Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease

• ClinicalTrials.gov Identifier: NCT02180217
• Recruitment Status: Completed
• First Posted: July 2, 2014
• Results First Posted: June 16, 2020
• Last Update Posted: January 6, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Cushings Disease
• Interventions: Drug: osilodrostat; Drug: LCI699 matching placebo
• Enrollment: 137

Participant Flow

Recruitment Details	132 patients were planned, 137 were enrolled and 137 were analyzed.
Pre-assignment Details

Arm/Group Title	Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Period Title: Overall Study
Started	36	35	66
Discontinued at/Prior to Week 12 (W12)	0	0	7
Discont. at/Prior to W26 But After W12	0	0	12
Discontinued Prior to W48 But After W26	0	2	3
Completed Week 48 (Core Phase)	36	33	44
Completed W48, Did Not Enter Ext. Phase	1	3	3
Completed W48, Entered Ext. Phase	35	30	41
Discontinued Extension Phase	12	6	16
Completed Ext. Phase	23	24	25
Completed [1]	24	27	28
Not Completed	12	8	38
Reason Not Completed
Adverse Event	3	2	22
Death	1	1	0
Withdrawal by Subject	1	1	4
Subject/Guardian decision	5	3	6
Physician Decision	1	1	6
Unsatisfactory therapeutic effect	1	0	0
[1] Completed = Completed Core/Extension Phase

Baseline Characteristics

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized	Total
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.	Total of all reporting groups
Overall Number of Baseline Participants		36	35	66	137
Baseline Analysis Population Description		Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	36 participants	35 participants	66 participants	137 participants
		44.3 (11.27)	42.0 (13.47)	39.0 (13.38)	41.2 (12.98)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	36 participants	35 participants	66 participants	137 participants
	Female	30 83.3%	22 62.9%	54 81.8%	106 77.4%
	Male	6 16.7%	13 37.1%	12 18.2%	31 22.6%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	36 participants	35 participants	66 participants	137 participants
Caucasian		27	23	39	89
Black		0	3	1	4
Asian		7	7	25	39
Other		2	2	1	5

Outcome Measures

1. Primary Outcome

Title	Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata
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
Time Frame	Week 34 (8 weeks)

Outcome Measure Data

Analysis Population Description

Randomized analysis set (RAS): comprises all randomized patients who received at least one dose of randomized drug (osilodrostat or placebo).

Arm/Group Title	Osilodrostat (LCI699)	LCI699 Placebo
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.
Overall Number of Participants Analyzed	36	34
Measure Type: Number; Unit of Measure: Percentage of participants
	86.1	29.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Osilodrostat (LCI699), LCI699 Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	13.71
	Confidence Interval	(2-Sided) 95%; 3.73 to 53.44
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)
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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title	All Participants
Arm/Group Description:	Consisted of all participants who were enrolled and treated in the open label osilodrostat.
Overall Number of Participants Analyzed	137
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	52.6; (43.9 to 61.1)

3. Secondary Outcome

Title	Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group
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.
Time Frame	8 weeks after randomization

Outcome Measure Data

Analysis Population Description

Randomized analysis set (RAS): comprised all randomized patients who received at least one dose of randomized drug (osilodrostat or placebo).

Arm/Group Title	Osilodrostat (LCI699)	LCI699 Placebo
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.
Overall Number of Participants Analyzed	36	34
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage
	5.6; (1.4 to 20.4)	61.1; (45.0 to 77.5)

4. Secondary Outcome

Title	Complete Response Rate (CRR)
Description	Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN
Time Frame	Week 12, Week 24, Week 48, Week 72, last observed value

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Measure Type: Number; Unit of Measure: Percentage of participants
Week 12	Number Analyzed	36 participants	35 participants	66 participants
		86.1	91.4	53.0
Week 24	Number Analyzed	36 participants	35 participants	66 participants
		100.0	97.1	34.8
Week 48	Number Analyzed	36 participants	35 participants	66 participants
		88.9	77.1	48.5
Week 72	Number Analyzed	35 participants	30 participants	41 participants
		82.9	83.3	78.0
Last observed value	Number Analyzed	36 participants	35 participants	66 participants
		69.4	74.3	53.0

5. Secondary Outcome

Title	Actual Change From Baseline in mUFC
Description	Actual change in mUFC from baseline.
Time Frame	Weeks 12, 24, 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: nmol/24h
Actual Baseline (BL)	Number Analyzed	36 participants	35 participants	66 participants
		890.0 (1275.66)	560.0 (548.84)	1305.8 (2012.21)
Wk 12: Act. change from BL	Number Analyzed	33 participants	34 participants	58 participants
		-848.4 (1335.66)	-510.3 (556.84)	-1021.3 (1825.55)
Wk 24: Act. change from BL	Number Analyzed	36 participants	35 participants	54 participants
		-821.2 (1283.03)	-485.5 (558.99)	-930.3 (1778.04)
Wk 48: Act. change from BL	Number Analyzed	34 participants	32 participants	42 participants
		-708.2 (983.14)	-477.1 (529.04)	-1189.9 (2042.48)
Wk 72: Act. change from BL	Number Analyzed	32 participants	29 participants	35 participants
		-680.7 (1003.63)	-536.7 (585.78)	-826.7 (1684.92)
Last avail. assess.: Act. change from BL	Number Analyzed	36 participants	35 participants	66 participants
		-795.2 (1286.22)	-387.3 (605.63)	-893.4 (1969.56)

6. Secondary Outcome

Title	Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose
Description	Actual change in fasting glucose from baseline.
Time Frame	Baseline, Weeks 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: mg/dL
Baseline	Number Analyzed	34 participants	33 participants	62 participants
		102.7 (35.23)	90.5 (18.53)	101.8 (31.00)
Wk 48	Number Analyzed	33 participants	30 participants	38 participants
		-7.9 (32.24)	-5.5 (12.13)	-14.1 (22.66)
Wk 72	Number Analyzed	30 participants	25 participants	32 participants
		-0.5 (16.84)	-4.4 (15.13)	-10.8 (24.02)
Last avail. assessment	Number Analyzed	34 participants	32 participants	62 participants
		-8.6 (37.05)	-0.6 (21.00)	-15.6 (26.62)

7. Secondary Outcome

Title	Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C)
Description	Actual change in glycosylated hemoglobin (HbA1c) from baseline.
Time Frame	Baseline, Weeks 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: percentage
Baseline	Number Analyzed	36 participants	35 participants	66 participants
		6.1 (0.98)	5.8 (0.93)	6.0 (0.97)
Wk 48	Number Analyzed	35 participants	33 participants	42 participants
		-0.3 (0.86)	-0.4 (0.56)	-0.4 (0.65)
Wk 72	Number Analyzed	33 participants	29 participants	35 participants
		-0.4 (0.66)	-0.4 (0.47)	-0.4 (0.64)
Last avail. assessment	Number Analyzed	36 participants	35 participants	66 participants
		-0.3 (0.78)	-0.2 (0.47)	-0.3 (0.68)

