Clinical trial NCT02180217: Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cushings Disease
Keywords: LCI699
osilodrostat
Cushings Disease
open-label dose titration
randomized withdrawal
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-07-02
Enrollment: 137
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata
timeFrame: Week 34 (8 weeks)
Secondary outcomes:
measure: Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)
timeFrame: Week 24
measure: Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group
timeFrame: 8 weeks after randomization
measure: Complete Response Rate (CRR)
timeFrame: Week 12, Week 24, Week 48, Week 72, last observed value
measure: Actual Change From Baseline in mUFC
timeFrame: Weeks 12, 24, 48, 72, last available assessment
measure: Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose
timeFrame: Baseline, Weeks 48, 72, last available assessment
measure: Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C)
timeFrame: Baseline, Weeks 48, 72, last available assessment
measure: Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride
timeFrame: Baseline, Weeks 48, 72, last available assessment
measure: Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP)
timeFrame: Baseline, Weeks 48, 72, last available assessment
measure: Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight
timeFrame: Baseline, Weeks 48, 72, last available assessment
measure: Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI)
timeFrame: Baseline, Weeks 48, 72, last available assessment
measure: Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference
timeFrame: Baseline, Weeks 48, 72, last available assessment
measure: Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score
timeFrame: Baseline, Week (W) 48, W72, Last available assessment
measure: Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)
timeFrame: Baseline, W48, W72, Last available assessment
measure: Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index
timeFrame: Baseline, W48, W72, Last available assessment
measure: Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)
timeFrame: Baseline, W48, W72, Last available assessment
measure: Change From Baseline in the Physical Features of Cushing's Disease by Photography
timeFrame: Week 48, Week 72, Last available assessment
measure: Change From Baseline in Bone Mineral Density - All Participants
timeFrame: Baseline, Week 48, Last observed value (LOV)
measure: Time-to-escape
timeFrame: From the first mUFC ≤ ULN to the first mUFC results > 1.5 x ULN with at least 2 individual UFC results > 1.5 x ULN
measure: LCI699 Exposures
timeFrame: from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose
measure: Percentage of Participants With Complete Response Rate (CRR)
timeFrame: Week 12, Week 24, Week 48, Week 72, last available assessment
measure: Percentage of Participants With Partial Response Rate (PRR)
timeFrame: Week 12, Week 24, Week 48, Week 72, last available assessment
measure: Percentage of Participants With Overall Response Rate (ORR)
timeFrame: Week 12, Week 24, Week 48, Week 72, last available assessment
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Hospital SC - LCI699C2301
state: Colorado
city: Atlanta
country: United States
facility: Emory University School of Medicine G2304 - C2301
state: Georgia
city: Chicago
country: United States
facility: Northwestern University SC - LCI699C2301
state: Illinois
city: Baltimore
country: United States
facility: The Johns Hopkins University School of Medicine Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Neuroendocrine Unit
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: New York
country: United States
facility: Mount Sinai School of Medicine SC - LCI699C2301
state: New York
city: New York
country: United States
facility: Columbia University Medical Center New York Presbyterian SC - LCI699C2301
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University SC LCI699C2301
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Clinical Studies Unit Unniv SC
state: Pennsylvania
city: Milwaukee
country: United States
facility: Medical College of Wisconsin MCW 2
state: Wisconsin
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Beijing
country: China
facility: Novartis Investigative Site
state: Beijing
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Beijing
country: China
facility: Novartis Investigative Site
city: Cali
country: Colombia
facility: Novartis Investigative Site
city: Le Kremlin Bicetre
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pessac Cedex
country: France
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Chandigarh
country: India
facility: Novartis Investigative Site
state: Punjab
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Messina
country: Italy
facility: Novartis Investigative Site
state: ME
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kobe-shi
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Nishinomiya
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Yokohama
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Bunkyo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Songkla
country: Thailand
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Sheffield
country: United Kingdom
facility: Novartis Investigative Site
state: South Yorkshire
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.