Trial Outcomes & Findings for Safety and Efficacy of Different Dose Levels of Pasireotide in Patients With de Novo, Persistent or Recurrent Cushing's Disease (NCT NCT00434148)

Last Updated: 2016-03-08

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

162 participants

Primary outcome timeframe

6 months

Results posted on

2016-03-08

Participant Flow

The enrollment number reflects the participants who were randomized and received at least one dose of drug.

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.

Participant milestones

Participant milestones
Measure	Pasireotide 900 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 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.	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.
Overall Study STARTED	80	82
Overall Study Completed Month 12	39	39
Overall Study Completed m. 12; Did Not Enter Extension	7	13
Overall Study Completed Month 12; Entered Extension	32	26
Overall Study COMPLETED	7	13
Overall Study NOT COMPLETED	73	69

Reasons for withdrawal

Reasons for withdrawal
Measure	Pasireotide 900 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 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.	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.
Overall Study Adverse Event	18	18
Overall Study Lack of Efficacy	28	25
Overall Study Withdrawal by Subject	15	15
Overall Study Protocol Violation	0	4
Overall Study Administrative problems	10	6
Overall Study Lost to Follow-up	1	0
Overall Study Condition no longer requires study drug	0	1
Overall Study Abnormal test procedure result	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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 n=162 Participants Total of all reporting groups
Age, Continuous	40.5 years STANDARD_DEVIATION 12.97 • n=5 Participants	39.9 years STANDARD_DEVIATION 10.77 • n=7 Participants	40.2 years STANDARD_DEVIATION 11.90 • n=5 Participants
Sex: Female, Male Female	62 Participants n=5 Participants	64 Participants n=7 Participants	126 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	16 Participants n=7 Participants	36 Participants n=5 Participants

PRIMARY outcome

Timeframe: 6 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Number of mUFC (Urinary Free Cortisol) Responders by Randomized Dose Group	12 Responders Interval 7.0 to 22.3	21 Responders Interval 16.6 to 35.9

SECONDARY outcome

Timeframe: baseline, 3 months, 12 months

Population: 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.

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

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Change From Baseline in mUFC month 3 (n=61,62)	-375.8 nmol/24h Standard Deviation 631.07	-343.4 nmol/24h Standard Deviation 485.48
Change From Baseline in mUFC month 12 (n=37,35)	-572.6 nmol/24h Standard Deviation 941.44	-350.7 nmol/24h Standard Deviation 380.25

SECONDARY outcome

Timeframe: 12 months

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

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

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Time to First UFC Response	1.0 months Interval 0.9 to 2.7	1.0 months Interval 0.9 to 2.7

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Percent Change From Baseline in Serum Cortisol month 0.5 (n=77,76)	-4.0 Percent change Standard Deviation 28.23	-10.8 Percent change Standard Deviation 30.57
Percent Change From Baseline in Serum Cortisol month 1 (n=78,72)	-7.3 Percent change Standard Deviation 30.13	-7.7 Percent change Standard Deviation 32.00
Percent Change From Baseline in Serum Cortisol month 1.5 (n=75,71)	-5.5 Percent change Standard Deviation 27.65	-7.1 Percent change Standard Deviation 31.34
Percent Change From Baseline in Serum Cortisol month 2 (n=73,67)	-0.7 Percent change Standard Deviation 35.81	-6.4 Percent change Standard Deviation 29.75
Percent Change From Baseline in Serum Cortisol month 2.5 (n=70,67)	-3.3 Percent change Standard Deviation 31.40	-10.1 Percent change Standard Deviation 31.23
Percent Change From Baseline in Serum Cortisol month 3 (n=70,67)	-2.6 Percent change Standard Deviation 35.79	-10.2 Percent change Standard Deviation 25.60
Percent Change From Baseline in Serum Cortisol month 4 (n=68,61)	-6.9 Percent change Standard Deviation 31.88	-10.8 Percent change Standard Deviation 28.10
Percent Change From Baseline in Serum Cortisol month 5 (n=62,58)	-4.3 Percent change Standard Deviation 36.96	-10.8 Percent change Standard Deviation 26.50
Percent Change From Baseline in Serum Cortisol month 6 (n=59,57)	-5.6 Percent change Standard Deviation 34.28	-9.3 Percent change Standard Deviation 31.45
Percent Change From Baseline in Serum Cortisol month 7 (n=52,53)	-9.8 Percent change Standard Deviation 34.44	-5.8 Percent change Standard Deviation 26.35
Percent Change From Baseline in Serum Cortisol month 8 (n=50,46)	-10.2 Percent change Standard Deviation 30.85	-9.9 Percent change Standard Deviation 35.79
Percent Change From Baseline in Serum Cortisol month 9 (n=46,48)	-5.4 Percent change Standard Deviation 33.49	-5.8 Percent change Standard Deviation 31.56
Percent Change From Baseline in Serum Cortisol month 10 (n=42,47)	-11.2 Percent change Standard Deviation 30.25	-9.3 Percent change Standard Deviation 28.39
Percent Change From Baseline in Serum Cortisol month 11 (n=41,41)	-8.2 Percent change Standard Deviation 38.19	-14.0 Percent change Standard Deviation 29.63
Percent Change From Baseline in Serum Cortisol month 12 (n=39,38)	-11.6 Percent change Standard Deviation 33.75	-15.2 Percent change Standard Deviation 21.99
Percent Change From Baseline in Serum Cortisol month 15 (n=26,26)	-10.5 Percent change Standard Deviation 30.14	-12.5 Percent change Standard Deviation 29.27
Percent Change From Baseline in Serum Cortisol month 18 (n=26,25)	-7.6 Percent change Standard Deviation 40.35	-17.8 Percent change Standard Deviation 28.39
Percent Change From Baseline in Serum Cortisol month 21 (n=21,25)	-12.1 Percent change Standard Deviation 34.23	-15.5 Percent change Standard Deviation 34.94
Percent Change From Baseline in Serum Cortisol month 24 (n=18,22)	-17.9 Percent change Standard Deviation 43.46	-18.1 Percent change Standard Deviation 34.27
Percent Change From Baseline in Serum Cortisol month 27 (n=16,18)	-9.0 Percent change Standard Deviation 41.71	-12.7 Percent change Standard Deviation 28.53
Percent Change From Baseline in Serum Cortisol month 30 (n=14,19)	-22.8 Percent change Standard Deviation 35.43	-22.7 Percent change Standard Deviation 32.46
Percent Change From Baseline in Serum Cortisol month 33 (n=13,15)	-9.5 Percent change Standard Deviation 44.64	-25.2 Percent change Standard Deviation 25.96
Percent Change From Baseline in Serum Cortisol month 36 (n=10,13)	-12.7 Percent change Standard Deviation 65.43	-13.3 Percent change Standard Deviation 37.84
Percent Change From Baseline in Serum Cortisol month 39 (n=10,12)	-26.6 Percent change Standard Deviation 42.89	-25.9 Percent change Standard Deviation 33.15
Percent Change From Baseline in Serum Cortisol month 42 (n=10,12)	-17.8 Percent change Standard Deviation 39.54	-18.1 Percent change Standard Deviation 35.25
Percent Change From Baseline in Serum Cortisol month 45 (n=10,11)	-12.5 Percent change Standard Deviation 44.89	-8.5 Percent change Standard Deviation 32.55
Percent Change From Baseline in Serum Cortisol month 48 (n=9,11)	-19.7 Percent change Standard Deviation 37.88	-20.1 Percent change Standard Deviation 39.42
Percent Change From Baseline in Serum Cortisol month 51 (n=9,9)	-17.6 Percent change Standard Deviation 34.60	-24.0 Percent change Standard Deviation 31.53
Percent Change From Baseline in Serum Cortisol month 54 (n=9,9)	-25.0 Percent change Standard Deviation 30.49	-6.8 Percent change Standard Deviation 28.07
Percent Change From Baseline in Serum Cortisol month 57 (n=8,8)	-11.0 Percent change Standard Deviation 56.61	-30.8 Percent change Standard Deviation 22.21
Percent Change From Baseline in Serum Cortisol month 60 (n=8,8)	-24.5 Percent change Standard Deviation 31.89	-18.9 Percent change Standard Deviation 22.05
Percent Change From Baseline in Serum Cortisol month 63 (n=6,7)	-28.6 Percent change Standard Deviation 31.20	-24.0 Percent change Standard Deviation 26.41
Percent Change From Baseline in Serum Cortisol month 66 (n=4,6)	-6.7 Percent change Standard Deviation 29.29	-22.5 Percent change Standard Deviation 36.19
Percent Change From Baseline in Serum Cortisol month 69 (n=3,5)	-13.4 Percent change Standard Deviation 42.68	-33.6 Percent change Standard Deviation 10.31
Percent Change From Baseline in Serum Cortisol month 72 (n=3,4)	-4.5 Percent change Standard Deviation 40.94	-22.7 Percent change Standard Deviation 23.57
Percent Change From Baseline in Serum Cortisol month 75 (n=2,3)	-63.3 Percent change Standard Deviation 41.13	-23.2 Percent change Standard Deviation 25.71
Percent Change From Baseline in Serum Cortisol month 78 (n=1,1)	14.5 Percent change Standard Deviation NA n=1; therefore, SD does not apply.	-53.3 Percent change Standard Deviation NA n=1; therefore, SD does not apply.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 0.5 (n=78,75)	9.3 percent change Standard Deviation 181.17	-15.9 percent change Standard Deviation 30.75
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 1 (n=78,71)	-10.0 percent change Standard Deviation 37.29	-19.1 percent change Standard Deviation 30.47
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 1.5 (n=74,69)	-13.4 percent change Standard Deviation 31.64	-10.5 percent change Standard Deviation 38.05
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 2 (n=72,66)	-7.7 percent change Standard Deviation 40.86	-13.2 percent change Standard Deviation 35.38
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 2.5 (n=69,65)	-8.2 percent change Standard Deviation 37.32	-12.0 percent change Standard Deviation 47.02
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 3 (n=69,66)	-9.2 percent change Standard Deviation 40.85	-16.3 percent change Standard Deviation 31.93
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 4 (n=66,61)	-7.2 percent change Standard Deviation 38.42	-12.8 percent change Standard Deviation 44.06
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 5 (n=62,55)	-3.0 percent change Standard Deviation 42.50	-15.0 percent change Standard Deviation 38.89
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 6 (n=58,55)	-8.4 percent change Standard Deviation 43.61	-17.3 percent change Standard Deviation 35.60
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 7 (n=52,52)	-11.4 percent change Standard Deviation 45.25	-14.6 percent change Standard Deviation 30.88
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 8 (n=48,46)	-5.0 percent change Standard Deviation 51.75	-17.0 percent change Standard Deviation 36.87
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 9 (n=46,47)	-5.3 percent change Standard Deviation 55.27	-18.2 percent change Standard Deviation 35.87
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 10 (n=42,46)	-10.2 percent change Standard Deviation 48.82	-18.2 percent change Standard Deviation 34.18
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 11 (n=42,40)	-11.5 percent change Standard Deviation 44.52	-17.4 percent change Standard Deviation 39.06
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 12 (n=39,39)	-7.4 percent change Standard Deviation 53.83	-26.5 percent change Standard Deviation 33.38
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 15 (n=26,26)	-14.5 percent change Standard Deviation 43.44	-16.3 percent change Standard Deviation 32.01
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 18 (n=26,25)	-5.9 percent change Standard Deviation 57.56	-21.2 percent change Standard Deviation 32.91
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 21 (n=20,23)	-1.5 percent change Standard Deviation 51.52	-17.3 percent change Standard Deviation 34.34
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 24 (n=18,21)	-10.9 percent change Standard Deviation 47.95	-18.0 percent change Standard Deviation 26.53
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 27 (n=16,18)	-10.4 percent change Standard Deviation 53.33	-12.5 percent change Standard Deviation 39.39
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 30 (n=14,18)	-14.7 percent change Standard Deviation 56.17	-20.0 percent change Standard Deviation 40.82
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 33 (n=13,14)	-9.4 percent change Standard Deviation 55.01	-2.4 percent change Standard Deviation 33.07
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 36 (n=10,13)	19.1 percent change Standard Deviation 112.26	1.2 percent change Standard Deviation 35.33
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 39 (n=10,12)	-20.9 percent change Standard Deviation 48.68	-5.3 percent change Standard Deviation 40.02
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 42 (n=10,12)	-6.7 percent change Standard Deviation 59.61	2.7 percent change Standard Deviation 42.35
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 45 (n=9,11)	11.9 percent change Standard Deviation 89.59	8.1 percent change Standard Deviation 50.09
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 48 (n=9,9)	-10.8 percent change Standard Deviation 65.52	11.7 percent change Standard Deviation 55.85
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 51 (n=9,9)	0.0 percent change Standard Deviation 65.82	-3.1 percent change Standard Deviation 48.21
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 54 (n=9,9)	4.6 percent change Standard Deviation 77.49	7.3 percent change Standard Deviation 52.94
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 57 (n=7,7)	9.6 percent change Standard Deviation 59.86	-5.0 percent change Standard Deviation 45.19
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 60 (n=8,8)	9.6 percent change Standard Deviation 61.38	-1.3 percent change Standard Deviation 39.01
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 63 (n=6,7)	11.9 percent change Standard Deviation 73.78	15.4 percent change Standard Deviation 50.66
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 66 (n=4,6)	25.3 percent change Standard Deviation 75.31	18.3 percent change Standard Deviation 61.35
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 69 (n=3,5)	38.9 percent change Standard Deviation 78.34	-1.2 percent change Standard Deviation 23.98
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 72 (n=3,3)	35.6 percent change Standard Deviation 78.48	22.0 percent change Standard Deviation 46.15
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 75 (n=2,3)	-5.0 percent change Standard Deviation 77.78	23.1 percent change Standard Deviation 110.92
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) month 78 (n=1,1)	50.0 percent change Standard Deviation NA n=1; therefore, SD does not apply.	-11.1 percent change Standard Deviation NA n=1; therefore, SD does not apply.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting SBP, month 3 (n=70,67)	-7.4 mmHg Standard Deviation 17.37	-9.9 mmHg Standard Deviation 17.01
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting SBP, month 6 (n=59,57)	-6.8 mmHg Standard Deviation 19.35	-11.4 mmHg Standard Deviation 15.92
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting SBP, month 12 (n=39,39)	-2.8 mmHg Standard Deviation 18.40	-9.4 mmHg Standard Deviation 14.61
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting SBP, month 24 (n=18,23)	-11.6 mmHg Standard Deviation 12.82	-11.0 mmHg Standard Deviation 11.58
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting SBP, month 36 (n=10,13)	-3.0 mmHg Standard Deviation 17.08	-11.5 mmHg Standard Deviation 16.23
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting SBP, month 48 (n=9,10)	-12.0 mmHg Standard Deviation 14.15	-3.6 mmHg Standard Deviation 14.56
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting SBP, month 60 (n=7,8)	-12.8 mmHg Standard Deviation 17.10	-2.0 mmHg Standard Deviation 11.83
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting DBP, month 3 (n=70,67)	-3.3 mmHg Standard Deviation 11.01	-4.1 mmHg Standard Deviation 13.11
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting DBP , month 6 (n=59,57)	-4.2 mmHg Standard Deviation 13.54	-5.0 mmHg Standard Deviation 11.56
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting DBP, month 12 (n=39,39)	-2.0 mmHg Standard Deviation 11.65	-5.4 mmHg Standard Deviation 10.86
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting DBP, month 24 (n=18,23)	-8.1 mmHg Standard Deviation 11.35	-6.4 mmHg Standard Deviation 9.37
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting DBP, month 36 (n=10,13)	-6.8 mmHg Standard Deviation 14.17	-7.3 mmHg Standard Deviation 8.25
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting DBP, month 48 (n=9,10)	-11.7 mmHg Standard Deviation 12.02	-1.0 mmHg Standard Deviation 9.30
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) Sitting DBP, month 60 (n=7,8)	-9.1 mmHg Standard Deviation 9.79	0.7 mmHg Standard Deviation 7.34

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) month 3 (n=70,67)	-1.0 kg/m^2 Standard Deviation 1.26	-1.4 kg/m^2 Standard Deviation 1.29
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) month 6 (n=59,57)	-1.2 kg/m^2 Standard Deviation 1.64	-2.1 kg/m^2 Standard Deviation 1.72
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) month 12 (n=40,39)	-2.1 kg/m^2 Standard Deviation 2.19	-2.8 kg/m^2 Standard Deviation 2.21
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) month 24 (n=18,23)	-3.4 kg/m^2 Standard Deviation 2.97	-3.0 kg/m^2 Standard Deviation 2.67
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) month 36 (n=10,13)	-2.9 kg/m^2 Standard Deviation 2.47	-3.3 kg/m^2 Standard Deviation 3.48
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) month 48 (n=9,10)	-3.1 kg/m^2 Standard Deviation 2.14	-2.4 kg/m^2 Standard Deviation 2.60
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) month 60 (n=8,8)	-2.8 kg/m^2 Standard Deviation 1.85	-2.0 kg/m^2 Standard Deviation 2.20

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference month 3 (n=64,66)	-1.0 cm Standard Deviation 10.47	-2.2 cm Standard Deviation 5.23
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference month 6 (n=53,54)	-1.9 cm Standard Deviation 8.33	-3.4 cm Standard Deviation 5.39
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference month 12(n=34,35)	-4.4 cm Standard Deviation 9.40	-5.6 cm Standard Deviation 7.86
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference month 24 ( n=17,22)	-8.7 cm Standard Deviation 9.54	-5.1 cm Standard Deviation 10.22
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference month 36 (n=9,13)	-7.8 cm Standard Deviation 10.46	-6.4 cm Standard Deviation 9.97
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference month 48 (n=8,10)	-8.3 cm Standard Deviation 11.59	-5.1 cm Standard Deviation 10.03
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference month 60 (n=7,8)	-7.3 cm Standard Deviation 12.08	-4.6 cm Standard Deviation 10.90

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Cholesterol, month 3 (n=70,67)	-0.2 mmol/L Standard Deviation 1.06	-0.3 mmol/L Standard Deviation 1.01
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Cholesterol, month 6 (n=59,55)	-0.4 mmol/L Standard Deviation 1.24	-0.4 mmol/L Standard Deviation 0.98
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Cholesterol, month 12 (n=40,39)	-0.5 mmol/L Standard Deviation 1.29	-0.6 mmol/L Standard Deviation 1.18
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Cholesterol, month 24 (n=18,22)	-0.6 mmol/L Standard Deviation 1.39	-0.3 mmol/L Standard Deviation 0.81
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Cholesterol, month 36 (n=10,12)	-0.8 mmol/L Standard Deviation 1.24	-0.1 mmol/L Standard Deviation 0.64
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Cholesterol, month 48 (n=9,10)	-0.9 mmol/L Standard Deviation 1.63	-0.4 mmol/L Standard Deviation 0.80
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Cholesterol, month 60 (n=8,8)	-1.5 mmol/L Standard Deviation 1.57	-0.4 mmol/L Standard Deviation 1.00
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Triglycerides, month 3 (n=70,67)	0.1 mmol/L Standard Deviation 1.07	0.1 mmol/L Standard Deviation 1.01
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Triglycerides, month 6 (n=59,55)	0 mmol/L Standard Deviation 0.92	0.1 mmol/L Standard Deviation 1.00
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Triglycerides, month 12 (n=40,39)	-0.1 mmol/L Standard Deviation 0.77	-0.2 mmol/L Standard Deviation 0.69
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Triglycerides, month 24 (n=18,22)	0 mmol/L Standard Deviation 1.05	0 mmol/L Standard Deviation 0.82
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Triglycerides, month 36 (n=10,12)	-0.2 mmol/L Standard Deviation 0.99	0.3 mmol/L Standard Deviation 1.38
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Triglycerides, month 48 (n=9,10)	-0.5 mmol/L Standard Deviation 0.94	0.4 mmol/L Standard Deviation 1.32
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides Triglycerides, month 60 (n=8,8)	-0.7 mmol/L Standard Deviation 1.01	0.2 mmol/L Standard Deviation 1.02

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score month 3 (n=66,65)	-4.6 score on a scale Standard Deviation 8.29	-1.9 score on a scale Standard Deviation 9.88
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score month 6 (n=56,55)	-4.6 score on a scale Standard Deviation 9.49	-5.5 score on a scale Standard Deviation 8.81
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score month 12 (n=38,37)	-4.6 score on a scale Standard Deviation 9.19	-5.2 score on a scale Standard Deviation 9.94
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score month 18 (n=6,6)	-1.3 score on a scale Standard Deviation 5.24	-7.8 score on a scale Standard Deviation 5.78
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score month 24 (n=0,1)	NA score on a scale Standard Deviation NA No participants had month 24 values.	-12.0 score on a scale Standard Deviation NA n=1; therefore, SD does not apply.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score month 48 (n=6,10)	-6.0 score on a scale Standard Deviation 3.85	-2.5 score on a scale Standard Deviation 2.84
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score month 60 (n=5,8)	-5.0 score on a scale Standard Deviation 3.32	-2.9 score on a scale Standard Deviation 3.23
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score month 3 (n=52,50)	-1.3 score on a scale Standard Deviation 3.02	-1.3 score on a scale Standard Deviation 3.46
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score month 6 (n=44,47)	-0.9 score on a scale Standard Deviation 2.88	-2.4 score on a scale Standard Deviation 4.70
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score month 12 (n=30,35)	-1.3 score on a scale Standard Deviation 1.99	-3.5 score on a scale Standard Deviation 4.65
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score month 24 (n=12,22)	-2.8 score on a scale Standard Deviation 2.72	-4.0 score on a scale Standard Deviation 4.34
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score month 36 (n=7,12)	-3.7 score on a scale Standard Deviation 2.69	-3.2 score on a scale Standard Deviation 4.09

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Lumbar vertebrae, month 12 (n=33,29)	0 mg/cm^3 Standard Deviation 0.07	0 mg/cm^3 Standard Deviation 0.05
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Lumbar vertebrae, month 48 (n=9,8)	0 mg/cm^3 Standard Deviation 0.12	0 mg/cm^3 Standard Deviation 0.05
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (total hip), month 3 (2,2)	0 mg/cm^3 Standard Deviation 0.04	0 mg/cm^3 Standard Deviation 0.01
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Lumbar vertebrae, month 3 (n=2,2)	0 mg/cm^3 Standard Deviation 0.02	0 mg/cm^3 Standard Deviation 0
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Lumbar vertebrae, month 6 (n=47,39)	0 mg/cm^3 Standard Deviation 0.06	0 mg/cm^3 Standard Deviation 0.04
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Lumbar vertebrae, month 24 (n=16,16)	0 mg/cm^3 Standard Deviation 0.04	0 mg/cm^3 Standard Deviation 0.05
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Lumbar vertebrae, month 36 (n=8,9)	0 mg/cm^3 Standard Deviation 0.09	0.1 mg/cm^3 Standard Deviation 0.12
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Lumbar vertebrae, month 60 (n=7,6)	0 mg/cm^3 Standard Deviation 0.14	0 mg/cm^3 Standard Deviation 0.08
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (total hip), month 6 (n=46,38)	0 mg/cm^3 Standard Deviation 0.07	0 mg/cm^3 Standard Deviation 0.05
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (total hip), month 12 (n=33,26)	0 mg/cm^3 Standard Deviation 0.04	0 mg/cm^3 Standard Deviation 0.03
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (total hip), month 24 (n=16,13)	0 mg/cm^3 Standard Deviation 0.04	0 mg/cm^3 Standard Deviation 0.03
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (total hip), month 36 (n=8,8)	0 mg/cm^3 Standard Deviation 0.03	0 mg/cm^3 Standard Deviation 0.06
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (total hip), month 48 (n=8,8)	0 mg/cm^3 Standard Deviation 0.04	0 mg/cm^3 Standard Deviation 0.05
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (total hip), month 60 (n=7,6)	-0.1 mg/cm^3 Standard Deviation 0.14	0 mg/cm^3 Standard Deviation 0.06
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (femur neck), month 3 (n=2,2)	0 mg/cm^3 Standard Deviation 0	0 mg/cm^3 Standard Deviation 0.03
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (femur neck), month 6 (n=46,38)	0 mg/cm^3 Standard Deviation 0.03	0 mg/cm^3 Standard Deviation 0.05
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (femur neck), month 12 (n=33,28)	0 mg/cm^3 Standard Deviation 0.04	0 mg/cm^3 Standard Deviation 0.07
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (femur neck), month 24 (n=16,14)	0 mg/cm^3 Standard Deviation 0.05	0 mg/cm^3 Standard Deviation 0.04
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (femur neck), month 36 (n=8,8)	0 mg/cm^3 Standard Deviation 0.02	0 mg/cm^3 Standard Deviation 0.04
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (femur neck), month 48 (n=9,7)	0 mg/cm^3 Standard Deviation 0.05	0 mg/cm^3 Standard Deviation 0.04
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) Proximal femur (femur neck), month 60 (7,6)	0 mg/cm^3 Standard Deviation 0.10	0 mg/cm^3 Standard Deviation 0.05

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition Month 3 (n=2,2)	2.9 Percentage of body fat Standard Deviation 1.48	0.3 Percentage of body fat Standard Deviation 0.78
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition Month 6 (n=39,32)	-0.4 Percentage of body fat Standard Deviation 3.77	-0.9 Percentage of body fat Standard Deviation 4.06
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition Month 12 (n=29,22)	-3.0 Percentage of body fat Standard Deviation 4.23	-1.6 Percentage of body fat Standard Deviation 4.27
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition Month 24 (n=13,14)	-1.9 Percentage of body fat Standard Deviation 3.24	-1.9 Percentage of body fat Standard Deviation 5.70
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition Month 36 (n=5,8)	-2.0 Percentage of body fat Standard Deviation 4.20	-1.1 Percentage of body fat Standard Deviation 4.94
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition Month 48 (n=4,7)	-2.0 Percentage of body fat Standard Deviation 5.07	0.1 Percentage of body fat Standard Deviation 5.63
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition Month 60 (n=4,6)	-2.8 Percentage of body fat Standard Deviation 4.64	-0.5 Percentage of body fat Standard Deviation 4.97

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Change From Baseline in Tumor Volume month 66 (n= 1, 1)	-100.0 cm^3 Standard Deviation NA n=1; therefore, SD does not apply.	269.8 cm^3 Standard Deviation NA n=1; therefore, SD does not apply.
Change From Baseline in Tumor Volume month 6 (n=25, 28)	9.3 cm^3 Standard Deviation 44.02	-19.0 cm^3 Standard Deviation 36.82
Change From Baseline in Tumor Volume month 12 (n=15, 18)	-8.1 cm^3 Standard Deviation 62.17	-43.8 cm^3 Standard Deviation 49.47
Change From Baseline in Tumor Volume month 18 (n=8, 11)	-18.1 cm^3 Standard Deviation 71.62	-36.0 cm^3 Standard Deviation 65.42
Change From Baseline in Tumor Volume month 24 (n=7, 13)	-27.4 cm^3 Standard Deviation 82.68	-11.5 cm^3 Standard Deviation 66.28
Change From Baseline in Tumor Volume month 30 (n=6, 8)	-52.1 cm^3 Standard Deviation 55.20	-20.9 cm^3 Standard Deviation 77.16
Change From Baseline in Tumor Volume month 36 (n=3, 5)	-94.1 cm^3 Standard Deviation 10.15	-27.6 cm^3 Standard Deviation 78.86
Change From Baseline in Tumor Volume month 42 (n=3, 3)	-95.2 cm^3 Standard Deviation 8.40	84.0 cm^3 Standard Deviation 282.60
Change From Baseline in Tumor Volume month 48 (n=3, 3)	-20.5 cm^3 Standard Deviation 130.90	29.2 cm^3 Standard Deviation 164.67
Change From Baseline in Tumor Volume month 54 (n=3, 2)	-29.1 cm^3 Standard Deviation 107.40	20.3 cm^3 Standard Deviation 170.15
Change From Baseline in Tumor Volume month 60 (n=3, 2)	-13.5 cm^3 Standard Deviation 136.97	127.6 cm^3 Standard Deviation 321.88
Change From Baseline in Tumor Volume month 72 (n=1, 0)	45.6 cm^3 Standard Deviation NA n=1; therefore, SD does not apply.	NA cm^3 Standard Deviation NA No participants in this arm had month 72 values.
Change From Baseline in Tumor Volume month 78 (n=1, 0)	77.2 cm^3 Standard Deviation NA n=1; therefore, SD does not apply.	NA cm^3 Standard Deviation NA No participants in this arm had month 78 values.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pasireotide 600 ug n=82 Participants 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.	Pasireotide 900 ug n=80 Participants 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.
Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score month 12 (n=20,20)	54.9 Percentage change in HRQL score Standard Deviation 95.83	111.5 Percentage change in HRQL score Standard Deviation 266.75
Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score month 3 (n=67,66)	20.7 Percentage change in HRQL score Standard Deviation 60.26	40.1 Percentage change in HRQL score Standard Deviation 135.47
Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score month 6 (n= 55,56)	19.6 Percentage change in HRQL score Standard Deviation 47.78	52.2 Percentage change in HRQL score Standard Deviation 169.47

Adverse Events

Pasireotide 600 ug

Serious events: 23 serious events

Other events: 78 other events

Deaths: 0 deaths

Pasireotide 900 ug

Serious events: 25 serious events

Other events: 79 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Pasireotide 600 ug n=82 participants at risk 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.	Pasireotide 900 ug n=80 participants at risk 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.
Cardiac disorders Atrioventricular block second degree	0.00% 0/82	1.2% 1/80
Ear and labyrinth disorders Ear haemorrhage	1.2% 1/82	0.00% 0/80
Ear and labyrinth disorders Tympanic membrane perforation	1.2% 1/82	0.00% 0/80
Ear and labyrinth disorders Vertigo positional	0.00% 0/82	1.2% 1/80
Endocrine disorders Adrenal insufficiency	0.00% 0/82	2.5% 2/80
Endocrine disorders Pituitary-dependent Cushing's syndrome	3.7% 3/82	3.8% 3/80
Gastrointestinal disorders Abdominal pain	0.00% 0/82	1.2% 1/80
Gastrointestinal disorders Anal fistula	1.2% 1/82	0.00% 0/80
Gastrointestinal disorders Constipation	0.00% 0/82	1.2% 1/80
Gastrointestinal disorders Diarrhoea	2.4% 2/82	0.00% 0/80
Gastrointestinal disorders Diverticular perforation	1.2% 1/82	0.00% 0/80
Gastrointestinal disorders Inguinal hernia	0.00% 0/82	1.2% 1/80
Gastrointestinal disorders Pancreatitis	1.2% 1/82	0.00% 0/80
Gastrointestinal disorders Tongue movement disturbance	0.00% 0/82	1.2% 1/80
Gastrointestinal disorders Umbilical hernia	0.00% 0/82	1.2% 1/80
General disorders Disease progression	1.2% 1/82	1.2% 1/80
General disorders Drug ineffective	1.2% 1/82	1.2% 1/80
General disorders Microlithiasis	0.00% 0/82	1.2% 1/80
Hepatobiliary disorders Bile duct stone	0.00% 0/82	1.2% 1/80
Hepatobiliary disorders Cholangitis	1.2% 1/82	0.00% 0/80
Hepatobiliary disorders Cholecystitis	0.00% 0/82	1.2% 1/80
Hepatobiliary disorders Cholecystitis acute	2.4% 2/82	0.00% 0/80
Hepatobiliary disorders Cholelithiasis	4.9% 4/82	2.5% 2/80
Infections and infestations Abscess intestinal	1.2% 1/82	0.00% 0/80
Infections and infestations Cellulitis	0.00% 0/82	1.2% 1/80
Infections and infestations Cervicitis	0.00% 0/82	1.2% 1/80
Infections and infestations Diverticulitis	1.2% 1/82	0.00% 0/80
Infections and infestations Escherichia urinary tract infection	1.2% 1/82	0.00% 0/80
Infections and infestations Nail infection	1.2% 1/82	0.00% 0/80
Infections and infestations Pneumonia	1.2% 1/82	0.00% 0/80
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/82	1.2% 1/80
Injury, poisoning and procedural complications Toxicity to various agents	1.2% 1/82	0.00% 0/80
Investigations Electrocardiogram QT prolonged	0.00% 0/82	1.2% 1/80
Investigations Lipase increased	1.2% 1/82	0.00% 0/80
Metabolism and nutrition disorders Diabetes mellitus	1.2% 1/82	3.8% 3/80
Metabolism and nutrition disorders Food intolerance	0.00% 0/82	1.2% 1/80
Metabolism and nutrition disorders Hyperglycaemia	1.2% 1/82	5.0% 4/80
Metabolism and nutrition disorders Hypoglycaemia	1.2% 1/82	0.00% 0/80
Metabolism and nutrition disorders Type 2 diabetes mellitus	1.2% 1/82	0.00% 0/80
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/82	1.2% 1/80
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pituitary tumour benign	1.2% 1/82	2.5% 2/80
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Secretory adenoma of pituitary	0.00% 0/82	1.2% 1/80
Nervous system disorders Cerebrovascular accident	0.00% 0/82	1.2% 1/80
Nervous system disorders Cranial nerve paralysis	0.00% 0/82	1.2% 1/80
Nervous system disorders Dizziness	0.00% 0/82	1.2% 1/80
Nervous system disorders Dysarthria	0.00% 0/82	1.2% 1/80
Nervous system disorders Intracranial aneurysm	0.00% 0/82	1.2% 1/80
Nervous system disorders Somnolence	0.00% 0/82	1.2% 1/80
Pregnancy, puerperium and perinatal conditions Pregnancy	1.2% 1/82	0.00% 0/80
Psychiatric disorders Agitation	0.00% 0/82	1.2% 1/80
Reproductive system and breast disorders Adenomyosis	0.00% 0/82	1.2% 1/80
Reproductive system and breast disorders Uterine polyp	1.2% 1/82	1.2% 1/80
Respiratory, thoracic and mediastinal disorders Epistaxis	1.2% 1/82	0.00% 0/80
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	1.2% 1/82	0.00% 0/80
Vascular disorders Hypertensive crisis	0.00% 0/82	1.2% 1/80
Vascular disorders Hypertensive emergency	0.00% 0/82	1.2% 1/80
Vascular disorders Hypotension	1.2% 1/82	1.2% 1/80

Other adverse events

Other adverse events
Measure	Pasireotide 600 ug n=82 participants at risk 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.	Pasireotide 900 ug n=80 participants at risk 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.
Blood and lymphatic system disorders Anaemia	1.2% 1/82	6.2% 5/80
Blood and lymphatic system disorders Iron deficiency anaemia	3.7% 3/82	5.0% 4/80
Cardiac disorders Sinus bradycardia	9.8% 8/82	2.5% 2/80
Ear and labyrinth disorders Vertigo	4.9% 4/82	7.5% 6/80
Endocrine disorders Hypothyroidism	3.7% 3/82	5.0% 4/80
Eye disorders Vision blurred	3.7% 3/82	5.0% 4/80
Gastrointestinal disorders Abdominal distension	7.3% 6/82	7.5% 6/80
Gastrointestinal disorders Abdominal pain	23.2% 19/82	26.2% 21/80
Gastrointestinal disorders Abdominal pain upper	13.4% 11/82	10.0% 8/80
Gastrointestinal disorders Constipation	11.0% 9/82	5.0% 4/80
Gastrointestinal disorders Diarrhoea	59.8% 49/82	57.5% 46/80
Gastrointestinal disorders Dyspepsia	1.2% 1/82	6.2% 5/80
Gastrointestinal disorders Faeces soft	3.7% 3/82	5.0% 4/80
Gastrointestinal disorders Haemorrhoids	3.7% 3/82	5.0% 4/80
Gastrointestinal disorders Nausea	48.8% 40/82	58.8% 47/80
Gastrointestinal disorders Vomiting	3.7% 3/82	11.2% 9/80
General disorders Asthenia	15.9% 13/82	7.5% 6/80
General disorders Fatigue	14.6% 12/82	30.0% 24/80
General disorders Injection site haemorrhage	1.2% 1/82	5.0% 4/80
General disorders Injection site pain	3.7% 3/82	5.0% 4/80
General disorders Malaise	2.4% 2/82	6.2% 5/80
General disorders Oedema peripheral	11.0% 9/82	7.5% 6/80
Hepatobiliary disorders Cholelithiasis	30.5% 25/82	31.2% 25/80
Infections and infestations Gastroenteritis	0.00% 0/82	5.0% 4/80
Infections and infestations Influenza	12.2% 10/82	6.2% 5/80
Infections and infestations Nasopharyngitis	14.6% 12/82	15.0% 12/80
Infections and infestations Upper respiratory tract infection	7.3% 6/82	2.5% 2/80
Infections and infestations Urinary tract infection	4.9% 4/82	7.5% 6/80
Injury, poisoning and procedural complications Contusion	0.00% 0/82	5.0% 4/80
Injury, poisoning and procedural complications Procedural pain	1.2% 1/82	5.0% 4/80
Investigations Alanine aminotransferase increased	14.6% 12/82	7.5% 6/80
Investigations Aspartate aminotransferase increased	7.3% 6/82	3.8% 3/80
Investigations Blood alkaline phosphatase increased	7.3% 6/82	1.2% 1/80
Investigations Blood glucose increased	7.3% 6/82	3.8% 3/80
Investigations Blood insulin decreased	1.2% 1/82	5.0% 4/80
Investigations Electrocardiogram QT prolonged	6.1% 5/82	8.8% 7/80
Investigations Gamma-glutamyltransferase increased	13.4% 11/82	8.8% 7/80
Investigations Glycosylated haemoglobin increased	12.2% 10/82	10.0% 8/80
Investigations International normalised ratio increased	1.2% 1/82	5.0% 4/80
Investigations Lipase increased	8.5% 7/82	6.2% 5/80
Investigations Low density lipoprotein increased	6.1% 5/82	3.8% 3/80
Investigations Prothrombin time prolonged	2.4% 2/82	5.0% 4/80
Investigations Weight decreased	3.7% 3/82	6.2% 5/80
Metabolism and nutrition disorders Decreased appetite	9.8% 8/82	11.2% 9/80
Metabolism and nutrition disorders Diabetes mellitus	20.7% 17/82	22.5% 18/80
Metabolism and nutrition disorders Hypercholesterolaemia	9.8% 8/82	15.0% 12/80
Metabolism and nutrition disorders Hyperglycaemia	37.8% 31/82	43.8% 35/80
Metabolism and nutrition disorders Hyperlipidaemia	6.1% 5/82	3.8% 3/80
Metabolism and nutrition disorders Hypertriglyceridaemia	7.3% 6/82	6.2% 5/80
Metabolism and nutrition disorders Hypoglycaemia	14.6% 12/82	6.2% 5/80
Metabolism and nutrition disorders Hypokalaemia	7.3% 6/82	7.5% 6/80
Metabolism and nutrition disorders Type 2 diabetes mellitus	12.2% 10/82	6.2% 5/80
Metabolism and nutrition disorders Vitamin B12 deficiency	2.4% 2/82	6.2% 5/80
Metabolism and nutrition disorders Vitamin D deficiency	6.1% 5/82	6.2% 5/80
Musculoskeletal and connective tissue disorders Arthralgia	7.3% 6/82	12.5% 10/80
Musculoskeletal and connective tissue disorders Back pain	6.1% 5/82	8.8% 7/80
Musculoskeletal and connective tissue disorders Muscle spasms	1.2% 1/82	5.0% 4/80
Musculoskeletal and connective tissue disorders Myalgia	13.4% 11/82	7.5% 6/80
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/82	5.0% 4/80
Musculoskeletal and connective tissue disorders Pain in extremity	8.5% 7/82	5.0% 4/80
Nervous system disorders Dizziness	11.0% 9/82	11.2% 9/80
Nervous system disorders Dysgeusia	3.7% 3/82	5.0% 4/80
Nervous system disorders Headache	30.5% 25/82	31.2% 25/80
Nervous system disorders Migraine	0.00% 0/82	5.0% 4/80
Nervous system disorders Somnolence	2.4% 2/82	5.0% 4/80
Psychiatric disorders Anxiety	7.3% 6/82	12.5% 10/80
Psychiatric disorders Depression	3.7% 3/82	5.0% 4/80
Psychiatric disorders Insomnia	3.7% 3/82	16.2% 13/80
Respiratory, thoracic and mediastinal disorders Cough	6.1% 5/82	3.8% 3/80
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	1.2% 1/82	5.0% 4/80
Skin and subcutaneous tissue disorders Acne	6.1% 5/82	2.5% 2/80
Skin and subcutaneous tissue disorders Alopecia	12.2% 10/82	13.8% 11/80
Skin and subcutaneous tissue disorders Dry skin	6.1% 5/82	6.2% 5/80
Skin and subcutaneous tissue disorders Ecchymosis	1.2% 1/82	5.0% 4/80
Skin and subcutaneous tissue disorders Pruritus	7.3% 6/82	8.8% 7/80
Skin and subcutaneous tissue disorders Rash	7.3% 6/82	5.0% 4/80
Skin and subcutaneous tissue disorders Skin exfoliation	6.1% 5/82	3.8% 3/80
Vascular disorders Hypertension	12.2% 10/82	10.0% 8/80
Vascular disorders Hypotension	4.9% 4/82	6.2% 5/80

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER