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    Clinical Trial Results:
    A Phase III, multi-center, randomized, double-blind, 48 week study with an initial 12 week placebo-controlled period to evaluate the safety and efficacy of osilodrostat in patients with Cushing’s disease

    Summary
    EudraCT number
    		 2014-004092-23
    Trial protocol
    		 ES   GR   BE   PL   PT  
    Global end of trial date
    31 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2021
    First version publication date
    21 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCI699C2302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02697734
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, 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
    31 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective: To demonstrate the superiority of osilodrostat compared to placebo in achieving a complete response (mUFC ≤ ULN) at Week 12.
    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
    03 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    China: 12
    Country: Number of subjects enrolled
    Costa Rica: 3
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    74
    EEA total number of subjects
    24
    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)
    72
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Number of subjects - enrolled: 74; analyzed: 73 (One patient was randomized but did not receive any study treatment as the patient experienced an SAE and discontinued the study)

    Pre-assignment
    Screening details
    		 Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). There are 73 participants in the FAS who were randomized and received treatment.

    Period 1
    Period 1 title
    Core phase - up to week 48
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 osilodrostat Group
    Arm description
    		 Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Osilodrostat
    Investigational medicinal product code
    LCI699
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose in Period 1 was 2 mg b.i.d. osilodrostat. Osildrostat dosing regimen included up-titration following a 5 mg b.i.d., 10 mg b.i.d. and 20 mg b.i.d. escalation sequence during Period 1.

    Arm title
    		 osilodrostat Placebo Group
    Arm description
    		 Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet for oral use

    Number of subjects in period 1 [1]
    		osilodrostat Group osilodrostat Placebo Group
    Started
    48
    25
    Completed
    42
    23
    Not completed
    6
    2
         Consent withdrawn by subject
    4
    -
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    2
    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: 5 participants completed core phase and did not enter the optional extension phase.
    Period 2
    Period 2 title
    Optional Extension phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 osilodrostat Group
    Arm description
    		 Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Osilodrostat
    Investigational medicinal product code
    LCI699
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In Period 2, the maximum starting dose of osilodrostat was 2 mg b.i.d., and could be <2 mg if they were receiving osilodrostat or placebo at a dose <2mg b.i.d. at the end of Period 1. Osilodrostat dosing regimen included up-titration following a 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg b.i.d. and 30 mg b.i.d. escalation sequence during Period 2.

    Arm title
    		 osilodrostat Placebo Group
    Arm description
    		 Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet for oral use

    Number of subjects in period 2 [2]
    		osilodrostat Group osilodrostat Placebo Group
    Started
    38
    22
    Completed
    33
    20
    Not completed
    5
    2
         Physician decision
    -
    1
         Adverse event, non-fatal
    5
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Number of subjects; enrolled: 74; analyzed: 73 (One patient was randomized but did not receive any study treatment as the patient experienced an SAE and discontinued the study)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    osilodrostat Group
    Reporting group description
    		 Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).

    Reporting group title
    osilodrostat Placebo Group
    Reporting group description
    		 Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).

    Reporting group values
    		 osilodrostat Group osilodrostat Placebo Group Total
    Number of subjects
    		 48 25 73
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 46 25 71
        >=65 years
    		 2 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 42.3 ( 13.82 ) 38.9 ( 12.33 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 43 18 61
        Male
    		 5 7 12
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 9 8 17
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 2 0 2
        White
    		 34 15 49
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 2 1 3
    Subject analysis sets

    Subject analysis set title
    All participants combined
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Consisted of all randomized participants who received at least one dose of osilodrostat.

    Subject analysis set title
    All Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Participants

    Subject analysis set title
    osilodrostat Incident Dose 1mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 1mg of osilodrostat.

    Subject analysis set title
    osilodrostat Incident Dose 2mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 2mg of osilodrostat.

    Subject analysis set title
    osilodrostat Incident Dose 5mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 5mg of osilodrostat.

    Subject analysis sets values
    		 All participants combined All Participants osilodrostat Incident Dose 1mg osilodrostat Incident Dose 2mg osilodrostat Incident Dose 5mg
    Number of subjects
    73
    73
    16
    55
    29
    Age Categorical
    Units: Participants
        <=18 years
        Between 18 and 65 years
        >=65 years
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    80.8 ( )
    2 ( )
    ( )
    ( )
    ( )
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported

    End points

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    End points reporting groups
    Reporting group title
    osilodrostat Group
    Reporting group description
    		 Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).

    Reporting group title
    osilodrostat Placebo Group
    Reporting group description
    		 Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).
    Reporting group title
    osilodrostat Group
    Reporting group description
    		 Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).

    Reporting group title
    osilodrostat Placebo Group
    Reporting group description
    		 Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).

    Subject analysis set title
    All participants combined
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Consisted of all randomized participants who received at least one dose of osilodrostat.

    Subject analysis set title
    All Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Participants

    Subject analysis set title
    osilodrostat Incident Dose 1mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 1mg of osilodrostat.

    Subject analysis set title
    osilodrostat Incident Dose 2mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 2mg of osilodrostat.

    Subject analysis set title
    osilodrostat Incident Dose 5mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 5mg of osilodrostat.

    Primary: Percentage of randomized participants with a complete response

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    End point title
    		 Percentage of randomized participants with a complete response
    End point description
    A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.
    End point type
    Primary
    End point timeframe
    at Week 12
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Participants
    37
    2
    Statistical analysis title
    		 osilodrostat Group v osilodrostat Placebo Group
    Comparison groups
    osilodrostat Group v osilodrostat Placebo Group
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    43.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.06
         upper limit
    		 343.19

    Secondary: Time-to-first control of mUFC - number (%) of participants with mUFC <=ULN

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    End point title
    		 Time-to-first control of mUFC - number (%) of participants with mUFC <=ULN
    End point description
    To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Participants
    45
    8
    No statistical analyses for this end point

    Secondary: Time-to-first control of mUFC - median time to first controlled mUFC response

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    End point title
    		 Time-to-first control of mUFC - median time to first controlled mUFC response
    End point description
    To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. The median time-to-first control and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Days
        number (confidence interval 95%)
    35 (34.0 to 52.0)
    999 (87.0 to 999)
    No statistical analyses for this end point

    Secondary: Time-to-first control of mUFC - % event probability estimates

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    End point title
    		 Time-to-first control of mUFC - % event probability estimates
    End point description
    To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. % Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for Confidence Interval (CI) of Kaplan-Meier (KM) estimates.
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Percentage
    number (confidence interval 95%)
        2 Weeks
    25.0 (15.0 to 39.8)
    16.0 (6.3 to 37.2)
        5 Weeks
    60.4 (47.0 to 74.1)
    20.0 (8.9 to 41.6)
        8 Weeks
    79.4 (67.0 to 89.4)
    28.0 (14.5 to 49.9)
        12 Weeks
    999 (999 to 999)
    28.0 (14.5 to 49.9)
    No statistical analyses for this end point

    Secondary: Time-to-escape during osilodrostat treatment from collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN - number (%) of participants

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    End point title
    		 Time-to-escape during osilodrostat treatment from collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN - number (%) of participants
    End point description
    To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks.
    End point type
    Secondary
    End point timeframe
    up to 48 weeks
    End point values
    		 osilodrostat Group osilodrostat Placebo Group All Participants
    Number of subjects analysed
    48
    25
    73
    Units: Participants
    0
    2
    2
    No statistical analyses for this end point

    Secondary: Time-to-escape during osilodrostat treatment from collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN - median time to escape from normal mUFC

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    End point title
    		 Time-to-escape during osilodrostat treatment from collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN - median time to escape from normal mUFC
    End point description
    To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks. The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
    End point type
    Secondary
    End point timeframe
    from week 26 to week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group All Participants
    Number of subjects analysed
    48
    25
    73
    Units: days
        number (confidence interval 95%)
    999 (999 to 999)
    999 (116.0 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Time-to-escape during osilodrostat treatment from collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN - % event probability estimates

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    End point title
    		 Time-to-escape during osilodrostat treatment from collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN - % event probability estimates
    End point description
    To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks. % Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for CI of KM estimates.
    End point type
    Secondary
    End point timeframe
    week 26 to week 36
    End point values
    		 osilodrostat Group osilodrostat Placebo Group All Participants
    Number of subjects analysed
    48
    25
    73
    Units: Percentage
    number (confidence interval 95%)
        26 Weeks
    0 (0 to 0)
    21.3 (5.7 to 61.9)
    15.6 (4.1 to 49.6)
        36 Weeks
    0 (0 to 0)
    999 (999 to 999)
    15.6 (4.1 to 49.6)
    No statistical analyses for this end point

    Secondary: Patients with a complete response (mUFC ≤ ULN) or a partial response (mUFC decrease ≥ 50% from baseline and >ULN) at week 12, 36 and 48

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    End point title
    		 Patients with a complete response (mUFC ≤ ULN) or a partial response (mUFC decrease ≥ 50% from baseline and >ULN) at week 12, 36 and 48
    End point description
    Overall response rate defined as percentage of complete responders (mUFC ≤ ULN) plus partial responders (≥ 50% reduction in mUFC from baseline and >ULN) at week 12, 36, 48 by treatment arms for all patients.
    End point type
    Secondary
    End point timeframe
    baseline, week 12, 36 and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Participants
        week 12 Complete responders
    37
    2
        week 12 Partial responders
    2
    2
        week 12 Overall responders (complete or partial)
    39
    4
        week 12 Non-responders
    9
    21
        week 36 Complete responders
    38
    21
        week 36 Partial responders
    2
    3
        week 36 Overall responders (complete or partial
    40
    24
        week 36 Non-responders
    8
    1
        week 48 Complete responders
    34
    16
        week 48 Partial responders
    5
    3
        week 48 Overall responders (complete or partial
    39
    19
        week 48 Non-responders
    9
    6
    No statistical analyses for this end point

    Secondary: Change from baseline to Week 12, Week 36, and Week 48 in clinical signs of Cushing’s disease

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    End point title
    		 Change from baseline to Week 12, Week 36, and Week 48 in clinical signs of Cushing’s disease
    End point description
    Change from baseline to Week 12, Week 36, and Week 48 in each of the following clinical signs of Cushing’s disease, captured by: a semi-quantitative Likert scale for facial rubor, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises) by randomized treatment arm. The number/proportion of participants with an improvement or no change compared to baseline are reported
    End point type
    Secondary
    End point timeframe
    baseline, Week 12, Week 36 and Week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Participants
        Facial Rubor - week 12 (n=42,20)
    36
    19
        Hirsutism - week 12 (n=36,16)
    34
    15
        Striae - week 12 (n=41,20)
    38
    19
        Supraclavicular Fat Pad - week 12 (n=42,21)
    41
    19
        Dorsal Fat Pad - week 12 (n=41,21)
    35
    17
        Proximal Muscle Atrophy - week 12 (n=42,21)
    38
    20
        Central Obesity - week 12 (n=42,21)
    37
    21
        Ecchymoses - week 12 (n=42,20)
    39
    19
        Facial Rubor - week 36 (n=41,23)
    39
    22
        Hirsutism - week 36 (n=34,17)
    28
    16
        Striae - week 36 (n=40,23)
    38
    23
        Supraclavicular Fat Pad - week 36 (n=41,24)
    40
    24
        Dorsal Fat Pad - week 36 (n=40,24)
    36
    22
        Proximal Muscle Atrophy - week 36 (n=41,23)
    37
    22
        Central Obesity - week 36 (n=41,24)
    37
    21
        Ecchymoses - week 36 (n=41,23)
    39
    22
        Facial Rubor - week 48 (n=39,21)
    37
    21
        Hirsutism - week 48 (n=33,15)
    29
    15
        Striae - week 48 (n=38,21)
    38
    21
        Supraclavicular Fat Pad - week 48 (n=39,22)
    38
    22
        Dorsal Fat Pad - week 48 (n=38,22)
    36
    20
        Proximal Muscle Atrophy - week 48 (n=39,22)
    35
    21
        Central Obesity - week 48 (n=39,22)
    35
    21
        Ecchymoses - week 48 (n=39,21)
    38
    20
    No statistical analyses for this end point

    Secondary: Change from baseline in EQ-5D-5L Utility Index

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    End point title
    		 Change from baseline in EQ-5D-5L Utility Index
    End point description
    EQ-5D-5L Utility Index: The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an "unconscious" health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Actual - baseline (n=48,24)
    0.825 ( 0.1486 )
    0.903 ( 0.1125 )
        Actual Change from Baseline at Week 12 (n=46,24)
    -0.000 ( 0.1402 )
    0.021 ( 0.0771 )
        Actual Change from Baseline at Week 48 (n=42,22)
    0.044 ( 0.1393 )
    0.033 ( 0.0826 )
        Actual Change from Week 12 at Week 36 (n=44,23)
    0.025 ( 0.1283 )
    0.010 ( 0.0487 )
        Actual Change from Week 36 at Week 48 (n=42,22)
    0.023 ( 0.0762 )
    -0.008 ( 0.0367 )
    No statistical analyses for this end point

    Secondary: Change from baseline in EQ-5D VAS

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    End point title
    		 Change from baseline in EQ-5D VAS
    End point description
    The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with a scale of 0-100, with endpoints labeled 100=‘the best health you can imagine’ and 0=‘the worst health you can imagine’. A single index value is analyzed for the EQ-5D-5L VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Actual - baseline (n=48,23)
    70.3 ( 17.26 )
    76.7 ( 17.88 )
        Actual Change from Baseline at week 12 (n=46,24)
    0.5 ( 13.57 )
    -0.3 ( 10.52 )
        Actual Change from Baseline at week 48 (n=42,22)
    9.4 ( 13.13 )
    5.8 ( 9.45 )
        Actual Change from Week 12 at Week 36 (n=44,23)
    6.0 ( 11.08 )
    3.7 ( 9.29 )
        Actual Change from Week 36 at Week 48 (n=42,22)
    3.2 ( 8.40 )
    -0.8 ( 4.44 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Beck Depression Inventory-II - Total Score Derived

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    End point title
    		 Change from baseline in Beck Depression Inventory-II - Total Score Derived
    End point description
    The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 items designed to assess the intensity of depression in clinical and normal patients in the preceding two weeks. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. A global score ranges from 0 to 63 and is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. A reduction from baseline in BDI-II is indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Actual - baseline (n=48,25)
    12.2 ( 10.22 )
    8.4 ( 7.82 )
        Actual Change from Baseline at Week 12 (n=46,24)
    -1.4 ( 7.99 )
    -3.9 ( 5.42 )
        Actual Change from Baseline at Week 48 (n=42,22)
    -4.3 ( 7.52 )
    -4.0 ( 7.70 )
        Actual Change from Week 12 at Week 36 (n=44,23)
    -2.0 ( 4.70 )
    0.6 ( 6.29 )
        Actual Change from Week 36 at Week 48 (n=42,22)
    -1.1 ( 4.83 )
    -0.4 ( 3.39 )
    No statistical analyses for this end point

    Secondary: Plasma osilodrostat concentrations (ng/mL)

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    End point title
    		 Plasma osilodrostat concentrations (ng/mL)
    End point description
    Plasma osilodrostat concentrations (ng/mL)
    End point type
    Secondary
    End point timeframe
    pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26
    End point values
    		 osilodrostat Incident Dose 1mg osilodrostat Incident Dose 2mg osilodrostat Incident Dose 5mg
    Number of subjects analysed
    16
    55
    29
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        week 1 1-2 hrs post dose (n=1,43,0)
    3.85 ( 999 )
    7.29 ( 101.0 )
    999 ( 999 )
        week 2 0 hrs pre dose (n=0,41,0)
    999 ( 999 )
    2.19 ( 107.5 )
    999 ( 999 )
        week 2 1-2 hrs post dose (n=0,42,0)
    999 ( 999 )
    9.76 ( 53.4 )
    999 ( 999 )
        week 5 pre dose (n=2,18,17)
    0.576 ( 141.9 )
    2.07 ( 82.1 )
    5.06 ( 109.6 )
        week 5 1-2 hrs post dose (n=2,9,29)
    3.64 ( 60.5 )
    11.1 ( 31.5 )
    25.8 ( 84.4 )
        week 8 0 hrs pre dose (n=2,4,13)
    0.971 ( 76.7 )
    2.64 ( 53.7 )
    4.99 ( 55.6 )
        week 8 1-2 hrs post dose (n=3,6,14)
    3.70 ( 47.6 )
    8.31 ( 45.6 )
    23.3 ( 68.1 )
        week 12 0 hrs pre dose (n=2,8,11)
    1.55 ( 3.7 )
    2.45 ( 39.2 )
    5.03 ( 74.6 )
        week 12 1-2 hrs post dose (n=4,34,0)
    4.93 ( 32.0 )
    11.7 ( 78.9 )
    999 ( 999 )
        week 14 0 hrs pre dose (n=4,55,0)
    0.974 ( 129.7 )
    1.96 ( 74.9 )
    999 ( 999 )
        week 14 1-2 hrs post dose (n=6,49,6)
    3.74 ( 161.4 )
    9.69 ( 35.8 )
    22.6 ( 37.8 )
        week 20 0 hrs pre dose (n=10,19,15)
    1.63 ( 71.1 )
    1.95 ( 68.1 )
    6.21 ( 74.3 )
        week 20 1-2 hrs post dose (n=13,18,12)
    6.09 ( 27.3 )
    8.66 ( 94.0 )
    26.0 ( 99.3 )
        week 26 0 hrs pre dose (n=12,13,10)
    1.77 ( 86.4 )
    2.12 ( 77.8 )
    6.89 ( 85.1 )
        week 26 1-2 hrs post dose (n=16,14,10)
    5.28 ( 31.5 )
    8.04 ( 50.7 )
    33.1 ( 31.4 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with mUFC ≤ ULN at week 36

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    End point title
    		 Percentage of participants with mUFC ≤ ULN at week 36
    End point description
    The complete response rate in both arms combined at Week 36. A complete responder at Week 36 is defined as a participant who had mean urine free cortisol <= upper limit of normal (mUFC <= ULN) at Week 36. Participants with missing mUFC at Week 36 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    At Week 36
    End point values
    		 All participants combined
    Number of subjects analysed
    73
    Units: Percentage of participants
        number (confidence interval 95%)
    80.8 (69.9 to 89.1)
    No statistical analyses for this end point

    Secondary: Change from baseline in mUFC

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    End point title
    		 Change from baseline in mUFC
    End point description
    To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: nmol/24hr
    arithmetic mean (standard deviation)
        actual - baseline
    421.4 ( 291.25 )
    451.5 ( 535.09 )
        change from baseline at week 2 (n=47,24)
    -139.3 ( 404.45 )
    164.9 ( 543.82 )
        change from baseline at week 5 (n=46,25)
    -252.8 ( 338.48 )
    -37.3 ( 280.84 )
        change from baseline at week 8 (n=44,25)
    -330.2 ( 303.35 )
    -35.0 ( 325.30 )
        change from baseline at week 12 (n=44,24)
    -332.7 ( 315.50 )
    -49.1 ( 332.29 )
        change from baseline at week 14 (n=45,25)
    -191.7 ( 446.77 )
    -209.5 ( 407.62 )
        change from baseline at week 17 (n=45,25)
    -238.8 ( 362.46 )
    -284.5 ( 557.47 )
        change from baseline at week 20 (n=44,24)
    -294.5 ( 316.65 )
    -355.1 ( 538.96 )
        change from baseline at week 23 (n=44,25)
    -314.1 ( 307.60 )
    -387.8 ( 466.15 )
        change from baseline at week 26 (n=43,25)
    -345.2 ( 306.35 )
    -365.4 ( 458.28 )
        change from baseline at week 29 (n=43,25)
    -331.4 ( 299.63 )
    -391.4 ( 534.57 )
        change from baseline at week 32 (n=44,25)
    -341.3 ( 298.96 )
    -298.0 ( 655.52 )
        change from baseline at week 36 (n=43,25)
    -349.6 ( 310.46 )
    -372.9 ( 519.17 )
        change from baseline at week 40 (n=43,23)
    -333.4 ( 307.63 )
    -364.7 ( 542.28 )
        change from baseline at week 48 (n=42,22)
    -325.1 ( 314.30 )
    -367.5 ( 554.16 )
        change from baseline at week 60 (n=33,19)
    -364.4 ( 339.57 )
    -335.2 ( 571.06 )
        change from baseline at week 72 (n=31,17)
    -381.2 ( 338.68 )
    -372.4 ( 624.69 )
        change from baseline at week 84 (n=23,17)
    -398.6 ( 377.81 )
    -196.0 ( 916.83 )
        change from baseline at week 96 (n=6,7)
    -414.5 ( 347.83 )
    -616.4 ( 881.92 )
    No statistical analyses for this end point

    Secondary: Change from baseline in bone mineral density (BMD) by Dual-energy X-ray absorptiometry (DXA) scan at the femoral neck, hip and spinal cord - QC corrected

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    End point title
    		 Change from baseline in bone mineral density (BMD) by Dual-energy X-ray absorptiometry (DXA) scan at the femoral neck, hip and spinal cord - QC corrected
    End point description
    The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: g/cm2
    arithmetic mean (standard deviation)
        FEMORAL NECK QC CORRECTED- b/l - (n=43,24)
    0.8 ( 0.16 )
    0.8 ( 0.14 )
        FEMORAL NECK QC CORR - week 48 - CFB (n=28,19)
    0.0 ( 0.04 )
    0.0 ( 0.03 )
        HIP QC CORRECTED - b/l - (n=43,24)
    0.9 ( 0.14 )
    0.9 ( 0.11 )
        HIP QC CORRECTED - week 48 - CFB (n=28,19)
    0.0 ( 0.03 )
    0.0 ( 0.02 )
        SPINAL CORD QC CORRECTED - b/l (n=42,23)
    1.0 ( 0.15 )
    1.0 ( 0.18 )
        SPINAL CORD QC CORRECTED - week 48 - CFB (n=28,18)
    0.0 ( 0.04 )
    0.0 ( 0.04 )
    No statistical analyses for this end point

    Secondary: Change from baseline in bone mineral density (BMD) T-score by Dual-energy X-ray absorptiometry (DXA) scan at the femoral neck, hip and spinal cord - QC corrected

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    End point title
    		 Change from baseline in bone mineral density (BMD) T-score by Dual-energy X-ray absorptiometry (DXA) scan at the femoral neck, hip and spinal cord - QC corrected
    End point description
    The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient. The WHO criteria are: Normal is a T-score of −1.0 or higher”. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: scores on a scale
    arithmetic mean (standard deviation)
        FEMORAL NECK QC CORRECTED - b/l (n=43,24)
    -1.2 ( 1.06 )
    -1.3 ( 0.89 )
        FEMORAL NECK QC CORRECTED - CFB at wk 48 (n=28,19)
    0.1 ( 0.30 )
    0.1 ( 0.21 )
        HIP QC CORRECTED - b/l - Actual (n=43,24)
    -0.7 ( 1.08 )
    -0.8 ( 0.84 )
        HIP QC CORRECTED - CFB at wk 48 (n=28,19)
    0.0 ( 0.27 )
    0.0 ( 0.16 )
        SPINAL CORD QC CORRECTED - baseline - (n=42,23)
    -1.2 ( 1.10 )
    -1.1 ( 1.40 )
        SPINAL CORD QC CORRECTED - CFB at wk 48 (n=28,18)
    0.1 ( 0.32 )
    0.1 ( 0.33 )
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose

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    End point title
    		 Change in fasting plasma glucose
    End point description
    Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mg/dL
    arithmetic mean (standard deviation)
        Fasting glucose (mg/dL) - baseline - (n=47,24)
    97.3 ( 18.14 )
    91.4 ( 15.15 )
        Fasting glucose (mg/dL) - CFB at week 12 (n=44,23)
    -4.3 ( 14.84 )
    -1.7 ( 10.59 )
        Fasting glucose (mg/dL) - CFB at week 36 (n=43,24)
    -6.7 ( 12.48 )
    -1.1 ( 12.93 )
        Fasting glucose (mg/dL) - CFB at week 48 (n=41,21)
    -5.6 ( 14.13 )
    1.8 ( 13.92 )
    No statistical analyses for this end point

    Secondary: Change in Hemoglobin A1C

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    End point title
    		 Change in Hemoglobin A1C
    End point description
    Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: percentage of Hemoglobin A1C
    arithmetic mean (standard deviation)
        Hemoglobin A1C (%) - baseline
    6.0 ( 0.92 )
    5.7 ( 0.56 )
        Hemoglobin A1C (%) - CFB at week 12 (n=46,24)
    -0.2 ( 0.44 )
    0.0 ( 0.27 )
        Hemoglobin A1C (%) CFB at week 36 (n=44,25)
    -0.2 ( 0.54 )
    -0.1 ( 0.46 )
        Hemoglobin A1C (%) CFB at week 48 (n=41,21)
    -0.2 ( 0.58 )
    0.1 ( 0.37 )
    No statistical analyses for this end point

