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    Clinical Trial Results:
    Prospective, single arm, open-label, multicenter, international study to assess the effects of metyrapone in patients with endogenous Cushing's syndrome during a 12-week treatment period followed by an extension period of 24 weeks.

    Summary
    EudraCT number
    		 2014-000162-22
    Trial protocol
    		 DE   IT   BE   ES   HU   PL   RO  
    Global end of trial date
    29 Apr 2020

    Results information
    Results version number
    		 v4(current)
    This version publication date
    29 Mar 2022
    First version publication date
    19 Aug 2021
    Other versions
    		 v1 , v2 , v3
    Version creation reason
    • Correction of full data set
    correction in the incidence of some Adverse events
    Summary report(s)
    		 summary CSR PROMPT

    Trial information

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    Trial identification
    Sponsor protocol code
    112025-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02297945
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 116160
    Sponsors
    Sponsor organisation name
    HRA Pharma
    Sponsor organisation address
    200 avenue de Paris , Chatillon, France, 92320
    Public contact
    Regulatory Affairs Department, HRA Pharma Rare Diseases, +33 1 40 33 24 85, a.japp@HRA-PHARMA.COM
    Scientific contact
    Medical Affairs Department, HRA Pharma Rare Diseases, +33 1 40 33 32 75, m.bostnavaron@HRA-PHARMA.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
    19 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of metyrapone (MTP) to normalize cortisol levels (mean Urinary Free Cortisol (of three 24hours urine samples) – mUFC) after 12 weeks of treatment in patients with endogenous Cushing’s syndrome (CS).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 Metyrapone (MTP), an inhibitor of the 11β-hydroxylase enzyme, blocks cortisol and aldosterone synthesis. MTP is used for the management of patients with endogenous Cushing's syndrome, and as a diagnostic test for ACTH insufficiency and in the differential diagnosis of ACTH-dependent Cushing's syndrome.
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    14 Apr 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
    Turkey: 3
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    50
    EEA total number of subjects
    47
    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
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Start of trial (first patient) 14 April 2015. (Last Patient First Visit) 10 June 2019 (Last Patient Last Visit) 29 April 2020

    Pre-assignment
    Screening details
    		 55 patients were planned, 50 were enrolled and analysed.

    Period 1
    Period 1 title
    Core Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Arm title
    		 Core Cohort
    Arm description
    		 Single arm, open label, Metyrapone dose titration based on individual patient response and tolerability up to week 12 Dose will be adjusted at least during control visits: planned at weeks 1,2,3,4,5,8 and 12 (weeks 3 and 5 were optional).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metyrapone
    Investigational medicinal product code
    V04CD01.
    Other name
    METOPIRONE, METOPIRON, METYCOR, CORMETO, CORMETO, METYRAPONE HRA Pharma
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Metyrapone was supplied as 250 mg soft capsules. The maximum dose is 6 g/day divided into 3 to 4 intakes: If the daily dose cannot be divided equally (i.e. in 250 mg increments), the highest dose will be given at night. Two possible initiation doses were used depending on the severity of hypercortisolism (based on the mUFC levels): For patients with moderate hypercortisolism, i.e. baseline mUFC levels ≤ 5-fold the ULN: MTP started at 750 mg/day. For patients with severe hypercortisolism, i.e. baseline mUFC levels > 5-fold the ULN: MTP started at 1,500 mg/day. Dose titration should be followed until normal UFC level is achieved: For patients with moderate Cushing’s syndrome who are initiated with MTP 750 mg/day: the daily dose can be decreased or increased by 250 to 500 mg/day. For patients with severe Cushing’s syndrome who will start with MTP 1500 mg/day: the daily dose can be decreased or increased by 500 to 1000 mg/day.

    Number of subjects in period 1
    		Core Cohort
    Started
    50
    Completed
    47
    Not completed
    3
         Physician decision
    2
         Adverse event, non-fatal
    1
    Period 2
    Period 2 title
    Optional extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Arm title
    		 Extension Cohort
    Arm description
    		 The duration of this optional extension period is up to 24 weeks.. After the first treatment period of 12 weeks , patients who achieved/maintained mUFC levels ≤ ULN or with mUFC levels above normal range but not exceeding 2-fold ULN at week 12, were offered to enter in the optional extension period to continue being treated with MTP for 24 additional weeks. Visits were performed at weeks 24 and 36.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metyrapone
    Investigational medicinal product code
    V04CD01.
    Other name
    METOPIRONE, METOPIRON, METYCOR, CORMETO, CORMETO, METYRAPONE HRA Pharma
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose adjustments (up and down titration) were allowed and possible during the entire period according to cortisol level and/or tolerability. Visits were performed at weeks 24 and 36

    Number of subjects in period 2 [1]
    		Extension Cohort
    Started
    41
    Completed
    35
    Not completed
    6
         Patient decision
    2
         Physician decision
    1
         Adverse event, non-fatal
    3
    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: At week 12, among the 50 treated patients (43/50) were eligible to enter the 6-month extension period (normal mUFC levels or mUFC levels above normal range but not exceeding 2-fold ULN at week 12). Of these 43 patients, 41 patients entered the extension period as two patients eligible for the extension period declined to continue.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Core Study
    Reporting group description
    		 -

    Reporting group values
    		 Core Study Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 43 43
        From 65-84 years
    		 7 7
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 47.0 (22 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 35 35
        Male
    		 15 15
    Race
    Units: Subjects
        White
    		 50 50
        Black or African American
    		 0 0
        Asian
    		 0 0
    Disease Characteristics Type of Cushing Syndrome
    Units: Subjects
        Cushing's disease
    		 44 44
        Ectopic ACTH syndrome
    		 5 5
        Adrenal cause
    		 1 1
    Baseline mUFC by categories
    Units: Subjects
        > ULN; ≤ 2xULN
    		 2 2
        > 2xULN; ≤5xULN
    		 31 31
        > 5xULN
    		 17 17
    Number of patients with prior radiotherapy and/or surgery for CD
    Units: Subjects
        Prior surgery
    		 25 25
        Prior surgery and radiotherapy
    		 5 5
        Not applicable
    		 20 20
    Baseline mUFC
    N=49 (mITT)
    Units: (nmol/24h)
        arithmetic mean (standard deviation)
    		 1041.7 ( 1337.0 ) -
    Subject analysis sets

    Subject analysis set title
    Dataset Efficacy Analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    From the 50 patients enrolled and treated, 49 were included in the mITT set. One patient was excluded from mITT as no post baseline evaluation was available for the primary efficacy criterion: UFC.

    Subject analysis set title
    Dataset Safety Analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who had received at least one dose of Metyrapone

    Subject analysis sets values
    		 Dataset Efficacy Analysis set Dataset Safety Analysis set
    Number of subjects
    49
    50
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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 65-84 years
    6
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    47.0 (22 to 73)
    Gender categorical
    Units: Subjects
        Female
    34
        Male
    15
    Race
    Units: Subjects
        White
    49
        Black or African American
    0
        Asian
    0
    Disease Characteristics Type of Cushing Syndrome
    Units: Subjects
        Cushing's disease
    44
        Ectopic ACTH syndrome
    4
        Adrenal cause
    1
    Baseline mUFC by categories
    Units: Subjects
        > ULN; ≤ 2xULN
    2
        > 2xULN; ≤5xULN
    31
        > 5xULN
    16
    Number of patients with prior radiotherapy and/or surgery for CD
    Units: Subjects
        Prior surgery
    25
        Prior surgery and radiotherapy
    5
        Not applicable
    20
    Baseline mUFC
    N=49 (mITT)
    Units: (nmol/24h)
        arithmetic mean (standard deviation)
    ( )
    1041.7 ( 1337.0 )

    End points

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    End points reporting groups
    Reporting group title
    Core Cohort
    Reporting group description
    		 Single arm, open label, Metyrapone dose titration based on individual patient response and tolerability up to week 12 Dose will be adjusted at least during control visits: planned at weeks 1,2,3,4,5,8 and 12 (weeks 3 and 5 were optional).
    Reporting group title
    Extension Cohort
    Reporting group description
    		 The duration of this optional extension period is up to 24 weeks.. After the first treatment period of 12 weeks , patients who achieved/maintained mUFC levels ≤ ULN or with mUFC levels above normal range but not exceeding 2-fold ULN at week 12, were offered to enter in the optional extension period to continue being treated with MTP for 24 additional weeks. Visits were performed at weeks 24 and 36.

    Subject analysis set title
    Dataset Efficacy Analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    From the 50 patients enrolled and treated, 49 were included in the mITT set. One patient was excluded from mITT as no post baseline evaluation was available for the primary efficacy criterion: UFC.

    Subject analysis set title
    Dataset Safety Analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who had received at least one dose of Metyrapone

    Primary: Normalization of 24h-mUFC at week 12

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    End point title
    		 Normalization of 24h-mUFC at week 12 [1]
    End point description
    Normalization of 24h-mUFC at week 12 is presented: In the mITT population of 49 patients, 23 patients normalized 24h mUFC at week 12.
    End point type
    Primary
    End point timeframe
    Week 12
    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: A Clopper Pearson 95% CI was done
    End point values
    		 Core Cohort Dataset Efficacy Analysis set
    Number of subjects analysed
    49
    49
    Units: subjects
    23
    23
    No statistical analyses for this end point

    Secondary: Mean Urinary Free Cortisol

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    End point title
    		 Mean Urinary Free Cortisol
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [2]
    Units: nmol/24h
    median (full range (min-max))
        Baseline
    570.3 (291.0 to 8476.2)
        week12: Change from baseline(%)
    -73.5 (-99.5 to 168.1)
        week24: Change from baseline (%)
    -72.6 (-99.8 to 52.0)
        week36: Change from baseline (%)
    -69.9 (-99.8 to 52.0)
    Notes
    [2] - Missing data: week 12: N=2 week24: N=9 week 36: N=14
    No statistical analyses for this end point

    Secondary: Time to first eucortisolemia

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    End point title
    		 Time to first eucortisolemia
    End point description
    mUFC ≤ ULN
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    Units: days
        median (confidence interval 95%)
    34.0 (16.0 to 57.0)
    No statistical analyses for this end point

    Secondary: Responders Rate

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    End point title
    		 Responders Rate
    End point description
    patients with mUFC ≤ ULN or patients with mUFC decrease ≥50% from baseline.
    End point type
    Secondary
    End point timeframe
    Week12, week 24, and week36.
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [3]
    Units: subjects
        week12
    39
        week24
    31
        week36
    25
    Notes
    [3] - Missing data: week12: 2 week24: 9 week36: 14
    No statistical analyses for this end point

    Secondary: Normalization of 24h-mean urinary free cortisol in extension period

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    End point title
    		 Normalization of 24h-mean urinary free cortisol in extension period
    End point description
    The number of patients with normalisation of 24h UFC during the extension period at weeks 24 and 36 are displayed.
    End point type
    Secondary
    End point timeframe
    week 24 and week 36
    End point values
    		 Extension Cohort
    Number of subjects analysed
    41 [4]
    Units: subjects
        week24
    21
        week36
    17
    Notes
    [4] - Missing data: week24: 9 week36: 14
    No statistical analyses for this end point

    Secondary: Morning serum cortisol-2h after MTP dose

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    End point title
    		 Morning serum cortisol-2h after MTP dose
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week24, and week36.
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [5]
    Units: nmol/L
    median (full range (min-max))
        Baseline
    578.0 (137 to 1286)
        Week12: Change from baseline (%)
    -67.4 (-89.2 to 50.2)
        Week24: Change from baseline(%)
    -67.5 (-92.0 to -2.2)
        Weeek36: Change from baseline(%)
    -71.20 (-95.2 to 35.2)
    Notes
    [5] - Missing data: Baseline: N=5 Week12: N=3 Week24: N=11 Week36: N=15
    No statistical analyses for this end point

    Secondary: Salivary Cortisol at 11 p.m.

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    End point title
    		 Salivary Cortisol at 11 p.m.
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week1, week12, and week 36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    Units: nmol/L
    median (full range (min-max))
        Baseline
    12.4 (1.2 to 64.7)
        Week1
    5.0 (0.4 to 159.0)
        Week12
    4.2 (0.8 to 25.9)
        Week36
    4.4 (0.4 to 17.7)
    No statistical analyses for this end point

    Secondary: Late night salivary cortisol

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    End point title
    		 Late night salivary cortisol
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week1, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    Units: nmol/L
    median (full range (min-max))
        week1: Change from baseline(%)
    -35.7 (-98.9 to 325.0)
        week12: Change from baseline(%)
    -55.4 (-98.0 to 138.8)
        week36: Change from baseline(%)
    -71.5 (-96.9 to 158.3)
    No statistical analyses for this end point

    Secondary: Fasting glucose

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    End point title
    		 Fasting glucose
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    Units: mmol/L
    median (full range (min-max))
        Baseline
    5.1 (3.9 to 11.3)
        week12: Change from baseline(%)
    -5.3 (-51.3 to 27.1)
        week36: Change from baseline(%)
    -6.1 (-44.6 to 39.4)
    No statistical analyses for this end point

