Cushings DiseasePhase 3NCT02180217
Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease
A Phase 3 study testing osilodrostat in people with Cushings Disease, run by Novartis Pharmaceuticals at 60 sites in 19 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Cushings Disease
- What is being tested?
- osilodrostat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 137 participants
- Where
- 60 sitesin 19 countries
- Study dates
- 6 Oct 2014to 4 Dec 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 with a history of prior pituitary surgery must be at least 30 days post-surgery to be eligible for inclusion in this study.
- 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.
Who cannot join
- 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.
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- 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.
- Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with defined elevated ALT/ AST/ Bilirubin.
- 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.
- Patients who have a history of alcohol or drug abuse in the 6 month period prior to study treatment.
- 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.
Trial locations and contacts
60 sites in 19 countries.
60 sites in 19 countries
United States12 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
Emory University School of Medicine G2304 - C2301
Atlanta, Georgia, 30322
University of Colorado Hospital SC - LCI699C2301
Aurora, Colorado, 80045
The Johns Hopkins University School of Medicine Johns Hopkins University
Baltimore, Maryland, 21205
Massachusetts General Hospital Neuroendocrine Unit
Boston, Massachusetts, 02114
Northwestern University SC - LCI699C2301
Chicago, Illinois, 60611
Medical College of Wisconsin MCW 2
Milwaukee, Wisconsin, 53226
Mount Sinai School of Medicine SC - LCI699C2301
New York, New York, 10029
Columbia University Medical Center New York Presbyterian SC - LCI699C2301
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of Pennsylvania Clinical Studies Unit Unniv SC
Philadelphia, Pennsylvania, 19104
Oregon Health and Science University SC LCI699C2301
Portland, Oregon, 97239
Italy7 sites
Novartis Investigative Site
Ancona, AN, 60126
Novartis Investigative Site
Genova, GE, 16132
Novartis Investigative Site
Messina, ME, 98125
Novartis Investigative Site
Milan, MI, 20122
Novartis Investigative Site
Naples, 80131
Novartis Investigative Site
Padova, PD, 35128
Novartis Investigative Site
Pisa, PI, 56124
Japan7 sites
Novartis Investigative Site
Bunkyo-ku, Tokyo, 113-8603
Novartis Investigative Site
Fukuoka, Fukuoka, 812-8582
Novartis Investigative Site
Kobe, Hyōgo, 650-0017
Novartis Investigative Site
Nagoya, Aichi-ken, 460-0001
Novartis Investigative Site
Nishinomiya, Hyōgo, 663 8501
Novartis Investigative Site
Shinjuku-ku, Tokyo, 160-0023
Novartis Investigative Site
Yokohama, Kanagawa, 245-8575
France5 sites
Novartis Investigative Site
Le Kremlin-Bicêtre, 94275
Novartis Investigative Site
Lille, 59037
Novartis Investigative Site
Marseille, 13385
Novartis Investigative Site
Paris, 75014
Novartis Investigative Site
Pessac, 33604
Canada4 sites
Novartis Investigative Site
Edmonton, Alberta, T6G 2B7
Novartis Investigative Site
Halifax, Nova Scotia, B3H 1V7
Novartis Investigative Site
Montreal, Quebec, H2W 1T8
Novartis Investigative Site
Sherbrooke, Quebec, J1H 5N4
India4 sites
Novartis Investigative Site
Bangalore, Karnataka, 560054
Novartis Investigative Site
Chandigarh, Punjab, 160012
Novartis Investigative Site
New Delhi, 110029
Novartis Investigative Site
Vellore, Tamil Nadu, 632004
China3 sites
Novartis Investigative Site
Beijing, Beijing Municipality, 100730
Novartis Investigative Site
Beijing, 100034
Novartis Investigative Site
Chengdu, Sichuan, 610041
South Korea3 sites
Novartis Investigative Site
Seoul, 03080
Novartis Investigative Site
Seoul, 03722
Novartis Investigative Site
Seoul, 06351
Spain3 sites
Novartis Investigative Site
Madrid, 28009
Novartis Investigative Site
Madrid, 28046
Novartis Investigative Site
Seville, Andalusia, 41013
Argentina2 sites
Novartis Investigative Site
CABA, Buenos Aires, C1180AAX
Novartis Investigative Site
CABA, Buenos Aires, C1426AAI
Germany2 sites
Novartis Investigative Site
Erlangen, 91054
Novartis Investigative Site
München, 81377
Turkey (Türkiye)1 site
Novartis Investigative Site
Istanbul, TUR, 34098
United Kingdom1 site
Novartis Investigative Site
Sheffield, South Yorkshire, S10 2JF
About this study
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
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.
