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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01915303
• Collaborator: (none)
• Enrollment: 68
• Locations: 29
• Arm: 1
• Actual Duration (Months): 66
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cushings Disease	Drug: Pasireotide with or without cabergoline	Phase 2

Detailed Description

This was an open-label, multi-center, international, non-comparative study with adult patients with confirmed diagnosis of Cushing's disease. Given the fact that CD patients may need a multimodality treatment approach, the trial design aimed to mimic CD treatment by using a medical stepwise approach. Therefore, the whole patient population started treatment with Pasireotide and only in patients within this population who did not achieve biochemical control, cabergoline was added.

The whole patient population had never received pasireotide or had received it in the past (reasons of discontinuation not related to safety).

Core Phase

• Pasireotide naïve patients started pasireotide monotherapy at the dose of 0.6 mg s.c. bid. If at the end of the 8 week treatment period, the biochemical control was not achieved and the 0.6mg bid dose was well tolerated, the pasireotide dose was increased to 0.9mg bid. If the 0.9mg bid dose of pasireotide did not lead to biochemical control, cabergoline was added with a starting dose of 0.5mg qd. If the combination dose of 0.9mg bid of pasireotide plus 0.5mg qd cabergolinedid not achieve biochemical control, the cabergoline dose will be increased to 1.0mg qd.

• Patients who were currently being treated with maximal tolerated doses of pasireotide monotherapy for at least 8 weeks at screening without achieving normal mUFC, entered the study with a combination therapy starting with cabergoline 0.5mg qd.

Extension Phase

• After 35 weeks of treatment in core phase, patients had the option to continue study treatment if pasireotide was not yet approved for commercial use and/or reimbursed - if country reimbursement was applicable - in each respective country, or until 31st December 2017, or once an applicable roll over protocol became available, or whichever occurred first.

Novartis had a local transition plan in order to ensure that all trial patients had access to the study medication without any delay in their treatment

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Mar 6, 2014
• Actual Primary Completion Date: Sep 5, 2016
• Actual Study Completion Date: Sep 4, 2019

Arms and Interventions

Arm

Intervention/Treatment

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

Drug: 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.

Outcome Measures

Primary Outcome Measures

1. Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35 [Baseline up to week 35]

   Participants who attained mUFC ≤ 1.0 x ULN (upper limit of normal) with pasireotide alone or in combination with cabergoline. The 24h-UFC concentration results from three samples, collected during the screening period, were averaged to obtain the Baseline urinary free cortisol level. mean 24h-UFC was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit. Imputation: subjects who completed the end of treatment visit at Week 35, but had missing evaluation of mean urinary free cortisol (mUFC). The last available mUFC assessment at or after previous visit (week) before last week was carried forward as the last week mUFC assessment.

Secondary Outcome Measures

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

   Mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.

2. Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN [Baseline up to week 235]

   Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.

3. Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC [Baseline up to week 235]

   Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.

4. Duration (Weeks) of Controlled or Partially Controlled Response [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]

   Duration of controlled or partially controlled response is defined as the period starting from the date of patient's first normalization (mUFC ≤ 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN and the reduction from baseline falls to less than 50% from the first time

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

   A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory.

6. Serum Cortisol Levels [Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension]

   A pre-dose blood draw for an 8 am fasting serum cortisol measurement were taken at visits. Samples were analyzed by a central laboratory.

7. Sitting Systolic Blood Pressure at Week 35 [Baseline and week 35]

   The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures

8. Sitting Diastolic Blood Pressure at Week 35 [Baseline and week 35]

   The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures

9. Body Weight at Week 35 [Baseline and week 35]

   Weight was was one of the measures of clinical symptoms of CD

10. Body Mass Index at Week 35 [Baseline and week 35]

    Body mass index was one of the measurements of clinical symptoms of CD. Body mass index=weight in kg divided by the square of the body height (in meters)

11. Waist Circumference at Week 35 [Baseline and week 35]

    Waist circumference was one of the measurements of clinical signs of CD

12. LDL, HDL and Total Cholesterol at Week 35 [Baseline and week 35]

    LDL=Low density lipoprotein, HDL=high density llipoprotein and total protein were analyzed by a central laboratory

13. Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 [Baseline and week 17 and 35]

    Patients who completed nine or more items for the 12-item Cushing's syndrome QoL questionaire were considered evaluable for that assessment. Raw scores were obtained for the 12 items using the following scoring: 1) always or very much, 2) often or quite a bit, 3) sometimes or somewhat, 4) rarely or very little, 5) never or not at all. Then the standardized score, Y, was calculated for each patient as follows: Y = 100* (X - n) / n*5 - n*1) = 100 * (X - n) / 4*n where X denoted the raw score and n the number of questions answered by the patient. The higher the score, the better the QoL. The best possible standardized score was 100 and the worst possible standardized score was 0

14. Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 [Baseline, week 17 and 35]

    SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.

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

    Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

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

    Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

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

    Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

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

    Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

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

    Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

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

    Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad were assessed. Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position will be taken to assess striae, and hirsutism. The photographs must be assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

21. Number of Patients With Shift From Standing Easily to Not Being Able to Stand [Baseline up to week 267]

    To test proximal muscle strength patients should be placed in a low seated position (for instance on an examination room stool). They should be asked to extend the arms in front of them. From this seated position patients will be asked to stand up. Patients will be evaluated using the following scale: 3. - completely unable to stand 2. - able to stand only by using arms as assistance 1. - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

3. The mean of three 24-hour urine samples collected within 2 weeks > 1xULN with 2 out of 3 samples >ULN

4. Morning plasma ACTH within the normal or above normal range

5. 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.

6. 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)

7. Male or female patients aged 18 years or greater

8. Karnofsky performance status ≥ 60 (i.e. required occasional assistance, but was able to care for most of their personal needs)

9. 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

1. 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

2. 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.

3. 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.

1. Patients with clinically significant valvular disease.

2. Patients with Cushing's syndrome due to ectopic ACTH secretion

3. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia

4. 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

5. 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

6. Patients with serum creatinine >2.0 X ULN

7. Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L

8. Patients with presence of Hepatitis B surface antigen (HbsAg)

9. Patients with presence of Hepatitis C antibody test (anti-HCV)

10. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline

11. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynauds syndrome.

12. 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)

13. Patients with end-stage renal failure and/or hemodialysis

14. Patients with presence of active or suspected acute or chronic uncontrolled infection

15. Patients with a history of non-complance to medical regimens or who were considered potentially unreliable or were unable to complete the entire study

16. Patients with presence of Hepatitis B surface antigen (HbsAg)

17. Patients with presence of Hepatitis C antibody test (anti-HCV)

18. Patients with severe hepatic impairment (Child Pugh C) and hpersensitivity to pasireotide or cabergoline

19. Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynaud's syndrome

20. 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)

21. Patients with end-stage renal failure and/or hemodialysis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham The Kirklin Clinic	Birmingham	Alabama	United States	35294
2	Oregon Health and Science University SOM230B2411	Portland	Oregon	United States	97239
3	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1280AEB
4	Novartis Investigative Site	Gent		Belgium	9000
5	Novartis Investigative Site	Leuven		Belgium	3000
6	Novartis Investigative Site	Curitiba	PR	Brazil	80030-110
7	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	21941-913
8	Novartis Investigative Site	Porto Alegre	RS	Brazil	90560-030
9	Novartis Investigative Site	Sao Paulo	SP	Brazil	05403 000
10	Novartis Investigative Site	Bogota	Cundinamarca	Colombia	110111
11	Novartis Investigative Site	Vandoeuvre Cedex		France	54511
12	Novartis Investigative Site	Erlangen		Germany	91054
13	Novartis Investigative Site	Athens		Greece	106 76
14	Novartis Investigative Site	Thessaloniki		Greece	GR 54636
15	Novartis Investigative Site	Budapest		Hungary	1062
16	Novartis Investigative Site	Budapest		Hungary	1085
17	Novartis Investigative Site	Vellore	Tamil Nadu	India	632004
18	Novartis Investigative Site	Chandigarh		India	160 012
19	Novartis Investigative Site	New Delhi		India	110029
20	Novartis Investigative Site	Napoli		Italy	80131
21	Novartis Investigative Site	Wilayah Persekutuan		Malaysia	62502
22	Novartis Investigative Site	México	Distrito Federal	Mexico	14269
23	Novartis Investigative Site	Durango		Mexico	34270
24	Novartis Investigative Site	Rotterdam		Netherlands	3015 GD
25	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
26	Novartis Investigative Site	Alzira	Comunidad Valenciana	Spain	46600
27	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
28	Novartis Investigative Site	Izmir		Turkey	35340
29	Novartis Investigative Site	Pendik / Istanbul		Turkey	34899

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 27, 2019
• Study Protocol - Jul 12, 2017

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01915303
• Other Study ID Numbers: CSOM230B2411
• First Posted: Aug 2, 2013
• Last Update Posted: Sep 18, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: pituitary tumors; pasireotide; cabergoline; combination treatment; UFC; hormone disorder; cortisol; adrenocorticotropic hormone; Cushing Disease
• Additional relevant MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Cabergoline; Pasireotide

Study Results

Participant Flow

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Period Title: Core Phase
STARTED	68
COMPLETED	52
NOT COMPLETED	16
Period Title: Core Phase
STARTED	29
COMPLETED	12
NOT COMPLETED	17

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Overall Participants	68
Age, Customized (participants) [Number]
< 65 years	64 94.1%
≥ 65 years	4 5.9%
Sex: Female, Male (Count of Participants)
Female	60 88.2%
Male	8 11.8%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	44 64.7%
Asian	9 13.2%
Native American	5 7.4%
Black	2 2.9%
Other	8 11.8%
Cushing's disease status (Number) [Number]
De novo	10 14.7%
Persistent/recurrent	58 85.3%
Clinical symptoms of facial rubor (Number) [Number]
None	10 14.7%
Mild	17 25%
Moderate	11 16.2%
Severe	4 5.9%
Not done	26 38.2%
Clinical symptoms of hirsutism (Number) [Number]
None	13 19.1%
Mild	12 17.6%
Moderate	7 10.3%
Severe	3 4.4%
Not done	33 48.5%
Clinical symptoms of striae (Number) [Number]
None	20 29.4%
Mild	10 14.7%
Moderate	4 5.9%
Severe	8 11.8%
Not done	26 38.2%
Clinical symptoms of supraclavicular fat pad (Number) [Number]
None	8 11.8%
Mild	17 25%
Moderate	13 19.1%
Severe	4 5.9%
Not done	26 38.2%
Clinical symptoms of dorsal fat pad (Number) [Number]
None	3 4.4%
Mild	19 27.9%
Moderate	14 20.6%
Severe	6 8.8%
Not done	26 38.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35
Description	Participants who attained mUFC ≤ 1.0 x ULN (upper limit of normal) with pasireotide alone or in combination with cabergoline. The 24h-UFC concentration results from three samples, collected during the screening period, were averaged to obtain the Baseline urinary free cortisol level. mean 24h-UFC was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit. Imputation: subjects who completed the end of treatment visit at Week 35, but had missing evaluation of mean urinary free cortisol (mUFC). The last available mUFC assessment at or after previous visit (week) before last week was carried forward as the last week mUFC assessment.
Time Frame	Baseline up to week 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Number (95% Confidence Interval) [percentage of responders]	50.0

2. Secondary Outcome

Title	Mean Urinary Free Cortisol (mUFC) at Scheduled Visits
Description	Mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	501.6 (488.66)
Core Week 2 n-8	217.0 (100.69)
Core Week 4 n=59	242.1 (203.47)
Core Week 8 n=58	230.0 (195.21)
Core Week 13 n=51	231.0 (240.98)
Core Week 17 n=57	310.3 (429.64)
Core Week 22 n=50	214.0 (202.80)
Core Week 26 n=54	211.6 (173.58)
Core Week 31 n=46	154.3 (104.16)
Core Week 35 n=45	184.8 (140.13)
Ext Week 43 n=22	136.1 (91.13)
Ext Week 51 n=20	156.8 (108.91)
Ext Week 59 n=24	157.7 (111.63)
Ext Week 67 n=17	213.8 (194.99)
Ext Week 75 n=18	157.6 (166.28)
Ext Week 83 n=20	157.9 (134.98)
Ext Week 91 n=18	180.0 (302.36)
Ext Week 99 n=13	222.5 (375.67)
Ext Week 107 n=12	118.5 (122.01)
Ext Week 115 n=13	126.0 (80.09)
Ext Week 123 n=13	147.5 (157.77)
Ext Week 131 n=11	76.4 (49.92)
Ext Week 139 n=9	92.9 (73.18)
Ext Week 147 n=9	90.1 (55.31)
Ext Week 155 n=4	76.3 (39.05)
Ext Week 163 n=6	141.1 (142.42)
Ext Week 171 n=6	89.5 (61.87)
Ext Week 179 n=4	61.3 (43.06)
Ext Week 187 n=4	89.9 (52.44)
Ext Week 195 n=3	46.1 (40.21)
Ext Week 203 n=4	194.0 (259.15)
Ext Week 211 n=3	107.3 (37.68)
Ext Week 219 n=2	70.6 (46.74)
Ext Week 227 n=2	47.1 (7.99)
Ext Week 235 n=3	62.0 (23.83)
Ext Week 243 n=1	117.7
Ext Week 251 n=1	202.9
Ext Week 267 n=1	249.0

3. Secondary Outcome

Title	Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN
Description	Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.
Time Frame	Baseline up to week 235

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	4.4
Core Week 17 n=57	28.1
Core Week 35 n=45	48.9
Ext Week 43 n=22	63.6
Ext Week 67 n=17	47.1
Ext Week 91 n=18	61.1
Ext Week 115 n=13	76.9
Ext Week 139 n=9	77.8
Ext Week 163 n=6	66.7
Ext Week 187 n=4	75.0
Ext Week 211 n=3	66.7
Ext Week 235 n=3	100

4. Secondary Outcome

Title	Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC
Description	Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.
Time Frame	Baseline up to week 235

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	4.4
Core Week 17 n=57	54.4
Core Week 35 n=45	68.9
Ext Week 43 n=22	86.4
Ext Week 67 n=17	76.5
Ext Week 91 n=18	83.3
Ext Week 115 n=13	92.3
Ext Week 139 n=9	77.8
Ext Week 163 n=6	83.3
Ext Week 187 n=4	100
Ext Week 211 n=3	66.7
Ext Week 235 n=3	100

5. Secondary Outcome

Title	Duration (Weeks) of Controlled or Partially Controlled Response
Description	Duration of controlled or partially controlled response is defined as the period starting from the date of patient's first normalization (mUFC ≤ 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN and the reduction from baseline falls to less than 50% from the first time
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

Outcome Measure Data

Analysis Population Description

Core and extension full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core n=36	13.1
Extension n=20	22.0

6. Secondary Outcome

Title	Plasma Adrenocorticotropic Hormone (ACTH)
Description	A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory.
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	16.3 (16.3)
Core Week 2 n-62	12.4 (9.91)
Core Week 4 n=63	14.2 (12.50)
Core Week 8 n=61	13.3 (11.90)
Core Week 13 n=53	11.9 (10.98)
Core Week 17 n=58	12.3 (9.03)
Core Week 22 n=49	13.7 (13.82)
Core Week 26 n=55	12.4 (12.09)
Core Week 31 n=49	12.1 (11.02)
Core Week 35 n=40	11.0 (8.71)
Ext Week 43 n=23	11.5 (8.12)
Ext Week 51 n=21	10.4 (6.80)
Ext Week 59 n=23	10.7 (6.89)
Ext Week 67 n=22	11.0 (7.23)
Ext Week 75 n=22	9.1 (4.16)
Ext Week 83 n=19	9.8 (8.20)
Ext Week 91 n=19	10.6 (8.34)
Ext Week 99 n=16	11.3 (8.50)
Ext Week 107 n=13	9.3 (6.61)
Ext Week 115 n=15	9.5 (7.22)
Ext Week 123 n=14	10.6 (8.24)
Ext Week 131 n=12	8.2 (6.01)
Ext Week 139 n=10	10.0 (7.01)
Ext Week 147 n=9	10.4 (7.02)
Ext Week 155 n=9	10.4 (7.02)
Ext Week 163 n=5	10.0 (4.85)
Ext Week 171 n=5	7.4 (3.36)
Ext Week 179 n=5	7.0 (3.32)
Ext Week 187 n=5	8.6 (5.32)
Ext Week 195 n=4	9.0 (4.76)
Ext Week 203 n=4	8.0 (2.94)
Ext Week 211 n=3	11.0 (4.58)
Ext Week 219 n=2	6.0 (0.00)
Ext Week 227 n=2	7.0 (1.41)
Ext Week 235 n=3	10.3 (3.21)
Ext Week 243 n=1	6.0
Ext Week 251 n=1	7.0
Ext Week 267 n=1	4.0

7. Secondary Outcome

Title	Serum Cortisol Levels
Description	A pre-dose blood draw for an 8 am fasting serum cortisol measurement were taken at visits. Samples were analyzed by a central laboratory.
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	738.6 (332.53)
Core Week 2 n-62	626.1 (281.57)
Core Week 4 n=64	663.6 (292.38)
Core Week 8 n=61	649.0 (297.11)
Core Week 13 n=53	628.8 (269.43)
Core Week 17 n=58	683.0 (282.28)
Core Week 22 n=49	625.4 (216.29)
Core Week 26 n=55	632.7 (278.75)
Core Week 31 n=49	597.5 (247.60)
Core Week 35 n=40	538.2 (205.40)
Ext Week 43 n=23	525.5 (178.63)
Ext Week 51 n=21	512.2 (243.59)
Ext Week 59 n=21	547.5 (193.67)
Ext Week 67 n=22	495.4 (213.03)
Ext Week 75 n=21	458.5 (170.88)
Ext Week 83 n=19	419.5 (141.26)
Ext Week 91 n=19	501.2 (235.89)
Ext Week 99 n=16	470.9 (248.0)
Ext Week 107 n=13	463.4 (189.27)
Ext Week 115 n=15	501.7 (212.27)
Ext Week 123 n=14	441.6 (150.98)
Ext Week 131 n=12	413.8 (325.5)
Ext Week 139 n=10	404.0 (90.87)
Ext Week 147 n=10	585.4 (216.92)
Ext Week 155 n=8	472.5 (122.96)
Ext Week 163 n=6	617.0 (212.11)
Ext Week 171 n=5	648.6 (243.79)
Ext Week 179 n=5	599.0 (388.78)
Ext Week 187 n=5	609.8 (292.85)
Ext Week 195 n=4	418.8 (138.69)
Ext Week 203 n=4	514.0 (212.27)
Ext Week 211 n=3	551.3 (339.87)
Ext Week 219 n=2	482.0 (25.46)
Ext Week 227 n=2	324.5 (177.48)
Ext Week 235 n=3	384.7 (165.17)
Ext Week 243 n=1	679.0
Ext Week 251 n=1	574.0
Ext Week 267 n=1	638.0

8. Secondary Outcome

Title	Sitting Systolic Blood Pressure at Week 35
Description	The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures
Time Frame	Baseline and week 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	125.9 (14.3)
Week 35 n=41	119.5 (18.6)

9. Secondary Outcome

Title	Sitting Diastolic Blood Pressure at Week 35
Description	The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures
Time Frame	Baseline and week 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	81.8 (9.12)
Week 35 n=41	77.2 (12.42)

10. Secondary Outcome

Title	Body Weight at Week 35
Description	Weight was was one of the measures of clinical symptoms of CD
Time Frame	Baseline and week 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	82.2 (19.1)
Week 35 n=41	75.6 (20.4)

11. Secondary Outcome

Title	Body Mass Index at Week 35
Description	Body mass index was one of the measurements of clinical symptoms of CD. Body mass index=weight in kg divided by the square of the body height (in meters)
Time Frame	Baseline and week 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	31.3 (6.6)
Week 35 n=41	28.4 (6.8)

12. Secondary Outcome

Title	Waist Circumference at Week 35
Description	Waist circumference was one of the measurements of clinical signs of CD
Time Frame	Baseline and week 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline	104.1 (19.1)
Week 35 n=41	99.1 (18.2)

13. Secondary Outcome

Title	LDL, HDL and Total Cholesterol at Week 35
Description	LDL=Low density lipoprotein, HDL=high density llipoprotein and total protein were analyzed by a central laboratory
Time Frame	Baseline and week 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
HDL Baseline	1.5 (0.3)
HDL Week 35 n=41	1.5 (0.4)
LDL Baseline	3.2 (1.0)
LDL Week 35 n=41	2.8 (1.0)
Total Baseline	69.4 (3.7)
Total Week 35 n=41	68.6 (4.8)

14. Secondary Outcome

Title	Mean Scores of Cushing QoL Standardized Score at Week 17 and 35
Description	Patients who completed nine or more items for the 12-item Cushing's syndrome QoL questionaire were considered evaluable for that assessment. Raw scores were obtained for the 12 items using the following scoring: 1) always or very much, 2) often or quite a bit, 3) sometimes or somewhat, 4) rarely or very little, 5) never or not at all. Then the standardized score, Y, was calculated for each patient as follows: Y = 100* (X - n) / n*5 - n*1) = 100 * (X - n) / 4*n where X denoted the raw score and n the number of questions answered by the patient. The higher the score, the better the QoL. The best possible standardized score was 100 and the worst possible standardized score was 0
Time Frame	Baseline and week 17 and 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline Mean	41.6 (20.2)
Week 17 n=54	46.3 (19.7)
Week 35 n=40	47.6 (20.8)

15. Secondary Outcome

Title	Mean Scores of SF-12v2 Domain Scores at Week 17 and 35
Description	SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.
Time Frame	Baseline, week 17 and 35

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Baseline Bodily pain scale	42.9 (11.93)
Week 17 n=52 Bodily pain scale	45.1 (10.75)
Week 35 n=40 Bodily pain scale	44.9 (10.79)
Baseline n=67 General health scale:	38.9 (9.23)
Week 17 n=52 General health scale:	40.9 (8.52)
Week 35 n=40 General health scale:	40.7 (8.94)
Baseline n=67 Mental component	42.4 (10.17)
Week 17 n=52 Mental component	41.9 (9.68)
Week 35 n=40 Mental component	42.1 (8.32)
Baseline n=67 Mental health	41.9 (10.48)
Week 17 n=52 Mental health	43.0 (9.54)
Week 35 n=40 Mental health	42.4 (8.44)
Baseline n=67 Physical component summary	42.7 (9.03)
Week 17 n=52 Physical component summary	44.0 (8.52)
Week 35 n=40 Physical component summary	43.4 (9.59)
Baseline n=67 Physical functioning	42.1 (10.17)
Week 17 n=52 Physical functioning	41.9 (8.93)
Week 35 n=40 Physical functioning	42.1 (11.10)
Baseline n=67 Role emotional	39.7 (11.67)
Week 17 n=52 Role emotional	38.0 (9.95)
Week 35 n=40 Role emotional	38.7 (10.70)
Baseline n=67 Role physical scale:	42.3 (10.45)
Week 17 n=52 Role physical scale:	42.8 (8.73)
Week 35 n=40 Role physical scale:	41.3 (9.63)
Baseline n=67 Social functioning	42.2 (11.22)
Week 17 n=52 Social functioning	43.0 (8.70)
Week 35 n=40 Social functioning	43.3 (9.66)
Baseline n=67 Vitality scale:	47.2 (10.02)
Week 17 n=52 Vitality scale:	45.7 (10.29)
Week 35 n=40 Vitality scale:	45.6 (8.78)

16. Secondary Outcome

Title	Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor
Description	Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core Week 1 n=40	5 7.4%
Core Week 2 n=37	8 11.8%
Core Week 4 n=38	8 11.8%
Core Week 8 n=37	12 17.6%
Core Week 13 n=32	11 16.2%
Core Week 17 n=32	11 16.2%
Core Week 22 n=28	10 14.7%
Core Week 26 n=31	14 20.6%
Core Week 31 n=32	15 22.1%
Core Week 35 n=26	13 19.1%
Ext Week 43 n=11	2 2.9%
Ext Week 59 n=11	3 4.4%
Ext Week 75 n=12	3 4.4%
Ext Week 91 n=10	3 4.4%
Ext Week 107 n=9	3 4.4%
Ext Week 123 n=10	2 2.9%
Ext Week 139 n=7	2 2.9%
Ext Week 155 n=4	0 0%
Ext Week 171 n=3	0 0%
Ext Week 187 n=3	0 0%
Ext Week 203 n=4	0 0%
Ext Week 219 n=2	0 0%
Ext Week 235 n=3	0 0%
Ext Week 251 n=1	0 0%
Ext Week 267 n=1	0 0%

17. Secondary Outcome

Title	Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism
Description	Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core Week 1 n=35	5 7.4%
Core Week 2 n-33	3 4.4%
Core Week 4 n=32	4 5.9%
Core Week 8 n=32	4 5.9%
Core Week 13 n=27	4 5.9%
Core Week 17 n=28	3 4.4%
Core Week 22 n=25	5 7.4%
Core Week 26 n=27	8 11.8%
Core Week 31 n=28	9 13.2%
Core Week 35 n=23	7 10.3%
Ext Week 43 n=10	2 2.9%
Ext Week 59 n=9	2 2.9%
Ext Week 75 n=10	3 4.4%
Ext Week 91 n=9	2 2.9%
Ext Week 107 n=8	1 1.5%
Ext Week 123 n=9	2 2.9%
Ext Week 139 n=7	2 2.9%
Ext Week 155 n=4	2 2.9%
Ext Week 171 n=4	2 2.9%
Ext Week 187 n=3	2 2.9%
Ext Week 203 n=4	2 2.9%
Ext Week 219 n=2	1 1.5%
Ext Week 235 n=3	1 1.5%
Ext Week 251 n=1	0 0%
Ext Week 267 n=1	0 0%

18. Secondary Outcome

Title	Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae
Description	Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core Week 1 n=40	5 7.4%
Core Week 2 n-37	2 2.9%
Core Week 4 n=38	5 7.4%
Core Week 8 n=37	8 11.8%
Core Week 13 n=32	7 10.3%
Core Week 17 n=32	7 10.3%
Core Week 22 n=28	7 10.3%
Core Week 26 n=31	9 13.2%
Core Week 31 n=32	12 17.6%
Core Week 35 n=26	8 11.8%
Ext Week 43 n11=	1 1.5%
Ext Week 59 n=11	1 1.5%
Ext Week 75 n=12	1 1.5%
Ext Week 91 n=10	1 1.5%
Ext Week 107 n=9	0 0%
Ext Week 123 n=10	0 0%
Ext Week 139 n=7	0 0%
Ext Week 155 n=4	1 1.5%
Ext Week 171 n=3	0 0%
Ext Week 187 n=3	0 0%
Ext Week 203 n=4	1 1.5%
Ext Week 219 n=2	0 0%
Ext Week 235 n=3	1 1.5%
Ext Week 251 n=1	0 0%
Ext Week 267 n=1	1 1.5%

