Clinical trial NCT01582061
Conditions: Cushing's Disease
Keywords: Cushing's disease Hormone disorder Cortisol Adrenocorticotropic hormone Pituitary tumor SOM230 adult
Sponsor: Novartis Pharmaceuticals
Start date: 2011-08-16; Completion date: 2017-01-26
Enrollment: 104 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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.

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.

Arms: arm 1: 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. arm 2: 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
Interventions: intervention 1: Pasireotide sub-cutaneous
Intervention descriptions: intervention 1: 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

Protocol documents:
Prot_001.pdf: 
Clinical Development & Medical Affairs
SOM230 (Pasireotide)
Clinical Trial Protocol CSOM230B2406 / NCT01582061
An open-label, multi-center, expanded access study of 
pasireotide s.c. in patients with Cushing’s disease 
(Seascape)
Document type
Amended Protocol Version
EUDRACT number
2010-024165-44
Version number
06 (Clean)
Development phase
IIIb
Document status
Final
Release date
13-Nov-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
 


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Protocol Summary
Study title:
An open-label, multi-center, expanded access study of pasireotide s.c. in patients with Cushing’s 
disease (Seascape)
Study phase:
IIIb
Study objectives:
Primary objective:

To document the safety of pasireotide s.c. in patients with Cushing’s Disease (CD).
Secondary objectives:

To document the efficacy of pasireotide s.c. in normalizing mean 24h-UFC at Week 12, 24
and 48, separately,

To document the efficacy of pasireotide s.c. in achieving at least 50% reduction of mean 24h-
UFC from baseline at Week 12, 24 and 48, separately,

To document the changes in clinical signs and symptoms,

To document the changes in patient-reported outcome questionnaires (CushingQoL and 
WPAI-GH),

To document the effects of pasireotide s.c. on the GH/IGF-I axis,

To document the overall safety and tolerability of pasireotide s.c. in patients with CD.
Study population:
Patients with persistent or recurrent Cushing’s disease or patients with de novo Cushing’s disease that 
are not considered candidates for pituitary surgery. A confirmed Cushing’s disease is required.
Key inclusion criteria:
Patients with confirmed diagnosis of Cushing’s disease as evidenced by mean 24h-UFC > ULN, 
normal or above normal morning plasma ACTH and MRI or IPSS, patients with de novo Cushing’s 
disease must not be considered 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.
Key exclusion criteria:
Radiotherapy of the pituitary < 4 weeks before screening or patient who has not recovered from side 
effects, compression of the optic chiasm causing acute clinically significant visual field defect, 
Cushing’s syndrome due to ectopic ACTH secretion, 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, diagnosis of glucocorticoid-remedial aldosteronism (GRA), 
symptomatic cholelithiasis, symptomatic bile duct dilation, acute or chronic pancreatitis, diabetes 
patients whose fasting blood glucose is poorly controlled as evidenced by HbA1C > 8%, clinically 
significant impairment in cardiovascular function or risk thereof, liver disease, patients with presence of 
Hepatitis B surface antigen, patients with presence of Hepatitis C antibody test, female patients 
pregnant or lactating, or of childbearing potential and not practicing a medically acceptable method of 
birth control.
 


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Number of patients:
The estimated sample size is 200 patients. The actual sample size may differ from this planned 
number.
Overview of study design:
This is an open-label, uncontrolled, single-arm, multi-center, multi-national expanded access study.
The starting dose will be:

[Applicable for countries in the European Union] 600 µg b.i.d. (twice daily) in all patients 
also including the ones with impaired glucose metabolism with the option to increase the dose 
to 900 µg b.i.d. if the patient is not controlled (i.e. 24h-mean UFC levels above the upper limit 
of normal) at earliest after 2 months of treatment provided the 600 µg b.i.d dose is well 
tolerated by the patient. Ongoing patients in the study at the time of approval of amendment 3 
will continue on their current dose.

[Applicable for countries outside the European Union] 900 µg b.i.d. (twice daily). The 
initial dose for patients with impaired glucose metabolism will be 600 µg b.i.d
Refer to Section 6.2.1 for allowed dose modifications.
After a 21-day screening period, patients who satisfy all the inclusion/exclusion criteria will start 
receiving pasireotide s.c. twice a day. During the first 24-week period, patients will have a visit on a 
weekly basis up to week 4 and will then be followed on a 4-week basis up to week 24. In the second 
study period, patients will be followed at 12-week intervals until the end of the study.
Patients will be treated until pasireotide is approved for commercial use and reimbursed in each 
respective country or until 31 December 2015 (until 31 December 2016 for sites in South Korea and 
Brazil), whichever occurs first.
Statistical considerations:
For the primary objective of the study, the number and percentage of patients having any drug-related 
adverse event that was recorded as a grade 3 or 4, or as a serious adverse event will be summarized 
by system organ class and/or preferred term, severity (based on CTCAE grades), type of adverse 
event and relation to study treatment.
Secondary endpoints:

The proportion of patients with mean 24h-UFC ≤ ULN at Week 12, 24 and 48, separately,

The proportion of patients achieving a reduction of mean 24h-UFC ≥ 50% from baseline at 
Week 12, 24 and 48, separately,

The change from baseline to Week 12, 24 and 48 in clinical signs and symptoms,

The change from baseline to Week 12, 24 and 48 in CushingQoL and WPAI-GH scores,

The change from baseline to Week 12, 24 and 48 in GH and IGF-I separately,

Incidence of AEs, and laboratory, vital signs and electrocardiographic abnormalities. Changes 
in laboratory values, electrocardiograms readings, and in vital signs values.
Categorical data will be presented as frequencies and percentages (with corresponding two-sided 95% 
CI, as appropriate). For continuous data, the mean, standard deviation, median, minimum, and 
maximum will be presented.
 


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Table of contents
Table of contents .................................................................................................................4
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 6 ....................................................................................................................12
Amendment 5 ....................................................................................................................13
Amendment 4 ....................................................................................................................15
Amendment 3 ....................................................................................................................17
Amendment 2 ....................................................................................................................20
Amendment 1 ....................................................................................................................23
1
Background........................................................................................................................24
1.1
Overview of disease pathogenesis, epidemiology and current treatments ............24
1.2
Introduction to investigational treatment...............................................................25
1.2.1
Overview of Pasireotide........................................................................25
1.2.2
Known undesirable effects of Pasireotide.............................................27
28
2
Rationale............................................................................................................................29
2.1
Study rationale and purpose...................................................................................29
2.2
Rationale for study design .....................................................................................29
2.3
Rationale for dose and regimen selection..............................................................29
3
Objectives and endpoints...................................................................................................30
4
Study design ......................................................................................................................32
4.1
Description of study design ...................................................................................32
4.2
Timing of interim analyses and design adaptations...............................................32
4.3
Definition of end of the study................................................................................32
4.4
Early study termination..........................................................................................33
5
Population..........................................................................................................................33
5.1
Patient population..................................................................................................33
5.2
Inclusion criteria ....................................................................................................33
5.3
Exclusion criteria...................................................................................................34
6
Treatment...........................................................................................................................35
6.1
Investigational treatment, other treatment, supportive treatment ..........................35
6.1.1
Dosing regimen.....................................................................................35
6.1.2
Treatment duration................................................................................36
 


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6.2
Dose escalation guidelines.....................................................................................36
6.2.1
Dose modifications................................................................................36
6.2.2
Treatment interruption and treatment discontinuation..........................42
6.3
Concomitant medications ......................................................................................43
6.3.1
Permitted concomitant therapy .............................................................44
6.3.2
Prohibited concomitant therapy ............................................................44
6.4
Patient numbering, treatment assignment and randomization...............................44
6.4.1
Patient numbering .................................................................................44
6.4.2
Treatment assignment and randomization ............................................44
6.4.3
Treatment blinding................................................................................44
6.5
Study drug supply..................................................................................................44
6.5.1
Study drug preparation and dispensation..............................................44
6.5.2
Study drug packaging and labeling.......................................................45
6.5.3
Drug supply and storage........................................................................45
6.5.4
Study drug compliance and accountability ...........................................45
6.5.5
Disposal and destruction .......................................................................45
7
Visit schedule and assessments .........................................................................................46
7.1
Study flow and visit schedule................................................................................46
7.1.1
Screening...............................................................................................50
7.1.2
Treatment period...................................................................................50
7.1.3
Study phase completion visit, including premature withdrawal and 
study discontinuation visit.....................................................................50
7.1.4
Follow up period ...................................................................................52
7.2
Assessment types...................................................................................................53
7.2.1
Efficacy assessments.............................................................................53
7.2.2
Safety and tolerability assessments.......................................................55
7.2.3
Biomarkers............................................................................................57
8
Safety monitoring and reporting........................................................................................58
8.1
Adverse events.......................................................................................................58
8.1.1
Definitions and reporting ......................................................................58
8.1.2
Laboratory test abnormalities................................................................59
8.2
Serious adverse events...........................................................................................60
8.2.1
Definitions.............................................................................................60
8.2.2
Reporting...............................................................................................60
8.3
Emergency unblinding of treatment assignment ...................................................61
8.4
Pregnancies............................................................................................................62
8.5
Warnings and precautions......................................................................................62
 


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8.6
Data Monitoring Committee..................................................................................62
8.7
Steering Committee ...............................................................................................62
9
Data collection and management.......................................................................................62
9.1
Data confidentiality ...............................................................................................62
9.2
Site monitoring ......................................................................................................63
9.3
Data collection.......................................................................................................63
9.4
Database management and quality control............................................................64
10 Statistical methods and data analysis ................................................................................64
10.1
Analysis sets ..........................................................................................................64
10.1.1
Full Analysis Set ...................................................................................64
10.1.2
Safety Set ..............................................................................................65
10.2
Patient demographics/other baseline characteristics .............................................65
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................65
10.4
Primary objective...................................................................................................65
10.4.1
Variable.................................................................................................65
10.4.2
Statistical hypothesis, model, and method of analysis..........................65
10.4.3
Handling of missing values/censoring/discontinuations.......................65
10.4.4
Supportive analyses...............................................................................65
10.5
Secondary objectives .............................................................................................65
10.5.1
Secondary efficacy variables.................................................................66
10.5.2
Safety objectives ...................................................................................68
10.5.3
Resource utilization...............................................................................70
10.5.4
Patient-reported outcomes.....................................................................70
10.6
70
70
71
71
10.7
Interim analysis......................................................................................................72
10.8
Sample size calculation..........................................................................................72
10.9
Power for analysis of key secondary variables......................................................72
11 Ethical considerations and administrative procedures ......................................................72
11.1
Regulatory and ethical compliance........................................................................72
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................72
11.3
Informed consent procedures.................................................................................73
11.4
Discontinuation of the study..................................................................................73
11.5
Publication of study protocol and results...............................................................73
11.6
Study documentation, record keeping and retention of documents.......................73
 


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11.7
Confidentiality of study documents and patient records .......................................74
11.8
Audits and inspections...........................................................................................74
11.9
Financial disclosures..............................................................................................74
12 Protocol adherence ............................................................................................................75
12.1
Amendments to the protocol..................................................................................75
13 References (available upon request)..................................................................................76
List of figures
Figure 1-1
Pasireotide structural and molecular formulae......................................26
Figure 6-1
Fasting self-monitoring blood glucose (SMBG) guidelines .................38
Figure 6-2
QT Prolongation Monitoring Flow Chart .............................................40
Figure 6-3
LFT management algorithm..................................................................42
List of tables
Table 3-1
Objectives and related endpoints ..........................................................31
Table 6-1
Guideline for treatment of patients experiencing adverse events .........43
Table 7-1
Visit evaluation schedule ......................................................................47
 


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List of abbreviations
ACTH
Adrenocorticotropic hormone
ADA
American Diabetes Association
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ALP
Alkaline Phosphatase
ANA
Antinuclear antibody
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
b.i.d.
bis in diem/twice a day
BIPSS
Bilateral inferior petrosal sinus sampling
BMI
Body mass index
cAMP
Cyclic adenosine monophosphate
CD
Cushing's disease
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
CMV
Cytomegalovirus
CRF
Case Report/Record Form
CRH
Corticotrophin-releasing hormone
CRO
Contract Research Organization
CS&E
Clinical Safety and Epidemiology
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR
CTCAE
Common Terminology Criteria for Adverse Events
CTH
Clinical Trial Head
DDAVP
1-Desamino-8-D-Arginin-Vasopressin (Desmopressin)
DM
Diabetes mellitus
DS&E
Drug Safety and Epidemiology
EASD
European Association for the Study of Diabetes
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ELISA
Enzyme Linked Immunosorbent Assay
FPFV
First patient first visit
FPG
Fasting Plasma Glucose
FU
Follow-up
GEP/NET
Gastroenteropancreatic neuroendocrine tumors
GGT
Gamma Glutamyl Transferase
GRA
Glucocorticoid-Remedial Aldosteronism
Gsα/Gsp
Alpha-subunit of the GTP-binding protein (non mutated/mutated)
HAV
Hepatitis A virus
HBc
Hepatitis B core
HbsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
 


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HEV
Hepatitis E virus
HIV
Human Immunodeficiency Virus
HPLC
High pressure liquid chromatography
HRQoL
Health-related quality of life
IgM
Immunoglobulin M
i.v.
intravenous(ly)
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
INR
International normalized ratio
IPSS
Inferior petrosal sinus sampling
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System 
and Interactive Web Response System
IVRS
Interactive Voice Response System
LAR
Long-acting release
LDDST
Low-dose dexamethasone suppression test
LDL
Low density lipoprotein
LFT
Liver Function Testing
LLN
Lower limit normal
LPLV
Last patient last visit
MAP
Master Analysis Plan documents project standards in the statistical methods which 
will be used within the individual clinical trial RAP documentation
MEN-1
Multiple Endocrine Neoplasia type-1
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NYHA
New York Heart Association
OTC
Over the counter medication
PCR
Polymerase Chain Reaction
PLT
Platelets
POC
Proof of Concept
PPG
Post-Prandial capillary Glucose
PT
Prothrombin time
PTT
Partial thromboplastin time
QoL
Quality of Life
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses
REB
Research Ethics Board
SAE
Serious Adverse Event
s.c.
Sub-cutaneous
SOP
Standard Operating Procedure
SR
Slow release
SRIFa
Somatostatin analog
 


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SSA
Somatostatin Analogs
SSC
Study Steering Committee
Sst
Somatostatin receptors
TC
Total Cholesterol
TdP
Torsades de Pointe
TSH
Thyrotropic hormone
UFC
Urinary free cortisol
ULN
Upper limit normal
WBC
White blood cells
WPAI-GH
Work Productivity and Activity Impairment-General Health
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational treatment
Drug whose properties are being testing in the study as well as their 
associated placebo and active treatment controls (when applicable).
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within 
approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package 
which is linked to one of the treatment groups of a study
Subject Number (Subject No.)
A unique identifying number assigned to each patient who enrolls in 
the study
Period
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, 
etc.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational 
treatment component relationship relative to a study treatment 
combination; study treatment in this case refers to the 
investigational and non-investigational treatments in combination.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment 
for any reason; may or may not also be the point/time of premature 
patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints
 


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Amendment 6
Amendment rationale
This protocol is being amended:
The current version of the study ends on 31 December 2015. Two participating countries, 
Brazil and South Korea, have not yet received pasireotide approval and reimbursement. To 
continue to provide access to these countries, the protocol has been extended to 31December 
2016, for these 2 countries only.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol.
The main change to the protocol and the section affected are detailed below:

Study duration is extended from 31December 2015 to 31December 2016 throughout the 
protocol for Brazil and South Korea.
IRB/IEC/REB Approval
A copy of this amended protocol must be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Amendment 5
Amendment rationale
This protocol is being amended:
Upon review of the program details for B2406 it was identified that this protocol was 
registered as a Phase IIIb clinical trial. 
Non-serious adverse event collection in the safety database is only required for expanded 
treatment programs not registered as clinical trials with the Health Authorities. Therefore,
monthly reporting of non-serious adverse events has been removed from this protocol 
amendment.
In recent months new standard language has been developed for the Inclusion/Exclusion 
Criteria checklists.  It is required now that sites must complete an Inclusion/Exclusion criteria 
checklist and submit it to Novartis for an approval prior to enrolling new patients into the 
trial. The relevant language was added to the protocol. 
This amended version of the protocol now states that an Interim Analysis may be performed 
per health authority requests or for publication purpose.
Lastly, this amended version of the protocol contains new standard safety language regarding 
QT prolonging medications.  All reference to medications that might lead to QT prolongation 
has been re-worded to state “medication with known risk of TdP”.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol.
The main change to the protocol and the section affected are detailed below:

Section 4.2 - updated this section to include wording that the Interim analysis may be used 
for publications purposes in addition to HA purposes.

Sections 5.3, 6.3.2 and 7.1.3.1 - Changed wording, “medication that might lead to QT 
Prolongation” to “medication with known risk of TdP” and also updated the link to the 
referenced website

Table 7-1 - Added completion of the inclusion / exclusion criteria checklist to the visit 
schedule at screening

Section 7.1.1 - Enrollment and eligibility confirmation section was added to describe the 
inclusion / exclusion criteria checklist in more detail

Section 10.7 - Added Interim Analysis may be performed for Health Authority purpose or
for publication purpose.

