SEASCAPE: An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01582061
• Collaborator: (none)
• Enrollment: 104
• Locations: 65
• Arms: 2
• Actual Duration (Months): 65.4
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study provided access to pasireotide sc in patients with Cushing's disease.and provided additional information for safety and efficacy of pasireotide s.c.

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

Detailed Description

Purpose of this study was to give access to pasireotide sc for patients with Cushing's disease as no medical treatment for Cushing's disease was approved at the time of the study initiation. The study population consisted of patients with persistent or recurrent Cushing's disease or patients with de novo Cushing's disease that were not considered candidates for pituitary surgery (poor surgery candidates, surgically unapproachable tumor, patients with no visible pituitary tumor, patients who refused surgery). A confirmed Cushing's disease diagnosis was required.

Study Design

• Study Type: Interventional
• Actual Enrollment: 104 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease (Seascape).
• Actual Study Start Date: Aug 16, 2011
• Actual Primary Completion Date: Jan 26, 2017
• Actual Study Completion Date: Jan 26, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pasireotide 600 μg Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Drug: Pasireotide sub-cutaneous; Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg, 600 μg, or 300 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg and 600 μg for glucose impaired metabolism patients; Other Names: SOM230 sub-cutaneous
Experimental: Pasireotide 900 μg Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Drug: Pasireotide sub-cutaneous; Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg, 600 μg, or 300 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg and 600 μg for glucose impaired metabolism patients; Other Names: SOM230 sub-cutaneous

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients With a Drug-related Adverse Event That is Recorded as Grade 3 or 4 or as a Serious Adverse Event (SAE) [Baseline up to approximately 256 weeks]

   Only AEs occurring on or after the start of study treatment and no more than 28 days after the discontinuation of study treatment. A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. A patient with multiple severity grades for an AE while on a treatment, is only counted under the maximum grade.

Secondary Outcome Measures

1. Percentage of Patients With Mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN) [Baseline, week 12, 24 and 48]

   The 24h-UFC concentration results from three samples during screening were averaged to obtain baseline. After baseline, mean 24h UFC was determined at week 24. At Week 4, 8, 16 and 20, mean 24h UFC was determined from two 24 hour urine collections collected on two consecutive days occurring before the visit. At Week 12, 24 and 48, the mean 24h-UFC from three 24 hour urine collections, collected over the week before the visit, was determined. After Week 24, the mean 24h UFC was determined at 12-week intervals until end of study visit, from two 24 hour collections during two consecutive days prior to each respective visit (except at Week 48). UFC was determined by liquid chromatography tandem mass spectroscopy (LC/MS/MS). The normal ranges were determined by the central laboratory's own reference range. All samples, including screening samples, were analyzed by a central laboratory.

2. Percentage of Patients Achieving a Reduction of Mean UFC ≥ 50% From Baseline [Baseline, week 12, 24 and 48]

   The 24h-UFC concentration results from three samples during screening were averaged to obtain baseline. After baseline, mean 24h UFC was determined at week 24. At Week 4, 8, 16 and 20, mean 24h UFC was determined from two 24 hour urine collections collected on two consecutive days occurring before the visit. At Week 12, 24 and 48, the mean 24h-UFC from three 24 hour urine collections, collected over the week before the visit, was determined. After Week 24, the mean 24h UFC was determined at 12-week intervals until end of study visit, from two 24 hour collections during two consecutive days prior to each respective visit (except at Week 48). UFC was determined by liquid chromatography tandem mass spectroscopy (LC/MS/MS). The normal ranges were determined by the central laboratory's own reference range. All samples, including screening samples, were analyzed by a central laboratory.

3. Percent Change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) Scores [Baseline, week 12, 24 and 48]

   A 12-item Cushing's syndrome HRQoL questionnaire (CushingQoL, cf. Webb et al 2008) was implemented and patients who completed 9 or more items at a visit were considered evaluable for that visit. The standardized scores were calculated as follows: 1) Obtain raw scores, denoted by X, as the sum of all the ratings on all the HRQoL questions for a single patient and the score can range from 12 (worst HRQoL) to 60 points (best HRQoL). Therefore, the lower the score, greater the negative impact on HRQoL and 2) obtain standardized score, Y, for a single patient • Y = 100 (X-12) / (60-12) = 100 (X-12)/48. For example, if a patient answers all 12 items with 'Sometimes' or 'Somewhat', X = 36 and Y = 100 ∙ 24/48 = 50 The WPAI-GH questionnaire was used to assess work productivity and activity impairment. However, there was very limited baseline data and therefore the results and outcomes of the objective, 'change from baseline in WPAI-GH scores' are not included.

4. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Blood Pressure (BP) [Baseline, week 12, 24 and 48]

   Standing systolic and diastolic BP based on 1 assessment and sitting systolic and diastolic BP was mean of 3 assessments.

5. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Pulse [Baseline, week 12, 24 and 48]

   Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)*100

6. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Temperature [Baseline week 12, 24 and 48]

   degrees celius

7. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Body Mass Index (BMI) [Baseline, week 12, 24 and 48]

   Percent change in patients reducing by at least one class level. Class levels: <25.0, 25.0 to <30.0, ≥ 30.0. Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)*100

8. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Weight [Baseline, week 12, 24 and 48]

   Clinically relevant threshold (at any time point) was reduction of ≥ 5%

9. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Muscle Strength [Baseline, week 12, 24 and 48]

   Direct observation of ability to stand unaided: 0=able to stand easily with arms extended, 1=able to stand after several efforts without using arms as assistance, 2=able to stand only by using arms as assistance 3=completely unable to stand

10. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Waist Circumference [Baseline, week 12, 24 and 48]

    Clinically relevant threshold (at any time point). Reduction of ≥ 5%, Reduction of ≥ 10%

11. Percent Change in Cushing's Disease Clinical Signs and Symptoms - Hirsutism [Baseline, week 12, 24 and 48]

    Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)*100. Ferriman-Gallway scoring was used: 0=minimum and 36 was maximum in females only.

12. Percent Change From Baseline in Growth Hormone (GH) Values [Baseline, week 12, 24 and 48]

    Descriptive summary of the effect of pasireotide on GH.

13. Percent Change From Baseline in Insulin Growth Factor - 1 (IGF - 1) Values [Baseline, week 12, 24 and 48]

    Descriptive summary of the effect of pasireotide on IGF-1

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Written informed consent obtained prior to any screening procedures

2. Male or female patients aged 18 years or greater

3. Patients with confirmed diagnosis of Cushing's disease as evidenced by mean urinary free cortisol of three 24-hour urine samples collected during the 3-week screening period above the upper limit of the laboratory normal range morning plasma ACTH within the normal or above normal range either MRI confirmation of pituitary adenoma (greater than or equal to 0.6 cm), or inferior petrosal sinus gradient >3 after CRH stimulation for those patients with a microadenoma less than 0.6 cm, or for patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma.

4. Patients with de novo Cushing's disease must not be considered as candidates for pituitary surgery (i.e. poor surgical candidates, surgically unapproachable tumors, patients with no visible pituitary tumor, patients who refuse to have surgical treatment)

5. Karnofsky performance status >60 (i.e. requires occasional assistance, but is able to care for most of his personal needs)

6. For patients on previous medical treatment for Cushing's disease the following washout periods must be completed before screening assessments are performed

• Inhibitors of steroidogenesis (e.g. ketoconazole, metyrapone, rosiglitazone): 1 week

• Dopamine agonists (e.g. bromocriptine, cabergoline): 4 weeks

• Mitotane: 6 months

• Octreotide LAR and Lanreotide autogel: 8 weeks

• Lanreotide SR: 4 weeks

• Octreotide (immediate release formulation): 1 week

• Glucocorticoid receptor inhibitor (mifepristone): 4 weeks

Exclusion criteria:

1. Radiotherapy of the pituitary <4 weeks before screening or patient who has not recovered from side effects

2. Patients with compression of the optic chiasm causing acute clinically significant visual field defect

3. Patients with Cushing's syndrome due to ectopic ACTH secretion

4. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia

5. Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)

6. Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)

7. Patients who have undergone major surgery within 1 month prior to screening

8. Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be included)

9. Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%

10. Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade AV block, history of acute MI less than one year prior to study entry

• QTcF >450 msec at screening

• History of syncope or family history of idiopathic sudden death

• Risk factors for Torsades de Pointes such as uncorrected hypokalemia, uncorrected hypomagnesemia, cardiac failure

• Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism, concomitant medication(s) with known risk for TdP

1. Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with ALT or AST more than 2 x ULN, serum creatinine >2.0 x ULN, serum bilirubin >1.5 x ULN, serum albumin < 0.67 x LLN at screening

2. Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as

• History of immunocompromise, including a positive HIV test result (Elisa and Western blot). An HIV test will not be required, however, previous medical history will be reviewed

• Presence of active or suspected acute or chronic uncontrolled infection

• History of, or current alcohol misuse/abuse in the 12 month period prior to screening

1. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for one month after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)

2. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with pasireotide

3. Known hypersensitivity to somatostatin analogues

4. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study

5. Patients with presence of Hepatitis B surface antigen (HbsAg)

6. Patients with presence of Hepatitis C antibody test (anti-HCV)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Advanced Research, LLC	Peoria	Arizona	United States	85381
2	St Josephs Hospital & Medical Center St Joes	Phoenix	Arizona	United States	85013
3	University of California at Los Angeles UCLA Tiverton	Los Angeles	California	United States	90095
4	LA Biomedical Research at Harbor UCLA Medical Center	Torrance	California	United States	90502
5	Emory University School of Medicine	Atlanta	Georgia	United States	30322
6	John H Stroger Jr Hospital of Cook County	Chicago	Illinois	United States	60644
7	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
8	Diabetes and Endocrinology Associates, PC	Omaha	Nebraska	United States	68131
9	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
10	University of New Mexico Hospital UNM	Albuquerque	New Mexico	United States	87106
11	Mount Sinai School of Medicine	New York	New York	United States	10029
12	Oregon Health and Science University OHSU 5	Portland	Oregon	United States	97239
13	University of Pennsylvania Medical Center Univ Penn	Philadelphia	Pennsylvania	United States	19104
14	Allegheny Endocrinology Associates	Pittsburgh	Pennsylvania	United States	15212
15	Mid South Endocrine Associates	Nashville	Tennessee	United States	37203
16	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212
17	Swedish Cancer Institute Swedish Cancer Institute (SC)	Seattle	Washington	United States	98104
18	Novartis Investigative Site	Fortaleza	CE	Brazil	04636-000
19	Novartis Investigative Site	Londrina	PR	Brazil	86015-520
20	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	21941-913
21	Novartis Investigative Site	Porto Alegre	RS	Brazil	90560-030
22	Novartis Investigative Site	Joinville	SC	Brazil	89201260
23	Novartis Investigative Site	Sao Paulo	SP	Brazil	05403 000
24	Novartis Investigative Site	São Paulo	SP	Brazil	04029-000
25	Novartis Investigative Site	Prague 2	Czech Republic	Czechia	128 00
26	Novartis Investigative Site	Aachen		Germany	52074
27	Novartis Investigative Site	Augsburg		Germany	86150
28	Novartis Investigative Site	Berlin		Germany	10098
29	Novartis Investigative Site	Berlin		Germany	13353
30	Novartis Investigative Site	Erlangen		Germany	91054
31	Novartis Investigative Site	Frankfurt		Germany	60329
32	Novartis Investigative Site	Frankfurt		Germany	60590
33	Novartis Investigative Site	Goettingen		Germany	37075
34	Novartis Investigative Site	Hamburg		Germany	22587
35	Novartis Investigative Site	Heidelberg		Germany	69120
36	Novartis Investigative Site	Leipzig		Germany	04103
37	Novartis Investigative Site	Mainz		Germany	55131
38	Novartis Investigative Site	Marburg		Germany	35039
39	Novartis Investigative Site	Muenchen		Germany	80804
40	Novartis Investigative Site	Oldenburg		Germany	26122
41	Novartis Investigative Site	Wurzburg		Germany	97080
42	Novartis Investigative Site	Athens	GR	Greece	115 27
43	Novartis Investigative Site	Thessaloniki	GR	Greece	546 42
44	Novartis Investigative Site	Athens		Greece	106 76
45	Novartis Investigative Site	Thessaloniki		Greece	546 36
46	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	02447
47	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	06351
48	Novartis Investigative Site	Seoul		Korea, Republic of	03080
49	Novartis Investigative Site	Seoul		Korea, Republic of	03722
50	Novartis Investigative Site	Ashrafieh		Lebanon	166830
51	Novartis Investigative Site	Bucharest		Romania	011461
52	Novartis Investigative Site	Bucuresti		Romania	011863
53	Novartis Investigative Site	Cluj		Romania	400006
54	Novartis Investigative Site	Iasi		Romania	700106
55	Novartis Investigative Site	Moscow		Russian Federation	129110
56	Novartis Investigative Site	Cordoba	Andalucia	Spain	14004
57	Novartis Investigative Site	Granada	Andalucia	Spain	18003
58	Novartis Investigative Site	Badalona	Catalunya	Spain	08916
59	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46014
60	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
61	Novartis Investigative Site	Orense	Galicia	Spain	32005
62	Novartis Investigative Site	Pontevedra	Galicia	Spain	36071
63	Novartis Investigative Site	Palma De Mallorca	Islas Baleares	Spain	07120
64	Novartis Investigative Site	Bangkok		Thailand	10330
65	Novartis Investigative Site	Songkla		Thailand	90110

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 10, 2017
• Study Protocol - Nov 13, 2015

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01582061
• Other Study ID Numbers: CSOM230B2406
• First Posted: Apr 20, 2012
• Last Update Posted: Jun 19, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Novartis Pharmaceuticals: Cushing's disease; Hormone disorder; Cortisol; Adrenocorticotropic hormone; Pituitary tumor; SOM230; adult
• Additional relevant MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Pasireotide

Study Results

Participant Flow

Pre-assignment Detail	After a 21-day screening period, patients who met the inclusion/exclusion criteria received pasireotide subcutaneous twice a day (BID)

