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Clinical Trial Results:
A Phase III, multi-center, double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period to evaluate the safety and efficacy of LCI699 for the treatment of patients with Cushing’s disease (CD) 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	2013-004766-34
Trial protocol	IT GB DE AT ES NL FR
Global end of trial date	04 Dec 2019

Results information
Results version number	v1(current)
This version publication date	31 Oct 2020
First version publication date	31 Oct 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CLCI699C2301

ISRCTN number

US NCT number

NCT02180217

WHO universal trial number (UTN)

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Dec 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Dec 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to compare the complete response rate at the end of the 8-week period of randomized withdrawal (Week 34) between patients randomized to continued osilodrostat therapy vs. placebo.

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

06 Oct 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 2

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Bulgaria: 3

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

China: 4

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

France: 9

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

India: 7

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Japan: 9

Country: Number of subjects enrolled

Korea, Republic of: 14

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Russian Federation: 4

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Thailand: 5

Country: Number of subjects enrolled

Turkey: 4

Country: Number of subjects enrolled

United States: 25

Worldwide total number of subjects

137

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

130

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

132 patients were planned, 137 were enrolled and 137 were analyzed.

Screening details

132 patients were planned, 137 were enrolled and 137 were analyzed.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

osilodrostat (LCI699)

Arm description

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.

Arm type

Experimental

Investigational medicinal product name

osilodrostat

Investigational medicinal product code

LCI699

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Osilodrostat was supplied in strengths of 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat was 30 mg bid. Osilodrostat dosing regimen included up-titration following a 2 mg bid, 5 mg bid, 10 mg bid, 20 mg bid, and 30 mg bid escalation sequence. If hypocortisolism occurred at 2 mg bid, the dose was lowered to 1 mg bid. The up-titration continued until the mUFC ≤ upper normal of limit (ULN).

LCI699 Placebo

Arm description

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

LCI699 placebo

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablets had the same size, color and imprint as the 1 mg, 5 mg, 10 mg, and 20 mg osilodrostat tablets.

Non-randomized

Arm description

All participants in this group took open label osilodrostat, before and after randomization.

Arm type

Experimental

Investigational medicinal product name

Osilodrostat

Investigational medicinal product code

LCI699

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Started	36	35	66
Discontinued at/prior to Week 12 (W12)	0 ^[1]	0 ^[2]	7 ^[3]
Discont. at/prior to W26 but after W12	0 ^[4]	0 ^[5]	12 ^[6]
Discontinued prior to W48 but after W26	0 ^[7]	2 ^[8]	3 ^[9]
Completed Week 48 (Core Phase)	36	33	44
Completed W48, did not enter Ext. phase	1 ^[10]	3 ^[11]	3 ^[12]
Completed W48, entered Ext. phase	35	30	41
Discontinued Extension Phase	12 ^[13]	6 ^[14]	16 ^[15]
Completed Ext. Phase	23 ^[16]	24 ^[17]	25 ^[18]
Completed	24	27	28
Not completed	12	8	38
Adverse event, serious fatal	1	1	-
Consent withdrawn by subject	1	1	4
Physician decision	1	1	6
Adverse event, non-fatal	3	2	22
Unsatisfactory therapeutic effect	1	-	-
Subject/Guardian decision	5	3	6

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[13] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[14] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[15] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[16] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[17] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm
[18] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects dropped off at different time points, thus changing the number of subjects in the arm

Baseline characteristics

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Reporting group title

osilodrostat (LCI699)

Reporting group description

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.

Reporting group title

LCI699 Placebo

Reporting group description

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.

Reporting group title

Non-randomized

Reporting group description

All participants in this group took open label osilodrostat, before and after randomization.

Reporting group values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized	Total
Number of subjects	36	35	66	137
Age categorical
Units: Subjects
Adults (18-64 years)	34	34	62	130
From 65-84 years	2	1	4	7
Age Continuous
Units: years
arithmetic mean (standard deviation)	44.3 ( 11.27 )	42.0 ( 13.47 )	39.0 ( 13.38 )	-
Sex: Female, Male
Units: Participants
Female	30	22	54	106
Male	6	13	12	31
Race/Ethnicity, Customized
Units: Subjects
Caucasian	27	23	39	89
Black	0	3	1	4
Asian	7	7	25	39
Other	2	2	1	5

End points

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Reporting group title

osilodrostat (LCI699)

Reporting group description

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.

Reporting group title

LCI699 Placebo

Reporting group description

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.

Reporting group title

Non-randomized

Reporting group description

All participants in this group took open label osilodrostat, before and after randomization.

Subject analysis set title

All Participants

Subject analysis set type

Full analysis

Subject analysis set description

Consisted of all participants who were enrolled and treated with open label osilodrostat.

Subject analysis set title

All participants (Escape analysis)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Consisted of all participants in the study under osilodrostat treatment. This is a subset of the Full analysis set which excludes patients randomized to placebo and patients that did not have mUFC <=ULN at any stage on the trial

Subject analysis set title

osilodrostat (LCI699) 2 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 2mg of osilodrostat

Subject analysis set title

osilodrostat (LCI699) 3 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 3mg of osilodrostat

Subject analysis set title

osilodrostat (LCI699) 5 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 5 mg of osilodrostat

Subject analysis set title

osilodrostat (LCI699) 7 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 7 mg of osilodrostat

Primary: Percentage of primary efficacy responder at Week 34 by randomized treatment and strata

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End point title

Percentage of primary efficacy responder at Week 34 by randomized treatment and strata ^[1]

End point description

To compare the complete response rate at the end of the 8-week period of randomized withdrawal between randomized patients.A primary efficacy responder is defined as a randomized patient who has mUFC ≤ ULN at Week 34 and who was neither discontinued (study or RW treatment) nor had osilodrostat dose increase above the level at Week 26 during the RW Period of the study. mUFC: mean urinary free cortisol; ULN: Upper Limit of Normal

End point type

Primary

End point timeframe

Week 34 (8 weeks)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not planned for this endpoint.

End point values	osilodrostat (LCI699)	LCI699 Placebo
Number of subjects analysed	36	34
Units: Percentage of participants
number (not applicable)	86.1	29.4

CMH exact test: Osilodrostat vs. Placebo

Comparison groups

osilodrostat (LCI699) v LCI699 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

13.71

Confidence interval

level

95%

sides

2-sided

lower limit

3.73

upper limit

53.44

Secondary: Percentage of secondary efficacy responder at Week 24 (Key Secondary endpoint)

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End point title

Percentage of secondary efficacy responder at Week 24 (Key Secondary endpoint)

End point description

To assess the complete response rate at the end of individual dose-titration and treatment with LCI699 in the initial single-arm, open label period. A Key secondary efficacy responder is defined as a patient in FAS who has mUFC ≤ ULN at Week 24 and the dose of osilodrostat during Study Period 2 (Weeks 13-24) was not increased above the level established at the end of Study Period 1 (Week 12). Patients who had missing mUFC assessment at Week 24 will be counted as non-responders for the key secondary endpoint.

End point type

Secondary

End point timeframe

Week 24

End point values	All Participants
Number of subjects analysed	137
Units: Percentage of participants
number (confidence interval 95%)	52.6 (43.9 to 61.1)

No statistical analyses for this end point

Secondary: Time-to-loss of control of mean urinary free cortisol (mUFC) by randomized treatment group

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End point title

Time-to-loss of control of mean urinary free cortisol (mUFC) by randomized treatment group ^[2]

End point description

Time-to-loss of control of mUFC during the RW Period, defined as the time (in days) from randomization to the first evidence of loss of control (defined as mUFC assessment >1.5 ULN based on central laboratory result & at least 2 of the associated individual urine samples showing UFC >1.5×ULN) within the RW period. A patient without evidence of loss of control was censored at the date of the last assessment with mUFC ≤ 1.5 ULN. If a patient discontinued randomized treatment without having a UFC assessment, they were censored at the date of randomization. The measure type (number) refers to an Event probability estimate 8 weeks after randomization.

End point type

Secondary

End point timeframe

8 weeks after randomization

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not planned for this endpoint.

End point values	osilodrostat (LCI699)	LCI699 Placebo
Number of subjects analysed	36	34
Units: Percentage
number (confidence interval 95%)	5.6 (1.4 to 20.4)	61.1 (45.0 to 77.5)

No statistical analyses for this end point

Secondary: Complete Response Rate (CRR)

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End point title

Complete Response Rate (CRR)

End point description

Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN

End point type

Secondary

End point timeframe

Week 12, Week 24, Week 48, Week 72, last observed value

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: Percentage of participants
number (not applicable)
Week 12	86.1	91.4	53.0
Week 24	100.0	97.1	34.8
Week 48	88.9	77.1	48.5
Week 72	82.9	83.3	78.0
Last observed value	69.4	74.3	53.0

No statistical analyses for this end point

Secondary: Change from baseline in mUFC (actual and percentage change)

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End point title

Change from baseline in mUFC (actual and percentage change)

End point description

Actual and percentage change in mUFC from baseline.

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: nmol/24h
arithmetic mean (standard deviation)
Actual Baseline (BL)	890.0 ( 1275.66 )	560.0 ( 548.84 )	1305.8 ( 2012.21 )
Wk 12: % change from BL (n = 33,34,58)	-80.6 ( 19.28 )	-81.7 ( 15.08 )	-74.9 ( 26.66 )
Wk 24: % change from BL (n=36,35,54)	-77.4 ( 34.04 )	-79.6 ( 18.35 )	-62.5 ( 61.56 )
Wk 48: % change from BL (n = 34,32,42)	-84.9 ( 13.70 )	-80.5 ( 18.68 )	-76.4 ( 34.39 )
Wk 72: % change from BL (n= 32,29,35)	-78.6 ( 33.09 )	-79.5 ( 18.99 )	-72.3 ( 50.93 )
Last avail. assess. % change from BL	-71.0 ( 48.20 )	-57.3 ( 66.80 )	-47.3 ( 80.78 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Fasting glucose

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End point title

Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Fasting glucose

End point description

Percentage change in fasting glucose from baseline.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: mg/dL
arithmetic mean (standard deviation)
Baseline (n = 34, 33, 62)	102.7 ( 35.23 )	90.5 ( 18.53 )	101.8 ( 31.00 )
Wk 48: (n = 33,30,38)	-3.1 ( 21.18 )	-4.7 ( 11.11 )	-12.4 ( 14.55 )
Wk 72: (n = 30,25,32)	0.9 ( 15.91 )	-3.5 ( 13.57 )	-8.8 ( 15.72 )
Last avail. assessment (n = 34,32,62)	-2.4 ( 29.32 )	-0.2 ( 18.09 )	-11.6 ( 16.04 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Hemoglobin A1C (HbA1C)

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End point title

Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Hemoglobin A1C (HbA1C)

End point description

Percentage change in glycosylated hemoglobin (HbA1c) from baseline.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: percentage
arithmetic mean (standard deviation)
Baseline	6.1 ( 0.98 )	5.8 ( 0.93 )	6.0 ( 0.97 )
Wk 48: (n = 35, 33, 42)	-4.2 ( 11.48 )	-6.0 ( 8.31 )	-5.8 ( 8.86 )
Wk 72: (n = 33,29,35)	-5.7 ( 8.88 )	-6.1 ( 6.61 )	-6.5 ( 8.88 )
Last avail. assessment	-4.9 ( 10.66 )	-2.8 ( 7.49 )	-4.5 ( 9.46 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride

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End point title

Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride

End point description

Percentage change in Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride from baseline.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: mmol/L
arithmetic mean (standard deviation)
Cholesterol: BL (n = 36, 34, 66)	5.5 ( 1.22 )	5.3 ( 0.90 )	5.1 ( 1.24 )
Cholesterol: Wk 48: (n = 35,32,41)	-11.6 ( 15.71 )	-6.3 ( 13.64 )	-8.5 ( 17.59 )
Cholesterol: Wk 72: (n = 33,27,33)	-6.3 ( 16.62 )	-6.6 ( 14.73 )	-5.4 ( 19.47 )
Cholesterol: Last avail. assessment	-3.6 ( 20.83 )	-5.4 ( 16.25 )	-4.6 ( 22.09 )
LDL Cholesterol: BL	3.2 ( 1.09 )	3.1 ( 0.77 )	2.9 ( 0.94 )
LDL Cholesterol: Wk 48 (n=35,32,40)	-9.5 ( 23.43 )	-5.1 ( 20.31 )	-2.1 ( 31.96 )
LDL Cholesterol: Wk 72 (n=33,27,33)	-5.0 ( 25.03 )	-5.4 ( 24.86 )	2.3 ( 33.70 )
LDL Cholesterol: Last avail asses. (n=36,34,65)	0.0 ( 33.36 )	-3.8 ( 23.37 )	2.0 ( 42.86 )
HDL Cholesterol: BL (n=36,34,66)	1.7 ( 0.55 )	1.5 ( 0.36 )	1.6 ( 0.42 )
HDL Cholesterol: Wk 48 (n=35,32,41)	-14.7 ( 16.47 )	-9.8 ( 9.79 )	-17.9 ( 18.17 )
HDL Cholesterol: Wk 72 (n=33,27,33)	-9.7 ( 20.20 )	-9.7 ( 16.38 )	-16.5 ( 15.87 )
HDL Cholesterol: Last avail assess. (n=36,34,66)	-8.5 ( 19.62 )	-6.3 ( 17.40 )	-13.4 ( 21.98 )
Triglyceride: BL (n= 36,34,66)	1.5 ( 0.78 )	1.4 ( 0.62 )	1.6 ( 1.74 )
Triglyceride: Wk 48 (n= 35,32,41)	-3.7 ( 28.68 )	0.8 ( 36.56 )	16.8 ( 160.90 )
Triglyceride: Wk 72 (n=33,28,33)	1.9 ( 37.12 )	0.2 ( 42.41 )	0.8 ( 36.50 )
Triglyceride: Last avail. Assess. (n= 36,34, 66)	3.1 ( 35.61 )	-0.3 ( 42.60 )	20.4 ( 92.91 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Sitting systolic blood pressure (SBP) & sitting diastolic blood pressure (DBP)

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End point title

Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Sitting systolic blood pressure (SBP) & sitting diastolic blood pressure (DBP)

End point description

Percentage change in sitting SBP & DBP from baseline.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: mmHg
arithmetic mean (standard deviation)
SBP: Baseline	132.2 ( 15.44 )	128.8 ( 11.93 )	134.0 ( 16.34 )
SBP: Wk 48: (n = 35,33,43)	-10.7 ( 12.44 )	-3.4 ( 9.52 )	-6.2 ( 11.14 )
SBP: Wk 72: (n = 34,29,36)	-8.4 ( 11.81 )	-5.6 ( 15.60 )	-5.9 ( 13.89 )
SBP: Last avail. assessment	-5.3 ( 10.96 )	-3.1 ( 11.53 )	-7.4 ( 11.00 )
DBP: Baseline	85.3 ( 11.38 )	85.0 ( 10.03 )	85.4 ( 10.53 )
DBP: Wk 48: (n = 35,33,43)	-8.1 ( 13.22 )	-5.4 ( 11.29 )	-6.3 ( 13.50 )
DBP: Wk 72: (n = 34,29,36)	-5.6 ( 13.05 )	-7.7 ( 11.76 )	-4.5 ( 15.15 )
DBP: Last avail. assessment	-2.7 ( 13.92 )	-3.4 ( 12.88 )	-5.3 ( 12.13 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Weight

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End point title

Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Weight

End point description

Percentage change in weight from baseline.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: kg
arithmetic mean (standard deviation)
Baseline	78.2 ( 19.02 )	83.4 ( 24.73 )	80.7 ( 23.06 )
Wk 48: (n = 36,33,43)	-3.9 ( 6.56 )	-4.8 ( 6.45 )	-5.0 ( 7.17 )
Wk 72: (n = 34,29,36)	-4.3 ( 7.67 )	-6.2 ( 6.99 )	-6.8 ( 8.58 )
Last avail. assessment	-3.4 ( 9.69 )	-4.6 ( 9.86 )	-4.9 ( 7.78 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Body Mass Index (BMI)

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End point title

Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Body Mass Index (BMI)

End point description

Percentage change in BMI from baseline.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: kg/m^2
arithmetic mean (standard deviation)
Baseline	29.6 ( 7.36 )	30.9 ( 8.38 )	30.4 ( 7.74 )
Wk 48: (n = 36,33,43)	-3.9 ( 6.56 )	-4.7 ( 6.46 )	-5.0 ( 7.18 )
Wk 72: (n = 34,29,36)	-4.3 ( 7.68 )	-6.2 ( 6.92 )	-6.8 ( 8.63 )
Last avail. assessment	-3.3 ( 9.68 )	-4.7 ( 9.85 )	-4.9 ( 7.80 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Waist Circumference

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End point title

Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Waist Circumference

End point description

Percentage change in waist circumference from baseline.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: cm
arithmetic mean (standard deviation)
Baseline	100.5 ( 16.81 )	103.7 ( 18.26 )	105.0 ( 21.15 )
Wk 48: (n = 34,32,43)	-4.8 ( 5.90 )	-3.5 ( 10.53 )	-4.3 ( 6.43 )
Wk 72: (n = 33,29,36)	-5.1 ( 7.18 )	-5.5 ( 10.23 )	-7.0 ( 7.25 )
Last avail. assessment (n =35,33,65)	-4.9 ( 6.44 )	-4.6 ( 11.61 )	-5.3 ( 8.04 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total score

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End point title

Percentage change from baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total score

End point description

Change in standardized score of Cushing QoL from baseline to Week 24 and Week 48. The Cushing’s Disease Health-Related Quality of Life Questionnaire (CushingQoL) (version 1.0) was developed to evaluate quality of life in patients with Cushing’s syndrome. The CushingQoL is comprised of 12 items that capture patient responses on seven concepts: daily activities, healing and pain, mood and self-confidence, social concerns, physical appearance, memory and concern about the future. Content reliability, sensitivity to change and psychometric properties have been validated in patients with Cushing’s disease. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. Increase from baseline for Cushing QoL total score are indicative of an improvement.

End point type

Secondary

End point timeframe

Baseline, Week (W) 48, W72, Last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: scales on a score
arithmetic mean (standard deviation)
Baseline (Actual)	44.4 ( 18.33 )	43.2 ( 22.45 )	40.5 ( 17.61 )
Week 48 (n = 35,32,43)	60.2 ( 128.33 )	40.3 ( 70.71 )	54.9 ( 112.79 )
Week 72 (n = 32,28, 37)	64.4 ( 158.86 )	57.6 ( 92.37 )	60.9 ( 125.13 )
Last available assess. (n = 36,35,65)	68.7 ( 172.98 )	58.3 ( 125.29 )	52.9 ( 109.56 )

No statistical analyses for this end point

Secondary: Percentage change from baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)

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End point title

Percentage change from baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)

End point description

Change in standardized score of Beck Depression Inventory-II (BDI-II0 from baseline to Week 24 and Week 48. 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. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. A reduction from baseline in BDI-II is indicative of an improvement.

End point type

Secondary

End point timeframe

Baseline, W48, W72, Last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: scores on a a scale
arithmetic mean (standard deviation)
Baseline	15.1 ( 11.14 )	17.8 ( 9.93 )	17.3 ( 10.67 )
W48 (n = 33,31,43)	-17.2 ( 97.71 )	-38.7 ( 42.90 )	-35.6 ( 60.50 )
W72 (n = 30,27,36)	4.7 ( 230.64 )	-39.0 ( 48.62 )	-44.3 ( 62.46 )
Last avail. assess.(n = 34,34,64)	-15.7 ( 125.96 )	-41.8 ( 46.25 )	-13.8 ( 86.05 )

No statistical analyses for this end point

Secondary: Percentage change in Patient-Reported Outcomes: EQ-5D-5L utility index

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End point title

Percentage change in Patient-Reported Outcomes: EQ-5D-5L utility index

End point description

Change in standardized score of EQ-5D-5L utility index from baseline to Week 24 and Week 48. 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. It provides a simple descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health care as well as in population health surveys. The EQ-5D-5L is designed for self-completion by respondents and is cognitively undemanding, taking only a few minutes to complete. 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 single index value is analyzed for the EQ-5D-5L score. An increase from baseline in EQ-5D-5L is indicative of an improvement.

End point type

Secondary

End point timeframe

Baseline, W48, W72, Last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: Scores on a scale
arithmetic mean (standard deviation)
Baseline	0.7 ( 0.24 )	0.7 ( 0.24 )	0.7 ( 0.28 )
Week 48 (n = 35,32,43)	19.9 ( 46.91 )	-12.5 ( 80.08 )	142.0 ( 854.94 )
Week 72 (n= 32,28,36)	24.2 ( 49.58 )	-8.6 ( 88.16 )	137.1 ( 706.16 )
Last avail. assess. (n = 36,35,65)	19.5 ( 49.47 )	-12.4 ( 91.85 )	64.0 ( 534.01 )

No statistical analyses for this end point

Secondary: Percentage change in Patient-Reported Outcomes: EQ-5D-5L vascular analog scale (VAS)

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End point title

Percentage change in Patient-Reported Outcomes: EQ-5D-5L vascular analog scale (VAS)

End point description

Change in standardized score of EQ-5D-5L VAS from baseline to Week 24 and Week 48. The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with on a scale of 0-100, with endpoints labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’. A single index value is analyzed for the VAS score. An increase from baseline in EQ-5D-5L VAS is indicative of an improvement.

End point type

Secondary

End point timeframe

Baseline, W48, W72, Last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: Scores on a scale
arithmetic mean (standard deviation)
Baseline	61.3 ( 18.97 )	64.2 ( 16.37 )	60.8 ( 21.09 )
Week 48 (n = 35,31,43)	29.7 ( 62.35 )	13.9 ( 22.93 )	30.5 ( 82.96 )
Week 72 (n= 32,27,36)	28.6 ( 56.36 )	13.8 ( 26.38 )	34.6 ( 94.43 )
Last avail. assess. (n = 36,35,65)	29.9 ( 56.00 )	14.4 ( 32.27 )	23.5 ( 82.72 )

No statistical analyses for this end point

Secondary: Change from baseline in the physical features of Cushing's disease by photography

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End point title

Change from baseline in the physical features of Cushing's disease by photography

End point description

Improvement from baseline to Weeks 48, 72 and End of Treatment (Extension period) in each of the following clinical signs of Cushing’s disease by photography: facial rubor, hirsutism, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises).

End point type

Secondary

End point timeframe

Week 48, Week 72, Last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: Percentage of participants
number (confidence interval 95%)
W48: Facial rubor (n=30,30,37)	50.0 (31.3 to 68.7)	46.7 (28.3 to 65.7)	43.2 (27.1 to 60.5)
W48: Striae (n=30,30, 37)	30.0 (14.7 to 49.4)	23.3 (9.9 to 42.3)	40.5 (24.8 to 57.9)
W48:Supraclavicular fat pad(n=30,30, 37)	56.7 (37.4 to 74.5)	43.3 (25.5 to 62.6)	54.1 (36.9 to 70.5)
W48: Dorsal fat pad(n=30,30, 37)	60.0 (40.6 to 77.3)	40.0 (22.7 to 59.4)	56.8 (39.5 to 72.9)
W48: Proximal muscle atrophy(n=30,30, 37)	40.0 (22.7 to 59.4)	26.7 (12.3 to 45.9)	45.9 (29.5 to 63.1)
W48: Central obesity(n=30,30, 37)	43.3 (25.5 to 62.6)	30.0 (14.7 to 49.4)	51.4 (34.4 to 68.1)
W48: Ecchymoses (n=30,30, 37)	33.3 (17.3 to 52.8)	26.7 (12.3 to 45.9)	43.2 (27.1 to 60.5)
W72: Facial rubor (n=29,27, 30)	48.3 (29.4 to 67.5)	55.6 (35.3 to 74.5)	53.3 (34.3 to 71.7)
W72: Striae (n=29,27, 30)	27.6 (12.7 to 47.2)	25.9 (11.1 to 46.3)	36.7 (19.9 to 56.1)
W72:Supraclavicular fat pad(n=29,27, 30)	55.2 (35.7 to 73.6)	51.9 (31.9 to 71.3)	53.3 (34.3 to 71.1)
W72: Dorsal fat pad(n=29,27, 30)	69.0 (49.2 to 84.7)	48.1 (28.7 to 68.1)	53.3 (34.3 to 71.7)
W72: Proximal muscle atrophy(n=29,27, 30)	31.0 (15.3 to 50.8)	25.9 (11.1 to 46.3)	46.7 (28.3 to 65.7)
W72: Central obesity(n=29,27, 30)	37.9 (20.7 to 57.7)	37.0 (19.4 to 57.6)	43.3 (25.5 to 62.6)
W72: Ecchymoses (n=29,27,30)	27.6 (12.7 to 47.2)	29.6 (13.8 to 50.2)	36.7 (19.9 to 56.1)
End of Trial (EOT):Facial rubor (n=25,23,26)	60.0 (38.7 to 78.9)	56.5 (34.5 to 76.8)	53.8 (33.4 to 73.4)
EOT: Striae (n=25,23,26)	32.0 (14.9 to 53.5)	34.8 (16.4 to 57.3)	30.8 (14.3 to 51.8)
EOT:Supraclavicular fat pad(n=25,23,26)	52.0 (31.3 to 72.2)	43.5 (23.2 to 65.5)	42.3 (23.4 to 63.1)
EOT: Dorsal fat pad (n=25,23, 26)	56.0 (34.9 to 75.6)	52.2 (30.6 to 73.2)	46.2 (26.6 to 66.6)
EOT: Proximal muscle atrophy (n=25,23,26)	36.0 (18.0 to 57.5)	21.7 (7.5 to 43.7)	50.0 (29.9 to 70.1)
EOT: Central obesity (n=25,23,26)	40.0 (21.1 to 61.3)	39.1 (19.7 to 61.5)	38.5 (20.0 to 59.4)
EOT: Ecchymoses (n=25,23, 26)	28.0 (12.1 to 49.4)	39.1 (19.7 to 61.5)	38.5 (20.2 to 59.4)

No statistical analyses for this end point

Secondary: Change from baseline in bone mineral density - All participants

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End point title

Change from baseline in bone mineral density - All participants

End point description

Actual and percent change from baseline to Week 48 and the LOV in bone mineral density as measured by DXA scan at the lumbar spine and total hip. An increase in bone mineral density is indicative of an improvement..

End point type

Secondary

End point timeframe

Baseline, Week 48, Last observed value (LOV)

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: g/cm2
arithmetic mean (standard error)
Baseline (L1-L4 Lumbar Spine): actual	1.0 ( 0.20 )	1.0 ( 0.17 )	1.0 ( 0.18 )
W48 (L1-L4 Lumbar Spine): actual (n=23,23,35)	1.0 ( 0.19 )	1.0 ( 0.17 )	1.0 ( 0.19 )
W48 (L1-L4 Lumbar Spine): % change (n=23,23,35)	1.3 ( 5.33 )	2.7 ( 5.06 )	4.3 ( 7.69 )
LOV (L1-L4 Lumbar Spine): actual (n=26,24,46)	1.0 ( 0.20 )	1.0 ( 0.18 )	1.0 ( 0.18 )
LOV (L1-L4 Lumbar Spine): % change (n=26,24,46)	3.2 ( 6.31 )	4.6 ( 7.55 )	5.2 ( 6.37 )
Baseline (Total Hip): actual	0.9 ( 0.18 )	0.8 ( 0.15 )	0.9 ( 0.16 )
W48 (Total Hip): actual (n = 24,21,35)	0.9 ( 0.17 )	0.8 ( 0.14 )	0.9 ( 0.16 )
W48 (Total Hip): % change (n = 24,21,35)	-0.2 ( 8.00 )	0.3 ( 4.91 )	0.8 ( 3.43 )
LOV (Total Hip): actual (n = 27,22, 46)	0.9 ( 0.17 )	0.8 ( 0.13 )	0.9 ( 0.16 )
LOV (Total Hip): % change (n = 27,22, 46)	0 ( 8.54 )	2.1 ( 6.31 )	1.8 ( 3.70 )

No statistical analyses for this end point

Secondary: Time-to-escape

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End point title

Time-to-escape

End point description

Escape was defined as the time (in days) from the first mUFC ≤ ULN to the first mUFC results > 1.5 x ULN with at least 2 individual UFC results > 1.5 x ULN the loss happened beyond 12-week dose titration period. Participants randomized to placebo were not included in the analysis.

End point type

Secondary

End point timeframe

From the first mUFC ≤ ULN to the first mUFC results > 1.5 x ULN with at least 2 individual UFC results > 1.5 x ULN

End point values	All participants (Escape analysis)
Number of subjects analysed	97
Units: days
median (confidence interval 95%)	546.0 (212.0 to 968.0)

No statistical analyses for this end point

Secondary: LCI699 exposures

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End point title

LCI699 exposures

End point description

To evaluate exposures of LCI699 in patients with Cushing's disease. Plasma concentrations (predose, 0.75 h, 1.5 h, and 4 h post-dose) of LCI699. These are the maximum number of PAS subjects analyzed for each incident dose. All 999 data represent not applicable (NA) values.

