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

• Register: EUCTR
• Last refreshed on: 7 December 2020
• Main ID: EUCTR2013-004766-34-DE
• Date of registration: 29/07/2014
• 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: 06/10/2014
• 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: Medizinischer Infoservice (MCC)
• Affiliation: Novartis Pharma GmbH

• Name: Medizinischer Infoservice (MCC)
• 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 (Mean of three 24-hour urine samples collected within 14 days)
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; OR
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

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: osilodrostat 1mg
Product Code: LCI699, 1 mg
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, 5 mg
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, 10 mg
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, 20 mg
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: 20-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

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.

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.

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

Secondary Objective: Key secondary:
To assess the complete response rate at the end of individual dosetitration
and treatment with LCI699 in the initial single-arm, open label
period (Week 24).
Other secondary:
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

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 (time 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: 06/10/2014
Contact:

Results

• Results available: Yes
• Date Posted: 31/10/2020
• Date Completed: 04/12/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004766-34/results