Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease
Condition: Cushings Disease
MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion
Study type: Interventional
Phase: Phase 3

Summary: 
      The study aimed to confirm long-term efficacy and safety of LCI699 for the treatment of
      patients with Cushing's disease. It was a pivotal trial which supported the registration of
      LCI699 for the treatment of patients with Cushing's disease in the US and the EU.

      This is a phase lll, multi-center, double-blind, randomized withdrawal study of LCI699
      following a 24 week, single-arm, open-label dose titration and treatment period which
      evaluated the safety and efficacy of LCI699 for the treatment of patients with Cushing's
      disease.
    

Detailed description: 
      The primary objective compared the complete response rate at the end of the 8-week period of
      randomized withdrawal (Week 34) between patients randomized to continued osilodrostat therapy
      vs.

      placebo. The key secondary objective assessed the complete response rate at the end of
      individual dose titration and treatment with osilodrostat in the initial single-arm, open
      label period (Week 24).

      Eligible patients were randomized in a double-blinded fashion at Week 26 at a 1:1 ratio
      either to continue treatment with osilodrostat at the same dose or to matching placebo.
      Randomization was stratified by osilodrostat dose at Week 24 (≤ 5mg bid vs. >5mg bid); and
      history of pituitary irradiation (yes/no).

      The study had four periods combined in the Core Period (Study Period 1 to 4) and an optional
      Extension Period. The optional Extension Period starting at Week 48.

      Study Period 1 consisted of a single-arm, open-label, osilodrostat dose-titration in
      individual patients (Week 1 to Week 12). Dose adjustments were based on the mean of three
      24-hour UFC (mUFC) values as measured by the central laboratory.

      During study Period 2 (Week 13 to Week 24), osilodrostat efficacy and safety were assessed at
      the therapeutic dose determined during study Period 1. Patients whose mUFC became elevated
      during this period had their osilodrostat dose increased further, if it was tolerated, up to
      30 mg bid. Such patients were followed for long-term safety and efficacy and were not
      considered responders for the key secondary endpoint, hence were not randomized in Study
      Period 3.

      Study Period 3 was a double-blind, placebo-controlled randomized withdrawal (RW) Period (Week
      26 to Week 34). In order to be eligible for randomization in study Period 3, patients had to
      have completed dose titration during study Period 1, and had to be classified as complete
      responders at Week 24 of study Period 2. Patients not eligible for randomization received
      open-label osilodrostat until the end of the Core Period (Week 48), unless there was a reason
      to discontinue from the study prematurely.

      During study Period 3, mUFC was measured at scheduled visits every 2 weeks. However, patients
      were also allowed to have unscheduled visits at any time during the RW if they reported
      symptoms of hypercortisolism or hypocortisolism.

      The dose of study drug remained unchanged for patients who maintained a normal mUFC and did
      not develop adverse events (AEs) related to study drug during RW. The Investigator could
      reduce or temporally withhold a dose of study drug for safety reasons at any time during the
      study, including the RW Period.

      During this study period, a patient was discontinued from the RW Period and declared a
      nonresponder, if the mUFC increased to >1.5×ULN. After discontinuation from RW treatment, or
      at the end of the RW Period (Week 34), whichever came first, the patient resumed open-label
      osilodrostat at a dose selected by the Investigator.

      Patients who discontinued from the study during the RW Period were no longer in the study,
      and consequently were not permitted to receive open-label osilodrostat and could not move to
      study Period 4.

      Patients who discontinued from RW treatment due to lack of efficacy resumed open-label
      osilodrostat at the time of discontinuation, which could occur before Week 34. Patients who
      were not discontinued during RW resumed open-label osilodrostat at the end of RW (Week 34)
      and continued osilodrostat thereafter (study Period 4).

      The Novartis study team, the patient, the Investigator, and all other site staff remained
      blinded to treatment assignment from the time of randomization to the time of database lock
      at the end of the Core Period. Novartis Drug Supply Management department members were
      unblinded in order to prepare the study drug supplies.

      Study Period 4 was a single-arm, open-label therapy (end of Week 34 to Week 48). At the end
      of Week 34, all patients received open-label osilodrostat treatment. The Investigator had the
      discretion to select the dose during this period.

      Patients continued open-label therapy until Week 48. At Week 48, patients had the option to
      enter an Extension Period, or discontinue osilodrostat at Week 48 to conclude with an end of
      Core Period visit 4 weeks off study drug (at Week 52).

      Patients who continued to receive clinical benefit, as assessed by the study Investigator,
      and who wished to enter the Extension Period were re-consented at Week 48. Patients entered
      the Extension period without interruption of study drug or assessments. At the end of the
      study, patients who continued to benefit from treatment were offered to participate in a
      separate long-term safety follow-up study. The optional Extension Period ended after all
      patients completed Week 72 or discontinued early.
    

Intervention name(s): osilodrostat; LCI699 matching placebo
Intervention type(s): Drug; Drug
Intervention description(s): Osilodrostat comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat was 30 mg bid.; Osilodrostat placebo comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat placebo was 30 mg bid.
Other intervention name(s): LCI699
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: It is a double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: LCI699; osilodrostat; Cushings Disease; open-label dose titration; randomized withdrawal