Safety and efficacy of osilodrostat (LCI699) for the treatment of patients with Cushing's disease

• Register: EUCTR
• Last refreshed on: 1 February 2020
• Main ID: EUCTR2013-004766-34-AT
• Date of registration: 31/07/2014
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Safety and efficacy of osilodrostat (LCI699) for the treatment of patients with Cushing's disease
• Scientific title: A 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
• Date of first enrolment: 05/08/2014
• Target sample size: 132
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004766-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: yes; Other trial design description: single-arm, open-label dose titration and treatment; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Bulgaria, Canada, China, Colombia, France, Germany, India, Italy, Japan, Korea, Republic of, Netherlands, Russian Federation, Spain, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Drug Regulatory Affairs
• Affiliation: Novartis Pharma GmbH

• Name: Drug Regulatory Affairs
• Affiliation: Novartis Pharma GmbH

Key inclusion & exclusion 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 as evidenced by:
a. mUFC > 1.5 x ULN at screening
b. Morning plasma ACTH above lower limit of normal
c. Confirmation of pituitary source of excess ACTH is defined by any of the following three criteria:
1. MRI confirmation of pituitary adenoma > 6 mm; OR
2. bilateral inferior petrosal sinus sampling (BIPSS) with either CRH or DDAVP
stimulation for patients with a tumor = 6mm. The criteria for a confirmatory
BIPSS test are any of the following:
• Pre-dose central to peripheral ACTH gradient > 2;
• Post-dose central to peripheral ACTH gradient > 3 after either CRH or DDAVP
stimulation
3. histopathologic confirmation of an ACTH-staining adenoma in patients who have had prior pituitary surgery.

Additional inclusion criteria as per full protocol may apply.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 119
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 13

Exclusion criteria:
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives 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 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.
3. Patients with risk factors for QTc prolongation or Torsade de Pointes, including: patients with a baseline QTcF > 450ms (males) or >460ms (females), personal or family history of long QT syndrome, or concomitant medications known to prolong the QT interval, hypokalemia, hypocalcaemia, or hypomagnesemia if not corrected before pre-dose Day 1.
4. Pregnant or nursing (lactating) women.

Additional exclusion criteria as per full protocol may apply.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cushing's disease
MedDRA version: 20.0 Level: LLT Classification code 10011651 Term: Cushing's disease System Organ Class: 100000004860

Therapeutic area: Diseases [C] - Hormonal diseases [C19]

Intervention(s)

Product Name: osilodrostat 1mg
Product Code: LCI699
Pharmaceutical Form: Tablet
INN or Proposed INN: osilodrostat
CAS Number: 928134-65-0
Current Sponsor code: LCI699
Other descriptive name: LCI699
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: osilodrostat 5mg
Product Code: LCI699
Pharmaceutical Form: Tablet
INN or Proposed INN: osilodrostat
CAS Number: 928134-65-0
Current Sponsor code: LCI699
Other descriptive name: LCI699
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: osilodrostat 10mg
Product Code: LCI699
Pharmaceutical Form: Tablet
INN or Proposed INN: osilodrostat
CAS Number: 928134-65-0
Current Sponsor code: LCI699
Other descriptive name: LCI699
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: osilodrostat 20mg
Product Code: LCI699

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 34 (8 weeks)

Secondary Objective: 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 (Week 24).
1. Compare the time-to-last control of mUFC during the randomized withdrawal period between patients randomized to continued LCI699 therapy and placebo.
2. Assess the complete, partial, and overall response rate at defined study timepoints.
3. Assess the change in mUFC at defined study timepoints.
4. Assess the change in cardiovascular-related parameters associated with Cushing’s disease at defined study timepoints.
5. Assess the change in Patient-Reported Outcomes (Health- Related Quality of Life) at defined study timepoints.
6. Assess the change in physical features of Cushing’s disease by photography at defined study timepoints.
7. Assess the change in bone mineral density at defined study timepoints.
Other objectives may apply.

Primary end point(s): Proportion of randomized patients in each arm with: mUFC = ULN at the end of 8 weeks of randomized withdrawal (Week 34), and were neither discontinued, nor had LCI699 dose increase above the level at week 26 during the randomized withdrawal period.

Main Objective: To compare the complete response rate at the end of the 8-week period of randomized withdrawal (Week 34) between patients randomized to continued LCI699 therapy vs. placebo.

Secondary Outcome(s)

Secondary end point(s): key secondary:
Proportion of enrolled patients with mUFC = ULN at Week 24 and had no dose increase above the level established at Week 12 between Week 13 and Week 24.

Other secondary:
1. 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
2. Complete response rate (proportion of enrolled patients with mUFC = ULN), partial response rate (proportion of enrolled patients with >=50% reduction from baseline in mUFC, but mUFC > ULN), and overall response rate (proportion of complete+partial responders)
3. Change in mUFC
4. Change in fasting glucose, HbA1c, fasting lipid profile, blood pressure, body weight, BMI and waist circumference
5. Change in standardized score of CushingQoL, Beck Depression Inventory-II, and EQ-5D-5L
6. Categorical change 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).
7. Change in bone mineral density as measured by DEXA scan at the lumbar spine and total hip

Additional secondary endpoints as per full protocol may apply.

Timepoint(s) of evaluation of this end point: Key secondary: Week 24

Other secondary:
1. time-to-last control of mUFC
2. Week 12, 24, 48, at scheduled time points during the extension phase and at last available assessment
3., 4. and 5. From baseline to each postbaseline visit during the core and extension at which parameter is collected, and from week 26 to week 34
6. Weeks 12, 24, 34, 48, 72 and EoT
7. From Baseline to Week 48 and to last available assessment

Secondary ID(s)

CLCI699C2301

2013-004766-34-IT

Source(s) of Monetary Support

Novartis Pharma Services AG

Ethics review

Status: Approved
Approval date: 02/07/2014
Contact: