Study of Efficacy and Safety of Osilodrostat in Cushing's Syndrome

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

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.

Study Overview

• Status: Completed
• Conditions: Cushing's Syndrome; Ectopic Corticotropin Syndrome; Adrenal Adenoma; Adrenal Carcinoma; AIMAH; PPNAD
• Intervention / Treatment: Drug: Osilodrostat

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 260 8677
    • Novartis Investigative Site
  • Fukushima
    • Fukushima city, Fukushima, Japan, 960 1295
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 245-8575
      • Novartis Investigative Site
  • Miyagi
    • Sendai city, Miyagi, Japan, 980 8574
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Osilodrostat; Patients in this arm took the study drug, osilodrostat.	Drug: Osilodrostat; Osirodrostat 1mg, 5mg & 10mg in the form of film-coated tablets was used for oral administration.; Other Names: LCI699

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in the Mean Urine Free Cortisol (mUFC) at the Individual Level at Week 12	Percent change from baseline in the mUFC at the individual patient level	Baseline, 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in the mUFC at Individual Patient Level at Week 24 (Day 169) and Week 48 (Day 337)	Percent change from baseline in the mUFC at the individual patient level	Baseline, Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337)	Absolute change from baseline in the mUFC	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337)	Percent change from baseline in the mUFC	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage of Participants With mUFC Response of Complete, Partial, and Overall Response	Complete response rate = percentage of participants who had mUFC≤ ULN; Partial response rate = Percentage of participants who had mUFC>ULN and at least 50% reduction from baseline in mUFC. Overall response rate = Percentage of participants who had mUFC ≤ ULN or at least 50% reduction from baseline.	12, 24 and 48 weeks
Absolute Change From Baseline in Morning Serum Cortisol at Individual Level	Absolute change from baseline in morning serum cortisol at the individual patient level	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Morning Serum Cortisol at Individual Level	Percentage change from baseline in morning serum cortisol at the individual patient level	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level	Absolute change from baseline in several steroid hormones at individual levels: ACTH, Serum 11-deoxycorticosterone, Aldosterone, Estradiol	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level	Percent change from baseline in several steroid hormones at individual levels: ACTH, Serum 11-deoxycorticosterone, Aldosterone, Estradiol	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in Other Adrenal Steroid Hormones at Individual Levels	Absolute change from baseline in several steroid hormones at individual levels: Serum 11-deoxycortisol, Testosterone	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Other Adrenal Steroid Hormones at Individual Levels	Percent change from baseline in several steroid hormones at individual levels: Serum 11-deoxycortisol, Testosterone	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Fasting Glucose, at Individual Level	Absolute change in cardiovascular-related metabolic parameter fasting glucose, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Fasting Glucose, at Individual Level	Percentasge change in cardiovascular-related metabolic parameter fasting glucose, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, HbA1c, at Individual Level	Absolute change in cardiovascular-related metabolic parameter HbA1c associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, HbA1c, at Individual Level	Percentage change in cardiovascular-related metabolic parameter HbA1c associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in Cardiovascular-related Metabolic Parameters, Cholesterol, HDL Cholesterol, LDL Cholesterol & Triglycerides, at Individual Level	Absolute change in cardiovascular-related metabolic parameters: cholesterol, HDL cholesterol, LDL cholesterol & triglycerides, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Cardiovascular-related Metabolic Parameters, Cholesterol, HDL Cholesterol, LDL Cholesterol & Triglycerides, at Individual Level	Percent change in cardiovascular-related metabolic parameters: cholesterol, HDL cholesterol, LDL cholesterol & triglycerides, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, BMI, at Individual Level	Absolute change in cardiovascular-related metabolic parameter: BMI, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, BMI, at Individual Level	Percent change in cardiovascular-related metabolic parameter: BMI, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Waist Circumference, at Individual Level	Absolute change in cardiovascular-related metabolic parameter: Waist circumference, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Waist Circumference, at Individual Level	Percent change in cardiovascular-related metabolic parameter: Waist circumference, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Sitting Blood Pressure (BP) at Individual Level	Absolute change in cardiovascular-related metabolic parameter: sitting systolic BP & sitting diastolic BP, associated with Cushing's syndrome (CS)	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Sitting Blood Pressure (BP) at Individual Level	Percentage change in cardiovascular-related metabolic parameter: sitting systolic BP & sitting diastolic BP, associated with Cushing's syndrome	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Total Scores in Patient-Reported Outcomes Health-related Quality of Life (QoL) as Assessed by Cushing QoL at Individual Level	The Cushing's Disease Health-Related Quality of Life Questionnaire (Cushing QoL) (version 1.0) was developed to evaluate quality of life in patients with Cushing's syndrome (Webb et al 2008). The Cushing QoL is comprised of 12 items that capture patient responses on seven concepts: daily activities, healing and pain, mood and self-confidence, social concerns, physical appearance, memory and concern about the future. Each questionnaire of the Cushing QOL has a scale of 1-5 where '1' corresponding to 'Always' or 'Very much' and '5' to 'Never' or 'Not at all'. The lower the score, the greater the impact on HRQoL. The score is the sum of all the item response and can range from 12 (worst) to 60 points (best).	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
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	The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 items designed to assess the intensity of depression in clinical & normal patients in the preceding two weeks. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. Each of 21 items corresponds to a symptom of depression and the sum of total score will be calculated where each item has a four-point scale ranging from 0 to 3, leading to a total score from zero to 63.	Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337)
Plasma Concentrations of Osilodrostat (LCI699) at Week 0	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 0
Plasma Concentrations of Osilodrostat (LCI699) at Week 1	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 1, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 2	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 2
Plasma Concentrations of Osilodrostat (LCI699) at Week 3	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 3, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 4	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 4, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 6	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 6, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 8	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 8, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 10	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 10, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 12	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 12
Plasma Concentrations of Osilodrostat (LCI699) at Week 16	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 16, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 20	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 20, 2 hours post-dose
Plasma Concentrations of Osilodrostat (LCI699) at Week 24	Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.	Week 24, 2 hours post-dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2015
• Primary Completion (Actual): June 7, 2018
• Study Completion (Actual): October 29, 2018

Study Registration Dates

• First Submitted: June 8, 2015
• First Submitted That Met QC Criteria: June 8, 2015
• First Posted (Estimate): June 10, 2015

Study Record Updates

• Last Update Posted (Actual): May 6, 2020
• Last Update Submitted That Met QC Criteria: April 23, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: osilodrostat; LCI699; PPNAD; Cushing's syndrome; ectopic corticotropin syndrome; adrenal adenoma; adrenal carcinoma; ACTH-Independent Macronodular Adrenal Hyperplasia; AIMAH; Primary Pigmented Nodular Adrenal Dysplasia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Disease; Endocrine Gland Neoplasms; Paraneoplastic Syndromes; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenal Cortex Diseases; Paraneoplastic Endocrine Syndromes; Syndrome; Adenoma; Cushing Syndrome; Adrenocortical Carcinoma; Adrenocortical Adenoma; ACTH Syndrome, Ectopic
• Other Study ID Numbers: CLCI699C1201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No