Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing's Disease

• Proportion of responders in each of the Pasireotide LAR (long acting release) 10 mg and 30 mg doses independently in patients with Cushing's disease after 7 months of treatment who did not up titrate the doses of Pasireotide at month 4. [ Time Frame: 7 months ] [ Designated as safety issue: No ]
  A responder is defined as a patient who attains mUFC ≤1.0 X ULN and had not had a dose increase at Month 4.
• Change in mean urinary free cortisol from baseline at every month in the core and every 3 months in extension within the two Pasireotide LAR regimens [ Time Frame: 26 months ] [ Designated as safety issue: Yes ]
• Proportion of responders in the two Pasireotide LAR regimens at every month in the core and every 3 months in the extension phases [ Time Frame: 26 months ] [ Designated as safety issue: No ]
• Proportion of responders in the two Pasireotide LAR regimens as measured by controlled and partially controlled mUFC(mean urinary free cortisol) combined responders at every month in the core and every 3 months in the extension [ Time Frame: 26 months ] [ Designated as safety issue: No ]
• Controlled mUFC (mean urinary free cortisol)response of the two Pasireotide regimens by month 7 and 12 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  To evaluate the frequency of controlled mUFC response of the two Pasireotide regimens by month 7 and 12.

This is a randomized, double-blind, multicenter, phase III study to evaluate the safety and efficacy of 2 dosing regiments of Pasireotide long acting release (LAR) in patients with Cushing's disease.

• Drug: SOM230 LAR 30 mg
  starting dose of 30 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of starting dose.
• Drug: SOM230 LAR 10 mg
  starting does of SOM230 LAR 10 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of the starting dose.

• Experimental: 10 mg LAR dose
  Intervention: Drug: SOM230 LAR 10 mg
• Experimental: 30 mg LAR dose
  Intervention: Drug: SOM230 LAR 30 mg

Inclusion Criteria:

• Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs)

• For patients on medical treatment for Cushing's disease the following washout periods must be completed before screening assessments are performed

  • Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
  • Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ agonists (rosiglitazone or pioglitazone): 4 weeks
  • Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks
  • Octreotide (immediate release formulation): 1 week

Exclusion Criteria:

• Patients who are considered candidates for surgical treatment at the time of study entry
• Patients who have received pituitary irradiation within the last ten years prior to visit 1
• Patients who have had any previous pasireotide treatment
• Patients who have been treated with mitotane during the last 6 months prior to Visit 1
• Diabetic patients on antihyperglycemic medications with poor glycemic control as evidenced by HbA1c >8%
• Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >470 ms, hypokalemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval
• Female patients who are pregnant or lactating, or are of childbearing potential (defined as all women physiologically capable of becoming pregnant) and not practicing an effective method of contraception/birth control. Sexually active males must use a condom during intercourse while taking the drug and for 2 months after the last dose of study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid