Trial Outcomes & Findings for Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease (NCT NCT02180217)

Last Updated: 2021-01-06

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

137 participants

Primary outcome timeframe

Week 34 (8 weeks)

Results posted on

2021-01-06

Participant Flow

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

Participant milestones

Participant milestones
Measure	Osilodrostat (LCI699) Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized All participants in this group took open label osilodrostat, before and after randomization.
Overall Study STARTED	36	35	66
Overall Study Discontinued at/Prior to Week 12 (W12)	0	0	7
Overall Study Discont. at/Prior to W26 But After W12	0	0	12
Overall Study Discontinued Prior to W48 But After W26	0	2	3
Overall Study Completed Week 48 (Core Phase)	36	33	44
Overall Study Completed W48, Did Not Enter Ext. Phase	1	3	3
Overall Study Completed W48, Entered Ext. Phase	35	30	41
Overall Study Discontinued Extension Phase	12	6	16
Overall Study Completed Ext. Phase	23	24	25
Overall Study COMPLETED	24	27	28
Overall Study NOT COMPLETED	12	8	38

Reasons for withdrawal

Reasons for withdrawal
Measure	Osilodrostat (LCI699) Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized All participants in this group took open label osilodrostat, before and after randomization.
Overall Study Adverse Event	3	2	22
Overall Study Death	1	1	0
Overall Study Withdrawal by Subject	1	1	4
Overall Study Subject/Guardian decision	5	3	6
Overall Study Physician Decision	1	1	6
Overall Study Unsatisfactory therapeutic effect	1	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Total n=137 Participants Total of all reporting groups
Age, Continuous	44.3 years STANDARD_DEVIATION 11.27 • n=5 Participants	42.0 years STANDARD_DEVIATION 13.47 • n=7 Participants	39.0 years STANDARD_DEVIATION 13.38 • n=5 Participants	41.2 years STANDARD_DEVIATION 12.98 • n=4 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	22 Participants n=7 Participants	54 Participants n=5 Participants	106 Participants n=4 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	13 Participants n=7 Participants	12 Participants n=5 Participants	31 Participants n=4 Participants
Race/Ethnicity, Customized Caucasian	27 Participants n=5 Participants	23 Participants n=7 Participants	39 Participants n=5 Participants	89 Participants n=4 Participants
Race/Ethnicity, Customized Black	0 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Race/Ethnicity, Customized Asian	7 Participants n=5 Participants	7 Participants n=7 Participants	25 Participants n=5 Participants	39 Participants n=4 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 34 (8 weeks)

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

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=34 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata	86.1 Percentage of participants	29.4 Percentage of participants	—	—

SECONDARY outcome

Timeframe: Week 24

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

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.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=137 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)	52.6 Percentage of participants Interval 43.9 to 61.1	—	—	—

SECONDARY outcome

Timeframe: 8 weeks after randomization

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

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.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=34 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group	5.6 Percentage Interval 1.4 to 20.4	61.1 Percentage Interval 45.0 to 77.5	—	—

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Complete Response Rate (CRR) Week 12	86.1 Percentage of participants	91.4 Percentage of participants	53.0 Percentage of participants	—
Complete Response Rate (CRR) Week 24	100.0 Percentage of participants	97.1 Percentage of participants	34.8 Percentage of participants	—
Complete Response Rate (CRR) Week 48	88.9 Percentage of participants	77.1 Percentage of participants	48.5 Percentage of participants	—
Complete Response Rate (CRR) Week 72	82.9 Percentage of participants	83.3 Percentage of participants	78.0 Percentage of participants	—
Complete Response Rate (CRR) Last observed value	69.4 Percentage of participants	74.3 Percentage of participants	53.0 Percentage of participants	—

SECONDARY outcome

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

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

Actual change in mUFC from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in mUFC Actual Baseline (BL)	890.0 nmol/24h Standard Deviation 1275.66	560.0 nmol/24h Standard Deviation 548.84	1305.8 nmol/24h Standard Deviation 2012.21	—
Actual Change From Baseline in mUFC Wk 12: Act. change from BL	-848.4 nmol/24h Standard Deviation 1335.66	-510.3 nmol/24h Standard Deviation 556.84	-1021.3 nmol/24h Standard Deviation 1825.55	—
Actual Change From Baseline in mUFC Wk 24: Act. change from BL	-821.2 nmol/24h Standard Deviation 1283.03	-485.5 nmol/24h Standard Deviation 558.99	-930.3 nmol/24h Standard Deviation 1778.04	—
Actual Change From Baseline in mUFC Wk 48: Act. change from BL	-708.2 nmol/24h Standard Deviation 983.14	-477.1 nmol/24h Standard Deviation 529.04	-1189.9 nmol/24h Standard Deviation 2042.48	—
Actual Change From Baseline in mUFC Wk 72: Act. change from BL	-680.7 nmol/24h Standard Deviation 1003.63	-536.7 nmol/24h Standard Deviation 585.78	-826.7 nmol/24h Standard Deviation 1684.92	—
Actual Change From Baseline in mUFC Last avail. assess.: Act. change from BL	-795.2 nmol/24h Standard Deviation 1286.22	-387.3 nmol/24h Standard Deviation 605.63	-893.4 nmol/24h Standard Deviation 1969.56	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48, 72, last available assessment

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

Actual change in fasting glucose from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose Baseline	102.7 mg/dL Standard Deviation 35.23	90.5 mg/dL Standard Deviation 18.53	101.8 mg/dL Standard Deviation 31.00	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose Wk 48	-7.9 mg/dL Standard Deviation 32.24	-5.5 mg/dL Standard Deviation 12.13	-14.1 mg/dL Standard Deviation 22.66	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose Wk 72	-0.5 mg/dL Standard Deviation 16.84	-4.4 mg/dL Standard Deviation 15.13	-10.8 mg/dL Standard Deviation 24.02	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose Last avail. assessment	-8.6 mg/dL Standard Deviation 37.05	-0.6 mg/dL Standard Deviation 21.00	-15.6 mg/dL Standard Deviation 26.62	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48, 72, last available assessment

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

Actual change in glycosylated hemoglobin (HbA1c) from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) Baseline	6.1 percentage Standard Deviation 0.98	5.8 percentage Standard Deviation 0.93	6.0 percentage Standard Deviation 0.97	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) Wk 48	-0.3 percentage Standard Deviation 0.86	-0.4 percentage Standard Deviation 0.56	-0.4 percentage Standard Deviation 0.65	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) Wk 72	-0.4 percentage Standard Deviation 0.66	-0.4 percentage Standard Deviation 0.47	-0.4 percentage Standard Deviation 0.64	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) Last avail. assessment	-0.3 percentage Standard Deviation 0.78	-0.2 percentage Standard Deviation 0.47	-0.3 percentage Standard Deviation 0.68	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48, 72, last available assessment

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

Actual change in Cholesterol, LDL Cholesterol, HDL Cholesterol \& Triglyceride from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Cholesterol: BL	5.5 mmol/L Standard Deviation 1.22	5.3 mmol/L Standard Deviation 0.90	5.1 mmol/L Standard Deviation 1.24	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Cholesterol: Wk 48	-0.7 mmol/L Standard Deviation 0.87	-0.4 mmol/L Standard Deviation 0.89	-0.5 mmol/L Standard Deviation 0.90	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Cholesterol: Wk 72	-0.4 mmol/L Standard Deviation 0.96	-0.3 mmol/L Standard Deviation 0.75	-0.4 mmol/L Standard Deviation 0.98	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Cholesterol: Last avail. assessment	-0.3 mmol/L Standard Deviation 1.16	-0.3 mmol/L Standard Deviation 1.03	-0.4 mmol/L Standard Deviation 1.15	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride LDL Cholesterol: BL	3.2 mmol/L Standard Deviation 1.09	3.1 mmol/L Standard Deviation 0.77	2.9 mmol/L Standard Deviation 0.94	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride LDL Cholesterol: Wk 48	-0.3 mmol/L Standard Deviation 0.75	-0.2 mmol/L Standard Deviation 0.74	-0.1 mmol/L Standard Deviation 0.82	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride LDL Cholesterol: Wk 72	-0.2 mmol/L Standard Deviation 0.77	-0.2 mmol/L Standard Deviation 0.66	-0.1 mmol/L Standard Deviation 0.86	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride LDL Cholesterol: Last avail asses	-0.1 mmol/L Standard Deviation 0.98	-0.2 mmol/L Standard Deviation 0.88	-0.1 mmol/L Standard Deviation 0.99	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride HDL Cholesterol: BL	1.7 mmol/L Standard Deviation 0.55	1.5 mmol/L Standard Deviation 0.36	1.6 mmol/L Standard Deviation 0.42	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride HDL Cholesterol: Wk 48	-0.3 mmol/L Standard Deviation 0.39	-0.2 mmol/L Standard Deviation 0.17	-0.3 mmol/L Standard Deviation 0.28	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride HDL Cholesterol: Wk 72	-0.2 mmol/L Standard Deviation 0.39	-0.2 mmol/L Standard Deviation 0.27	-0.3 mmol/L Standard Deviation 0.28	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride HDL Cholesterol: Last avail assess	-0.2 mmol/L Standard Deviation 0.40	-0.1 mmol/L Standard Deviation 0.27	-0.2 mmol/L Standard Deviation 0.34	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Triglyceride: BL	1.5 mmol/L Standard Deviation 0.78	1.4 mmol/L Standard Deviation 0.62	1.6 mmol/L Standard Deviation 1.74	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Triglyceride: Wk 48	-0.1 mmol/L Standard Deviation 0.49	0.0 mmol/L Standard Deviation 0.54	0.0 mmol/L Standard Deviation 1.22	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Triglyceride: Wk 72	0.0 mmol/L Standard Deviation 0.57	-0.1 mmol/L Standard Deviation 0.67	0.0 mmol/L Standard Deviation 0.60	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride Triglyceride: Last avail. assess	0.0 mmol/L Standard Deviation 0.64	-0.1 mmol/L Standard Deviation 0.75	0.1 mmol/L Standard Deviation 1.48	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48, 72, last available assessment

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

Actual change in sitting SBP \& DBP from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) SBP: Baseline	132.2 mmHg Standard Deviation 15.44	128.8 mmHg Standard Deviation 11.93	134.0 mmHg Standard Deviation 16.34	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) SBP: Wk 48	-15.2 mmHg Standard Deviation 17.00	-4.8 mmHg Standard Deviation 12.28	-9.2 mmHg Standard Deviation 15.48	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) SBP: Wk 72	-12.2 mmHg Standard Deviation 15.90	-8.2 mmHg Standard Deviation 19.41	-9.4 mmHg Standard Deviation 19.08	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) SBP: Last avail. assessment	-8.2 mmHg Standard Deviation 15.25	-4.6 mmHg Standard Deviation 15.20	-10.8 mmHg Standard Deviation 15.31	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) DBP: Baseline	85.3 mmHg Standard Deviation 11.38	85.0 mmHg Standard Deviation 10.03	85.4 mmHg Standard Deviation 10.53	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) DBP: Wk 48	-7.8 mmHg Standard Deviation 11.63	-5.1 mmHg Standard Deviation 9.66	-6.0 mmHg Standard Deviation 11.79	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) DBP: Wk 72	-5.9 mmHg Standard Deviation 11.17	-7.0 mmHg Standard Deviation 10.33	-4.8 mmHg Standard Deviation 12.26	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) DBP: Last avail. assessment	-3.4 mmHg Standard Deviation 11.79	-3.5 mmHg Standard Deviation 11.50	-5.0 mmHg Standard Deviation 10.45	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48, 72, last available assessment

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

Actual change in weight from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight Baseline	78.2 kg Standard Deviation 19.02	83.4 kg Standard Deviation 24.73	80.7 kg Standard Deviation 23.06	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight Wk 48	-3.4 kg Standard Deviation 5.64	-3.9 kg Standard Deviation 5.77	-4.0 kg Standard Deviation 5.82	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight Wk 72	-3.7 kg Standard Deviation 6.93	-5.0 kg Standard Deviation 6.03	-5.6 kg Standard Deviation 6.75	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight Last avail. assessment	-2.9 kg Standard Deviation 8.28	-3.7 kg Standard Deviation 11.13	-4.2 kg Standard Deviation 6.35	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48, 72, last available assessment

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

Actual change in BMI from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) Baseline	29.6 kg/m^2 Standard Deviation 7.36	30.9 kg/m^2 Standard Deviation 8.38	30.4 kg/m^2 Standard Deviation 7.74	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) Wk 48	-1.3 kg/m^2 Standard Deviation 2.22	-1.5 kg/m^2 Standard Deviation 2.12	-1.5 kg/m^2 Standard Deviation 2.17	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) Wk 72	-1.4 kg/m^2 Standard Deviation 2.79	-1.8 kg/m^2 Standard Deviation 2.14	-2.0 kg/m^2 Standard Deviation 2.55	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) Last avail. assessment	-1.2 kg/m^2 Standard Deviation 3.34	-1.5 kg/m^2 Standard Deviation 3.94	-1.6 kg/m^2 Standard Deviation 2.41	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48, 72, last available assessment

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

Actual change in waist circumference from baseline.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference Baseline	100.5 cm Standard Deviation 16.81	103.7 cm Standard Deviation 18.26	105.0 cm Standard Deviation 21.15	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference Wk 48	-5.1 cm Standard Deviation 6.26	-4.2 cm Standard Deviation 10.12	-4.7 cm Standard Deviation 7.07	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference Wk 72	-5.1 cm Standard Deviation 7.18	-6.1 cm Standard Deviation 9.86	-7.4 cm Standard Deviation 8.53	—
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference Last avail. assessment	-4.7 cm Standard Deviation 10.05	-5.2 cm Standard Deviation 12.24	-6.2 cm Standard Deviation 9.96	—

SECONDARY outcome

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

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

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.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score Baseline	44.4 scores on a scale Standard Deviation 18.33	43.2 scores on a scale Standard Deviation 22.45	40.5 scores on a scale Standard Deviation 17.61	—
Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score Week 48	16.1 scores on a scale Standard Deviation 15.15	10.2 scores on a scale Standard Deviation 16.57	13.2 scores on a scale Standard Deviation 17.79	—
Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score Week 72	15.8 scores on a scale Standard Deviation 16.08	12.6 scores on a scale Standard Deviation 20.68	16.3 scores on a scale Standard Deviation 21.31	—
Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score Last available assess.	16.1 scores on a scale Standard Deviation 15.99	11.8 scores on a scale Standard Deviation 20.51	12.9 scores on a scale Standard Deviation 18.91	—

SECONDARY outcome

Timeframe: Baseline, W48, W72, Last available assessment

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

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.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) Baseline	15.1 scores on a a scale Standard Deviation 11.14	17.8 scores on a a scale Standard Deviation 9.93	17.3 scores on a a scale Standard Deviation 10.67	—
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) W48	-4.8 scores on a a scale Standard Deviation 9.84	-5.3 scores on a a scale Standard Deviation 7.99	-7.0 scores on a a scale Standard Deviation 10.17	—
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) W72	-6.0 scores on a a scale Standard Deviation 9.55	-4.6 scores on a a scale Standard Deviation 9.41	-9.0 scores on a a scale Standard Deviation 12.34	—
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) Last avail. assess.	-6.2 scores on a a scale Standard Deviation 9.93	-5.0 scores on a a scale Standard Deviation 9.49	-4.9 scores on a a scale Standard Deviation 10.66	—

SECONDARY outcome

Timeframe: Baseline, W48, W72, Last available assessment

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

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.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index Baseline	0.7 Scores on a scale Standard Deviation 0.24	0.7 Scores on a scale Standard Deviation 0.24	0.7 Scores on a scale Standard Deviation 0.28	—
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index Week 48	0.1 Scores on a scale Standard Deviation 0.18	0 Scores on a scale Standard Deviation 0.25	0.1 Scores on a scale Standard Deviation 0.18	—
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index Week 72	0.1 Scores on a scale Standard Deviation 0.18	0.1 Scores on a scale Standard Deviation 0.26	0.1 Scores on a scale Standard Deviation 0.19	—
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index Last avail. assess.	0.1 Scores on a scale Standard Deviation 0.22	0 Scores on a scale Standard Deviation 0.28	0.1 Scores on a scale Standard Deviation 0.23	—

SECONDARY outcome

Timeframe: Baseline, W48, W72, Last available assessment

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

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.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) Baseline	61.3 Scores on a scale Standard Deviation 18.97	64.2 Scores on a scale Standard Deviation 16.37	60.8 Scores on a scale Standard Deviation 21.09	—
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) Week 48	12.6 Scores on a scale Standard Deviation 20.64	6.9 Scores on a scale Standard Deviation 12.56	9.7 Scores on a scale Standard Deviation 17.16	—
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) Week 72	11.2 Scores on a scale Standard Deviation 18.98	6.6 Scores on a scale Standard Deviation 15.47	10.1 Scores on a scale Standard Deviation 19.80	—
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) Last avail. assess.	12.1 Scores on a scale Standard Deviation 19.71	6.4 Scores on a scale Standard Deviation 18.65	6.2 Scores on a scale Standard Deviation 20.42	—

SECONDARY outcome

Timeframe: Week 48, Week 72, Last available assessment

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

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).

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Change From Baseline in the Physical Features of Cushing's Disease by Photography W72: Dorsal fat pad	69.0 Percentage of participants Interval 49.2 to 84.7	48.1 Percentage of participants Interval 28.7 to 68.1	53.3 Percentage of participants Interval 34.3 to 71.7	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W72: Proximal muscle atrophy	31.0 Percentage of participants Interval 15.3 to 50.8	25.9 Percentage of participants Interval 11.1 to 46.3	46.7 Percentage of participants Interval 28.3 to 65.7	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W48: Facial rubor	50.0 Percentage of participants Interval 31.3 to 68.7	46.7 Percentage of participants Interval 28.3 to 65.7	43.2 Percentage of participants Interval 27.1 to 60.5	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W48: Striae	30.0 Percentage of participants Interval 14.7 to 49.4	23.3 Percentage of participants Interval 9.9 to 42.3	40.5 Percentage of participants Interval 24.8 to 57.9	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W48:Supraclavicular fat pad	56.7 Percentage of participants Interval 37.4 to 74.5	43.3 Percentage of participants Interval 25.5 to 62.6	54.1 Percentage of participants Interval 36.9 to 70.5	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W48: Dorsal fat pad	60.0 Percentage of participants Interval 40.6 to 77.3	40.0 Percentage of participants Interval 22.7 to 59.4	56.8 Percentage of participants Interval 39.5 to 72.9	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W48: Proximal muscle atrophy	40.0 Percentage of participants Interval 22.7 to 59.4	26.7 Percentage of participants Interval 12.3 to 45.9	45.9 Percentage of participants Interval 29.5 to 63.1	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W48: Central obesity	43.3 Percentage of participants Interval 25.5 to 62.6	30.0 Percentage of participants Interval 14.7 to 49.4	51.4 Percentage of participants Interval 34.4 to 68.1	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W48: Ecchymoses	33.3 Percentage of participants Interval 17.3 to 52.8	26.7 Percentage of participants Interval 12.3 to 45.9	43.2 Percentage of participants Interval 27.1 to 60.5	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W72: Facial rubor	48.3 Percentage of participants Interval 29.4 to 67.5	55.6 Percentage of participants Interval 35.3 to 74.5	53.3 Percentage of participants Interval 34.3 to 71.7	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W72: Striae	27.6 Percentage of participants Interval 12.7 to 47.2	25.9 Percentage of participants Interval 11.1 to 46.3	36.7 Percentage of participants Interval 19.9 to 56.1	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W72:Supraclavicular fat pad	55.2 Percentage of participants Interval 35.7 to 73.6	51.9 Percentage of participants Interval 31.9 to 71.3	53.3 Percentage of participants Interval 34.3 to 71.1	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W72: Central obesity	37.9 Percentage of participants Interval 20.7 to 57.7	37.0 Percentage of participants Interval 19.4 to 57.6	43.3 Percentage of participants Interval 25.5 to 62.6	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography W72: Ecchymoses	27.6 Percentage of participants Interval 12.7 to 47.2	29.6 Percentage of participants Interval 13.8 to 50.2	36.7 Percentage of participants Interval 19.9 to 56.1	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography End of Trial (EOT):Facial rubor	60.0 Percentage of participants Interval 38.7 to 78.9	56.5 Percentage of participants Interval 34.5 to 76.8	53.8 Percentage of participants Interval 33.4 to 73.4	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography EOT: Striae	32.0 Percentage of participants Interval 14.9 to 53.5	34.8 Percentage of participants Interval 16.4 to 57.3	30.8 Percentage of participants Interval 14.3 to 51.8	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography EOT:Supraclavicular fat pad	52.0 Percentage of participants Interval 31.3 to 72.2	43.5 Percentage of participants Interval 23.2 to 65.5	42.3 Percentage of participants Interval 23.4 to 63.1	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography EOT: Dorsal fat pad	56.0 Percentage of participants Interval 34.9 to 75.6	52.2 Percentage of participants Interval 30.6 to 73.2	46.2 Percentage of participants Interval 26.6 to 66.6	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography EOT: Proximal muscle atrophy	36.0 Percentage of participants Interval 18.0 to 57.5	21.7 Percentage of participants Interval 7.5 to 43.7	50.0 Percentage of participants Interval 29.9 to 70.1	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography EOT: Central obesity	40.0 Percentage of participants Interval 21.1 to 61.3	39.1 Percentage of participants Interval 19.7 to 61.5	38.5 Percentage of participants Interval 20.0 to 59.4	—
Change From Baseline in the Physical Features of Cushing's Disease by Photography EOT: Ecchymoses	28.0 Percentage of participants Interval 12.1 to 49.4	39.1 Percentage of participants Interval 19.7 to 61.5	38.5 Percentage of participants Interval 20.2 to 59.4	—

SECONDARY outcome

Timeframe: Baseline, Week 48, Last observed value (LOV)

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

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..

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Change From Baseline in Bone Mineral Density - All Participants Baseline (L1-L4 Lumbar Spine)	1.0 g/cm2 Standard Error 0.20	1.0 g/cm2 Standard Error 0.17	1.0 g/cm2 Standard Error 0.18	—
Change From Baseline in Bone Mineral Density - All Participants W48 (L1-L4 Lumbar Spine)	1.0 g/cm2 Standard Error 0.19	1.0 g/cm2 Standard Error 0.17	1.0 g/cm2 Standard Error 0.19	—
Change From Baseline in Bone Mineral Density - All Participants LOV (L1-L4 Lumbar Spine)	1.0 g/cm2 Standard Error 0.20	1.0 g/cm2 Standard Error 0.18	1.0 g/cm2 Standard Error 0.18	—
Change From Baseline in Bone Mineral Density - All Participants Baseline (Total Hip)	0.9 g/cm2 Standard Error 0.18	0.8 g/cm2 Standard Error 0.15	0.9 g/cm2 Standard Error 0.16	—
Change From Baseline in Bone Mineral Density - All Participants W48 (Total Hip)	0.9 g/cm2 Standard Error 0.17	0.8 g/cm2 Standard Error 0.14	0.9 g/cm2 Standard Error 0.16	—
Change From Baseline in Bone Mineral Density - All Participants LOV (Total Hip)	0.9 g/cm2 Standard Error 0.17	0.8 g/cm2 Standard Error 0.13	0.9 g/cm2 Standard Error 0.16	—

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=97 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Time-to-escape	546.0 days Interval 212.0 to 968.0	—	—	—

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Percentage of Participants With Complete Response Rate (CRR) Week 12	6.1 Percentage of participants	91.4 Percentage of participants	53.0 Percentage of participants	—
Percentage of Participants With Complete Response Rate (CRR) Week 24	100 Percentage of participants	97.1 Percentage of participants	34.8 Percentage of participants	—
Percentage of Participants With Complete Response Rate (CRR) Week 48	88.9 Percentage of participants	77.1 Percentage of participants	48.5 Percentage of participants	—
Percentage of Participants With Complete Response Rate (CRR) Week 72	82.9 Percentage of participants	83.3 Percentage of participants	78.0 Percentage of participants	—
Percentage of Participants With Complete Response Rate (CRR) Last available assess.	69.4 Percentage of participants	74.3 Percentage of participants	53.0 Percentage of participants	—

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Percentage of Participants With Partial Response Rate (PRR) Week 72	8.6 Percentage of participants	13.3 Percentage of participants	2.4 Percentage of participants	—
Percentage of Participants With Partial Response Rate (PRR) Week 12	2.8 Percentage of participants	5.7 Percentage of participants	24.2 Percentage of participants	—
Percentage of Participants With Partial Response Rate (PRR) Week 24	0.0 Percentage of participants	0.0 Percentage of participants	30.3 Percentage of participants	—
Percentage of Participants With Partial Response Rate (PRR) Week 48	5.6 Percentage of participants	11.4 Percentage of participants	10.6 Percentage of participants	—
Percentage of Participants With Partial Response Rate (PRR) Last available assess.	22.2 Percentage of participants	11.4 Percentage of participants	22.7 Percentage of participants	—

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Osilodrostat (LCI699) n=36 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=35 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=66 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg Participants received 7 mg of osilodrostat
Percentage of Participants With Overall Response Rate (ORR) Week 12	88.9 Percentage of participants	97.1 Percentage of participants	77.3 Percentage of participants	—
Percentage of Participants With Overall Response Rate (ORR) Week 24	100 Percentage of participants	97.1 Percentage of participants	65.2 Percentage of participants	—
Percentage of Participants With Overall Response Rate (ORR) Week 48	94.4 Percentage of participants	88.6 Percentage of participants	59.1 Percentage of participants	—
Percentage of Participants With Overall Response Rate (ORR) Week 72	91.4 Percentage of participants	96.7 Percentage of participants	80.5 Percentage of participants	—
Percentage of Participants With Overall Response Rate (ORR) Last available assess.	91.7 Percentage of participants	85.7 Percentage of participants	75.8 Percentage of participants	—

Adverse Events

Osilodrostat

Serious events: 13 serious events

Other events: 34 other events

Deaths: 1 deaths

LCI699 Placebo

Serious events: 10 serious events

Other events: 35 other events

Deaths: 1 deaths

Non-randomized

Serious events: 32 serious events

Other events: 65 other events

Deaths: 0 deaths

All Participants

Serious events: 55 serious events

Other events: 134 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Osilodrostat (LCI699) n=132 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.	LCI699 Placebo n=39 Participants Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.	Non-randomized n=105 Participants All participants in this group took open label osilodrostat, before and after randomization.	Osilodrostat (LCI699) 7 mg n=24 Participants Participants received 7 mg of osilodrostat
LCI699 Exposures Week (Wk) 2: Predose	1.904 ng/ml Geometric Coefficient of Variation 110.4	—	—	—
LCI699 Exposures Wk 2: 0.75h	1.907 ng/ml Geometric Coefficient of Variation 132.5	—	—	—
LCI699 Exposures Wk 2: 1.5h	5.1 ng/ml Geometric Coefficient of Variation 62.7	—	—	—
LCI699 Exposures Wk 2: 4h	5.818 ng/ml Geometric Coefficient of Variation 66.3	—	—	—
LCI699 Exposures Wk 4: Predose	2.104 ng/ml Geometric Coefficient of Variation 108.0	2.898 ng/ml Geometric Coefficient of Variation 109.1	3.584 ng/ml Geometric Coefficient of Variation 126.3	—
LCI699 Exposures Wk 4: 0.75h	0.859 ng/ml Geometric Coefficient of Variation 254.3	—	7.091 ng/ml Geometric Coefficient of Variation 137.8	—
LCI699 Exposures Wk 4: 1.5h	8.737 ng/ml Geometric Coefficient of Variation 3.6	—	24.2 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	—
LCI699 Exposures Wk 4: 4h	8.930 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	—	15.985 ng/ml Geometric Coefficient of Variation 48.3	—
LCI699 Exposures Wk 6: Predose	2.037 ng/ml Geometric Coefficient of Variation 63.5	2.392 ng/ml Geometric Coefficient of Variation 285.6	5.087 ng/ml Geometric Coefficient of Variation 122.9	8.065 ng/ml Geometric Coefficient of Variation 8.6
LCI699 Exposures Wk 6: 0.75h	3.110 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	—	5.223 ng/ml Geometric Coefficient of Variation 229.4	—
LCI699 Exposures Wk 6: 1.5h	—	22.4 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	21.4 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	—
LCI699 Exposures Wk 6: 4h	8.380 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	18.6 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	18.373 ng/ml Geometric Coefficient of Variation 36.5	—
LCI699 Exposures Wk 8: Predose	2.198 ng/ml Geometric Coefficient of Variation 108.9	4.061 ng/ml Geometric Coefficient of Variation 67.4	4.487 ng/ml Geometric Coefficient of Variation 106.9	6.718 ng/ml Geometric Coefficient of Variation 34.2
LCI699 Exposures Wk 8: 1.5h	10.8 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	20.4 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	—	32.1 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient.
LCI699 Exposures Wk 8: 4h	6.65 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	—	—	32 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient.
LCI699 Exposures Wk 10: Predose	1.862 ng/ml Geometric Coefficient of Variation 128.9	3.007 ng/ml Geometric Coefficient of Variation 64.8	4.704 ng/ml Geometric Coefficient of Variation 106.8	5.451 ng/ml Geometric Coefficient of Variation 93.1
LCI699 Exposures Wk 10: 0.75h	—	6.7 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient.	—	17.1 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient.
LCI699 Exposures Wk 10: 1.5h	12.1 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	18.3 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	34.2 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	—
LCI699 Exposures Wk 10: 4h	—	15.8 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	27.2 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient	35.5 ng/ml Geometric Coefficient of Variation NA NA: CV% geo-mean could not be calculated with just 1 patient