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    Clinical Trial Results:
    A proof-of-concept (PoC), open-label, forced titration, multi-center study to assess the safety/tolerability and efficacy of 10-weeks treatment of LCI699 followed by a 12-week treatment period in patients with Cushing’s disease. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2010-022403-22
    Trial protocol
    		 IT  
    Global end of trial date
    22 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Nov 2020
    First version publication date
    06 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCI699C2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01331239
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.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
    22 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing’s disease
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Mar 2011
    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
    France: 9
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    27
    EEA total number of subjects
    15
    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)
    27
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 27 were enrolled in the study: 12 in Part l and 19 in Part ll Core. Four of the participants in the Part II Core were previously enrolled in the Part I Core.

    Pre-assignment
    Screening details
    		 For overall study: 27 patients were planned; For Part l of the study, 12 - 15 patients were planned to be enrolled. For Part ll Core 19 patients were planned to be enrolled.

    Period 1
    Period 1 title
    Part I: Core Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part l: Core cohort
    Arm description
    		 Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part l of this study. 4 patients in this cohort moved to Part II of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    LCI699
    Investigational medicinal product code
    LCI699
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose of 2 mg b.i.d increasing to 50 mg b.i.d as detailed above.

    Number of subjects in period 1 [1]
    		Part l: Core cohort
    Started
    12
    Completed
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In this period there were fewer subjects were enrolled than in the whole study. More subjects joined in the next period.
    Period 2
    Period 2 title
    Part II: Core Study
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part II Core: Expansion cohort
    Arm description
    		 Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Expansion of this study. These patients were all newly enrolled into the phase ll part of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    osilodrostat
    Investigational medicinal product code
    LCI699
    Other name
    Pharmaceutical forms
    Capsule, soft, Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients started the sequential dose- escalation treatment period at 2 mg bid of osilodrostat, or 5 mg bid if their UFC was greater than 3xULN on Day 1. This schedule of events continued every 2 weeks (i.e. Day 28, 42, 56) with potential interim dose escalation visits (on Days 35, 49, 63) during the dose escalation period, with the dose of LCI699 increasing. If at any time, the patient's UFC was less than ULN, dose escalation was to be halted and the patient remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow dose adjustments if necessary. If at any time the patient experienced side effects, which were either intolerable or met dose adjustment criteria, the prescribed dose was to be adjusted. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 06.

    Arm title
    		 Part ll Core: Follow-up cohort
    Arm description
    		 Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Follow-up of this study. These patients were patients who transferred from Part l Core phase of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    osilodrostat
    Investigational medicinal product code
    LCI699
    Other name
    Pharmaceutical forms
    Capsule, soft, Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to start at the penultimate osilodrostat dose that was efficacious and well tolerated during their previous treatment, with the possibility to up- titrate the dose within 1 week based on tolerability. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 06.

    Number of subjects in period 2
    		Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Started
    15
    4
    Completed
    7
    3
    Not completed
    8
    1
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    3
    -
         Administrative problems
    1
    -
         Subj's cond. no longer require treatment
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part l: Core cohort
    Reporting group description
    		 Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part l of this study. 4 patients in this cohort moved to Part II of the study

    Reporting group values
    		 Part l: Core cohort Total
    Number of subjects
    		 12 12
    Age Categorical
    Units: years
        18 - 64 years
    		 12 12
        >65 years
    		 0 0
    Sex: Female, Male
    Units: Participants
        Female
    		 8 8
        Male
    		 4 4
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 12 12
        Black or African American
    		 0 0
        Asian
    		 0 0
    Subject analysis sets

    Subject analysis set title
    2mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 2mg of osilodrostat

    Subject analysis set title
    5mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 5mg of osilodrostat

    Subject analysis set title
    10mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 10mg of osilodrostat

    Subject analysis set title
    20mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 20mg of osilodrostat

    Subject analysis set title
    30mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 30mg of osilodrostat

    Subject analysis set title
    2mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 2mg of osilodrostat

    Subject analysis set title
    5mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 5mg of osilodrostat

    Subject analysis set title
    10mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 10mg of osilodrostat

    Subject analysis set title
    20mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 20mg of osilodrostat

    Subject analysis set title
    2mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 2mg of osilodrostat

    Subject analysis set title
    5mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 5mg of osilodrostat

    Subject analysis set title
    Phase ll Core: Expansion cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Expansion of this study. These patients were all newly enrolled into the phase ll part of the study.

    Subject analysis sets values
    		 2mg bid 5mg bid 10mg bid 20mg bid 30mg bid 2mg bid 5mg bid 10mg bid 20mg bid 2mg bid 5mg bid Phase ll Core: Expansion cohort
    Number of subjects
    4
    13
    6
    1
    1
    6
    14
    8
    2
    2
    11
    15
    Age Categorical
    Units: years
        18 - 64 years
    15
        >65 years
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Sex: Female, Male
    Units: Participants
        Female
    11
        Male
    4
    Race/Ethnicity, Customized
    Units: Subjects
        White
    11
        Black or African American
    3
        Asian
    1

    End points

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    End points reporting groups
    Reporting group title
    Part l: Core cohort
    Reporting group description
    		 Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part l of this study. 4 patients in this cohort moved to Part II of the study
    Reporting group title
    Part II Core: Expansion cohort
    Reporting group description
    		 Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Expansion of this study. These patients were all newly enrolled into the phase ll part of the study.

    Reporting group title
    Part ll Core: Follow-up cohort
    Reporting group description
    		 Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Follow-up of this study. These patients were patients who transferred from Part l Core phase of the study.

    Subject analysis set title
    2mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 2mg of osilodrostat

    Subject analysis set title
    5mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 5mg of osilodrostat

    Subject analysis set title
    10mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 10mg of osilodrostat

    Subject analysis set title
    20mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 20mg of osilodrostat

    Subject analysis set title
    30mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 30mg of osilodrostat

    Subject analysis set title
    2mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 2mg of osilodrostat

    Subject analysis set title
    5mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 5mg of osilodrostat

    Subject analysis set title
    10mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 10mg of osilodrostat

    Subject analysis set title
    20mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 20mg of osilodrostat

    Subject analysis set title
    2mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 2mg of osilodrostat

    Subject analysis set title
    5mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Expansion cohort who took 5mg of osilodrostat

    Subject analysis set title
    Phase ll Core: Expansion cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Expansion of this study. These patients were all newly enrolled into the phase ll part of the study.

    Primary: Percentage of responders to LCI699 based on the change in mean urinary free cortisol (UFC) from baseline to Week 10

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    End point title
    		 Percentage of responders to LCI699 based on the change in mean urinary free cortisol (UFC) from baseline to Week 10 [1]
    End point description
    A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ ULN (as defined by the local laboratories) or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced <50% decrease in UFC were classified as non-responders.
    End point type
    Primary
    End point timeframe
    10 weeks
    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: No statistical analysis was planned for this endpoint
    End point values
    		 Part l: Core cohort
    Number of subjects analysed
    9
    Units: Percentage of participants
        number (not applicable)
    100.0
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: 11- Deoxycorticosterone (Overall)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: 11- Deoxycorticosterone (Overall)
    End point description
    Change in Deoxycorticosterone over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: pmol/L
    arithmetic mean (standard deviation)
        BL: 11-Deoxycorticosterone (n =12, 4)
    292.8 ( 371.54 )
    188.0 ( 105.21 )
        WK 22: 11-Deoxycorticosterone (n= 10, 4)
    6957.8 ( 9627.77 )
    3670.0 ( 2734.34 )
        WK 70: 11-Deoxycorticosterone (n= 7, 4)
    2523.1 ( 1597.39 )
    1743.0 ( 1048.22 )
        LOV: 11-Deoxycorticosterone (n=12, 4)
    1640.8 ( 2097.16 )
    1822.3 ( 1452.72 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: 11-Deoxycortisol (Overall)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: 11-Deoxycortisol (Overall)
    End point description
    Change in Deoxycortisol over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: nmol/L
    arithmetic mean (standard deviation)
        BL: 11-Deoxycortisol (n= 14, 4)
    4.21 ( 4.648 )
    5.48 ( 6.549 )
        WK 22: 11-Deoxycortisol (n= 12, 4 )
    45.48 ( 44.880 )
    54.75 ( 60.676 )
        WK 70: 11-Deoxycortisol (n= 9, 4)
    15.32 ( 13.463 )
    9.03 ( 7.934 )
        LOV: 11-Deoxycortisol
    8.60 ( 18.910 )
    11.83 ( 19.101 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Aldosterone, Thyroxine, free (T4)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Aldosterone, Thyroxine, free (T4)
    End point description
    Change in aldosterone & thyroxine, free over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: pmol/L
    arithmetic mean (standard deviation)
        BL: Aldosterone (n = 14, 4)
    165.5 ( 255.07 )
    127.0 ( 177.04 )
        WK 22: Aldosterone (n =12, 4)
    -151.1 ( 290.53 )
    -64.5 ( 247.93 )
        WK 70: Aldosterone (n = 9, 4)
    -101.9 ( 153.82 )
    -120.0 ( 182.11 )
        LOV: Aldosterone (n =14, 4)
    -135.1 ( 258.36 )
    -99.5 ( 149.06 )
        BL: Thyroxine, free (n = 14, 4)
    14.02 ( 3.233 )
    18.40 ( 8.050 )
        WK 22: Thyroxine, free (n =11, 4)
    -1.17 ( 3.254 )
    -3.63 ( 3.247 )
        WK 70: Thyroxine, free (n = 9, 4)
    0.46 ( 2.355 )
    -3.78 ( 7.951 )
        LOV: Thyroxine, free (n =14, 4)
    1.69 ( 3.281 )
    -2.33 ( 5.324 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Estradiol (Female)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Estradiol (Female)
    End point description
    Change in Estradiol in females over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    11
    3
    Units: pmol/L
    arithmetic mean (standard deviation)
        BL: Female Estradiol (n =10, 3)
    209.60 ( 282.423 )
    307.23 ( 263.028 )
        WK 22: Female Estradiol (n =8, 3 )
    -42.19 ( 223.444 )
    -24.63 ( 234.288 )
        WK 70: Female Estradiol (n =6, 3)
    10.55 ( 187.443 )
    -141.00 ( 376.080 )
        LOV: Female Estradiol (n =10, 3)
    -114.24 ( 305.334 )
    666.93 ( 1108.794 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Estradiol (Male)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Estradiol (Male)
    End point description
    Change in Estradiol in males over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    4
    1
    Units: pmol/L
    arithmetic mean (standard deviation)
        BL: Male Estradiol
    55.00 ( 25.755 )
    77.10 ( 999 )
        WK 22: Male Estradiol
    35.00 ( 68.005 )
    18.30 ( 999 )
        WK 70: Male Estradiol (n =3, 1)
    -1.00 ( 16.523 )
    110.10 ( 999 )
        LOV: Male Estradiol
    2.50 ( 55.729 )
    -33.10 ( 999 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female)
    End point description
    Change in FSH in females over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    11
    3
    Units: U/L
    arithmetic mean (standard deviation)
        BL: Female FSH (n =10, 3)
    9.09 ( 13.277 )
    2.43 ( 0.929 )
        WK 22: Female FSH (n =7, 3 )
    14.89 ( 28.673 )
    2.90 ( 2.476 )
        WK 70: Female FSH (n =6, 3)
    3.58 ( 14.021 )
    3.20 ( 2.081 )
        LOV: Female FSH (n =10, 3)
    15.41 ( 23.613 )
    3.70 ( 2.524 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Follicle Stimulation Hormone (Male)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Follicle Stimulation Hormone (Male)
    End point description
    Change in FSH in males over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    4
    1
    Units: U/L
    arithmetic mean (standard deviation)
        BL: Male FSH
    5.88 ( 3.241 )
    5.80 ( 999 )
        WK 22: Male FSH
    -1.20 ( 1.560 )
    -5.20 ( 999 )
        WK 70: Male FSH (n =3, 1)
    -1.80 ( 1.735 )
    -5.80 ( 999 )
        LOV: Male FSH
    -1.38 ( 5.660 )
    -2.90 ( 999 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Renin, Insulin, Tyrotropin

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Renin, Insulin, Tyrotropin
    End point description
    Change in Renin, Insulin & Tyrotropin over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: mU/L
    arithmetic mean (standard deviation)
        BL: Renin (n =14, 4)
    23.706 ( 18.0642 )
    73.973 ( 102.338 )
        WK 22: Renin (n= 12, 4)
    45.899 ( 144.9575 )
    -16.838 ( 145.6609 )
        WK 70: Renin (n= 9, 4)
    70.051 ( 117.9931 )
    -55.638 ( 88.9155 )
        LOV: Renin (n=14, 4)
    24.209 ( 52.0438 )
    -43.718 ( 70.5958 )
        BL: Insulin (n =14, 4)
    25.61 ( 27.166 )
    22.38 ( 7.071 )
        WK 22: Insulin (n= 12, 4)
    -10.63 ( 20.247 )
    -8.58 ( 4.456 )
        WK 70: Insulin (n= 9, 4)
    -8.69 ( 24.132 )
    -12.53 ( 8.772 )
        LOV: Insulin (n=14, 4)
    -8.11 ( 23.169 )
    -5.78 ( 11.771 )
        BL: Thyrotropin (n =14, 4)
    0.659 ( 0.6827 )
    0.815 ( 0.8364 )
        WK 22: Thyrotropin(n= 11, 3)
    1.445 ( 2.3295 )
    0.280 ( 0.3118 )
        WK 70: Thyrotropin (n= 9, 4)
    2.387 ( 4.0991 )
    0.395 ( 0.4674 )
        LOV: Thyrotropin (n=14, 4)
    1.244 ( 3.4627 )
    0.885 ( 0.5994 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Insulin-like Growth Factor-1