    Secondary: Change in Cholesterol

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    End point title
    		 Change in Cholesterol
    End point description
    Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmol/L
    arithmetic mean (standard deviation)
        Cholesterol (mmol/L) - baseline (n=45,25)
    5.7 ( 1.30 )
    5.3 ( 1.15 )
        Cholesterol (mmol/L) - CFB at week 12 (n=44,24)
    -0.8 ( 0.95 )
    0.0 ( 0.65 )
        Cholesterol (mmol/L) - CFB at week 36 (n=44,25)
    -1.0 ( 1.28 )
    -0.4 ( 0.89 )
        Cholesterol (mmol/L) - CFB at week 48 (n=42,22)
    -0.6 ( 1.36 )
    -0.4 ( 1.18 )
    No statistical analyses for this end point

    Secondary: Change in LDL Cholesterol

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    End point title
    		 Change in LDL Cholesterol
    End point description
    Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmol/L
    arithmetic mean (standard deviation)
        LDL Cholesterol (mmol/L) - baseline (n=45,24)
    3.4 ( 1.12 )
    3.0 ( 1.07 )
        LDL Cholesterol (mmol/L) - CBF at wk 12 (n=44,23)
    -0.5 ( 0.80 )
    0.1 ( 0.47 )
        LDL Cholesterol (mmol/L) - CFB at wk 36 (n=44,24)
    -0.6 ( 1.08 )
    -0.2 ( 0.70 )
        LDL Cholesterol (mmol/L) - CFB at wk 48 (n=41,21)
    -0.5 ( 0.99 )
    -0.2 ( 0.92 )
    No statistical analyses for this end point

    Secondary: Change in HDL Cholesterol

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    End point title
    		 Change in HDL Cholesterol
    End point description
    Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmol/L
    arithmetic mean (standard deviation)
        HDL Cholesterol (mmol/L) - baseline (n=45,25)
    1.6 ( 0.35 )
    1.5 ( 0.38 )
        HDL Cholesterol (mmol/L)-CFB at week 12 (n=44,24)
    -0.3 ( 0.29 )
    0.0 ( 0.28 )
        HDL Cholesterol (mmol/L)-CFB at week 36 (n=44,25)
    -0.3 ( 0.27 )
    -0.2 ( 0.25 )
        HDL Cholesterol (mmol/L)-CFB at week 48 (n=42,22)
    -0.2 ( 0.27 )
    -0.1 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Change in Triglyceride

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    End point title
    		 Change in Triglyceride
    End point description
    Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmol/L
    arithmetic mean (standard deviation)
        Triglyceride (mmol/L)- baseline (n=45,25)
    1.5 ( 0.79 )
    1.7 ( 0.85 )
        Triglyceride (mmol/L)-CFB at week 12(n=44,24)
    0.0 ( 0.53 )
    -0.2 ( 0.54 )
        Triglyceride (mmol/L)-CFB at week 36 (n=44,25)
    -0.1 ( 0.55 )
    -0.1 ( 0.71 )
        Triglyceride (mmol/L)-CFB at week 48 (n=42,22)
    0.1 ( 0.92 )
    -0.2 ( 0.62 )
    No statistical analyses for this end point

    Secondary: Change in Standing Systolic Blood Pressure

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    End point title
    		 Change in Standing Systolic Blood Pressure
    End point description
    Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline BP = blood pressure
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmHg
    arithmetic mean (standard deviation)
        Standing Systolic Blood Pressure -b/l (n=46,25)
    132.4 ( 19.16 )
    130.0 ( 17.72 )
        Standing Systolic BP - CFB at week 12 (n=44,24)
    -7.1 ( 18.08 )
    -0.9 ( 11.77 )
        Standing Systolic BP - CFB at week 36 (n=42,25)
    -9.3 ( 19.09 )
    -7.0 ( 21.04 )
        Standing Systolic BP - CFB at week 48 (n=41,22)
    -9.1 ( 19.45 )
    -11.0 ( 22.30 )
    No statistical analyses for this end point

    Secondary: Change in Supine Systolic Blood Pressure

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    End point title
    		 Change in Supine Systolic Blood Pressure
    End point description
    Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline BP = blood pressure
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmHg
    arithmetic mean (standard deviation)
        Supine Systolic BP - baseline (n=48,25)
    131.7 ( 18.33 )
    127.8 ( 18.69 )
        Supine Systolic BP - CFB at week 12 (n=46,24)
    -8.0 ( 17.54 )
    2.3 ( 15.91 )
        Supine Systolic BP - CFB at week 36 (n=42,25)
    -9.7 ( 19.88 )
    -4.4 ( 17.43 )
        Supine Systolic BP - CFB at week 48 (n=42,22)
    -7.4 ( 19.38 )
    -7.5 ( 18.91 )
    No statistical analyses for this end point

    Secondary: Change in Standing Diastolic Blood Pressure

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    End point title
    		 Change in Standing Diastolic Blood Pressure
    End point description
    Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline BP = blood pressure
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmHg
    arithmetic mean (standard deviation)
        Standing Diastolic BP - baseline (n=46,25)
    87.2 ( 12.74 )
    88.2 ( 10.83 )
        Standing Diastolic BP - CFB at week 12 (n=44,24)
    -4.8 ( 11.14 )
    -1.4 ( 9.84 )
        Standing Diastolic BP - CFB at week 36 (n=42,25)
    -6.0 ( 12.09 )
    -4.4 ( 13.98 )
        Standing Diastolic BP - CFB at week 48 (n=41,22)
    -4.4 ( 11.64 )
    -3.9 ( 13.36 )
    No statistical analyses for this end point

    Secondary: Change in Supine Diastolic Blood Pressure

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    End point title
    		 Change in Supine Diastolic Blood Pressure
    End point description
    Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline BP = blood pressure
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: mmHg
    arithmetic mean (standard deviation)
        Supine Diastolic BP - baseline (n=48,25)
    83.9 ( 11.71 )
    81.4 ( 11.21 )
        Supine Diastolic BP - CFB at week 12 (n=46,24)
    -6.3 ( 11.05 )
    -0.1 ( 8.31 )
        Supine Diastolic BP - CFB at week 36 (n=44,25)
    -7.7 ( 11.92 )
    -3.4 ( 11.37 )
        Supine Diastolic BP - CFB at week 48 (n=41,22)
    -5.8 ( 11.60 )
    -3.7 ( 10.92 )
    No statistical analyses for this end point

