An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease.
An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease.
This study provided access to pasireotide sc in patients with Cushing's disease.and provided
 additional information for safety and efficacy of pasireotide s.c.
Purpose of this study was to give access to pasireotide sc for patients with Cushing's
 disease as no medical treatment for Cushing's disease was approved at the time of the study
 initiation. The study population consisted of patients with persistent or recurrent Cushing's
 disease or patients with de novo Cushing's disease that were not considered candidates for
 pituitary surgery (poor surgery candidates, surgically unapproachable tumor, patients with no
 visible pituitary tumor, patients who refused surgery). A confirmed Cushing's disease
 diagnosis was required.
Inclusion criteria:

 1. Written informed consent obtained prior to any screening procedures

 2. Male or female patients aged 18 years or greater

 3. Patients with confirmed diagnosis of Cushing's disease as evidenced by mean urinary
 free cortisol of three 24-hour urine samples collected during the 3-week screening
 period above the upper limit of the laboratory normal range morning plasma ACTH within
 the normal or above normal range either MRI confirmation of pituitary adenoma (greater
 than or equal to 0.6 cm), or inferior petrosal sinus gradient >3 after CRH stimulation
 for those patients with a microadenoma less than 0.6 cm, or for patients who have had
 prior pituitary surgery, histopathology confirming an ACTH staining adenoma.

 4. Patients with de novo Cushing's disease must not be considered as candidates for
 pituitary surgery (i.e. poor surgical candidates, surgically unapproachable tumors,
 patients with no visible pituitary tumor, patients who refuse to have surgical
 treatment)

 5. Karnofsky performance status >60 (i.e. requires occasional assistance, but is able to
 care for most of his personal needs)

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

 -  Inhibitors of steroidogenesis (e.g. ketoconazole, metyrapone, rosiglitazone): 1
 week

 -  Dopamine agonists (e.g. bromocriptine, cabergoline): 4 weeks

 -  Mitotane: 6 months

 -  Octreotide LAR and Lanreotide autogel: 8 weeks

 -  Lanreotide SR: 4 weeks

 -  Octreotide (immediate release formulation): 1 week

 -  Glucocorticoid receptor inhibitor (mifepristone): 4 weeks

 Exclusion criteria:

 1. Radiotherapy of the pituitary <4 weeks before screening or patient who has not
 recovered from side effects

 2. Patients with compression of the optic chiasm causing acute clinically significant
 visual field defect

 3. Patients with Cushing's syndrome due to ectopic ACTH secretion

 4. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary)
 bilateral adrenal hyperplasia

 5. Patients who have a known inherited syndrome as the cause for hormone over secretion
 (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)

 6. Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)

 7. Patients who have undergone major surgery within 1 month prior to screening

 8. Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis
 (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be
 included)

 9. Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%

 10. Patients who have clinically significant impairment in cardiovascular function or are
 at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV),
 unstable angina, sustained ventricular tachycardia, clinically significant
 bradycardia, high grade AV block, history of acute MI less than one year prior to
 study entry

 -  QTcF >450 msec at screening

 -  History of syncope or family history of idiopathic sudden death

 -  Risk factors for Torsades de Pointes such as uncorrected hypokalemia, uncorrected
 hypomagnesemia, cardiac failure

 -  Concomitant disease(s) that could prolong the QT interval such as autonomic
 neuropathy (caused by diabetes or Parkinson's disease), HIV, cirrhosis,
 uncontrolled hypothyroidism, concomitant medication(s) with known risk for TdP

 11. Patients with liver disease or history of liver disease such as cirrhosis, chronic
 active hepatitis B and C, or chronic persistent hepatitis, or patients with ALT or AST
 more than 2 x ULN, serum creatinine >2.0 x ULN, serum bilirubin >1.5 x ULN, serum
 albumin < 0.67 x LLN at screening

 12. Patients who have any current or prior medical condition that can interfere with the
 conduct of the study or the evaluation of its results, such as

 -  History of immunocompromise, including a positive HIV test result (Elisa and
 Western blot). An HIV test will not be required, however, previous medical
 history will be reviewed

 -  Presence of active or suspected acute or chronic uncontrolled infection

 -  History of, or current alcohol misuse/abuse in the 12 month period prior to
 screening

 13. Female patients who are pregnant or lactating, or are of childbearing potential and
 not practicing a medically acceptable method of birth control. If a woman is
 participating in the trial then one form of contraception is sufficient (pill or
 diaphragm) and the partner should use a condom. If oral contraception is used in
 addition to condoms, the patient must have been practicing this method for at least
 two months prior to screening and must agree to continue the oral contraceptive
 throughout the course of the study and for one month after the study has ended. Male
 patients who are sexually active are required to use condoms during the study and for
 three month afterwards as a precautionary measure (available data do not suggest any
 increased reproductive risk with the study drugs)

 14. Patients who have participated in any clinical investigation with an investigational
 drug within 1 month prior to screening or patients who have previously been treated
 with pasireotide

 15. Known hypersensitivity to somatostatin analogues

 16. 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

 17. Patients with presence of Hepatitis B surface antigen (HbsAg)

 18. Patients with presence of Hepatitis C antibody test (anti-HCV)