Clinical trial NCT02468193: Study of Efficacy and Safety of Osilodrostat in Cushing's Syndrome
Official title: A Phase II, Open-label, Dose Titration, Multi-center Study to Assess the Safety/Tolerability and Efficacy of Osilodrostat in Patients With All Types of Endogenous Cushing's Syndrome Except Cushing's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cushing's Syndrome
Ectopic Corticotropin Syndrome
Adrenal Adenoma
Adrenal Carcinoma
AIMAH
PPNAD
Keywords: Cushing's syndrome
osilodrostat
LCI699
ectopic corticotropin syndrome
adrenal adenoma
adrenal carcinoma
ACTH-Independent Macronodular Adrenal Hyperplasia
AIMAH
Primary Pigmented Nodular Adrenal Dysplasia
PPNAD
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-06-10
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The study aim was to investigate the efficacy and safety of Osilodrostat in patients with Cushing's syndrome due to causes other than Cushing's disease in Japan.

Detailed description: This was a Phase II, single arm, open-label, dose titration, multi-center study which consisted of two distinct Study Periods plus an optional extension period in non-CD patients with CS. The 3 Study Periods (two distinct Study Periods plus an optional extension period) were as follows:

Study Period I \[Week 0 (Day 1) to Week-12\]: Study Period I was the dose titration period to achieve a stable therapeutic dose and to assess the efficacy and safety of osilodrostat.

The dosing regimen of osilodrostat in this study was titrated according to the following escalation sequence: osilodrostat 2 mg bid, 5 mg bid, 10 mg bid, 20 mg bid, and 30 mg bid. Dose adjustments were based on the serum cortisol values measured by the local lab at each site. Osilodrostat titration was done weekly for the initial 4-weeks, up to a maximum dose of 10 mg bid.

The mean of three 24-hour UFC (mUFC) values were measured to evaluate the efficacy in this period.

Study Period II (After Week-12 to Week-48): Study Period II was the period to assess the sustainability of efficacy and long term safety.

During Study Period II, only patients who tolerated and agreed to continue osilodrostat treatment continued on the study. The patient was administered with the stable therapeutic dose which was achieved in the Study Period I.

Optional extension period (After Week-48): Patients who continued to receive clinical benefit, as assessed by the study Investigator and who wished to enter the extension period were reconsented at Week-48. Patients who entered the extension period continued to be treated with the study drug without interruption to be assessed for efficacy and safety. Patients who continued to benefit from study treatment as assessed by the study investigator and who completed Week-72 were offered to participate in a separate long-term safety follow-up study. The optional extension period ended after all patients had completed Week-72 or had discontinued early.

Post-treatment Follow-up: All patients had 30 days safety follow-up after the last dose of study treatment.

Eligibility criteria: Inclusion Criteria:

* Patients with confirmed Cushing's syndrome \[i.e. ectopic corticotropin syndrome, adrenal adenoma, adrenal carcinoma, ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH), or Primary Pigmented Nodular Adrenal Dysplasia (PPNAD)\]
* For patients on medical treatment for hypercortisolism due to Cushing's syndrome, the washout periods had to be completed prior to baseline efficacy assessments

Exclusion Criteria:

* Patients with Cushing's disease
* History of hypersensitivity to osilodrostat or to drugs of similar chemical classes
* History of malignancy of any organ system, treated or untreated, within the past 5 years
* Patients receiving treatment for within 4 weeks or ≤5 x half-life of the agent (whichever is longer) before first dose of osilodrostat
* Patients with risk factors for QTc prolongation or Torsade de Pointes

Primary outcomes:
measure: Percent Change in the Mean Urine Free Cortisol (mUFC) at the Individual Level at Week 12
timeFrame: Baseline, 12 weeks
Secondary outcomes:
measure: Percent Change From Baseline in the mUFC at Individual Patient Level at Week 24 (Day 169) and Week 48 (Day 337)
timeFrame: Baseline, Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337)
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337)
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage of Participants With mUFC Response of Complete, Partial, and Overall Response
timeFrame: 12, 24 and 48 weeks
measure: Absolute Change From Baseline in Morning Serum Cortisol at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Morning Serum Cortisol at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in Other Adrenal Steroid Hormones at Individual Levels
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Other Adrenal Steroid Hormones at Individual Levels
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Fasting Glucose, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Fasting Glucose, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, HbA1c, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, HbA1c, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in Cardiovascular-related Metabolic Parameters, Cholesterol, HDL Cholesterol, LDL Cholesterol & Triglycerides, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Cardiovascular-related Metabolic Parameters, Cholesterol, HDL Cholesterol, LDL Cholesterol & Triglycerides, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, BMI, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, BMI, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Waist Circumference, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Waist Circumference, at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Sitting Blood Pressure (BP) at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Sitting Blood Pressure (BP) at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Total Scores in Patient-Reported Outcomes Health-related Quality of Life (QoL) as Assessed by Cushing QoL at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Total Scores in Patient-Reported Outcomes Health-related Quality of Life (QoL) as Assessed by Beck Depression Inventory II (BDI-ll) Depression Score at Individual Level
timeFrame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 0
timeFrame: Week 0
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 1
timeFrame: Week 1, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 2
timeFrame: Week 2
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 3
timeFrame: Week 3, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 4
timeFrame: Week 4, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 6
timeFrame: Week 6, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 8
timeFrame: Week 8, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 10
timeFrame: Week 10, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 12
timeFrame: Week 12
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 16
timeFrame: Week 16, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 20
timeFrame: Week 20, 2 hours post-dose
measure: Plasma Concentrations of Osilodrostat (LCI699) at Week 24
timeFrame: Week 24, 2 hours post-dose
Other outcomes:
Locations:
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Yokohama
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Sendai city
country: Japan
facility: Novartis Investigative Site
state: Miyagi
city: Chiba
country: Japan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: