Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease

A Phase III, Multi-center, Randomized, Double-blind, 48 Week Study With an Initial 12 Week Placebo-controlled Period to Evaluate the Safety and Efficacy of Osilodrostat in Patients With Cushing's Disease

ClinicalTrials.gov Identifier: NCT02697734

Novartis Reference Number: CLCI699C2302

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

Purpose of study is to aim to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy

Condition 
Cushing's Disease
Phase 
Phase 3
Overall status 
Active, not recruiting
Enrollment count 
73 participants
Start date 
Oct 03, 2016
Completion date 
Jan 26, 2021
Gender 
All
Age(s)
18 Years - 75 Years (Adult, Older Adult)

Interventions

Drug
osilodrostat
In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg. Each strength has a unique size and color. The osilodrostat 1 mg, 5 mg, 10 mg and 20 mg film coated tablets are approximately 6 mm, 7 mm, 9 mm, and 11 mm respectively in diameter and pale yellow, yellow, pale orange brown and light brown respectively in color.
Drug
osilodrostat Placebo
Matching Placebo in the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg. Each strength has a unique size and color.

Eligibility Criteria

Key inclusion criteria:

Confirmed 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 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. MRI confirmation of pituitary adenoma > 6 mm OR iii. 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

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).

Key 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 QTc prolongation or Torsade de Pointes, including:

patients with a baseline 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. Other protocol-defined inclusion/exclusion criteria may apply.

Study Locations

United States
University of Colorado Endocrinology Clinical Trials Unit
-
Aurora, 80045
Colorado
United States
University of Michigan Comprehensive Cancer Center
-
Ann Arbor, 48109
Michigan
United States
Columbia University Medical Center New York Presbyterian Neuroendocrine Unit
-
New York, 10032
New York
United States
Memorial Sloan Kettering Cancer Center
-
New York, 10065
New York
United States
Oregon Health and Science University SC LCI699C2301
-
Portland, 97239
Oregon
United States
University of Pennsylvania Medical Center University of Pennsylvania
-
Philadelphia, 19104
Pennsylvania
United States
Belgium
Novartis Investigative Site
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Leuven, 3000
-
Belgium
Brazil
Novartis Investigative Site
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Fortaleza, 60430-275
CE
Brazil
Novartis Investigative Site
-
Rio de Janeiro, 21941-590
RJ
Brazil
Novartis Investigative Site
-
Sao Paulo, 04039 004
SP
Brazil
Novartis Investigative Site
-
Sao Paulo, 05403 000
SP
Brazil
Canada
Novartis Investigative Site
-
Halifax, B3H 1V7
Nova Scotia
Canada
Novartis Investigative Site
-
Montreal, H2W 1T8
Quebec
Canada
Novartis Investigative Site
-
Sherbrooke, J1H 5N4
Quebec
Canada
China
Novartis Investigative Site
-
Chengdu, 610041
Sichuan
China
Novartis Investigative Site
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Beijing, 100034
-
China
Novartis Investigative Site
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Beijing, 100730
-
China
Novartis Investigative Site
-
Guang Zhou, 510080
-
China
Costa Rica
Novartis Investigative Site
-
San Pedro, 1406 1200
San Jose, Costa Rica
Costa Rica
Greece
Novartis Investigative Site
-
Athens, 106 76
-
Greece
Poland
Novartis Investigative Site
-
Warszawa, 04-305
Mazowieckie
Poland
Novartis Investigative Site
-
Krakow, 31-501
-
Poland
Novartis Investigative Site
-
Warszawa, 03 242
-
Poland
Portugal
Novartis Investigative Site
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Porto, 4200-319
-
Portugal
Russian Federation
Novartis Investigative Site
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Moscow, 117036
-
Russian Federation
Spain
Novartis Investigative Site
-
Malaga, 29009
Andalucia
Spain
Novartis Investigative Site
-
Sevilla, 41013
Andalucia
Spain
Novartis Investigative Site
-
Alzira, 46600
Comunidad Valenciana
Spain
Novartis Investigative Site
-
Valencia, 46026
Comunidad Valenciana
Spain
Novartis Investigative Site
-
La Coruna, 15006
Galicia
Spain
Novartis Investigative Site
-
Madrid, 28009
-
Spain
Switzerland
Novartis Investigative Site
-
Luzern, 6000
-
Switzerland
Thailand
Novartis Investigative Site
-
Bangkok, 10330
THA
Thailand
Novartis Investigative Site
-
Bangkok, 10700
-
Thailand
Turkey
Novartis Investigative Site
-
Istanbul, 34890
-
Turkey
Novartis Investigative Site
-
Kocaeli, 41380
-
Turkey

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