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Completed

NCT Number: NCT02468193

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

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.

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Key information

Conditions

Cushing's Syndrome ACTH Syndrome, Ectopic AIMAH Acth-Independent Macronodular Adrenal Hyperplasia Adrenal Adenoma Adrenal Carcinoma Adrenal Cortex Diseases Adrenal Cortex Neoplasms Adrenal Gland Diseases Adrenal Gland Neoplasms Adrenocortical Hyperfunction Cushing Syndrome Ectopic Corticotropin Syndrome Endocrine Gland Neoplasms Endocrine System Diseases Neoplasms Neoplasms by Site PPNAD Paraneoplastic Endocrine Syndromes Paraneoplastic Syndromes

Age range

18 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Novartis Investigative Site, Fukushima, Japan

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Osilodrostat

Drug

Osirodrostat 1mg, 5mg & 10mg in the form of film-coated tablets was used for oral administration.

Other names: LCI699

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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)

  12. 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)

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 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)

  19. 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)

  20. 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)

  21. 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)

  22. 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

  23. 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).

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study 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

Important dates

Study start
2015
Primary completion
2018
Study completion
2018
First posted
Jun 10, 2015
Registry last updated
May 6, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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