Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing's Disease

• ClinicalTrials.gov Identifier: NCT01374906
• Recruitment Status: Completed
• First Posted: June 16, 2011
• Results First Posted: April 11, 2018
• Last Update Posted: May 22, 2018
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Cushing's Disease
• Interventions: Drug: pasireotide LAR; Drug: SOM230 LAR 30 mg; Drug: SOM230 LAR 10 mg
• Enrollment: 150

Participant Flow

Recruitment Details	At least 148 patients (Pts.) were planned & 150 were randomized & analyzed. Pts. were all treated with either pasireotide long-acting 10 mg or pasireotide long-acting 30 mg. 81 Pts. completed the Core phase & entered the Extension phase with 39 completing the Extension phase.
Pre-assignment Details

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Period Title: Overall Study
Started	74	76
DC Dur Core Phs at/Prior to Data Cutoff	24	22
Completed Core Phase	50	54
Completed Core/Did Not Enter Ext. Phase	10	13
Completed Core Phase/Entered Ext. Phase	40	41
DC Dur Ext Phs at/Prior to Data Cutoff	16	26
Completed Extension Phase	24	15
Completed	34	28
Not Completed	40	48
Reason Not Completed
Abnormal laboratory value(s)	0	3
Administrative problems	2	2
Adverse Event	10	11
Death	0	2
Protocol Violation	2	2
Withdrawal by Subject	15	9
Unsatisfactory therapeutic effect	11	19

Baseline Characteristics

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose	Total
Arm/Group Description		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.	Total of all reporting groups
Overall Number of Baseline Participants		74	76	150
Baseline Analysis Population Description		Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	74 participants	76 participants	150 participants
		38.3 (12.52)	38.6 (12.99)	38.5 (12.72)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	74 participants	76 participants	150 participants
	Female	58 78.4%	60 78.9%	118 78.7%
	Male	16 21.6%	16 21.1%	32 21.3%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	74 participants	76 participants	150 participants
Caucasian		39	44	83
Asian		27	24	51
Black		2	0	2
Other		6	8	14

Outcome Measures

1. Primary Outcome

Title	Percentage Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 Regardless of Dose Titration
Description	Percentage of participants that attained a mean urinary free cortisol (mUFC) <= 1.0 x upper limit of normal (ULN) at Month 7 regardless of dose up-titration at Month 4. Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value.
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	41.9; (30.51 to 53.94)	40.8; (29.65 to 52.67)

2. Secondary Outcome

Title	Percentage of Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4
Description	Percentage of participants that attain a mUFC ≤ 1.0×ULN at Month 7 and had not had a dose increase at Month 4. Patients who had a dose increase prior to Month 7 were counted as non-responders in this analysis. Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. A responder was defined as a patient who attains mUFC ≤1.0 X ULN and had not had a dose increase at Month 4.
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	28.4; (18.50 to 40.05)	31.6; (21.39 to 43.25)

3. Secondary Outcome

Title	Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline
Description	Actual change in mUFC (nmol/24h) from baseline by randomized groups.
Time Frame	baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: nmol/24h
M7	Number Analyzed	57 participants	67 participants
		-192.4 (271.59)	-234.3 (362.86)
M12	Number Analyzed	50 participants	54 participants
		-195.1 (282.46)	-247.6 (387.05)
M24	Number Analyzed	33 participants	25 participants
		-236.2 (292.91)	-265.2 (313.47)
M36	Number Analyzed	14 participants	4 participants
		-398.4 (136.09)	-164.6 (66.76)

4. Secondary Outcome

Title	Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline
Description	Percentage change in mUFC (nmol/24h) from baseline by randomized groups.
Time Frame	M7, M12, M24, M36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: percentage change
M7	Number Analyzed	57 participants	67 participants
		-29.3 (102.76)	-33.2 (61.37)
M12	Number Analyzed	50 participants	54 participants
		-30.3 (79.73)	-31.1 (78.41)
M24	Number Analyzed	33 participants	25 participants
		-50.9 (76.48)	-51.2 (35.41)
M36	Number Analyzed	14 participants	4 participants
		-71.6 (20.44)	-48.8 (11.36)

5. Secondary Outcome

Title	Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN
Description	Controlled responder: mUFC ≤ 1.0×ULN by randomized groups.
Time Frame	M7, M12, M24, M36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
M7 - Controlled responder	Number Analyzed	74 participants	76 participants
		39.2; (28.04 to 51.23)	40.8; (29.65 to 52.67)
M12 - Controlled responder	Number Analyzed	74 participants	76 participants
		35.1; (24.39 to 47.11)	25.0; (15.77 to 36.26)
M24 - Controlled responder	Number Analyzed	63 participants	61 participants
		39.7; (27.57 to 52.80)	21.3; (11.86 to 33.68)
M36 - Controlled responder	Number Analyzed	50 participants	50 participants
		22.0; (11.53 to 35.96)	4.0; (0.49 to 13.71)