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
Period Title: Overall Study
STARTED	49	55
COMPLETED	21	19
NOT COMPLETED	28	36

Baseline Characteristics

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	Total
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Total of all reporting groups
Overall Participants	49	55	104
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.5 (13.14)	39.9 (12.55)	42.5 (13.07)
Sex: Female, Male (Count of Participants)
Female	37 75.5%	47 85.5%	84 80.8%
Male	12 24.5%	8 14.5%	20 19.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	6 12.2%	15 27.3%	21 20.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 6.1%	2 3.6%	5 4.8%
White	39 79.6%	36 65.5%	75 72.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2%	2 3.6%	3 2.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients With a Drug-related Adverse Event That is Recorded as Grade 3 or 4 or as a Serious Adverse Event (SAE)
Description	Only AEs occurring on or after the start of study treatment and no more than 28 days after the discontinuation of study treatment. A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. A patient with multiple severity grades for an AE while on a treatment, is only counted under the maximum grade.
Time Frame	Baseline up to approximately 256 weeks

Outcome Measure Data

Analysis Population Description

Three additional arms were created to display subset of subjects with specific criteria.

Arm/Group Title	600 µg Bid - All Grades	600 μg - Grades 3/4	900 μg - All Grades	900 μg - Grades 3/4	All Patients - All Grades	All Patients - Grades 3/4
Arm/Group Description	All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Adverse event grades 3 and 4. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients	All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Adverse event grades 3 and 4. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg	All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.	All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.
Measure Participants	49	49	55	55	104	104
Any primary system organ class	53.1 108.4%	53.1 96.5%	29.1 28%	27.3 NaN	40.4 NaN	39.4 NaN
Metabolism and nutrition disorders	26.5 54.1%	26.5 48.2%	12.7 12.2%	10.9 NaN	19.2 NaN	18.3 NaN
Gastrointestinal disorders	18.4 37.6%	18.4 33.5%	7.3 7%	7.3 NaN	12.5 NaN	12.5 NaN
Investigations	8.2 16.7%	8.2 14.9%	3.6 3.5%	3.6 NaN	5.8 NaN	5.8 NaN
Hepatobiliary disorders	2.0 4.1%	2.0 3.6%	5.5 5.3%	5.5 NaN	3.8 NaN	3.8 NaN
Endocrine disorders	6.1 12.4%	6.1 11.1%	0 0%	0 NaN	2.9 NaN	2.9 NaN
Gen disorders,admin site conditions	4.1 8.4%	4.1 7.5%	0 0%	0 NaN	1.9 NaN	1.9 NaN
Ear and labyrinth disorders	2.0 4.1%	2.0 3.6%	0 0%	0 NaN	1.0 NaN	1.0 NaN
Infections and infestations	2.0 4.1%	2.0 3.6%	0 0%	0 NaN	1.0 NaN	1.0 NaN
Musculoskeletal and connective tissue disorders	2.0 4.1%	2.0 3.6%	0 0%	0 NaN	1.0 NaN	1.0 NaN
Neoplasms benign, malignant and unspecified	2.0 4.1%	2.0 3.6%	0 0%	0 NaN	1.0 NaN	1.0 NaN
Nervous system disorders	2.0 4.1%	2.0 3.6%	0 0%	0 NaN	1.0 NaN	1.0 NaN
Psychiatric disorders	0 0%	0 0%	1.8 1.7%	1.8 NaN	1.0 NaN	1.0 NaN
Respiratory, thoracic, mediastinal disorders	0 0%	0 0%	1.8 1.7%	0 NaN	1.0 NaN	0 NaN

2. Secondary Outcome

Title	Percentage of Patients With Mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)
Description	The 24h-UFC concentration results from three samples during screening were averaged to obtain baseline. After baseline, mean 24h UFC was determined at week 24. At Week 4, 8, 16 and 20, mean 24h UFC was determined from two 24 hour urine collections collected on two consecutive days occurring before the visit. At Week 12, 24 and 48, the mean 24h-UFC from three 24 hour urine collections, collected over the week before the visit, was determined. After Week 24, the mean 24h UFC was determined at 12-week intervals until end of study visit, from two 24 hour collections during two consecutive days prior to each respective visit (except at Week 48). UFC was determined by liquid chromatography tandem mass spectroscopy (LC/MS/MS). The normal ranges were determined by the central laboratory's own reference range. All samples, including screening samples, were analyzed by a central laboratory.
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

LOCF Week 24: last available mean 24h-UFC of at least two samples between and including week 12 and week 24; LOCF Week 48: last available mean 24h-UFC of at least two samples between and including week 12 and week 48. Two-sided 95% confidence intervals for proportions are calculated using the exact method

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Week 12	77.8 158.8%	38.5 70%	54.5 52.4%
Week 24	68.2 139.2%	29.2 53.1%	47.8 46%
Week 48	70.0 142.9%	18.2 33.1%	42.9 41.3%
Week 24 (LOCF)	54.1 110.4%	28.6 52%	39.5 38%
Week 48 (LOCF)	51.4 104.9%	22.4 40.7%	34.9 33.6%

3. Secondary Outcome

Title	Percentage of Patients Achieving a Reduction of Mean UFC ≥ 50% From Baseline
Description	The 24h-UFC concentration results from three samples during screening were averaged to obtain baseline. After baseline, mean 24h UFC was determined at week 24. At Week 4, 8, 16 and 20, mean 24h UFC was determined from two 24 hour urine collections collected on two consecutive days occurring before the visit. At Week 12, 24 and 48, the mean 24h-UFC from three 24 hour urine collections, collected over the week before the visit, was determined. After Week 24, the mean 24h UFC was determined at 12-week intervals until end of study visit, from two 24 hour collections during two consecutive days prior to each respective visit (except at Week 48). UFC was determined by liquid chromatography tandem mass spectroscopy (LC/MS/MS). The normal ranges were determined by the central laboratory's own reference range. All samples, including screening samples, were analyzed by a central laboratory.
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

LOCF Week 24: last available mean 24h-UFC of at least two samples between and including week 12 and week 24; LOCF Week 48: last available mean 24h-UFC of at least two samples between and including week 12 and week 48. Two-sided 95% confidence intervals for proportions are calculated using the exact method

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Week 12	74.1 151.2%	48.7 88.5%	59.1 56.8%
Week 24	68.2 139.2%	33.3 60.5%	50.00 48.1%
Week 48	60.0 122.4%	54.5 99.1%	57.1 54.9%
Week 24 (LOCF)	56.8 115.9%	38.8 70.5%	46.5 44.7%
Week 48 (LOCF)	51.4 104.9%	42.9 78%	46.5 44.7%

4. Secondary Outcome

Title	Percent Change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) Scores
Description	A 12-item Cushing's syndrome HRQoL questionnaire (CushingQoL, cf. Webb et al 2008) was implemented and patients who completed 9 or more items at a visit were considered evaluable for that visit. The standardized scores were calculated as follows: 1) Obtain raw scores, denoted by X, as the sum of all the ratings on all the HRQoL questions for a single patient and the score can range from 12 (worst HRQoL) to 60 points (best HRQoL). Therefore, the lower the score, greater the negative impact on HRQoL and 2) obtain standardized score, Y, for a single patient • Y = 100 (X-12) / (60-12) = 100 (X-12)/48. For example, if a patient answers all 12 items with 'Sometimes' or 'Somewhat', X = 36 and Y = 100 ∙ 24/48 = 50 The WPAI-GH questionnaire was used to assess work productivity and activity impairment. However, there was very limited baseline data and therefore the results and outcomes of the objective, 'change from baseline in WPAI-GH scores' are not included.
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Only patients who completed at least 9 questions on questionnaire were included for that visit.

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	47	54	101
Week 12	21.3 (47.03)	100.8 (252.25)	67.1 (197.09)
Week 24	36.7 (59.25)	119.7 (321.61)	82.3 (243.19)
Week 48	24.0 (37.76)	42.3 (60.75)	34.4 (52.29)

5. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Blood Pressure (BP)
Description	Standing systolic and diastolic BP based on 1 assessment and sitting systolic and diastolic BP was mean of 3 assessments.
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Sitting systolic Week 12	-6.8 (12.04)	-1.4 (14.40)	-3.8 (13.61)
Sitting systolic Week 24	-7.4 (8.97)	-5.7 (11.09)	-6.5 (10.13)
Sitting systolic Week 48	-5.1 (8.57)	-4.7 (12.55)	-4.9 (10.87)
Standing systolic Week 12	-7.9 (12.49)	-3.6 (15.38)	-5.5 (14.27)
Standing systolic Week 24	-10.9 (10.30)	-6.7 (14.09)	-8.6 (12.62)
Standing systolic Week 48	-6.5 (9.45)	-4.4 (13.86)	-5.3 (12.10)
Sitting diastolic Week 12	-4.6 (15.13)	-0.2 (14.40)	-2.1 (14.79)
Sitting diastolic Week 24	-6.2 (7.29)	-3.8 (15.83)	-4.9 (12.65)
Sitting diastolic Week 48	-3.3 (10.38)	-4.3 (13.93)	-3.8 (12.37)
Standing diastolic Week 12	-5.5 (16.02)	-1.9 (17.63)	-3.5 (16.93)
Standing diastolic Week 24	-7.6 (10.30)	-5.3 (16.74)	-6.3 (14.18)
Standing diastolic Week 48	-2.1 (13.78)	-4.4 (14.13)	-3.4 (13.83)

6. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Pulse
Description	Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)*100
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Sitting pulse Week 12	2.3 (18.93)	-7.5 (11.50)	-3.2 (15.87)
Sitting pulse Week 24	-1.8 (17.05)	-2.6 (18.07)	-2.2 (17.46)
Sitting pulse Week 48	2.9 (16.39)	3.7 (15.46)	3.3 (15.65)

7. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Temperature
Description	degrees celius
Time Frame	Baseline week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	600 µg Bid - All Grades	900 μg - All Grades	All Patients - All Grades
Arm/Group Description	All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.
Measure Participants	49	55	104
Week 12	0.1 (1.26)	-0.3 (1.06)	-0.1 (1.17)
Week 24	-0.1 (1.15)	-0.1 (1.26)	-0.1 (1.20)
Week 48	0.03 (1.47)	-0.1 (1.19)	0.1 (1.31)

8. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Body Mass Index (BMI)
Description	Percent change in patients reducing by at least one class level. Class levels: <25.0, 25.0 to <30.0, ≥ 30.0. Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)*100
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Week 12	-4.2 (3.70)	-4.8 (5.38)	-4.5 (4.69)
Week 24	-7.3 (5.46)	-5.2 (6.51)	-6.1 (6.10)
Week 48	-8.0 (6.82)	-6.3 (7.88)	-7.0 (7.39)

9. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Weight
Description	Clinically relevant threshold (at any time point) was reduction of ≥ 5%
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Week 12	-4.2 (3.70)	-4.8 (5.38)	-4.5 (4.69)
Week 24	-7.3 (5.46)	-5.2 (6.51)	-6.1 (6.10)
Week 48	-8.0 (6.82)	-6.3 (7.88)	-7.0 (7.39)

10. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Muscle Strength
Description	Direct observation of ability to stand unaided: 0=able to stand easily with arms extended, 1=able to stand after several efforts without using arms as assistance, 2=able to stand only by using arms as assistance 3=completely unable to stand
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Week 12	-34.6 (62.53)	-53.7 (46.98)	-42.4 (56.28)
Week 24	-28.6 (48.80)	-47.6 (50.40)	-38.1 (48.67)
Week 48	-30.0 (44.72)	-75.0 (50.0)	-50.0 (50.00)

11. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Waist Circumference
Description	Clinically relevant threshold (at any time point). Reduction of ≥ 5%, Reduction of ≥ 10%
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	49	55	104
Week 12	-2.0 (4.29)	-2.9 (6.70)	-2.5 (5.72)
Week 24	-5.8 (6.28)	-3.1 (5.48)	-4.4 (5.96)
Week 48	-5.1 (5.74)	-4.1 (5.64)	-4.6 (5.62)

12. Secondary Outcome

Title	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Hirsutism
Description	Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)*100. Ferriman-Gallway scoring was used: 0=minimum and 36 was maximum in females only.
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	37	47	84
Week 12	-12.2 (24.57)	-8.2 (35.30)	-10.0 (30.88)
Week 24	-21.2 (32.72)	-16.2 (46.99)	18.4 (40.79)
Week 48	-18.2 (30.12)	9.6 (143.83)	-2.2 (110.20)

13. Secondary Outcome

Title	Percent Change From Baseline in Growth Hormone (GH) Values
Description	Descriptive summary of the effect of pasireotide on GH.
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	48	55	103
Week 12	-17.3 (109.89)	-20.90 (156.60)	-19.3 (137.33)
Week 24	-22.2 (62.43)	-26.2 (105.44)	-24.4 (88.70)
Week 48	23.1 (127.30)	-1.0 (134.97)	9.7 (130.32)

14. Secondary Outcome

Title	Percent Change From Baseline in Insulin Growth Factor - 1 (IGF - 1) Values
Description	Descriptive summary of the effect of pasireotide on IGF-1
Time Frame	Baseline, week 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Number of patients with available data differed at visits

Arm/Group Title	Pasireotide 600 μg	Pasireotide 900 μg	All Patients
Arm/Group Description	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.	Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day	Patients received pasireotide 600 μg or 900 μg BID
Measure Participants	48	53	101
Week 12	-53.4 (23.66)	-57.8 (23.93)	-55.9 (23.76)
Week 24	-49.2 (26.56)	-56.2 (26.55)	-53.1 (26.53)
Week 48	-41.8 (35.72)	-52.1 (21.87)	-47.6 (28.71)

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 256 weeks
Adverse Event Reporting Description	Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator
Arm/Group Title	600 µg Bid		900 µg Bid		All Patients
Arm/Group Description	600 µg bid		900 µg bid		All patients
All Cause Mortality
	600 µg Bid		900 µg Bid		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Serious Adverse Events
	600 µg Bid		900 µg Bid		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/49 (26.5%)		17/55 (30.9%)		30/104 (28.8%)
Blood and lymphatic system disorders
Anaemia	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Cardiac disorders
Atrial fibrillation	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Endocrine disorders
Adrenal insufficiency	1/49 (2%)		0/55 (0%)		1/104 (1%)
Glucocorticoid deficiency	1/49 (2%)		0/55 (0%)		1/104 (1%)
Hyperprolactinaemia	1/49 (2%)		0/55 (0%)		1/104 (1%)
Pituitary-dependent Cushing's syndrome	1/49 (2%)		0/55 (0%)		1/104 (1%)
Gastrointestinal disorders
Abdominal pain	1/49 (2%)		0/55 (0%)		1/104 (1%)
Diarrhoea	2/49 (4.1%)		1/55 (1.8%)		3/104 (2.9%)
Gastrointestinal ulcer	1/49 (2%)		0/55 (0%)		1/104 (1%)
Pancreatitis	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Pancreatitis necrotising	1/49 (2%)		0/55 (0%)		1/104 (1%)
General disorders
Death	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Drug ineffective	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Hepatobiliary disorders
Bile duct stone	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Cholangitis acute	1/49 (2%)		0/55 (0%)		1/104 (1%)
Cholecystitis acute	0/49 (0%)		3/55 (5.5%)		3/104 (2.9%)
Cholelithiasis	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Hepatic lesion	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Infections and infestations
Cellulitis	1/49 (2%)		0/55 (0%)		1/104 (1%)
Dengue fever	1/49 (2%)		0/55 (0%)		1/104 (1%)
Meningitis	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Pneumonia	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Investigations
Blood cortisol increased	1/49 (2%)		0/55 (0%)		1/104 (1%)
Lipase abnormal	1/49 (2%)		0/55 (0%)		1/104 (1%)
Transaminases increased	1/49 (2%)		0/55 (0%)		1/104 (1%)
Weight increased	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Metabolism and nutrition disorders
Diabetes mellitus	2/49 (4.1%)		1/55 (1.8%)		3/104 (2.9%)
Hyperglycaemia	2/49 (4.1%)		0/55 (0%)		2/104 (1.9%)
Hypoglycaemia	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Hypokalaemia	0/49 (0%)		2/55 (3.6%)		2/104 (1.9%)
Type 2 diabetes mellitus	1/49 (2%)		0/55 (0%)		1/104 (1%)
Musculoskeletal and connective tissue disorders
Myalgia	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign	1/49 (2%)		0/55 (0%)		1/104 (1%)
Nervous system disorders
Headache	1/49 (2%)		0/55 (0%)		1/104 (1%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/49 (2%)		0/55 (0%)		1/104 (1%)
Psychiatric disorders
Suicide attempt	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/49 (2%)		0/55 (0%)		1/104 (1%)
Pulmonary embolism	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Rhinorrhoea	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Vascular disorders
Embolism venous	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Venous thrombosis	0/49 (0%)		1/55 (1.8%)		1/104 (1%)
Other (Not Including Serious) Adverse Events
	600 µg Bid		900 µg Bid		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/49 (100%)		54/55 (98.2%)		103/104 (99%)
Cardiac disorders
Bradycardia	2/49 (4.1%)		3/55 (5.5%)		5/104 (4.8%)
Sinus bradycardia	4/49 (8.2%)		1/55 (1.8%)		5/104 (4.8%)
Endocrine disorders
Adrenal insufficiency	4/49 (8.2%)		1/55 (1.8%)		5/104 (4.8%)
Hypothyroidism	3/49 (6.1%)		1/55 (1.8%)		4/104 (3.8%)
Gastrointestinal disorders
Abdominal discomfort	1/49 (2%)		3/55 (5.5%)		4/104 (3.8%)
Abdominal pain	10/49 (20.4%)		9/55 (16.4%)		19/104 (18.3%)
Abdominal pain upper	2/49 (4.1%)		6/55 (10.9%)		8/104 (7.7%)
Constipation	1/49 (2%)		4/55 (7.3%)		5/104 (4.8%)
Diarrhoea	28/49 (57.1%)		23/55 (41.8%)		51/104 (49%)
Dry mouth	5/49 (10.2%)		3/55 (5.5%)		8/104 (7.7%)
Dyspepsia	2/49 (4.1%)		4/55 (7.3%)		6/104 (5.8%)
Faeces soft	4/49 (8.2%)		1/55 (1.8%)		5/104 (4.8%)
Flatulence	6/49 (12.2%)		5/55 (9.1%)		11/104 (10.6%)
Frequent bowel movements	3/49 (6.1%)		2/55 (3.6%)		5/104 (4.8%)
Nausea	22/49 (44.9%)		26/55 (47.3%)		48/104 (46.2%)
Vomiting	3/49 (6.1%)		7/55 (12.7%)		10/104 (9.6%)
General disorders
Asthenia	4/49 (8.2%)		7/55 (12.7%)		11/104 (10.6%)
Fatigue	11/49 (22.4%)		12/55 (21.8%)		23/104 (22.1%)
Injection site erythema	3/49 (6.1%)		2/55 (3.6%)		5/104 (4.8%)
Oedema peripheral	9/49 (18.4%)		3/55 (5.5%)		12/104 (11.5%)
Hepatobiliary disorders
Cholelithiasis	8/49 (16.3%)		22/55 (40%)		30/104 (28.8%)
Hepatic steatosis	1/49 (2%)		4/55 (7.3%)		5/104 (4.8%)
Infections and infestations
Gastroenteritis	3/49 (6.1%)		2/55 (3.6%)		5/104 (4.8%)
Influenza	1/49 (2%)		3/55 (5.5%)		4/104 (3.8%)
Nasopharyngitis	2/49 (4.1%)		7/55 (12.7%)		9/104 (8.7%)
Upper respiratory tract infection	1/49 (2%)		6/55 (10.9%)		7/104 (6.7%)
Urinary tract infection	0/49 (0%)		4/55 (7.3%)		4/104 (3.8%)
Injury, poisoning and procedural complications
Procedural nausea	3/49 (6.1%)		5/55 (9.1%)		8/104 (7.7%)
Procedural pain	0/49 (0%)		3/55 (5.5%)		3/104 (2.9%)
Investigations
Alanine aminotransferase increased	3/49 (6.1%)		1/55 (1.8%)		4/104 (3.8%)
Blood cortisol decreased	3/49 (6.1%)		1/55 (1.8%)		4/104 (3.8%)
Blood glucose increased	4/49 (8.2%)		9/55 (16.4%)		13/104 (12.5%)
Electrocardiogram QT prolonged	3/49 (6.1%)		1/55 (1.8%)		4/104 (3.8%)
Gamma-glutamyltransferase increased	3/49 (6.1%)		4/55 (7.3%)		7/104 (6.7%)
Insulin-like growth factor decreased	5/49 (10.2%)		5/55 (9.1%)		10/104 (9.6%)
Weight decreased	3/49 (6.1%)		2/55 (3.6%)		5/104 (4.8%)
Metabolism and nutrition disorders
Decreased appetite	6/49 (12.2%)		1/55 (1.8%)		7/104 (6.7%)
Diabetes mellitus	9/49 (18.4%)		14/55 (25.5%)		23/104 (22.1%)
Hypercholesterolaemia	1/49 (2%)		3/55 (5.5%)		4/104 (3.8%)
Hyperglycaemia	19/49 (38.8%)		22/55 (40%)		41/104 (39.4%)
Hypoglycaemia	4/49 (8.2%)		3/55 (5.5%)		7/104 (6.7%)
Hypokalaemia	1/49 (2%)		3/55 (5.5%)		4/104 (3.8%)
Type 2 diabetes mellitus	5/49 (10.2%)		3/55 (5.5%)		8/104 (7.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/49 (4.1%)		5/55 (9.1%)		7/104 (6.7%)
Back pain	1/49 (2%)		4/55 (7.3%)		5/104 (4.8%)
Muscle spasms	2/49 (4.1%)		3/55 (5.5%)		5/104 (4.8%)
Myalgia	3/49 (6.1%)		1/55 (1.8%)		4/104 (3.8%)
Pain in extremity	5/49 (10.2%)		3/55 (5.5%)		8/104 (7.7%)
Nervous system disorders
Dizziness	6/49 (12.2%)		8/55 (14.5%)		14/104 (13.5%)
Headache	12/49 (24.5%)		19/55 (34.5%)		31/104 (29.8%)
Presyncope	3/49 (6.1%)		1/55 (1.8%)		4/104 (3.8%)
Syncope	3/49 (6.1%)		0/55 (0%)		3/104 (2.9%)
Psychiatric disorders
Anxiety	2/49 (4.1%)		3/55 (5.5%)		5/104 (4.8%)
Depression	4/49 (8.2%)		3/55 (5.5%)		7/104 (6.7%)
Insomnia	1/49 (2%)		4/55 (7.3%)		5/104 (4.8%)
Skin and subcutaneous tissue disorders
Alopecia	4/49 (8.2%)		7/55 (12.7%)		11/104 (10.6%)
Hyperhidrosis	0/49 (0%)		3/55 (5.5%)		3/104 (2.9%)
Pruritus	1/49 (2%)		3/55 (5.5%)		4/104 (3.8%)
Rash	2/49 (4.1%)		4/55 (7.3%)		6/104 (5.8%)
Vascular disorders
Hypertension	3/49 (6.1%)		4/55 (7.3%)		7/104 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.