Section 8.2.2 - Removed monthly AE reporting language

 
 
 


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IRB/IEC/REB Approval
A copy of this amended protocol must be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Amendment 4
Amendment rationale
This protocol is being amended:
To be in compliance with the standard maximum half-life of mifepristone s.c. of 
approximately 12 hours as indicated in the US Prescribing Information, the amendment has 
extended the washout period of mifepristone from one to four weeks in inclusion criterion #6. 
As the SOM program has recently standardized the use of oral contraception after the end of 
the study to one month based on pasireotide s.c half-life of approximately 12 hours, the 
amendment has reduced the use of oral contraception after the end of the study from 3 months 
to 1 month.
As per recently issued 2012 ADA and EASD guidelines, the SOM program has added further 
guidelines on the hyperglycemia management and monitoring of blood glucose for all SOM 
studies. These new guidelines have been incorporated into this amendment.
The current version of the study ends on 31December 2013. Several participating countries 
have not received pasireotide approval. To continue to provide access to these countries, the 
protocol has been extended to 31December 2015.
To be in compliance with the Expanded Access Program requirements, the amendment has 
added the new process of monthly AE reporting. Per SOM program’s new guidance for AE 
reporting, the amendment has added events of special interest for pasireotide s.c. for targeted 
follow-up. Events of special interest should be notified to Novartis DS&E in the same manner 
as a SAE.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol.
The main change to the protocol and the section affected are detailed below:

Study duration is extended from 31December 2013 to 31December 2015 throughout the 
protocol

5.2 Inclusion criteria

The washout period for glucocorticoid receptor inhibitor (mifepristone) has been 
extended from 1 to 4 weeks before patients can be considered for screening

5.3 Exclusion criteria

The duration of oral contraception to be used after the end of the study has been 
reduced from 3 months to 1 month

6.2.1.1 Follow-up for toxicities

This section was updated by removing the language for Glucose metabolism and 
adding the language for Hyperglycemia, Monitoring of blood glucose and adding 
Figure 6-1 for Fasting self-monitoring blood glucose (SMBG) guidelines

8.2.2 Reporting
 


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
This section was updated to introduce the language for all AE collection and updated 
in the study database on a periodic basis. Additionally, to add the events of special 
interest for pasireotide s.c. for targeted follow-up in the same manner as a SAE.
IRB/IEC/REB Approval
A copy of this amended protocol must be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Amendment 3
Amendment rationale
Based on the positive opinion and recommendation from the Committee for Medicinal 
Products for Human Use (CHMP) of the European Medicines Agency on 19 January 2012, 
the starting dose of commercial pasireotide s.c for the treatment of Cushing’s disease will be 
600 µg b.i.d in all countries of the European Union with the option to increase the dose to 
900 µg b.i.d. if the patient is not controlled (i.e. 24h-mean UFC levels above the upper limit 
of normal) at earliest after 2 months of treatment provided the 600 µg b.i.d dose is well 
tolerated by the patient. This protocol was adapted accordingly in order to be consistent with 
the future label, i.e. all patients included in countries of the European Union will start 
treatment with pasireotide 600 µg b.i.d. However ongoing patients in the study at the time of 
approval of amendment 3 will continue on their current dose. This change is not applicable for 
countries outside of the European Union. The results of study SOM230B2305 support the 
initial dose of 900 µg b.i.d. Therefore, countries outside the European Union will continue to 
use 900 µg b.i.d. as the starting dose in this trial.
In order to facilitate bridging the timeframe between the end of this study and the approval 
and reimbursement of commercial pasireotide, the treatment duration of maximum 1 year per 
country has been extended to the latest expected approval date in all participating countries.
Therefore all patients will remain in the study until pasireotide is approved for commercial 
use and reimbursed or until 31 December 2013, whichever comes first.
In order to ensure collection of all efficacy and safety data at the time of the last study drug 
administration, a study phase completion visit has been introduced on the day of the last study 
drug administration including all safety and efficacy assessments. A study completion visit
will then be performed 28 days after the last study drug administration with a limited number 
of assessments.
A timeframe for the transition from study drug to commercial pasireotide has been added in 
this amendment.
One secondary safety objective and corresponding endpoints have been added to be aligned 
with the Statistical section of the protocol.
A newly approved medication for the treatment of Cushing syndrome has been added in 
inclusion criterion 6 which lists previous medical treatments to be washed out before 
screening procedures are performed.
Preclinical data is available to show that pasireotide does not adversely affect the sperm. The 
fertility and early embryonic development study in the rat showed no effect on male 
reproductive parameters. Therefore the language describing the requirements for pregnancy 
outcomes for a female partner of any males who took study drug in this study has been 
removed. The protocol has been updated to allow for additional, country specific interim 
analysis in case of regulatory requirements.
The remaining changes/corrections were made to maintain consistency throughout the 
protocol and to correct minor editorial issues. As of the release date of this amendment, 
 


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approximately 20 patients have been included in the study and are in the treatment phase. As a 
consequence of extension of study duration (see above), there is an impact of this amendment 
on the duration of recruitment and on the release of the results.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The main changes to the protocol and the sections affected are detailed below:

Protocol Summary

Changes in the main body of the protocol (see bullet points below) are also 
implemented in the relevant sections of the protocol summary

2.3 Rationale for dose and regimen selection

Rationale for the 600 µg b.i.d starting dose in European Union has been added

3 Objectives and endpoints

As a consequence of extension of study duration, objectives and endpoints have been 
updated to include an additional timepoint for analysis at week 48

One secondary safety objective and corresponding endpoints have been added to be 
aligned with the Statistical section of the protocol

4.1 Description of study design

This section has been updated to reflect the change of the starting dose in the 
European Union and the change of study duration

4.2 Timing of interim analysis and design adaptations

This section has been updated to reflect the change of the study duration and to allow 
for selected efficacy and safety analyses to be repeated for subgroups of patients from 
specific countries

4.3 Definition of end of study

This section has been updated to reflect the change of the study duration

5.2 Inclusion criteria

A newly approved medication for the treatment of Cushing syndrome has been added 
in inclusion criterion 6

6.1.1 Dosing regimen

This section has been updated to reflect the change of the starting dose in the 
European Union

6.1.2 Treatment duration

This section has been updated to reflect the change of the study duration

6.3.1 Dose modifications

This section has been revised to describe the dose adjustments permitted for patients 
in the European Union starting with the 600 µg b.i.d dose

6.3.2 Treatment interruption and treatment discontinuation
 


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
This section has been updated to introduce a study phase completion visit to be 
performed at the time of the last study drug administration and to provide a timeframe 
for the transition from study drug to commercial pasireotide

Table 7-1 Visit evaluation schedule

This table has been updated to reflect the extension of the study duration and to 
introduce a study phase completion visit to be performed at the time of the last study 
drug administration as well as to reduce the number of assessments done at study 
completion visit.

