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

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ClinicalTrials.gov Identifier: NCT02468193
Recruitment Status : Completed
First Posted : June 10, 2015
Results First Posted : March 11, 2020
Last Update Posted : May 6, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE June 8, 2015
First Posted Date  ICMJE June 10, 2015
Results First Submitted Date  ICMJE October 25, 2019
Results First Posted Date  ICMJE March 11, 2020
Last Update Posted Date May 6, 2020
Actual Study Start Date  ICMJE September 24, 2015
Actual Primary Completion Date June 7, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2020)
Percent Change in the Mean Urine Free Cortisol (mUFC) at the Individual Level at Week 12 [ Time Frame: Baseline, 12 weeks ]
Percent change from baseline in the mUFC at the individual patient level
Original Primary Outcome Measures  ICMJE
 (submitted: June 8, 2015)
Percent change in the mean Urine Free Cortisol (mUFC) at Week 12 [ Time Frame: 12 weeks ]
Percent change from baseline in the mUFC at the individual patient level
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2020)
  • Percent Change From Baseline in the mUFC at Individual Patient Level at Week 24 (Day 169) and Week 48 (Day 337) [ Time Frame: Baseline, Week 24 (day 169) and Week 48 (day 337) ]
    Percent change from baseline in the mUFC at the individual patient level
  • Absolute Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337) [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change from baseline in the mUFC
  • Percentage Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337) [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percent change from baseline in the mUFC
  • Percentage of Participants With mUFC Response of Complete, Partial, and Overall Response [ Time Frame: 12, 24 and 48 weeks ]
    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.
  • Absolute Change From Baseline in Morning Serum Cortisol at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change from baseline in morning serum cortisol at the individual patient level
  • Percentage Change From Baseline in Morning Serum Cortisol at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percentage change from baseline in morning serum cortisol at the individual patient level
  • Absolute Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change from baseline in several steroid hormones at individual levels: ACTH, Serum 11-deoxycorticosterone, Aldosterone, Estradiol
  • Percentage Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percent change from baseline in several steroid hormones at individual levels: ACTH, Serum 11-deoxycorticosterone, Aldosterone, Estradiol
  • Absolute Change From Baseline in Other Adrenal Steroid Hormones at Individual Levels [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change from baseline in several steroid hormones at individual levels: Serum 11-deoxycortisol, Testosterone
  • Percentage Change From Baseline in Other Adrenal Steroid Hormones at Individual Levels [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percent change from baseline in several steroid hormones at individual levels: Serum 11-deoxycortisol, Testosterone
  • Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Fasting Glucose, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change in cardiovascular-related metabolic parameter fasting glucose, associated with Cushing's syndrome (CS)
  • Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Fasting Glucose, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percentasge change in cardiovascular-related metabolic parameter fasting glucose, associated with Cushing's syndrome (CS)
  • Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, HbA1c, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change in cardiovascular-related metabolic parameter HbA1c associated with Cushing's syndrome (CS)
  • Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, HbA1c, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percentage change in cardiovascular-related metabolic parameter HbA1c associated with Cushing's syndrome (CS)
  • Absolute Change From Baseline in Cardiovascular-related Metabolic Parameters, Cholesterol, HDL Cholesterol, LDL Cholesterol & Triglycerides, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change in cardiovascular-related metabolic parameters: cholesterol, HDL cholesterol, LDL cholesterol & triglycerides, associated with Cushing's syndrome (CS)
  • Percentage Change From Baseline in Cardiovascular-related Metabolic Parameters, Cholesterol, HDL Cholesterol, LDL Cholesterol & Triglycerides, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percent change in cardiovascular-related metabolic parameters: cholesterol, HDL cholesterol, LDL cholesterol & triglycerides, associated with Cushing's syndrome (CS)
  • Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, BMI, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change in cardiovascular-related metabolic parameter: BMI, associated with Cushing's syndrome (CS)
  • Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, BMI, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percent change in cardiovascular-related metabolic parameter: BMI, associated with Cushing's syndrome (CS)
  • Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Waist Circumference, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change in cardiovascular-related metabolic parameter: Waist circumference, associated with Cushing's syndrome (CS)
  • Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Waist Circumference, at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percent change in cardiovascular-related metabolic parameter: Waist circumference, associated with Cushing's syndrome (CS)
  • Absolute Change From Baseline in Cardiovascular-related Metabolic Parameter, Sitting Blood Pressure (BP) at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Absolute change in cardiovascular-related metabolic parameter: sitting systolic BP & sitting diastolic BP, associated with Cushing's syndrome (CS)
  • Percentage Change From Baseline in Cardiovascular-related Metabolic Parameter, Sitting Blood Pressure (BP) at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    Percentage change in cardiovascular-related metabolic parameter: sitting systolic BP & sitting diastolic BP, associated with Cushing's syndrome
  • Total Scores in Patient-Reported Outcomes Health-related Quality of Life (QoL) as Assessed by Cushing QoL at Individual Level [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    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).