End point type

Secondary

End point timeframe

from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose

End point values	osilodrostat (LCI699) 2 mg	osilodrostat (LCI699) 3 mg	osilodrostat (LCI699) 5 mg	osilodrostat (LCI699) 7 mg
Number of subjects analysed	132	39	105	24
Units: unit
geometric mean (geometric coefficient of variation)
Week (Wk) 2: Predose (n = 79,0,0,0)	1.904 ( 110.4 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
Wk 2: 0.75h (n = 14,0,0,0)	1.907 ( 132.5 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
Wk 2: 1.5h (n = 3,0,0,0)	5.1 ( 62.7 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
Wk 2: 4h (n = 18,0,0,0)	5.818 ( 66.3 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
Wk 4: Predose (n= 50,2,31,0)	2.104 ( 108.0 )	2.898 ( 109.1 )	3.584 ( 126.3 )	999 ( 999 )
Wk 4: 0.75h (n= 2,0,9,0)	0.859 ( 254.3 )	999 ( 999 )	7.091 ( 137.8 )	999 ( 999 )
Wk 4: 1.5h (n = 2,0,1,0)	8.737 ( 3.6 )	999 ( 999 )	24.2 ( 999 )	999 ( 999 )
Wk 4: 4h (n = 1,0,9,0)	8.930 ( 999 )	999 ( 999 )	15.985 ( 48.3 )	999 ( 999 )
Wk 6: Predose (n = 17,3,46,2)	2.037 ( 63.5 )	2.392 ( 285.6 )	5.087 ( 122.9 )	8.065 ( 8.6 )
Wk 6: 0.75h (n = 1,0,5,0)	3.110 ( 999 )	999 ( 999 )	5.223 ( 229.4 )	999 ( 999 )
Wk 6: 1.5h (n = 0,1,1,0)	999 ( 999 )	22.4 ( 999 )	21.4 ( 999 )	999 ( 999 )
Wk 6: 4h (n = 1,1,5,0)	8.380 ( 999 )	18.6 ( 999 )	18.373 ( 36.5 )	999 ( 999 )
Wk 8: Predose (n = 13,5,35,3)	2.198 ( 108.9 )	4.061 ( 67.4 )	4.487 ( 106.9 )	6.718 ( 34.2 )
Wk 8: 0.75h (n = 0,0,0,0)	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
Wk 8: 1.5h (n = 1,1,0,1)	10.8 ( 999 )	20.4 ( 999 )	999 ( 999 )	32.1 ( 999 )
Wk 8: 4h (n = 1,0,0,1)	6.65 ( 999 )	999 ( 999 )	999 ( 999 )	32 ( 999 )
Wk 10: Predose (n = 10,9,29,6)	1.862 ( 128.9 )	3.007 ( 64.8 )	4.704 ( 106.8 )	5.451 ( 93.1 )
Wk 10: 0.75h (n = 0,1,0,1)	999 ( 999 )	6.7 ( 999 )	999 ( 999 )	17.1 ( 999 )
Wk 10: 1.5h (n = 1,1,1,0)	12.1 ( 999 )	18.3 ( 999 )	34.2 ( 999 )	999 ( 999 )
Wk 10: 4h (n = 0,1,1,1)	999 ( 999 )	15.8 ( 999 )	27.2 ( 999 )	35.5 ( 999 )

No statistical analyses for this end point

Secondary: Percentage of participants with Complete Response Rate (CRR)

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End point title

Percentage of participants with Complete Response Rate (CRR)

End point description

Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN.

End point type

Secondary

End point timeframe

Week 12, Week 24, Week 48, Week 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: Percentage of participants
number (not applicable)
Week 12	6.1	91.4	53.0
Week 24	100	97.1	34.8
Week 48	88.9	77.1	48.5
Week 72	82.9	83.3	78.0
Last observed value	69.4	74.3	53.0

No statistical analyses for this end point

Secondary: Percentage of participants with Partial Response Rate (PRR)

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End point title

Percentage of participants with Partial Response Rate (PRR)

End point description

Partial response rate is defined as percentage of enrolled participants with ≥ 50% reduction from baseline in mUFC, but mUFC>ULN)

End point type

Secondary

End point timeframe

Week 12, Week 24, Week 48, Week 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: Percentage of participants
number (not applicable)
Week 12	2.8	5.7	24.2
Week 24	0.0	0.0	30.3
Week 48	5.6	11.4	10.6
Week 72	8.6	13.3	2.4
Last observed value	22.2	11.4	22.7

No statistical analyses for this end point

Secondary: Percentage of participants with Overall Response Rate (ORR)

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End point title

Percentage of participants with Overall Response Rate (ORR)

End point description

Overall response rate is defined as percentage of enrolled participants with mUFC ≤ ULN or at least 50% reduction from baseline.

End point type

Secondary

End point timeframe

Week 12, Week 24, Week 48, Week 72, last available assessment

End point values	osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Number of subjects analysed	36	35	66
Units: Percentage of participants
number (not applicable)
Week 12	88.9	97.1	77.3
Week 24	100	97.1	65.2
Week 48	94.4	88.6	59.1
Week 72	91.4	96.7	80.5
Last avail data	91.7	85.7	75.8

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Event (AE) timeframe: Adverse events were collected from first dose of study treatment until 30 days after the last dose administration, up to maximum duration of about 245.1 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 name

MedDRA

Dictionary version

22.1

Reporting group title

Osilodrostat

Reporting group description

Osilodrostat

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Non-randomized

Reporting group description

Non-randomized

Reporting group title

All Patients

Reporting group description

All Patients

Serious adverse events	Osilodrostat	Placebo	Non-randomized	All Patients
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 36 (36.11%)	10 / 35 (28.57%)	32 / 66 (48.48%)	55 / 137 (40.15%)
number of deaths (all causes)	1	1	0	2
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pituitary tumour
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	2 / 66 (3.03%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pituitary tumour
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	4 / 66 (6.06%)	6 / 137 (4.38%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 4	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pituitary tumour benign
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	2 / 66 (3.03%)	3 / 137 (2.19%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour invasion
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Venous thrombosis
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Metrorrhagia
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory disorder
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord polyp
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Completed suicide
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Depression
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Investigations
Haemoglobin decreased
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Head injury
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural headache
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiopulmonary failure
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Nervous system disorders
Cranial nerve disorder
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	2 / 66 (3.03%)	3 / 137 (2.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Idiopathic intracranial hypertension
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
VIth nerve paralysis
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	3 / 66 (4.55%)	3 / 137 (2.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune neutropenia
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Visual impairment
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	1 / 66 (1.52%)	3 / 137 (2.19%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	1 / 66 (1.52%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	1 / 66 (1.52%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hidradenitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis glandularis
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	6 / 66 (9.09%)	8 / 137 (5.84%)
occurrences causally related to treatment / all	1 / 1	1 / 1	9 / 9	11 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adrenocortical insufficiency acute
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	3 / 66 (4.55%)	4 / 137 (2.92%)
occurrences causally related to treatment / all	1 / 1	0 / 0	5 / 5	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glucocorticoid deficiency
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	2 / 66 (3.03%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pituitary infarction
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pituitary-dependent Cushing's syndrome
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Foot deformity
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Groin pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	3 / 66 (4.55%)	4 / 137 (2.92%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 3	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Influenza
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	2 / 66 (3.03%)	3 / 137 (2.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Keratitis fungal
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	1 / 66 (1.52%)	2 / 137 (1.46%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	0 / 66 (0.00%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	1 / 66 (1.52%)	1 / 137 (0.73%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Osilodrostat	Placebo	Non-randomized	All Patients
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 36 (94.44%)	35 / 35 (100.00%)	65 / 66 (98.48%)	134 / 137 (97.81%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	6 / 66 (9.09%)	9 / 137 (6.57%)
occurrences all number	2	1	6	9
Vascular disorders
Hypertension
subjects affected / exposed	5 / 36 (13.89%)	5 / 35 (14.29%)	14 / 66 (21.21%)	24 / 137 (17.52%)
occurrences all number	5	9	17	31
Hypotension
subjects affected / exposed	7 / 36 (19.44%)	3 / 35 (8.57%)	3 / 66 (4.55%)	13 / 137 (9.49%)
occurrences all number	10	3	3	16
Varicose vein
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
General disorders and administration site conditions
Application site rash
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	0	2	0	2
Asthenia
subjects affected / exposed	11 / 36 (30.56%)	5 / 35 (14.29%)	11 / 66 (16.67%)	27 / 137 (19.71%)
occurrences all number	18	5	14	37
Chest discomfort
subjects affected / exposed	1 / 36 (2.78%)	0 / 35 (0.00%)	4 / 66 (6.06%)	5 / 137 (3.65%)
occurrences all number	1	0	4	5
Chills
subjects affected / exposed	1 / 36 (2.78%)	3 / 35 (8.57%)	2 / 66 (3.03%)	6 / 137 (4.38%)
occurrences all number	1	3	2	6
Fatigue
subjects affected / exposed	8 / 36 (22.22%)	13 / 35 (37.14%)	24 / 66 (36.36%)	45 / 137 (32.85%)
occurrences all number	9	19	39	67
Gait disturbance
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Influenza like illness
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	1 / 66 (1.52%)	3 / 137 (2.19%)
occurrences all number	0	2	1	3
Malaise
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	7 / 66 (10.61%)	10 / 137 (7.30%)
occurrences all number	1	2	7	10
Oedema
subjects affected / exposed	1 / 36 (2.78%)	3 / 35 (8.57%)	5 / 66 (7.58%)	9 / 137 (6.57%)
occurrences all number	2	5	6	13
Oedema peripheral
subjects affected / exposed	8 / 36 (22.22%)	5 / 35 (14.29%)	9 / 66 (13.64%)	22 / 137 (16.06%)
occurrences all number	10	5	13	28
Pain
subjects affected / exposed	2 / 36 (5.56%)	3 / 35 (8.57%)	1 / 66 (1.52%)	6 / 137 (4.38%)
occurrences all number	2	6	1	9
Pyrexia
subjects affected / exposed	4 / 36 (11.11%)	3 / 35 (8.57%)	13 / 66 (19.70%)	20 / 137 (14.60%)
occurrences all number	4	4	18	26
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	0	2	0	2
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	2 / 66 (3.03%)	4 / 137 (2.92%)
occurrences all number	0	2	2	4
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 36 (13.89%)	4 / 35 (11.43%)	10 / 66 (15.15%)	19 / 137 (13.87%)
occurrences all number	6	5	10	21
Dyspnoea
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	4 / 66 (6.06%)	6 / 137 (4.38%)
occurrences all number	2	1	4	7
Nasal congestion
subjects affected / exposed	3 / 36 (8.33%)	0 / 35 (0.00%)	3 / 66 (4.55%)	6 / 137 (4.38%)
occurrences all number	4	0	5	9
Oropharyngeal pain
subjects affected / exposed	3 / 36 (8.33%)	4 / 35 (11.43%)	7 / 66 (10.61%)	14 / 137 (10.22%)
occurrences all number	3	4	7	14
Rhinitis allergic
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	4 / 66 (6.06%)	4 / 137 (2.92%)
occurrences all number	0	0	4	4
Rhinorrhoea
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	4 / 66 (6.06%)	7 / 137 (5.11%)
occurrences all number	2	2	4	8
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 36 (8.33%)	2 / 35 (5.71%)	7 / 66 (10.61%)	12 / 137 (8.76%)
occurrences all number	3	2	9	14
Depression
subjects affected / exposed	3 / 36 (8.33%)	3 / 35 (8.57%)	7 / 66 (10.61%)	13 / 137 (9.49%)
occurrences all number	4	4	9	17
Insomnia
subjects affected / exposed	4 / 36 (11.11%)	2 / 35 (5.71%)	7 / 66 (10.61%)	13 / 137 (9.49%)
occurrences all number	4	2	8	14
Irritability
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	4 / 66 (6.06%)	6 / 137 (4.38%)
occurrences all number	1	2	4	7
Panic attack
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	0	2	0	2
Sleep disorder
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	5 / 66 (7.58%)	7 / 137 (5.11%)
occurrences all number	2	0	5	7
Investigations
11-deoxycortisol increased
subjects affected / exposed	3 / 36 (8.33%)	1 / 35 (2.86%)	2 / 66 (3.03%)	6 / 137 (4.38%)
occurrences all number	3	1	2	6
Activated partial thromboplastin time prolonged
subjects affected / exposed	3 / 36 (8.33%)	1 / 35 (2.86%)	1 / 66 (1.52%)	5 / 137 (3.65%)
occurrences all number	4	1	1	6
Alanine aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	4 / 66 (6.06%)	4 / 137 (2.92%)
occurrences all number	0	0	6	6
Aspartate aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	4 / 66 (6.06%)	4 / 137 (2.92%)
occurrences all number	0	0	4	4
Blood cholesterol increased
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	1 / 66 (1.52%)	3 / 137 (2.19%)
occurrences all number	2	0	3	5
Blood corticotrophin increased
subjects affected / exposed	8 / 36 (22.22%)	6 / 35 (17.14%)	14 / 66 (21.21%)	28 / 137 (20.44%)
occurrences all number	10	6	14	30
Blood testosterone increased
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	13 / 66 (19.70%)	16 / 137 (11.68%)
occurrences all number	3	1	14	18
Cortisol decreased
subjects affected / exposed	3 / 36 (8.33%)	0 / 35 (0.00%)	1 / 66 (1.52%)	4 / 137 (2.92%)
occurrences all number	3	0	3	6
Cortisol free urine decreased
subjects affected / exposed	8 / 36 (22.22%)	2 / 35 (5.71%)	1 / 66 (1.52%)	11 / 137 (8.03%)
occurrences all number	9	3	1	13
Cortisol free urine increased
subjects affected / exposed	6 / 36 (16.67%)	1 / 35 (2.86%)	1 / 66 (1.52%)	8 / 137 (5.84%)
occurrences all number	6	1	1	8
Haemoglobin decreased
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	4	0	0	4
Hormone level abnormal
subjects affected / exposed	5 / 36 (13.89%)	1 / 35 (2.86%)	12 / 66 (18.18%)	18 / 137 (13.14%)
occurrences all number	9	2	15	26
Lipase increased
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	1 / 66 (1.52%)	4 / 137 (2.92%)
occurrences all number	1	3	1	5
Low density lipoprotein increased
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	1 / 66 (1.52%)	3 / 137 (2.19%)
occurrences all number	2	0	2	4
Renin increased
subjects affected / exposed	3 / 36 (8.33%)	0 / 35 (0.00%)	3 / 66 (4.55%)	6 / 137 (4.38%)
occurrences all number	4	0	4	8
Weight decreased
subjects affected / exposed	2 / 36 (5.56%)	2 / 35 (5.71%)	5 / 66 (7.58%)	9 / 137 (6.57%)
