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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02180217
• Collaborator: (none)
• Enrollment: 137
• Locations: 60
• Arms: 2
• Actual Duration (Months): 61.9
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The study aimed to confirm long-term efficacy and safety of LCI699 for the treatment of patients with Cushing's disease. It was a pivotal trial which supported the registration of LCI699 for the treatment of patients with Cushing's disease in the US and the EU.

This is a phase lll, multi-center, double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period which evaluated the safety and efficacy of LCI699 for the treatment of patients with Cushing's disease.

Condition or Disease	Intervention/Treatment	Phase
Cushings Disease	Drug: osilodrostat; Drug: LCI699 matching placebo	Phase 3

Detailed Description

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

placebo. The key secondary objective assessed the complete response rate at the end of individual dose titration and treatment with osilodrostat in the initial single-arm, open label period (Week 24).

Eligible patients were randomized in a double-blinded fashion at Week 26 at a 1:1 ratio either to continue treatment with osilodrostat at the same dose or to matching placebo. Randomization was stratified by osilodrostat dose at Week 24 (≤ 5mg bid vs. >5mg bid); and history of pituitary irradiation (yes/no).

The study had four periods combined in the Core Period (Study Period 1 to 4) and an optional Extension Period. The optional Extension Period starting at Week 48.

Study Period 1 consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients (Week 1 to Week 12). Dose adjustments were based on the mean of three 24-hour UFC (mUFC) values as measured by the central laboratory.

During study Period 2 (Week 13 to Week 24), osilodrostat efficacy and safety were assessed at the therapeutic dose determined during study Period 1. Patients whose mUFC became elevated during this period had their osilodrostat dose increased further, if it was tolerated, up to 30 mg bid. Such patients were followed for long-term safety and efficacy and were not considered responders for the key secondary endpoint, hence were not randomized in Study Period 3.

Study Period 3 was a double-blind, placebo-controlled randomized withdrawal (RW) Period (Week 26 to Week 34). In order to be eligible for randomization in study Period 3, patients had to have completed dose titration during study Period 1, and had to be classified as complete responders at Week 24 of study Period 2. Patients not eligible for randomization received open-label osilodrostat until the end of the Core Period (Week 48), unless there was a reason to discontinue from the study prematurely.

During study Period 3, mUFC was measured at scheduled visits every 2 weeks. However, patients were also allowed to have unscheduled visits at any time during the RW if they reported symptoms of hypercortisolism or hypocortisolism.

The dose of study drug remained unchanged for patients who maintained a normal mUFC and did not develop adverse events (AEs) related to study drug during RW. The Investigator could reduce or temporally withhold a dose of study drug for safety reasons at any time during the study, including the RW Period.

During this study period, a patient was discontinued from the RW Period and declared a nonresponder, if the mUFC increased to >1.5×ULN. After discontinuation from RW treatment, or at the end of the RW Period (Week 34), whichever came first, the patient resumed open-label osilodrostat at a dose selected by the Investigator.

Patients who discontinued from the study during the RW Period were no longer in the study, and consequently were not permitted to receive open-label osilodrostat and could not move to study Period 4.

Patients who discontinued from RW treatment due to lack of efficacy resumed open-label osilodrostat at the time of discontinuation, which could occur before Week 34. Patients who were not discontinued during RW resumed open-label osilodrostat at the end of RW (Week 34) and continued osilodrostat thereafter (study Period 4).

The Novartis study team, the patient, the Investigator, and all other site staff remained blinded to treatment assignment from the time of randomization to the time of database lock at the end of the Core Period. Novartis Drug Supply Management department members were unblinded in order to prepare the study drug supplies.

Study Period 4 was a single-arm, open-label therapy (end of Week 34 to Week 48). At the end of Week 34, all patients received open-label osilodrostat treatment. The Investigator had the discretion to select the dose during this period.

Patients continued open-label therapy until Week 48. At Week 48, patients had the option to enter an Extension Period, or discontinue osilodrostat at Week 48 to conclude with an end of Core Period visit 4 weeks off study drug (at Week 52).

Patients who continued to receive clinical benefit, as assessed by the study Investigator, and who wished to enter the Extension Period were re-consented at Week 48. Patients entered the Extension period without interruption of study drug or assessments. At the end of the study, patients who continued to benefit from treatment were offered to participate in a separate long-term safety follow-up study. The optional Extension Period ended after all patients completed Week 72 or discontinued early.

Study Design

• Study Type: Interventional
• Actual Enrollment: 137 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: It is a double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period.It is a double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase III, Multi-center, Double-blind, Randomized Withdrawal Study of LCI699 Following a 24 Week, Single-arm, Open-label Dose Titration and Treatment Period to Evaluate the Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease
• Actual Study Start Date: Oct 6, 2014
• Actual Primary Completion Date: Feb 21, 2018
• Actual Study Completion Date: Dec 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: osilodrostat; Osilodrostat comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat was 30 mg bid.; Other Names: LCI699
Placebo Comparator: 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.	Drug: LCI699 matching placebo; Osilodrostat placebo comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat placebo was 30 mg bid.

Outcome Measures

Primary Outcome Measures

1. Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata [Week 34 (8 weeks)]

   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

Secondary Outcome Measures

1. Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint) [Week 24]

   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.

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

   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.

3. Complete Response Rate (CRR) [Week 12, Week 24, Week 48, Week 72, last observed value]

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

4. Actual Change From Baseline in mUFC [Weeks 12, 24, 48, 72, last available assessment]

   Actual change in mUFC from baseline.

5. Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose [Baseline, Weeks 48, 72, last available assessment]

   Actual change in fasting glucose from baseline.

6. Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C) [Baseline, Weeks 48, 72, last available assessment]

   Actual change in glycosylated hemoglobin (HbA1c) from baseline.

7. Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride [Baseline, Weeks 48, 72, last available assessment]

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

8. Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP) [Baseline, Weeks 48, 72, last available assessment]

   Actual change in sitting SBP & DBP from baseline.

9. Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight [Baseline, Weeks 48, 72, last available assessment]

   Actual change in weight from baseline.

10. Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI) [Baseline, Weeks 48, 72, last available assessment]

    Actual change in BMI from baseline.

11. Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference [Baseline, Weeks 48, 72, last available assessment]

    Actual change in waist circumference from baseline.

12. Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score [Baseline, Week (W) 48, W72, Last available assessment]

    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.

13. Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) [Baseline, W48, W72, Last available assessment]

    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.

14. Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index [Baseline, W48, W72, Last available assessment]

    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.

15. Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) [Baseline, W48, W72, Last available assessment]

    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.

16. Change From Baseline in the Physical Features of Cushing's Disease by Photography [Week 48, Week 72, Last available assessment]

    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).

17. Change From Baseline in Bone Mineral Density - All Participants [Baseline, Week 48, Last observed value (LOV)]

    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..

18. Time-to-escape [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]

    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.

19. LCI699 Exposures [from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose]

    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.

20. Percentage of Participants With Complete Response Rate (CRR) [Week 12, Week 24, Week 48, Week 72, last available assessment]

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

21. Percentage of Participants With Partial Response Rate (PRR) [Week 12, Week 24, Week 48, Week 72, last available assessment]

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

22. Percentage of Participants With Overall Response Rate (ORR) [Week 12, Week 24, Week 48, Week 72, last available assessment]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. Male or female patients aged 18 - 75 years.

3. Patients must have confirmed Cushing's disease that is persistent or recurrent.

4. Patients with a history of prior pituitary surgery must be at least 30 days post-surgery to be eligible for inclusion in this study.

5. Patients that received glucocorticoid replacement therapy post-operatively must have discontinued such therapy for at least one week, or 5 half-lives, whichever is longer, prior to screening.

6. Patients with de novo Cushing's disease can be included only if they are not considered candidates for surgery.

7. Patients with a history of pituitary irradiation can be included, provided that at least 2 years (stereotactic radiosurgery) or 3 years (conventional radiation) have elapsed from the time of last radiation treatment to the time of enrollment into this study.

8. Patients are permitted to washout current drug therapy to meet these entry criteria if they have a known diagnosis of Cushing's disease.

Exclusion Criteria:

1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half lives at the time of enrollment, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations.

2. History of hypersensitivity to LCI699 or to drugs of similar chemical classes.

3. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

4. Patients with risk factors for QTc prolongation or Torsade de Pointes.

5. Pregnant or nursing (lactating) women.

6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after completion of dosing.

7. Patients with compression of the optic chiasm due to a macroadenoma or patients at high risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm).

8. Patients who have a known inherited syndrome as the cause for hormone over secretion.

9. Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH-independent (adrenal) Cushing's syndrome.

10. Patients who have undergone major surgery within 1 month prior to screening.

11. Hypertensive patients with uncontrolled blood pressure.

12. Diabetic patients with poorly controlled diabetes.

13. Patients who are not euthyroid as judged by the investigator.

14. Patients who have a history of: congestive heart failure, unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, acute MI less than one year prior to study entry, or clinically significant impairment in cardiovascular function.

15. Patients with moderate to severe renal impairment.

16. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with defined elevated ALT/ AST/ Bilirubin.

17. Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator or the sponsor's medical monitor.

18. Patients who have a history of alcohol or drug abuse in the 6 month period prior to study treatment.

19. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Hospital SC - LCI699C2301	Aurora	Colorado	United States	80045
2	Emory University School of Medicine G2304 - C2301	Atlanta	Georgia	United States	30322
3	Northwestern University SC - LCI699C2301	Chicago	Illinois	United States	60611
4	The Johns Hopkins University School of Medicine Johns Hopkins University	Baltimore	Maryland	United States	21205
5	Massachusetts General Hospital Neuroendocrine Unit	Boston	Massachusetts	United States	02114
6	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
7	Mount Sinai School of Medicine SC - LCI699C2301	New York	New York	United States	10029
8	Columbia University Medical Center New York Presbyterian SC - LCI699C2301	New York	New York	United States	10032
9	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
10	Oregon Health and Science University SC LCI699C2301	Portland	Oregon	United States	97239
11	University of Pennsylvania Clinical Studies Unit Unniv SC	Philadelphia	Pennsylvania	United States	19104
12	Medical College of Wisconsin MCW 2	Milwaukee	Wisconsin	United States	53226
13	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1180AAX
14	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1426AAI
15	Novartis Investigative Site	Wien		Austria	1090
16	Novartis Investigative Site	Sofia		Bulgaria	1431
17	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 2B7
18	Novartis Investigative Site	Halifax	Nova Scotia	Canada	B3H 1V7
19	Novartis Investigative Site	Montreal	Quebec	Canada	H2W 1T8
20	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1H 5N4
21	Novartis Investigative Site	Beijing	Beijing	China	100730
22	Novartis Investigative Site	Chengdu	Sichuan	China	610041
23	Novartis Investigative Site	Beijing		China	100034
24	Novartis Investigative Site	Cali		Colombia
25	Novartis Investigative Site	Le Kremlin Bicetre		France	94275
26	Novartis Investigative Site	Lille Cedex		France	59037
27	Novartis Investigative Site	Marseille		France	13385
28	Novartis Investigative Site	Paris		France	75014
29	Novartis Investigative Site	Pessac Cedex		France	33604
30	Novartis Investigative Site	Erlangen		Germany	91054
31	Novartis Investigative Site	Muenchen		Germany	81377
32	Novartis Investigative Site	Bangalore	Karnataka	India	560054
33	Novartis Investigative Site	Chandigarh	Punjab	India	160012
34	Novartis Investigative Site	Vellore	Tamil Nadu	India	632004
35	Novartis Investigative Site	New Delhi		India	110029
36	Novartis Investigative Site	Ancona	AN	Italy	60126
37	Novartis Investigative Site	Genova	GE	Italy	16132
38	Novartis Investigative Site	Messina	ME	Italy	98125
39	Novartis Investigative Site	Milano	MI	Italy	20122
40	Novartis Investigative Site	Padova	PD	Italy	35128
41	Novartis Investigative Site	Pisa	PI	Italy	56124
42	Novartis Investigative Site	Napoli		Italy	80131
43	Novartis Investigative Site	Nagoya	Aichi	Japan	460-0001
44	Novartis Investigative Site	Fukuoka city	Fukuoka	Japan	812-8582
45	Novartis Investigative Site	Kobe-shi	Hyogo	Japan	650-0017
46	Novartis Investigative Site	Nishinomiya	Hyogo	Japan	663 8501
47	Novartis Investigative Site	Yokohama	Kanagawa	Japan	245-8575
48	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8603
49	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	160-0023
50	Novartis Investigative Site	Seoul		Korea, Republic of	03080
51	Novartis Investigative Site	Seoul		Korea, Republic of	03722
52	Novartis Investigative Site	Seoul		Korea, Republic of	06351
53	Novartis Investigative Site	Rotterdam		Netherlands	3015 GD
54	Novartis Investigative Site	Moscow		Russian Federation	117036
55	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
56	Novartis Investigative Site	Madrid		Spain	28009
57	Novartis Investigative Site	Madrid		Spain	28046
58	Novartis Investigative Site	Songkla		Thailand	90110
59	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
60	Novartis Investigative Site	Sheffield	South Yorkshire	United Kingdom	S10 2JF