    Secondary: Change in Weight

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    End point title
    		 Change in Weight
    End point description
    Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: kg
    arithmetic mean (standard deviation)
        Weight - baseline (n=48,25)
    78.8 ( 17.46 )
    77.3 ( 16.90 )
        Weight - change from baseline at wk 12(n=46,24)
    -0.8 ( 3.09 )
    -0.1 ( 2.12 )
        Weight - change from baseline at wk 36 (n=44,25)
    -3.0 ( 5.53 )
    -4.8 ( 5.63 )
        Weight - change from baseline at wk 48 (n=42,22)
    -3.6 ( 6.53 )
    -5.5 ( 6.38 )
    No statistical analyses for this end point

    Secondary: Change in Waist Circumference

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    End point title
    		 Change in Waist Circumference
    End point description
    Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm. CFB = change from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12, 36, and 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: cm
    arithmetic mean (standard deviation)
        Waist Circumference - baseline (n=48,25)
    102.5 ( 17.01 )
    103.4 ( 15.52 )
        Waist Circumference- CFB at week 12 (n=46,24)
    -1.0 ( 4.43 )
    -0.5 ( 3.35 )
        Waist Circumference- CFB at week 36 (n=44,25)
    -3.9 ( 6.36 )
    -2.1 ( 8.60 )
        Waist Circumference - CFB at week 48 (n=42,22)
    -4.1 ( 6.10 )
    -5.3 ( 5.68 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Standardized Health Related Quality of Life score, using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment

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    End point title
    		 Change from baseline in Standardized Health Related Quality of Life score, using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
    End point description
    The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing’s syndrome and has been validated in patients with Cushing’s disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. ‘I bruise easily’), psychological aspects (e.g. ‘I am more irritable, I have sudden mood swings and angry outbursts’), and social aspects (e.g. ‘I have had to give up my social or leisure activities due to my illness’). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient’s Cushing’s disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Actual - Baseline (n=48,25)
    49.1 ( 19.60 )
    56.9 ( 18.99 )
        Actual Change from Baseline at Week 12 (n=46,24)
    6.2 ( 14.85 )
    8.6 ( 12.06 )
        Actual Change from Baseline at Week 48 (n=42,22)
    11.7 ( 16.30 )
    12.8 ( 14.24 )
        Actual Change from Week 12 at Week 36 (n=44,23)
    4.7 ( 9.01 )
    -0.5 ( 9.99 )
        Actual Change from Week 36 at Week 48 (n=42,22)
    0.1 ( 8.43 )
    2.5 ( 7.52 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Standardized Psychosocial issues score, using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment

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    End point title
    		 Change from baseline in Standardized Psychosocial issues score, using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
    End point description
    The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing’s syndrome and has been validated in patients with Cushing’s disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. ‘I bruise easily’), psychological aspects (e.g. ‘I am more irritable, I have sudden mood swings and angry outbursts’), and social aspects (e.g. ‘I have had to give up my social or leisure activities due to my illness’). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient’s Cushing’s disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Actual - baseline (n=48,25)
    49.9 ( 20.34 )
    56.7 ( 21.11 )
        Actual Change from Baseline at Week 12 (n=46,24)
    6.1 ( 17.21 )
    9.6 ( 13.61 )
        Actual Change from Baseline at Week 48 (n=42,22)
    11.1 ( 17.84 )
    13.0 ( 16.30 )
        Actual Change from Week 12 at Week 36 (n=44,23)
    4.1 ( 9.94 )
    -1.3 ( 12.36 )
        Actual Change from Week 36 at Week 48 (n=42,22)
    0.1 ( 9.60 )
    2.4 ( 8.96 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Standardized Physical problems score, using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment

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    End point title
    		 Change from baseline in Standardized Physical problems score, using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
    End point description
    The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing’s syndrome and has been validated in patients with Cushing’s disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. ‘I bruise easily’), psychological aspects (e.g. ‘I am more irritable, I have sudden mood swings and angry outbursts’), and social aspects (e.g. ‘I have had to give up my social or leisure activities due to my illness’). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient’s Cushing’s disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Actual - baseline (n=48,25)
    46.9 ( 22.32 )
    57.7 ( 21.91 )
        Actual Change from Baseline at Week 12 (n=46,24)
    6.3 ( 13.29 )
    5.6 ( 13.38 )
        Actual Change from Baseline at Week 48 (n=42,22)
    13.3 ( 19.83 )
    12.1 ( 15.59 )
        Actual Change from Week 12 at Week 36 (n=44,23)
    6.6 ( 12.40 )
    2.2 ( 12.11 )
        Actual Change from Week 36 at Week 48 (n=42,22)
    23.59 ( 11.27 )
    2.7 ( 12.17 )
    No statistical analyses for this end point

    Secondary: Change from baseline in serum cortisol

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    End point title
    		 Change from baseline in serum cortisol
    End point description
    Change from baseline in serum cortisol
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, Week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline - actual (n=47,25)
    565.8 ( 169.01 )
    486.1 ( 198.12 )
        Actual Change from Baseline at Week 12 (n=44,24)
    -276.0 ( 178.43 )
    73.0 ( 185.29 )
        Actual Change from Baseline at Week 36 (n=42,25)
    -267.0 ( 174.18 )
    -157.8 ( 225.56 )
        Actual Change from Baseline at Week 48 (n=41,22)
    -210.7 ( 161.07 )
    -131.0 ( 236.88 )
    No statistical analyses for this end point

    Secondary: Change from baseline in late night saliva cortisol

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    End point title
    		 Change from baseline in late night saliva cortisol
    End point description
    Change from baseline in late night saliva cortisol (nmol/L)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, Week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline - actual (n=48,25)
    11.7 ( 28.68 )
    9.0 ( 6.74 )
        Actual Change from Baseline at Week 12 (n=46,24)
    -8.5 ( 29.60 )
    1.3 ( 8.87 )
        Actual Change from Baseline at Week 36 (n=42,25)
    -9.6 ( 30.82 )
    -5.8 ( 6.84 )
        Actual Change from Baseline at Week 48 (n=41,22)
    -9.3 ( 29.05 )
    -5.0 ( 5.75 )
    No statistical analyses for this end point

    Secondary: Change from baseline in morning saliva cortisol

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    End point title
    		 Change from baseline in morning saliva cortisol
    End point description
    Change from baseline in morning saliva cortisol (nmol/L)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, Week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline - actual (n=48,25)
    17.2 ( 30.00 )
    14.1 ( 12.29 )
        Actual Change from Baseline at Week 12 (n=46,24)
    -11.6 ( 30.05 )
    -0.3 ( 11.21 )
        Actual Change from Baseline at Week 36 (n=40,25)
    -11.8 ( 30.74 )
    -9.3 ( 11.82 )
        Actual Change from Baseline at Week 48 (n=41,22)
    -11.8 ( 31.74 )
    -6.0 ( 10.97 )
    No statistical analyses for this end point

    Secondary: Change from baseline in hair cortisol levels

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    End point title
    		 Change from baseline in hair cortisol levels
    End point description
    Change from baseline in hair cortisol levels
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, Week 48
    End point values
    		 osilodrostat Group osilodrostat Placebo Group
    Number of subjects analysed
    48
    25
    Units: pg/mg
    arithmetic mean (standard deviation)
        Baseline - actual (n=19,9)
    38.9 ( 37.48 )
    10.5 ( 10.47 )
        Actual Change from Baseline at Week 26 (n=16,7)
    -15.8 ( 32.83 )
    -1.1 ( 12.72 )
        Actual Change from Baseline at Week 48 (n=14,6)
    -17.8 ( 26.66 )
    -9.7 ( 8.90 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo controlled period@ Osilodrostat arm
    Reporting group description
    		 Placebo controlled period@ Osilodrostat arm

    Reporting group title
    Placebo controlled period@ Placebo arm
    Reporting group description
    		 Placebo controlled period@ Placebo arm

    Reporting group title
    Overall study period@ Osilodrostat@(Osilodrostat arm)
    Reporting group description
    		 Overall study period@ Osilodrostat@(Osilodrostat arm)

    Reporting group title
    Overall study period@ Osilodrostat@(Placebo arm)
    Reporting group description
    		 Overall study period@ Osilodrostat@(Placebo arm)

    Reporting group title
    Overall study period@ All Patients
    Reporting group description
    		 Overall study period@ All Patients