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Insulin-like Growth Factor-1
    End point description
    Change in Insulin-like Growth Factor-1 over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: ug/L
    arithmetic mean (standard deviation)
        BL: Insulin-like Growth Factor-1 (n =14, 3)
    157.56 ( 109.044 )
    235.30 ( 110.249 )
        WK 22: Insulin-like Growth Factor-1 (n =12, 3)
    -9.78 ( 67.387 )
    -35.20 ( 153.817 )
        WK 70: Insulin-like Growth Factor-1 (n= 9, 3)
    -41.23 ( 76.969 )
    -113.43 ( 86.529 )
        LOV: Insulin-like Growth Factor-1 (n=14, 3)
    -56.76 ( 105.936 )
    -46.07 ( 62.155 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Luteinising Hormone (LH) (Female)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Luteinising Hormone (LH) (Female)
    End point description
    Change in LH in females over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    11
    3
    Units: U/L
    arithmetic mean (standard deviation)
        BL: Female LH (n =10, 3)
    2.78 ( 2.220 )
    1.00 ( 1.000 )
        WK 22: Female LH (n =8, 2)
    7.45 ( 17.051 )
    4.40 ( 0.990 )
        WK 70: Female LH (n =6, 3)
    7.47 ( 15.267 )
    2.63 ( 3.235 )
        LOV: Female LH (n =10, 3)
    7.30 ( 10.885 )
    3.37 ( 2.060 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: LH (Male)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: LH (Male)
    End point description
    Change in LH in males over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    4
    1
    Units: U/L
    arithmetic mean (standard deviation)
        BL: Male LH
    2.48 ( 1.328 )
    5.90 ( 999 )
        WK 22: Male LH
    0.48 ( 1.081 )
    -5.70 ( 999 )
        WK 70: Male LH (n =3, 1)
    -0.53 ( 1.021 )
    -5.90 ( 999 )
        LOV: Male LH
    -0.05 ( 2.610 )
    -2.70 ( 999 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Testosterone (Female)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Testosterone (Female)
    End point description
    Change in Testosterone in females over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    11
    3
    Units: nmol/L
    arithmetic mean (standard deviation)
        BL: Female Testosterone (n = 10, 3)
    1.18 ( 0.820 )
    1.43 ( 0.404 )
        WK 22: Female Testosterone (n= 8, 3)
    1.85 ( 1.790 )
    5.27 ( 5.353 )
        WK 70: Female Testosterone (n= 6, 3)
    0.53 ( 1.409 )
    0.50 ( 1.400 )
        LOV: Female Testosterone (n=10, 3)
    0.25 ( 1.532 )
    0.17 ( 1.266 )
    No statistical analyses for this end point

    Secondary: Actual Change from baseline (BL) in steroid hormones of HPA-axis: Testosterone (Male)

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    End point title
    		 Actual Change from baseline (BL) in steroid hormones of HPA-axis: Testosterone (Male)
    End point description
    Change in Testosterone in males over time.
    End point type
    Secondary
    End point timeframe
    baseline, Week 22, Week 70, Last observed value (LOV)
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    4
    1
    Units: nmol/L
    arithmetic mean (standard deviation)
        BL: Male Testosterone (n = 3, 1)
    7.53 ( 4.076 )
    7.10 ( 999 )
        WK 22: Male Testosterone (n= 4, 1)
    6.55 ( 4.751 )
    2.40 ( 999 )
        WK 70: Male Testosterone (n= 3, 1)
    5.17 ( 1.504 )
    32.60 ( 999 )
        LOV: Male Testosterone (n=4, 1)
    8.15 ( 7.859 )
    0.00 ( 999 )
    No statistical analyses for this end point

    Secondary: Actual change from BL in Cardiovascular and other metabolic parameters: Fasting glucose

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    End point title
    		 Actual change from BL in Cardiovascular and other metabolic parameters: Fasting glucose
    End point description
    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 70, Last observed value
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: mg/dL
    arithmetic mean (standard deviation)
        BL
    108.1 ( 55.12 )
    96.3 ( 14.43 )
        WK 22 (n = 13, 4)
    -14.5 ( 32.45 )
    -16.3 ( 14.93 )
        WK 70 (n = 10, 4)
    -22.5 ( 36.87 )
    -20.8 ( 24.62 )
        LOV
    -17.9 ( 35.99 )
    -13.8 ( 22.88 )
    No statistical analyses for this end point

    Secondary: Actual change from BL in Cardiovascular and other metabolic parameters: Hemoglobin A1C

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    End point title
    		 Actual change from BL in Cardiovascular and other metabolic parameters: Hemoglobin A1C
    End point description
    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 70, Last observed value
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: Percentage
    arithmetic mean (standard deviation)
        BL (n =13, 4)
    5.7 ( 0.77 )
    6.0 ( 0.61 )
        WK 22 (n = 11, 4)
    -0.1 ( 0.27 )
    -0.3 ( 0.28 )
        WK 70 (n = 8, 4)
    -0.1 ( 0.43 )
    -0.6 ( 0.74 )
        LOV (n = 11, 4)
    -0.1 ( 0.56 )
    -0.4 ( 0.49 )
    No statistical analyses for this end point

    Secondary: Actual change from BL in Cardiovascular and other metabolic parameters: Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides

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    End point title
    		 Actual change from BL in Cardiovascular and other metabolic parameters: Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides
    End point description
    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 70, Last observed value
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: mmo1/L
    arithmetic mean (standard deviation)
        BL Cholesterol (n =15, 4)
    5.2 ( 1.36 )
    5.7 ( 1.44 )
        WK 22 Cholesterol (n = 13, 4)
    -0.7 ( 1.58 )
    -0.5 ( 0.56 )
        WK 70 Cholesterol (n = 10, 4)
    -0.1 ( 1.35 )
    -1.2 ( 1.74 )
        LOV Cholesterol (n = 15, 4)
    0.5 ( 2.39 )
    1.5 ( 5.22 )
        BL LDL Cholesterol (n =15, 4)
    3.0 ( 1.32 )
    4.8 ( 2.31 )
        WK 22 LDL Cholesterol (n = 13, 4)
    -0.3 ( 1.35 )
    -1.5 ( 1.98 )
        WK 70 LDL Cholesterol (n = 10, 4)
    0.0 ( 1.17 )
    -2.2 ( 2.11 )
        LOV LDL Cholesterol (n = 15, 4)
    0.3 ( 1.58 )
    -0.7 ( 1.83 )
        BL HDL Cholesterol (n = 15, 4)
    1.6 ( 0.39 )
    2.1 ( 1.85 )
        WK 22 HDL Cholesterol (n = 13, 4)
    -0.3 ( 0.32 )
    -0.9 ( 1.58 )
        WK 70 HDL Cholesterol (n = 10, 4)
    -0.3 ( 0.42 )
    -0.9 ( 1.60 )
        LOV HDL Cholesterol (n = 15, 4)
    0.1 ( 0.66 )
    -0.0 ( 0.49 )
        BL Triglycerides (n = 15, 4)
    1.5 ( 0.70 )
    1.4 ( 0.32 )
        WK 22 Triglycerides (n = 13, 4)
    -0.1 ( 0.42 )
    0.1 ( 0.49 )
        WK 70 Triglycerides (n = 10, 4)
    0.3 ( 0.76 )
    -0.2 ( 0.25 )
        LOV Triglycerides (n = 15, 4)
    0.1 ( 0.64 )
    -0.1 ( 0.54 )
    No statistical analyses for this end point

    Secondary: Actual change from BL in Cardiovascular and other metabolic parameters: Sitting Diastolic Blood Pressure (DPB), Sitting Systolic Blood Pressure (SBP)

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    End point title
    		 Actual change from BL in Cardiovascular and other metabolic parameters: Sitting Diastolic Blood Pressure (DPB), Sitting Systolic Blood Pressure (SBP)
    End point description
    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 70, Last observed value
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: mmHG
    arithmetic mean (standard deviation)
        BL DBP (n =15, 4)
    84.5 ( 7.01 )
    87.3 ( 4.21 )
        WK 22 DPB (n = 13, 3)
    0.8 ( 9.59 )
    2.6 ( 11.36 )
        WK 70 DPB (n = 10, 4)
    -3.4 ( 11.65 )
    -5.8 ( 12.14 )
        LOV DPB (n = 15, 4)
    -1.3 ( 9.23 )
    -3.2 ( 7.07 )
        BL SBP (n =15, 4)
    133.2 ( 12.51 )
    130.3 ( 7.75 )
        WK 22 SPB (n = 13, 4)
    -4.0 ( 12.46 )
    8.8 ( 24.74 )
        WK 70 SPB (n = 10, 4)
    -9.5 ( 15.78 )
    -4.7 ( 26.09 )
        LOV SPB (n = 15, 4)
    -6.2 ( 16.50 )
    0.3 ( 20.60 )
    No statistical analyses for this end point

    Secondary: Actual change from BL in Cardiovascular and other metabolic parameters: Weight

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    End point title
    		 Actual change from BL in Cardiovascular and other metabolic parameters: Weight
    End point description
    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 70, Last observed value
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: Kg
    arithmetic mean (standard deviation)
        BL (n =15, 4)
    85.4 ( 23.52 )
    84.0 ( 23.32 )
        WK 22 (n = 13, 4)
    -2.1 ( 4.02 )
    0.6 ( 2.64 )
        WK 70 (n = 10, 4)
    -5.2 ( 4.56 )
    -3.2 ( 5.61 )
        LOV (n = 15, 4)
    -4.5 ( 6.68 )
    -4.4 ( 7.00 )
    No statistical analyses for this end point

    Secondary: Actual change from BL in Cardiovascular and other metabolic parameters: Body Mass index (BMI)

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    End point title
    		 Actual change from BL in Cardiovascular and other metabolic parameters: Body Mass index (BMI)
    End point description
    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 70, Last observed value
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: Kg/m^2
    arithmetic mean (standard deviation)
        BL (n =15, 4)
    30.6 ( 7.46 )
    31.3 ( 5.49 )
        WK 22 (n = 13, 4)
    -0.7 ( 1.42 )
    0.2 ( 1.09 )
        WK 70 (n = 10, 4)
    -1.9 ( 1.93 )
    -1.4 ( 2.25 )
        LOV (n = 15, 4)
    -1.6 ( 2.73 )
    -2.0 ( 2.73 )
    No statistical analyses for this end point

    Secondary: Actual change from BL in Cardiovascular and other metabolic parameters: Quantitative Insulin Sensitivity Check Index (QUICKI)

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    End point title
    		 Actual change from BL in Cardiovascular and other metabolic parameters: Quantitative Insulin Sensitivity Check Index (QUICKI)
    End point description
    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline. QUICKI is the quantitative insulin sensitivity check index and is derived using the inverse of the sum of algorithms (base 10) of the fasting insulin and fasting glucose
    End point type
    Secondary
    End point timeframe
    Baseline, Week 22, Week 70, Last observed value
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: Kg/m^2
    arithmetic mean (standard deviation)
        BL (n =13, 4)
    0.3 ( 0.03 )
    0.3 ( 0.02 )
        WK 22 (n = 11, 4)
    0.0 ( 0.02 )
    0.0 ( 0.01 )
        WK 70 (n = 8, 4)
    0.0 ( 0.03 )
    0.0 ( 0.06 )
        LOV (n = 13, 4)
    0.0 ( 0.04 )
    0.0 ( 0.04 )
    No statistical analyses for this end point

    Secondary: PK Parameters: AUC0-6h ss, AUC0-12h ss

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    End point title
    		 PK Parameters: AUC0-6h ss, AUC0-12h ss
    End point description
    Trough PK concentrations and PK profiles at steady-state were collected.
    End point type
    Secondary
    End point timeframe
    pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
    End point values
    		 2mg bid 5mg bid 10mg bid 20mg bid 30mg bid
    Number of subjects analysed
    4
    13
    6
    1
    1
    Units: hr•ng/mL
    geometric mean (geometric coefficient of variation)
        AUC0-6h,ss
    37.79 ( 42.7 )
    94.21 ( 37.0 )
    236.83 ( 29.9 )
    999 ( 999 )
    999 ( 999 )
        AUC0-12h,ss (n = 3,13,6,1,1)
    69.96 ( 32.6 )
    140.65 ( 43.9 )
    339.62 ( 37.6 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: PK Parameters: Cmax ss, Ctrough ss

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    End point title
    		 PK Parameters: Cmax ss, Ctrough ss
    End point description
    Trough PK concentrations and PK profiles at steady-state were collected.
    End point type
    Secondary
    End point timeframe
    pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
    End point values
    		 30mg bid 2mg bid 5mg bid 10mg bid 20mg bid
    Number of subjects analysed
    1
    6
    14
    8
    2
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cmax,ss (n =4,13,6,1,1)
    999 ( 999 )
    8.76 ( 46.1 )
    23.09 ( 31.5 )
    59.17 ( 25.5 )
    999 ( 999 )
        Ctrough, ss
    999 ( 999 )
    2.73 ( 49.1 )
    4.30 ( 112.9 )
    10.60 ( 104.8 )
    19.69 ( 53.6 )
    No statistical analyses for this end point

    Secondary: PK Parameters: Tmax ss,

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    End point title
    		 PK Parameters: Tmax ss,
    End point description
    Trough PK concentrations and PK profiles at steady-state were collected.
    End point type
    Secondary
    End point timeframe
    pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
    End point values
    		 2mg bid 5mg bid 10mg bid 20mg bid 30mg bid
    Number of subjects analysed
    4
    13
    6
    1
    1
    Units: hour (hr)
        median (full range (min-max))
    1.50 (1.0 to 4.1)
    1.50 (1.0 to 4.0)
    1.26 (1.0 to 2.0)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: PK Parameters: T1/2 ss,

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    End point title
    		 PK Parameters: T1/2 ss,
    End point description
    Trough PK concentrations and PK profiles at steady-state were collected.
    End point type
    Secondary
    End point timeframe
    pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
    End point values
    		 10mg bid 20mg bid 30mg bid 2mg bid 5mg bid
    Number of subjects analysed
    6
    1
    1
    2
    11
    Units: hour (hr)
        geometric mean (geometric coefficient of variation)
    4.32 ( 47.8 )
    999 ( 999 )
    999 ( 999 )
    6.39 ( 13.8 )
    3.54 ( 49.8 )
    No statistical analyses for this end point

    Secondary: Percentage of participants who were responders on 24-hour urine free cortisol (UFC) at Week 22

