Safety and Efficacy of Different Dose Levels of Pasireotide in Patients With de Novo, Persistent or Recurrent Cushing's Disease

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00434148
• Collaborator: (none)
• Enrollment: 162
• Locations: 68
• Arms: 2
• Duration (Months): 89
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study will evaluate the safety and efficacy of two different doses of Pasireotide in patients with de novo or recurrent/persistent Cushing's Disease.

Condition or Disease	Intervention/Treatment	Phase
Cushing's Disease	Drug: Pasireotide	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 162 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind Study to Assess the Safety and Efficacy of Different Dose Levels of Pasireotide (SOM230) Subcutaneous (sc) Over a 6 Month Treatment Period in Patients With de Novo, Persistent or Recurrent Cushing's Disease
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pasireotide 600 ug At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	Drug: Pasireotide
Experimental: Pasireotide 900 ug At randomization, participants received 900 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	Drug: Pasireotide

Outcome Measures

Primary Outcome Measures

1. Number of mUFC (Urinary Free Cortisol) Responders by Randomized Dose Group [6 months]

   A responder in the primary efficacy analysis was a patient with a mUFC≤ULN at Month 6 and whose dose was not increased prior to Month 6.

Secondary Outcome Measures

1. Change From Baseline in mUFC [baseline, 3 months, 12 months]

   Twenty four hour urine samples were collected to obtain mUFC measurements. A negative change from baseline indicates improvement.

2. Time to First UFC Response [12 months]

   Time to first UFC response is defined as the number of months from baseline to first attainment of UFC response.

3. Percent Change From Baseline in Serum Cortisol [baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months]

   Blood samlpes were drawn to obtain serum cortisol levels. A negative change from baseline indicates improvement.

4. Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) [baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months]

   Blood samples were drawn to obtain ACTH levels. A negative change from baseline indicates improvement.

5. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) [baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60]

   Sitting blood pressure assessments were performed at every study visit. A negative change from baseline indicates improvement.

6. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) [baseline, month 3, month 6, month 12, month 24, month 36, month 48 and month 60]

   BMI was determined by using height and weight measurements. A negative change from baseline indicates improvement.

7. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference [baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60]

   Waist circumference was measured with a measuring tape correctly positioned. A negative change from baseline indicates improvement.

8. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides [baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60]

   Blood samples were drawn to obtain total cholesterol and triglycerides' levels. A negative change from baseline indicates improvement.

9. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score [baseline, month 3, month 6, month 12, month 18, month 24]

   The BDI-II is a 21 item self-report rating inventory measuring characteristic attitudes and symptoms of depression. The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The scores range as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression. A negative change from baseline indicates imrpovement.

10. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score [baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60]

    The Ferriman Gallwey scoring system is used to score the degree of excess male pattern body hair. The scorecard of every body location under survey begins from 0 (no excessive terminal hair growth) to 4 (extensive terminal hair growth) and the numbers are added up to a maximum count of 36. A score >= 6 indicates the hirsutism. A negative change from baseline indicates imrpovement.

11. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) [baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60]

    BMD was measured using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done in the lumbar vertebrae (L1-L4), proximal femur (total hip) and proximal femur (femur neck). A negative change from baseline indicates imrpovement.

12. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition [baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60]

    Body composition as in percentage of body fat by region was assessed by total body scan. A negative change from baseline indicates improvement.

13. Change From Baseline in Tumor Volume [baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 months]

    Pituitary magnetic resonance imaging (MRI) was performed to determine tumor volume. A negative change from baseline indicates imrpovement.

14. Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score [baseline, 3 months, 6 months, 12 months]

    A Cushing's syndrome health related quality of life (HRQL) questionnaire was completed. The Cushing's Syndrome HRQL questionnaire contains 12 sentences with 5 possible answers each. The answers are based on Likert scales, with 5 response categories: Always, Often, Sometimes, Rarely and Never; or Very much, Quite a bit, Somewhat, Very little, and Not at all. The answers to each of the items are rated on a scale of 1 to 5. "1" corresponds to the response category "Always" or "Very much" and "5" corresponds to the category "Never" or "Not at all". The score is the sum of all item responses and can range from 12 to 60 points. The lower the score, the greater the Cushing's Syndrome impacts on HRQoL. A positive change from baseline indicates improvement.

Eligibility Criteria

Criteria

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

Inclusion criteria

• 18 years or greater

• Confirmed diagnosis of ACTH-dependent Cushing's disease

• Not considered candidate for pituitary surgery

Exclusion criteria

• History of pituitary irradiation in the last 10 years

• Cushing's syndrome not caused by pituitary tumor

• Patients with active malignant disease (cancer) in the last 5 years

• Women who are pregnant or lactating

Other protocol-defined inclusion/exclusion criteria apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center Stanford Cancer Center (3)	Stanford	California	United States	94304
2	University Chicago Hospital Dept. of Univ of Chicago	Chicago	Illinois	United States	60637
3	Dana Farber Cancer Institute The Melanoma Program	Boston	Massachusetts	United States	02115
4	Columbia University Medical Center- New York Presbyterian Columbia University DeptofMed	New York	New York	United States	10032
5	Cleveland Clinic Foundation Dept. of Cleveland Clinic (6)	Cleveland	Ohio	United States	44195
6	Oregon Health & Sciences University Dept.ofOregonHealth&SciencesU.	Portland	Oregon	United States	97239
7	University of Texas Southwestern Medical Center Clinical-TranslationalRes.Ctr.	Dallas	Texas	United States	75390-8527
8	University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(8)	Houston	Texas	United States	77030-4009
9	Baylor College of Medicine	Houston	Texas	United States	77030
10	Swedish Medical Center Dept.ofSeattle Neuroscience(2)	Seattle	Washington	United States
11	Novartis Investigative Site	Capital Federal	Buenos Aires	Argentina	1425EKP
12	Novartis Investigative Site	Buenos Aires		Argentina	C1232AAC
13	Novartis Investigative Site	Buenos Aires		Argentina	C1405BCH
14	Novartis Investigative Site	Edegem		Belgium	2650
15	Novartis Investigative Site	Gent		Belgium	9000
16	Novartis Investigative Site	Curitiba	PR	Brazil	80060-900
17	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	21941-913
18	Novartis Investigative Site	Porto Alegre	RS	Brazil	90560-030
19	Novartis Investigative Site	Ribeirao Preto	SP	Brazil	14048-900
20	Novartis Investigative Site	Sao Paulo	SP	Brazil	05403-000
21	Novartis Investigative Site	São Paulo	SP	Brazil	01401-901
22	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 2S2
23	Novartis Investigative Site	Halifax	Nova Scotia	Canada	B3H 2Y9
24	Novartis Investigative Site	Montreal	Quebec	Canada	H2W 1T8
25	Novartis Investigative Site	Beijing	Beijing	China	100730
26	Novartis Investigative Site	Beijing		China	100028
27	Novartis Investigative Site	Shanghai		China	200025
28	Novartis Investigative Site	Arhus		Denmark	8000
29	Novartis Investigative Site	Copenhagen		Denmark	DK-2100
30	Novartis Investigative Site	Herlev		Denmark	DK-2730
31	Novartis Investigative Site	Helsinki		Finland	FIN-00290
32	Novartis Investigative Site	Angers		France	49033
33	Novartis Investigative Site	Grenoble Cédex 9		France	38043
34	Novartis Investigative Site	LILLE Cedex		France	59037
35	Novartis Investigative Site	Limoges cedex		France	87042
36	Novartis Investigative Site	Marseille cedex 05		France	13385
37	Novartis Investigative Site	Paris		France	75014
38	Novartis Investigative Site	Pessac Cedex		France	33604
39	Novartis Investigative Site	St Priest en Jarez Cedex		France	42277
40	Novartis Investigative Site	Toulouse Cedex 9		France	31000
41	Novartis Investigative Site	Berlin		Germany	10098
42	Novartis Investigative Site	Essen		Germany	45122
43	Novartis Investigative Site	Muenchen		Germany	80336
44	Novartis Investigative Site	Würzburg		Germany	97080
45	Novartis Investigative Site	Athens	GR	Greece	105 52
46	Novartis Investigative Site	Athens	GR	Greece	115 27
47	Novartis Investigative Site	Haifa		Israel	3339419
48	Novartis Investigative Site	Heifa		Israel	35152
49	Novartis Investigative Site	Jerusalem		Israel	9112001
50	Novartis Investigative Site	Petach Tikva		Israel	49100
51	Novartis Investigative Site	Ancona	AN	Italy	60126
52	Novartis Investigative Site	Cona	FE	Italy	44100
53	Novartis Investigative Site	Milano	MI	Italy	20149
54	Novartis Investigative Site	Milano	MI	Italy	20162
55	Novartis Investigative Site	Padova	PD	Italy	35128
56	Novartis Investigative Site	Pisa	PI	Italy	56124
57	Novartis Investigative Site	Orbassano	TO	Italy	10043
58	Novartis Investigative Site	Torino	TO	Italy	10126
59	Novartis Investigative Site	Napoli		Italy	80131
60	Novartis Investigative Site	México	Distrito Federal	Mexico	06720
61	Novartis Investigative Site	México	Distrito Federal	Mexico	14269
62	Novartis Investigative Site	Warszawa		Poland	01 809
63	Novartis Investigative Site	Porto		Portugal	4200-319
64	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
65	Novartis Investigative Site	Barcelona		Spain	08041
66	Novartis Investigative Site	Ankara		Turkey	06100
67	Novartis Investigative Site	Balcova / Izmir		Turkey	35340
68	Novartis Investigative Site	Fatih / Istanbul		Turkey	34098

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.
• Related Info

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00434148
• Other Study ID Numbers: CSOM230B2305; 2006-004111-22
• First Posted: Feb 12, 2007
• Last Update Posted: Mar 8, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Cushing's Disease; pasireotide; SOM230
• Additional relevant MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Pasireotide

Study Results

Participant Flow

Recruitment Details	The enrollment number reflects the participants who were randomized and received at least one dose of drug.
Pre-assignment Detail	A total of 165 participants were randomized, but 1 participant from the 600ug group and 2 participants from the 900ug group were not treated. Participants who completed month 12 and did not enter the extension phase were not counted as discontinuations.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Period Title: Overall Study
STARTED	82	80
Completed Month 12	39	39
Completed m. 12; Did Not Enter Extension	13	7
Completed Month 12; Entered Extension	26	32
COMPLETED	13	7
NOT COMPLETED	69	73

Baseline Characteristics

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug	Total
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.	Total of all reporting groups
Overall Participants	82	80	162
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.5 (12.97)	39.9 (10.77)	40.2 (11.90)
Sex: Female, Male (Count of Participants)
Female	62 75.6%	64 80%	126 77.8%
Male	20 24.4%	16 20%	36 22.2%

Outcome Measures

1. Primary Outcome

Title	Number of mUFC (Urinary Free Cortisol) Responders by Randomized Dose Group
Description	A responder in the primary efficacy analysis was a patient with a mUFC≤ULN at Month 6 and whose dose was not increased prior to Month 6.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) was the primary population for efficacy and consisted of all 162 randomized patients who received at least one dose of paseriotide.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
Number (95% Confidence Interval) [Responders]	12	21

2. Secondary Outcome

Title	Change From Baseline in mUFC
Description	Twenty four hour urine samples were collected to obtain mUFC measurements. A negative change from baseline indicates improvement.
Time Frame	baseline, 3 months, 12 months

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 3 (n=61,62)	-375.8 (631.07)	-343.4 (485.48)
month 12 (n=37,35)	-572.6 (941.44)	-350.7 (380.25)

3. Secondary Outcome

Title	Time to First UFC Response
Description	Time to first UFC response is defined as the number of months from baseline to first attainment of UFC response.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
Median (Inter-Quartile Range) [months]	1.0	1.0

4. Secondary Outcome

Title	Percent Change From Baseline in Serum Cortisol
Description	Blood samlpes were drawn to obtain serum cortisol levels. A negative change from baseline indicates improvement.
Time Frame	baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 0.5 (n=77,76)	-4.0 (28.23)	-10.8 (30.57)
month 1 (n=78,72)	-7.3 (30.13)	-7.7 (32.00)
month 1.5 (n=75,71)	-5.5 (27.65)	-7.1 (31.34)
month 2 (n=73,67)	-0.7 (35.81)	-6.4 (29.75)
month 2.5 (n=70,67)	-3.3 (31.40)	-10.1 (31.23)
month 3 (n=70,67)	-2.6 (35.79)	-10.2 (25.60)
month 4 (n=68,61)	-6.9 (31.88)	-10.8 (28.10)
month 5 (n=62,58)	-4.3 (36.96)	-10.8 (26.50)
month 6 (n=59,57)	-5.6 (34.28)	-9.3 (31.45)
month 7 (n=52,53)	-9.8 (34.44)	-5.8 (26.35)
month 8 (n=50,46)	-10.2 (30.85)	-9.9 (35.79)
month 9 (n=46,48)	-5.4 (33.49)	-5.8 (31.56)
month 10 (n=42,47)	-11.2 (30.25)	-9.3 (28.39)
month 11 (n=41,41)	-8.2 (38.19)	-14.0 (29.63)
month 12 (n=39,38)	-11.6 (33.75)	-15.2 (21.99)
month 15 (n=26,26)	-10.5 (30.14)	-12.5 (29.27)
month 18 (n=26,25)	-7.6 (40.35)	-17.8 (28.39)
month 21 (n=21,25)	-12.1 (34.23)	-15.5 (34.94)
month 24 (n=18,22)	-17.9 (43.46)	-18.1 (34.27)
month 27 (n=16,18)	-9.0 (41.71)	-12.7 (28.53)
month 30 (n=14,19)	-22.8 (35.43)	-22.7 (32.46)
month 33 (n=13,15)	-9.5 (44.64)	-25.2 (25.96)
month 36 (n=10,13)	-12.7 (65.43)	-13.3 (37.84)
month 39 (n=10,12)	-26.6 (42.89)	-25.9 (33.15)
month 42 (n=10,12)	-17.8 (39.54)	-18.1 (35.25)
month 45 (n=10,11)	-12.5 (44.89)	-8.5 (32.55)
month 48 (n=9,11)	-19.7 (37.88)	-20.1 (39.42)
month 51 (n=9,9)	-17.6 (34.60)	-24.0 (31.53)
month 54 (n=9,9)	-25.0 (30.49)	-6.8 (28.07)
month 57 (n=8,8)	-11.0 (56.61)	-30.8 (22.21)
month 60 (n=8,8)	-24.5 (31.89)	-18.9 (22.05)
month 63 (n=6,7)	-28.6 (31.20)	-24.0 (26.41)
month 66 (n=4,6)	-6.7 (29.29)	-22.5 (36.19)
month 69 (n=3,5)	-13.4 (42.68)	-33.6 (10.31)
month 72 (n=3,4)	-4.5 (40.94)	-22.7 (23.57)
month 75 (n=2,3)	-63.3 (41.13)	-23.2 (25.71)
month 78 (n=1,1)	14.5 (NA)	-53.3 (NA)

5. Secondary Outcome

Title	Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH)
Description	Blood samples were drawn to obtain ACTH levels. A negative change from baseline indicates improvement.
Time Frame	baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 0.5 (n=78,75)	9.3 (181.17)	-15.9 (30.75)
month 1 (n=78,71)	-10.0 (37.29)	-19.1 (30.47)
month 1.5 (n=74,69)	-13.4 (31.64)	-10.5 (38.05)
month 2 (n=72,66)	-7.7 (40.86)	-13.2 (35.38)
month 2.5 (n=69,65)	-8.2 (37.32)	-12.0 (47.02)
month 3 (n=69,66)	-9.2 (40.85)	-16.3 (31.93)
month 4 (n=66,61)	-7.2 (38.42)	-12.8 (44.06)
month 5 (n=62,55)	-3.0 (42.50)	-15.0 (38.89)
month 6 (n=58,55)	-8.4 (43.61)	-17.3 (35.60)
month 7 (n=52,52)	-11.4 (45.25)	-14.6 (30.88)
month 8 (n=48,46)	-5.0 (51.75)	-17.0 (36.87)
month 9 (n=46,47)	-5.3 (55.27)	-18.2 (35.87)
month 10 (n=42,46)	-10.2 (48.82)	-18.2 (34.18)
month 11 (n=42,40)	-11.5 (44.52)	-17.4 (39.06)
month 12 (n=39,39)	-7.4 (53.83)	-26.5 (33.38)
month 15 (n=26,26)	-14.5 (43.44)	-16.3 (32.01)
month 18 (n=26,25)	-5.9 (57.56)	-21.2 (32.91)
month 21 (n=20,23)	-1.5 (51.52)	-17.3 (34.34)
month 24 (n=18,21)	-10.9 (47.95)	-18.0 (26.53)
month 27 (n=16,18)	-10.4 (53.33)	-12.5 (39.39)
month 30 (n=14,18)	-14.7 (56.17)	-20.0 (40.82)
month 33 (n=13,14)	-9.4 (55.01)	-2.4 (33.07)
month 36 (n=10,13)	19.1 (112.26)	1.2 (35.33)
month 39 (n=10,12)	-20.9 (48.68)	-5.3 (40.02)
month 42 (n=10,12)	-6.7 (59.61)	2.7 (42.35)
month 45 (n=9,11)	11.9 (89.59)	8.1 (50.09)
month 48 (n=9,9)	-10.8 (65.52)	11.7 (55.85)
month 51 (n=9,9)	0.0 (65.82)	-3.1 (48.21)
month 54 (n=9,9)	4.6 (77.49)	7.3 (52.94)
month 57 (n=7,7)	9.6 (59.86)	-5.0 (45.19)
month 60 (n=8,8)	9.6 (61.38)	-1.3 (39.01)
month 63 (n=6,7)	11.9 (73.78)	15.4 (50.66)
month 66 (n=4,6)	25.3 (75.31)	18.3 (61.35)
month 69 (n=3,5)	38.9 (78.34)	-1.2 (23.98)
month 72 (n=3,3)	35.6 (78.48)	22.0 (46.15)
month 75 (n=2,3)	-5.0 (77.78)	23.1 (110.92)
month 78 (n=1,1)	50.0 (NA)	-11.1 (NA)

6. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP)
Description	Sitting blood pressure assessments were performed at every study visit. A negative change from baseline indicates improvement.
Time Frame	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
Sitting SBP, month 3 (n=70,67)	-7.4 (17.37)	-9.9 (17.01)
Sitting SBP, month 6 (n=59,57)	-6.8 (19.35)	-11.4 (15.92)
Sitting SBP, month 12 (n=39,39)	-2.8 (18.40)	-9.4 (14.61)
Sitting SBP, month 24 (n=18,23)	-11.6 (12.82)	-11.0 (11.58)
Sitting SBP, month 36 (n=10,13)	-3.0 (17.08)	-11.5 (16.23)
Sitting SBP, month 48 (n=9,10)	-12.0 (14.15)	-3.6 (14.56)
Sitting SBP, month 60 (n=7,8)	-12.8 (17.10)	-2.0 (11.83)
Sitting DBP, month 3 (n=70,67)	-3.3 (11.01)	-4.1 (13.11)
Sitting DBP , month 6 (n=59,57)	-4.2 (13.54)	-5.0 (11.56)
Sitting DBP, month 12 (n=39,39)	-2.0 (11.65)	-5.4 (10.86)
Sitting DBP, month 24 (n=18,23)	-8.1 (11.35)	-6.4 (9.37)
Sitting DBP, month 36 (n=10,13)	-6.8 (14.17)	-7.3 (8.25)
Sitting DBP, month 48 (n=9,10)	-11.7 (12.02)	-1.0 (9.30)
Sitting DBP, month 60 (n=7,8)	-9.1 (9.79)	0.7 (7.34)

7. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI)
Description	BMI was determined by using height and weight measurements. A negative change from baseline indicates improvement.
Time Frame	baseline, month 3, month 6, month 12, month 24, month 36, month 48 and month 60

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 3 (n=70,67)	-1.0 (1.26)	-1.4 (1.29)
month 6 (n=59,57)	-1.2 (1.64)	-2.1 (1.72)
month 12 (n=40,39)	-2.1 (2.19)	-2.8 (2.21)
month 24 (n=18,23)	-3.4 (2.97)	-3.0 (2.67)
month 36 (n=10,13)	-2.9 (2.47)	-3.3 (3.48)
month 48 (n=9,10)	-3.1 (2.14)	-2.4 (2.60)
month 60 (n=8,8)	-2.8 (1.85)	-2.0 (2.20)

8. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference
Description	Waist circumference was measured with a measuring tape correctly positioned. A negative change from baseline indicates improvement.
Time Frame	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 3 (n=64,66)	-1.0 (10.47)	-2.2 (5.23)
month 6 (n=53,54)	-1.9 (8.33)	-3.4 (5.39)
month 12(n=34,35)	-4.4 (9.40)	-5.6 (7.86)
month 24 ( n=17,22)	-8.7 (9.54)	-5.1 (10.22)
month 36 (n=9,13)	-7.8 (10.46)	-6.4 (9.97)
month 48 (n=8,10)	-8.3 (11.59)	-5.1 (10.03)
month 60 (n=7,8)	-7.3 (12.08)	-4.6 (10.90)

9. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides
Description	Blood samples were drawn to obtain total cholesterol and triglycerides' levels. A negative change from baseline indicates improvement.
Time Frame	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
Cholesterol, month 3 (n=70,67)	-0.2 (1.06)	-0.3 (1.01)
Cholesterol, month 6 (n=59,55)	-0.4 (1.24)	-0.4 (0.98)
Cholesterol, month 12 (n=40,39)	-0.5 (1.29)	-0.6 (1.18)
Cholesterol, month 24 (n=18,22)	-0.6 (1.39)	-0.3 (0.81)
Cholesterol, month 36 (n=10,12)	-0.8 (1.24)	-0.1 (0.64)
Cholesterol, month 48 (n=9,10)	-0.9 (1.63)	-0.4 (0.80)
Cholesterol, month 60 (n=8,8)	-1.5 (1.57)	-0.4 (1.00)
Triglycerides, month 3 (n=70,67)	0.1 (1.07)	0.1 (1.01)
Triglycerides, month 6 (n=59,55)	0 (0.92)	0.1 (1.00)
Triglycerides, month 12 (n=40,39)	-0.1 (0.77)	-0.2 (0.69)
Triglycerides, month 24 (n=18,22)	0 (1.05)	0 (0.82)
Triglycerides, month 36 (n=10,12)	-0.2 (0.99)	0.3 (1.38)
Triglycerides, month 48 (n=9,10)	-0.5 (0.94)	0.4 (1.32)
Triglycerides, month 60 (n=8,8)	-0.7 (1.01)	0.2 (1.02)

10. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score
Description	The BDI-II is a 21 item self-report rating inventory measuring characteristic attitudes and symptoms of depression. The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The scores range as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression. A negative change from baseline indicates imrpovement.
Time Frame	baseline, month 3, month 6, month 12, month 18, month 24

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 3 (n=66,65)	-4.6 (8.29)	-1.9 (9.88)
month 6 (n=56,55)	-4.6 (9.49)	-5.5 (8.81)
month 12 (n=38,37)	-4.6 (9.19)	-5.2 (9.94)
month 18 (n=6,6)	-1.3 (5.24)	-7.8 (5.78)
month 24 (n=0,1)	NA (NA)	-12.0 (NA)

11. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score
Description	The Ferriman Gallwey scoring system is used to score the degree of excess male pattern body hair. The scorecard of every body location under survey begins from 0 (no excessive terminal hair growth) to 4 (extensive terminal hair growth) and the numbers are added up to a maximum count of 36. A score >= 6 indicates the hirsutism. A negative change from baseline indicates imrpovement.
Time Frame	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 3 (n=52,50)	-1.3 (3.02)	-1.3 (3.46)
month 6 (n=44,47)	-0.9 (2.88)	-2.4 (4.70)
month 12 (n=30,35)	-1.3 (1.99)	-3.5 (4.65)
month 24 (n=12,22)	-2.8 (2.72)	-4.0 (4.34)
month 36 (n=7,12)	-3.7 (2.69)	-3.2 (4.09)
month 48 (n=6,10)	-6.0 (3.85)	-2.5 (2.84)
month 60 (n=5,8)	-5.0 (3.32)	-2.9 (3.23)

12. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD)
Description	BMD was measured using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done in the lumbar vertebrae (L1-L4), proximal femur (total hip) and proximal femur (femur neck). A negative change from baseline indicates imrpovement.
Time Frame	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
Lumbar vertebrae, month 3 (n=2,2)	0 (0.02)	0 (0)
Lumbar vertebrae, month 6 (n=47,39)	0 (0.06)	0 (0.04)
Lumbar vertebrae, month 12 (n=33,29)	0 (0.07)	0 (0.05)
Lumbar vertebrae, month 24 (n=16,16)	0 (0.04)	0 (0.05)
Lumbar vertebrae, month 36 (n=8,9)	0 (0.09)	0.1 (0.12)
Lumbar vertebrae, month 48 (n=9,8)	0 (0.12)	0 (0.05)
Lumbar vertebrae, month 60 (n=7,6)	0 (0.14)	0 (0.08)
Proximal femur (total hip), month 3 (2,2)	0 (0.04)	0 (0.01)
Proximal femur (total hip), month 6 (n=46,38)	0 (0.07)	0 (0.05)
Proximal femur (total hip), month 12 (n=33,26)	0 (0.04)	0 (0.03)
Proximal femur (total hip), month 24 (n=16,13)	0 (0.04)	0 (0.03)
Proximal femur (total hip), month 36 (n=8,8)	0 (0.03)	0 (0.06)
Proximal femur (total hip), month 48 (n=8,8)	0 (0.04)	0 (0.05)
Proximal femur (total hip), month 60 (n=7,6)	-0.1 (0.14)	0 (0.06)
Proximal femur (femur neck), month 3 (n=2,2)	0 (0)	0 (0.03)
Proximal femur (femur neck), month 6 (n=46,38)	0 (0.03)	0 (0.05)
Proximal femur (femur neck), month 12 (n=33,28)	0 (0.04)	0 (0.07)
Proximal femur (femur neck), month 24 (n=16,14)	0 (0.05)	0 (0.04)
Proximal femur (femur neck), month 36 (n=8,8)	0 (0.02)	0 (0.04)
Proximal femur (femur neck), month 48 (n=9,7)	0 (0.05)	0 (0.04)
Proximal femur (femur neck), month 60 (7,6)	0 (0.10)	0 (0.05)

13. Secondary Outcome

Title	Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition
Description	Body composition as in percentage of body fat by region was assessed by total body scan. A negative change from baseline indicates improvement.
Time Frame	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
Month 3 (n=2,2)	2.9 (1.48)	0.3 (0.78)
Month 6 (n=39,32)	-0.4 (3.77)	-0.9 (4.06)
Month 12 (n=29,22)	-3.0 (4.23)	-1.6 (4.27)
Month 24 (n=13,14)	-1.9 (3.24)	-1.9 (5.70)
Month 36 (n=5,8)	-2.0 (4.20)	-1.1 (4.94)
Month 48 (n=4,7)	-2.0 (5.07)	0.1 (5.63)
Month 60 (n=4,6)	-2.8 (4.64)	-0.5 (4.97)

14. Secondary Outcome

Title	Change From Baseline in Tumor Volume
Description	Pituitary magnetic resonance imaging (MRI) was performed to determine tumor volume. A negative change from baseline indicates imrpovement.
Time Frame	baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 months

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 6 (n=25, 28)	9.3 (44.02)	-19.0 (36.82)
month 12 (n=15, 18)	-8.1 (62.17)	-43.8 (49.47)
month 18 (n=8, 11)	-18.1 (71.62)	-36.0 (65.42)
month 24 (n=7, 13)	-27.4 (82.68)	-11.5 (66.28)
month 30 (n=6, 8)	-52.1 (55.20)	-20.9 (77.16)
month 36 (n=3, 5)	-94.1 (10.15)	-27.6 (78.86)
month 42 (n=3, 3)	-95.2 (8.40)	84.0 (282.60)
month 48 (n=3, 3)	-20.5 (130.90)	29.2 (164.67)
month 54 (n=3, 2)	-29.1 (107.40)	20.3 (170.15)
month 60 (n=3, 2)	-13.5 (136.97)	127.6 (321.88)
month 66 (n= 1, 1)	-100.0 (NA)	269.8 (NA)
month 72 (n=1, 0)	45.6 (NA)	NA (NA)
month 78 (n=1, 0)	77.2 (NA)	NA (NA)

15. Secondary Outcome

Title	Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score
Description	A Cushing's syndrome health related quality of life (HRQL) questionnaire was completed. The Cushing's Syndrome HRQL questionnaire contains 12 sentences with 5 possible answers each. The answers are based on Likert scales, with 5 response categories: Always, Often, Sometimes, Rarely and Never; or Very much, Quite a bit, Somewhat, Very little, and Not at all. The answers to each of the items are rated on a scale of 1 to 5. "1" corresponds to the response category "Always" or "Very much" and "5" corresponds to the category "Never" or "Not at all". The score is the sum of all item responses and can range from 12 to 60 points. The lower the score, the greater the Cushing's Syndrome impacts on HRQoL. A positive change from baseline indicates improvement.
Time Frame	baseline, 3 months, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

Only participants from the full analysis set, who had measurements at baseline and the post baseline time point, were included in the analysis for that post baseline time point. The full analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Pasireotide 600 ug	Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
Measure Participants	82	80
month 3 (n=67,66)	20.7 (60.26)	40.1 (135.47)
month 6 (n= 55,56)	19.6 (47.78)	52.2 (169.47)
month 12 (n=20,20)	54.9 (95.83)	111.5 (266.75)

Adverse Events

Arm/Group Title	Pasireotide 600 ug		Pasireotide 900 ug
Arm/Group Description	At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.		At randomization, participants received 900 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
All Cause Mortality
	Pasireotide 600 ug		Pasireotide 900 ug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pasireotide 600 ug		Pasireotide 900 ug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/82 (28%)		25/80 (31.3%)
Cardiac disorders
Atrioventricular block second degree	0/82 (0%)		1/80 (1.3%)
Ear and labyrinth disorders
Ear haemorrhage	1/82 (1.2%)		0/80 (0%)
Tympanic membrane perforation	1/82 (1.2%)		0/80 (0%)
Vertigo positional	0/82 (0%)		1/80 (1.3%)
Endocrine disorders
Adrenal insufficiency	0/82 (0%)		2/80 (2.5%)
Pituitary-dependent Cushing's syndrome	3/82 (3.7%)		3/80 (3.8%)
Gastrointestinal disorders
Abdominal pain	0/82 (0%)		1/80 (1.3%)
Anal fistula	1/82 (1.2%)		0/80 (0%)
Constipation	0/82 (0%)		1/80 (1.3%)
Diarrhoea	2/82 (2.4%)		0/80 (0%)
Diverticular perforation	1/82 (1.2%)		0/80 (0%)
Inguinal hernia	0/82 (0%)		1/80 (1.3%)
Pancreatitis	1/82 (1.2%)		0/80 (0%)
Tongue movement disturbance	0/82 (0%)		1/80 (1.3%)
Umbilical hernia	0/82 (0%)		1/80 (1.3%)
General disorders
Disease progression	1/82 (1.2%)		1/80 (1.3%)
Drug ineffective	1/82 (1.2%)		1/80 (1.3%)
Microlithiasis	0/82 (0%)		1/80 (1.3%)
Hepatobiliary disorders
Bile duct stone	0/82 (0%)		1/80 (1.3%)
Cholangitis	1/82 (1.2%)		0/80 (0%)
Cholecystitis	0/82 (0%)		1/80 (1.3%)
Cholecystitis acute	2/82 (2.4%)		0/80 (0%)
Cholelithiasis	4/82 (4.9%)		2/80 (2.5%)
Infections and infestations
Abscess intestinal	1/82 (1.2%)		0/80 (0%)
Cellulitis	0/82 (0%)		1/80 (1.3%)
Cervicitis	0/82 (0%)		1/80 (1.3%)
Diverticulitis	1/82 (1.2%)		0/80 (0%)
Escherichia urinary tract infection	1/82 (1.2%)		0/80 (0%)
Nail infection	1/82 (1.2%)		0/80 (0%)
Pneumonia	1/82 (1.2%)		0/80 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/82 (0%)		1/80 (1.3%)
Toxicity to various agents	1/82 (1.2%)		0/80 (0%)
Investigations
Electrocardiogram QT prolonged	0/82 (0%)		1/80 (1.3%)
Lipase increased	1/82 (1.2%)		0/80 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	1/82 (1.2%)		3/80 (3.8%)
Food intolerance	0/82 (0%)		1/80 (1.3%)
Hyperglycaemia	1/82 (1.2%)		4/80 (5%)
Hypoglycaemia	1/82 (1.2%)		0/80 (0%)
Type 2 diabetes mellitus	1/82 (1.2%)		0/80 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/82 (0%)		1/80 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign	1/82 (1.2%)		2/80 (2.5%)
Secretory adenoma of pituitary	0/82 (0%)		1/80 (1.3%)
Nervous system disorders
Cerebrovascular accident	0/82 (0%)		1/80 (1.3%)
Cranial nerve paralysis	0/82 (0%)		1/80 (1.3%)
Dizziness	0/82 (0%)		1/80 (1.3%)
Dysarthria	0/82 (0%)		1/80 (1.3%)
Intracranial aneurysm	0/82 (0%)		1/80 (1.3%)
Somnolence	0/82 (0%)		1/80 (1.3%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/82 (1.2%)		0/80 (0%)
Psychiatric disorders
Agitation	0/82 (0%)		1/80 (1.3%)
Reproductive system and breast disorders
Adenomyosis	0/82 (0%)		1/80 (1.3%)
Uterine polyp	1/82 (1.2%)		1/80 (1.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/82 (1.2%)		0/80 (0%)
Oropharyngeal pain	1/82 (1.2%)		0/80 (0%)
Vascular disorders
Hypertensive crisis	0/82 (0%)		1/80 (1.3%)
Hypertensive emergency	0/82 (0%)		1/80 (1.3%)
Hypotension	1/82 (1.2%)		1/80 (1.3%)
Other (Not Including Serious) Adverse Events
	Pasireotide 600 ug		Pasireotide 900 ug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	78/82 (95.1%)		79/80 (98.8%)
Blood and lymphatic system disorders
Anaemia	1/82 (1.2%)		5/80 (6.3%)
Iron deficiency anaemia	3/82 (3.7%)		4/80 (5%)
Cardiac disorders
Sinus bradycardia	8/82 (9.8%)		2/80 (2.5%)
Ear and labyrinth disorders
Vertigo	4/82 (4.9%)		6/80 (7.5%)