19. Secondary Outcome

Title	Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad
Description	Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core Week 1 n=40	6 8.8%
Core Week 2 n-37	7 10.3%
Core Week 4 n=37	6 8.8%
Core Week 8 n=37	8 11.8%
Core Week 13 n=32	8 11.8%
Core Week 17 n=32	9 13.2%
Core Week 22 n=28	9 13.2%
Core Week 26 n=31	10 14.7%
Core Week 31 n=32	12 17.6%
Core Week 35 n=26	11 16.2%
Ext Week 43 n=11	1 1.5%
Ext Week 59 n=11	0 0%
Ext Week 75 n=12	1 1.5%
Ext Week 91 n=10	1 1.5%
Ext Week 107 n=9	0 0%
Ext Week 123 n=10	1 1.5%
Ext Week 139 n=7	1 1.5%
Ext Week 155 n=4	1 1.5%
Ext Week 171 n=3	1 1.5%
Ext Week 187 n=3	1 1.5%
Ext Week 203 n=4	1 1.5%
Ext Week 219 n=2	1 1.5%
Ext Week 235 n=3	2 2.9%
Ext Week 251 n=1	0 0%
Ext Week 267 n=1	0 0%

20. Secondary Outcome

Title	Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad
Description	Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time Frame	Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core Week 1 n=40	6 8.8%
Core Week 2 n-37	4 5.9%
Core Week 4 n=37	5 7.4%
Core Week 8 n=37	5 7.4%
Core Week 13 n=32	4 5.9%
Core Week 17 n=32	8 11.8%
Core Week 22 n=28	8 11.8%
Core Week 26 n=31	12 17.6%
Core Week 31 n=32	13 19.1%
Core Week 35 n=26	9 13.2%
Ext Week 43 n=11	3 4.4%
Ext Week 59 n=10	4 5.9%
Ext Week 75 n=12	5 7.4%
Ext Week 91 n=10	3 4.4%
Ext Week 107 n=9	2 2.9%
Ext Week 123 n=10	3 4.4%
Ext Week 139 n=7	3 4.4%
Ext Week 155 n=4	1 1.5%
Ext Week 171 n=3	1 1.5%
Ext Week 187 n=3	2 2.9%
Ext Week 203 n=4	1 1.5%
Ext Week 219 n=2	1 1.5%
Ext Week 235 n=3	2 2.9%
Ext Week 251 n=1	0 0%
Ext Week 267 n=1	0 0%

21. Secondary Outcome

Title	Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism
Description	Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad were assessed. Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position will be taken to assess striae, and hirsutism. The photographs must be assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time Frame	Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core Week 4 Facial rubor baseline n=17	1 1.5%
Core Week 35 Facial rubor baseline n=17	1 1.5%
Ext Week 43 Facial rubor baseline n=17	1 1.5%
Ext Week 59 Facial rubor baseline n=17	1 1.5%
Ext Week 67 Facial rubor baseline n=17	1 1.5%
Ext Week 83 Facial rubor baseline n=17	1 1.5%
Ext Week 91 Facial rubor baseline n=17	1 1.5%
Ext Week 99 Facial rubor baseline n=17	1 1.5%
Ext Week 107 Facial rubor baseline n=17	1 1.5%
Ext Week 115 Facial rubor baseline n=17	1 1.5%
Ext Week 123 Facial rubor baseline n=17	1 1.5%
Core Week 1 Hirsutism baseline n=12	1 1.5%
Core Week 2 Hirsutism baseline n=12	1 1.5%
Ext Week 59 Striae baseline n=10	1 1.5%
Ext Week 99 Striae baseline n=10	1 1.5%
Ext Week 107 Striae baseline n=10	1 1.5%
Ext Week 115 Striae baseline n=10	1 1.5%
Ext Week 123 Striae baseline n=10	1 1.5%
Ext Week 99 Supraclavicular fat pad BL n=17	1 1.5%
Ext Week 107 Supraclavicular fat pad BL n=17	1 1.5%

22. Secondary Outcome

Title	Number of Patients With Shift From Standing Easily to Not Being Able to Stand
Description	To test proximal muscle strength patients should be placed in a low seated position (for instance on an examination room stool). They should be asked to extend the arms in front of them. From this seated position patients will be asked to stand up. Patients will be evaluated using the following scale: 3. - completely unable to stand 2. - able to stand only by using arms as assistance 1. - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended
Time Frame	Baseline up to week 267

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
Measure Participants	68
Core Week 26	1 1.5%
Core Week 35	1 1.5%

