Clinical trial: Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease (NCT02697734)

Eligibility criteria:
Key inclusion criteria:

          -  Confirmed 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 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. MRI confirmation of pituitary adenoma > 6 mm OR iii.
             Bilateral inferior petrosal sinus sampling (BIPSS) with either CRH or 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 QTc prolongation or Torsade de Pointes, including:

        patients with a baseline 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. Other
             protocol-defined inclusion/exclusion criteria may apply.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.
Subject must be at most 75 Years

Patient description (medical language): A 47-year-old man comes to the office due to weight gain and fatigue.  He is not able to lift heavy objects or climb stairs. Family history is positive for DM type 2 and HTN in his father.  Blood pressure is 165/90 mm Hg and pulse is 85/min.  On physical examination, there is symmetric proximal muscle weakness of the upper and lower extremities.  Fasting plasma glucose level is 138 mg/dL and 24-hour urinary cortisol is twice the upper normal limit.  Further evaluation reveals that high-dose, but not low-dose, dexamethasone suppresses serum cortisol levels.  Serum ACTH levels are high-normal. This patient's findings are consistent with endogenous Cushing Syndrome.

Patient description (patient's own words): I'm a 47-year-old man. I went to the clinic because I had been gaining weight and had increased fatigue over the past few weeks. I was not able to lift heavy objects or even climb the stairs. My dad was diagnosed with type 2 diabetes and high blood pressure. During the exam, they took my blood pressure, which was 165/90 mm Hg, and my pulse was 85/min. They found out that I have weaknesses in both of my arms and legs. I also did a blood test on an empty stomach, and I had a glucose level of 138 mg/dL, and twice the upper normal limit of cortisol. I had high-normal levels of ACTH. The doctor said I suffer from endogenous Cushing Syndrome.

Does the patient match the trial criteria? Contradiction