6. Secondary Outcome

Title	Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC
Description	Controlled responder: mUFC ≤ 1.0×ULN. Partially controlled responder: at least 50% reduction in mUFC from Baseline, and mUFC >1.0×ULN.
Time Frame	M7, M12, M24, M36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
M7	Number Analyzed	74 participants	76 participants
		44.6; (33.02 to 56.61)	53.9; (42.13 to 65.45)
M12	Number Analyzed	74 participants	76 participants
		45.9; (34.29 to 57.93)	42.1; (30.86 to 53.98)
M24	Number Analyzed	63 participants	61 participants
		46.0; (33.39 to 59.06)	27.9; (17.15 to 40.83)
M36	Number Analyzed	50 participants	50 participants
		28.0; (16.23 to 42.49)	6.0; (1.25 to 16.55)

7. Secondary Outcome

Title	Percentage of Patients Who Are Controlled Responders (mUFC ≤ 1.0 xULN) on at Least 4 of the 7 mUFC Assessments by Month 7 & on at Least 7 of the 12 mUFC Assessments by Month 12.
Description	Percentage of patients with mUFC ≤ 1.0 x ULN at a minimum of 4 months up to and including Month 7, and at a minimum of 7 months up to and including Month 12 by randomized groups.
Time Frame	Month 7, Month 12

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Month 7	25.7; (16.22 to 37.16)	31.6; (21.39 to 43.25)
Month 12	25.7; (16.22 to 37.16)	25.0; (15.77 to 36.26)

8. Secondary Outcome

Title	Percentage of Patients With Uncontrolled Response at Month 7 & Month 12 Within the Subset of Patients Who Had Uncontrolled Response at a) Months 1 and 2; b) Months 1, 2, and 3
Description	Percentage of patients with mUFC > 1.0 xULN at Month 7 and Month 12 within the subset of patients who were uncontrolled at a) Months 1 & 2, b) Months 1, 2, & 3 by randomized groups.
Time Frame	Month 7, Month12

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Measure Type: Number; Unit of Measure: percentage of participants
Uncontrolled Resp @ M7: subset: M1 & 2	Number Analyzed	33 participants	33 participants
		60.6	60.6
Uncontrolled Resp @ M7: subset: M1,2 & 3	Number Analyzed	31 participants	29 participants
		61.3	65.5
Uncontrolled Resp @ M12: subset: M1 & 2	Number Analyzed	33 participants	33 participants
		69.7	69.7
Uncontrolled Resp @ M12: subset: M1, 2 & 3	Number Analyzed	31 participants	29 participants
		74.2	72.4

9. Secondary Outcome

Title	Percent of Participants Attaining a mUFC ≤ 1.0 x ULN or at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points
Description	Time to first achievement of attaining a mUFC ≤ 1.0 x ULN or at least a 50% reduction in mUFC from baseline by randomized groups.
Time Frame	Momth 7, Month 12

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Month 7	86.2; (76.1 to 93.5)	83.4; (72.6 to 91.8)
Month 12	90.1; (80.7 to 96.2)	94.5; (81.0 to 99.4)

10. Secondary Outcome

Title	Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points
Description	Duration of controlled or partially controlled response is defined as the period starting from the date of patient’s first normalization (mUFC≤ 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient’s mUFC >1.0 x ULN and the reduction from baseline falls to less than 50% for the first time.
Time Frame	Month 6, 12, 18

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Month 6	78.0; (66.5 to 87.7)	72.9; (61.2 to 83.4)
Month 12	84.0; (73.1 to 92.2)	82.8; (71.5 to 91.5)
Month 18	84.0; (73.1 to 92.2)	87.1; (74.6 to 95.3)

11. Secondary Outcome

Title	Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time
Description	Percentage change in ACTH (pmol/L) from Baseline by randomized groups.
Time Frame	Months 7, 12, 24 & 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: Percentage change
M7	Number Analyzed	54 participants	62 participants
		2.7 (57.14)	-13.5 (46.75)
M12	Number Analyzed	44 participants	52 participants
		-10.2 (57.57)	-14.5 (38.72)
M24	Number Analyzed	31 participants	23 participants
		-12.1 (43.51)	2.5 (68.69)
M36	Number Analyzed	13 participants	5 participants
		-15.4 (36.90)	-0.6 (48.13)