  • 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 [ Time Frame: Baseline, Week 12 (day 85), Week 24 (day 169) and Week 48 (day 337) ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 0 [ Time Frame: 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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 1 [ Time Frame: Week 1, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 2 [ Time Frame: 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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 3 [ Time Frame: Week 3, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 4 [ Time Frame: Week 4, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 6 [ Time Frame: Week 6, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 8 [ Time Frame: Week 8, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 10 [ Time Frame: Week 10, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 12 [ Time Frame: 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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 16 [ Time Frame: Week 16, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 20 [ Time Frame: Week 20, 2 hours post-dose ]
    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.
  • Plasma Concentrations of Osilodrostat (LCI699) at Week 24 [ Time Frame: Week 24, 2 hours post-dose ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2015)
  • Percent change in the mUFC at Week 24 and Week 48 [ Time Frame: 24 and 48 weeks ]
    Percent change from baseline in the mUFC at the individual patient level
  • Change from baseline in the mUFC at Week 12, Week 24 and Week 48 [ Time Frame: Baseline, 12, 24 and 48 weeks ]
    Absolute and percent change from baseline in the mUFC
  • Complete, partial, and overall response rate [ Time Frame: 12, 24 and 48 weeks ]
    Complete and Partial response rate Overall response rate: proportion of patients with complete or partial responses
  • Change in serum cortisol [ Time Frame: 12, 24 and 48 weeks ]
    Absolute and percent change from baseline in morning serum cortisol at the individual patient level
  • Change in serum cortisol [ Time Frame: 12, 24 and 48 weeks ]
    Absolute and percent change from baseline in morning serum cortisol
  • Change in steroid hormones [ Time Frame: 12, 24 and 48 weeks ]
    Absolute and percent change from baseline in several hormones
  • Change in cardiovascular-related metabolic parameters associated with Cushing's syndrome [ Time Frame: 12, 24 and 48 weeks ]
    Absolute and percent change in metabolic parameters associated with Cushing's syndrome
  • General safety of LCI699 [ Time Frame: every visit for 96 weeks ]
    Adverse events and laboratory abnormalities will be assessed using the National Cancer Institute-Common Toxicology Criteria grading scale
  • Change from baseline in Patient-Reported Outcomes [ Time Frame: Baseline, 12, 24 and 48 weeks ]
    Change from baseline in standardized score of Patient-Reported Outcomes will be assessed
  • Plasma concentrations of LCI699 [ Time Frame: 48 weeks ]
    Exposures of LCI699 in patients with Cushing's syndrome will be evaluated at the scheduled time point
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Efficacy and Safety of Osilodrostat in Cushing's Syndrome
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cushing's Syndrome
  • Ectopic Corticotropin Syndrome
  • Adrenal Adenoma
  • Adrenal Carcinoma
  • AIMAH
  • PPNAD
Intervention  ICMJE Drug: Osilodrostat
Osirodrostat 1mg, 5mg & 10mg in the form of film-coated tablets was used for oral administration.
Other Name: LCI699
Study Arms  ICMJE Experimental: Osilodrostat
Patients in this arm took the study drug, osilodrostat.
Intervention: Drug: Osilodrostat
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 28, 2018)
9
Original Estimated Enrollment  ICMJE
 (submitted: June 8, 2015)
10
Actual Study Completion Date  ICMJE October 29, 2018
Actual Primary Completion Date June 7, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02468193
Other Study ID Numbers  ICMJE CLCI699C1201
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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

URL: https://www.clinicalstudydatarequest.com
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP