| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011651 |
| E.1.2 | Term | Cushing's disease |
| E.1.2 | System Organ Class | 100000004860 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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. |
|
| E.5.2.1 | 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
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient-Reported Outcomes (Health-Related Quality of Life) |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| single-arm, open-label dose titration and treatment |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Completion of the study as a whole (last patient last visit) will occur after the last patient completes the core period or discontinued early from the core period |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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