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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01915303




Registration number
NCT01915303
Ethics application status
Date submitted
10/06/2013
Date registered
2/08/2013
Date last updated
18/09/2020

Titles & IDs
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
Secondary ID [1] 0 0
CSOM230B2411
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cushings Disease 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Other endocrine disorders
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pasireotide with or without cabergoline

Experimental: pasireotide +/- cabergoline - pasireotide alone or with cabergoline


Treatment: Drugs: Pasireotide with or without cabergoline
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 code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Responders With Mean Urinary Free Cortisol (mUFC) = 1.0xULN Collected or Imputed at Week 35
Timepoint [1] 0 0
Baseline up to week 35
Secondary outcome [1] 0 0
Mean Urinary Free Cortisol (mUFC) at Scheduled Visits
Timepoint [1] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Secondary outcome [2] 0 0
Percentage of Responders With Mean Urinary Free Cortisol (mUFC) = 1.0xULN
Timepoint [2] 0 0
Baseline up to week 235
Secondary outcome [3] 0 0
Percentage of Participants Who Attain mUFC = 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC
Timepoint [3] 0 0
Baseline up to week 235
Secondary outcome [4] 0 0
Duration (Weeks) of Controlled or Partially Controlled Response
Timepoint [4] 0 0
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
Secondary outcome [5] 0 0
Plasma Adrenocorticotropic Hormone (ACTH)
Timepoint [5] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Secondary outcome [6] 0 0
Serum Cortisol Levels
Timepoint [6] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Secondary outcome [7] 0 0
Sitting Systolic Blood Pressure at Week 35
Timepoint [7] 0 0
Baseline and week 35
Secondary outcome [8] 0 0
Sitting Diastolic Blood Pressure at Week 35
Timepoint [8] 0 0
Baseline and week 35
Secondary outcome [9] 0 0
Body Weight at Week 35
Timepoint [9] 0 0
Baseline and week 35
Secondary outcome [10] 0 0
Body Mass Index at Week 35
Timepoint [10] 0 0
Baseline and week 35
Secondary outcome [11] 0 0
Waist Circumference at Week 35
Timepoint [11] 0 0
Baseline and week 35
Secondary outcome [12] 0 0
LDL, HDL and Total Cholesterol at Week 35
Timepoint [12] 0 0
Baseline and week 35
Secondary outcome [13] 0 0
Mean Scores of Cushing QoL Standardized Score at Week 17 and 35
Timepoint [13] 0 0
Baseline and week 17 and 35
Secondary outcome [14] 0 0
Mean Scores of SF-12v2 Domain Scores at Week 17 and 35
Timepoint [14] 0 0
Baseline, week 17 and 35
Secondary outcome [15] 0 0
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor
Timepoint [15] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Secondary outcome [16] 0 0
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism
Timepoint [16] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Secondary outcome [17] 0 0
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae
Timepoint [17] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Secondary outcome [18] 0 0
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad
Timepoint [18] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Secondary outcome [19] 0 0
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad
Timepoint [19] 0 0
Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Secondary outcome [20] 0 0
Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism
Timepoint [20] 0 0
Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Secondary outcome [21] 0 0
Number of Patients With Shift From Standing Easily to Not Being Able to Stand
Timepoint [21] 0 0
Baseline up to week 267

Eligibility
Key inclusion 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
6/03/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/09/2019
Sample size
Target
Accrual to date
Final
68
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Oregon
Country [3] 0 0
Argentina
State/province [3] 0 0
Buenos Aires
Country [4] 0 0
Belgium
State/province [4] 0 0
Gent
Country [5] 0 0
Belgium
State/province [5] 0 0
Leuven
Country [6] 0 0
Brazil
State/province [6] 0 0
PR
Country [7] 0 0
Brazil
State/province [7] 0 0
RJ
Country [8] 0 0
Brazil
State/province [8] 0 0
RS
Country [9] 0 0
Brazil
State/province [9] 0 0
SP
Country [10] 0 0
Colombia
State/province [10] 0 0
Cundinamarca
Country [11] 0 0
France
State/province [11] 0 0
Vandoeuvre Cedex
Country [12] 0 0
Germany
State/province [12] 0 0
Erlangen
Country [13] 0 0
Greece
State/province [13] 0 0
Athens
Country [14] 0 0
Greece
State/province [14] 0 0
Thessaloniki
Country [15] 0 0
Hungary
State/province [15] 0 0
Budapest
Country [16] 0 0
India
State/province [16] 0 0
Tamil Nadu
Country [17] 0 0
India
State/province [17] 0 0
Chandigarh
Country [18] 0 0
India
State/province [18] 0 0
New Delhi
Country [19] 0 0
Italy
State/province [19] 0 0
Napoli
Country [20] 0 0
Malaysia
State/province [20] 0 0
Wilayah Persekutuan
Country [21] 0 0
Mexico
State/province [21] 0 0
Distrito Federal
Country [22] 0 0
Mexico
State/province [22] 0 0
Durango
Country [23] 0 0
Netherlands
State/province [23] 0 0
Rotterdam
Country [24] 0 0
Spain
State/province [24] 0 0
Andalucia
Country [25] 0 0
Spain
State/province [25] 0 0
Comunidad Valenciana
Country [26] 0 0
Turkey
State/province [26] 0 0
TUR
Country [27] 0 0
Turkey
State/province [27] 0 0
Izmir
Country [28] 0 0
Turkey
State/province [28] 0 0
Pendik / Istanbul

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01915303
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01915303