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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02180217
• Date of registration: 17/06/2014
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharmaceuticals
• 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
• Date of first enrolment: October 6, 2014
• Target sample size: 137
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02180217
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

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: Novartis Pharmaceuticals
• Affiliation: Novartis Pharmaceuticals

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.

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.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Cushings Disease

Intervention(s)

Drug: osilodrostat

Drug: LCI699 matching placebo

Primary Outcome(s)

Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata [Time Frame: Week 34 (8 weeks)]

Secondary Outcome(s)

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]

Change in Patient-Reported Outcomes (Health-Related Quality of Life) [Time Frame: From baseline to W24, W48, W72, W96 and EOT Ext (28 days since last visit); and from the randomization to the end of randomized withdrawal period or the last measurement prior to early discontinuation; whichever occurs earlier]

General Safety and AEs of Special Interest [Time Frame: Every visit for a minimum of 72 weeks]

LCI699 Exposures [Time Frame: Predose, 0.5 h, 1.5 h, and 3.5 h post-dose]

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]

Change in the Physical Features of Cushing's Disease by Photography [Time Frame: Week 12, 24, 34, 48, and from baseline to Week 12, 24, 34, 48 and during the extension at week 72 and EOT extension (28 days since last visit)]

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]

Change in Cardiovascular-related Parameters Associated With Cushing's Disease [Time Frame: From baseline to each scheduled visit (visits every 2, 4 or 12 weeks based on study phases (provided adequate follow-up as per SAP)]

Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint) [Time Frame: Week 24]

Change in Bone Mineral Density [Time Frame: From Baseline to Week 48 and the last available assessment]

Change in mUFC [Time Frame: From baseline to each scheduled visit (visits every 2, 4 or 12 weeks based on study phases (provided adequate follow-up as per SAP)]

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-last Control of Mean Urinary Free Cortisol (mUFC) During RW Period Changed to: Time-to-loss of Control of mUFC) by Randomized Treatment Group [Time Frame: Between Week 26 and Week 34, up to a maximum of 8 weeks after randomizaion]

Secondary ID(s)

CLCI699C2301

2013-004766-34

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 16/06/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02180217