8. Secondary Outcome

Title	Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride
Description	Actual change in Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride from baseline.
Time Frame	Baseline, Weeks 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: mmol/L
Cholesterol: BL	Number Analyzed	36 participants	34 participants	66 participants
		5.5 (1.22)	5.3 (0.90)	5.1 (1.24)
Cholesterol: Wk 48	Number Analyzed	35 participants	32 participants	41 participants
		-0.7 (0.87)	-0.4 (0.89)	-0.5 (0.90)
Cholesterol: Wk 72	Number Analyzed	33 participants	27 participants	33 participants
		-0.4 (0.96)	-0.3 (0.75)	-0.4 (0.98)
Cholesterol: Last avail. assessment	Number Analyzed	36 participants	34 participants	66 participants
		-0.3 (1.16)	-0.3 (1.03)	-0.4 (1.15)
LDL Cholesterol: BL	Number Analyzed	36 participants	34 participants	66 participants
		3.2 (1.09)	3.1 (0.77)	2.9 (0.94)
LDL Cholesterol: Wk 48	Number Analyzed	35 participants	32 participants	40 participants
		-0.3 (0.75)	-0.2 (0.74)	-0.1 (0.82)
LDL Cholesterol: Wk 72	Number Analyzed	33 participants	27 participants	33 participants
		-0.2 (0.77)	-0.2 (0.66)	-0.1 (0.86)
LDL Cholesterol: Last avail asses	Number Analyzed	36 participants	34 participants	65 participants
		-0.1 (0.98)	-0.2 (0.88)	-0.1 (0.99)
HDL Cholesterol: BL	Number Analyzed	36 participants	34 participants	66 participants
		1.7 (0.55)	1.5 (0.36)	1.6 (0.42)
HDL Cholesterol: Wk 48	Number Analyzed	35 participants	32 participants	41 participants
		-0.3 (0.39)	-0.2 (0.17)	-0.3 (0.28)
HDL Cholesterol: Wk 72	Number Analyzed	33 participants	27 participants	33 participants
		-0.2 (0.39)	-0.2 (0.27)	-0.3 (0.28)
HDL Cholesterol: Last avail assess	Number Analyzed	36 participants	34 participants	66 participants
		-0.2 (0.40)	-0.1 (0.27)	-0.2 (0.34)
Triglyceride: BL	Number Analyzed	36 participants	34 participants	66 participants
		1.5 (0.78)	1.4 (0.62)	1.6 (1.74)
Triglyceride: Wk 48	Number Analyzed	35 participants	32 participants	41 participants
		-0.1 (0.49)	0.0 (0.54)	0.0 (1.22)
Triglyceride: Wk 72	Number Analyzed	33 participants	28 participants	33 participants
		0.0 (0.57)	-0.1 (0.67)	0.0 (0.60)
Triglyceride: Last avail. assess	Number Analyzed	36 participants	34 participants	66 participants
		0.0 (0.64)	-0.1 (0.75)	0.1 (1.48)

9. Secondary Outcome

Title	Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP)
Description	Actual change in sitting SBP & DBP from baseline.
Time Frame	Baseline, Weeks 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: mmHg
SBP: Baseline	Number Analyzed	36 participants	35 participants	66 participants
		132.2 (15.44)	128.8 (11.93)	134.0 (16.34)
SBP: Wk 48	Number Analyzed	35 participants	33 participants	43 participants
		-15.2 (17.00)	-4.8 (12.28)	-9.2 (15.48)
SBP: Wk 72	Number Analyzed	34 participants	29 participants	36 participants
		-12.2 (15.90)	-8.2 (19.41)	-9.4 (19.08)
SBP: Last avail. assessment	Number Analyzed	36 participants	35 participants	66 participants
		-8.2 (15.25)	-4.6 (15.20)	-10.8 (15.31)
DBP: Baseline	Number Analyzed	36 participants	35 participants	66 participants
		85.3 (11.38)	85.0 (10.03)	85.4 (10.53)
DBP: Wk 48	Number Analyzed	35 participants	33 participants	43 participants
		-7.8 (11.63)	-5.1 (9.66)	-6.0 (11.79)
DBP: Wk 72	Number Analyzed	34 participants	29 participants	36 participants
		-5.9 (11.17)	-7.0 (10.33)	-4.8 (12.26)
DBP: Last avail. assessment	Number Analyzed	36 participants	35 participants	66 participants
		-3.4 (11.79)	-3.5 (11.50)	-5.0 (10.45)

10. Secondary Outcome

Title	Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight
Description	Actual change in weight from baseline.
Time Frame	Baseline, Weeks 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: kg
Baseline	Number Analyzed	36 participants	35 participants	66 participants
		78.2 (19.02)	83.4 (24.73)	80.7 (23.06)
Wk 48	Number Analyzed	36 participants	33 participants	43 participants
		-3.4 (5.64)	-3.9 (5.77)	-4.0 (5.82)
Wk 72	Number Analyzed	34 participants	29 participants	36 participants
		-3.7 (6.93)	-5.0 (6.03)	-5.6 (6.75)
Last avail. assessment	Number Analyzed	36 participants	35 participants	66 participants
		-2.9 (8.28)	-3.7 (11.13)	-4.2 (6.35)

11. Secondary Outcome

Title	Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI)
Description	Actual change in BMI from baseline.
Time Frame	Baseline, Weeks 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: kg/m^2
Baseline	Number Analyzed	36 participants	35 participants	66 participants
		29.6 (7.36)	30.9 (8.38)	30.4 (7.74)
Wk 48	Number Analyzed	36 participants	33 participants	43 participants
		-1.3 (2.22)	-1.5 (2.12)	-1.5 (2.17)
Wk 72	Number Analyzed	34 participants	29 participants	36 participants
		-1.4 (2.79)	-1.8 (2.14)	-2.0 (2.55)
Last avail. assessment	Number Analyzed	36 participants	35 participants	66 participants
		-1.2 (3.34)	-1.5 (3.94)	-1.6 (2.41)

12. Secondary Outcome

Title	Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference
Description	Actual change in waist circumference from baseline.
Time Frame	Baseline, Weeks 48, 72, last available assessment

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: cm
Baseline	Number Analyzed	35 participants	33 participants	65 participants
		100.5 (16.81)	103.7 (18.26)	105.0 (21.15)
Wk 48	Number Analyzed	34 participants	32 participants	43 participants
		-5.1 (6.26)	-4.2 (10.12)	-4.7 (7.07)
Wk 72	Number Analyzed	33 participants	29 participants	36 participants
		-5.1 (7.18)	-6.1 (9.86)	-7.4 (8.53)
Last avail. assessment	Number Analyzed	35 participants	33 participants	65 participants
		-4.7 (10.05)	-5.2 (12.24)	-6.2 (9.96)

13. Secondary Outcome

Title	Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score
Description	Cushing's Disease Health-Related Quality of Life Questionnaire was developed to evaluate quality of life in patients with Cushing's syndrome. It is comprised of 12 items that capture patient responses on 7 concepts: daily activities, healing & pain, mood & self-confidence, social concerns, physical appearance, memory & concern about the future. These items are measured on a 5- point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous 4 weeks. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Content reliability, sensitivity to change & psychometric properties have been validated in patients with Cushing's disease. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. Increases from baseline are indicative of an improvement.
Time Frame	Baseline, Week (W) 48, W72, Last available assessment

Outcome Measure Data

Analysis Population Description

FAS: Comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: scores on a scale
Baseline	Number Analyzed	36 participants	35 participants	66 participants
		44.4 (18.33)	43.2 (22.45)	40.5 (17.61)
Week 48	Number Analyzed	35 participants	32 participants	43 participants
		16.1 (15.15)	10.2 (16.57)	13.2 (17.79)
Week 72	Number Analyzed	32 participants	28 participants	37 participants
		15.8 (16.08)	12.6 (20.68)	16.3 (21.31)
Last available assess.	Number Analyzed	36 participants	35 participants	65 participants
		16.1 (15.99)	11.8 (20.51)	12.9 (18.91)

14. Secondary Outcome

Title	Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)
Description	BDI-II is a patient-reported instrument developed to measure the severity of depression in adults & adolescents aged 13 years & older. It is designed to be completed by the patient on paper & takes approximately 5 minutes to complete. The BDI-II consists of 21 items designed to assess the intensity of depression in clinical & normal patients in the preceding 2 weeks. Items are rated on a 4-point severity scale of 0 ('not at all') to 3 ('extreme' form of each symptom) with differing response options for each item. A global score ranging from 0 to 63 is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. 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.
Time Frame	Baseline, W48, W72, Last available assessment

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: scores on a a scale
Baseline	Number Analyzed	36 participants	35 participants	66 participants
		15.1 (11.14)	17.8 (9.93)	17.3 (10.67)
W48	Number Analyzed	35 participants	32 participants	43 participants
		-4.8 (9.84)	-5.3 (7.99)	-7.0 (10.17)
W72	Number Analyzed	32 participants	28 participants	36 participants
		-6.0 (9.55)	-4.6 (9.41)	-9.0 (12.34)
Last avail. assess.	Number Analyzed	36 participants	35 participants	65 participants
		-6.2 (9.93)	-5.0 (9.49)	-4.9 (10.66)

15. Secondary Outcome

Title	Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index
Description	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 is cognitively undemanding, taking only a few minutes to complete. Instructions to respondents are included in the questionnaire. 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, & extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an "unconscious" health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement.
Time Frame	Baseline, W48, W72, Last available assessment

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Baseline	Number Analyzed	36 participants	35 participants	66 participants
		0.7 (0.24)	0.7 (0.24)	0.7 (0.28)
Week 48	Number Analyzed	35 participants	32 participants	43 participants
		0.1 (0.18)	0 (0.25)	0.1 (0.18)
Week 72	Number Analyzed	32 participants	28 participants	36 participants
		0.1 (0.18)	0.1 (0.26)	0.1 (0.19)
Last avail. assess.	Number Analyzed	36 participants	35 participants	65 participants
		0.1 (0.22)	0 (0.28)	0.1 (0.23)

16. Secondary Outcome

Title	Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)
Description	The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with on a scale of 0-100, with endpoints labeled 100 = 'the best health you can imagine' and 0 = 'the worst health you can imagine'. A single index value is analyzed for the VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.
Time Frame	Baseline, W48, W72, Last available assessment

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Baseline	Number Analyzed	36 participants	35 participants	66 participants
		61.3 (18.97)	64.2 (16.37)	60.8 (21.09)
Week 48	Number Analyzed	35 participants	31 participants	43 participants
		12.6 (20.64)	6.9 (12.56)	9.7 (17.16)
Week 72	Number Analyzed	32 participants	27 participants	36 participants
		11.2 (18.98)	6.6 (15.47)	10.1 (19.80)
Last avail. assess.	Number Analyzed	36 participants	34 participants	65 participants
		12.1 (19.71)	6.4 (18.65)	6.2 (20.42)

17. Secondary Outcome

Title	Change From Baseline in the Physical Features of Cushing's Disease by Photography
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).
Time Frame	Week 48, Week 72, Last available assessment

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
W48: Facial rubor	Number Analyzed	30 participants	30 participants	37 participants
		50.0; (31.3 to 68.7)	46.7; (28.3 to 65.7)	43.2; (27.1 to 60.5)
W48: Striae	Number Analyzed	30 participants	30 participants	37 participants
		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	Number Analyzed	30 participants	30 participants	37 participants
		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	Number Analyzed	30 participants	30 participants	37 participants
		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	Number Analyzed	30 participants	30 participants	37 participants
		40.0; (22.7 to 59.4)	26.7; (12.3 to 45.9)	45.9; (29.5 to 63.1)
W48: Central obesity	Number Analyzed	30 participants	30 participants	37 participants
		43.3; (25.5 to 62.6)	30.0; (14.7 to 49.4)	51.4; (34.4 to 68.1)
W48: Ecchymoses	Number Analyzed	30 participants	30 participants	37 participants
		33.3; (17.3 to 52.8)	26.7; (12.3 to 45.9)	43.2; (27.1 to 60.5)
W72: Facial rubor	Number Analyzed	29 participants	27 participants	30 participants
		48.3; (29.4 to 67.5)	55.6; (35.3 to 74.5)	53.3; (34.3 to 71.7)
W72: Striae	Number Analyzed	29 participants	27 participants	30 participants
		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	Number Analyzed	29 participants	27 participants	30 participants
		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	Number Analyzed	29 participants	27 participants	30 participants
		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	Number Analyzed	29 participants	27 participants	30 participants
		31.0; (15.3 to 50.8)	25.9; (11.1 to 46.3)	46.7; (28.3 to 65.7)
W72: Central obesity	Number Analyzed	29 participants	27 participants	30 participants
		37.9; (20.7 to 57.7)	37.0; (19.4 to 57.6)	43.3; (25.5 to 62.6)
W72: Ecchymoses	Number Analyzed	29 participants	27 participants	30 participants
		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	Number Analyzed	25 participants	23 participants	26 participants
		60.0; (38.7 to 78.9)	56.5; (34.5 to 76.8)	53.8; (33.4 to 73.4)
EOT: Striae	Number Analyzed	25 participants	23 participants	26 participants
		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	Number Analyzed	25 participants	23 participants	26 participants
		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	Number Analyzed	25 participants	23 participants	26 participants
		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	Number Analyzed	25 participants	23 participants	26 participants
		36.0; (18.0 to 57.5)	21.7; (7.5 to 43.7)	50.0; (29.9 to 70.1)
EOT: Central obesity	Number Analyzed	25 participants	23 participants	26 participants
		40.0; (21.1 to 61.3)	39.1; (19.7 to 61.5)	38.5; (20.0 to 59.4)
EOT: Ecchymoses	Number Analyzed	25 participants	23 participants	26 participants
		28.0; (12.1 to 49.4)	39.1; (19.7 to 61.5)	38.5; (20.2 to 59.4)

