Safety and Efficacy of LCI699 in Cushing's Disease Patients

NCT01331239 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: CLCI699C22012010-022403-22
• Study Type: interventional
• Target: 31
• Locations: 4 countries
• Sites: 10

Brief Summary

This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease. In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long term optional extension. A second extension provided patients who were clinically benefitting from LCI699 an opportunity to continue to have access to the drug until LCI699 was commercially available and reimbursed or through the availability of a local access program.

Conditions

Cushings Disease; Cushing Disease

Keywords

Cushing Disease; osilodrostat; LCI699; Pituitary Gland; Adrenocorticotropic Hormone

Outcome Measures

Primary Outcomes (1)

• Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10

  A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ Upper Limit of Normal (ULN), as defined by the local laboratories, or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced \<50% decrease in UFC were classified as non-responders.

  10 weeks

Secondary Outcomes (26)

• Actual Change From Baseline (BL) in Steroid Hormones of Hypothalamic-Pituitary-Adrenal (HPA)-Axis: 11- Deoxycorticosterone (Overall)

  baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

• Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: 11-Deoxycortisol (Overall)

  baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

• Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Aldosterone, Thyroxine, Free (T4)

  baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

• Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Female)

  baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

• Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Male)

  baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

Study Arms (3)

Part l: Core cohort

EXPERIMENTAL

Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study

Drug: LCI699

Part II Core: Expansion cohort

EXPERIMENTAL

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study

Drug: LCI699

Part II Core: Follow-up cohort

EXPERIMENTAL

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study

Drug: LCI699

Interventions

LCI699 DRUG

Osilodrostat 1 mg and 5 mg capsules, was prepared by Novartis and supplied to the Investigator. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 6. Osilodrostat was open labeled 1 mg, 5 mg, 10 mg and 20 mg tablets.

Also known as: osilodrastat

Part II Core: Expansion cohort; Part II Core: Follow-up cohort; Part l: Core cohort

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a confirmed diagnosis of Cushing's Disease (persistent or recurrent) as evidenced by increased 24-hour urine free cortisol (UFC), normal or increased morning plasma Adrenocorticotropic Hormone (ACTH), and pituitary origin of excess ACTH.
• Patients with de novo Cushing's disease can be included only if they are not considered candidate for surgery

You may not qualify if:

• Patients treated with mitotane 6 months prior to Visit 1
• Patients with compression of the optic chiasm
• Patients with a known inherited syndrome as the cause for hormone over secretion
• Patients with Cushing's syndrome due to ectopic ACTH secretion or adrenal Cushing's syndrome
• Patients with pseudo-Cushing's syndrome
• Patients who are not biochemically euthyroid
• Diabetic patients with poorly controlled diabetes (HbA1c \>9%)
• 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.
• Patients who have received pituitary irradiation within five years prior to Visit 1.
• Patients with risk factors for QTc prolongation or Torsade de Pointes.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (10)

Northwestern University Endo, Metabolism and Molecular

Chicago, Illinois, 60611-3308, United States

Location

Massachusetts General Hospital Neuroendocrine Unit

Boston, Massachusetts, 02114, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Oregon Health and Science University SC

Portland, Oregon, 97239-3098, United States

Location

Novartis Investigative Site

Le Kremlin-Bicêtre, 94275, France

Location

Novartis Investigative Site

Paris, 75014, France

Location

Novartis Investigative Site

Ancona, L60020, Italy

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Novartis Investigative Site

Sapporo, Hokkaido, 060 8648, Japan

Location

Novartis Investigative Site

Chiba, 260 8677, Japan

Location

Related Publications (2)

• Fleseriu M, Pivonello R, Lacroix A, Biller BMK, Feelders R, Gadelha M, Bertherat J, Belaya Z, Piacentini A, Pedroncelli AM, Newell-Price J. Osilodrostat dose impact on efficacy/safety in Cushing's disease: large, pooled analysis of LINC 2, 3, and 4. Eur J Endocrinol. 2025 Oct 30;193(5):606-617. doi: 10.1093/ejendo/lvaf207.

  PMID: 41052284 DERIVED

• Bertagna X, Pivonello R, Fleseriu M, Zhang Y, Robinson P, Taylor A, Watson CE, Maldonado M, Hamrahian AH, Boscaro M, Biller BM. LCI699, a potent 11beta-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014 Apr;99(4):1375-83. doi: 10.1210/jc.2013-2117. Epub 2013 Dec 11.

  PMID: 24423285 DERIVED

MeSH Terms

Conditions

Adrenocortical Hyperfunction; Pituitary ACTH Hypersecretion; Pituitary Diseases

Interventions

Osilodrostat

Condition Hierarchy (Ancestors)

Adrenal Gland Diseases; Endocrine System Diseases; Hyperpituitarism; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2011
• First Posted: April 8, 2011
• Study Start: March 23, 2011
• Primary Completion: October 22, 2019
• Study Completion: October 22, 2019
• Last Updated: January 22, 2021
• Results First Posted: January 22, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share

Locations

FR (2); IT (2); US (4); JP (2)