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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02180217




Registration number
NCT02180217
Ethics application status
Date submitted
17/06/2014
Date registered
2/07/2014

Titles & IDs
Public title
Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease
Scientific 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
Secondary ID [1] 0 0
2013-004766-34
Secondary ID [2] 0 0
CLCI699C2301
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cushings Disease 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Other endocrine disorders
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - osilodrostat
Treatment: Drugs - LCI699 matching placebo

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.

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.


Treatment: Drugs: 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.

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata
Assessment method [1] 0 0
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
Timepoint [1] 0 0
Week 34 (8 weeks)
Secondary outcome [1] 0 0
Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Week 24
Secondary outcome [2] 0 0
Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group
Assessment method [2] 0 0
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.
Timepoint [2] 0 0
8 weeks after randomization
Secondary outcome [3] 0 0
Complete Response Rate (CRR)
Assessment method [3] 0 0
Complete response rate is defined as percentage of enrolled participants with mUFC = ULN
Timepoint [3] 0 0
Week 12, Week 24, Week 48, Week 72, last observed value
Secondary outcome [4] 0 0
Actual Change From Baseline in mUFC
Assessment method [4] 0 0
Actual change in mUFC from baseline.
Timepoint [4] 0 0
Weeks 12, 24, 48, 72, last available assessment
Secondary outcome [5] 0 0
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose
Assessment method [5] 0 0
Actual change in fasting glucose from baseline.
Timepoint [5] 0 0
Baseline, Weeks 48, 72, last available assessment
Secondary outcome [6] 0 0
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C)
Assessment method [6] 0 0
Actual change in glycosylated hemoglobin (HbA1c) from baseline.
Timepoint [6] 0 0
Baseline, Weeks 48, 72, last available assessment
Secondary outcome [7] 0 0
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride
Assessment method [7] 0 0
Actual change in Cholesterol, LDL Cholesterol, HDL Cholesterol \& Triglyceride from baseline.
Timepoint [7] 0 0
Baseline, Weeks 48, 72, last available assessment
Secondary outcome [8] 0 0
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP)
Assessment method [8] 0 0
Actual change in sitting SBP \& DBP from baseline.
Timepoint [8] 0 0
Baseline, Weeks 48, 72, last available assessment
Secondary outcome [9] 0 0
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight
Assessment method [9] 0 0
Actual change in weight from baseline.
Timepoint [9] 0 0
Baseline, Weeks 48, 72, last available assessment
Secondary outcome [10] 0 0
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI)
Assessment method [10] 0 0
Actual change in BMI from baseline.
Timepoint [10] 0 0
Baseline, Weeks 48, 72, last available assessment
Secondary outcome [11] 0 0
Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference
Assessment method [11] 0 0
Actual change in waist circumference from baseline.
Timepoint [11] 0 0
Baseline, Weeks 48, 72, last available assessment
Secondary outcome [12] 0 0
Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score
Assessment method [12] 0 0
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.
Timepoint [12] 0 0
Baseline, Week (W) 48, W72, Last available assessment
Secondary outcome [13] 0 0
Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)
Assessment method [13] 0 0
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.
Timepoint [13] 0 0
Baseline, W48, W72, Last available assessment
Secondary outcome [14] 0 0
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index
Assessment method [14] 0 0
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.
Timepoint [14] 0 0
Baseline, W48, W72, Last available assessment
Secondary outcome [15] 0 0
Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)
Assessment method [15] 0 0
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.
Timepoint [15] 0 0
Baseline, W48, W72, Last available assessment
Secondary outcome [16] 0 0
Change From Baseline in the Physical Features of Cushing's Disease by Photography
Assessment method [16] 0 0
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).
Timepoint [16] 0 0
Week 48, Week 72, Last available assessment
Secondary outcome [17] 0 0
Change From Baseline in Bone Mineral Density - All Participants
Assessment method [17] 0 0
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..
Timepoint [17] 0 0
Baseline, Week 48, Last observed value (LOV)
Secondary outcome [18] 0 0
Time-to-escape
Assessment method [18] 0 0
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.
Timepoint [18] 0 0
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
Secondary outcome [19] 0 0
LCI699 Exposures
Assessment method [19] 0 0
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.
Timepoint [19] 0 0
from week 2 to 10 at Predose, 0.75h, 1.5h, and 4h post-dose
Secondary outcome [20] 0 0
Percentage of Participants With Complete Response Rate (CRR)
Assessment method [20] 0 0
Complete response rate is defined as percentage of enrolled participants with mUFC = ULN.
Timepoint [20] 0 0
Week 12, Week 24, Week 48, Week 72, last available assessment
Secondary outcome [21] 0 0
Percentage of Participants With Partial Response Rate (PRR)
Assessment method [21] 0 0
Partial response rate is defined as percentage of enrolled participants with = 50% reduction from baseline in mUFC, but mUFC\>ULN)
Timepoint [21] 0 0
Week 12, Week 24, Week 48, Week 72, last available assessment
Secondary outcome [22] 0 0
Percentage of Participants With Overall Response Rate (ORR)
Assessment method [22] 0 0
Overall response rate is defined as percentage of enrolled participants with mUFC = ULN or at least 50% reduction from baseline.
Timepoint [22] 0 0
Week 12, Week 24, Week 48, Week 72, last available assessment

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
6/10/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/12/2019
Sample size
Target
Accrual to date
Final
137
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
Georgia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Maryland
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Oregon
Country [9] 0 0
United States of America
State/province [9] 0 0
Pennsylvania
Country [10] 0 0
United States of America
State/province [10] 0 0
Wisconsin
Country [11] 0 0
Argentina
State/province [11] 0 0
Buenos Aires
Country [12] 0 0
Austria
State/province [12] 0 0
Wien
Country [13] 0 0
Bulgaria
State/province [13] 0 0
Sofia
Country [14] 0 0
Canada
State/province [14] 0 0
Alberta
Country [15] 0 0
Canada
State/province [15] 0 0
Nova Scotia
Country [16] 0 0
Canada
State/province [16] 0 0
Quebec
Country [17] 0 0
China
State/province [17] 0 0
Beijing
Country [18] 0 0
China
State/province [18] 0 0
Sichuan
Country [19] 0 0
Colombia
State/province [19] 0 0
Cali
Country [20] 0 0
France
State/province [20] 0 0
Le Kremlin Bicetre
Country [21] 0 0
France
State/province [21] 0 0
Lille Cedex
Country [22] 0 0
France
State/province [22] 0 0
Marseille
Country [23] 0 0
France
State/province [23] 0 0
Paris
Country [24] 0 0
France
State/province [24] 0 0
Pessac Cedex
Country [25] 0 0
Germany
State/province [25] 0 0
Erlangen
Country [26] 0 0
Germany
State/province [26] 0 0
Muenchen
Country [27] 0 0
India
State/province [27] 0 0
Karnataka
Country [28] 0 0
India
State/province [28] 0 0
Punjab
Country [29] 0 0
India
State/province [29] 0 0
Tamil Nadu
Country [30] 0 0
India
State/province [30] 0 0
New Delhi
Country [31] 0 0
Italy
State/province [31] 0 0
AN
Country [32] 0 0
Italy
State/province [32] 0 0
GE
Country [33] 0 0
Italy
State/province [33] 0 0
ME
Country [34] 0 0
Italy
State/province [34] 0 0
MI
Country [35] 0 0
Italy
State/province [35] 0 0
PD
Country [36] 0 0
Italy
State/province [36] 0 0
PI
Country [37] 0 0
Italy
State/province [37] 0 0
Napoli
Country [38] 0 0
Japan
State/province [38] 0 0
Aichi
Country [39] 0 0
Japan
State/province [39] 0 0
Fukuoka
Country [40] 0 0
Japan
State/province [40] 0 0
Hyogo
Country [41] 0 0
Japan
State/province [41] 0 0
Kanagawa
Country [42] 0 0
Japan
State/province [42] 0 0
Tokyo
Country [43] 0 0
Korea, Republic of
State/province [43] 0 0
Seoul
Country [44] 0 0
Netherlands
State/province [44] 0 0
Rotterdam
Country [45] 0 0
Russian Federation
State/province [45] 0 0
Moscow
Country [46] 0 0
Spain
State/province [46] 0 0
Andalucia
Country [47] 0 0
Spain
State/province [47] 0 0
Madrid
Country [48] 0 0
Thailand
State/province [48] 0 0
Songkla
Country [49] 0 0
Turkey
State/province [49] 0 0
TUR
Country [50] 0 0
United Kingdom
State/province [50] 0 0
South Yorkshire

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT02180217