An Open-label, Multi-center, Expanded Access Study of Pas... | NCT01582061

Label	Type	Description	Intervention Names
Pasireotide 600 μg	Experimental	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 900 μg	Experimental	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

Name	Type	Description	Arm Group Labels	Other Names
Pasireotide sub-cutaneous	Drug	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

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

Measure	Description	Time Frame
Percentage of Patients With Mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)	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.

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Written informed consent obtained prior to any screening procedures
Male or female patients aged 18 years or greater
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.
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)
Karnofsky performance status >60 (i.e. requires occasional assistance, but is able to care for most of his personal needs)
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:

Radiotherapy of the pituitary <4 weeks before screening or patient who has not recovered from side effects
Patients with compression of the optic chiasm causing acute clinically significant visual field defect
Patients with Cushing's syndrome due to ectopic ACTH secretion
Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
Patients who have undergone major surgery within 1 month prior to screening
Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be included)
Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%
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
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
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
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)
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
Known hypersensitivity to somatostatin analogues
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
Patients with presence of Hepatitis B surface antigen (HbsAg)
Patients with presence of Hepatitis C antibody test (anti-HCV)

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Advanced Research, LLC		Peoria	Arizona	85381	United States
St Josephs Hospital & Medical Center St Joes

PubMed Identifier	Type	Citation	Retractions
31379734	Derived	Fleseriu M, Iweha C, Salgado L, Mazzuco TL, Campigotto F, Maamari R, Limumpornpetch P. Safety and Efficacy of Subcutaneous Pasireotide in Patients With Cushing's Disease: Results From an Open-Label, Multicenter, Single-Arm, Multinational, Expanded-Access Study. Front Endocrinol (Lausanne). 2019 Jul 16;10:436. doi: 10.3389/fendo.2019.00436. eCollection 2019.

ID	Title	Description
FG000	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Mar 10, 2017	Jan 26, 2018

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Patients With a Drug-related Adverse Event That is Recorded as Grade 3 or 4 or as a Serious Adverse Event (SAE)

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.

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

Posted

Number

percentage of participants

Baseline up to approximately 256 weeks

ID	Title	Description
OG000	600 µg Bid - All Grades	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.
OG001	600 μg - Grades 3/4	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
OG002	900 μg - All Grades	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
OG003	900 μg - Grades 3/4	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
OG004	All Patients - All Grades	All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.
OG005	All Patients - Grades 3/4	All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.

Units	Counts
Participants	OG00049 OG00149 OG00255 OG003

Title	Denominators	Categories
Any primary system organ class	ParticipantsOG00049 ParticipantsOG00149 ParticipantsOG00255 ParticipantsOG003

Secondary

Percentage of Patients With Mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)

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.

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

Posted

Number

95% Confidence Interval

percentage of participants

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.

Secondary

Percentage of Patients Achieving a Reduction of Mean UFC ≥ 50% From Baseline

Posted

Number

95% Confidence Interval

percentage of participants

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.

Secondary

Percent Change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) Scores

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.

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

Posted

Mean

Standard Deviation

percent change in score

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Blood Pressure (BP)

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

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change of mmhg

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Pulse

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

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change in bpm

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Temperature

degrees celius

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change in celius

Baseline week 12, 24 and 48

ID	Title	Description
OG000	600 µg Bid - All Grades	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.
OG001	900 μg - All Grades	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
OG002	All Patients - All Grades	All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Body Mass Index (BMI)

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

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change in kg/m2

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Weight

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

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change in kg

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Muscle Strength

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

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change in scores

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Waist Circumference

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

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change of centimeters

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Hirsutism

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.

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change in scores

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change From Baseline in Growth Hormone (GH) Values

Descriptive summary of the effect of pasireotide on GH.

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change of µg/L

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Secondary

Percent Change From Baseline in Insulin Growth Factor - 1 (IGF - 1) Values

Descriptive summary of the effect of pasireotide on IGF-1

Number of patients with available data differed at visits

Posted

Mean

Standard Deviation

percent change of ng/ml

Baseline, week 12, 24 and 48

ID	Title	Description
OG000	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: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
OG001	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 : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
OG002	All Patients	Patients received pasireotide 600 μg or 900 μg BID

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Adrenal insufficiency	Endocrine disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Glucocorticoid deficiency	Endocrine disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Hyperprolactinaemia	Endocrine disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Pituitary-dependent Cushing's syndrome	Endocrine disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0011 affected55 at risk EG0023 affected104 at risk
Gastrointestinal ulcer	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Pancreatitis necrotising	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Death	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Drug ineffective	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Bile duct stone	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Cholangitis acute	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0013 affected55 at risk EG0023 affected104 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Hepatic lesion	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Cellulitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Dengue fever	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Meningitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Pneumonia	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Blood cortisol increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Lipase abnormal	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Transaminases increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Weight increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0011 affected55 at risk EG0023 affected104 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0010 affected55 at risk EG0022 affected104 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0012 affected55 at risk EG0022 affected104 at risk
Type 2 diabetes mellitus	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Pituitary tumour benign	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Headache	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Suicide attempt	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0010 affected55 at risk EG0021 affected104 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Embolism venous	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk
Venous thrombosis	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0011 affected55 at risk EG0021 affected104 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bradycardia	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0013 affected55 at risk EG0025 affected104 at risk
Sinus bradycardia	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0011 affected55 at risk EG0025 affected104 at risk
Adrenal insufficiency	Endocrine disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0011 affected55 at risk EG0025 affected104 at risk
Hypothyroidism	Endocrine disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0011 affected55 at risk EG0024 affected104 at risk
Abdominal discomfort	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0013 affected55 at risk EG0024 affected104 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00010 affected49 at risk EG0019 affected55 at risk EG00219 affected104 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0016 affected55 at risk EG0028 affected104 at risk
Constipation	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0014 affected55 at risk EG0025 affected104 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00028 affected49 at risk EG00123 affected55 at risk EG00251 affected104 at risk
Dry mouth	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected49 at risk EG0013 affected55 at risk EG0028 affected104 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0014 affected55 at risk EG0026 affected104 at risk
Faeces soft	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0011 affected55 at risk EG0025 affected104 at risk
Flatulence	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0006 affected49 at risk EG0015 affected55 at risk EG00211 affected104 at risk
Frequent bowel movements	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0012 affected55 at risk EG0025 affected104 at risk
Nausea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00022 affected49 at risk EG00126 affected55 at risk EG00248 affected104 at risk
Vomiting	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0017 affected55 at risk EG00210 affected104 at risk
Asthenia	General disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0017 affected55 at risk EG00211 affected104 at risk
Fatigue	General disorders	MedDRA (19.0)	Systematic Assessment	EG00011 affected49 at risk EG00112 affected55 at risk EG00223 affected104 at risk
Injection site erythema	General disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0012 affected55 at risk EG0025 affected104 at risk
Oedema peripheral	General disorders	MedDRA (19.0)	Systematic Assessment	EG0009 affected49 at risk EG0013 affected55 at risk EG00212 affected104 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0008 affected49 at risk EG00122 affected55 at risk EG00230 affected104 at risk
Hepatic steatosis	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0014 affected55 at risk EG0025 affected104 at risk
Gastroenteritis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0012 affected55 at risk EG0025 affected104 at risk
Influenza	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0013 affected55 at risk EG0024 affected104 at risk
Nasopharyngitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0017 affected55 at risk EG0029 affected104 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0016 affected55 at risk EG0027 affected104 at risk
Urinary tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0014 affected55 at risk EG0024 affected104 at risk
Procedural nausea	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0015 affected55 at risk EG0028 affected104 at risk
Procedural pain	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0013 affected55 at risk EG0023 affected104 at risk
Alanine aminotransferase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0011 affected55 at risk EG0024 affected104 at risk
Blood cortisol decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0011 affected55 at risk EG0024 affected104 at risk
Blood glucose increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0019 affected55 at risk EG00213 affected104 at risk
Electrocardiogram QT prolonged	Investigations	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0011 affected55 at risk EG0024 affected104 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0014 affected55 at risk EG0027 affected104 at risk
Insulin-like growth factor decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0005 affected49 at risk EG0015 affected55 at risk EG00210 affected104 at risk
Weight decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0012 affected55 at risk EG0025 affected104 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0006 affected49 at risk EG0011 affected55 at risk EG0027 affected104 at risk
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0009 affected49 at risk EG00114 affected55 at risk EG00223 affected104 at risk
Hypercholesterolaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0013 affected55 at risk EG0024 affected104 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG00019 affected49 at risk EG00122 affected55 at risk EG00241 affected104 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0013 affected55 at risk EG0027 affected104 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0013 affected55 at risk EG0024 affected104 at risk
Type 2 diabetes mellitus	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected49 at risk EG0013 affected55 at risk EG0028 affected104 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0015 affected55 at risk EG0027 affected104 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0014 affected55 at risk EG0025 affected104 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0013 affected55 at risk EG0025 affected104 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0011 affected55 at risk EG0024 affected104 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected49 at risk EG0013 affected55 at risk EG0028 affected104 at risk
Dizziness	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0006 affected49 at risk EG0018 affected55 at risk EG00214 affected104 at risk
Headache	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG00012 affected49 at risk EG00119 affected55 at risk EG00231 affected104 at risk
Presyncope	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0011 affected55 at risk EG0024 affected104 at risk
Syncope	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0010 affected55 at risk EG0023 affected104 at risk
Anxiety	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0013 affected55 at risk EG0025 affected104 at risk
Depression	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0013 affected55 at risk EG0027 affected104 at risk
Insomnia	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0014 affected55 at risk EG0025 affected104 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected49 at risk EG0017 affected55 at risk EG00211 affected104 at risk
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected49 at risk EG0013 affected55 at risk EG0023 affected104 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected49 at risk EG0013 affected55 at risk EG0024 affected104 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected49 at risk EG0014 affected55 at risk EG0026 affected104 at risk
Hypertension	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected49 at risk EG0014 affected55 at risk EG0027 affected104 at risk

ID	Term
D047748	Pituitary ACTH Hypersecretion
D010911	Pituitary Neoplasms

ID	Term
D006964	Hyperpituitarism
D010900	Pituitary Diseases
D007027	Hypothalamic Diseases
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D004700	Endocrine System Diseases
D004701	Endocrine Gland Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D007029	Hypothalamic Neoplasms
D015173	Supratentorial Neoplasms
D001932	Brain Neoplasms
D016543	Central Nervous System Neoplasms
D009423	Nervous System Neoplasms

ID	Title	Description
BG000	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.
BG001	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
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	600 µg Bid	600 µg bid	0	49	13	49	49	49
EG001	900 µg Bid	900 µg bid	1	55	17	55	54	55
EG002	All Patients	All patients	1	104	30	104	103	104