7.1.2 Treatment period

This section has been updated to reflect the change of the study duration

7.1.3 Study phase completion visit, including premature withdrawal and study 
discontinuation visit

This section has been updated to introduce a study phase completion visit to be 
performed at the time of the last study drug administration

7.1.3.1 Criteria for premature patient withdrawal

Change of magnesium value from 0.7 mmol/L to 0.5 mmol/L since a magnesium 
value of 0.5 mmol/L does not have a significant negative effect on the cardiac status 
i.e., any magnesium value greater than 0.5 mmol/L is considered in the normal range.

8.4 Pregnancies

Removal of the language describing the requirements for pregnancy outcomes for a 
female partner of any males who took study drug in this study.

10 Statistical methods and data analysis

This section has been updated to reflect the change of the study duration

10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4

As a consequence of extending the study duration, those sections have been revised to 
include an additional timepoint for analysis at week 48


10.7 Interim analysis

This section has been updated to reflect the change of the study duration and to allow 
for selected efficacy and safety analyses to be repeated for subgroups of patients from 
specific countries
The remaining changes/corrections were made to maintain consistency throughout the 
protocol and to correct minor editorial issues.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Amendment 2
Amendment rationale
This protocol is being amended to include additional hepatic-related safety measures as a 
result of an internal hepatic medical review of pasireotide trials. During this internal medical 
review of liver related laboratory values, 3 healthy volunteers were identified with elevations 
in liver function tests. Three subjects met the criteria for Hy’s Law (i.e. ALT > 3 x ULN with 
concurrent total bilirubin >2 x ULN, without increases in alkaline phosphatase (ALP) and no 
other cause(s) identified for the abnormal findings). One subject received pasireotide 600 µg 
bid s.c. for 7 days, while the second subject received pasireotide 1950 µg bid s.c. for 5 days. 
The third subject (pasireotide 600 µg bid s.c. for 7 days) had ALT and total bilirubin increases 
that met the criteria for Hy’s Law but the alkaline phosphatase was not assessed and the 
subject received a potentially confounding concomitant medication. ALT values for all 3 
subjects were greater than 3 x ULN but < 4 x ULN and total bilirubin values were ≤4 x ULN. 
All 3 cases were asymptomatic, presented within 10 days after initial pasireotide s.c. 
administration, and were reversible with discontinuation of pasireotide. None of the cases 
were reported as adverse events and the subjects completed the respective studies per 
protocol.
An assessment of liver enzyme categorical outliers has been completed across the pasireotide 
s.c. development program (up to October 2011). The 3 healthy volunteers that met Hy’s Law 
criteria (including the subject without the ALP value) are included amongst the 654 healthy 
volunteers as presented below. None of the other patients (i.e. Cushing’s disease, carcinoid 
syndrome or acromegaly) in the development program met the criteria for Hy’s Law.

654 healthy volunteers have been exposed to pasireotide s.c.:

3 out of 654 (0.5%) met the biochemical criteria of Hy's Law

16 out of 654 (2.4%) subjects had an ALT or AST > 3x ULN

3 out of 654 (0.5%) of the healthy volunteers had an ALT or AST > 5xULN

17 out of 654 (2.6%) subjects had a total bilirubin of 2xULN (including 7 patients 
with pre-existing liver disease and elevations of total bilirubin)

156 patients in phase 1 and phase 2 trials have been exposed to pasireotide s.c.:

None of the patients met the biochemical criteria of Hy's Law

6 out of 156 (3.8%) patients had an ALT or AST > 3xULN

4 out of 156 (2.6%) patients had an ALT or AST > 5xULN

2 out of 156 (1.3%) patients had a total bilirubin of ≥ 2xULN;

162 patients with Cushing’s disease in phase 3 trials have been exposed to pasireotide 
(s.c.):

None of the patients met the biochemical criteria of Hy's Law

8 out of 162 (4.9%) patients had an ALT or AST > 3x ULN

1 out of 162 (0.6%) patients had an ALT or AST > 5x ULN
 


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
None of the patients out of 162 with Cushing’s disease had a total bilirubin of ≥ 
2xULN
The pasireotide Compassionate Use Program (approximately 200 patients as of October 2011) 
was also reviewed. A single Cushing’s disease patient (PHHO2010AU13717) who was 
previously presented in an Investigator Notification in September 2010 was the only patient 
identified as meeting Hy’s Law criteria.
A review of the unblinded data from the clinical program with the pasireotide long acting 
release (LAR) formulation did not reveal cases meeting the Hy’s law criteria.
As a consequence of these observations, enhanced hepatic-related safety measures will be 
taken to ensure patient safety.
As of the release date of this amendment, approximately 5 patients have been included in the 
study and are in the treatment phase. There is no anticipated impact of this amendment on the 
duration of recruitment or on the release of the results.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The major changes to the protocol and the sections affected are detailed below:

Protocol Summary

Update of key exclusion criteria section reflecting new exclusion criteria 8, 17 and 18 
of Section 5.3

5.3 Exclusion criteria

Exclusion criteria 11 and 12 have been revised

Exclusion criteria 17 and 18 have been added

Exclusion criterion 8 has been replaced by a more detailed exclusion criterion which 
still covers the former information of exclusion criterion 8.

6.3.1.1 Follow-up for toxicities

This section has been revised to describe the measures to be followed if the abnormal 
liver function criteria are observed.

Figure 6-2 has been added and describes the liver function test management algorithm

Table 6-1 Guideline for treatment of patients experiencing adverse events

Clarification that detailed guidance in Section 6.3.1.1 has to be followed for hepatic 
safety management

7.1 Study flow and visit schedule

Figure 7-1 has been revised to reflect the additional LFT, PT/INR and serology
assessments to be performed at screening and during the study

7.1.3.1 Criteria for premature patient withdrawal

Hepatic-related discontinuation criteria have been added

7.2.2.4.3 Clinical chemistry
 


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
This section has been revised. A sub-section “Liver function tests (LFT)” has been 
added and lists all parameters included in the LFT panel.

7.2.2.4.6 Serology

This section has been added to reflect the new serology assessments to be performed 
at screening.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes in this 
amended protocol include the measures which have already been implemented as part of the 
Urgent Safety Communication, however still require submission to the IRB/IEC and approval.
In addition, as the changes herein affect the Informed Consent, sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this amended protocol.
 


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Amendment 1
Amendment rationale
In order to ensure a better standardization and quality of the laboratory results, it has been 
decided to use a central laboratory for the assessment of all parameters (except urinalysis) 
instead of local ones.
As of the release date of this amendment, no patient has been screened to the study. There is 
no anticipated impact of this amendment on the duration of recruitment or on the release of 
results.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The changes to the protocol and the sections affected are detailed below:

Removal of the sentences stating that laboratory parameters will be assessed by local 
laboratories in

Section 7.2.2.4 Laboratory evaluations and

Section 10.5.2.3 Laboratory abnormalities.
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatments
Cushing’s disease (CD) is a devastating endocrine disease that is caused by an 
adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Epidemiological studies 
indicated an annual incidence of 0.7-2.4 per million population (Lindholm et al 2001). 
However, a recent study performed in Belgium reported a much higher prevalence of CD
(Daly et al 2006): 55 per million population. Eighty percent of these tumors can be classified 
as microadenomas, and 20% as macroadenomas. The elevated ACTH levels secreted by these 
tumors stimulate the adrenal glands to produce excess cortisol, leading to the subsequent 
development of the clinical signs and symptoms of hypercortisolism. Cushing’s disease is 
rare, associated with severe morbidity and premature mortality and most commonly affects 
adults aged 20-50, primarily females. Patients suffer from this disease for many years before 
coming to medical attention and appropriate diagnosis.
The most common pathological finding in these patients is bilateral hyperplasia of the adrenal 
cortex due to excessive ACTH secretion. The primary clinical symptoms of Cushing’s disease 
are due to hypercortisolism, and include the following:

Change in body habitus: moon facies, supraclavicular fat pad, buffalo hump

Hirsutism on face, neck, chest, abdomen, thighs

Skin changes with easy bruising, purplish striae, reddening of the cheeks due to weakened 
connective tissue

Generalized weakness and fatigue

Wasting of musculature, particularly proximal muscles

Menstrual disorders in females

Decreased fertility and/or libido

Hypertension

Weight gain

Diabetes mellitus

Depression, mood and behavior disorders

Sleep disturbances

Osteopenia/osteoporosis
Most patients also develop a high set-point for feedback inhibition of ACTH secretion by 
cortisol.
In addition to the patient’s medical history and physical examination, several laboratory test 
and diagnostic techniques are available for the diagnosis of Cushing’s disease. Twenty four 
hour urinary free cortisol (UFC) measurements, blood sampling for serum cortisol levels, and 
the low-dose dexamethasone suppression test (LDDST) are widely used as screening tests for 
the diagnosis of Cushing’s disease (Newell-Price et al 1998). To distinguish Cushing’s 
 


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disease from other forms of hypercortisolism, a confirmation of a pituitary source of ACTH 
secretion is needed. This includes an inappropriately normal or elevated plasma ACTH level 
and evidence of pituitary tumor on magnetic resonance imaging (MRI) scan or confirmed by 
bilateral inferior petrosal sinus sampling (BIPSS) after corticotrophin-releasing hormone 
(CRH) stimulation test (evidence of a pituitary source of ACTH). It is generally accepted that 
if the ratio of adrenocorticotrophin concentration in the inferior petrosal sinuses to peripheral-
blood is greater than or equal to 3.0 after CRH stimulation, a diagnosis of Cushing’s disease 
can be made (Oldfield et al 1991).
The incidence of Cushing’s disease ranges from 1-3 patients per million per year.
Pituitary resection of the adenoma is the current first-line therapy for Cushing’s disease, but 
surgical failure rates are as high as 25-30% even in the hands of the most experienced 
neurosurgeons. Additionally postoperative recurrence rates are as high as 20% by 5 years 
(Bochicchio 1995, Sonino 1996). Surgery is in many cases complicated by hypopituitarism, 
which requires complicated life-long hormonal replacement therapy necessary to sustain life. 
Treatment usually focuses on replacing the target hormones rather than the pituitary 
hormones, and in patients who have multiple axis deficiencies maintenance with multiple 
replacement hormones can be difficult, and requiring close and constant medical monitoring, 
and can be expensive (Swearingen et al 1999).
Irradiation of the pituitary is another option but it may take many years to be effective and it is 
curative in only 15 to 45% of the cases. In addition, due to its lack of specificity the procedure 
also often results in panhypopituitarism. Furthermore, there is a 1 to 2% risk of development 
of secondary tumors in the field of radiation over subsequent years (Orth 1995).
When surgery and/or irradiation fail, or for those patients for whom such therapies are not an 
option, the remaining alternative is pharmacological treatment. No drug is currently approved 
for the treatment of Cushing’s disease and the ones which physicians are using are fraught 
with suboptimal results and significant side effects (Miller 1993, Nieman 2002) preventing 
their long term use required in the management of CD. Therefore, a safe and effective 
targeted medical therapy is highly desirable in this patient population.
1.2
Introduction to investigational treatment
1.2.1
Overview of Pasireotide
Pasireotide is an injectable somatostatin analogue. It is a novel cyclohexapeptide containing 
the structural elements [[[(2-aminoethyl)amino]carbonyl]oxy]-L-proline, phenylglycine and 
tyrosine (benzyl), with the following structural and molecular formula:
 


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Figure 1-1
Pasireotide structural and molecular formulae
N H
N
O
O
O
N
H
N
H
O
NH
O
O
NH
O
NH
NH
O
O
NH2
N
H2
N
H2
O
O
OH
OH
N
H2
O
O
OH
OH
Pasireotide free base on anhydrous basis: C58H66N10O9
di-aspartate salt form on anhydrous basis: C58H66N10O9 • 2 C4H7NO4
Like natural somatostatin and other somatostatin analogues (SRIFa), pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors (sst). There are five known 
somatostatin receptors: sst 1, 2, 3, 4 and 5. Somatostatin receptors are expressed in different 
tissues under normal physiological conditions. Somatostatin analogues activate these 
receptors with different potencies (Schmid and Schoeffter 2004) and this activation results in 
a reduced cellular activity and inhibition of hormone secretion. Somatostatin receptors are 
strongly expressed in many solid tumors, especially in neuroendocrine and pituitary tumors 
where hormones are excessively secreted e.g. acromegaly (Freda 2002), GEP/NET tumors 
(Oberg 2004) and Cushing’s disease (van der Hoek et al 2005a).
The SRIFa currently approved for use in the clinic (octreotide and lanreotide) have a high 
affinity to the sst subtype 2 (sst2), with moderate or no affinity to the remaining subtypes. 
While these SRIFa are effective for the pharmacological management of acromegaly and 
GEP/NET tumors patients, clinical studies with Cushing’s disease have been unsuccessful 
(Lamberts 1989, Stalla 1994).
In vitro studies have shown that corticotroph tumor cells from Cushing’s patients display a 
strong expression of sst5 whereas the other receptor subtypes are either not expressed or are 
expressed at a significantly lower level. In addition, sst2 receptors but not sst5 receptors on 
corticotroph cells are down-regulated in the presence of glucocorticoids (Hofland 2005, van 
der Hoek 2005b). Cushing’s disease patients have high levels of circulating cortisol, which 
probably leads to a reduced expression of sst2 receptors. This observation could explain why 
currently available SRIF analogues have been largely unsuccessful in the treatment of these 
patients.
In contrast to other SRIFs, pasireotide has a high affinity to four of the five known sst 
subtypes (sst1, 2, 3 and 5) resulting in a unique binding profile, the closest to-date to the 
natural somatostatin. The broader binding profile of pasireotide, especially its high affinity to 
sst5, suggests it may be effective for the treatment of Cushing’s disease patients. Several 
functional pre-clinical data derived from rats (Silva et al 2005), AtT20 cells and human 
corticotroph adenoma cells strongly support this assumption (Hofland 2005, van der Hoek 
 


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2005a). Additionally, clinical data from the POC study [CSOM230B2208] show that 
pasireotide has activity in Cushing’s disease patients. In this study, pasireotide produced a 
decrease in UFC levels in 76 % of patients with Cushing’s disease during the treatment period 
of 15 days. Serum cortisol levels and plasma ACTH levels were also reduced (Boscaro et al 
2009).
Data from the recently completed [SOM230B2305] study showed the efficacy of pasireotide 
in reducing UFC in patients with Cushing’s disease. In this randomized, double-blind, Phase 
III study, 162 adult patients with Cushing’s disease and UFC >1.5x the upper limit of normal 
(ULN) were randomly allocated to received pasireotide 600 µg (n=82) or 900 µg (n=80) s.c.
bid for 12 months. At the end of the study, patients entered an open-end extension study.
Patients with UFC ≤2xULN and ≤baseline at month 3 continued on their randomized dose 
until month 6. All other patients received a dose increase of 300μg bid. At month 6, 14.6% 
(600μg) and 26.3% (900μg) of patients met the primary endpoint (i.e. patients with 
UFC≤ULN at month 6 without up-titration). Mean UFC decreased by approximately 50% in 
both groups of patients within 2 months and remained stable throughout the study. Patients 
with baseline UFC ≤5xULN were more likely to achieve normal UFC. Serum and salivary 
cortisol and plasma ACTH had a similar decrease, and clinical signs and symptoms of 
Cushing’s disease improved as UFC decreased. The safety profile of pasireotide was similar 
to that of other somatostatin analogues (mostly transient GI discomfort), except for the degree 
of hyperglycemia.
The [SOM230B2305] study showed a rapid and sustained UFC reduction in the majority of 
patients: achieving normalization in a subset of them. In addition, clinical benefit was 
observed irrespective of achieving normal UFC. Pasireotide is a pituitary-directed medical 
treatment that has shown benefits to patients with CD.
Pasireotide has also shown activity in the treatment of acromegalic and carcinoid tumor 
patients inadequately controlled by other somatostatin analogs. Pasireotide appears to be well 
tolerated at doses up 600 µg b.i.d. and 1200 µg b.i.d. by acromegalic and carcinoid tumors 
patients respectively.
1.2.2
Known undesirable effects of Pasireotide
In healthy volunteers the adverse events most frequently reported during pasireotide treatment 
are gastrointestinal, most commonly being diarrhea and loose stools. Mild nausea and 
vomiting have also been reported. Generally these events do not require treatment and event 
frequency and severity appears to decrease with continued exposure to pasireotide.
Pasireotide administration may transiently increase fasting and/or post-prandial blood glucose 
levels. In a mechanistic study in healthy volunteers [SOM230B2216], pasireotide at doses of 
600 and 900 µg b.i.d. decreased the hyperglycemia-induced and arginine-maximal-stimulated 
insulin secretion (AIR max.) with no changes in peripheral or hepatic insulin sensitivity. 
Pasireotide s.c. was also associated with a significantly decreased insulin-incretin response 
(i.e., GLP-1 and GIP levels) following an OGTT. These elevations are commonly transient, 
showing a clear attenuation of effect with subsequent exposure to pasireotide. Glucagon 
secretion is also suppressed. These finding are similar to those observed with other 
somatostatin analogues.
 