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    End point title
    		 Percentage of participants who were responders on 24-hour urine free cortisol (UFC) at Week 22
    End point description
    A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 22 was ≤ ULN (as defined by the local laboratories) or represented a ≥50% decrease from baseline. Participants with controlled or partially controlled UFC were defined as: Controlled UFC: mean UFC level <= upper limit of normal (ULN). Partially controlled UFC: mean UFC level > ULN but with >= 50% reduction from baseline.
    End point type
    Secondary
    End point timeframe
    Week 22
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: Percentage pf participants
    number (confidence interval 95%)
        Responders
    80.0 (51.91 to 95.67)
    75.0 (19.41 to 99.37)
        Controlled UFC responders
    80.0 (51.91 to 95.67)
    75.0 (19.41 to 99.37)
        Partially controlled UFC responders
    0 (0.00 to 21.80)
    0 (0.00 to 60.24)
    No statistical analyses for this end point

    Secondary: Number of participants with Escape

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    End point title
    		 Number of participants with Escape
    End point description
    Escape is defined as loss of UFC control (i.e. UFC > ULN) on at least 2 consecutive visits at the highest tolerated dose after previously attaining UFC normalization)
    End point type
    Secondary
    End point timeframe
    approx. 7 years
    End point values
    		 Part II Core: Expansion cohort Part ll Core: Follow-up cohort
    Number of subjects analysed
    15
    4
    Units: Participants
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Event (AE) timeframe: Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration of 350.6 weeks.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Part l: Core cohort
    Reporting group description
    		 Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study

    Reporting group title
    Part ll Core: Expansion cohort
    Reporting group description
    		 Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study

    Reporting group title
    Part ll Core: Follow-up cohort
    Reporting group description
    		 Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study.

    Serious adverse events
    		 Part l: Core cohort Part ll Core: Expansion cohort Part ll Core: Follow-up cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 15 (33.33%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Takayasu's arteritis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (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
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (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
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (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
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pituitary-dependent Cushing's syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part l: Core cohort Part ll Core: Expansion cohort Part ll Core: Follow-up cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    15 / 15 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    4
    1
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 15 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    0
    5
    3
    Chest discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Chills
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    7 / 12 (58.33%)
    3 / 15 (20.00%)
    3 / 4 (75.00%)
         occurrences all number
    9
    3
    3
    Feeling drunk
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Generalised oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    2
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 15 (26.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    5
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Breast pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Menstruation delayed
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Menorrhagia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Oligomenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    Dysphonia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Laryngeal oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Nasal congestion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus congestion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Abnormal sleep-related event
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    3
    2
    0
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 15 (13.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    2
    Disorientation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Libido decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    2
    Investigations
    Aldosterone urine increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Amylase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Blood aldosterone decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Blood corticotrophin increased
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 15 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    0
    5
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 15 (26.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood gonadotrophin abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood luteinising hormone decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood phosphorus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    2
    Blood pressure decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Blood prolactin increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Blood testosterone free increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Blood testosterone increased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    4 / 4 (100.00%)
         occurrences all number
    0
    2
    3
    Blood uric acid increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Cortisol decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Cortisol free urine decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Cortisol free urine increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Gastric pH decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Heart rate increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    High density lipoprotein decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hormone level abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 15 (26.67%)
    3 / 4 (75.00%)
         occurrences all number
    0
    4
    3
    Lipase increased
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 15 (6.67%)
    2 / 4 (50.00%)
         occurrences all number
    2
    1
    3
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    2
    Oestradiol increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Protein total increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Renin decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Urine analysis abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Urine leukocyte esterase
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Weight decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Weight increased
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 15 (13.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Animal bite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Arthropod bite
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 15 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    3
    0
    Contusion
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    0
    Foot fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Heat illness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle injury
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Bundle branch block right
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Cold-stimulus headache
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    3
    2
    Dizziness postural
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    3 / 12 (25.00%)
    6 / 15 (40.00%)
    2 / 4 (50.00%)
         occurrences all number
    4
    8
    3
    Hypersomnia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypogeusia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 15 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Eosinophilia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    2
    Polycythaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Inner ear disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Middle ear effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    2
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 15 (13.33%)
    3 / 4 (75.00%)
         occurrences all number
    3
    2
    4
    Abdominal pain upper
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 12 (25.00%)
    4 / 15 (26.67%)
    3 / 4 (75.00%)
         occurrences all number
    3
    4
    7
    Dry mouth
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Dysphagia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    0
    Gastric disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    5 / 12 (41.67%)
    8 / 15 (53.33%)
    2 / 4 (50.00%)
         occurrences all number
    6
    10
    3
    Tongue disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    2
    Vomiting
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 15 (6.67%)
    2 / 4 (50.00%)
         occurrences all number
    4
    1
    4
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Acanthosis nigricans
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Acne
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 15 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    0
    Dermal cyst
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Ecchymosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hair growth abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hirsutism
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Hypertrichosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    2
    Melanoderma
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Papule
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    5
    3
    1
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 15 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Skin discolouration
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    6 / 15 (40.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    6
    3
    Diabetes insipidus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pituitary-dependent Cushing's syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 15 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    2
    7
    1
    Back pain
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    Bone pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Bursitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Joint effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    1
    Muscular weakness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Osteopenia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    4
    0
    Tendonitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    6
    Cystitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Fungal infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Furuncle
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Groin abscess
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Helicobacter gastritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    1
    Laryngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 15 (20.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    3
    7
    Onychomycosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Skin infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Tongue fungal infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 15 (13.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 15 (20.00%)
    3 / 4 (75.00%)
         occurrences all number
    1
    4
    5
    Viral rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Folate deficiency
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hypercreatininaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 15 (6.67%)
    2 / 4 (50.00%)
         occurrences all number
    3
    1
    3
    Hypomagnesaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Hypoproteinaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hyposideraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2010
    Amended the inclusion criteria to ensure that only Cushing’s disease patients are enrolled; Defined responders as having a normalization of UFC or a 5 50% decrease in UFC; Revised the assumptions and power calculations to support the study sample size were revised and remove the originally planned interim analysis; Amended stopping rules to minimize premature termination of a patient from the study for AEs that were expected in this population or were efficacy related
    31 Jan 2011
    Changed the blood volume required for PD assessments.
    16 Mar 2011
    Revised and clarify the statistical analysis; Removed the need for a UFC measurement at Screening
    26 Mar 2012
    Confirmed the preliminary observations from the PoC study by: - Enrolling a new cohort (Expansion cohort) of patients. - Reenrolling the patients from the first cohort (Core PoC Follow-up cohort). - Evaluated the long-term efficacy and safety of osilodrostat treatment at 22 weeks and up to 12 months.
    26 Apr 2013
    Intensified ECG monitoring for potential risk of QTc prolongation; Excluded patients with a history of pituitary irradiation within 5 years prior to study entry; Replaced the highest dosing regimen (50 mg bid) from the dose titration schedule with a dose of 30 mg bid for those patients who did not have normalization of UFC at 20 mg bid.
    14 Mar 2014
    The purpose of this protocol amendment was to continue the study to monitor patients for long-term safety and efficacy, and to provide continued access to osilodrostat to patients who have completed long term extension-1; Provided that the investigator’s assessment was that the patient would benefit from continued treatment with osilodrostat, and did not meet the protocol's termination criteria, the patient had the option to enter a second-long term extension period (extension-2), which was to continue until osilodrostat was commercially available and reimbursed or through the availability of a local access program; In addition, the protocol was updated to indicate that the formulation of osilodrostat was changed from capsules to tablets during long term extension-2.
    16 Feb 2016
    The primary purpose of this protocol amendment was to ensure patient safety by adding specific criteria for the identification and management of patients with potential drug-induced liver injury (DILI). Although there are no known cases of suspected DILI in patients treated with osilodrostat to date, these criteria are added in the event that a case of suspected DILI arises in the future; Update to the requirement for contraception by male study participants. For male subjects participating in clinical trials, contraception was no longer required; Clarification of protocol language regarding withdrawal of consent, study treatment discontinuation, and discontinuation procedures.
    11 Jul 2017
    The main purpose of this amendment was to provide continued access to the study treatment for those patients benefitting from the treatment into a separate long-term safety follow-up study (roll-over study). Based on this, the end of study (EOS) definition was updated. The EOS definition was changed throughout the protocol from “until osilodrostat is commercially available & reimbursed or through the availability of a local access program" to “patient treatment in Long Term Extension-2 will end at each site within 4 months after a separate roll-over study is opened at their site, or by 31 December 2018 (whichever occurred earlier). The roll-over study was to provide an opportunity of continued treatment for patients who were still ongoing at that time & were clinically benefitting from osilodrostat. For sites where a separate roll-over study was not an option, the patient had to be offered a local alternative treatment option. In addition, the option of an earlier End of Trial visit (i.e. earlier than the 6 month interval visits in Long Term Extension-2) was implemented to allow seamless transition of patients into the separate rollover study; The risks section was updated to include neutropenia, which is a known effect related to the decrease of cortisol in patients with Cushing’s disease, in line with cases observed in clinical trials with osilodrostat. The QT-specific concomitant medication guidance for osilodrostat was revised to limit the list of prohibited drugs to medications with a ‘Known risk to cause TdP" and ‘Possible risk to cause TdP", instead of all drugs known to prolong QT. This change was also in alignment with the terminology used in the QT Drug Lists (CredibleMeds®); Interim Analysis was updated to allow for an additional database lock in support of future market authorization applications for osilodrostat
    03 May 2018
    The purpose of this amendment was to extend the study end date by a year from 31-Dec-2018 to 31-Dec-2019 to allow continued access to the study treatment for those patients benefitting from the treatment until a separate long-term safety follow-up study (roll-over study) was set up at participating sites; Additional updates were made to the Protocol glossary and withdrawal of informed consent section to align with the new Personal Data and Withdrawal of Consent language requirement.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novforcomplete trial results.
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