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

NCT02180217 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: CLCI699C23012013-004766-34
• Study Type: interventional
• Target: 137
• Locations: 19 countries
• Sites: 60

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.

Conditions

Cushings Disease

Keywords

LCI699; osilodrostat; Cushings Disease; open-label dose titration; randomized withdrawal

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (22)

• Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)

  Week 24

• Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group

  8 weeks after randomization

• Complete Response Rate (CRR)

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

• Actual Change From Baseline in mUFC

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

• Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose

  Baseline, Weeks 48, 72, last available assessment

Study Arms (2)

osilodrostat (LCI699)

EXPERIMENTAL

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

LCI699 Placebo

PLACEBO COMPARATOR

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

Interventions

osilodrostat DRUG

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.

Also known as: LCI699

osilodrostat (LCI699)

LCI699 matching placebo DRUG

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.

LCI699 Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent must be obtained before any assessment is performed.
• Male or female patients aged 18 - 75 years.
• Patients must have confirmed Cushing's disease that is persistent or recurrent.
• 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.
• Patients with de novo Cushing's disease can be included only if they are not considered candidates for surgery.
• 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.
• Patients are permitted to washout current drug therapy to meet these entry criteria if they have a known diagnosis of Cushing's disease.

You may not qualify if:

• 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.
• History of hypersensitivity to LCI699 or to drugs of similar chemical classes.
• 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.
• Patients with risk factors for QTc prolongation or Torsade de Pointes.
• Pregnant or nursing (lactating) women.
• 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.
• 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).
• Patients who have a known inherited syndrome as the cause for hormone over secretion.
• Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH-independent (adrenal) Cushing's syndrome.
• Patients who have undergone major surgery within 1 month prior to screening.
• Hypertensive patients with uncontrolled blood pressure.
• Diabetic patients with poorly controlled diabetes.
• Patients who are not euthyroid as judged by the investigator.
• 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.
• Patients with moderate to severe renal impairment.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (60)

University of Colorado Hospital SC - LCI699C2301

Aurora, Colorado, 80045, United States

Location

Emory University School of Medicine G2304 - C2301

Atlanta, Georgia, 30322, United States

Location

Northwestern University SC - LCI699C2301

Chicago, Illinois, 60611, United States

Location

The Johns Hopkins University School of Medicine Johns Hopkins University

Baltimore, Maryland, 21205, United States

Location

Massachusetts General Hospital Neuroendocrine Unit

Boston, Massachusetts, 02114, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Mount Sinai School of Medicine SC - LCI699C2301

New York, New York, 10029, United States

Location

Columbia University Medical Center New York Presbyterian SC - LCI699C2301

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Oregon Health and Science University SC LCI699C2301

Portland, Oregon, 97239, United States

Location

University of Pennsylvania Clinical Studies Unit Unniv SC

Philadelphia, Pennsylvania, 19104, United States

Location

Medical College of Wisconsin MCW 2

Milwaukee, Wisconsin, 53226, United States

Location

Novartis Investigative Site

CABA, Buenos Aires, C1180AAX, Argentina

Location

Novartis Investigative Site

CABA, Buenos Aires, C1426AAI, Argentina

Location

Novartis Investigative Site

Vienna, 1090, Austria

Location

Novartis Investigative Site

Sofia, 1431, Bulgaria

Location

Novartis Investigative Site

Edmonton, Alberta, T6G 2B7, Canada

Location

Novartis Investigative Site

Halifax, Nova Scotia, B3H 1V7, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H2W 1T8, Canada

Location

Novartis Investigative Site

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Novartis Investigative Site

Beijing, Beijing Municipality, 100730, China

Location

Novartis Investigative Site

Chengdu, Sichuan, 610041, China

Location

Novartis Investigative Site

Beijing, 100034, China

Location

Novartis Investigative Site

Cali, Colombia

Location

Novartis Investigative Site

Le Kremlin-Bicêtre, 94275, France

Location

Novartis Investigative Site

Lille, 59037, France

Location

Novartis Investigative Site

Marseille, 13385, France

Location

Novartis Investigative Site

Paris, 75014, France

Location

Novartis Investigative Site

Pessac, 33604, France

Location

Novartis Investigative Site

Erlangen, 91054, Germany

Location

Novartis Investigative Site

München, 81377, Germany

Location

Novartis Investigative Site

Bangalore, Karnataka, 560054, India

Location

Novartis Investigative Site

Chandigarh, Punjab, 160012, India

Location

Novartis Investigative Site

Vellore, Tamil Nadu, 632004, India

Location

Novartis Investigative Site

New Delhi, 110029, India

Location

Novartis Investigative Site

Ancona, AN, 60126, Italy

Location

Novartis Investigative Site

Genova, GE, 16132, Italy

Location

Novartis Investigative Site

Messina, ME, 98125, Italy

Location

Novartis Investigative Site

Milan, MI, 20122, Italy

Location

Novartis Investigative Site

Padua, PD, 35128, Italy

Location

Novartis Investigative Site

Pisa, PI, 56124, Italy

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Novartis Investigative Site

Nagoya, Aichi-ken, 460-0001, Japan

Location

Novartis Investigative Site

Fukuoka, Fukuoka, 812-8582, Japan

Location

Novartis Investigative Site

Kobe, Hyōgo, 650-0017, Japan

Location

Novartis Investigative Site

Nishinomiya, Hyōgo, 663 8501, Japan

Location

Novartis Investigative Site

Yokohama, Kanagawa, 245-8575, Japan

Location

Novartis Investigative Site

Bunkyo-ku, Tokyo, 113-8603, Japan

Location

Novartis Investigative Site

Shinjuku-ku, Tokyo, 160-0023, Japan

Location

Novartis Investigative Site

Rotterdam, 3015 GD, Netherlands

Location

Novartis Investigative Site

Moscow, 117036, Russia

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Seoul, 03722, South Korea

Location

Novartis Investigative Site

Seoul, 06351, South Korea

Location

Novartis Investigative Site

Seville, Andalusia, 41013, Spain

Location

Novartis Investigative Site

Madrid, 28009, Spain

Location

Novartis Investigative Site

Madrid, 28046, Spain

Location

Novartis Investigative Site

Songkhla, 90110, Thailand

Location

Novartis Investigative Site

Istanbul, TUR, 34098, Turkey (Türkiye)

Location

Novartis Investigative Site

Sheffield, South Yorkshire, S10 2JF, United Kingdom

Location

Related Publications (6)

• Fleseriu M, Pivonello R, Lacroix A, Biller BMK, Feelders R, Gadelha M, Bertherat J, Belaya Z, Piacentini A, Pedroncelli AM, Newell-Price J. Osilodrostat dose impact on efficacy/safety in Cushing's disease: large, pooled analysis of LINC 2, 3, and 4. Eur J Endocrinol. 2025 Oct 30;193(5):606-617. doi: 10.1093/ejendo/lvaf207.

  PMID: 41052284 DERIVED

• Newell-Price J, Fleseriu M, Pivonello R, Feelders RA, Gadelha MR, Lacroix A, Witek P, Heaney AP, Piacentini A, Pedroncelli AM, Biller BMK. Improved Clinical Outcomes During Long-term Osilodrostat Treatment of Cushing Disease With Normalization of Late-night Salivary Cortisol and Urinary Free Cortisol. J Endocr Soc. 2024 Nov 12;9(1):bvae201. doi: 10.1210/jendso/bvae201. eCollection 2024 Nov 26.

  PMID: 39610378 DERIVED

• Pivonello R, Fleseriu M, Newell-Price J, Shimatsu A, Feelders RA, Kadioglu P, Tabarin A, Brue TC, Geer EB, Piacentini A, Pedroncelli AM, Biller BMK. Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial in Cushing's disease. J Endocrinol Invest. 2024 Oct;47(10):2437-2448. doi: 10.1007/s40618-024-02359-6. Epub 2024 May 2.

  PMID: 38696122 DERIVED

• Gadelha M, Snyder PJ, Witek P, Bex M, Belaya Z, Turcu AF, Feelders RA, Heaney AP, Paul M, Pedroncelli AM, Auchus RJ. Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension. Front Endocrinol (Lausanne). 2023 Aug 23;14:1236465. doi: 10.3389/fendo.2023.1236465. eCollection 2023.

  PMID: 37680892 DERIVED

• 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.

  PMID: 33074401 DERIVED

• 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.

  PMID: 32730798 DERIVED

MeSH Terms

Conditions

Adrenocortical Hyperfunction

Interventions

Osilodrostat

Condition Hierarchy (Ancestors)

Adrenal Gland Diseases; Endocrine System Diseases

Limitations and Caveats

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: It is a double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period.

Study Record Dates

• First Submitted: June 17, 2014
• First Posted: July 2, 2014
• Study Start: October 6, 2014
• Primary Completion: February 21, 2018
• Study Completion: December 4, 2019
• Last Updated: January 6, 2021
• Results First Posted: June 16, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will share

Locations

CA (4); DE (2); IT (7); CO (1); JP (7); TH (1); US (12); IN (4); ES (3); KR (3); AU (1); TU (1); FR (5); BU (1); AR (2); CN (3); GB (1); RU (1); NL (1)