Clinical trial NCT02697734: Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cushing's Disease
Keywords: Cushing's disease
LCI699
osilodrostat
Pituitary Gland
Adrenocorticotropic
Hormone
ACTH
UFC
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-03-03
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Key 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).

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 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.

Primary outcomes:
measure: Percentage of Randomized Participants With a Complete Response
timeFrame: at Week 12
Secondary outcomes:
measure: Percentage of Participants With mUFC ≤ ULN at Week 36
timeFrame: At Week 36
measure: Change From Baseline in mUFC
timeFrame: Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96
measure: Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN
timeFrame: up to 12 weeks
measure: Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response
timeFrame: up to 12 weeks
measure: Time-to-first Control of mUFC - % Event Probability Estimates
timeFrame: up to 12 weeks
measure: Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants
timeFrame: up to 48 weeks
measure: Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC
timeFrame: from week 26 to week 48
measure: Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates
timeFrame: week 26 and week 36
measure: Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
timeFrame: Baseline, week 48
measure: Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
timeFrame: Baseline, week 48
measure: Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48
timeFrame: baseline, week 12, 36 and 48
measure: Change in Fasting Plasma Glucose
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Hemoglobin A1C
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Cholesterol
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in LDL Cholesterol
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in HDL Cholesterol
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Triglyceride
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Standing Systolic Blood Pressure
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Supine Systolic Blood Pressure
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Standing Diastolic Blood Pressure
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Supine Diastolic Blood Pressure
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Weight
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change in Waist Circumference
timeFrame: Baseline, weeks 12, 36, and 48
measure: Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease
timeFrame: baseline, Week 12, Week 36 and Week 48
measure: Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
timeFrame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
measure: Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
timeFrame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
measure: Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
timeFrame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
measure: Change From Baseline in EQ-5D-5L Utility Index
timeFrame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
measure: Change From Baseline in EQ-5D VAS
timeFrame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
measure: Change From Baseline in Beck Depression Inventory-II - Total Score Derived
timeFrame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
measure: Change From Baseline in Serum Cortisol
timeFrame: Baseline, Week 12, Week 36, Week 48
measure: Change From Baseline in Late Night Saliva Cortisol
timeFrame: Baseline, Week 12, Week 36, Week 48
measure: Change From Baseline in Morning Saliva Cortisol
timeFrame: Baseline, Week 12, Week 36, Week 48
measure: Change From Baseline in Hair Cortisol Levels
timeFrame: Baseline, Week 26, Week 48
measure: Plasma Osilodrostat Concentrations (ng/mL)
timeFrame: pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Endocrinology Clinical Trials Unit
state: Colorado
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: New York
country: United States
facility: Columbia University Medical Center New York Presbyterian Neuroendocrine Unit
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University SC LCI699C2301
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center University of Pennsylvania
state: Pennsylvania
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Fortaleza
country: Brazil
facility: Novartis Investigative Site
state: CE
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guang Zhou
country: China
facility: Novartis Investigative Site
city: San Pedro
country: Costa Rica
facility: Novartis Investigative Site
state: San Jose, Costa Rica
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
state: Mazowieckie
city: Krakow
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Alzira
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Luzern
country: Switzerland
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.