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Hydrocortisone

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Pasireotide

Adrenocorticotropic Hormone

Melanocyte-Stimulating Hormones

beta-Endorphin

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Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms.

Pasireotide long-acting was administered as an intra-muscular depot intragluteal injection once every 28 days (±2 days). Patients were administered pasireotide long-acting 10 mg or 30 mg for four months, followed by either continuation of the starting dose, or dose up-titration (if mUFC was still \>1.5xULN unless titration was precluded by safety reasons).

pasireotide LAR

starting dose of 30 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of starting dose.

SOM230 LAR 30 mg

starting does of SOM230 LAR 10 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of the starting dose.

SOM230 LAR 10 mg

Novartis Pharmaceuticals

This is a randomized, double-blind, multicenter, phase III study to evaluate the safety and efficacy of 2 dosing regiments of Pasireotide long acting release (LAR) in patients with Cushing's disease.

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

A Randomized, Double-blind, Multicenter, Phase III Study to Evaluate the Efficacy and Safety of Pasireotide LAR in Patients With Cushing's Disease

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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.

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.

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

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

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

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

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.

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 to first achievement of attaining a mUFC ≤ 1.0 x ULN or at least a 50% reduction in mUFC from baseline by randomized groups.

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.

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

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

Change in blood pressure measurements from Baseline

Change in weight measurements from Baseline

Change in body composition: region measurements from Baseline

Change in waist circumference measurements from Baseline

Change in parameter measurements: cholesterol \& triglycerides from Baseline

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

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.

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

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

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

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.

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.

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.

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.

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.

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 30 mg of Pasireotide LAR.

30 mg Pasireotide LAR Dose

All Patients from both the 10 mg and 30 mg groups.

All Patients

Total

Age, Continuous

Sex: Female, Male

Caucasian

Asian

Black

Other

Race/Ethnicity, Customized

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

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.

Study Director

Percentage Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 Regardless of Dose Titration

Percentage of Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4

Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline

Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline

M7 - Controlled responder

M12 - Controlled responder

M24 - Controlled responder

M36 - Controlled responder

Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN

Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC

Month 7

Month 12

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.

Uncontrolled Resp @ M7: subset: M1 & 2

Uncontrolled Resp @ M7: subset: M1,2 & 3

Uncontrolled Resp @ M12: subset: M1 & 2

Uncontrolled Resp @ M12: subset: M1, 2 & 3

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

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 6

Month 18

Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points

Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time

Percentage Change From Baseline on Serum Cortisol Over Time

Supine systolic blood pressure (SBP)

Supine diastolic blood (DBP) pressure

Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure

Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI)

Actual Change From Baseline in Clinical Signs Over Time: Weight

Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region

Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference

Total cholesterol

HDL cholesterol

Triglycerides

Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides

Weight

Waist circumference

Body composition

Percentage Change From Baseline in Clinical Signs Over Time

Facial rubor

Hirsutism (females only)

Striae

Bruising

Supraclavicular fat pad

Dorsal fat pad

Muscle strength

Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs

stratum:1.5 x ULN to < 2.0 x ULN

stratum:2.0 x ULN to <= 5.0 x ULN

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.

Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline

Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points

Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points

Day 29

Day 57

Day 85

Day 113

Day 141

Day 169

Day 197

Day 225

Day 253

Day 281

Day 309

Day 337

These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).

5 mg Pasireotide LAR Dose

These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).

40 mg Pasireotide LAR Dose

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).

Spots Global Cancer Trial Database for mean urinary free cortisol