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

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

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.

Study Overview

• Status: Completed
• Conditions: Cushings Disease
• Intervention / Treatment: Drug: osilodrostat; Drug: LCI699 matching placebo

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 Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1180AAX
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1426AAI
      • Novartis Investigative Site
• Austria
  • Wien, Austria, 1090
    • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Novartis Investigative Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Novartis Investigative Site
• China
  • Beijing, China, 100034
    • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100730
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
• Colombia
  • Cali, Colombia
    • Novartis Investigative Site
• France
  • Le Kremlin Bicetre, France, 94275
    • Novartis Investigative Site
  • Lille Cedex, France, 59037
    • Novartis Investigative Site
  • Marseille, France, 13385
    • Novartis Investigative Site
  • Paris, France, 75014
    • Novartis Investigative Site
  • Pessac Cedex, France, 33604
    • Novartis Investigative Site
• Germany
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Muenchen, Germany, 81377
    • Novartis Investigative Site
• India
  • New Delhi, India, 110029
    • Novartis Investigative Site
  • Karnataka
    • Bangalore, Karnataka, India, 560054
      • Novartis Investigative Site
  • Punjab
    • Chandigarh, Punjab, India, 160012
      • Novartis Investigative Site
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632004
      • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • ME
    • Messina, ME, Italy, 98125
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 460-0001
      • Novartis Investigative Site
  • Fukuoka
    • Fukuoka city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
  • Hyogo
    • Kobe-shi, Hyogo, Japan, 650-0017
      • Novartis Investigative Site
    • Nishinomiya, Hyogo, Japan, 663 8501
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 245-8575
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8603
      • Novartis Investigative Site
    • Shinjuku-ku, Tokyo, Japan, 160-0023
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 117036
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
• Thailand
  • Songkla, Thailand, 90110
    • Novartis Investigative Site
• Turkey
  • TUR
    • Istanbul, TUR, Turkey, 34098
      • Novartis Investigative Site
• United Kingdom
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Novartis Investigative Site
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital SC - LCI699C2301
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine G2304 - C2301
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University SC - LCI699C2301
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • The Johns Hopkins University School of Medicine Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Neuroendocrine Unit
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine SC - LCI699C2301
    • New York, New York, United States, 10032
      • Columbia University Medical Center New York Presbyterian SC - LCI699C2301
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University SC LCI699C2301
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Clinical Studies Unit Unniv SC
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin MCW 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)	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.	Week 24
Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group	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.	8 weeks after randomization
Complete Response Rate (CRR)	Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN	Week 12, Week 24, Week 48, Week 72, last observed value
Actual Change From Baseline in mUFC	Actual change in mUFC from baseline.	Weeks 12, 24, 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose	Actual change in fasting glucose from baseline.	Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C)	Actual change in glycosylated hemoglobin (HbA1c) from baseline.	Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride	Actual change in Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride from baseline.	Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP)	Actual change in sitting SBP & DBP from baseline.	Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight	Actual change in weight from baseline.	Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI)	Actual change in BMI from baseline.	Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference	Actual change in waist circumference from baseline.	Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score	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.	Baseline, Week (W) 48, W72, Last available assessment
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)	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.	Baseline, W48, W72, Last available assessment
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index	The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. 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.	Baseline, W48, W72, Last available assessment
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)	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.	Baseline, W48, W72, Last available assessment
Change From Baseline in the Physical Features of Cushing's Disease by Photography	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).	Week 48, Week 72, Last available assessment
Change From Baseline in Bone Mineral Density - All Participants	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..	Baseline, Week 48, Last observed value (LOV)
Time-to-escape	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.	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
LCI699 Exposures	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.	from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose
Percentage of Participants With Complete Response Rate (CRR)	Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN.	Week 12, Week 24, Week 48, Week 72, last available assessment
Percentage of Participants With Partial Response Rate (PRR)	Partial response rate is defined as percentage of enrolled participants with ≥ 50% reduction from baseline in mUFC, but mUFC>ULN)	Week 12, Week 24, Week 48, Week 72, last available assessment
Percentage of Participants With Overall Response Rate (ORR)	Overall response rate is defined as percentage of enrolled participants with mUFC ≤ ULN or at least 50% reduction from baseline.	Week 12, Week 24, Week 48, Week 72, last available assessment

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Fontaine-Sylvestre C, Letourneau-Guillon L, Moumdjian RA, Berthelet F, Lacroix A. Corticotroph tumor progression during long-term therapy with osilodrostat in a patient with persistent Cushing's disease. Pituitary. 2021 Apr;24(2):207-215. doi: 10.1007/s11102-020-01097-1. Epub 2020 Oct 19.
• Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, Gu F, Auchus R, Leelawattana R, Lee EJ, Kim JH, Lacroix A, Laplanche A, O'Connell P, Tauchmanova L, Pedroncelli AM, Biller BMK; LINC 3 investigators. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020 Sep;8(9):748-761. doi: 10.1016/S2213-8587(20)30240-0. Epub 2020 Jul 27. Erratum In: Lancet Diabetes Endocrinol. 2020 Aug 5;:

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2014
• Primary Completion (Actual): February 21, 2018
• Study Completion (Actual): December 4, 2019

Study Registration Dates

• First Submitted: June 17, 2014
• First Submitted That Met QC Criteria: June 30, 2014
• First Posted (Estimate): July 2, 2014

Study Record Updates

• Last Update Posted (Actual): January 6, 2021
• Last Update Submitted That Met QC Criteria: December 11, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: osilodrostat; LCI699; randomized withdrawal; Cushings Disease; open-label dose titration
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Hypothalamic Diseases; Hyperpituitarism; Pituitary Diseases; Adenoma; Pituitary Neoplasms; ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion
• Other Study ID Numbers: CLCI699C2301; 2013-004766-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No