Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease
Condition: Cushings Disease
MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion
Intervention: Pasireotide with or without cabergoline
Intervention description: The trial consisted of Pasireotide-untreated patients who started pasireotide 0.6mg twice a day for 8 weeks. If biochemical control was not achieved by the end of the 8 weeks, and the 0.6mg dose is well-tolerated, the dose was increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not achieved, cabergoline was added and patients began combination treatment with cabergoline at the starting dose of 0.5mg once a day for 8 weeks. If biochemical control is still not achieved at the end of the third 8 week period, the dose of cabergoline was increased to 1.0mg once a day. Patients could also immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current maximal tolerated dose of pasireotide. Patients continued with the combination treatment for 8 weeks. If biochemical control was not not achieved by the end of the 8 week period, the dose of cabergoline was increased to 1mg once a day.
Intervention MeSH terms: Cabergoline; Pasireotide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 68.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: pituitary tumors; pasireotide; cabergoline; combination treatment; UFC; hormone disorder; cortisol; adrenocorticotropic hormone; Cushing Disease

Summary:

      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.
    

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