Read the 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
- Being tested
- osilodrostat, LCI699 matching placebo
- Keywords
- LCI699, osilodrostat, Cushings Disease, open-label dose titration, randomized withdrawal
- Medical subject headings
- Adrenocortical Hyperfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
osilodrostatDrug
Also called LCI699
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 matching placeboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: LCI699 matching placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Week 34 (8 weeks)
Secondary outcomes (22)
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.
Measured: 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.
Measured: 8 weeks after randomization
Complete Response Rate (CRR)
Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN
Measured: Week 12, Week 24, Week 48, Week 72, last observed value
Actual Change From Baseline in mUFC
Actual change in mUFC from baseline.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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..
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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)
Measured: 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.
Measured: Week 12, Week 24, Week 48, Week 72, last available assessment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2014 (estimated)
- Study start6 Oct 2014
- Primary completion21 Feb 2018
- Study completion4 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Cushings DiseaseStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 137 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02180217
- Sponsor's protocol ID
- CLCI699C2301
- Other IDs
- 2013-004766-34
- Status last verified
- Dec 2020
- First submitted
- 17 Jun 2014
- Last updated
- 6 Jan 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Publications
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.
PubMed 41052284Newell-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.
PubMed 39610378Pivonello 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.
PubMed 38696122Gadelha 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.
PubMed 37680892Fontaine-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.
PubMed 33074401Pivonello 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.
PubMed 32730798
Study at a glance
From the registry record, last updated by the sponsor on 6 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02180217
- Acronym / sponsor ID
- CLCI699C2301
- Conditions
- Cushings Disease
- Keywords
- LCI699, osilodrostat, Cushings Disease, open-label dose titration, randomized withdrawal
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 137 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 6 Oct 2014 (actual)
- Primary completion
- 21 Feb 2018 (actual)
- Study completion
- 4 Dec 2019 (actual)
- First posted
- 2 Jul 2014 (estimated)
- Results
- Posted 16 Jun 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| osilodrostat (LCI699) | Experimental | Drug: osilodrostatConsisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period. |
| LCI699 Placebo | Placebo comparator | Drug: LCI699 matching placeboConsisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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 with a history of prior pituitary surgery must be at least 30 days post-surgery to be eligible for inclusion in this study.
- 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.
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| osilodrostatAlso: LCI699Osilodrostat 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. | Drug | osilodrostat (LCI699) |
| LCI699 matching placeboOsilodrostat 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. | Drug | LCI699 Placebo |
Primary outcome
Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata
Time frame: 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
22 secondary outcomes
Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)
Time frame: Week 24
Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group
Time frame: 8 weeks after randomization
Complete Response Rate (CRR)
Time frame: Week 12, Week 24, Week 48, Week 72, last observed value
Actual Change From Baseline in mUFC
Time frame: Weeks 12, 24, 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose
Time frame: Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C)
Time frame: 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
Time frame: 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)
Time frame: Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight
Time frame: Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI)
Time frame: Baseline, Weeks 48, 72, last available assessment
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference
Time frame: 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
Time frame: Baseline, Week (W) 48, W72, Last available assessment
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)
Time frame: Baseline, W48, W72, Last available assessment
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index
Time frame: Baseline, W48, W72, Last available assessment
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)
Time frame: Baseline, W48, W72, Last available assessment
Change From Baseline in the Physical Features of Cushing's Disease by Photography
Time frame: Week 48, Week 72, Last available assessment
Change From Baseline in Bone Mineral Density - All Participants
Time frame: Baseline, Week 48, Last observed value (LOV)
Time-to-escape
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
LCI699 Exposures
Time frame: from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose
Percentage of Participants With Complete Response Rate (CRR)
Time frame: Week 12, Week 24, Week 48, Week 72, last available assessment
Percentage of Participants With Partial Response Rate (PRR)
Time frame: Week 12, Week 24, Week 48, Week 72, last available assessment
Percentage of Participants With Overall Response Rate (ORR)
Time frame: Week 12, Week 24, Week 48, Week 72, last available assessment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jan 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41052284Fleseriu 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.
- Derived from this study: PubMed 39610378Newell-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.
- Derived from this study: PubMed 38696122Pivonello 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.
- Derived from this study: PubMed 37680892Gadelha 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.
- Derived from this study: PubMed 33074401Fontaine-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.
- Derived from this study: PubMed 32730798Pivonello 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.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
60 sites in 19 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing osilodrostat in people with Cushings Disease, run by Novartis Pharmaceuticals at 60 sites in 19 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 60 sites in United States, Italy, Japan, France, Canada and 14 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata (time frame: Week 34 (8 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02180217, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jan 2021.