occurrences all number	3	2	5	10
Weight increased
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	2 / 66 (3.03%)	5 / 137 (3.65%)
occurrences all number	1	2	2	5
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	4 / 66 (6.06%)	7 / 137 (5.11%)
occurrences all number	1	2	6	9
Ligament sprain
subjects affected / exposed	3 / 36 (8.33%)	1 / 35 (2.86%)	1 / 66 (1.52%)	5 / 137 (3.65%)
occurrences all number	3	1	1	5
Cardiac disorders
Bundle branch block right
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	0	2	0	2
Tachycardia
subjects affected / exposed	2 / 36 (5.56%)	3 / 35 (8.57%)	3 / 66 (4.55%)	8 / 137 (5.84%)
occurrences all number	2	3	3	8
Nervous system disorders
Amnesia
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Carpal tunnel syndrome
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	0 / 66 (0.00%)	3 / 137 (2.19%)
occurrences all number	3	2	0	5
Dizziness
subjects affected / exposed	5 / 36 (13.89%)	4 / 35 (11.43%)	17 / 66 (25.76%)	26 / 137 (18.98%)
occurrences all number	6	5	25	36
Headache
subjects affected / exposed	11 / 36 (30.56%)	7 / 35 (20.00%)	32 / 66 (48.48%)	50 / 137 (36.50%)
occurrences all number	23	10	61	94
Hypoaesthesia
subjects affected / exposed	1 / 36 (2.78%)	4 / 35 (11.43%)	4 / 66 (6.06%)	9 / 137 (6.57%)
occurrences all number	1	6	4	11
Memory impairment
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	2 / 66 (3.03%)	5 / 137 (3.65%)
occurrences all number	2	1	2	5
Migraine
subjects affected / exposed	0 / 36 (0.00%)	1 / 35 (2.86%)	4 / 66 (6.06%)	5 / 137 (3.65%)
occurrences all number	0	1	4	5
Paraesthesia
subjects affected / exposed	1 / 36 (2.78%)	4 / 35 (11.43%)	0 / 66 (0.00%)	5 / 137 (3.65%)
occurrences all number	1	5	0	6
Somnolence
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	3 / 66 (4.55%)	5 / 137 (3.65%)
occurrences all number	2	0	3	5
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 36 (11.11%)	5 / 35 (14.29%)	6 / 66 (9.09%)	15 / 137 (10.95%)
occurrences all number	6	8	6	20
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	1 / 66 (1.52%)	3 / 137 (2.19%)
occurrences all number	2	0	1	3
Eye disorders
Dry eye
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	2 / 66 (3.03%)	4 / 137 (2.92%)
occurrences all number	2	0	2	4
Eye pruritus
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	0	2	0	2
Photophobia
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	0	3	0	3
Vision blurred
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	4 / 66 (6.06%)	4 / 137 (2.92%)
occurrences all number	0	0	5	5
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	3 / 66 (4.55%)	6 / 137 (4.38%)
occurrences all number	3	2	5	10
Abdominal pain
subjects affected / exposed	5 / 36 (13.89%)	2 / 35 (5.71%)	8 / 66 (12.12%)	15 / 137 (10.95%)
occurrences all number	6	3	9	18
Abdominal pain upper
subjects affected / exposed	3 / 36 (8.33%)	3 / 35 (8.57%)	3 / 66 (4.55%)	9 / 137 (6.57%)
occurrences all number	3	4	3	10
Constipation
subjects affected / exposed	4 / 36 (11.11%)	1 / 35 (2.86%)	5 / 66 (7.58%)	10 / 137 (7.30%)
occurrences all number	5	1	10	16
Dental caries
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Diarrhoea
subjects affected / exposed	5 / 36 (13.89%)	8 / 35 (22.86%)	14 / 66 (21.21%)	27 / 137 (19.71%)
occurrences all number	7	10	30	47
Dry mouth
subjects affected / exposed	0 / 36 (0.00%)	0 / 35 (0.00%)	4 / 66 (6.06%)	4 / 137 (2.92%)
occurrences all number	0	0	4	4
Dyspepsia
subjects affected / exposed	2 / 36 (5.56%)	5 / 35 (14.29%)	8 / 66 (12.12%)	15 / 137 (10.95%)
occurrences all number	2	5	9	16
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	1 / 66 (1.52%)	4 / 137 (2.92%)
occurrences all number	1	2	1	4
Nausea
subjects affected / exposed	17 / 36 (47.22%)	11 / 35 (31.43%)	34 / 66 (51.52%)	62 / 137 (45.26%)
occurrences all number	30	15	49	94
Toothache
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	3 / 66 (4.55%)	5 / 137 (3.65%)
occurrences all number	2	0	7	9
Vomiting
subjects affected / exposed	7 / 36 (19.44%)	5 / 35 (14.29%)	21 / 66 (31.82%)	33 / 137 (24.09%)
occurrences all number	11	7	35	53
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	2 / 36 (5.56%)	2 / 35 (5.71%)	9 / 66 (13.64%)	13 / 137 (9.49%)
occurrences all number	2	4	11	17
Alopecia
subjects affected / exposed	0 / 36 (0.00%)	3 / 35 (8.57%)	7 / 66 (10.61%)	10 / 137 (7.30%)
occurrences all number	0	3	7	10
Dermatitis
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	2 / 66 (3.03%)	4 / 137 (2.92%)
occurrences all number	0	2	2	4
Dermatitis contact
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	2 / 66 (3.03%)	5 / 137 (3.65%)
occurrences all number	2	1	2	5
Dry skin
subjects affected / exposed	0 / 36 (0.00%)	3 / 35 (8.57%)	7 / 66 (10.61%)	10 / 137 (7.30%)
occurrences all number	0	3	7	10
Eczema
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	2 / 66 (3.03%)	5 / 137 (3.65%)
occurrences all number	1	2	2	5
Hirsutism
subjects affected / exposed	4 / 36 (11.11%)	3 / 35 (8.57%)	5 / 66 (7.58%)	12 / 137 (8.76%)
occurrences all number	4	3	5	12
Hyperhidrosis
subjects affected / exposed	3 / 36 (8.33%)	3 / 35 (8.57%)	3 / 66 (4.55%)	9 / 137 (6.57%)
occurrences all number	3	3	3	9
Onychoclasis
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Pruritus
subjects affected / exposed	5 / 36 (13.89%)	1 / 35 (2.86%)	7 / 66 (10.61%)	13 / 137 (9.49%)
occurrences all number	7	1	7	15
Rash
subjects affected / exposed	8 / 36 (22.22%)	3 / 35 (8.57%)	10 / 66 (15.15%)	21 / 137 (15.33%)
occurrences all number	10	3	12	25
Skin hyperpigmentation
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	4 / 66 (6.06%)	6 / 137 (4.38%)
occurrences all number	2	2	5	9
Skin lesion
subjects affected / exposed	3 / 36 (8.33%)	0 / 35 (0.00%)	1 / 66 (1.52%)	4 / 137 (2.92%)
occurrences all number	4	0	1	5
Urticaria
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	2 / 66 (3.03%)	4 / 137 (2.92%)
occurrences all number	2	0	2	4
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	0 / 66 (0.00%)	3 / 137 (2.19%)
occurrences all number	1	2	0	3
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	7 / 36 (19.44%)	10 / 35 (28.57%)	17 / 66 (25.76%)	34 / 137 (24.82%)
occurrences all number	12	14	35	61
Glucocorticoid deficiency
subjects affected / exposed	10 / 36 (27.78%)	9 / 35 (25.71%)	8 / 66 (12.12%)	27 / 137 (19.71%)
occurrences all number	19	16	14	49
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 36 (19.44%)	10 / 35 (28.57%)	12 / 66 (18.18%)	29 / 137 (21.17%)
occurrences all number	11	19	24	54
Back pain
subjects affected / exposed	9 / 36 (25.00%)	13 / 35 (37.14%)	7 / 66 (10.61%)	29 / 137 (21.17%)
occurrences all number	9	15	10	34
Limb discomfort
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Muscle spasms
subjects affected / exposed	0 / 36 (0.00%)	2 / 35 (5.71%)	6 / 66 (9.09%)	8 / 137 (5.84%)
occurrences all number	0	2	6	8
Musculoskeletal pain
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	3 / 66 (4.55%)	6 / 137 (4.38%)
occurrences all number	2	1	4	7
Myalgia
subjects affected / exposed	2 / 36 (5.56%)	7 / 35 (20.00%)	11 / 66 (16.67%)	20 / 137 (14.60%)
occurrences all number	2	7	14	23
Neck pain
subjects affected / exposed	2 / 36 (5.56%)	2 / 35 (5.71%)	3 / 66 (4.55%)	7 / 137 (5.11%)
occurrences all number	2	2	4	8
Osteoarthritis
subjects affected / exposed	3 / 36 (8.33%)	0 / 35 (0.00%)	1 / 66 (1.52%)	4 / 137 (2.92%)
occurrences all number	4	0	1	5
Osteopenia
subjects affected / exposed	2 / 36 (5.56%)	2 / 35 (5.71%)	1 / 66 (1.52%)	5 / 137 (3.65%)
occurrences all number	3	2	1	6
Osteoporosis
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Pain in extremity
subjects affected / exposed	2 / 36 (5.56%)	5 / 35 (14.29%)	6 / 66 (9.09%)	13 / 137 (9.49%)
occurrences all number	3	5	7	15
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 36 (2.78%)	1 / 35 (2.86%)	6 / 66 (9.09%)	8 / 137 (5.84%)
occurrences all number	1	1	6	8
Cystitis
subjects affected / exposed	3 / 36 (8.33%)	2 / 35 (5.71%)	1 / 66 (1.52%)	6 / 137 (4.38%)
occurrences all number	8	2	1	11
Folliculitis
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	0 / 66 (0.00%)	3 / 137 (2.19%)
occurrences all number	4	2	0	6
Fungal skin infection
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	0 / 66 (0.00%)	3 / 137 (2.19%)
occurrences all number	1	2	0	3
Gastroenteritis
subjects affected / exposed	4 / 36 (11.11%)	3 / 35 (8.57%)	5 / 66 (7.58%)	12 / 137 (8.76%)
occurrences all number	4	4	7	15
Gastroenteritis viral
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Hordeolum
subjects affected / exposed	0 / 36 (0.00%)	3 / 35 (8.57%)	2 / 66 (3.03%)	5 / 137 (3.65%)
occurrences all number	0	3	4	7
Influenza
subjects affected / exposed	5 / 36 (13.89%)	8 / 35 (22.86%)	10 / 66 (15.15%)	23 / 137 (16.79%)
occurrences all number	7	10	19	36
Nasopharyngitis
subjects affected / exposed	9 / 36 (25.00%)	11 / 35 (31.43%)	13 / 66 (19.70%)	33 / 137 (24.09%)
occurrences all number	14	26	32	72
Sinusitis
subjects affected / exposed	3 / 36 (8.33%)	1 / 35 (2.86%)	4 / 66 (6.06%)	8 / 137 (5.84%)
occurrences all number	4	1	4	9
Tooth abscess
subjects affected / exposed	2 / 36 (5.56%)	1 / 35 (2.86%)	0 / 66 (0.00%)	3 / 137 (2.19%)
occurrences all number	2	1	0	3
Upper respiratory tract infection
subjects affected / exposed	2 / 36 (5.56%)	5 / 35 (14.29%)	7 / 66 (10.61%)	14 / 137 (10.22%)
occurrences all number	3	8	12	23
Urinary tract infection
subjects affected / exposed	6 / 36 (16.67%)	4 / 35 (11.43%)	14 / 66 (21.21%)	24 / 137 (17.52%)
occurrences all number	12	11	15	38
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 36 (8.33%)	7 / 35 (20.00%)	11 / 66 (16.67%)	21 / 137 (15.33%)
occurrences all number	3	7	15	25
Hypercholesterolaemia
subjects affected / exposed	1 / 36 (2.78%)	2 / 35 (5.71%)	1 / 66 (1.52%)	4 / 137 (2.92%)
occurrences all number	1	2	2	5
Hyperglycaemia
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	1 / 66 (1.52%)	3 / 137 (2.19%)
occurrences all number	4	0	2	6
Hypertriglyceridaemia
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	2 / 66 (3.03%)	4 / 137 (2.92%)
occurrences all number	5	0	4	9
Hypokalaemia
subjects affected / exposed	3 / 36 (8.33%)	3 / 35 (8.57%)	11 / 66 (16.67%)	17 / 137 (12.41%)
occurrences all number	4	5	13	22
Iron deficiency
subjects affected / exposed	2 / 36 (5.56%)	0 / 35 (0.00%)	0 / 66 (0.00%)	2 / 137 (1.46%)
occurrences all number	2	0	0	2
Vitamin D deficiency
subjects affected / exposed	3 / 36 (8.33%)	1 / 35 (2.86%)	2 / 66 (3.03%)	6 / 137 (4.38%)
occurrences all number	3	1	2	6

