Trial Outcomes & Findings for Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing's Disease (NCT NCT01374906)

Last Updated: 2018-05-22

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

150 participants

Primary outcome timeframe

Month 7

Results posted on

2018-05-22

Participant Flow

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.

Participant milestones

Participant milestones
Measure	10 mg Pasireotide LAR Dose 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.	30 mg Pasireotide LAR Dose 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 Study STARTED	74	76
Overall Study DC Dur Core Phs at/Prior to Data Cutoff	24	22
Overall Study Completed Core Phase	50	54
Overall Study Completed Core/Did Not Enter Ext. Phase	10	13
Overall Study Completed Core Phase/Entered Ext. Phase	40	41
Overall Study DC Dur Ext Phs at/Prior to Data Cutoff	16	26
Overall Study Completed Extension Phase	24	15
Overall Study COMPLETED	34	28
Overall Study NOT COMPLETED	40	48

Reasons for withdrawal

Reasons for withdrawal
Measure	10 mg Pasireotide LAR Dose 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.	30 mg Pasireotide LAR Dose 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 Study Abnormal laboratory value(s)	0	3
Overall Study Administrative problems	2	2
Overall Study Adverse Event	10	11
Overall Study Death	0	2
Overall Study Protocol Violation	2	2
Overall Study Withdrawal by Subject	15	9
Overall Study Unsatisfactory therapeutic effect	11	19

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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 n=150 Participants Total of all reporting groups
Age, Continuous	38.3 years STANDARD_DEVIATION 12.52 • n=5 Participants	38.6 years STANDARD_DEVIATION 12.99 • n=7 Participants	38.5 years STANDARD_DEVIATION 12.72 • n=5 Participants
Sex: Female, Male Female	58 Participants n=5 Participants	60 Participants n=7 Participants	118 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	16 Participants n=7 Participants	32 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	39 Participants n=5 Participants	44 Participants n=7 Participants	83 Participants n=5 Participants
Race/Ethnicity, Customized Asian	27 Participants n=5 Participants	24 Participants n=7 Participants	51 Participants n=5 Participants
Race/Ethnicity, Customized Black	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Other	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: Month 7

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

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 Regardless of Dose Titration	41.9 percentage of participants Interval 30.51 to 53.94	40.8 percentage of participants Interval 29.65 to 52.67	—	—

SECONDARY outcome

Timeframe: Month 7

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage of Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4	28.4 percentage of participants Interval 18.5 to 40.05	31.6 percentage of participants Interval 21.39 to 43.25	—	—

SECONDARY outcome

Timeframe: baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36)

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

Actual change in mUFC (nmol/24h) from baseline by randomized groups.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline M7	-192.4 nmol/24h Standard Deviation 271.59	-234.3 nmol/24h Standard Deviation 362.86	—	—
Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline M12	-195.1 nmol/24h Standard Deviation 282.46	-247.6 nmol/24h Standard Deviation 387.05	—	—
Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline M24	-236.2 nmol/24h Standard Deviation 292.91	-265.2 nmol/24h Standard Deviation 313.47	—	—
Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline M36	-398.4 nmol/24h Standard Deviation 136.09	-164.6 nmol/24h Standard Deviation 66.76	—	—

SECONDARY outcome

Timeframe: M7, M12, M24, M36

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

Percentage change in mUFC (nmol/24h) from baseline by randomized groups.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline M7	-29.3 percentage change Standard Deviation 102.76	-33.2 percentage change Standard Deviation 61.37	—	—
Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline M12	-30.3 percentage change Standard Deviation 79.73	-31.1 percentage change Standard Deviation 78.41	—	—
Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline M24	-50.9 percentage change Standard Deviation 76.48	-51.2 percentage change Standard Deviation 35.41	—	—
Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline M36	-71.6 percentage change Standard Deviation 20.44	-48.8 percentage change Standard Deviation 11.36	—	—

SECONDARY outcome

Timeframe: M7, M12, M24, M36

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

Controlled responder: mUFC ≤ 1.0×ULN by randomized groups.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN M7 - Controlled responder	39.2 percentage of participants Interval 28.04 to 51.23	40.8 percentage of participants Interval 29.65 to 52.67	—	—
Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN M12 - Controlled responder	35.1 percentage of participants Interval 24.39 to 47.11	25.0 percentage of participants Interval 15.77 to 36.26	—	—
Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN M24 - Controlled responder	39.7 percentage of participants Interval 27.57 to 52.8	21.3 percentage of participants Interval 11.86 to 33.68	—	—
Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN M36 - Controlled responder	22.0 percentage of participants Interval 11.53 to 35.96	4.0 percentage of participants Interval 0.49 to 13.71	—	—

SECONDARY outcome

Timeframe: M7, M12, M24, M36

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

Controlled responder: mUFC ≤ 1.0×ULN. Partially controlled responder: at least 50% reduction in mUFC from Baseline, and mUFC \>1.0×ULN.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC M7	44.6 percentage of participants Interval 33.02 to 56.61	53.9 percentage of participants Interval 42.13 to 65.45	—	—
Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC M12	45.9 percentage of participants Interval 34.29 to 57.93	42.1 percentage of participants Interval 30.86 to 53.98	—	—
Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC M24	46.0 percentage of participants Interval 33.39 to 59.06	27.9 percentage of participants Interval 17.15 to 40.83	—	—
Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC M36	28.0 percentage of participants Interval 16.23 to 42.49	6.0 percentage of participants Interval 1.25 to 16.55	—	—

SECONDARY outcome

Timeframe: Month 7, Month 12

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
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. Month 7	25.7 percentage of participants Interval 16.22 to 37.16	31.6 percentage of participants Interval 21.39 to 43.25	—	—
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. Month 12	25.7 percentage of participants Interval 16.22 to 37.16	25.0 percentage of participants Interval 15.77 to 36.26	—	—

SECONDARY outcome

Timeframe: Month 7, Month12

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
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 Uncontrolled Resp @ M12: subset: M1 & 2	69.7 percentage of participants	69.7 percentage of participants	—	—
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 Uncontrolled Resp @ M7: subset: M1 & 2	60.6 percentage of participants	60.6 percentage of participants	—	—
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 Uncontrolled Resp @ M7: subset: M1,2 & 3	61.3 percentage of participants	65.5 percentage of participants	—	—
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 Uncontrolled Resp @ M12: subset: M1, 2 & 3	74.2 percentage of participants	72.4 percentage of participants	—	—

SECONDARY outcome

Timeframe: Momth 7, Month 12

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percent of Participants Attaining a mUFC ≤ 1.0 x ULN or at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points Month 7	86.2 Percentage of participants Interval 76.1 to 93.5	83.4 Percentage of participants Interval 72.6 to 91.8	—	—
Percent of Participants Attaining a mUFC ≤ 1.0 x ULN or at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points Month 12	90.1 Percentage of participants Interval 80.7 to 96.2	94.5 Percentage of participants Interval 81.0 to 99.4	—	—

SECONDARY outcome

Timeframe: Month 6, 12, 18

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points Month 12	84.0 Percentage of participants Interval 73.1 to 92.2	82.8 Percentage of participants Interval 71.5 to 91.5	—	—
Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points Month 6	78.0 Percentage of participants Interval 66.5 to 87.7	72.9 Percentage of participants Interval 61.2 to 83.4	—	—
Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points Month 18	84.0 Percentage of participants Interval 73.1 to 92.2	87.1 Percentage of participants Interval 74.6 to 95.3	—	—

SECONDARY outcome

Timeframe: Months 7, 12, 24 & 36

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

Percentage change in ACTH (pmol/L) from Baseline by randomized groups.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time M7	2.7 Percentage change Standard Deviation 57.14	-13.5 Percentage change Standard Deviation 46.75	—	—
Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time M12	-10.2 Percentage change Standard Deviation 57.57	-14.5 Percentage change Standard Deviation 38.72	—	—
Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time M24	-12.1 Percentage change Standard Deviation 43.51	2.5 Percentage change Standard Deviation 68.69	—	—
Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time M36	-15.4 Percentage change Standard Deviation 36.90	-0.6 Percentage change Standard Deviation 48.13	—	—

SECONDARY outcome

Timeframe: Months 7, 12, 24 & 36

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

Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage Change From Baseline on Serum Cortisol Over Time M7	-8.2 Percentage change Standard Deviation 37.83	-5.1 Percentage change Standard Deviation 40.20	—	—
Percentage Change From Baseline on Serum Cortisol Over Time M12	-12.1 Percentage change Standard Deviation 29.69	-0.4 Percentage change Standard Deviation 35.91	—	—
Percentage Change From Baseline on Serum Cortisol Over Time M24	-15.6 Percentage change Standard Deviation 30.67	-7.4 Percentage change Standard Deviation 38.37	—	—
Percentage Change From Baseline on Serum Cortisol Over Time M36	0.6 Percentage change Standard Deviation 55.67	-23.2 Percentage change Standard Deviation 31.19	—	—

SECONDARY outcome

Timeframe: Month 7

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

Change in blood pressure measurements from Baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure Supine systolic blood pressure (SBP)	-6.8 mmHg Standard Deviation 15.64	-4.6 mmHg Standard Deviation 14.51	—	—
Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure Supine diastolic blood (DBP) pressure	-4.8 mmHg Standard Deviation 12.06	-3.0 mmHg Standard Deviation 12.12	—	—

SECONDARY outcome

Timeframe: Month 7

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

Change in BMI measurements from Baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)	-0.7 kg/m2 Standard Deviation 1.60	-1.8 kg/m2 Standard Deviation 2.05	—	—

SECONDARY outcome

Timeframe: Month 7

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

Change in weight measurements from Baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change From Baseline in Clinical Signs Over Time: Weight	-1.8 kg Standard Deviation 4.16	-4.6 kg Standard Deviation 5.08	—	—

SECONDARY outcome

Timeframe: Month 7

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

Change in body composition: region measurements from Baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region	-1.0 percentage fat Standard Deviation 2.64	-1.8 percentage fat Standard Deviation 3.97	—	—

SECONDARY outcome

Timeframe: Month 7

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

Change in waist circumference measurements from Baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference	-1.6 cm Standard Deviation 8.47	-7.1 cm Standard Deviation 11.78	—	—

SECONDARY outcome

Timeframe: Month 7

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

Change in parameter measurements: cholesterol \& triglycerides from Baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides Total cholesterol	-0.5 mmol/L Standard Deviation 1.07	-0.4 mmol/L Standard Deviation 1.00	—	—
Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides HDL cholesterol	-0.1 mmol/L Standard Deviation 0.28	0 mmol/L Standard Deviation 0.32	—	—
Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides Triglycerides	0 mmol/L Standard Deviation 0.53	-0.2 mmol/L Standard Deviation 0.64	—	—

SECONDARY outcome

Timeframe: Month 7

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

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

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage Change From Baseline in Clinical Signs Over Time DBP	-4.7 Percentage change Standard Deviation 14.19	-2.6 Percentage change Standard Deviation 13.78	—	—
Percentage Change From Baseline in Clinical Signs Over Time BMI	-2.6 Percentage change Standard Deviation 5.26	-6.1 Percentage change Standard Deviation 6.94	—	—
Percentage Change From Baseline in Clinical Signs Over Time Weight	-2.6 Percentage change Standard Deviation 5.26	-6.1 Percentage change Standard Deviation 6.91	—	—
Percentage Change From Baseline in Clinical Signs Over Time SBP	-4.3 Percentage change Standard Deviation 11.46	-3.0 Percentage change Standard Deviation 10.18	—	—
Percentage Change From Baseline in Clinical Signs Over Time Waist circumference	-1.4 Percentage change Standard Deviation 8.60	-6.6 Percentage change Standard Deviation 10.06	—	—
Percentage Change From Baseline in Clinical Signs Over Time HDL	-6.7 Percentage change Standard Deviation 15.18	0.3 Percentage change Standard Deviation 20.91	—	—
Percentage Change From Baseline in Clinical Signs Over Time Total cholesterol	-7.2 Percentage change Standard Deviation 16.86	-6.6 Percentage change Standard Deviation 16.40	—	—
Percentage Change From Baseline in Clinical Signs Over Time Triglycerides	4.2 Percentage change Standard Deviation 39.54	-0.9 Percentage change Standard Deviation 39.61	—	—
Percentage Change From Baseline in Clinical Signs Over Time Body composition	-2.4 Percentage change Standard Deviation 6.68	-3.6 Percentage change Standard Deviation 10.47	—	—

SECONDARY outcome

Timeframe: Month 7

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs Striae	23.1 Percentage of participants	23.6 Percentage of participants	—	—
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs Facial rubor	32.7 Percentage of participants	53.6 Percentage of participants	—	—
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs Hirsutism (females only)	22.2 Percentage of participants	32.6 Percentage of participants	—	—
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs Bruising	25.0 Percentage of participants	14.3 Percentage of participants	—	—
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs Supraclavicular fat pad	40.4 Percentage of participants	28.6 Percentage of participants	—	—
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs Dorsal fat pad	28.8 Percentage of participants	40.0 Percentage of participants	—	—
Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs Muscle strength	8.9 Percentage of participants	4.5 Percentage of participants	—	—

SECONDARY outcome

Timeframe: Month 7

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

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

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
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. stratum:2.0 x ULN to <= 5.0 x ULN	36.7 percentage of participants Interval 23.42 to 51.71	35.3 percentage of participants Interval 22.43 to 49.93	—	—
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. stratum:1.5 x ULN to < 2.0 x ULN	52.0 percentage of participants Interval 31.31 to 72.2	52.0 percentage of participants Interval 31.31 to 72.2	—	—

SECONDARY outcome

Timeframe: Months 7, 12, 24 & 36

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

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline M7	35.1 percentage of participants Interval 24.39 to 47.11	43.4 percentage of participants Interval 32.08 to 55.29	—	—
Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline M12	35.1 percentage of participants Interval 24.39 to 47.11	38.2 percentage of participants Interval 27.25 to 50.02	—	—
Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline M24	83.3 percentage of participants Interval 62.62 to 95.26	57.1 percentage of participants Interval 28.86 to 82.34	—	—
Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline M36	100 percentage of participants Interval 63.06 to 100.0	33.33 percentage of participants Interval 0.84 to 90.57	—	—

SECONDARY outcome

Timeframe: 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)

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

Time to first achievement of a 5by randomized groups.0% reduction in mUFC from baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points M7	80.5 Percentage of participants Interval 69.7 to 89.3	73.4 Percentage of participants Interval 62.4 to 83.4	—	—
Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points M12	84.4 Percentage of participants Interval 74.0 to 92.3	80.7 Percentage of participants Interval 69.4 to 89.8	—	—

SECONDARY outcome

Timeframe: Months 6, 12 & 18

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

Duration of 50% reduction from baseline is defined as the period starting from the date of patient's first 50% reduction from baseline

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points M6	78.4 Percentage of participants Interval 66.6 to 88.3	77.8 Percentage of participants Interval 66.0 to 87.7	—	—
Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points M12	84.9 Percentage of participants Interval 73.7 to 93.1	83.7 Percentage of participants Interval 72.6 to 92.1	—	—
Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points M18	84.9 Percentage of participants Interval 73.7 to 93.1	83.7 Percentage of participants Interval 72.6 to 92.1	—	—

SECONDARY outcome

Timeframe: Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337

Population: 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).

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=65 Participants 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.	30 mg Pasireotide LAR Dose n=64 Participants 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.	5 mg Pasireotide LAR Dose n=5 Participants These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose n=44 Participants These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Pharmacokinetic (PK) Parameter: Ctrough Day 57	2.35 ng/mL Standard Deviation 1.15	7.82 ng/mL Standard Deviation 4.22	0.83 ng/mL Standard Deviation NA N/A = not enough patients on this day to derive data	—
Pharmacokinetic (PK) Parameter: Ctrough Day 85	2.39 ng/mL Standard Deviation 1.32	8.56 ng/mL Standard Deviation 4.26	1.03 ng/mL Standard Deviation 0.63	—
Pharmacokinetic (PK) Parameter: Ctrough Day 29	2.03 ng/mL Standard Deviation 1.25	7.63 ng/mL Standard Deviation 4.58	—	—
Pharmacokinetic (PK) Parameter: Ctrough Day 113	2.40 ng/mL Standard Deviation 1.11	8.31 ng/mL Standard Deviation 3.87	1.29 ng/mL Standard Deviation 0.24	—
Pharmacokinetic (PK) Parameter: Ctrough Day 141	2.47 ng/mL Standard Deviation 0.94	7.88 ng/mL Standard Deviation 4.00	1.04 ng/mL Standard Deviation 0.68	10.7 ng/mL Standard Deviation 4.91
Pharmacokinetic (PK) Parameter: Ctrough Day 169	2.47 ng/mL Standard Deviation 0.95	8.46 ng/mL Standard Deviation 3.51	2.01 ng/mL Standard Deviation 0.22	12.0 ng/mL Standard Deviation 5.08
Pharmacokinetic (PK) Parameter: Ctrough Day 197	2.88 ng/mL Standard Deviation 1.29	9.13 ng/mL Standard Deviation 4.25	0.72 ng/mL Standard Deviation 0.39	11.9 ng/mL Standard Deviation 5.87
Pharmacokinetic (PK) Parameter: Ctrough Day 225	2.68 ng/mL Standard Deviation 0.98	8.57 ng/mL Standard Deviation 4.70	1.19 ng/mL Standard Deviation 0.43	11.3 ng/mL Standard Deviation 5.18
Pharmacokinetic (PK) Parameter: Ctrough Day 253	2.87 ng/mL Standard Deviation 1.57	9.00 ng/mL Standard Deviation 4.93	1.77 ng/mL Standard Deviation 0.88	12.1 ng/mL Standard Deviation 5.21
Pharmacokinetic (PK) Parameter: Ctrough Day 281	3.36 ng/mL Standard Deviation 1.48	8.18 ng/mL Standard Deviation 4.23	1.24 ng/mL Standard Deviation 0.52	11.4 ng/mL Standard Deviation 5.85
Pharmacokinetic (PK) Parameter: Ctrough Day 309	2.50 ng/mL Standard Deviation 0.99	9.34 ng/mL Standard Deviation 5.61	0.66 ng/mL Standard Deviation NA N/A = not enough patients on this day to derive data	12.0 ng/mL Standard Deviation 4.58
Pharmacokinetic (PK) Parameter: Ctrough Day 337	3.07 ng/mL Standard Deviation 1.62	8.90 ng/mL Standard Deviation 4.37	1.91 ng/mL Standard Deviation 1.79	12.6 ng/mL Standard Deviation 6.21

SECONDARY outcome

Timeframe: Days 22, 106, 190

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=67 Participants 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.	30 mg Pasireotide LAR Dose n=69 Participants 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.	5 mg Pasireotide LAR Dose n=3 Participants These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose n=22 Participants These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Pharmacokinetic (PK) Parameter: Cmax Day 22 (M 0.75)	3.0 ng/mL Standard Deviation 1.50	8.2 ng/mL Standard Deviation 3.99	—	—
Pharmacokinetic (PK) Parameter: Cmax Day 106 (M 3.75)	3.3 ng/mL Standard Deviation 1.92	9.4 ng/mL Standard Deviation 3.72	1.7 ng/mL Standard Deviation 0.42	—
Pharmacokinetic (PK) Parameter: Cmax Day 190 (M6.75)	4.0 ng/mL Standard Deviation 1.73	10.0 ng/mL Standard Deviation 3.91	1.4 ng/mL Standard Deviation 0.78	12.1 ng/mL Standard Deviation 5.21

SECONDARY outcome

Timeframe: Months 7, 12, 24 & 36

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline M7	5.7 scores on a scale Standard Deviation 15.97	7.8 scores on a scale Standard Deviation 11.63	—	—
Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline M12	6.4 scores on a scale Standard Deviation 17.56	6.8 scores on a scale Standard Deviation 14.42	—	—
Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline M24	5.9 scores on a scale Standard Deviation 15.56	8.7 scores on a scale Standard Deviation 12.80	—	—
Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline M36	1.4 scores on a scale Standard Deviation 9.10	14.6 scores on a scale Standard Deviation 5.10	—	—

SECONDARY outcome

Timeframe: Months 7, 12 & 24

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

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.

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change in SF-12v2 Score From Baseline - Mental Component Summary M7	4.1 scores on a scale Standard Deviation 8.81	4.3 scores on a scale Standard Deviation 8.05	—	—
Actual Change in SF-12v2 Score From Baseline - Mental Component Summary M12	2.3 scores on a scale Standard Deviation 9.97	3.3 scores on a scale Standard Deviation 8.26	—	—
Actual Change in SF-12v2 Score From Baseline - Mental Component Summary M24	3.3 scores on a scale Standard Deviation 10.43	6.4 scores on a scale Standard Deviation 2.53	—	—

SECONDARY outcome

Timeframe: Months 7, 12 & 24

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

Outcome measures

Outcome measures
Measure	10 mg Pasireotide LAR Dose n=74 Participants 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.	30 mg Pasireotide LAR Dose n=76 Participants 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.	5 mg Pasireotide LAR Dose These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).	40 mg Pasireotide LAR Dose These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).
Actual Change in SF-12v2 Score From Baseline - Physical Component Summary M7	1.9 scores on a scale Standard Deviation 8.50	-0.8 scores on a scale Standard Deviation 7.46	—	—
Actual Change in SF-12v2 Score From Baseline - Physical Component Summary M12	4.9 scores on a scale Standard Deviation 5.56	-0.5 scores on a scale Standard Deviation 6.73	—	—
Actual Change in SF-12v2 Score From Baseline - Physical Component Summary M24	5.3 scores on a scale Standard Deviation 4.32	-1.1 scores on a scale Standard Deviation 5.54	—	—

Adverse Events

10 mg Pasireotide LAR Dose

Serious events: 22 serious events

Other events: 73 other events

Deaths: 0 deaths

30 mg Pasireotide LAR Dose

Serious events: 19 serious events

Other events: 76 other events

Deaths: 0 deaths

All Patients

Serious events: 41 serious events

Other events: 149 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER