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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02180217
Recruitment Status : Completed
First Posted : July 2, 2014
Results First Posted : June 16, 2020
Last Update Posted : January 6, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.


Condition or disease Intervention/treatment Phase
Cushings Disease Drug: osilodrostat Drug: LCI699 matching placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 137 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : October 6, 2014
Actual Primary Completion Date : February 21, 2018
Actual Study Completion Date : December 4, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: osilodrostat (LCI699)
Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.
Drug: osilodrostat
Osilodrostat comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat was 30 mg bid.
Other Name: LCI699

Placebo Comparator: LCI699 Placebo
Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.
Drug: LCI699 matching placebo
Osilodrostat placebo comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat placebo was 30 mg bid.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint) [ Time Frame: Week 24 ]
    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.

  2. Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group [ Time Frame: 8 weeks after randomization ]
    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.

  3. Complete Response Rate (CRR) [ Time Frame: Week 12, Week 24, Week 48, Week 72, last observed value ]
    Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN

  4. Actual Change From Baseline in mUFC [ Time Frame: Weeks 12, 24, 48, 72, last available assessment ]
    Actual change in mUFC from baseline.

  5. 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 in fasting glucose from baseline.

  6. 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 in glycosylated hemoglobin (HbA1c) from baseline.

  7. 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 in Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride from baseline.

  8. 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 in sitting SBP & DBP from baseline.

  9. 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 in weight from baseline.

  10. 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 in BMI from baseline.

  11. 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 in waist circumference from baseline.

  12. 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 ]
    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.

  13. Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II) [ Time Frame: Baseline, W48, W72, Last available assessment ]
    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.

  14. Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index [ Time Frame: Baseline, W48, W72, Last available assessment ]
    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.

  15. Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS) [ Time Frame: Baseline, W48, W72, Last available assessment ]
    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.

  16. Change From Baseline in the Physical Features of Cushing's Disease by Photography [ Time Frame: Week 48, Week 72, Last available assessment ]
    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).

  17. Change From Baseline in Bone Mineral Density - All Participants [ Time Frame: Baseline, Week 48, Last observed value (LOV) ]
    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..

  18. 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 ]
    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.

  19. LCI699 Exposures [ Time Frame: from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose ]
    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.

  20. Percentage of Participants With Complete Response Rate (CRR) [ Time Frame: Week 12, Week 24, Week 48, Week 72, last available assessment ]
    Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN.

  21. Percentage of Participants With Partial Response Rate (PRR) [ Time Frame: Week 12, Week 24, Week 48, Week 72, last available assessment ]
    Partial response rate is defined as percentage of enrolled participants with ≥ 50% reduction from baseline in mUFC, but mUFC>ULN)

  22. Percentage of Participants With Overall Response Rate (ORR) [ Time Frame: Week 12, Week 24, Week 48, Week 72, last available assessment ]
    Overall response rate is defined as percentage of enrolled participants with mUFC ≤ ULN or at least 50% reduction from baseline.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02180217


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Statistical Analysis Plan  [PDF] December 2, 2019
Study Protocol  [PDF] June 29, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02180217    
Other Study ID Numbers: CLCI699C2301
2013-004766-34 ( EudraCT Number )
First Posted: July 2, 2014    Key Record Dates
Results First Posted: June 16, 2020
Last Update Posted: January 6, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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

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

URL: https://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
LCI699
osilodrostat
Cushings Disease
open-label dose titration
randomized withdrawal
Additional relevant MeSH terms:
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ACTH-Secreting Pituitary Adenoma
Pituitary ACTH Hypersecretion
Hyperpituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pituitary Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site