More information

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Were there any global substantial amendments to the protocol? Yes

15 Jul 2014

Harmonization Procedure review. Changes were made to: - Revise the definition of the optional Extension Period. - Clarify the time-to-escape definition. - Revise the premature patient withdrawal criteria. - Revise QTcF based withdrawal criteria. - Revise visit evaluation schedule. - Revise electrocardiogram collection schedule.

11 Mar 2015

Issued when 12 patients had been treated to: - Add country-specific (China) intensive PK sampling in order to investigate potential ethnic differences in osilodrostat pharmacokinetics. - Update inclusion and exclusion criteria.

29 Mar 2016

Issued when 75 patients had been treated to: - Expand the description of the dose dispensation process. - Elaborate on dose adjustments and communication of dosing instructions. - Add specific criteria for the identification and management of patients with potential drug-induced liver injury.

06 Jul 2017

Issued when 137 patients had been treated to: - Further increase the duration of the optional Extension Period. - Provide continued access to the study drug for those patients benefitting from the treatment until a separate long-term safety follow-up study is set up at participating sites.

29 Jun 2018

Enrollment was completed under Amendment 4. Issued when 91 patients were ongoing to: - Increase the maximum duration of the optional extension period by one additional year. - Add the central pituitary magnetic resonance imaging/computed tomography assessment for tumor re-occurrence and tumor invasiveness.

Were there any global interruptions to the trial? No

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.nov for complete trial results.

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of primary efficacy responder at Week 34 by randomized treatment and strata

Primary: Percentage of primary efficacy responder at Week 34 by randomized treatment and strata

Secondary: Percentage of secondary efficacy responder at Week 24 (Key Secondary endpoint)

Secondary: Percentage of secondary efficacy responder at Week 24 (Key Secondary endpoint)

Secondary: Time-to-loss of control of mean urinary free cortisol (mUFC) by randomized treatment group

Secondary: Time-to-loss of control of mean urinary free cortisol (mUFC) by randomized treatment group

Secondary: Complete Response Rate (CRR)

Secondary: Complete Response Rate (CRR)

Secondary: Change from baseline in mUFC (actual and percentage change)

Secondary: Change from baseline in mUFC (actual and percentage change)

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Fasting glucose

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Fasting glucose

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Hemoglobin A1C (HbA1C)

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Hemoglobin A1C (HbA1C)

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Sitting systolic blood pressure (SBP) & sitting diastolic blood pressure (DBP)

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Sitting systolic blood pressure (SBP) & sitting diastolic blood pressure (DBP)

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Weight

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Weight

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Body Mass Index (BMI)

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Body Mass Index (BMI)

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Waist Circumference

Secondary: Percentage change from baseline in cardiovascular-related parameter associated with Cushing's disease: Waist Circumference

Secondary: Percentage change from baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total score

Secondary: Percentage change from baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total score

Secondary: Percentage change from baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)

Secondary: Percentage change from baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)

Secondary: Percentage change in Patient-Reported Outcomes: EQ-5D-5L utility index

Secondary: Percentage change in Patient-Reported Outcomes: EQ-5D-5L utility index

Secondary: Percentage change in Patient-Reported Outcomes: EQ-5D-5L vascular analog scale (VAS)

Secondary: Percentage change in Patient-Reported Outcomes: EQ-5D-5L vascular analog scale (VAS)

Secondary: Change from baseline in the physical features of Cushing's disease by photography

Secondary: Change from baseline in the physical features of Cushing's disease by photography

Secondary: Change from baseline in bone mineral density - All participants

Secondary: Change from baseline in bone mineral density - All participants

Secondary: Time-to-escape

Secondary: Time-to-escape

Secondary: LCI699 exposures

Secondary: LCI699 exposures

Secondary: Percentage of participants with Complete Response Rate (CRR)

Secondary: Percentage of participants with Complete Response Rate (CRR)

Secondary: Percentage of participants with Partial Response Rate (PRR)

Secondary: Percentage of participants with Partial Response Rate (PRR)

Secondary: Percentage of participants with Overall Response Rate (ORR)

Secondary: Percentage of participants with Overall Response Rate (ORR)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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