    Serious adverse events
    		 Placebo controlled period@ Osilodrostat arm Placebo controlled period@ Placebo arm Overall study period@ Osilodrostat@(Osilodrostat arm) Overall study period@ Osilodrostat@(Placebo arm) Overall study period@ All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 25 (4.00%)
    10 / 48 (20.83%)
    0 / 25 (0.00%)
    10 / 73 (13.70%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Conjunctival laceration
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye injury
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal injury
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral vascular occlusion
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo controlled period@ Osilodrostat arm Placebo controlled period@ Placebo arm Overall study period@ Osilodrostat@(Osilodrostat arm) Overall study period@ Osilodrostat@(Placebo arm) Overall study period@ All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 48 (93.75%)
    21 / 25 (84.00%)
    47 / 48 (97.92%)
    24 / 25 (96.00%)
    71 / 73 (97.26%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 48 (14.58%)
    7 / 25 (28.00%)
    12 / 48 (25.00%)
    4 / 25 (16.00%)
    16 / 73 (21.92%)
         occurrences all number
    7
    7
    18
    10
    28
    Hypotension
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 25 (0.00%)
    9 / 48 (18.75%)
    3 / 25 (12.00%)
    12 / 73 (16.44%)
         occurrences all number
    5
    0
    10
    4
    14
    Orthostatic hypotension
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    7 / 48 (14.58%)
    1 / 25 (4.00%)
    8 / 73 (10.96%)
         occurrences all number
    4
    0
    8
    1
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 48 (22.92%)
    0 / 25 (0.00%)
    15 / 48 (31.25%)
    2 / 25 (8.00%)
    17 / 73 (23.29%)
         occurrences all number
    11
    0
    18
    2
    20
    Fatigue
         subjects affected / exposed
    12 / 48 (25.00%)
    4 / 25 (16.00%)
    23 / 48 (47.92%)
    6 / 25 (24.00%)
    29 / 73 (39.73%)
         occurrences all number
    13
    4
    36
    10
    46
    Oedema peripheral
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 25 (0.00%)
    12 / 48 (25.00%)
    0 / 25 (0.00%)
    12 / 73 (16.44%)
         occurrences all number
    6
    0
    13
    0
    13
    Pyrexia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    5 / 48 (10.42%)
    0 / 25 (0.00%)
    5 / 73 (6.85%)
         occurrences all number
    2
    0
    5
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    0
    4
    0
    4
    Dyspnoea
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
         occurrences all number
    1
    0
    2
    2
    4
    Epistaxis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    2 / 73 (2.74%)
         occurrences all number
    0
    0
    0
    2
    2
    Nasal congestion
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
         occurrences all number
    1
    0
    3
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    0
    2
    3
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    3 / 48 (6.25%)
    3 / 25 (12.00%)
    6 / 73 (8.22%)
         occurrences all number
    2
    2
    3
    3
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    2 / 48 (4.17%)
    3 / 25 (12.00%)
    5 / 73 (6.85%)
         occurrences all number
    1
    0
    2
    4
    6
    Blood cholesterol increased
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 25 (4.00%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
         occurrences all number
    2
    1
    8
    0
    8
    Blood potassium decreased
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 25 (4.00%)
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
         occurrences all number
    1
    1
    2
    3
    5
    Blood pressure increased
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 25 (4.00%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
         occurrences all number
    1
    1
    3
    0
    3
    Blood testosterone increased
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 25 (0.00%)
    13 / 48 (27.08%)
    5 / 25 (20.00%)
    18 / 73 (24.66%)
         occurrences all number
    5
    0
    13
    6
    19
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    2 / 73 (2.74%)
         occurrences all number
    0
    1
    0
    2
    2
    Renin increased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 48 (2.08%)
    4 / 25 (16.00%)
    5 / 73 (6.85%)
         occurrences all number
    1
    0
    1
    4
    5
    Weight decreased
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    4 / 73 (5.48%)
         occurrences all number
    2
    0
    3
    1
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    2
    0
    4
    0
    4
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
         occurrences all number
    0
    2
    2
    0
    2
    Tachycardia
         subjects affected / exposed
    6 / 48 (12.50%)
    0 / 25 (0.00%)
    8 / 48 (16.67%)
    1 / 25 (4.00%)
    9 / 73 (12.33%)
         occurrences all number
    6
    0
    8
    3
    11
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 48 (18.75%)
    4 / 25 (16.00%)
    19 / 48 (39.58%)
    3 / 25 (12.00%)
    22 / 73 (30.14%)
         occurrences all number
    12
    4
    25
    3
    28
    Paraesthesia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    0
    4
    0
    4
    Headache
         subjects affected / exposed
    7 / 48 (14.58%)
    6 / 25 (24.00%)
    17 / 48 (35.42%)
    8 / 25 (32.00%)
    25 / 73 (34.25%)
         occurrences all number
    8
    8
    27
    13
    40
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    2 / 48 (4.17%)
    1 / 25 (4.00%)
    3 / 73 (4.11%)
         occurrences all number
    2
    2
    2
    1
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    3
    1
    4
    0
    4
    Abdominal pain
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    10 / 48 (20.83%)
    2 / 25 (8.00%)
    12 / 73 (16.44%)
         occurrences all number
    4
    0
    11
    9
    20
    Abdominal pain upper
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 25 (4.00%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
         occurrences all number
    1
    1
    3
    0
    3
    Diarrhoea
         subjects affected / exposed
    10 / 48 (20.83%)
    0 / 25 (0.00%)
    14 / 48 (29.17%)
    3 / 25 (12.00%)
    17 / 73 (23.29%)
         occurrences all number
    11
    0
    20
    4
    24
    Nausea
         subjects affected / exposed
    15 / 48 (31.25%)
    3 / 25 (12.00%)
    22 / 48 (45.83%)
    5 / 25 (20.00%)
    27 / 73 (36.99%)
         occurrences all number
    21
    5
    40
    7
    47
    Vomiting
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 25 (0.00%)
    9 / 48 (18.75%)
    0 / 25 (0.00%)
    9 / 73 (12.33%)
         occurrences all number
    5
    0
    9
    0
    9
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    9 / 48 (18.75%)
    1 / 25 (4.00%)
    10 / 73 (13.70%)
         occurrences all number
    3
    0
    11
    1
    12
    Alopecia
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 25 (4.00%)
    4 / 48 (8.33%)
    1 / 25 (4.00%)
    5 / 73 (6.85%)
         occurrences all number
    1
    1
    7
    1
    8
    Dry skin
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    4 / 73 (5.48%)
         occurrences all number
    3
    0
    6
    1
    7
    Eczema
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    0
    3
    2
    5
    Pruritus
         subjects affected / exposed
    6 / 48 (12.50%)
    0 / 25 (0.00%)
    7 / 48 (14.58%)
    2 / 25 (8.00%)
    9 / 73 (12.33%)
         occurrences all number
    6
    0
    11
    2
    13
    Hirsutism
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    6 / 48 (12.50%)
    1 / 25 (4.00%)
    7 / 73 (9.59%)
         occurrences all number
    0
    1
    6
    1
    7
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    4 / 73 (5.48%)
         occurrences all number
    2
    0
    5
    1
    6
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    2 / 73 (2.74%)
         occurrences all number
    0
    1
    0
    3
    3
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    7 / 48 (14.58%)
    0 / 25 (0.00%)
    12 / 48 (25.00%)
    6 / 25 (24.00%)
    18 / 73 (24.66%)
         occurrences all number
    8
    0
    18
    9
    27
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 48 (35.42%)
    3 / 25 (12.00%)
    26 / 48 (54.17%)
    7 / 25 (28.00%)
    33 / 73 (45.21%)
         occurrences all number
    20
    3
    48
    8
    56
    Back pain
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    8 / 48 (16.67%)
    2 / 25 (8.00%)
    10 / 73 (13.70%)
         occurrences all number
    2
    0
    9
    3
    12
    Muscle spasms
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    4 / 73 (5.48%)
         occurrences all number
    2
    0
    4
    1
    5
    Muscular weakness
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    4 / 48 (8.33%)
    2 / 25 (8.00%)
    6 / 73 (8.22%)
         occurrences all number
    2
    0
    5
    6
    11
    Myalgia
         subjects affected / exposed
    10 / 48 (20.83%)
    1 / 25 (4.00%)
    15 / 48 (31.25%)
    3 / 25 (12.00%)
    18 / 73 (24.66%)
         occurrences all number
    11
    2
    26
    4
    30
    Pain in extremity
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    2 / 25 (8.00%)
    5 / 73 (6.85%)
         occurrences all number
    2
    0
    3
    2
    5
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    1
    0
    5
    0
    5
    Influenza
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    2
    0
    8
    0
    8
    Laryngitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
         occurrences all number
    0
    0
    3
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 25 (4.00%)
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
         occurrences all number
    2
    1
    4
    2
    6
    Oral herpes
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
         occurrences all number
    1
    0
    3
    0
    3
    Pharyngitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    5 / 48 (10.42%)
    1 / 25 (4.00%)
    6 / 73 (8.22%)
         occurrences all number
    1
    0
    6
    1
    7
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 25 (0.00%)
    12 / 48 (25.00%)
    4 / 25 (16.00%)
    16 / 73 (21.92%)
         occurrences all number
    5
    0
    20
    4
    24
    Urinary tract infection
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    8 / 48 (16.67%)
    4 / 25 (16.00%)
    12 / 73 (16.44%)
         occurrences all number
    4
    0
    12
    5
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 48 (37.50%)
    4 / 25 (16.00%)
    24 / 48 (50.00%)
    10 / 25 (40.00%)
    34 / 73 (46.58%)
         occurrences all number
    21
    4
    37
    11
    48
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    6 / 48 (12.50%)
    0 / 25 (0.00%)
    6 / 73 (8.22%)
         occurrences all number
    3
    1
    6
    0
    6
    Hypoglycaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    4 / 73 (5.48%)
         occurrences all number
    1
    0
    3
    1
    4
    Hypokalaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    6 / 48 (12.50%)
    2 / 25 (8.00%)
    8 / 73 (10.96%)
         occurrences all number
    1
    0
    9
    3
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2017
    - Issued when 18 patients had been enrolled in the study. The following key changes were made: - The list of prohibited medications was revised to remove “all drugs known to prolong QT”. The list of prohibited medications known to cause TdP, or with a possible risk to cause TdP, was reduced. This was based on evidence from the thorough QT study CLCI699C2105. - The risks section was updated to include neutropenia. - The duration of the optional extension period was increased in order to collect additional long-term safety and efficacy data and allow continued access to the study drug as required. - Secondary objective endpoints were added: change from baseline in serum, salivary and hair cortisol levels, actual and percentage change in biomarkers of hypercortisolism.
    20 Dec 2019
    Issued when all patients had been enrolled. The following key changes were made: - Changed the end of study definition - Removed Beck Depression Inventory (BDI) from Appendix 3 as Beck’s Depression Inventory was not used in the study. For this study, the BDI-II was used - Appendix 3 (Patient Quality of Life questionnaires) removed

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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