12. Secondary Outcome

Title	Percentage Change From Baseline on Serum Cortisol Over Time
Description	Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups.
Time Frame	Months 7, 12, 24 & 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: Percentage change
M7	Number Analyzed	55 participants	66 participants
		-8.2 (37.83)	-5.1 (40.20)
M12	Number Analyzed	46 participants	54 participants
		-12.1 (29.69)	-0.4 (35.91)
M24	Number Analyzed	32 participants	25 participants
		-15.6 (30.67)	-7.4 (38.37)
M36	Number Analyzed	14 participants	5 participants
		0.6 (55.67)	-23.2 (31.19)

13. Secondary Outcome

Title	Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure
Description	Change in blood pressure measurements from Baseline
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: mmHg
Supine systolic blood pressure (SBP)	Number Analyzed	57 participants	67 participants
		-6.8 (15.64)	-4.6 (14.51)
Supine diastolic blood (DBP) pressure	Number Analyzed	57 participants	67 participants
		-4.8 (12.06)	-3.0 (12.12)

14. Secondary Outcome

Title	Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)
Description	Change in BMI measurements from Baseline
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Mean (Standard Deviation); Unit of Measure: kg/m2
	-0.7 (1.60)	-1.8 (2.05)

15. Secondary Outcome

Title	Actual Change From Baseline in Clinical Signs Over Time: Weight
Description	Change in weight measurements from Baseline
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Mean (Standard Deviation); Unit of Measure: kg
	-1.8 (4.16)	-4.6 (5.08)

16. Secondary Outcome

Title	Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region
Description	Change in body composition: region measurements from Baseline
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Mean (Standard Deviation); Unit of Measure: percentage fat
	-1.0 (2.64)	-1.8 (3.97)

17. Secondary Outcome

Title	Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference
Description	Change in waist circumference measurements from Baseline
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Mean (Standard Deviation); Unit of Measure: cm
	-1.6 (8.47)	-7.1 (11.78)

18. Secondary Outcome

Title	Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides
Description	Change in parameter measurements: cholesterol & triglycerides from Baseline
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: mmol/L
Total cholesterol	Number Analyzed	56 participants	64 participants
		-0.5 (1.07)	-0.4 (1.00)
HDL cholesterol	Number Analyzed	55 participants	64 participants
		-0.1 (0.28)	0 (0.32)
Triglycerides	Number Analyzed	56 participants	64 participants
		0 (0.53)	-0.2 (0.64)

19. Secondary Outcome

Title	Percentage Change From Baseline in Clinical Signs Over Time
Description	Percentage change in parameter measurements: blood pressure, body mass index, waist circumference, fasting serum lipid profile, weight, bone density and body composition (examined by DXA scan) from Baseline
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: Percentage change
SBP	Number Analyzed	57 participants	67 participants
		-4.3 (11.46)	-3.0 (10.18)
DBP	Number Analyzed	57 participants	67 participants
		-4.7 (14.19)	-2.6 (13.78)
BMI	Number Analyzed	57 participants	67 participants
		-2.6 (5.26)	-6.1 (6.94)
Weight	Number Analyzed	57 participants	67 participants
		-2.6 (5.26)	-6.1 (6.91)
Waist circumference	Number Analyzed	53 participants	63 participants
		-1.4 (8.60)	-6.6 (10.06)
HDL	Number Analyzed	55 participants	64 participants
		-6.7 (15.18)	0.3 (20.91)
Total cholesterol	Number Analyzed	56 participants	64 participants
		-7.2 (16.86)	-6.6 (16.40)
Triglycerides	Number Analyzed	56 participants	64 participants
		4.2 (39.54)	-0.9 (39.61)
Body composition	Number Analyzed	41 participants	48 participants
		-2.4 (6.68)	-3.6 (10.47)

20. Secondary Outcome

Title	Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs
Description	This includes patients with improvements in symptoms from baseline. Clinical signs over time include: facial rubor, fat pads, hirsutism, striae, (via photographs by a second local physician who was blinded to the treatment dose and time point of the photograph) and muscle strength.
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Measure Type: Number; Unit of Measure: Percentage of participants
Facial rubor	Number Analyzed	52 participants	56 participants
		32.7	53.6
Hirsutism (females only)	Number Analyzed	42 participants	76 participants
		22.2	32.6
Striae	Number Analyzed	52 participants	55 participants
		23.1	23.6
Bruising	Number Analyzed	52 participants	56 participants
		25.0	14.3
Supraclavicular fat pad	Number Analyzed	52 participants	56 participants
		40.4	28.6
Dorsal fat pad	Number Analyzed	52 participants	55 participants
		28.8	40.0
Muscle strength	Number Analyzed	56 participants	66 participants
		8.9	4.5

21. Secondary Outcome

Title	Percentage of Participants That Attained a Mean Urinary Free Cortisol (mUFC) <= 1.0 x Upper Limit of Normal (ULN) at Month 7 Regardless of Dose Up-titration at Month 4.
Description	All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. Analysis split by screening strata of mUFC Stratum 1: mUFC 1.5x to < 2.0 x ULN Stratum 2: mUFC 2.0x to <= 5.0 x ULN
Time Frame	Month 7

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
stratum:1.5 x ULN to < 2.0 x ULN	Number Analyzed	25 participants	25 participants
		52.0; (31.31 to 72.20)	52.0; (31.31 to 72.20)
stratum:2.0 x ULN to <= 5.0 x ULN	Number Analyzed	49 participants	51 participants
		36.7; (23.42 to 51.71)	35.3; (22.43 to 49.93)

22. Secondary Outcome

Title	Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline
Description	All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. Analysis split by screening strata of mUFC Stratum 1:
Time Frame	Months 7, 12, 24 & 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
M7	Number Analyzed	74 participants	76 participants
		35.1; (24.39 to 47.11)	43.4; (32.08 to 55.29)
M12	Number Analyzed	74 participants	76 participants
		35.1; (24.39 to 47.11)	38.2; (27.25 to 50.02)
M24	Number Analyzed	24 participants	14 participants
		83.3; (62.62 to 95.26)	57.1; (28.86 to 82.34)
M36	Number Analyzed	8 participants	3 participants
		100; (63.06 to 100.00)	33.33; (0.84 to 90.57)

23. Secondary Outcome

Title	Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points
Description	Time to first achievement of a 5by randomized groups.0% reduction in mUFC from baseline
Time Frame	every month in the core phase and every 3 months in the extension phase) up to and including the cut-off date for the Month 12 CSR (10-Nov-2015)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
M7	80.5; (69.7 to 89.3)	73.4; (62.4 to 83.4)
M12	84.4; (74.0 to 92.3)	80.7; (69.4 to 89.8)

24. Secondary Outcome

Title	Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points
Description	Duration of 50% reduction from baseline is defined as the period starting from the date of patient’s first 50% reduction from baseline
Time Frame	Months 6, 12 & 18

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed	74	76
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
M6	78.4; (66.6 to 88.3)	77.8; (66.0 to 87.7)
M12	84.9; (73.7 to 93.1)	83.7; (72.6 to 92.1)
M18	84.9; (73.7 to 93.1)	83.7; (72.6 to 92.1)

25. Secondary Outcome

Title	Pharmacokinetic (PK) Parameter: Ctrough
Description	Pasireotide trough levels (Ctrough) was 1 of the parameters used for PK assessments. Ctrough is the pre-dose PK concentration with an elapsed time from previous injection of 28+/-2 days. All patients randomized to the study had at least 1 PK observation & were therefore included in the pharmacokinetic analysis set. PK observations with missing concentrations, missing dose, missing elapsed time or an elapsed time from previous injection outside of 28 ±2 days window were excluded. Given that SOM230 LAR was administered once a month, Ctrough was collected every 28 days and thus this provides a summary of Ctrough values provided by incident dose (last dose administered prior to PK sample collection), not by randomized dose, hence each column is equivalent to an incident dose & not an arm/group. Patients randomized to either 10mg or 30mg could be titrated down to 5mg due to safety, or titrated up to 40mg, hence the 4 incident doses/columns that were allowed per protocol during this study.
Time Frame	Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PAS): The PAS consists of all randomized patients who have received at least one dose of study drug and had at least one post dosing PK assessment.

Patients were analyzed according to incident dose (defined as the last dose prior to the PK sample).

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose	5 mg Pasireotide LAR Dose	40 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.	These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Overall Number of Participants Analyzed		65	64	5	44
Mean (Standard Deviation); Unit of Measure: ng/mL
Day 29	Number Analyzed	65 participants	64 participants	0 participants	0 participants
		2.03 (1.25)	7.63 (4.58)
Day 57	Number Analyzed	57 participants	61 participants	1 participants	0 participants
		2.35 (1.15)	7.82 (4.22)	0.83 [1] (NA)
Day 85	Number Analyzed	59 participants	51 participants	2 participants	0 participants
		2.39 (1.32)	8.56 (4.26)	1.03 (0.63)
Day 113	Number Analyzed	51 participants	49 participants	3 participants	0 participants
		2.40 (1.11)	8.31 (3.87)	1.29 (0.24)
Day 141	Number Analyzed	25 participants	50 participants	2 participants	20 participants
		2.47 (0.94)	7.88 (4.00)	1.04 (0.68)	10.7 (4.91)
Day 169	Number Analyzed	29 participants	51 participants	2 participants	22 participants
		2.47 (0.95)	8.46 (3.51)	2.01 (0.22)	12.0 (5.08)
Day 197	Number Analyzed	35 participants	44 participants	2 participants	21 participants
		2.88 (1.29)	9.13 (4.25)	0.72 (0.39)	11.9 (5.87)
Day 225	Number Analyzed	22 participants	28 participants	3 participants	34 participants
		2.68 (0.98)	8.57 (4.70)	1.19 (0.43)	11.3 (5.18)
Day 253	Number Analyzed	17 participants	27 participants	5 participants	33 participants
		2.87 (1.57)	9.00 (4.93)	1.77 (0.88)	12.1 (5.21)
Day 281	Number Analyzed	13 participants	16 participants	3 participants	44 participants
		3.36 (1.48)	8.18 (4.23)	1.24 (0.52)	11.4 (5.85)
Day 309	Number Analyzed	23 participants	19 participants	1 participants	43 participants
		2.50 (0.99)	9.34 (5.61)	0.66 [1] (NA)	12.0 (4.58)
Day 337	Number Analyzed	21 participants	15 participants	3 participants	41 participants
		3.07 (1.62)	8.90 (4.37)	1.91 (1.79)	12.6 (6.21)

[1]

N/A = not enough patients on this day to derive data

26. Secondary Outcome

Title	Pharmacokinetic (PK) Parameter: Cmax
Description	Pasireotide peak levels (Cmax) was one of the parameters used for PK assessments. Cmax is the post-dose PK concentration with an elapsed time from the previous injection of 21+/-2 days. All patients randomized to the study had at least one PK observation and were therefore included in the pharmacokinetic analysis set (PAS). Cmax PK observations ("Day 20" and "Day 104") with an elapsed time from the previous injection outside of 21+/-2 days window were excluded. Given that SOM230 LAR was administered once a month, the Cmax were collected every 28 days in this study, thus this provides a summary of Cmax values provided by incident dose (last dose administered prior to PK sample collection), not by randomized dose, hence each column is equivalent to an incident dose and not an arm/group. Patients randomized to either the 10mg or 30mg could be titrated down to 5mg due to safety, or titrated up to 40mg, hence the 4 incident doses/columns that were allowed per protocol during this study.
Time Frame	Days 22, 106, 190

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PAS): The PAS consists of all randomized patients who have received at least one dose of study drug and had at least one post dosing PK assessment.

Patients were analyzed according to incident dose (defined as the last dose prior to the PK sample).

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose	5 mg Pasireptide LAR Dose	40 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.	These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Overall Number of Participants Analyzed		67	69	3	22
Mean (Standard Deviation); Unit of Measure: ng/mL
Day 22 (M 0.75)	Number Analyzed	67 participants	69 participants	0 participants	0 participants
		3.0 (1.50)	8.2 (3.99)
Day 106 (M 3.75)	Number Analyzed	54 participants	51 participants	3 participants	0 participants
		3.3 (1.92)	9.4 (3.72)	1.7 (0.42)
Day 190 (M6.75)	Number Analyzed	32 participants	40 participants	2 participants	22 participants
		4.0 (1.73)	10.0 (3.91)	1.4 (0.78)	12.1 (5.21)

27. Secondary Outcome

Title	Actual Change in Standardized Score of Cushing’s Disease HRQoL (CushingQOL) Score From Baseline
Description	CushingQol is a disease-specific patient-reported outcome instrument. It is a single-domain 12 item Cushing's disease quality of life instrument. The Cushing’s syndrome quality of life (CushingQoL) questionnaire is a single domain questionnaire which includes 12 self-report items scored using a five point Likert scale anchored at (1=always/very much and 5=never/not at all). The patient is asked to report what they think or feel about their Cushing’s syndrome and how much the illness has interfered in usual activities over the past 4 weeks. The total score is standardized on a 0-100 scale with lower scores indicating a greater impact on quality of life.
Time Frame	Months 7, 12, 24 & 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: scores on a scale
M7	Number Analyzed	56 participants	64 participants
		5.7 (15.97)	7.8 (11.63)
M12	Number Analyzed	47 participants	53 participants
		6.4 (17.56)	6.8 (14.42)
M24	Number Analyzed	32 participants	25 participants
		5.9 (15.56)	8.7 (12.80)
M36	Number Analyzed	13 participants	4 participants
		1.4 (9.10)	14.6 (5.10)

28. Secondary Outcome

Title	Actual Change in SF-12v2 Score From Baseline - Mental Component Summary
Description	SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.
Time Frame	Months 7, 12 & 24

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: scores on a scale
M7	Number Analyzed	33 participants	37 participants
		4.1 (8.81)	4.3 (8.05)
M12	Number Analyzed	28 participants	33 participants
		2.3 (9.97)	3.3 (8.26)
M24	Number Analyzed	9 participants	5 participants
		3.3 (10.43)	6.4 (2.53)

29. Secondary Outcome

Title	Actual Change in SF-12v2 Score From Baseline - Physical Component Summary
Description	SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.
Time Frame	Months 7, 12 & 24

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): The FAS comprises all randomized patients who received at least one dose of study drug.

Arm/Group Title		10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose
Arm/Group Description:		Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
Overall Number of Participants Analyzed		74	76
Mean (Standard Deviation); Unit of Measure: scores on a scale
M7	Number Analyzed	33 participants	37 participants
		1.9 (8.50)	-0.8 (7.46)
M12	Number Analyzed	28 participants	33 participants
		4.9 (5.56)	-0.5 (6.73)
M24	Number Analyzed	9 participants	5 participants
		5.3 (4.32)	-1.1 (5.54)

Adverse Events

Time Frame	Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 5 years.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose	All Patients
Arm/Group Description	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.	Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.	All Patients from both the 10 mg and 30 mg groups.
All-Cause Mortality
	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	22/74 (29.73%)	19/76 (25.00%)	41/150 (27.33%)
Blood and lymphatic system disorders
Anaemia † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Cardiac disorders
Angina pectoris † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Angina unstable † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Cardiac arrest † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Cardiac failure † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Cardiopulmonary failure † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Coronary artery occlusion † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Sinus bradycardia † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Endocrine disorders
Adrenal insufficiency † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Hyperadrenocorticism † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Pituitary-dependent Cushing's syndrome † 1	2/74 (2.70%)	1/76 (1.32%)	3/150 (2.00%)
Gastrointestinal disorders
Anogenital dysplasia † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Gastric ulcer † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Haemorrhoids † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Large intestine polyp † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Oedematous pancreatitis † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
General disorders
Injection site pain † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Malaise † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Hepatobiliary disorders
Cholecystitis acute † 1	2/74 (2.70%)	0/76 (0.00%)	2/150 (1.33%)
Cholelithiasis † 1	2/74 (2.70%)	3/76 (3.95%)	5/150 (3.33%)
Infections and infestations
Cellulitis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Diverticulitis † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Pneumonia † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Sepsis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Septic shock † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Subcutaneous abscess † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Injury, poisoning and procedural complications
Femoral neck fracture † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Road traffic accident † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Stress fracture † 1	2/74 (2.70%)	0/76 (0.00%)	2/150 (1.33%)
Investigations
Blood cortisol decreased † 1	1/74 (1.35%)	1/76 (1.32%)	2/150 (1.33%)
Blood cortisol increased † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Gamma-glutamyltransferase increased † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Metabolism and nutrition disorders
Diabetes mellitus † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Hyperglycaemia † 1	1/74 (1.35%)	1/76 (1.32%)	2/150 (1.33%)
Musculoskeletal and connective tissue disorders
Arthritis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Osteoarthritis † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Osteoporosis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Spondylolisthesis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer † 1	1/74 (1.35%)	1/76 (1.32%)	2/150 (1.33%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Renal and urinary disorders
Acute kidney injury † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Nephrolithiasis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Reproductive system and breast disorders
Endometrial hyperplasia † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Ovarian cyst † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Respiratory, thoracic and mediastinal disorders
Dysphonia † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
Dyspnoea † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Pulmonary artery thrombosis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Pulmonary embolism † 1	0/74 (0.00%)	2/76 (2.63%)	2/150 (1.33%)
Vascular disorders
Deep vein thrombosis † 1	0/74 (0.00%)	1/76 (1.32%)	1/150 (0.67%)
Hypertensive crisis † 1	1/74 (1.35%)	0/76 (0.00%)	1/150 (0.67%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (19.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	10 mg Pasireotide LAR Dose	30 mg Pasireotide LAR Dose	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	73/74 (98.65%)	76/76 (100.00%)	149/150 (99.33%)
Blood and lymphatic system disorders
Anaemia † 1	4/74 (5.41%)	5/76 (6.58%)	9/150 (6.00%)
Cardiac disorders
Palpitations † 1	4/74 (5.41%)	3/76 (3.95%)	7/150 (4.67%)
Sinus bradycardia † 1	4/74 (5.41%)	5/76 (6.58%)	9/150 (6.00%)
Ear and labyrinth disorders
Vertigo † 1	5/74 (6.76%)	0/76 (0.00%)	5/150 (3.33%)
Endocrine disorders
Adrenal insufficiency † 1	4/74 (5.41%)	6/76 (7.89%)	10/150 (6.67%)
Hypothyroidism † 1	1/74 (1.35%)	4/76 (5.26%)	5/150 (3.33%)
Gastrointestinal disorders
Abdominal discomfort † 1	4/74 (5.41%)	2/76 (2.63%)	6/150 (4.00%)
Abdominal distension † 1	4/74 (5.41%)	5/76 (6.58%)	9/150 (6.00%)
Abdominal pain † 1	11/74 (14.86%)	13/76 (17.11%)	24/150 (16.00%)
Abdominal pain upper † 1	3/74 (4.05%)	8/76 (10.53%)	11/150 (7.33%)
Constipation † 1	5/74 (6.76%)	5/76 (6.58%)	10/150 (6.67%)
Diarrhoea † 1	26/74 (35.14%)	35/76 (46.05%)	61/150 (40.67%)
Dry mouth † 1	4/74 (5.41%)	1/76 (1.32%)	5/150 (3.33%)
Flatulence † 1	3/74 (4.05%)	5/76 (6.58%)	8/150 (5.33%)
Frequent bowel movements † 1	4/74 (5.41%)	0/76 (0.00%)	4/150 (2.67%)
Nausea † 1	17/74 (22.97%)	16/76 (21.05%)	33/150 (22.00%)
Vomiting † 1	7/74 (9.46%)	2/76 (2.63%)	9/150 (6.00%)
General disorders
Asthenia † 1	10/74 (13.51%)	5/76 (6.58%)	15/150 (10.00%)
Fatigue † 1	13/74 (17.57%)	15/76 (19.74%)	28/150 (18.67%)
Oedema peripheral † 1	9/74 (12.16%)	12/76 (15.79%)	21/150 (14.00%)
Pyrexia † 1	5/74 (6.76%)	2/76 (2.63%)	7/150 (4.67%)
Hepatobiliary disorders
Cholelithiasis † 1	15/74 (20.27%)	33/76 (43.42%)	48/150 (32.00%)
Cholestasis † 1	4/74 (5.41%)	2/76 (2.63%)	6/150 (4.00%)
Gallbladder cholesterolosis † 1	2/74 (2.70%)	4/76 (5.26%)	6/150 (4.00%)
Hepatic function abnormal † 1	2/74 (2.70%)	4/76 (5.26%)	6/150 (4.00%)
Hepatic steatosis † 1	1/74 (1.35%)	6/76 (7.89%)	7/150 (4.67%)
Infections and infestations
Bronchitis † 1	5/74 (6.76%)	2/76 (2.63%)	7/150 (4.67%)
Gastroenteritis † 1	7/74 (9.46%)	2/76 (2.63%)	9/150 (6.00%)
Influenza † 1	12/74 (16.22%)	6/76 (7.89%)	18/150 (12.00%)
Nasopharyngitis † 1	18/74 (24.32%)	13/76 (17.11%)	31/150 (20.67%)
Upper respiratory tract infection † 1	5/74 (6.76%)	6/76 (7.89%)	11/150 (7.33%)
Urinary tract infection † 1	10/74 (13.51%)	9/76 (11.84%)	19/150 (12.67%)
Injury, poisoning and procedural complications
Contusion † 1	4/74 (5.41%)	1/76 (1.32%)	5/150 (3.33%)
Investigations
Alanine aminotransferase increased † 1	6/74 (8.11%)	5/76 (6.58%)	11/150 (7.33%)
Blood cortisol decreased † 1	4/74 (5.41%)	2/76 (2.63%)	6/150 (4.00%)
Blood creatine phosphokinase increased † 1	1/74 (1.35%)	6/76 (7.89%)	7/150 (4.67%)
Blood glucose increased † 1	6/74 (8.11%)	7/76 (9.21%)	13/150 (8.67%)
Gamma-glutamyltransferase increased † 1	7/74 (9.46%)	6/76 (7.89%)	13/150 (8.67%)
Glycosylated haemoglobin increased † 1	4/74 (5.41%)	4/76 (5.26%)	8/150 (5.33%)
Lipase increased † 1	2/74 (2.70%)	4/76 (5.26%)	6/150 (4.00%)
Weight decreased † 1	4/74 (5.41%)	3/76 (3.95%)	7/150 (4.67%)
Metabolism and nutrition disorders
Decreased appetite † 1	3/74 (4.05%)	12/76 (15.79%)	15/150 (10.00%)
Diabetes mellitus † 1	15/74 (20.27%)	20/76 (26.32%)	35/150 (23.33%)
Hypercholesterolaemia † 1	3/74 (4.05%)	6/76 (7.89%)	9/150 (6.00%)
Hyperglycaemia † 1	36/74 (48.65%)	35/76 (46.05%)	71/150 (47.33%)
Hyperlipidaemia † 1	1/74 (1.35%)	4/76 (5.26%)	5/150 (3.33%)
Hyperuricaemia † 1	5/74 (6.76%)	5/76 (6.58%)	10/150 (6.67%)
Hypoglycaemia † 1	10/74 (13.51%)	12/76 (15.79%)	22/150 (14.67%)
Type 2 diabetes mellitus † 1	3/74 (4.05%)	4/76 (5.26%)	7/150 (4.67%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	9/74 (12.16%)	4/76 (5.26%)	13/150 (8.67%)
Back pain † 1	8/74 (10.81%)	8/76 (10.53%)	16/150 (10.67%)
Muscle spasms † 1	1/74 (1.35%)	5/76 (6.58%)	6/150 (4.00%)
Musculoskeletal chest pain † 1	0/74 (0.00%)	4/76 (5.26%)	4/150 (2.67%)
Myalgia † 1	4/74 (5.41%)	4/76 (5.26%)	8/150 (5.33%)
Pain in extremity † 1	6/74 (8.11%)	6/76 (7.89%)	12/150 (8.00%)
Nervous system disorders
Dizziness † 1	10/74 (13.51%)	8/76 (10.53%)	18/150 (12.00%)
Headache † 1	18/74 (24.32%)	10/76 (13.16%)	28/150 (18.67%)
Paraesthesia † 1	1/74 (1.35%)	4/76 (5.26%)	5/150 (3.33%)
Psychiatric disorders
Insomnia † 1	8/74 (10.81%)	5/76 (6.58%)	13/150 (8.67%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	2/74 (2.70%)	4/76 (5.26%)	6/150 (4.00%)
Skin and subcutaneous tissue disorders
Alopecia † 1	2/74 (2.70%)	5/76 (6.58%)	7/150 (4.67%)
Dry skin † 1	2/74 (2.70%)	5/76 (6.58%)	7/150 (4.67%)
Erythema † 1	2/74 (2.70%)	4/76 (5.26%)	6/150 (4.00%)
Pruritus † 1	5/74 (6.76%)	6/76 (7.89%)	11/150 (7.33%)
Rash † 1	4/74 (5.41%)	2/76 (2.63%)	6/150 (4.00%)
Skin exfoliation † 1	3/74 (4.05%)	4/76 (5.26%)	7/150 (4.67%)
Vascular disorders
Hypertension † 1	11/74 (14.86%)	13/76 (17.11%)	24/150 (16.00%)
Hypotension † 1	4/74 (5.41%)	5/76 (6.58%)	9/150 (6.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (19.1)

Limitations and Caveats

All analyses in this study were descriptive in nature. No comparisons were made between the two arms, and no p-values are reported. For the primary and key-secondary, success was based on estimating the response rate (and 95% CI) in each arm.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights 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 or disclosure of trial results in their entirety.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300
• EMail: novartis.email@novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fleseriu M, Petersenn S, Biller BMK, Kadioglu P, De Block C, T'Sjoen G, Vantyghem MC, Tauchmanova L, Wojna J, Roughton M, Lacroix A, Newell-Price J. Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study. Clin Endocrinol (Oxf). 2019 Dec;91(6):776-785. doi: 10.1111/cen.14081. Epub 2019 Oct 1.

Lacroix A, Gu F, Gallardo W, Pivonello R, Yu Y, Witek P, Boscaro M, Salvatori R, Yamada M, Tauchmanova L, Roughton M, Ravichandran S, Petersenn S, Biller BMK, Newell-Price J; Pasireotide G2304 Study Group. Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial. Lancet Diabetes Endocrinol. 2018 Jan;6(1):17-26. doi: 10.1016/S2213-8587(17)30326-1. Epub 2017 Oct 12. Erratum in: Lancet Diabetes Endocrinol. 2018 Jan;6(1):e1.

Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing's disease or acromegaly. Pituitary. 2016 Oct;19(5):536-43. doi: 10.1007/s11102-016-0734-1. Review.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT01374906 History of Changes
• Other Study ID Numbers: CSOM230G2304; 2009-011128-70 ( EudraCT Number )
• First Submitted: June 14, 2011
• First Posted: June 16, 2011
• Results First Submitted: December 11, 2017
• Results First Posted: April 11, 2018
• Last Update Posted: May 22, 2018