    Secondary: Fasting Insulin

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    End point title
    		 Fasting Insulin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [6]
    Units: pmol/L
    median (full range (min-max))
        Baseline
    93.4 (13.9 to 287.8)
        week12: Change from baseline(%)
    -8.7 (-72.1 to 195.0)
        week36: Change from baseline(%)
    -15.4 (-86.6 to 161.4)
    Notes
    [6] - Missing data: Baseline: N=3 week12: N=11 week36: N=19
    No statistical analyses for this end point

    Secondary: Hemoglobin A1c (HbA1c)

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    End point title
    		 Hemoglobin A1c (HbA1c)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [7]
    Units: percentage
    median (full range (min-max))
        Baseline
    5.8 (3.2 to 8.1)
        Week12: Change from baseline(%)
    -2.3 (-23.9 to 13.2)
        Week36: Change from baseline(%)
    -3.9 (-37.0 to 22.2)
    Notes
    [7] - Missing data: Baseline: N=2 week12: N=10 week36: N=15
    No statistical analyses for this end point

    Secondary: Total cholesterol

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    End point title
    		 Total cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [8]
    Units: mmol/L
    median (full range (min-max))
        Baseline
    5.4 (3.5 to 9.2)
        week12: Change from baseline(%)
    -13.5 (-35.9 to 18.4)
        week36: change from baseline(%)
    -18.8 (-46.5 to 34.0)
    Notes
    [8] - Missing data: Baseline: N=1 week12: N=8 week36: N=13
    No statistical analyses for this end point

    Secondary: HDL-Cholesterol

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    End point title
    		 HDL-Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [9]
    Units: mmol/L
    median (full range (min-max))
        Baseline
    1.5 (0.9 to 2.5)
        week12: change from baseline(%)
    -16.4 (-51.7 to 12.0)
        week36: Change from baseline (%)
    -23.0 (-49.0 to 7.1)
    Notes
    [9] - Missing data: Baseline: N=1 week12: N=9 week36: N=14
    No statistical analyses for this end point

    Secondary: LDL-Cholesterol

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    End point title
    		 LDL-Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [10]
    Units: mmol/L
    median (full range (min-max))
        Baseline
    3.4 (1.8 to 7.1)
        week12: Change from baseline(%)
    -12.4 (-42.2 to 57.9)
        week36: Change from baseline(%)
    -11.0 (-57.8 to 63.2)
    Notes
    [10] - Missing data: Baseline: N=3 week12: N=11 week36: N=18
    No statistical analyses for this end point

    Secondary: Triglycerides

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    End point title
    		 Triglycerides
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [11]
    Units: mmol/L
    median (full range (min-max))
        Baseline
    1.5 (0.5 to 6.6)
        week12: Change from baseline(%)
    0.2 (-64.2 to 73.6)
        week36: Change from baseline(%)
    3.6 (-61.7 to 93.1)
    Notes
    [11] - Missing data: Baseline: N=1 week1é: N=9 week36: N=14
    No statistical analyses for this end point

    Secondary: Systolic Blood Pressure

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    End point title
    		 Systolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [12]
    Units: mmHg
    median (full range (min-max))
        Baseline
    131.8 (87.5 to 172.0)
        Week12: Change from baseline(%)
    -3.2 (-18.5 to 30.0)
        Week24: Change from baseline(%)
    -0.6 (-23.0 to 35.3)
        Week36: Change from baseline(%)
    -2.6 (-33.1 to 26.7)
    Notes
    [12] - Missing data: Baseline: N=0 Week12: N=3 Week24: N=10 Week36: N=14
    No statistical analyses for this end point

    Secondary: Diastolic blood pressure

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    End point title
    		 Diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [13]
    Units: mmHg
    median (full range (min-max))
        Baseline
    85.3 (52.5 to 113.0)
        Week12: Change from baseline(%)
    -5.9 (-21.6 to 50.0)
        Week24: Change from baseline(%)
    -0.9 (-40.6 to 60.6)
        Week36: Change from baseline(%)
    -5.4 (-30.4 to 27.8)
    Notes
    [13] - Missing data: Baseline: N=0 Week12: N=3 Week24: N=10 Week36: N=14
    No statistical analyses for this end point

    Secondary: Overall evaluation of Cushing’s Syndrome clinical signs related to hypercortisolism

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    End point title
    		 Overall evaluation of Cushing’s Syndrome clinical signs related to hypercortisolism
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week4, week12, week24, and week36
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [14]
    Units: subjects
        week4 improvement or normalization
    24
        week12 improvement or normalization
    31
        week24 improvement or normalization
    25
        week36 improvement or normalization
    28
    Notes
    [14] - Missing data: week4: N=3 week12: N=2 week24: N=9 week36: N=13
    No statistical analyses for this end point

    Secondary: Physical Examination – BMI

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    End point title
    		 Physical Examination – BMI
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [15]
    Units: Kg/m²)
    arithmetic mean (standard deviation)
        Baseline
    30.5 ( 7.3 )
        week12: Change from baseline
    -0.04 ( 1.1 )
        week36: Change from baseline
    -0.65 ( 2.2 )
    Notes
    [15] - Missing data: Baseline: N=1 week12: N=3 week36: N=14
    No statistical analyses for this end point

    Secondary: Physical Examination – Waist circumference

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    End point title
    		 Physical Examination – Waist circumference
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [16]
    Units: cm
    arithmetic mean (standard deviation)
        Baseline
    106.2 ( 14.2 )
        week12: Change from baseline
    -0.4 ( 9.6 )
        week36: Change from baseline
    -3.7 ( 7.4 )
    Notes
    [16] - Misssing data: Baseline: N=3 Week12: N=6 Week36: N=16
    No statistical analyses for this end point

    Secondary: Cushing’s Quality of Life

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    End point title
    		 Cushing’s Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [17]
    Units: --
    arithmetic mean (standard deviation)
        Baseline
    41.5 ( 19.4 )
        week12: Change from baseline
    9.8 ( 13.8 )
        week24: Change from baseline
    11.3 ( 13.2 )
        week36: Change from baseline
    10.4 ( 13.1 )
    Notes
    [17] - Missing data: Baseline: N=0 week12: N=3 week24: N=11 week36: N=14
    No statistical analyses for this end point

    Secondary: Tuebingen Cushing’s Disease Quality of Life – Total score

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    End point title
    		 Tuebingen Cushing’s Disease Quality of Life – Total score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [18]
    Units: ..
    arithmetic mean (standard deviation)
        Baseline
    41.0 ( 22.8 )
        week12: Change from baseline
    -5.3 ( 13.0 )
        week24: Change from baseline
    -10.4 ( 13.7 )
        week36: Change from baseline
    -8.7 ( 16.3 )
    Notes
    [18] - Missing data: Baseline: N=0 week12: N=3 week24: N=11 week36: N=14
    No statistical analyses for this end point

    Secondary: Tuebingen Cushing’s Disease Quality of Life – Depression subscore

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    End point title
    		 Tuebingen Cushing’s Disease Quality of Life – Depression subscore
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [19]
    Units: --
    arithmetic mean (standard deviation)
        Baseline
    36.3 ( 25.1 )
        week12: Change from baseline
    -4.8 ( 18.2 )
        week24: Change from baseline
    -8.4 ( 18.6 )
        week36: Change from baseline
    -6.7 ( 16.2 )
    Notes
    [19] - Missing data: Baseline: N=0 week12: N=3 week24: N=11 week36: N=14
    No statistical analyses for this end point

    Secondary: Tuebingen Cushing’s Disease Quality of Life – Sexual Activity subscore

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    End point title
    		 Tuebingen Cushing’s Disease Quality of Life – Sexual Activity subscore
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [20]
    Units: --
    arithmetic mean (standard deviation)
        Baseline
    37.5 ( 29.1 )
        week12: Change from baseline
    -2.5 ( 17.4 )
        week24: Change from baseline
    -8.6 ( 18.3 )
        week36: Change from baseline
    -9.38 ( 15.41 )
    Notes
    [20] - Missing data: Baseline: N=4 week12: N=7 week24: N=13 week36: N=16
    No statistical analyses for this end point

    Secondary: Tuebingen Cushing’s Disease Quality of Life – Environment subscore

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    End point title
    		 Tuebingen Cushing’s Disease Quality of Life – Environment subscore
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [21]
    Units: --
    arithmetic mean (standard deviation)
        Baseline
    39.3 ( 27.3 )
        week12: Change from baseline
    -3.4 ( 18.2 )
        week24: Change from baseline
    -8.1 ( 17.2 )
        week36: Change from baseline
    -8.1 ( 18.4 )
    Notes
    [21] - Missing data: Baseline: N=0 week12: N=3 week24: N=11 week36: N=14
    No statistical analyses for this end point

    Secondary: Tuebingen Cushing’s Disease Quality of Life – Eating behavior subscore

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    End point title
    		 Tuebingen Cushing’s Disease Quality of Life – Eating behavior subscore
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week12, week24, and week36
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50 [22]
    Units: --
    arithmetic mean (standard deviation)
        Baseline
    45.7 ( 29.7 )
        week12: Change from baseline
    -13.8 ( 23.0 )
        week24: Change from baseline
    -22.9 ( 27.5 )
        week36: Change from baseline
    -13.0 ( 30.9 )
    Notes
    [22] - Missing data: Baseline: N=0 week12: N=3 week24: N=11 week36: N=14
    No statistical analyses for this end point

    Secondary: Duration of treatment

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    End point title
    		 Duration of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    globally
    End point values
    		 Dataset Safety Analysis set
    Number of subjects analysed
    50
    Units: weeks
    arithmetic mean (standard deviation)
        Duration of treatment globally
    30.6 ( 10.9 )
    No statistical analyses for this end point

    Secondary: Final MTP dose

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    End point title
    		 Final MTP dose
    End point description
    End point type
    Secondary
    End point timeframe
    Global
    End point values
    		 Dataset Efficacy Analysis set
    Number of subjects analysed
    49 [23]
    Units: mg/day
    median (full range (min-max))
        week12
    1500.0 (250 to 5500)
        week24
    1500.0 (500 to 5750)
        week36
    1500.0 (250 to 5750)
    Notes
    [23] - Missing data: week12: N=2 week24: N=9 week36: N=14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from when the subject signs the informed consent to the last visit planned in the protocol.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Baseline to week 12
    Reporting group description
    		 All patients are treated for up to 12 weeks with Metyrapone. After the first administration of MTP (750 mg or 1500 mg/day according to baseline UFC levels), the daily dose is adjusted at scheduled times on the basis of UFC and/or morning serum cortisol measurements and tolerability.

    Reporting group title
    Baseline to week 36
    Reporting group description
    		 Patients were treated for up to 36 weeks with Metyrapone. After the first administration of MTP (750 mg or 1500 mg/day according to baseline UFC levels), the daily dose is adjusted at scheduled times on the basis of UFC and/or morning serum cortisol measurements and tolerability.

    Serious adverse events
    		 Baseline to week 12 Baseline to week 36
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 50 (20.00%)
    12 / 50 (24.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour recurrent
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    6 / 50 (12.00%)
    6 / 50 (12.00%)
         occurrences causally related to treatment / all
    5 / 6
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Baseline to week 12 Baseline to week 36
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 50 (84.00%)
    47 / 50 (94.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 50 (10.00%)
    6 / 50 (12.00%)
         occurrences all number
    6
    8
    Hypotension
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 50 (20.00%)
    11 / 50 (22.00%)
         occurrences all number
    19
    24
    Dizziness
         subjects affected / exposed
    6 / 50 (12.00%)
    7 / 50 (14.00%)
         occurrences all number
    6
    7
    Paraesthesia
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 50 (18.00%)
    13 / 50 (26.00%)
         occurrences all number
    19
    32
    Oedema peripheral
         subjects affected / exposed
    6 / 50 (12.00%)
    6 / 50 (12.00%)
         occurrences all number
    8
    9
    Asthenia
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 50 (32.00%)
    19 / 50 (38.00%)
         occurrences all number
    24
    30
    Diarrhoea
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 50 (10.00%)
         occurrences all number
    4
    8
    Dyspepsia
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 50 (10.00%)
         occurrences all number
    4
    6
    Abdominal pain upper
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Abdominal pain
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    5
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 50 (10.00%)
    6 / 50 (12.00%)
         occurrences all number
    9
    12
    Pain in extremity
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 50 (6.00%)
         occurrences all number
    4
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 50 (18.00%)
    9 / 50 (18.00%)
         occurrences all number
    12
    14
    Hypokalaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 50 (6.00%)
         occurrences all number
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2015
    Spain: The protocol has been updated further to German Competent Authorities’ comments. This has also been the opportunity to update the protocol as the study will no more take place in the US and some other minor modifications have been done to improve the first version of the document.
    07 Dec 2015
    Spain, Italy, Belgium, Hungary, and Germany: Further to the Investigator’s meeting and first inclusions in the study, investigators have requested some clarifications on the study protocol notably collection of urinary free cortisol samples at baseline.

    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.
    Absence of control or placebo arm
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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