Safety and Efficacy of LCI699 in Cushing's Disease Patients
Condition: Cushings Disease; Cushing Disease
MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion
Study type: Interventional
Phase: Phase 2

Summary: 
      This exploratory study is a proof of concept study to determine whether LCI699 can safely
      reduce the level of urinary free cortisol in patients with Cushing's disease.

      In addition, this study evaluated the long term efficacy and safety of LCI699 including an
      additional 12 week of treatment followed by a 12 month long term optional extension.

      A second extension provided patients who were clinically benefitting from LCI699 an
      opportunity to continue to have access to the drug until LCI699 was commercially available
      and reimbursed or through the availability of a local access program.
    

Detailed description: 
      The Primary objective of this study was to assess the effect of 10-week treatment
      osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease.

      The study consisted of a screening period of up to 60 days (to allow an adequate washout
      period for any medications that modified cortisol levels), a 10-14-day baseline period, a
      10-week sequential dose escalation treatment period and a 14-day washout period followed by a
      Study Completion evaluation approximately 14 days after the last drug administration. Twelve
      patients were recruited and completed Part l of the study.

      Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be
      increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at
      anytime, the subject's UFC was < Upper Limit of Normal (ULN), dose escalation was halted and
      the subject remained on the current, efficacious dose through Week 10, with continued
      monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary.
      If at any time the subject experienced side effects which were either intolerable or met dose
      adjustment criteria, the prescribed dose was adjusted.

      The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients.
      Subsequently, in order to confirm these observations, protocol was amended (Protocol
      amendment 4) and new patients were enrolled and investigated for a longer treatment period.

      Following Protocol amendment 4, the study design was modified to include patients in Part II
      of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for
      22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who
      participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort
      in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to
      re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days
      (Week 10), all patients (both patients entering for the first time and those reentering the
      study) entered the 12-week assessment period. At Day 154, patients completed the End of
      Treatment-Core visit.

      On Day 154 (Week 22), patients had the option to enter the 12-month extension phase
      (long-term extension 1). On Day 490, patients who continued in the study had the option to
      enter a second long term extension phase (extension-2) at the Investigator's discretion,
      provided they did not meet any of the study discontinuation criteria.
    

Intervention name(s): LCI699
Intervention type(s): Drug
Intervention description(s): Osilodrostat 1 mg and 5 mg capsules, was prepared by Novartis and supplied to the Investigator. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 6. Osilodrostat was open labeled 1 mg, 5 mg, 10 mg and 20 mg tablets.
Other intervention name(s): osilodrastat
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cushing Disease; osilodrostat; LCI699; Pituitary Gland; Adrenocorticotropic Hormone