Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease
Condition: Cushing's Disease
MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion
Intervention: osilodrostat; osilodrostat Placebo
Intervention description: In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg.; Matching Placebo in the form of filmcoated tablets for oral administration
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 73.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Cushing's disease; LCI699; osilodrostat; Pituitary Gland; Adrenocorticotropic; Hormone; ACTH; UFC

Summary:

      The purpose of this study was to confirm efficacy and safety of osilodrostat for the
      treatment of patients with Cushing's disease who are candidates for medical therapy.
    

Eligibility criteria:

        Key inclusion criteria:

          -  Confirmed Cushing's Disease (CD) that is persistent or recurrent as evidenced by all
             of the following criteria being met (i.e., a, b and c):

               1. mUFC > 1.3 x ULN (Mean of three 24-hour urine samples collected preferably on 3
                  consecutive days, during screening after washout of prior medical therapy for CD
                  (if applicable), confirmed by the central laboratory and available before Day 1),
                  with ≥2 of the individual UFC values being > 1.3 x ULN.

               2. Morning plasma Adrenocorticotropic hormone (ACTH) above Lower Limit of Normal

               3. Confirmation (based on medical history) of pituitary source of excess

                  ACTH as defined by any one or more of the following three criteria:

             i. Histopathologic confirmation of an ACTH-staining adenoma in patients who have had
             prior pituitary surgery. OR ii. Magnetic resonance imaging (MRI) confirmation of
             pituitary adenoma > 6 mm OR iii. Bilateral inferior petrosal sinus sampling (BIPSS)
             with either corticotropic-releasing hormone (CRH) or desmopressin (DDAVP) stimulation
             for patients with a tumor ≤ 6mm. The criteria for a confirmatory BIPSS test are any of
             the following: Pre-dose central to peripheral ACTH gradient > 2; Post-dose central to
             peripheral ACTH gradient > 3 after either CRH or DDAVP stimulation

          -  Patients that received glucocorticoid replacement therapy must have discontinued such
             therapy for at least seven days or 5 half-lives prior to screening, whichever is
             longer.

          -  Patients with de novo CD can be included only if they are not considered candidates
             for surgery (e.g., poor surgical candidates due to co-morbidities, inoperable tumors,
             patients who refuse to have surgical treatment, or surgical treatment is not
             available).

        Key exclusion criteria:

          -  Patients with pseudo-Cushing's syndrome. This may be diagnosed by a normal late night
             salivary cortisol value collected during the screening period and after washout of
             prior CD medication.

          -  Patients with risk factors for QT corrected (QTc) prolongation or Torsade de Pointes,
             including:

        patients with a baseline QT corrected (Fridericia QT formula) (QTcF) > 450 ms for males and
        QTcF > 460 ms for females; personal or family history of long QT syndrome; concomitant
        medications known to prolong the QT interval; patients with hypokalemia, hypocalcaemia, or
        hypomagnesaemia, if not corrected before pre-dose Day 1.

          -  Patients likely to require adrenalectomy, pituitary surgery, or radiation therapy
             during the placebo-controlled period (Weeks 1-12) for the treatment of severe
             hypercortisolism or pituitary tumor growth causing compression of the optic chiasm.

          -  Patients with compression of the optic chiasm due to a macroadenoma or patients at
             high risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm).

          -  Patients who have a known inherited syndrome as the cause for hormone over secretion
             (i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP).

          -  Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH independent
             (adrenal) Cushing's syndrome. Pregnant or nursing (lactating) women. 8. Women of
             child-bearing potential, defined as all women physiologically capable of becoming
             pregnant, unless they are using highly effective methods of contraception during
             dosing and for 1 week after completion of dosing. Highly effective contraception
             methods include: A. Total abstinence (when this is in line with the preferred and
             usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
             symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
             contraception. B. Female sterilization (have had surgical bilateral oophorectomy with
             or without hysterectomy) or tubal ligation at least six weeks before taking study
             drug. In case of bilateral oophorectomy, documentation is required (e.g. operative
             report, pelvic ultrasound or other reliable imaging method). C. Male sterilization (at
             least 6 months prior to screening). For female subjects on the study the vasectomized
             male partner should be the sole partner for that subject.

        D. Combination of any two of the following (a+b or a+c, or b+c):

          1. Use of oral*, injected, or implanted hormonal methods of contraception or other forms
             of hormonal contraception that have comparable efficacy (failure rate <1%), for
             example hormone vaginal ring or transdermal hormone contraception

          2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

          3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault
             caps) with spermicidal foam/gel/film/cream/vaginal suppository. *In the case of use of
             oral contraception, women should have been stable on the same pill for a minimum of 3
             months before taking study drug. Women are considered post-menopausal and not of child
             bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with
             an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms)
             or have had surgical bilateral oophorectomy (with or without hysterectomy), total
             hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy
             alone, only when the reproductive status of the woman has been confirmed by follow-up
             hormone level assessment is she considered not of child bearing potential.