An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease. (SEASCAPE)

Novartis

Status and phase: Completed; Phase 3

Conditions: Cushing's Disease

Treatments: Drug: Pasireotide sub-cutaneous

Study type: Interventional

Funder types: Industry

Identifiers

NCT01582061

CSOM230B2406

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 104 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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104 participants in 2 patient groups

Pasireotide 600 μg

Experimental group

Description:

Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose \< 1500 μg /day.

Treatment:

Drug: Pasireotide sub-cutaneous

Pasireotide 900 μg

Experimental group

Description:

Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day

Treatment:

Drug: Pasireotide sub-cutaneous