18. Secondary Outcome

Title	Change From Baseline in Bone Mineral Density - All Participants
Description	Actual 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..
Time Frame	Baseline, Week 48, Last observed value (LOV)

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Mean (Standard Error); Unit of Measure: g/cm2
Baseline (L1-L4 Lumbar Spine)	Number Analyzed	28 participants	27 participants	58 participants
		1.0 (0.20)	1.0 (0.17)	1.0 (0.18)
W48 (L1-L4 Lumbar Spine)	Number Analyzed	23 participants	23 participants	35 participants
		1.0 (0.19)	1.0 (0.17)	1.0 (0.19)
LOV (L1-L4 Lumbar Spine)	Number Analyzed	26 participants	24 participants	46 participants
		1.0 (0.20)	1.0 (0.18)	1.0 (0.18)
Baseline (Total Hip)	Number Analyzed	29 participants	26 participants	58 participants
		0.9 (0.18)	0.8 (0.15)	0.9 (0.16)
W48 (Total Hip)	Number Analyzed	24 participants	21 participants	35 participants
		0.9 (0.17)	0.8 (0.14)	0.9 (0.16)
LOV (Total Hip)	Number Analyzed	27 participants	22 participants	46 participants
		0.9 (0.17)	0.8 (0.13)	0.9 (0.16)

19. Secondary Outcome

Title	Time-to-escape
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat. This is a subset of the FAS participants who met all the criteria for Escape. The placebo patients + patients that did not reach mUFC <= ULN at some stage during the study are excluded from the denominator.

Arm/Group Title	All Participants
Arm/Group Description:	Consisted of all participants in the study under osilodrostat treatment
Overall Number of Participants Analyzed	97
Median (95% Confidence Interval); Unit of Measure: days
	546.0; (212.0 to 968.0)

20. Secondary Outcome

Title	LCI699 Exposures
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.
Time Frame	from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetics analysis set (PAS) consists of all enrolled patients who receive at least one dose of osilodrostat and have at least one evaluable post-dosing PK assessment.

Arm/Group Title		Osilodrostat (LCI699) 2 mg	Osilodrostat (LCI699) 3 mg	Osilodrostat (LCI699) 5 mg	Osilodrostat (LCI699) 7 mg
Arm/Group Description:		Participants received 2mg of osilodrostat	Participants received 3mg of osilodrostat	Participants received 5 mg of osilodrostat	Participants received 7 mg of osilodrostat
Overall Number of Participants Analyzed		132	39	105	24
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/ml
Week (Wk) 2: Predose	Number Analyzed	79 participants	0 participants	0 participants	0 participants
		1.904; (110.4%)
Wk 2: 0.75h	Number Analyzed	14 participants	0 participants	0 participants	0 participants
		1.907; (132.5%)
Wk 2: 1.5h	Number Analyzed	3 participants	0 participants	0 participants	0 participants
		5.1; (62.7%)
Wk 2: 4h	Number Analyzed	18 participants	0 participants	0 participants	0 participants
		5.818; (66.3%)
Wk 4: Predose	Number Analyzed	50 participants	2 participants	31 participants	0 participants
		2.104; (108.0%)	2.898; (109.1%)	3.584; (126.3%)
Wk 4: 0.75h	Number Analyzed	2 participants	0 participants	9 participants	0 participants
		0.859; (254.3%)		7.091; (137.8%)
Wk 4: 1.5h	Number Analyzed	2 participants	0 participants	1 participants	0 participants
		8.737; (3.6%)		24.2 [1]; (NA%)
Wk 4: 4h	Number Analyzed	1 participants	0 participants	9 participants	0 participants
		8.930 [1]; (NA%)		15.985; (48.3%)
Wk 6: Predose	Number Analyzed	17 participants	3 participants	46 participants	2 participants
		2.037; (63.5%)	2.392; (285.6%)	5.087; (122.9%)	8.065; (8.6%)
Wk 6: 0.75h	Number Analyzed	1 participants	0 participants	5 participants	0 participants
		3.110 [1]; (NA%)		5.223; (229.4%)
Wk 6: 1.5h	Number Analyzed	0 participants	1 participants	1 participants	0 participants
			22.4 [1]; (NA%)	21.4 [1]; (NA%)
Wk 6: 4h	Number Analyzed	1 participants	1 participants	5 participants	0 participants
		8.380 [1]; (NA%)	18.6 [1]; (NA%)	18.373; (36.5%)
Wk 8: Predose	Number Analyzed	13 participants	5 participants	35 participants	3 participants
		2.198; (108.9%)	4.061; (67.4%)	4.487; (106.9%)	6.718; (34.2%)
Wk 8: 0.75h	Number Analyzed	0 participants	0 participants	0 participants	0 participants
Wk 8: 1.5h	Number Analyzed	1 participants	1 participants	0 participants	1 participants
		10.8 [1]; (NA%)	20.4 [1]; (NA%)		32.1 [2]; (NA%)
Wk 8: 4h	Number Analyzed	1 participants	0 participants	0 participants	1 participants
		6.65 [1]; (NA%)			32 [2]; (NA%)
Wk 10: Predose	Number Analyzed	10 participants	9 participants	29 participants	6 participants
		1.862; (128.9%)	3.007; (64.8%)	4.704; (106.8%)	5.451; (93.1%)
Wk 10: 0.75h	Number Analyzed	0 participants	1 participants	0 participants	1 participants
			6.7 [2]; (NA%)		17.1 [2]; (NA%)
Wk 10: 1.5h	Number Analyzed	1 participants	1 participants	1 participants	0 participants
		12.1 [1]; (NA%)	18.3 [1]; (NA%)	34.2 [1]; (NA%)
Wk 10: 4h	Number Analyzed	0 participants	1 participants	1 participants	1 participants
			15.8 [1]; (NA%)	27.2 [1]; (NA%)	35.5 [1]; (NA%)

[1]

NA: CV% geo-mean could not be calculated with just 1 patient

[2]

NA: CV% geo-mean could not be calculated with just 1 patient.

21. Secondary Outcome

Title	Percentage of Participants With Complete Response Rate (CRR)
Description	Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN.
Time Frame	Week 12, Week 24, Week 48, Week 72, last available assessment

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Measure Type: Number; Unit of Measure: Percentage of participants
Week 12	Number Analyzed	36 participants	35 participants	66 participants
		6.1	91.4	53.0
Week 24	Number Analyzed	36 participants	35 participants	66 participants
		100	97.1	34.8
Week 48	Number Analyzed	36 participants	35 participants	66 participants
		88.9	77.1	48.5
Week 72	Number Analyzed	35 participants	30 participants	41 participants
		82.9	83.3	78.0
Last available assess.	Number Analyzed	36 participants	35 participants	66 participants
		69.4	74.3	53.0

22. Secondary Outcome

Title	Percentage of Participants With Partial Response Rate (PRR)
Description	Partial response rate is defined as percentage of enrolled participants with ≥ 50% reduction from baseline in mUFC, but mUFC>ULN)
Time Frame	Week 12, Week 24, Week 48, Week 72, last available assessment

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Measure Type: Number; Unit of Measure: Percentage of participants
Week 12	Number Analyzed	36 participants	35 participants	66 participants
		2.8	5.7	24.2
Week 24	Number Analyzed	36 participants	35 participants	66 participants
		0.0	0.0	30.3
Week 48	Number Analyzed	36 participants	35 participants	66 participants
		5.6	11.4	10.6
Week 72	Number Analyzed	35 participants	30 participants	41 participants
		8.6	13.3	2.4
Last available assess.	Number Analyzed	36 participants	35 participants	66 participants
		22.2	11.4	22.7

23. Secondary Outcome

Title	Percentage of Participants With Overall Response Rate (ORR)
Description	Overall response rate is defined as percentage of enrolled participants with mUFC ≤ ULN or at least 50% reduction from baseline.
Time Frame	Week 12, Week 24, Week 48, Week 72, last available assessment

Outcome Measure Data

Analysis Population Description

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Arm/Group Title		Osilodrostat (LCI699)	LCI699 Placebo	Non-randomized
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.
Overall Number of Participants Analyzed		36	35	66
Measure Type: Number; Unit of Measure: Percentage of participants
Week 12	Number Analyzed	36 participants	35 participants	66 participants
		88.9	97.1	77.3
Week 24	Number Analyzed	36 participants	35 participants	66 participants
		100	97.1	65.2
Week 48	Number Analyzed	36 participants	35 participants	66 participants
		94.4	88.6	59.1
Week 72	Number Analyzed	35 participants	30 participants	41 participants
		91.4	96.7	80.5
Last available assess.	Number Analyzed	36 participants	35 participants	66 participants
		91.7	85.7	75.8

Adverse Events

Time Frame	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 Description	Adverse Event: Any sign or symptom that occurs during the study treatment plus up to 30 days after the last dose administration.
Arm/Group Title	Osilodrostat	LCI699 Placebo	Non-randomized	All Participants
Arm/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.	Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	All participants in this group took open label osilodrostat, before and after randomization.	Consisted of all participants who were enrolled and treated with open label osilodrostat.
All-Cause Mortality
	Osilodrostat	LCI699 Placebo	Non-randomized	All Participants
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/36 (2.78%)	1/35 (2.86%)	0/66 (0.00%)	2/137 (1.46%)
Serious Adverse Events
	Osilodrostat	LCI699 Placebo	Non-randomized	All Participants
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	13/36 (36.11%)	10/35 (28.57%)	32/66 (48.48%)	55/137 (40.15%)
Blood and lymphatic system disorders
Anaemia † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Autoimmune neutropenia † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Lymphadenopathy † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Neutropenia † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Cardiac disorders
Cardiopulmonary failure † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Endocrine disorders
Adrenal insufficiency † 1	1/36 (2.78%)	1/35 (2.86%)	6/66 (9.09%)	8/137 (5.84%)
Adrenocortical insufficiency acute † 1	1/36 (2.78%)	0/35 (0.00%)	3/66 (4.55%)	4/137 (2.92%)
Glucocorticoid deficiency † 1	0/36 (0.00%)	0/35 (0.00%)	2/66 (3.03%)	2/137 (1.46%)
Inappropriate antidiuretic hormone secretion † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Pituitary infarction † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Pituitary-dependent Cushing's syndrome † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Eye disorders
Diplopia † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Visual impairment † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Gastrointestinal disorders
Abdominal pain † 1	1/36 (2.78%)	1/35 (2.86%)	1/66 (1.52%)	3/137 (2.19%)
Gastritis † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Nausea † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Pancreatitis acute † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Vomiting † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
General disorders
Chills † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Influenza like illness † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Non-cardiac chest pain † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Pain † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Pyrexia † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Hepatobiliary disorders
Cholecystitis † 1	0/36 (0.00%)	1/35 (2.86%)	1/66 (1.52%)	2/137 (1.46%)
Cholelithiasis † 1	1/36 (2.78%)	0/35 (0.00%)	1/66 (1.52%)	2/137 (1.46%)
Immune system disorders
Anaphylactic shock † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Infections and infestations
Cellulitis † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Chronic sinusitis † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Gastroenteritis † 1	0/36 (0.00%)	1/35 (2.86%)	3/66 (4.55%)	4/137 (2.92%)
Gastroenteritis viral † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Influenza † 1	1/36 (2.78%)	0/35 (0.00%)	2/66 (3.03%)	3/137 (2.19%)
Keratitis fungal † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Pneumonia † 1	0/36 (0.00%)	1/35 (2.86%)	1/66 (1.52%)	2/137 (1.46%)
Urinary tract infection † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Injury, poisoning and procedural complications
Head injury † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Overdose † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Procedural headache † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Investigations
Haemoglobin decreased † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Transaminases increased † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Metabolism and nutrition disorders
Decreased appetite † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Dehydration † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Hypercalcaemia † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Hypokalaemia † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Hyponatraemia † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Musculoskeletal and connective tissue disorders
Foot deformity † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Groin pain † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Pain in extremity † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pituitary tumour † 1	0/36 (0.00%)	0/35 (0.00%)	2/66 (3.03%)	2/137 (1.46%)
Metastases to liver † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Pituitary tumour † 1	1/36 (2.78%)	1/35 (2.86%)	4/66 (6.06%)	6/137 (4.38%)
Pituitary tumour benign † 1	1/36 (2.78%)	0/35 (0.00%)	2/66 (3.03%)	3/137 (2.19%)
Tumour invasion † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Nervous system disorders
Cranial nerve disorder † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Headache † 1	0/36 (0.00%)	1/35 (2.86%)	2/66 (3.03%)	3/137 (2.19%)
Idiopathic intracranial hypertension † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Migraine † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Seizure † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Syncope † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
VIth nerve paralysis † 1	0/36 (0.00%)	0/35 (0.00%)	3/66 (4.55%)	3/137 (2.19%)
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Psychiatric disorders
Anxiety † 1	1/36 (2.78%)	1/35 (2.86%)	0/66 (0.00%)	2/137 (1.46%)
Completed suicide † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Depression † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Suicidal ideation † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Renal and urinary disorders
Acute kidney injury † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Cystitis glandularis † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Reproductive system and breast disorders
Metrorrhagia † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Uterine polyp † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Vaginal haemorrhage † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Dyspnoea † 1	0/36 (0.00%)	1/35 (2.86%)	0/66 (0.00%)	1/137 (0.73%)
Epistaxis † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Pulmonary oedema † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Respiratory disorder † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Respiratory failure † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Vocal cord polyp † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Skin and subcutaneous tissue disorders
Hidradenitis † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
Urticaria † 1	1/36 (2.78%)	0/35 (0.00%)	0/66 (0.00%)	1/137 (0.73%)
Vascular disorders
Venous thrombosis † 1	0/36 (0.00%)	0/35 (0.00%)	1/66 (1.52%)	1/137 (0.73%)
1 Term from vocabulary, MedDRA (22.1); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Osilodrostat	LCI699 Placebo	Non-randomized	All Participants
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	34/36 (94.44%)	35/35 (100.00%)	65/66 (98.48%)	134/137 (97.81%)
Blood and lymphatic system disorders
Anaemia † 1	4/36 (11.11%)	5/35 (14.29%)	6/66 (9.09%)	15/137 (10.95%)
Cardiac disorders
Bundle branch block right † 1	0/36 (0.00%)	2/35 (5.71%)	0/66 (0.00%)	2/137 (1.46%)
Tachycardia † 1	2/36 (5.56%)	3/35 (8.57%)	3/66 (4.55%)	8/137 (5.84%)
Ear and labyrinth disorders
Ear pain † 1	2/36 (5.56%)	0/35 (0.00%)	1/66 (1.52%)	3/137 (2.19%)
Endocrine disorders
Adrenal insufficiency † 1	7/36 (19.44%)	10/35 (28.57%)	17/66 (25.76%)	34/137 (24.82%)
Glucocorticoid deficiency † 1	10/36 (27.78%)	9/35 (25.71%)	8/66 (12.12%)	27/137 (19.71%)
Eye disorders
Dry eye † 1	2/36 (5.56%)	0/35 (0.00%)	2/66 (3.03%)	4/137 (2.92%)
Eye pruritus † 1	0/36 (0.00%)	2/35 (5.71%)	0/66 (0.00%)	2/137 (1.46%)
Photophobia † 1	0/36 (0.00%)	2/35 (5.71%)	0/66 (0.00%)	2/137 (1.46%)
Vision blurred † 1	0/36 (0.00%)	0/35 (0.00%)	4/66 (6.06%)	4/137 (2.92%)
Gastrointestinal disorders
Abdominal distension † 1	2/36 (5.56%)	1/35 (2.86%)	3/66 (4.55%)	6/137 (4.38%)
Abdominal pain † 1	5/36 (13.89%)	2/35 (5.71%)	8/66 (12.12%)	15/137 (10.95%)
Abdominal pain upper † 1	3/36 (8.33%)	3/35 (8.57%)	3/66 (4.55%)	9/137 (6.57%)
Constipation † 1	4/36 (11.11%)	1/35 (2.86%)	5/66 (7.58%)	10/137 (7.30%)
Dental caries † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Diarrhoea † 1	5/36 (13.89%)	8/35 (22.86%)	14/66 (21.21%)	27/137 (19.71%)
Dry mouth † 1	0/36 (0.00%)	0/35 (0.00%)	4/66 (6.06%)	4/137 (2.92%)
Dyspepsia † 1	2/36 (5.56%)	5/35 (14.29%)	8/66 (12.12%)	15/137 (10.95%)
Gastrooesophageal reflux disease † 1	1/36 (2.78%)	2/35 (5.71%)	1/66 (1.52%)	4/137 (2.92%)
Nausea † 1	17/36 (47.22%)	11/35 (31.43%)	34/66 (51.52%)	62/137 (45.26%)
Toothache † 1	2/36 (5.56%)	0/35 (0.00%)	3/66 (4.55%)	5/137 (3.65%)
Vomiting † 1	7/36 (19.44%)	5/35 (14.29%)	21/66 (31.82%)	33/137 (24.09%)
General disorders
Application site rash † 1	0/36 (0.00%)	2/35 (5.71%)	0/66 (0.00%)	2/137 (1.46%)
Asthenia † 1	11/36 (30.56%)	5/35 (14.29%)	11/66 (16.67%)	27/137 (19.71%)
Chest discomfort † 1	1/36 (2.78%)	0/35 (0.00%)	4/66 (6.06%)	5/137 (3.65%)
Chills † 1	1/36 (2.78%)	3/35 (8.57%)	2/66 (3.03%)	6/137 (4.38%)
Fatigue † 1	8/36 (22.22%)	13/35 (37.14%)	24/66 (36.36%)	45/137 (32.85%)
Gait disturbance † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Influenza like illness † 1	0/36 (0.00%)	2/35 (5.71%)	1/66 (1.52%)	3/137 (2.19%)
Malaise † 1	1/36 (2.78%)	2/35 (5.71%)	7/66 (10.61%)	10/137 (7.30%)
Oedema † 1	1/36 (2.78%)	3/35 (8.57%)	5/66 (7.58%)	9/137 (6.57%)
Oedema peripheral † 1	8/36 (22.22%)	5/35 (14.29%)	9/66 (13.64%)	22/137 (16.06%)
Pain † 1	2/36 (5.56%)	3/35 (8.57%)	1/66 (1.52%)	6/137 (4.38%)
Pyrexia † 1	4/36 (11.11%)	3/35 (8.57%)	13/66 (19.70%)	20/137 (14.60%)
Immune system disorders
Seasonal allergy † 1	0/36 (0.00%)	2/35 (5.71%)	0/66 (0.00%)	2/137 (1.46%)
Infections and infestations
Bronchitis † 1	1/36 (2.78%)	1/35 (2.86%)	6/66 (9.09%)	8/137 (5.84%)
Cystitis † 1	3/36 (8.33%)	2/35 (5.71%)	1/66 (1.52%)	6/137 (4.38%)
Folliculitis † 1	1/36 (2.78%)	2/35 (5.71%)	0/66 (0.00%)	3/137 (2.19%)
Fungal skin infection † 1	1/36 (2.78%)	2/35 (5.71%)	0/66 (0.00%)	3/137 (2.19%)
Gastroenteritis † 1	4/36 (11.11%)	3/35 (8.57%)	5/66 (7.58%)	12/137 (8.76%)
Gastroenteritis viral † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Hordeolum † 1	0/36 (0.00%)	3/35 (8.57%)	2/66 (3.03%)	5/137 (3.65%)
Influenza † 1	5/36 (13.89%)	8/35 (22.86%)	10/66 (15.15%)	23/137 (16.79%)
Nasopharyngitis † 1	9/36 (25.00%)	11/35 (31.43%)	13/66 (19.70%)	33/137 (24.09%)
Sinusitis † 1	3/36 (8.33%)	1/35 (2.86%)	4/66 (6.06%)	8/137 (5.84%)
Tooth abscess † 1	2/36 (5.56%)	1/35 (2.86%)	0/66 (0.00%)	3/137 (2.19%)
Upper respiratory tract infection † 1	2/36 (5.56%)	5/35 (14.29%)	7/66 (10.61%)	14/137 (10.22%)
Urinary tract infection † 1	6/36 (16.67%)	4/35 (11.43%)	14/66 (21.21%)	24/137 (17.52%)
Injury, poisoning and procedural complications
Contusion † 1	1/36 (2.78%)	2/35 (5.71%)	4/66 (6.06%)	7/137 (5.11%)
Ligament sprain † 1	3/36 (8.33%)	1/35 (2.86%)	1/66 (1.52%)	5/137 (3.65%)
Investigations
11-deoxycortisol increased † 1	3/36 (8.33%)	1/35 (2.86%)	2/66 (3.03%)	6/137 (4.38%)
Activated partial thromboplastin time prolonged † 1	3/36 (8.33%)	1/35 (2.86%)	1/66 (1.52%)	5/137 (3.65%)
Alanine aminotransferase increased † 1	0/36 (0.00%)	0/35 (0.00%)	4/66 (6.06%)	4/137 (2.92%)
Aspartate aminotransferase increased † 1	0/36 (0.00%)	0/35 (0.00%)	4/66 (6.06%)	4/137 (2.92%)
Blood cholesterol increased † 1	2/36 (5.56%)	0/35 (0.00%)	1/66 (1.52%)	3/137 (2.19%)
Blood corticotrophin increased † 1	8/36 (22.22%)	6/35 (17.14%)	14/66 (21.21%)	28/137 (20.44%)
Blood testosterone increased † 1	2/36 (5.56%)	1/35 (2.86%)	13/66 (19.70%)	16/137 (11.68%)
Cortisol decreased † 1	3/36 (8.33%)	0/35 (0.00%)	1/66 (1.52%)	4/137 (2.92%)
Cortisol free urine decreased † 1	8/36 (22.22%)	2/35 (5.71%)	1/66 (1.52%)	11/137 (8.03%)
Cortisol free urine increased † 1	6/36 (16.67%)	1/35 (2.86%)	1/66 (1.52%)	8/137 (5.84%)
Haemoglobin decreased † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Hormone level abnormal † 1	5/36 (13.89%)	1/35 (2.86%)	12/66 (18.18%)	18/137 (13.14%)
Lipase increased † 1	1/36 (2.78%)	2/35 (5.71%)	1/66 (1.52%)	4/137 (2.92%)
Low density lipoprotein increased † 1	2/36 (5.56%)	0/35 (0.00%)	1/66 (1.52%)	3/137 (2.19%)
Renin increased † 1	3/36 (8.33%)	0/35 (0.00%)	3/66 (4.55%)	6/137 (4.38%)
Weight decreased † 1	2/36 (5.56%)	2/35 (5.71%)	5/66 (7.58%)	9/137 (6.57%)
Weight increased † 1	1/36 (2.78%)	2/35 (5.71%)	2/66 (3.03%)	5/137 (3.65%)
Metabolism and nutrition disorders
Decreased appetite † 1	3/36 (8.33%)	7/35 (20.00%)	11/66 (16.67%)	21/137 (15.33%)
Hypercholesterolaemia † 1	1/36 (2.78%)	2/35 (5.71%)	1/66 (1.52%)	4/137 (2.92%)
Hyperglycaemia † 1	2/36 (5.56%)	0/35 (0.00%)	1/66 (1.52%)	3/137 (2.19%)
Hypertriglyceridaemia † 1	2/36 (5.56%)	0/35 (0.00%)	2/66 (3.03%)	4/137 (2.92%)
Hypokalaemia † 1	3/36 (8.33%)	3/35 (8.57%)	11/66 (16.67%)	17/137 (12.41%)
Iron deficiency † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Vitamin D deficiency † 1	3/36 (8.33%)	1/35 (2.86%)	2/66 (3.03%)	6/137 (4.38%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	7/36 (19.44%)	10/35 (28.57%)	12/66 (18.18%)	29/137 (21.17%)
Back pain † 1	9/36 (25.00%)	13/35 (37.14%)	7/66 (10.61%)	29/137 (21.17%)
Limb discomfort † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Muscle spasms † 1	0/36 (0.00%)	2/35 (5.71%)	6/66 (9.09%)	8/137 (5.84%)
Musculoskeletal pain † 1	2/36 (5.56%)	1/35 (2.86%)	3/66 (4.55%)	6/137 (4.38%)
Myalgia † 1	2/36 (5.56%)	7/35 (20.00%)	11/66 (16.67%)	20/137 (14.60%)
Neck pain † 1	2/36 (5.56%)	2/35 (5.71%)	3/66 (4.55%)	7/137 (5.11%)
Osteoarthritis † 1	3/36 (8.33%)	0/35 (0.00%)	1/66 (1.52%)	4/137 (2.92%)
Osteopenia † 1	2/36 (5.56%)	2/35 (5.71%)	1/66 (1.52%)	5/137 (3.65%)
Osteoporosis † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Pain in extremity † 1	2/36 (5.56%)	5/35 (14.29%)	6/66 (9.09%)	13/137 (9.49%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign † 1	2/36 (5.56%)	1/35 (2.86%)	6/66 (9.09%)	9/137 (6.57%)
Nervous system disorders
Amnesia † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Carpal tunnel syndrome † 1	2/36 (5.56%)	1/35 (2.86%)	0/66 (0.00%)	3/137 (2.19%)
Dizziness † 1	5/36 (13.89%)	4/35 (11.43%)	17/66 (25.76%)	26/137 (18.98%)
Headache † 1	11/36 (30.56%)	7/35 (20.00%)	32/66 (48.48%)	50/137 (36.50%)
Hypoaesthesia † 1	1/36 (2.78%)	4/35 (11.43%)	4/66 (6.06%)	9/137 (6.57%)
Memory impairment † 1	2/36 (5.56%)	1/35 (2.86%)	2/66 (3.03%)	5/137 (3.65%)
Migraine † 1	0/36 (0.00%)	1/35 (2.86%)	4/66 (6.06%)	5/137 (3.65%)
Paraesthesia † 1	1/36 (2.78%)	4/35 (11.43%)	0/66 (0.00%)	5/137 (3.65%)
Somnolence † 1	2/36 (5.56%)	0/35 (0.00%)	3/66 (4.55%)	5/137 (3.65%)
Psychiatric disorders
Anxiety † 1	3/36 (8.33%)	2/35 (5.71%)	7/66 (10.61%)	12/137 (8.76%)
Depression † 1	3/36 (8.33%)	3/35 (8.57%)	7/66 (10.61%)	13/137 (9.49%)
Insomnia † 1	4/36 (11.11%)	2/35 (5.71%)	7/66 (10.61%)	13/137 (9.49%)
Irritability † 1	1/36 (2.78%)	1/35 (2.86%)	4/66 (6.06%)	6/137 (4.38%)
Panic attack † 1	0/36 (0.00%)	2/35 (5.71%)	0/66 (0.00%)	2/137 (1.46%)
Sleep disorder † 1	2/36 (5.56%)	0/35 (0.00%)	5/66 (7.58%)	7/137 (5.11%)
Renal and urinary disorders
Nephrolithiasis † 1	1/36 (2.78%)	2/35 (5.71%)	0/66 (0.00%)	3/137 (2.19%)
Reproductive system and breast disorders
Menstruation irregular † 1	0/36 (0.00%)	2/35 (5.71%)	2/66 (3.03%)	4/137 (2.92%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	5/36 (13.89%)	4/35 (11.43%)	10/66 (15.15%)	19/137 (13.87%)
Dyspnoea † 1	1/36 (2.78%)	1/35 (2.86%)	4/66 (6.06%)	6/137 (4.38%)
Nasal congestion † 1	3/36 (8.33%)	0/35 (0.00%)	3/66 (4.55%)	6/137 (4.38%)
Oropharyngeal pain † 1	3/36 (8.33%)	4/35 (11.43%)	7/66 (10.61%)	14/137 (10.22%)
Rhinitis allergic † 1	0/36 (0.00%)	0/35 (0.00%)	4/66 (6.06%)	4/137 (2.92%)
Rhinorrhoea † 1	2/36 (5.56%)	1/35 (2.86%)	4/66 (6.06%)	7/137 (5.11%)
Skin and subcutaneous tissue disorders
Acne † 1	2/36 (5.56%)	2/35 (5.71%)	9/66 (13.64%)	13/137 (9.49%)
Alopecia † 1	0/36 (0.00%)	3/35 (8.57%)	7/66 (10.61%)	10/137 (7.30%)
Dermatitis † 1	0/36 (0.00%)	2/35 (5.71%)	2/66 (3.03%)	4/137 (2.92%)
Dermatitis contact † 1	2/36 (5.56%)	1/35 (2.86%)	2/66 (3.03%)	5/137 (3.65%)
Dry skin † 1	0/36 (0.00%)	3/35 (8.57%)	7/66 (10.61%)	10/137 (7.30%)
Eczema † 1	1/36 (2.78%)	2/35 (5.71%)	2/66 (3.03%)	5/137 (3.65%)
Hirsutism † 1	4/36 (11.11%)	3/35 (8.57%)	5/66 (7.58%)	12/137 (8.76%)
Hyperhidrosis † 1	3/36 (8.33%)	3/35 (8.57%)	3/66 (4.55%)	9/137 (6.57%)
Onychoclasis † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
Pruritus † 1	5/36 (13.89%)	1/35 (2.86%)	7/66 (10.61%)	13/137 (9.49%)
Rash † 1	8/36 (22.22%)	3/35 (8.57%)	10/66 (15.15%)	21/137 (15.33%)
Skin hyperpigmentation † 1	1/36 (2.78%)	1/35 (2.86%)	4/66 (6.06%)	6/137 (4.38%)
Skin lesion † 1	3/36 (8.33%)	0/35 (0.00%)	1/66 (1.52%)	4/137 (2.92%)
Urticaria † 1	2/36 (5.56%)	0/35 (0.00%)	2/66 (3.03%)	4/137 (2.92%)
Vascular disorders
Hypertension † 1	5/36 (13.89%)	5/35 (14.29%)	14/66 (21.21%)	24/137 (17.52%)
Hypotension † 1	7/36 (19.44%)	3/35 (8.57%)	3/66 (4.55%)	13/137 (9.49%)
Varicose vein † 1	2/36 (5.56%)	0/35 (0.00%)	0/66 (0.00%)	2/137 (1.46%)
1 Term from vocabulary, MedDRA (22.1); † Indicates events were collected by systematic assessment

Limitations and Caveats

The first 12 weeks of the study consisted of an individual dose-titration period.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e. data from all sites) in clinical trial or disclosure of trial results in their entirety.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300
• EMail: novartis.email@novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fontaine-Sylvestre C, Letourneau-Guillon L, Moumdjian RA, Berthelet F, Lacroix A. Corticotroph tumor progression during long-term therapy with osilodrostat in a patient with persistent Cushing's disease. Pituitary. 2021 Apr;24(2):207-215. doi: 10.1007/s11102-020-01097-1. Epub 2020 Oct 19.

Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, Gu F, Auchus R, Leelawattana R, Lee EJ, Kim JH, Lacroix A, Laplanche A, O'Connell P, Tauchmanova L, Pedroncelli AM, Biller BMK; LINC 3 investigators. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020 Sep;8(9):748-761. doi: 10.1016/S2213-8587(20)30240-0. Epub 2020 Jul 27. Erratum In: Lancet Diabetes Endocrinol. 2020 Aug 5;:

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT02180217
• Other Study ID Numbers: CLCI699C2301; 2013-004766-34 ( EudraCT Number )
• First Submitted: June 17, 2014
• First Posted: July 2, 2014
• Results First Submitted: April 3, 2020
• Results First Posted: June 16, 2020
• Last Update Posted: January 6, 2021