Endocrine disorders
Hypothyroidism	3/82 (3.7%)		4/80 (5%)
Eye disorders
Vision blurred	3/82 (3.7%)		4/80 (5%)
Gastrointestinal disorders
Abdominal distension	6/82 (7.3%)		6/80 (7.5%)
Abdominal pain	19/82 (23.2%)		21/80 (26.3%)
Abdominal pain upper	11/82 (13.4%)		8/80 (10%)
Constipation	9/82 (11%)		4/80 (5%)
Diarrhoea	49/82 (59.8%)		46/80 (57.5%)
Dyspepsia	1/82 (1.2%)		5/80 (6.3%)
Faeces soft	3/82 (3.7%)		4/80 (5%)
Haemorrhoids	3/82 (3.7%)		4/80 (5%)
Nausea	40/82 (48.8%)		47/80 (58.8%)
Vomiting	3/82 (3.7%)		9/80 (11.3%)
General disorders
Asthenia	13/82 (15.9%)		6/80 (7.5%)
Fatigue	12/82 (14.6%)		24/80 (30%)
Injection site haemorrhage	1/82 (1.2%)		4/80 (5%)
Injection site pain	3/82 (3.7%)		4/80 (5%)
Malaise	2/82 (2.4%)		5/80 (6.3%)
Oedema peripheral	9/82 (11%)		6/80 (7.5%)
Hepatobiliary disorders
Cholelithiasis	25/82 (30.5%)		25/80 (31.3%)
Infections and infestations
Gastroenteritis	0/82 (0%)		4/80 (5%)
Influenza	10/82 (12.2%)		5/80 (6.3%)
Nasopharyngitis	12/82 (14.6%)		12/80 (15%)
Upper respiratory tract infection	6/82 (7.3%)		2/80 (2.5%)
Urinary tract infection	4/82 (4.9%)		6/80 (7.5%)
Injury, poisoning and procedural complications
Contusion	0/82 (0%)		4/80 (5%)
Procedural pain	1/82 (1.2%)		4/80 (5%)
Investigations
Alanine aminotransferase increased	12/82 (14.6%)		6/80 (7.5%)
Aspartate aminotransferase increased	6/82 (7.3%)		3/80 (3.8%)
Blood alkaline phosphatase increased	6/82 (7.3%)		1/80 (1.3%)
Blood glucose increased	6/82 (7.3%)		3/80 (3.8%)
Blood insulin decreased	1/82 (1.2%)		4/80 (5%)
Electrocardiogram QT prolonged	5/82 (6.1%)		7/80 (8.8%)
Gamma-glutamyltransferase increased	11/82 (13.4%)		7/80 (8.8%)
Glycosylated haemoglobin increased	10/82 (12.2%)		8/80 (10%)
International normalised ratio increased	1/82 (1.2%)		4/80 (5%)
Lipase increased	7/82 (8.5%)		5/80 (6.3%)
Low density lipoprotein increased	5/82 (6.1%)		3/80 (3.8%)
Prothrombin time prolonged	2/82 (2.4%)		4/80 (5%)
Weight decreased	3/82 (3.7%)		5/80 (6.3%)
Metabolism and nutrition disorders
Decreased appetite	8/82 (9.8%)		9/80 (11.3%)
Diabetes mellitus	17/82 (20.7%)		18/80 (22.5%)
Hypercholesterolaemia	8/82 (9.8%)		12/80 (15%)
Hyperglycaemia	31/82 (37.8%)		35/80 (43.8%)
Hyperlipidaemia	5/82 (6.1%)		3/80 (3.8%)
Hypertriglyceridaemia	6/82 (7.3%)		5/80 (6.3%)
Hypoglycaemia	12/82 (14.6%)		5/80 (6.3%)
Hypokalaemia	6/82 (7.3%)		6/80 (7.5%)
Type 2 diabetes mellitus	10/82 (12.2%)		5/80 (6.3%)
Vitamin B12 deficiency	2/82 (2.4%)		5/80 (6.3%)
Vitamin D deficiency	5/82 (6.1%)		5/80 (6.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/82 (7.3%)		10/80 (12.5%)
Back pain	5/82 (6.1%)		7/80 (8.8%)
Muscle spasms	1/82 (1.2%)		4/80 (5%)
Myalgia	11/82 (13.4%)		6/80 (7.5%)
Neck pain	0/82 (0%)		4/80 (5%)
Pain in extremity	7/82 (8.5%)		4/80 (5%)
Nervous system disorders
Dizziness	9/82 (11%)		9/80 (11.3%)
Dysgeusia	3/82 (3.7%)		4/80 (5%)
Headache	25/82 (30.5%)		25/80 (31.3%)
Migraine	0/82 (0%)		4/80 (5%)
Somnolence	2/82 (2.4%)		4/80 (5%)
Psychiatric disorders
Anxiety	6/82 (7.3%)		10/80 (12.5%)
Depression	3/82 (3.7%)		4/80 (5%)
Insomnia	3/82 (3.7%)		13/80 (16.3%)
Respiratory, thoracic and mediastinal disorders
Cough	5/82 (6.1%)		3/80 (3.8%)
Oropharyngeal pain	1/82 (1.2%)		4/80 (5%)
Skin and subcutaneous tissue disorders
Acne	5/82 (6.1%)		2/80 (2.5%)
Alopecia	10/82 (12.2%)		11/80 (13.8%)
Dry skin	5/82 (6.1%)		5/80 (6.3%)
Ecchymosis	1/82 (1.2%)		4/80 (5%)
Pruritus	6/82 (7.3%)		7/80 (8.8%)
Rash	6/82 (7.3%)		4/80 (5%)
Skin exfoliation	5/82 (6.1%)		3/80 (3.8%)
Vascular disorders
Hypertension	10/82 (12.2%)		8/80 (10%)
Hypotension	4/82 (4.9%)		5/80 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. 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 pooled data (i.e.,data from all sites) in clinical trial.