Clinical trial: Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease (NCT01915303)

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
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 47-year-old man comes to the office due to weight gain and fatigue.  He is not able to lift heavy objects or climb stairs. Family history is positive for DM type 2 and HTN in his father.  Blood pressure is 165/90 mm Hg and pulse is 85/min.  On physical examination, there is symmetric proximal muscle weakness of the upper and lower extremities.  Fasting plasma glucose level is 138 mg/dL and 24-hour urinary cortisol is twice the upper normal limit.  Further evaluation reveals that high-dose, but not low-dose, dexamethasone suppresses serum cortisol levels.  Serum ACTH levels are high-normal. This patient's findings are consistent with endogenous Cushing Syndrome.

Patient description (patient's own words): I'm a 47-year-old man. I went to the clinic because I had been gaining weight and had increased fatigue over the past few weeks. I was not able to lift heavy objects or even climb the stairs. My dad was diagnosed with type 2 diabetes and high blood pressure. During the exam, they took my blood pressure, which was 165/90 mm Hg, and my pulse was 85/min. They found out that I have weaknesses in both of my arms and legs. I also did a blood test on an empty stomach, and I had a glucose level of 138 mg/dL, and twice the upper normal limit of cortisol. I had high-normal levels of ACTH. The doctor said I suffer from endogenous Cushing Syndrome.

Does the patient match the trial criteria? 0