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Dec 2, 2019
• Study Protocol - Jun 29, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02180217
• Other Study ID Numbers: CLCI699C2301; 2013-004766-34
• First Posted: Jul 2, 2014
• Last Update Posted: Jan 6, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: LCI699; osilodrostat; Cushings Disease; open-label dose titration; randomized withdrawal
• Additional relevant MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion

Study Results

Participant Flow

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

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	24	27	28
NOT COMPLETED	12	8	38

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 Participants	36	35	66	137
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.3 (11.27)	42.0 (13.47)	39.0 (13.38)	41.2 (12.98)
Sex: Female, Male (Count of 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 (Number) [Number]
Caucasian	27 75%	23 65.7%	39 59.1%	89 65%
Black	0 0%	3 8.6%	1 1.5%	4 2.9%
Asian	7 19.4%	7 20%	25 37.9%	39 28.5%
Other	2 5.6%	2 5.7%	1 1.5%	5 3.6%

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.
Measure Participants	36	34
Number [Percentage of participants]	86.1 239.2%	29.4 84%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Osilodrostat (LCI699), LCI699 Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	13.71
	Confidence Interval	(2-Sided) 95%; 3.73 to 53.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	137
Number (95% Confidence Interval) [Percentage of participants]	52.6 146.1%

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.
Measure Participants	36	34
Number (95% Confidence Interval) [Percentage]	5.6	61.1

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.
Measure Participants	36	35	66
Week 12	86.1 239.2%	91.4 261.1%	53.0 80.3%
Week 24	100.0 277.8%	97.1 277.4%	34.8 52.7%
Week 48	88.9 246.9%	77.1 220.3%	48.5 73.5%
Week 72	82.9 230.3%	83.3 238%	78.0 118.2%
Last observed value	69.4 192.8%	74.3 212.3%	53.0 80.3%

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.
Measure Participants	36	35	66
Actual Baseline (BL)	890.0 (1275.66)	560.0 (548.84)	1305.8 (2012.21)
Wk 12: Act. change from BL	-848.4 (1335.66)	-510.3 (556.84)	-1021.3 (1825.55)
Wk 24: Act. change from BL	-821.2 (1283.03)	-485.5 (558.99)	-930.3 (1778.04)
Wk 48: Act. change from BL	-708.2 (983.14)	-477.1 (529.04)	-1189.9 (2042.48)
Wk 72: Act. change from BL	-680.7 (1003.63)	-536.7 (585.78)	-826.7 (1684.92)
Last avail. assess.: Act. change from BL	-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.
Measure Participants	36	35	66
Baseline	102.7 (35.23)	90.5 (18.53)	101.8 (31.00)
Wk 48	-7.9 (32.24)	-5.5 (12.13)	-14.1 (22.66)
Wk 72	-0.5 (16.84)	-4.4 (15.13)	-10.8 (24.02)
Last avail. assessment	-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.
Measure Participants	36	35	66
Baseline	6.1 (0.98)	5.8 (0.93)	6.0 (0.97)
Wk 48	-0.3 (0.86)	-0.4 (0.56)	-0.4 (0.65)
Wk 72	-0.4 (0.66)	-0.4 (0.47)	-0.4 (0.64)
Last avail. assessment	-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.
Measure Participants	36	35	66
Cholesterol: BL	5.5 (1.22)	5.3 (0.90)	5.1 (1.24)
Cholesterol: Wk 48	-0.7 (0.87)	-0.4 (0.89)	-0.5 (0.90)
Cholesterol: Wk 72	-0.4 (0.96)	-0.3 (0.75)	-0.4 (0.98)
Cholesterol: Last avail. assessment	-0.3 (1.16)	-0.3 (1.03)	-0.4 (1.15)
LDL Cholesterol: BL	3.2 (1.09)	3.1 (0.77)	2.9 (0.94)
LDL Cholesterol: Wk 48	-0.3 (0.75)	-0.2 (0.74)	-0.1 (0.82)
LDL Cholesterol: Wk 72	-0.2 (0.77)	-0.2 (0.66)	-0.1 (0.86)
LDL Cholesterol: Last avail asses	-0.1 (0.98)	-0.2 (0.88)	-0.1 (0.99)
HDL Cholesterol: BL	1.7 (0.55)	1.5 (0.36)	1.6 (0.42)
HDL Cholesterol: Wk 48	-0.3 (0.39)	-0.2 (0.17)	-0.3 (0.28)
HDL Cholesterol: Wk 72	-0.2 (0.39)	-0.2 (0.27)	-0.3 (0.28)
HDL Cholesterol: Last avail assess	-0.2 (0.40)	-0.1 (0.27)	-0.2 (0.34)
Triglyceride: BL	1.5 (0.78)	1.4 (0.62)	1.6 (1.74)
Triglyceride: Wk 48	-0.1 (0.49)	0.0 (0.54)	0.0 (1.22)
Triglyceride: Wk 72	0.0 (0.57)	-0.1 (0.67)	0.0 (0.60)
Triglyceride: Last avail. assess	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.
Measure Participants	36	35	66
SBP: Baseline	132.2 (15.44)	128.8 (11.93)	134.0 (16.34)
SBP: Wk 48	-15.2 (17.00)	-4.8 (12.28)	-9.2 (15.48)
SBP: Wk 72	-12.2 (15.90)	-8.2 (19.41)	-9.4 (19.08)
SBP: Last avail. assessment	-8.2 (15.25)	-4.6 (15.20)	-10.8 (15.31)
DBP: Baseline	85.3 (11.38)	85.0 (10.03)	85.4 (10.53)
DBP: Wk 48	-7.8 (11.63)	-5.1 (9.66)	-6.0 (11.79)
DBP: Wk 72	-5.9 (11.17)	-7.0 (10.33)	-4.8 (12.26)
DBP: Last avail. assessment	-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.
Measure Participants	36	35	66
Baseline	78.2 (19.02)	83.4 (24.73)	80.7 (23.06)
Wk 48	-3.4 (5.64)	-3.9 (5.77)	-4.0 (5.82)
Wk 72	-3.7 (6.93)	-5.0 (6.03)	-5.6 (6.75)
Last avail. assessment	-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.
Measure Participants	36	35	66
Baseline	29.6 (7.36)	30.9 (8.38)	30.4 (7.74)
Wk 48	-1.3 (2.22)	-1.5 (2.12)	-1.5 (2.17)
Wk 72	-1.4 (2.79)	-1.8 (2.14)	-2.0 (2.55)
Last avail. assessment	-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.
Measure Participants	36	35	66
Baseline	100.5 (16.81)	103.7 (18.26)	105.0 (21.15)
Wk 48	-5.1 (6.26)	-4.2 (10.12)	-4.7 (7.07)
Wk 72	-5.1 (7.18)	-6.1 (9.86)	-7.4 (8.53)
Last avail. assessment	-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.
Measure Participants	36	35	66
Baseline	44.4 (18.33)	43.2 (22.45)	40.5 (17.61)
Week 48	16.1 (15.15)	10.2 (16.57)	13.2 (17.79)
Week 72	15.8 (16.08)	12.6 (20.68)	16.3 (21.31)
Last available assess.	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.
Measure Participants	36	35	66
Baseline	15.1 (11.14)	17.8 (9.93)	17.3 (10.67)
W48	-4.8 (9.84)	-5.3 (7.99)	-7.0 (10.17)
W72	-6.0 (9.55)	-4.6 (9.41)	-9.0 (12.34)
Last avail. assess.	-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.
Measure Participants	36	35	66
Baseline	0.7 (0.24)	0.7 (0.24)	0.7 (0.28)
Week 48	0.1 (0.18)	0 (0.25)	0.1 (0.18)
Week 72	0.1 (0.18)	0.1 (0.26)	0.1 (0.19)
Last avail. assess.	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.
Measure Participants	36	35	66
Baseline	61.3 (18.97)	64.2 (16.37)	60.8 (21.09)
Week 48	12.6 (20.64)	6.9 (12.56)	9.7 (17.16)
Week 72	11.2 (18.98)	6.6 (15.47)	10.1 (19.80)
Last avail. assess.	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.
Measure Participants	36	35	66
W48: Facial rubor	50.0 138.9%	46.7 133.4%	43.2 65.5%
W48: Striae	30.0 83.3%	23.3 66.6%	40.5 61.4%
W48:Supraclavicular fat pad	56.7 157.5%	43.3 123.7%	54.1 82%
W48: Dorsal fat pad	60.0 166.7%	40.0 114.3%	56.8 86.1%
W48: Proximal muscle atrophy	40.0 111.1%	26.7 76.3%	45.9 69.5%
W48: Central obesity	43.3 120.3%	30.0 85.7%	51.4 77.9%
W48: Ecchymoses	33.3 92.5%	26.7 76.3%	43.2 65.5%
W72: Facial rubor	48.3 134.2%	55.6 158.9%	53.3 80.8%
W72: Striae	27.6 76.7%	25.9 74%	36.7 55.6%
W72:Supraclavicular fat pad	55.2 153.3%	51.9 148.3%	53.3 80.8%
W72: Dorsal fat pad	69.0 191.7%	48.1 137.4%	53.3 80.8%
W72: Proximal muscle atrophy	31.0 86.1%	25.9 74%	46.7 70.8%
W72: Central obesity	37.9 105.3%	37.0 105.7%	43.3 65.6%
W72: Ecchymoses	27.6 76.7%	29.6 84.6%	36.7 55.6%
End of Trial (EOT):Facial rubor	60.0 166.7%	56.5 161.4%	53.8 81.5%
EOT: Striae	32.0 88.9%	34.8 99.4%	30.8 46.7%
EOT:Supraclavicular fat pad	52.0 144.4%	43.5 124.3%	42.3 64.1%
EOT: Dorsal fat pad	56.0 155.6%	52.2 149.1%	46.2 70%
EOT: Proximal muscle atrophy	36.0 100%	21.7 62%	50.0 75.8%
EOT: Central obesity	40.0 111.1%	39.1 111.7%	38.5 58.3%
EOT: Ecchymoses	28.0 77.8%	39.1 111.7%	38.5 58.3%

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.
Measure Participants	36	35	66
Baseline (L1-L4 Lumbar Spine)	1.0 (0.20)	1.0 (0.17)	1.0 (0.18)
W48 (L1-L4 Lumbar Spine)	1.0 (0.19)	1.0 (0.17)	1.0 (0.19)
LOV (L1-L4 Lumbar Spine)	1.0 (0.20)	1.0 (0.18)	1.0 (0.18)
Baseline (Total Hip)	0.9 (0.18)	0.8 (0.15)	0.9 (0.16)
W48 (Total Hip)	0.9 (0.17)	0.8 (0.14)	0.9 (0.16)
LOV (Total Hip)	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
Measure Participants	97
Median (95% Confidence Interval) [days]	546.0

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
Measure Participants	132	39	105	24
Week (Wk) 2: Predose	1.904 (110.4)
Wk 2: 0.75h	1.907 (132.5)
Wk 2: 1.5h	5.1 (62.7)
Wk 2: 4h	5.818 (66.3)
Wk 4: Predose	2.104 (108.0)	2.898 (109.1)	3.584 (126.3)
Wk 4: 0.75h	0.859 (254.3)	7.091 (137.8)
Wk 4: 1.5h	8.737 (3.6)	24.2 (NA)
Wk 4: 4h	8.930 (NA)	15.985 (48.3)
Wk 6: Predose	2.037 (63.5)	2.392 (285.6)	5.087 (122.9)	8.065 (8.6)
Wk 6: 0.75h	3.110 (NA)	5.223 (229.4)
Wk 6: 1.5h	22.4 (NA)	21.4 (NA)
Wk 6: 4h	8.380 (NA)	18.6 (NA)	18.373 (36.5)
Wk 8: Predose	2.198 (108.9)	4.061 (67.4)	4.487 (106.9)	6.718 (34.2)
Wk 8: 1.5h	10.8 (NA)	20.4 (NA)	32.1 (NA)
Wk 8: 4h	6.65 (NA)	32 (NA)
Wk 10: Predose	1.862 (128.9)	3.007 (64.8)	4.704 (106.8)	5.451 (93.1)
Wk 10: 0.75h	6.7 (NA)	17.1 (NA)
Wk 10: 1.5h	12.1 (NA)	18.3 (NA)	34.2 (NA)
Wk 10: 4h	15.8 (NA)	27.2 (NA)	35.5 (NA)

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.
Measure Participants	36	35	66
Week 12	6.1 16.9%	91.4 261.1%	53.0 80.3%
Week 24	100 277.8%	97.1 277.4%	34.8 52.7%
Week 48	88.9 246.9%	77.1 220.3%	48.5 73.5%
Week 72	82.9 230.3%	83.3 238%	78.0 118.2%
Last available assess.	69.4 192.8%	74.3 212.3%	53.0 80.3%

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.
Measure Participants	36	35	66
Week 12	2.8 7.8%	5.7 16.3%	24.2 36.7%
Week 24	0.0 0%	0.0 0%	30.3 45.9%
Week 48	5.6 15.6%	11.4 32.6%	10.6 16.1%
Week 72	8.6 23.9%	13.3 38%	2.4 3.6%
Last available assess.	22.2 61.7%	11.4 32.6%	22.7 34.4%

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.
Measure Participants	36	35	66
Week 12	88.9 246.9%	97.1 277.4%	77.3 117.1%
Week 24	100 277.8%	97.1 277.4%	65.2 98.8%
Week 48	94.4 262.2%	88.6 253.1%	59.1 89.5%
Week 72	91.4 253.9%	96.7 276.3%	80.5 122%
Last available assess.	91.7 254.7%	85.7 244.9%	75.8 114.8%

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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/36 (2.8%)		1/35 (2.9%)		0/66 (0%)		2/137 (1.5%)
Serious Adverse Events
	Osilodrostat		LCI699 Placebo		Non-randomized		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/36 (36.1%)		10/35 (28.6%)		32/66 (48.5%)		55/137 (40.1%)
Blood and lymphatic system disorders
Anaemia	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Autoimmune neutropenia	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Lymphadenopathy	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Neutropenia	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Cardiac disorders
Cardiopulmonary failure	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Endocrine disorders
Adrenal insufficiency	1/36 (2.8%)		1/35 (2.9%)		6/66 (9.1%)		8/137 (5.8%)
Adrenocortical insufficiency acute	1/36 (2.8%)		0/35 (0%)		3/66 (4.5%)		4/137 (2.9%)
Glucocorticoid deficiency	0/36 (0%)		0/35 (0%)		2/66 (3%)		2/137 (1.5%)
Inappropriate antidiuretic hormone secretion	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Pituitary infarction	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Pituitary-dependent Cushing's syndrome	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Eye disorders
Diplopia	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Visual impairment	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Gastrointestinal disorders
Abdominal pain	1/36 (2.8%)		1/35 (2.9%)		1/66 (1.5%)		3/137 (2.2%)
Gastritis	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Nausea	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Pancreatitis acute	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Vomiting	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
General disorders
Chills	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Influenza like illness	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Non-cardiac chest pain	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Pain	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Pyrexia	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Hepatobiliary disorders
Cholecystitis	0/36 (0%)		1/35 (2.9%)		1/66 (1.5%)		2/137 (1.5%)
Cholelithiasis	1/36 (2.8%)		0/35 (0%)		1/66 (1.5%)		2/137 (1.5%)
Immune system disorders
Anaphylactic shock	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Infections and infestations
Cellulitis	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Chronic sinusitis	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Gastroenteritis	0/36 (0%)		1/35 (2.9%)		3/66 (4.5%)		4/137 (2.9%)
Gastroenteritis viral	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Influenza	1/36 (2.8%)		0/35 (0%)		2/66 (3%)		3/137 (2.2%)
Keratitis fungal	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Pneumonia	0/36 (0%)		1/35 (2.9%)		1/66 (1.5%)		2/137 (1.5%)
Urinary tract infection	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Injury, poisoning and procedural complications
Head injury	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Overdose	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Procedural headache	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Investigations
Haemoglobin decreased	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Transaminases increased	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Metabolism and nutrition disorders
Decreased appetite	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Dehydration	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Hypercalcaemia	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Hypokalaemia	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Hyponatraemia	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Musculoskeletal and connective tissue disorders
Foot deformity	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Groin pain	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Pain in extremity	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pituitary tumour	0/36 (0%)		0/35 (0%)		2/66 (3%)		2/137 (1.5%)
Metastases to liver	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Pituitary tumour	1/36 (2.8%)		1/35 (2.9%)		4/66 (6.1%)		6/137 (4.4%)
Pituitary tumour benign	1/36 (2.8%)		0/35 (0%)		2/66 (3%)		3/137 (2.2%)
Tumour invasion	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Nervous system disorders
Cranial nerve disorder	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Headache	0/36 (0%)		1/35 (2.9%)		2/66 (3%)		3/137 (2.2%)
Idiopathic intracranial hypertension	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Migraine	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Seizure	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Syncope	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
VIth nerve paralysis	0/36 (0%)		0/35 (0%)		3/66 (4.5%)		3/137 (2.2%)
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Psychiatric disorders
Anxiety	1/36 (2.8%)		1/35 (2.9%)		0/66 (0%)		2/137 (1.5%)
Completed suicide	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Depression	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Suicidal ideation	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Renal and urinary disorders
Acute kidney injury	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Cystitis glandularis	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Reproductive system and breast disorders
Metrorrhagia	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Uterine polyp	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Vaginal haemorrhage	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Respiratory, thoracic and mediastinal disorders
Cough	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Dyspnoea	0/36 (0%)		1/35 (2.9%)		0/66 (0%)		1/137 (0.7%)
Epistaxis	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Pulmonary oedema	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Respiratory disorder	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Respiratory failure	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Vocal cord polyp	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Skin and subcutaneous tissue disorders
Hidradenitis	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Urticaria	1/36 (2.8%)		0/35 (0%)		0/66 (0%)		1/137 (0.7%)
Vascular disorders
Venous thrombosis	0/36 (0%)		0/35 (0%)		1/66 (1.5%)		1/137 (0.7%)
Other (Not Including Serious) Adverse Events
	Osilodrostat		LCI699 Placebo		Non-randomized		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/36 (94.4%)		35/35 (100%)		65/66 (98.5%)		134/137 (97.8%)
Blood and lymphatic system disorders
Anaemia	4/36 (11.1%)		5/35 (14.3%)		6/66 (9.1%)		15/137 (10.9%)
Cardiac disorders
Bundle branch block right	0/36 (0%)		2/35 (5.7%)		0/66 (0%)		2/137 (1.5%)
Tachycardia	2/36 (5.6%)		3/35 (8.6%)		3/66 (4.5%)		8/137 (5.8%)
Ear and labyrinth disorders
Ear pain	2/36 (5.6%)		0/35 (0%)		1/66 (1.5%)		3/137 (2.2%)
Endocrine disorders
Adrenal insufficiency	7/36 (19.4%)		10/35 (28.6%)		17/66 (25.8%)		34/137 (24.8%)
Glucocorticoid deficiency	10/36 (27.8%)		9/35 (25.7%)		8/66 (12.1%)		27/137 (19.7%)
Eye disorders
Dry eye	2/36 (5.6%)		0/35 (0%)		2/66 (3%)		4/137 (2.9%)
Eye pruritus	0/36 (0%)		2/35 (5.7%)		0/66 (0%)		2/137 (1.5%)
Photophobia	0/36 (0%)		2/35 (5.7%)		0/66 (0%)		2/137 (1.5%)
Vision blurred	0/36 (0%)		0/35 (0%)		4/66 (6.1%)		4/137 (2.9%)
Gastrointestinal disorders
Abdominal distension	2/36 (5.6%)		1/35 (2.9%)		3/66 (4.5%)		6/137 (4.4%)
Abdominal pain	5/36 (13.9%)		2/35 (5.7%)		8/66 (12.1%)		15/137 (10.9%)
Abdominal pain upper	3/36 (8.3%)		3/35 (8.6%)		3/66 (4.5%)		9/137 (6.6%)
Constipation	4/36 (11.1%)		1/35 (2.9%)		5/66 (7.6%)		10/137 (7.3%)
Dental caries	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Diarrhoea	5/36 (13.9%)		8/35 (22.9%)		14/66 (21.2%)		27/137 (19.7%)
Dry mouth	0/36 (0%)		0/35 (0%)		4/66 (6.1%)		4/137 (2.9%)
Dyspepsia	2/36 (5.6%)		5/35 (14.3%)		8/66 (12.1%)		15/137 (10.9%)
Gastrooesophageal reflux disease	1/36 (2.8%)		2/35 (5.7%)		1/66 (1.5%)		4/137 (2.9%)
Nausea	17/36 (47.2%)		11/35 (31.4%)		34/66 (51.5%)		62/137 (45.3%)
Toothache	2/36 (5.6%)		0/35 (0%)		3/66 (4.5%)		5/137 (3.6%)
Vomiting	7/36 (19.4%)		5/35 (14.3%)		21/66 (31.8%)		33/137 (24.1%)
General disorders
Application site rash	0/36 (0%)		2/35 (5.7%)		0/66 (0%)		2/137 (1.5%)
Asthenia	11/36 (30.6%)		5/35 (14.3%)		11/66 (16.7%)		27/137 (19.7%)
Chest discomfort	1/36 (2.8%)		0/35 (0%)		4/66 (6.1%)		5/137 (3.6%)
Chills	1/36 (2.8%)		3/35 (8.6%)		2/66 (3%)		6/137 (4.4%)
Fatigue	8/36 (22.2%)		13/35 (37.1%)		24/66 (36.4%)		45/137 (32.8%)
Gait disturbance	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Influenza like illness	0/36 (0%)		2/35 (5.7%)		1/66 (1.5%)		3/137 (2.2%)
Malaise	1/36 (2.8%)		2/35 (5.7%)		7/66 (10.6%)		10/137 (7.3%)
Oedema	1/36 (2.8%)		3/35 (8.6%)		5/66 (7.6%)		9/137 (6.6%)
Oedema peripheral	8/36 (22.2%)		5/35 (14.3%)		9/66 (13.6%)		22/137 (16.1%)
Pain	2/36 (5.6%)		3/35 (8.6%)		1/66 (1.5%)		6/137 (4.4%)
Pyrexia	4/36 (11.1%)		3/35 (8.6%)		13/66 (19.7%)		20/137 (14.6%)
Immune system disorders
Seasonal allergy	0/36 (0%)		2/35 (5.7%)		0/66 (0%)		2/137 (1.5%)
Infections and infestations
Bronchitis	1/36 (2.8%)		1/35 (2.9%)		6/66 (9.1%)		8/137 (5.8%)
Cystitis	3/36 (8.3%)		2/35 (5.7%)		1/66 (1.5%)		6/137 (4.4%)
Folliculitis	1/36 (2.8%)		2/35 (5.7%)		0/66 (0%)		3/137 (2.2%)
Fungal skin infection	1/36 (2.8%)		2/35 (5.7%)		0/66 (0%)		3/137 (2.2%)
Gastroenteritis	4/36 (11.1%)		3/35 (8.6%)		5/66 (7.6%)		12/137 (8.8%)
Gastroenteritis viral	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Hordeolum	0/36 (0%)		3/35 (8.6%)		2/66 (3%)		5/137 (3.6%)
Influenza	5/36 (13.9%)		8/35 (22.9%)		10/66 (15.2%)		23/137 (16.8%)
Nasopharyngitis	9/36 (25%)		11/35 (31.4%)		13/66 (19.7%)		33/137 (24.1%)
Sinusitis	3/36 (8.3%)		1/35 (2.9%)		4/66 (6.1%)		8/137 (5.8%)
Tooth abscess	2/36 (5.6%)		1/35 (2.9%)		0/66 (0%)		3/137 (2.2%)
Upper respiratory tract infection	2/36 (5.6%)		5/35 (14.3%)		7/66 (10.6%)		14/137 (10.2%)
Urinary tract infection	6/36 (16.7%)		4/35 (11.4%)		14/66 (21.2%)		24/137 (17.5%)
Injury, poisoning and procedural complications
Contusion	1/36 (2.8%)		2/35 (5.7%)		4/66 (6.1%)		7/137 (5.1%)
Ligament sprain	3/36 (8.3%)		1/35 (2.9%)		1/66 (1.5%)		5/137 (3.6%)
Investigations
11-deoxycortisol increased	3/36 (8.3%)		1/35 (2.9%)		2/66 (3%)		6/137 (4.4%)
Activated partial thromboplastin time prolonged	3/36 (8.3%)		1/35 (2.9%)		1/66 (1.5%)		5/137 (3.6%)
Alanine aminotransferase increased	0/36 (0%)		0/35 (0%)		4/66 (6.1%)		4/137 (2.9%)
Aspartate aminotransferase increased	0/36 (0%)		0/35 (0%)		4/66 (6.1%)		4/137 (2.9%)
Blood cholesterol increased	2/36 (5.6%)		0/35 (0%)		1/66 (1.5%)		3/137 (2.2%)
Blood corticotrophin increased	8/36 (22.2%)		6/35 (17.1%)		14/66 (21.2%)		28/137 (20.4%)
Blood testosterone increased	2/36 (5.6%)		1/35 (2.9%)		13/66 (19.7%)		16/137 (11.7%)
Cortisol decreased	3/36 (8.3%)		0/35 (0%)		1/66 (1.5%)		4/137 (2.9%)
Cortisol free urine decreased	8/36 (22.2%)		2/35 (5.7%)		1/66 (1.5%)		11/137 (8%)
Cortisol free urine increased	6/36 (16.7%)		1/35 (2.9%)		1/66 (1.5%)		8/137 (5.8%)
Haemoglobin decreased	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Hormone level abnormal	5/36 (13.9%)		1/35 (2.9%)		12/66 (18.2%)		18/137 (13.1%)
Lipase increased	1/36 (2.8%)		2/35 (5.7%)		1/66 (1.5%)		4/137 (2.9%)
Low density lipoprotein increased	2/36 (5.6%)		0/35 (0%)		1/66 (1.5%)		3/137 (2.2%)
Renin increased	3/36 (8.3%)		0/35 (0%)		3/66 (4.5%)		6/137 (4.4%)
Weight decreased	2/36 (5.6%)		2/35 (5.7%)		5/66 (7.6%)		9/137 (6.6%)
Weight increased	1/36 (2.8%)		2/35 (5.7%)		2/66 (3%)		5/137 (3.6%)
Metabolism and nutrition disorders
Decreased appetite	3/36 (8.3%)		7/35 (20%)		11/66 (16.7%)		21/137 (15.3%)
Hypercholesterolaemia	1/36 (2.8%)		2/35 (5.7%)		1/66 (1.5%)		4/137 (2.9%)
Hyperglycaemia	2/36 (5.6%)		0/35 (0%)		1/66 (1.5%)		3/137 (2.2%)
Hypertriglyceridaemia	2/36 (5.6%)		0/35 (0%)		2/66 (3%)		4/137 (2.9%)
Hypokalaemia	3/36 (8.3%)		3/35 (8.6%)		11/66 (16.7%)		17/137 (12.4%)
Iron deficiency	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Vitamin D deficiency	3/36 (8.3%)		1/35 (2.9%)		2/66 (3%)		6/137 (4.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/36 (19.4%)		10/35 (28.6%)		12/66 (18.2%)		29/137 (21.2%)
Back pain	9/36 (25%)		13/35 (37.1%)		7/66 (10.6%)		29/137 (21.2%)
Limb discomfort	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Muscle spasms	0/36 (0%)		2/35 (5.7%)		6/66 (9.1%)		8/137 (5.8%)
Musculoskeletal pain	2/36 (5.6%)		1/35 (2.9%)		3/66 (4.5%)		6/137 (4.4%)
Myalgia	2/36 (5.6%)		7/35 (20%)		11/66 (16.7%)		20/137 (14.6%)
Neck pain	2/36 (5.6%)		2/35 (5.7%)		3/66 (4.5%)		7/137 (5.1%)
Osteoarthritis	3/36 (8.3%)		0/35 (0%)		1/66 (1.5%)		4/137 (2.9%)
Osteopenia	2/36 (5.6%)		2/35 (5.7%)		1/66 (1.5%)		5/137 (3.6%)
Osteoporosis	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Pain in extremity	2/36 (5.6%)		5/35 (14.3%)		6/66 (9.1%)		13/137 (9.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign	2/36 (5.6%)		1/35 (2.9%)		6/66 (9.1%)		9/137 (6.6%)
Nervous system disorders
Amnesia	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Carpal tunnel syndrome	2/36 (5.6%)		1/35 (2.9%)		0/66 (0%)		3/137 (2.2%)
Dizziness	5/36 (13.9%)		4/35 (11.4%)		17/66 (25.8%)		26/137 (19%)
Headache	11/36 (30.6%)		7/35 (20%)		32/66 (48.5%)		50/137 (36.5%)
Hypoaesthesia	1/36 (2.8%)		4/35 (11.4%)		4/66 (6.1%)		9/137 (6.6%)
Memory impairment	2/36 (5.6%)		1/35 (2.9%)		2/66 (3%)		5/137 (3.6%)
Migraine	0/36 (0%)		1/35 (2.9%)		4/66 (6.1%)		5/137 (3.6%)
Paraesthesia	1/36 (2.8%)		4/35 (11.4%)		0/66 (0%)		5/137 (3.6%)
Somnolence	2/36 (5.6%)		0/35 (0%)		3/66 (4.5%)		5/137 (3.6%)
Psychiatric disorders
Anxiety	3/36 (8.3%)		2/35 (5.7%)		7/66 (10.6%)		12/137 (8.8%)
Depression	3/36 (8.3%)		3/35 (8.6%)		7/66 (10.6%)		13/137 (9.5%)
Insomnia	4/36 (11.1%)		2/35 (5.7%)		7/66 (10.6%)		13/137 (9.5%)
Irritability	1/36 (2.8%)		1/35 (2.9%)		4/66 (6.1%)		6/137 (4.4%)
Panic attack	0/36 (0%)		2/35 (5.7%)		0/66 (0%)		2/137 (1.5%)
Sleep disorder	2/36 (5.6%)		0/35 (0%)		5/66 (7.6%)		7/137 (5.1%)
Renal and urinary disorders
Nephrolithiasis	1/36 (2.8%)		2/35 (5.7%)		0/66 (0%)		3/137 (2.2%)
Reproductive system and breast disorders
Menstruation irregular	0/36 (0%)		2/35 (5.7%)		2/66 (3%)		4/137 (2.9%)
Respiratory, thoracic and mediastinal disorders
Cough	5/36 (13.9%)		4/35 (11.4%)		10/66 (15.2%)		19/137 (13.9%)
Dyspnoea	1/36 (2.8%)		1/35 (2.9%)		4/66 (6.1%)		6/137 (4.4%)
Nasal congestion	3/36 (8.3%)		0/35 (0%)		3/66 (4.5%)		6/137 (4.4%)
Oropharyngeal pain	3/36 (8.3%)		4/35 (11.4%)		7/66 (10.6%)		14/137 (10.2%)
Rhinitis allergic	0/36 (0%)		0/35 (0%)		4/66 (6.1%)		4/137 (2.9%)
Rhinorrhoea	2/36 (5.6%)		1/35 (2.9%)		4/66 (6.1%)		7/137 (5.1%)
Skin and subcutaneous tissue disorders
Acne	2/36 (5.6%)		2/35 (5.7%)		9/66 (13.6%)		13/137 (9.5%)
Alopecia	0/36 (0%)		3/35 (8.6%)		7/66 (10.6%)		10/137 (7.3%)
Dermatitis	0/36 (0%)		2/35 (5.7%)		2/66 (3%)		4/137 (2.9%)
Dermatitis contact	2/36 (5.6%)		1/35 (2.9%)		2/66 (3%)		5/137 (3.6%)
Dry skin	0/36 (0%)		3/35 (8.6%)		7/66 (10.6%)		10/137 (7.3%)
Eczema	1/36 (2.8%)		2/35 (5.7%)		2/66 (3%)		5/137 (3.6%)
Hirsutism	4/36 (11.1%)		3/35 (8.6%)		5/66 (7.6%)		12/137 (8.8%)
Hyperhidrosis	3/36 (8.3%)		3/35 (8.6%)		3/66 (4.5%)		9/137 (6.6%)
Onychoclasis	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)
Pruritus	5/36 (13.9%)		1/35 (2.9%)		7/66 (10.6%)		13/137 (9.5%)
Rash	8/36 (22.2%)		3/35 (8.6%)		10/66 (15.2%)		21/137 (15.3%)
Skin hyperpigmentation	1/36 (2.8%)		1/35 (2.9%)		4/66 (6.1%)		6/137 (4.4%)
Skin lesion	3/36 (8.3%)		0/35 (0%)		1/66 (1.5%)		4/137 (2.9%)
Urticaria	2/36 (5.6%)		0/35 (0%)		2/66 (3%)		4/137 (2.9%)
Vascular disorders
Hypertension	5/36 (13.9%)		5/35 (14.3%)		14/66 (21.2%)		24/137 (17.5%)
Hypotension	7/36 (19.4%)		3/35 (8.6%)		3/66 (4.5%)		13/137 (9.5%)
Varicose vein	2/36 (5.6%)		0/35 (0%)		0/66 (0%)		2/137 (1.5%)

Limitations/Caveats

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

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Certain Agreements

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

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.