description
    Hematology, clinical chemistry, urinalysis and additional parameters were tested at visits throughout the study. Safety population: subjects who received at least one dose of CNV1014802. Subjects were analysed according to the actual treatment and dose they received. Safety population for the open-label phase: subjects who received at least one dose of open-label study medication. Safety population for the double-blind phase: subjects who received at least one dose of study medication after randomization.
    End point type
    Secondary
    End point timeframe
    Screening through Day 56
    End point values
    Open-label CNV1014802 Double-blind CNV1014802 Double-blind Placebo
    Number of subjects analysed
    67
    15
    14
    Units: subjects
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from start of Run-in (Day -7) through follow up (Day 56)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Open-label CNV1014802
    Reporting group description
    Subjects received CNV1014802 150 mg tid for 21 days. (Any subjects who were not responders in this phase were discontinued from the study and did not enter the randomised, double-blind, placebo-controlled phase.)

    Reporting group title
    Double-blind CNV1014802
    Reporting group description
    Subjects received CNV1014802 150 mg tid for up to 28 days.

    Reporting group title
    Double-blind placebo
    Reporting group description
    Subjects received placebo tid for up to 28 days.

    Serious adverse events
    Open-label CNV1014802 Double-blind CNV1014802 Double-blind placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial food poisoning
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Open-label CNV1014802 Double-blind CNV1014802 Double-blind placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 67 (52.24%)
    4 / 15 (26.67%)
    5 / 14 (35.71%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 67 (5.97%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    4
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 67 (4.48%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    5
    1
    0
    Chills
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Thirst
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    Restlessness
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Abnormal dreams
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Injury, poisoning and procedural complications
    Heat exhaustion
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood sodium decreased
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Skin turgor decreased
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal mucosal disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 67 (19.40%)
    1 / 15 (6.67%)
    1 / 14 (7.14%)
         occurrences all number
    26
    5
    3
    Dizziness
         subjects affected / exposed
    6 / 67 (8.96%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    8
    0
    2
    Memory impairment
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Balance disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    10
    0
    0
    Disturbance in attention
         subjects affected / exposed
    3 / 67 (4.48%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    Tremor
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Diplopia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Visual impairment
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    4 / 67 (5.97%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    20
    0
    0
    Diarrhoea
         subjects affected / exposed
    4 / 67 (5.97%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    6
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    4 / 67 (5.97%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    5
    0
    0
    Constipation
         subjects affected / exposed
    3 / 67 (4.48%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 67 (4.48%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    0
    1
    Enterocele
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Gingival disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Melaena
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pruritus
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2012
    The protocol was amended to increase the age limit of subjects to 80 years of age. The rationale for this amendment was that TN is a condition that is associated with increasing age. Many subjects are diagnosed in the 60-70 year age range and consequently the population of subjects requiring treatment extends into subjects aged 80 and older. Following review of the demographic data for TN subjects the sponsor changed the maximum age for inclusion in this study to 80 years. The population within the study would therefore more closely reflect the final intended target population.
    27 Mar 2013
    1) Addition of a genotyping sample. The rationale was that a genetic substrate for neuropathic pain is an accepted hypothesis in the scientific community. Recently, sodium channel gene mutations causing cell hyperexcitability have been identified in groups of subjects with painful neuropathy. Calcium channelopathies have also been linked to migraine and epilepsy. Given the importance of sodium and calcium channels in the generation, propagation and plasticity of pain signals, it was decided to genotype five sodium channel (Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7) and two calcium channel (Cav2.2 and Cav2.1) genes in all subjects entering the study to explore whether mutations in these genes are present in TN and whether these are related to response to treatment with CNV1014802. Genotyping was not mandatory for subjects participating in the study and was carried out for research purposes only. 2) Clarification of Withdrawal criteria for Primary Endpoint. This amendment updated the primary endpoint withdrawal criteria to require at least three paroxysms within a 7 day period to be experienced and that thereafter a 50% increase in either the number of paroxysms or in severity of pain would result in the need to withdraw subjects. Data from the planned interim analysis on the first 10 subjects treated in the open label indicated that some subjects had a very marked response to CNV1014802, such that they had no paroxysms in the final week of open label treatment. To avoid withdrawing subjects who only had one paroxysm in a 7 day period, the withdrawal criterion concerning number of paroxysms was changed to require at least three paroxysms/7 day period and thereafter a 50% increase in number or severity of paroxysms. The other withdrawal criteria remained unchanged.
    15 Aug 2013
    Increase Subject numbers. The number of subjects recruited to the open-label period of the study was increased from up to 40 subjects to up to 70 subjects. The target recruitment for the trial was to randomize 30 subjects with TN. At the outset of the trial, Convergence estimated that 'Approximately 40 subjects will be recruited into the open-label period to aim to randomize 30 subjects into the double-blind phase'. At the time of the amendment, 37 subjects had been enrolled into the open-label treatment period of study and only 14 had been eligible for randomisation to the double-blind period. It was apparent from the enrolment at this time point that a greater number of subjects would be required to enter the open-label treatment period than was stated in the protocol.

    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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