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

NCT ID: NCT02180217

Last Updated: 2021-01-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 137 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-06
• Study Completion Date: 2019-12-04

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.

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.

Conditions

Cushings Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

osilodrostat

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

LCI699 matching placebo

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

LCI699

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

University of Colorado Hospital SC - LCI699C2301

Aurora, Colorado, United States

Emory University School of Medicine G2304 - C2301

Atlanta, Georgia, United States

Northwestern University SC - LCI699C2301

Chicago, Illinois, United States

The Johns Hopkins University School of Medicine Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts General Hospital Neuroendocrine Unit

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Mount Sinai School of Medicine SC - LCI699C2301

New York, New York, United States

Columbia University Medical Center New York Presbyterian SC - LCI699C2301

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Oregon Health and Science University SC LCI699C2301

Portland, Oregon, United States

University of Pennsylvania Clinical Studies Unit Unniv SC

Philadelphia, Pennsylvania, United States

Medical College of Wisconsin MCW 2

Milwaukee, Wisconsin, United States

Novartis Investigative Site

CABA, Buenos Aires, Argentina

Novartis Investigative Site

CABA, Buenos Aires, Argentina

Novartis Investigative Site

Vienna, , Austria

Novartis Investigative Site

Sofia, , Bulgaria

Novartis Investigative Site

Edmonton, Alberta, Canada

Novartis Investigative Site

Halifax, Nova Scotia, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Sherbrooke, Quebec, Canada

Novartis Investigative Site

Beijing, Beijing Municipality, China

Novartis Investigative Site

Chengdu, Sichuan, China

Novartis Investigative Site

Beijing, , China

Novartis Investigative Site

Cali, , Colombia

Novartis Investigative Site

Le Kremlin-Bicêtre, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Marseille, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Pessac, , France

Novartis Investigative Site

Erlangen, , Germany

Novartis Investigative Site

München, , Germany

Novartis Investigative Site

Bangalore, Karnataka, India

Novartis Investigative Site

Chandigarh, Punjab, India

Novartis Investigative Site

Vellore, Tamil Nadu, India

Novartis Investigative Site

New Delhi, , India

Novartis Investigative Site

Ancona, AN, Italy

Novartis Investigative Site

Genova, GE, Italy

Novartis Investigative Site

Messina, ME, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Padua, PD, Italy

Novartis Investigative Site

Pisa, PI, Italy

Novartis Investigative Site

Napoli, , Italy

Novartis Investigative Site

Nagoya, Aichi-ken, Japan

Novartis Investigative Site

Fukuoka, Fukuoka, Japan

Novartis Investigative Site

Kobe, Hyōgo, Japan

Novartis Investigative Site

Nishinomiya, Hyōgo, Japan

Novartis Investigative Site

Yokohama, Kanagawa, Japan

Novartis Investigative Site

Bunkyo-ku, Tokyo, Japan

Novartis Investigative Site

Shinjuku-ku, Tokyo, Japan

Novartis Investigative Site

Rotterdam, , Netherlands

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Songkhla, , Thailand

Novartis Investigative Site

Istanbul, TUR, Turkey (Türkiye)

Novartis Investigative Site

Sheffield, South Yorkshire, United Kingdom

Countries

United States; Argentina; Austria; Bulgaria; Canada; China; Colombia; France; Germany; India; Italy; Japan; Netherlands; Russia; South Korea; Spain; Thailand; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: DERIVED

PMID: 39610378 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38696122 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37680892 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33074401 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32730798 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

2013-004766-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLCI699C2301

Identifier Type: -

Identifier Source: org_study_id