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
Intervention: osilodrostat; LCI699 matching placebo
Intervention description: 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.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
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)
Enrollment: 137.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: LCI699; osilodrostat; Cushings Disease; open-label dose titration; randomized withdrawal

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written informed consent must be obtained before any assessment is performed.

          2. Male or female patients aged 18 - 75 years.

          3. Patients must have confirmed Cushing's disease that is persistent or recurrent.

          4. Patients with a history of prior pituitary surgery must be at least 30 days
             post-surgery to be eligible for inclusion in this study.

          5. Patients that received glucocorticoid replacement therapy post-operatively must have
             discontinued such therapy for at least one week, or 5 half-lives, whichever is longer,
             prior to screening.

          6. Patients with de novo Cushing's disease can be included only if they are not
             considered candidates for surgery.

          7. Patients with a history of pituitary irradiation can be included, provided that at
             least 2 years (stereotactic radiosurgery) or 3 years (conventional radiation) have
             elapsed from the time of last radiation treatment to the time of enrollment into this
             study.

          8. Patients are permitted to washout current drug therapy to meet these entry criteria if
             they have a known diagnosis of Cushing's disease.

        Exclusion Criteria:

          1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5
             half lives at the time of enrollment, whichever is longer; or longer if required by
             local regulations, and for any other limitation of participation in an investigational
             trial based on local regulations.

          2. History of hypersensitivity to LCI699 or to drugs of similar chemical classes.

          3. History of malignancy of any organ system (other than localized basal cell carcinoma
             of the skin), treated or untreated, within the past 5 years, regardless of whether
             there is evidence of local recurrence or metastases.

          4. Patients with risk factors for QTc prolongation or Torsade de Pointes.

          5. Pregnant or nursing (lactating) women.

          6. 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.

          7. 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).

          8. Patients who have a known inherited syndrome as the cause for hormone over secretion.

          9. Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH-independent
             (adrenal) Cushing's syndrome.

         10. Patients who have undergone major surgery within 1 month prior to screening.

         11. Hypertensive patients with uncontrolled blood pressure.

         12. Diabetic patients with poorly controlled diabetes.

         13. Patients who are not euthyroid as judged by the investigator.

         14. Patients who have a history of: congestive heart failure, unstable angina, sustained
             ventricular tachycardia, clinically significant bradycardia, advanced heart block,
             acute MI less than one year prior to study entry, or clinically significant impairment
             in cardiovascular function.

         15. Patients with moderate to severe renal impairment.

         16. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic
             persistent hepatitis, or patients with defined elevated ALT/ AST/ Bilirubin.

         17. Patients who have any current or prior medical condition that can interfere with the
             conduct of the study or the evaluation of its results in the opinion of the
             investigator or the sponsor's medical monitor.

         18. Patients who have a history of alcohol or drug abuse in the 6 month period prior to
             study treatment.

         19. Patients with a history of non-compliance to medical regimens or who are considered
             potentially unreliable or will be unable to complete the entire study.