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration of 272 weeks
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus 28 days post treatment
Arm/Group Title	All Patients
Arm/Group Description	Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	3/68 (4.4%)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	15/68 (22.1%)
Blood and lymphatic system disorders
Anaemia	1/68 (1.5%)
Cardiac disorders
Coronary artery disease	1/68 (1.5%)
Endocrine disorders
Glucocorticoid deficiency	1/68 (1.5%)
Gastrointestinal disorders
Abdominal pain	2/68 (2.9%)
Intra-abdominal haematoma	1/68 (1.5%)
General disorders
Death	1/68 (1.5%)
Multiple organ dysfunction syndrome	1/68 (1.5%)
Hepatobiliary disorders
Bile duct stone	1/68 (1.5%)
Cholecystitis	1/68 (1.5%)
Cholelithiasis	2/68 (2.9%)
Infections and infestations
Abscess limb	1/68 (1.5%)
Cellulitis	1/68 (1.5%)
Varicella	1/68 (1.5%)
Injury, poisoning and procedural complications
Hip fracture	1/68 (1.5%)
Muscle rupture	1/68 (1.5%)
Radius fracture	1/68 (1.5%)
Wound	1/68 (1.5%)
Investigations
Alanine aminotransferase increased	1/68 (1.5%)
Aspartate aminotransferase increased	1/68 (1.5%)
Gamma-glutamyltransferase increased	1/68 (1.5%)
Metabolism and nutrition disorders
Diabetes mellitus	1/68 (1.5%)
Hypoglycaemia	1/68 (1.5%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/68 (1.5%)
Osteoarthritis	1/68 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	1/68 (1.5%)
Pituitary tumour benign	1/68 (1.5%)
Nervous system disorders
Headache	1/68 (1.5%)
Presyncope	1/68 (1.5%)
Syncope	1/68 (1.5%)
Renal and urinary disorders
Renal failure	1/68 (1.5%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/68 (1.5%)
Vascular disorders
Hypertension	1/68 (1.5%)
Shock haemorrhagic	1/68 (1.5%)
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	67/68 (98.5%)
Blood and lymphatic system disorders
Anaemia	6/68 (8.8%)
Cardiac disorders
Bradycardia	4/68 (5.9%)
Mitral valve incompetence	5/68 (7.4%)
Gastrointestinal disorders
Abdominal pain	11/68 (16.2%)
Abdominal pain upper	6/68 (8.8%)
Diarrhoea	30/68 (44.1%)
Flatulence	4/68 (5.9%)
Nausea	35/68 (51.5%)
Vomiting	4/68 (5.9%)
General disorders
Asthenia	7/68 (10.3%)
Fatigue	13/68 (19.1%)
Oedema peripheral	6/68 (8.8%)
Pyrexia	4/68 (5.9%)
Hepatobiliary disorders
Cholelithiasis	22/68 (32.4%)
Hepatic steatosis	4/68 (5.9%)
Infections and infestations
Influenza	4/68 (5.9%)
Nasopharyngitis	11/68 (16.2%)
Urinary tract infection	6/68 (8.8%)
Investigations
Alanine aminotransferase increased	5/68 (7.4%)
Gamma-glutamyltransferase increased	11/68 (16.2%)
Metabolism and nutrition disorders
Decreased appetite	6/68 (8.8%)
Diabetes mellitus	12/68 (17.6%)
Glucose tolerance impaired	4/68 (5.9%)
Hypercholesterolaemia	5/68 (7.4%)
Hyperglycaemia	35/68 (51.5%)
Hypertriglyceridaemia	5/68 (7.4%)
Hyperuricaemia	5/68 (7.4%)
Hypoglycaemia	11/68 (16.2%)
Vitamin B12 deficiency	4/68 (5.9%)
Vitamin D deficiency	6/68 (8.8%)
Musculoskeletal and connective tissue disorders
Back pain	13/68 (19.1%)
Muscular weakness	4/68 (5.9%)
Musculoskeletal pain	6/68 (8.8%)
Myalgia	6/68 (8.8%)
Pain in extremity	9/68 (13.2%)
Nervous system disorders
Dizziness	19/68 (27.9%)
Headache	20/68 (29.4%)
Somnolence	4/68 (5.9%)
Tremor	4/68 (5.9%)
Psychiatric disorders
Depression	8/68 (11.8%)
Insomnia	7/68 (10.3%)
Skin and subcutaneous tissue disorders
Alopecia	10/68 (14.7%)
Pruritus	9/68 (13.2%)
Rash	8/68 (11.8%)
Vascular disorders
Hypertension	5/68 (7.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.