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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02180217
First Posted: July 2, 2014
Last Update Posted: October 18, 2017
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.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
June 17, 2014
July 2, 2014
October 18, 2017
October 6, 2014
March 23, 2018   (Final data collection date for primary outcome measure)
Proportion of randomized patients in each arm with mUFC ≤ ULN [ Time Frame: Week 34 (8 weeks) ]

To compare the complete response rate at the end of the 8-week period of randomized withdrawal between patients randomized (patients were neither discontinued, nor had LCI699 dose increase above the level at week 26 during the randomized withdrawal period.) to continued LCI699 therapy vs. placebo.

ULN: Upper Limit of Normal

Proportion of randomized patients with: mUFC </= ULN [ Time Frame: Week 34 (8 weeks) ]

To compare the complete response rate at the end of the 8-week period. These patients will not have discountinued during the randomized withdrawal period, between patients randomized to continue LCI699 therapy and placebo.

mUFC: mean Urinary free Cortisol) ULN: Upper Limit of Normal

Complete list of historical versions of study NCT02180217 on ClinicalTrials.gov Archive Site
  • Proportion of enrolled patients with mUFC ≤ ULN at Week 24 [ 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. These patients would have had no dose increase above the level established at Week 12 between Week 13 and Week 24.
  • Time-to-last control of mUFC [ Time Frame: Between Week 26 and Week 34, up to a maximum of 8 weeks (56 days) ]
    Time-to-last control of mUFC, which is defined as the time (in days) from randomization to the last mUFC collection that was ≤ ULN before early discontinuation or completion of randomized withdrawal period, whichever is earlier.
  • 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
  • Change in mUFC [ Time Frame: From baseline to each post-baseline visit during the core and extension ]

    Actual and percentage change in mUFC from baseline to each post baseline visit during the core and extension (provided adequate follow-up as specified in the 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.

  • Change in cardiovascular-related parameters associated with Cushing's disease [ Time Frame: Core and extension periods ]
    Actual and percentage change from baseline during the core and extension periods (provided adequate follow-up as specified in the SAP) of the study 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.
  • Change in Patient-Reported Outcomes (Health-Related Quality of Life) [ Time Frame: Core and extension periods ]

    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

  • Change in the physical features of Cushing's disease by photography [ Time Frame: Week 12, 24, 34, 48, and during the extension phase. ]
    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).
  • 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
  • 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.
  • 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.

  • 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
  • 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.
  • 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.
  • Proportion of enrolled patients with mUFC </= ULN [ 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. These patients would have had no dose increase above the level established at Week 12 between Week 13 and Week 24.
  • Time-to-last control of mUFC [ Time Frame: Betwwen week 26 and week 34, up to a maximum of 8 weeks (56 days) ]
    Time-to-last control of mUFC is defined as the time (in days) from randomization to the last mUFC collection that was </= ULN before early discontinuation or completion of randomized withrdrawal period, whichever is earlier.
  • Complete Response Rate (CRR) [ Time Frame: Week 12, Week 24, Week 48 ]
    Complete response rate is defined as proportion of enrolled patients with mUFC</= ULN at Week 12, Week 24 and Week 48.
  • Change in mUFC [ Time Frame: baseline, post-baseline, Week 26, Week 34 ]
    Actual and percentage change in mUFC from baseline to each post-baseline visit during the core and extension at which UFC is collected. Actual and percentage change in mUFC from the time of randomization (Week 26) to the end of the randomized withdrawal period (Week 34), or the last mUFC measurement prior to early discontinuation, whichever occurs earlier.
  • Change in cardiovascular-related parameters associated with Cushing's disease [ Time Frame: Baseline, Week 12, 24, 26, 34 and 48 ]
    This is for the actual and percentage change. The cardiovascular-related parameters include fasting glucose, HbA1c, fasting lipid profile, blood pressure, body weight, BMI and waist circumference.
  • Change in Patient-Reported Outcomes (Health-Related Quality of Life) [ Time Frame: Baseline, Week 24, 26, 34 and 48 ]
    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 (Week 26) to the end of randomized withdrawal period (Week 34), or the last measurement prior to early discontinuation, whichever occurs earlier.
  • Change in the physical features of Cushing's disease by photography [ Time Frame: Weeks 12, 24, 34, and 48. ]
    Mean change from baseline to Week 12, 24, 34, and 48 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).
  • Change in bone mineral density [ Time Frame: Baseline, Week 48 ]
    Actual and percent change from baseline to Week 48 in bone mineral density as measured by DEXA scan at the lumbar spine and total hip.
  • Time-to-escape [ Time Frame: At first mUFC results > 1.5 x ULN ]
    Time-to-escape is defined as time (in days) from the first mUFC </= ULN to the first mUFC results > 1.5 x ULN.
  • Number of patients with adverse events (AEs) [ Time Frame: Every visit for 96 weeks ]
    For safety and tolerabuility, adverse events and laboratory abnormalities will be assessed using the National Cancer Institute-Common Toxicology Criteria (NCI-CTC) grading scale (version 4.0). AEs of special interest, as reported by the investigator, or by laboratory evaluation, electrocardiogam (ECG), Holter recording, and pituitary magnetic resonance imaging (MRI).
  • Plasma concentration of LCI699 [ 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
  • Partial Response Rate (PRR) [ Time Frame: Week 12, Week 24, Week 48 ]
    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 and Week 48.
  • Overall Response Rate (ORR) [ Time Frame: Week 12, Week 24, Week 48 ]
    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.
  • Actual and percentage change in mUFC [ Time Frame: Start of randomization (Week 26) to end of randomization (Week 34) ]
    Actual and percentage change in mUFC from baseline to each post-baseline visit during the core and extension at which UFC is collected. Actual and percentage change in mUFC from the time of randomization (Week 26) to the end of the randomized withdrawal period (Week 34), or the last mUFC measurement prior to early discontinuation, whichever occurs earlier.
  • Correlation between salivary cortisol and mUFC [ Time Frame: Core and extension periods ]
    Pearson's correlation and Spearman's rank correlation between morning and late night salivary cortisol and mUFC
  • Correlation between urine metabolomic pattern and LCI699 response [ Time Frame: Core period visits ]
    Correlation of efficacy endpoints and safety endpoints with urine metabolomic pattern at baseline, Week 12, Week 24, and Week 48.
  • PK/PD analyses for efficacy and safety [ Time Frame: Core period visits ]
    Correlation of efficacy endpoints and safety endpoints with appropriate PK parameters
Not Provided
 
Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease
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 aims to confirm long-term efficacy and safety of LCI699 for the treatment of patients with Cushing's disease. It is a pivotal trial intended to support the registration of LCI699 for the treatment of patients with Cushing's disease in the EU, Japan, and other countries.
Not Provided
Interventional
Phase 3
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Cushing's Disease
Drug: LCI699
Experimental: LCI699
Intervention: Drug: LCI699
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
137
December 7, 2018
March 23, 2018   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Argentina,   Austria,   Bulgaria,   Canada,   China,   Colombia,   France,   Germany,   India,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Russian Federation,   Spain,   Thailand,   Turkey,   United Kingdom,   United States
Australia
 
NCT02180217
CLCI699C2301
2013-004766-34 ( EudraCT Number )
No
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: Undecided
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

Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP