Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease

NCT ID: NCT02697734

Last Updated: 2021-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-03
• Study Completion Date: 2020-12-31

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.

Detailed Description

The study LCI699C2302 (LINC-4) is a multi-center, randomized, double-blind study to evaluate the safety and efficacy of osilodrostat in patients with Cushing's disease.

Enrolled patients were initially randomized to either osilodrostat or placebo, in a 2:1 ratio, for a 12-week double-blind period (Period 1). Randomization was stratified by history of pituitary radiation. After Week 12, all patients received open-label osilodrostat until the end of the Core phase at Week 48 (Period 2).

After Week 48, patients could join an optional 48 week extension period.

Conditions

Cushing's Disease

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

osilodrostat Group

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)

Group Type: EXPERIMENTAL

osilodrostat

Intervention Type: DRUG

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

osilodrostat Placebo Group

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)

Group Type: PLACEBO_COMPARATOR

osilodrostat Placebo

Intervention Type: DRUG

Matching Placebo in the form of filmcoated tablets for oral administration

Interventions

osilodrostat

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

Intervention Type: DRUG

osilodrostat Placebo

Matching Placebo in the form of filmcoated tablets for oral administration

Intervention Type: DRUG

Other Intervention Names

LCI699

Eligibility Criteria

Inclusion Criteria

• 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):

1. 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.

2. Morning plasma Adrenocorticotropic hormone (ACTH) above Lower Limit of Normal

3. 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).

Exclusion Criteria

• 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):

1. 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

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

University of Colorado Endocrinology Clinical Trials Unit

Aurora, Colorado, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Columbia University Medical Center New York Presbyterian Neuroendocrine Unit

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Oregon Health and Science University SC LCI699C2301

Portland, Oregon, United States

University of Pennsylvania Medical Center University of Pennsylvania

Philadelphia, Pennsylvania, United States

Novartis Investigative Site

Leuven, , Belgium

Novartis Investigative Site

Fortaleza, Ceará, Brazil

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Halifax, Nova Scotia, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Sherbrooke, Quebec, Canada

Novartis Investigative Site

Chengdu, Sichuan, China

Novartis Investigative Site

Beijing, , China

Novartis Investigative Site

Beijing, , China

Novartis Investigative Site

Guangzhou, , China

Novartis Investigative Site

San Pedro, San Jose, Costa Rica, Costa Rica

Novartis Investigative Site

Athens, , Greece

Novartis Investigative Site

Warsaw, Masovian Voivodeship, Poland

Novartis Investigative Site

Krakow, , Poland

Novartis Investigative Site

Warsaw, , Poland

Novartis Investigative Site

Porto, , Portugal

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Málaga, Andalusia, Spain

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

A Coruña, Galicia, Spain

Novartis Investigative Site

Alzira, Valencia, Spain

Novartis Investigative Site

Valencia, Valencia, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Lucerne, , Switzerland

Novartis Investigative Site

Bangkok, THA, Thailand

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Istanbul, , Turkey (Türkiye)

Novartis Investigative Site

Kocaeli, , Turkey (Türkiye)

Countries

United States; Belgium; Brazil; Canada; China; Costa Rica; Greece; Poland; Portugal; Russia; Spain; Switzerland; Thailand; Turkey (Türkiye)

References

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.

Reference Type: DERIVED

PMID: 39610378 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35325149 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

CLCI699C2302

Identifier Type: -

Identifier Source: org_study_id