Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease

NCT02697734 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: CLCI699C2302
• Study Type: interventional
• Target: 73
• Locations: 14 countries
• Sites: 36

Brief Summary

The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy.

Conditions

Cushing's Disease

Keywords

Cushing's disease; LCI699; osilodrostat; Pituitary Gland; Adrenocorticotropic; Hormone; ACTH; UFC

Outcome Measures

Primary Outcomes (1)

• Percentage of Randomized Participants With a Complete Response

  A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.

  at Week 12

Secondary Outcomes (35)

• Percentage of Participants With mUFC ≤ ULN at Week 36

  At Week 36

• Change From Baseline in mUFC

  Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96

• Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN

  up to 12 weeks

• Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response

  up to 12 weeks

• Time-to-first Control of mUFC - % Event Probability Estimates

  up to 12 weeks

Study Arms (2)

osilodrostat Group

EXPERIMENTAL

Participants in this arm were randomized to receive the study drug, osilodrostat followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration)

Drug: osilodrostat

osilodrostat Placebo Group

PLACEBO COMPARATOR

Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration)

Drug: osilodrostat Placebo

Interventions

osilodrostat DRUG

In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg.

Also known as: LCI699

osilodrostat Group

osilodrostat Placebo DRUG

Matching Placebo in the form of filmcoated tablets for oral administration

osilodrostat Placebo Group

Eligibility Criteria

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

You may qualify if:

• Confirmed Cushing's Disease (CD) that is persistent or recurrent as evidenced by all of the following criteria being met (i.e., a, b and c):
• mUFC \> 1.3 x ULN (Mean of three 24-hour urine samples collected preferably on 3 consecutive days, during screening after washout of prior medical therapy for CD (if applicable), confirmed by the central laboratory and available before Day 1), with ≥2 of the individual UFC values being \> 1.3 x ULN.
• Morning plasma Adrenocorticotropic hormone (ACTH) above Lower Limit of Normal
• Confirmation (based on medical history) of pituitary source of excess
• ACTH as defined by any one or more of the following three criteria:
• i. Histopathologic confirmation of an ACTH-staining adenoma in patients who have had prior pituitary surgery. OR ii. Magnetic resonance imaging (MRI) confirmation of pituitary adenoma \> 6 mm OR iii. Bilateral inferior petrosal sinus sampling (BIPSS) with either corticotropic-releasing hormone (CRH) or desmopressin (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
• Patients that received glucocorticoid replacement therapy must have discontinued such therapy for at least seven days or 5 half-lives prior to screening, whichever is longer.
• Patients with de novo CD can be included only if they are not considered candidates for surgery (e.g., poor surgical candidates due to co-morbidities, inoperable tumors, patients who refuse to have surgical treatment, or surgical treatment is not available).

You may not qualify if:

• Patients with pseudo-Cushing's syndrome. This may be diagnosed by a normal late night salivary cortisol value collected during the screening period and after washout of prior CD medication.
• Patients with risk factors for QT corrected (QTc) prolongation or Torsade de Pointes, including:
• patients with a baseline QT corrected (Fridericia QT formula) (QTcF) \> 450 ms for males and QTcF \> 460 ms for females; personal or family history of long QT syndrome; concomitant medications known to prolong the QT interval; patients with hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected before pre-dose Day 1.
• Patients likely to require adrenalectomy, pituitary surgery, or radiation therapy during the placebo-controlled period (Weeks 1-12) for the treatment of severe hypercortisolism or pituitary tumor growth causing compression of the optic chiasm.
• 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).
• Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP).
• Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH independent (adrenal) Cushing's syndrome. Pregnant or nursing (lactating) women. 8. 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. Highly effective contraception methods include: A. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. B. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study drug. In case of bilateral oophorectomy, documentation is required (e.g. operative report, pelvic ultrasound or other reliable imaging method). C. Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
• D. Combination of any two of the following (a+b or a+c, or b+c):
• Use of oral\*, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. \*In the case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study drug. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (36)

University of Colorado Endocrinology Clinical Trials Unit

Aurora, Colorado, 80045, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Columbia University Medical Center New York Presbyterian Neuroendocrine Unit

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Oregon Health and Science University SC LCI699C2301

Portland, Oregon, 97239, United States

Location

University of Pennsylvania Medical Center University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Fortaleza, Ceará, 60430-275, Brazil

Location

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 21941-590, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 04039 004, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 05403 000, Brazil

Location

Novartis Investigative Site

Halifax, Nova Scotia, B3H 1V7, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H2W 1T8, Canada

Location

Novartis Investigative Site

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Novartis Investigative Site

Chengdu, Sichuan, 610041, China

Location

Novartis Investigative Site

Beijing, 100034, China

Location

Novartis Investigative Site

Beijing, 100730, China

Location

Novartis Investigative Site

Guangzhou, 510080, China

Location

Novartis Investigative Site

San Pedro, San Jose, Costa Rica, 1406 1200, Costa Rica

Location

Novartis Investigative Site

Athens, 106 76, Greece

Location

Novartis Investigative Site

Warsaw, Masovian Voivodeship, 04-305, Poland

Location

Novartis Investigative Site

Krakow, 31-501, Poland

Location

Novartis Investigative Site

Warsaw, 03 242, Poland

Location

Novartis Investigative Site

Porto, 4200-319, Portugal

Location

Novartis Investigative Site

Moscow, 117036, Russia

Location

Novartis Investigative Site

Málaga, Andalusia, 29009, Spain

Location

Novartis Investigative Site

Seville, Andalusia, 41013, Spain

Location

Novartis Investigative Site

A Coruña, Galicia, 15006, Spain

Location

Novartis Investigative Site

Alzira, Valencia, 46600, Spain

Location

Novartis Investigative Site

Valencia, Valencia, 46026, Spain

Location

Novartis Investigative Site

Madrid, 28009, Spain

Location

Novartis Investigative Site

Lucerne, 6000, Switzerland

Location

Novartis Investigative Site

Bangkok, THA, 10330, Thailand

Location

Novartis Investigative Site

Bangkok, 10700, Thailand

Location

Novartis Investigative Site

Istanbul, 34890, Turkey (Türkiye)

Location

Novartis Investigative Site

Kocaeli, 41380, Turkey (Türkiye)

Location

Related Publications (3)

• 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

• Newell-Price J, Fleseriu M, Pivonello R, Feelders RA, Gadelha MR, Lacroix A, Witek P, Heaney AP, Piacentini A, Pedroncelli AM, Biller BMK. Improved Clinical Outcomes During Long-term Osilodrostat Treatment of Cushing Disease With Normalization of Late-night Salivary Cortisol and Urinary Free Cortisol. J Endocr Soc. 2024 Nov 12;9(1):bvae201. doi: 10.1210/jendso/bvae201. eCollection 2024 Nov 26.

  PMID: 39610378 DERIVED

• Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, Witek P, Belaya Z, Yu Y, Liao Z, Ku CHC, Carvalho D, Roughton M, Wojna J, Pedroncelli AM, Snyder PJ. Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2882-e2895. doi: 10.1210/clinem/dgac178.

  PMID: 35325149 DERIVED

MeSH Terms

Conditions

Pituitary ACTH Hypersecretion; Pituitary Diseases

Interventions

Osilodrostat

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 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 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2016
• First Posted: March 3, 2016
• Study Start: October 3, 2016
• Primary Completion: June 19, 2019
• Study Completion: December 31, 2020
• Last Updated: November 1, 2021
• Results First Posted: October 19, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share

Locations

CH (1); BR (4); BE (1); PT (1); PL (3); RU (1); TH (2); CN (4); CA (3); CO (1); GR (1); ES (6); TU (2); US (6)