Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease

The main purpose of this prospective, multicenter, open-label phase II study, was to evaluate the efficacy and safety of pasireotide alone or in combination with cabergoline in patients with Cushing's disease.

This was an open-label, multi-center, international, non-comparative study with adult patients with confirmed diagnosis of Cushing's disease. Given the fact that CD patients may need a multimodality treatment approach, the trial design aimed to mimic CD treatment by using a medical stepwise approach. Therefore, the whole patient population started treatment with Pasireotide and only in patients within this population who did not achieve biochemical control, cabergoline was added.

The whole patient population had never received pasireotide or had received it in the past (reasons of discontinuation not related to safety).

Core Phase

* Pasireotide naïve patients started pasireotide monotherapy at the dose of 0.6 mg s.c. bid. If at the end of the 8 week treatment period, the biochemical control was not achieved and the 0.6mg bid dose was well tolerated, the pasireotide dose was increased to 0.9mg bid. If the 0.9mg bid dose of pasireotide did not lead to biochemical control, cabergoline was added with a starting dose of 0.5mg qd. If the combination dose of 0.9mg bid of pasireotide plus 0.5mg qd cabergolinedid not achieve biochemical control, the cabergoline dose will be increased to 1.0mg qd.
* Patients who were currently being treated with maximal tolerated doses of pasireotide monotherapy for at least 8 weeks at screening without achieving normal mUFC, entered the study with a combination therapy starting with cabergoline 0.5mg qd.

Extension Phase

• After 35 weeks of treatment in core phase, patients had the option to continue study treatment if pasireotide was not yet approved for commercial use and/or reimbursed - if country reimbursement was applicable - in each respective country, or until 31st December 2017, or once an applicable roll over protocol became available, or whichever occurred first.

Novartis had a local transition plan in order to ensure that all trial patients had access to the study medication without any delay in their treatment

Eligibility Criteria:
Inclusion criteria:

1. Written informed consent obtained prior to screening procedures
2. Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following:

   1. The mean of three 24-hour urine samples collected within 2 weeks \> 1xULN with 2 out of 3 samples \>ULN
   2. Morning plasma ACTH within the normal or above normal range
   3. Either MRI confirmation of pituitary adenoma \> 6 mm, or inferior petrosal sinus gradient \>3 after CRH stimulation for those patients with a tumor less than or equal to 6 mm\*. For patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma \*If IPSS had previously been performed without CRH (e.g. with DDAVP), then a central to peripheral pre-stimulation gradient \> 2 was required. If IPSS had not previously been performed, IPSS with CRH stimulation was required.
3. Patients with de novo Cushing's disease could only be included only if they were not considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable tumors, patients who refused to have surgical treatment)
4. Male or female patients aged 18 years or greater
5. Karnofsky performance status ≥ 60 (i.e. required occasional assistance, but was able to care for most of their personal needs)
6. Patients on medical treatment for Cushing's disease the following washout periods must have been completed before screening assessments were 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
   * Progesterone receptor antagonist (mifepristone): 4 weeks
7. Patients could have been considered to enter the trial if they met any one of the following criteria: 1) They were naive to pasireotide 2) They had received pasireotide in the past and have been discontinued because of lack of efficacy (2 weeks for washout prior to screening for patients treated with pasireotide subcutaneously and 12 weeks of washout prior to screening for patients treated with pasireotide LAR) 3) Patients who were on maximal tolerated dose but had not achieved biochemical control
8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they were using highly effective methods of contraception during dosing and for 30 days after stopping study medication.
9. Male participants in the trial must have agreed to use a condom during intercourse, and not to father a child during the study and for the period of 30 days following stopping of the study treatment.

Exclusion criteria:

1. Patients with compression of the optic chiasm that caused any visual field defect that required surgical intervention
2. Diabetic patients with poor glycemic control as evidenced by HbA1c \>8%
3. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF \>450 ms in males, and \> 460 ms in females. hypokalemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval.
4. Patients with clinically significant valvular disease.
5. Patients with Cushing's syndrome due to ectopic ACTH secretion
6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
7. Patients who had congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function
8. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST \> 2 X ULN, serum bilirubin \>2.0 X ULN
9. Patients with serum creatinine \>2.0 X ULN
10. Patients with WBC \<3 X 10e9/L; Hb 90% \< LLN; PLT \<100 X 10e9/L
11. Patients with presence of Hepatitis B surface antigen (HbsAg)
12. Patients with presence of Hepatitis C antibody test (anti-HCV)
13. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline
14. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynauds syndrome.
15. Pregnant or nursing (lactating) women where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5 mIU/ml)
16. Patients with end-stage renal failure and/or hemodialysis
17. Patients with presence of active or suspected acute or chronic uncontrolled infection
18. Patients with a history of non-complance to medical regimens or who were considered potentially unreliable or were unable to complete the entire study
19. Patients with presence of Hepatitis B surface antigen (HbsAg)
20. Patients with presence of Hepatitis C antibody test (anti-HCV)
21. Patients with severe hepatic impairment (Child Pugh C) and hpersensitivity to pasireotide or cabergoline
22. Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynaud's syndrome
23. Pregnant or nursing (lactating) women where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5mIU/mL)
24. Patients with end-stage renal failure and/or hemodialysis