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    Clinical Trial Results:
    Validation of stimulated ∆FGF19 for diagnosing bile acid diarrhoea

    Summary
    EudraCT number
    		 2016-002217-22
    Trial protocol
    		 DK  
    Global end of trial date
    27 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jan 2021
    First version publication date
    28 Jan 2021
    Other versions
    Summary report(s)
    		 journal paper

    Trial information

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    Trial identification
    Sponsor protocol code
    SJ-546
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03059537
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zealand University Hospital
    Sponsor organisation address
    Lykkebaekvej 1, DK-Koege, Denmark, 4600
    Public contact
    Departement of internal medicine, Sjællands University Hospital, Køge, 0045 47322400, christianborup@hotmail.com
    Scientific contact
    Departement of internal medicine, Sjællands University Hospital, Køge, 0045 47322400, christianborup@hotmail.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
    01 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Validation of stimulated ∆FGF19 for diagnosis of BAD in patients referred to SeHCAT
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Mar 2017
    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
    Denmark: 78
    Worldwide total number of subjects
    78
    EEA total number of subjects
    78
    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)
    61
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruited from 22 March 2017 until 3 Nov 2017.

    Pre-assignment
    Screening details
    		 Invited 209 patients, recruited 78 (n=131 declined invitation). 71 competed the protocol; n=7 dropped out (protocol violations: n=1 not fasting at visit 2, n=1 current treatment with colestyramine not paused, n= 2current treatment w oral budesonide; n=3 withdrew consent between study visit 1 and visit2)

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

    Arms
    Arm title
    		 Meal+CDCA
    Arm description
    		 Meal+CDCA stimulation of bile acid homeostasis
    Arm type
    		 Experimental

    Investigational medicinal product name
    chenodeoxycholic acid
    Investigational medicinal product code
    ATC: A05AA01
    Other name
    CDCA, 3 alpha-, 7 alpha dihydroxycholic acid
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    5 capsules of 250 mg (in total 1,250 mg administered with a defined solid meal.

    Number of subjects in period 1
    		Meal+CDCA
    Started
    78
    Completed
    71
    Not completed
    7
         Consent withdrawn by subject
    3
         Protocol deviation
    4

    Baseline characteristics

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

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 78 78
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 61 61
        From 65-84 years
    		 17 17
    Gender categorical
    Units: Subjects
        Female
    		 50 50
        Male
    		 28 28
    Subject analysis sets

    Subject analysis set title
    SeHCAT retention <=10%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients with bile acid diarrhea (defined by SeHCAT <= 10%)

    Subject analysis set title
    SeHCAT >10%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PAtients with idiopathic (non-bile acid diarrhea) defined by SeHCAT retention > 10%

    Subject analysis set title
    SeHCAT <=5%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PAtients with severe bile acid diarrhea

    Subject analysis set title
    SeHCAT >5%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PAtients who do not have severe bile acid diarrhea

    Subject analysis sets values
    		 SeHCAT retention <=10% SeHCAT >10% SeHCAT <=5% SeHCAT >5%
    Number of subjects
    26
    45
    17
    54
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    23
    36
        From 65-84 years
    3
    9
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    17
    27
        Male
    9
    18

    End points

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    End points reporting groups
    Reporting group title
    Meal+CDCA
    Reporting group description
    		 Meal+CDCA stimulation of bile acid homeostasis

    Subject analysis set title
    SeHCAT retention <=10%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients with bile acid diarrhea (defined by SeHCAT <= 10%)

    Subject analysis set title
    SeHCAT >10%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PAtients with idiopathic (non-bile acid diarrhea) defined by SeHCAT retention > 10%

    Subject analysis set title
    SeHCAT <=5%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PAtients with severe bile acid diarrhea

    Subject analysis set title
    SeHCAT >5%
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PAtients who do not have severe bile acid diarrhea

    Primary: Negative predictive value (NPV) of stimulated delta FGF19 > 2.5 pg/mL for ruling out bile acid diarrhea

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    End point title
    		 Negative predictive value (NPV) of stimulated delta FGF19 > 2.5 pg/mL for ruling out bile acid diarrhea
    End point description
    End point type
    Primary
    End point timeframe
    visit 2
    End point values
    		 SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    26
    45
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    36 (-14 to 104)
    10 (-28 to 51)
    Statistical analysis title
    		 ROC analysis w pred valuea
    Statistical analysis description
    "exact" Clopper-Pearson
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.17 [2]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 NPV for stim d FGF19 vs SeHCAT 10%
    Point estimate
    68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 54
         upper limit
    		 80
    Notes
    [1] - AREA under the ROC curve compared with true area = 0.5
    [2] - p value for ROC curve

    Secondary: PPV for C4 > 5.5 ng/mL for SeHCAT <10%

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    End point title
    		 PPV for C4 > 5.5 ng/mL for SeHCAT <10%
    End point description
    End point type
    Secondary
    End point timeframe
    visit2
    End point values
    		 Meal+CDCA SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    71
    26
    45
    Units: %
        number (confidence interval 95%)
    44 (39 to 49)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Diag 2x2 table w CI for predictive values
    Statistical analysis description
    "exact" Clopper-Pearson confidence intervals
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 PPV for C4 >5.5 for SeHCAT 10%
    Point estimate
    44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 39
         upper limit
    		 49
    Notes
    [3] - for True ROC-AUC=0.5

    Secondary: ROC analysis accuracy for stim delta FGF19 > 2.5 pg/mL for detecting SeHCAT < 5%

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    End point title
    		 ROC analysis accuracy for stim delta FGF19 > 2.5 pg/mL for detecting SeHCAT < 5%
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2
    End point values
    		 Meal+CDCA SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    71
    26
    45
    Units: %
        number (confidence interval 95%)
    52 (39 to 63)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Diag 2x2 table w CI for predictive values
    Statistical analysis description
    "exact" Clopper-Pearson confidence intervals
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.903 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - value for true ROC-AUC=0.5

    Secondary: ROC analysis accuracy for C4 > 5.5 for detecting BAD compared with SeHCAT <5%

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    End point title
    		 ROC analysis accuracy for C4 > 5.5 for detecting BAD compared with SeHCAT <5%
    End point description
    End point type
    Secondary
    End point timeframe
    visit2
    End point values
    		 SeHCAT <=5% SeHCAT >5%
    Number of subjects analysed
    17
    54
    Units: %
        number (confidence interval 95%)
    42.5 (28.2 to 63.9)
    9.4 (7.3 to 12.2)
    Statistical analysis title
    		 Diag 2x2 table w CI for predictive values ie accur
    Statistical analysis description
    "exact" Clopper-Pearson confidence intervals
    Comparison groups
    SeHCAT <=5% v SeHCAT >5%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.00001 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Accuracy for C4>5.5 comp SeHCTA 10%
    Point estimate
    44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32
         upper limit
    		 56
    Notes
    [5] - p value for true ROC-AUC=0.5

    Secondary: correlation(spearman) between stim delta FGF19 and mean number of stools per day

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    End point title
    		 correlation(spearman) between stim delta FGF19 and mean number of stools per day
    End point description
    End point type
    Secondary
    End point timeframe
    vivsit2
    End point values
    		 Meal+CDCA SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    71
    26
    45
    Units: none
        number (not applicable)
    0.064
    0
    0
    Statistical analysis title
    		 Spearman correlation
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.593
    Method
    		 spearman corr
    Parameter type
    		 spearman corr
    Point estimate
    0.593
    Confidence interval
         level
    		 1%
         sides
    2-sided
         lower limit
    		 0.593
         upper limit
    		 0.593

    Secondary: correlation between SHS item general well being and SF36v2 general well being for patients with Hjortswang criteria pos diarrhea

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    End point title
    		 correlation between SHS item general well being and SF36v2 general well being for patients with Hjortswang criteria pos diarrhea
    End point description
    End point type
    Secondary
    End point timeframe
    vivist2
    End point values
    		 Meal+CDCA SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    71
    26
    45
    Units: none
        number (not applicable)
    -0.602
    -0.766
    -0.503
    Statistical analysis title
    		 Spearman corr
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.00001 [6]
    Method
    		 Spearman corr
    Parameter type
    		 spearman corr
    Point estimate
    -0.587
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.587
         upper limit
    		 -0.587
    Notes
    [6] - p value for spearman corr

    Secondary: Median stimulated delta FGF19 in SeHCAT strata

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    End point title
    		 Median stimulated delta FGF19 in SeHCAT strata
    End point description
    End point type
    Secondary
    End point timeframe
    visit 2
    End point values
    		 SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    26
    45
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    36 (-14 to 104)
    10 (-28 to 51)
    Statistical analysis title
    		 Comp of median stim delta FGF19 in SeHCAT gruops
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.17
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Mean (lognorm + backtransf) C4 in SeHCAT groups

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    End point title
    		 Mean (lognorm + backtransf) C4 in SeHCAT groups
    End point description
    End point type
    Secondary
    End point timeframe
    visit 2
    End point values
    		 SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    26
    45
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    30 (19 to 46)
    8 (7 to 11)
    Statistical analysis title
    		 Comp of mean C4 in SeHCAT groups
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.00001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Median FGF19 values in SeHCAT groups

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    End point title
    		 Median FGF19 values in SeHCAT groups
    End point description
    End point type
    Secondary
    End point timeframe
    visit 2
    End point values
    		 SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    26
    45
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    72 (53 to 146)
    119 (84 to 240)
    Statistical analysis title
    		 Comp of fasting median FGF19
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.004
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Post-hoc: Negative predictive value for C4 < 15ng/mL for SeHCAT >10%

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    End point title
    		 Negative predictive value for C4 < 15ng/mL for SeHCAT >10%
    End point description
    End point type
    Post-hoc
    End point timeframe
    visit 2
    End point values
    		 Meal+CDCA SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    71
    26
    45
    Units: %
        number (confidence interval 95%)
    85 (74 to 96)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Diag 2x2 table w CI for predictive values
    Statistical analysis description
    "exact" Clopper-Pearson confidence intervals
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.0001 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 NPV for C4<15 comp SeHCAT10%
    Point estimate
    85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 74
         upper limit
    		 96
    Notes
    [7] - p value for ROC curve real AUC = 0.5

    Post-hoc: positive predictive value of C4 > 48 ng/mL for SeHCAT < 10%

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    End point title
    		 positive predictive value of C4 > 48 ng/mL for SeHCAT < 10%
    End point description
    End point type
    Post-hoc
    End point timeframe
    vsisit2
    End point values
    		 Meal+CDCA SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    71
    26
    45
    Units: %
        number (confidence interval 95%)
    82 (59 to 100)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 ROC analysis w pred valuea
    Statistical analysis description
    "exact" Clopper-Pearson confidence intervals
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.001 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 PPV for C4 > 48ng/mL comp SeHCAT 10%
    Point estimate
    82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 59
         upper limit
    		 100
    Notes
    [8] - p value for true ROC-AUC=0.5

    Post-hoc: Accuracy of C4 cutoff 30ng/ml for SeHCAT 10%

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    End point title
    		 Accuracy of C4 cutoff 30ng/ml for SeHCAT 10%
    End point description
    End point type
    Post-hoc
    End point timeframe
    visit2
    End point values
    		 Meal+CDCA SeHCAT retention <=10% SeHCAT >10%
    Number of subjects analysed
    71
    26
    45
    Units: %
        number (confidence interval 95%)
    78 (66 to 87)
    30 (19 to 46)
    8 (7 to 11)
    Statistical analysis title
    		 Diag 2x2 table w CI for predictive values
    Statistical analysis description
    "exact" Clopper-Pearson confidence intervals
    Comparison groups
    SeHCAT retention <=10% v SeHCAT >10%
    Number of subjects included in analysis
    71
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.01
    Method
    		 Fisher exact
    Parameter type
    		 Accuracy of C4>30ng/mL for SeHCAT 10%
    Point estimate
    78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 66
         upper limit
    		 87

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reg strat at visit 2 with adm of IMP (CDCA) and for seven days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Meal+CDCA
    Reporting group description
    		 Meal+CDCA stimulation of bile acid homeostasis

    Serious adverse events
    		 Meal+CDCA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 71 (2.82%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Gastroenteritis norovirus
    Additional description: Acute norovirus gastrienterits (pt age 78) with dehydration. Pt hospitalized for fluid therapy. Full recovery.
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Meal+CDCA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 71 (52.11%)
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Acute diarrhoea
         subjects affected / exposed
    20 / 71 (28.17%)
         occurrences all number
    20
    Abdominal pain
         subjects affected / exposed
    17 / 71 (23.94%)
         occurrences all number
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32740083
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