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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01915303
• Date of registration: 10/06/2013
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharmaceuticals
• Public title: Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease
• Scientific title: A Phase II Trial to Assess the Efficacy and Safety of Pasireotide s.c. Alone or in Combination With Cabergoline in Patients With Cushing's Disease
• Date of first enrolment: March 6, 2014
• Target sample size: 68
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT01915303
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Bulgaria, Colombia, France, Germany, Greece, Hungary, India, Italy, Malaysia, Mexico, Netherlands, Spain, Turkey, United States, Venezuela

Contacts

• Name: Novartis Pharmaceuticals
• Affiliation: Novartis Pharmaceuticals

Key inclusion & exclusion 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
PPAR? 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



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Cushings Disease

Intervention(s)

Drug: Pasireotide with or without cabergoline

Primary Outcome(s)

Percentage of Responders With Mean Urinary Free Cortisol (mUFC) = 1.0xULN Collected or Imputed at Week 35 [Time Frame: Baseline up to week 35]

Secondary Outcome(s)

Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 [Time Frame: Baseline and week 17 and 35]

Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension]

Percentage of Participants Who Attain mUFC = 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC [Time Frame: Baseline up to week 235]

Duration (Weeks) of Controlled or Partially Controlled Response [Time Frame: from the date patient's first normalization (mUFC = 1.0xULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN]

Mean Urinary Free Cortisol (mUFC) at Scheduled Visits [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension]

Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism [Time Frame: Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension]

Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension]

Plasma Adrenocorticotropic Hormone (ACTH) [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension]

Waist Circumference at Week 35 [Time Frame: Baseline and week 35]

Body Mass Index at Week 35 [Time Frame: Baseline and week 35]

Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension]

Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 [Time Frame: Baseline, week 17 and 35]

Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension]

Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension]

Number of Patients With Shift From Standing Easily to Not Being Able to Stand [Time Frame: Baseline up to week 267]

Serum Cortisol Levels [Time Frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension]

Percentage of Responders With Mean Urinary Free Cortisol (mUFC) = 1.0xULN [Time Frame: Baseline up to week 235]

Sitting Systolic Blood Pressure at Week 35 [Time Frame: Baseline and week 35]

Body Weight at Week 35 [Time Frame: Baseline and week 35]

LDL, HDL and Total Cholesterol at Week 35 [Time Frame: Baseline and week 35]

Sitting Diastolic Blood Pressure at Week 35 [Time Frame: Baseline and week 35]

Secondary ID(s)

CSOM230B2411

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 18/09/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01915303