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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 : June 16, 2020
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, the EU, Japan, and other countries.

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-last Control of Mean Urinary Free Cortisol (mUFC) During RW Period Changed to: Time-to-loss of Control of mUFC) by Randomized Treatment Group [ Time Frame: Between Week 26 and Week 34, up to a maximum of 8 weeks after randomizaion ]
    Time-to-last control of mUFC, defined as time from randomization to the last normal UFC assessment (mUFC ≤ ULN based on the central laboratory result) within the randomized withdrawal (RW) Period. This was changed to 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 rationale for the change was to provide a clear definition of events & censoring which is based on mUFC values & to align with the criteria for discontinuing a patient from randomized treatment due to loss of control.

  3. Complete Response Rate (CRR) [ Time Frame: Week 12, Week 24, Week 48, and at scheduled time points during the extension phase and the last available assessment ]

    Complete response rate is defined as proportion of enrolled patients with mUFC ≤ ULN at Week 12, Week 24, Week 48, and at scheduled time points during the extension phase (provided adequate follow-up as specified in the SAP), and the last available assessment.

    SAP: Statistical Analysis Plan


  4. Change in mUFC [ Time Frame: From baseline to each scheduled visit (visits every 2, 4 or 12 weeks based on study phases (provided adequate follow-up as per SAP) ]

    Actual and percentage change in mUFC from baseline to each post baseline visit during the core and extension (provided adequate follow-up as per statistical analysis plan (SAP)) at which UFC is collected.

    Actual and percentage change in mUFC from the time of randomization to the end of the randomized withdrawal period, or the last mUFC measurement prior to early discontinuation, whichever occurs earlier.


  5. Change in Cardiovascular-related Parameters Associated With Cushing's Disease [ Time Frame: From baseline to each scheduled visit (visits every 2, 4 or 12 weeks based on study phases (provided adequate follow-up as per SAP) ]

    Actual and percentage change from baseline during the core and extension periods (provided adequate follow-up as per SAP) in fasting glucose, HbA1c, fasting lipid profile, blood pressure, body weight, BMI and waist circumference.

    Actual and percentage change from the randomization to the end of randomized withdrawal period, or the last measurement available prior to early discontinuation, whichever occurs earlier.


  6. Change in Patient-Reported Outcomes (Health-Related Quality of Life) [ Time Frame: From baseline to W24, W48, W72, W96 and EOT Ext (28 days since last visit); and from the randomization to the end of randomized withdrawal period or the last measurement prior to early discontinuation; whichever occurs earlier ]

    Change in standardized score of CushingQoL, Beck Depression Inventory-II, and EQ-5D-5L, from baseline to Week 24 and Week 48.

    Change in standardized score of CushingQoL, Beck Depression Inventory-II, and EQ-5D-5L, from the randomization to the end of randomized withdrawal period, or the last measurement prior to early discontinuation, whichever occurs earlier.

    Change from baseline in standardized score of CushingQoL, Beck Depression Inventory-II, and EQ-5D-5L, from baseline to Week 72, 96 and the EOT extension.

    EOT Extension (EOT Ext): End of Treatment Extension, 28 days since last visit


  7. Change in the Physical Features of Cushing's Disease by Photography [ Time Frame: Week 12, 24, 34, 48, and from baseline to Week 12, 24, 34, 48 and during the extension at week 72 and EOT extension (28 days since last visit) ]
    Categorical change from baseline to Week 12, 24, 34, 48, during the extension at week 72 and EOT extension 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).

  8. Change in Bone Mineral Density [ Time Frame: From Baseline to Week 48 and the last available assessment ]
    Actual and percent change from baseline to Week 48 and the last available assessment in bone mineral density as measured by DXA scan at the lumbar spine and total hip

  9. 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 ]
    Time-to-escape is 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.

  10. General Safety and AEs of Special Interest [ Time Frame: Every visit for a minimum of 72 weeks ]

    Adverse events and laboratory abnormalities will be assessed using the National Cancer Institute-Common Toxicology Criteria (NCI-CTC) grading scale (version 4.03).

    AEs of special interest, as reported by the investigator, or by laboratory evaluation, ECG, Holter recording, and pituitary MRI.


  11. LCI699 Exposures [ Time Frame: Predose, 0.5 h, 1.5 h, and 3.5 h post-dose ]
    To evaluate exposures of LCI699 in patients with Cushing's disease. Plasma concentrations (predose, 0.5 h, 1.5 h, and 3.5 h post-dose) of LCI699

  12. Partial Response Rate (PRR) [ Time Frame: Week 12, Week 24, Week 48, and at scheduled time points during the extension phase and the last available assessment ]
    Partial response rate is defined as proportion of enrolled patients with ≥ 50% reduction from baseline in mUFC, but mUFC>ULN) at Week 12, Week 24, Week 48, and at scheduled time points during the extension phase (provided adequate follow-up as specified in the SAP), and the last available assessment.

  13. Overall Response Rate (ORR) [ Time Frame: Week 12, Week 24, Week 48, and at scheduled time points during the extension phase and the last available assessment ]
    Overall response rate is defined as proportion of enrolled patients with mUFC≤ULN or at least 50% reduction from baseline at Week 12, Week 24, Week 48, and at scheduled time points during the extension phase (provided adequate follow-up as specified in the SAP), and the last available assessment.



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
Show Show 66 study locations
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] July 6, 2018
Study Protocol  [PDF] July 6, 2017

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: June 16, 2020
Last Verified: May 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