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Increases in blood glucose in patients with Cushing’s disease were observed during the Phase 
II study. Blood glucose increases tended to occur with increasing dose, and were most 
prominent in patients with a history of hyperglycemia or diabetes mellitus. In general 
however, when needed, the increases were managed by adjustment or addition of 
hypoglycemic medications.
Laboratory abnormalities in liver function tests and pancreatic enzymes have been observed at 
higher doses in some subjects receiving the continuous infusion of pasireotide administered 
subcutaneously via an insulin pump. These events, however, have all been transient and 
asymptomatic at doses as high as 2250 µg s.c.
Furthermore, results from the thorough QT/QTc (TQT) study [CSOM230B2113] provided 
data on the QT/QTc intervals of a supra-therapeutic dose of pasireotide in healthy volunteers. 
The study was divided in two parts. In part 1, a maximum tolerated dose (MTD) of 1950 μg 
b.i.d. was identified. In part 2, the effects of pasireotide at MTD on the cardiac intervals were 
investigated. Pasireotide showed a peak effect on QTcF at 2 hours post-dose. There was a 
+10.0ms increase from baseline that correlates to a 17.5 msec difference versus placebo, while 
placebo had a -7.4 msec decrease from the baseline 2 hour post-dose. A similar effect was 
demonstrated on QTcI, but not observed on QTcB interval. Pasireotide subjects also showed a 
reduction of the heart rate at 0 to 4 hours post-dose with the maximum change versus baseline 
of 10.7 bpm.
A second thorough QT study [CSOM230B2125] is ongoing to further investigate the effect of 
pasireotide on QT/QTc intervals.
Study [CSOM230B2305] has shown that the safety profile of pasireotide is similar to other 
somatostatin analogues with the exception of hyperglycemia. As expected with effective 
treatment for Cushing’s disease, some patients [13/162 (8%) randomized patients]
experienced symptoms of hypocortisolism. No deaths were observed during pasireotide 
treatment, and the most frequently reported AEs included gastrointestinal AEs similar to 
approved somatostatin analogues: diarrhea (54.9 %), nausea (46.9%), cholelithiasis (29.6%), 
abdominal pain (20.4%). 70% of patients had at least one hyperglycemia-related AE.
 


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2
Rationale
2.1
Study rationale and purpose
The trial is planned as an Expanded Access study to provide access and to further document
the safety and the efficacy of pasireotide in patients affected by Cushing’s disease. While 
regulatory approval is sought, there are no means available for patients with Cushing’s disease
to receive pasireotide outside of a clinical trial. Patients with post-surgery active disease or 
patients who recur after surgery and de novo patients that are not candidates to surgery do not 
have an access path to this new agent. Implementation of an Expanded Access Program will 
allow access to pasireotide for patients with Cushing’s disease.
2.2
Rationale for study design
The rationale for this study is to give patients with Cushing’s disease access to pasireotide s.c. 
as no medical treatment for Cushing’s disease is approved. Thus, a single arm, open label 
design is justified in this context
2.3
Rationale for dose and regimen selection
Results from the pivotal study [SOM230B2305] showed that the 900 µg b.i.d dose met the 
primary endpoint and can be used as a starting dose. In addition, it was observed that patients 
with impaired glucose metabolism had a less pronounced increase in blood glucose when 
using the 600 µg b.i.d dosing. [Applicable for countries outside the European Union] 
Therefore, this study will use the 900 µg b.i.d as starting dose in all patients except the ones 
affected by impaired glucose metabolism that will have the 600 µg b.i.d as starting dose
 


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[Applicable for countries in the European Union] Based on the positive opinion and 
recommendation from CHMP on 19 January 2012, the starting dose of commercial 
pasireotide s.c for the treatment of Cushing’s disease will be 600 µg b.i.d for all patients 
coming from European Union countries. Accordingly, the starting dose in this study will be 
600 µg b.i.d in all patients (including the ones affected by impaired glucose metabolism) with 
the option to increase the dose to 900 µg b.i.d. if the patient is not controlled (i.e. 24h-mean 
UFC levels above the upper limit of normal) at earliest after 2 months of treatment provided 
the 600 µg b.i.d dose is well tolerated by the patient. However patients on going in the study 
at the time of approval of amendment 3 will continue on their current dose.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
 


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
To document the safety of pasireotide s.c. in patients with CD
The proportion of patients having a drug-related adverse 
event that is recorded as grade 3 or 4 or as a serious 
adverse event.
Secondary
Refer to Section 10.5.1.
To document the efficacy of pasireotide s.c. in normalizing 
mean 24h-UFC at Week 12, 24 and 48, separately
To document the efficacy of pasireotide s.c. in achieving at 
least 50% reduction of mean 24h-UFC from baseline at Week 
12, 24 and 48, separately
To document the changes in clinical signs and symptoms
To document the changes in patient-reported outcome 
questionnaires (CushingQoL and WPAI-GH)
To document the effects of pasireotide s.c. on the GH/IGF-I 
axis
To document the overall safety and tolerability of pasireotide 
s.c. in patients with CD
The proportion of patients with mean 24h-UFC ≤ ULN at 
Week 12, 24 and 48, separately
The proportion of patients achieving a reduction of mean 
24h-UFC ≥50% from baseline at Week 12, 24 and 48, 
separately
The change from baseline to Week 12, 24 and 48 in clinical 
signs and symptoms
The change from baseline to Week 12, 24 and 48 in 
CushingQoL and WPAI-GH scores
The change from baseline to Week 12, 24 and 48 in GH and 
IGF-I separately
Incidence of AEs, and laboratory, vital signs and 
electrocardiographic abnormalities. Changes in laboratory 
values, electrocardiograms readings, and in vital signs 
values.
 


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4
Study design
4.1
Description of study design
This is an open-label, uncontrolled, single-arm, multi-center, multi-national expanded access 
study. The starting dose will be:

[Applicable for countries in the European Union] 600 µg b.i.d. (twice daily) in all patients 
also including the ones with impaired glucose metabolism with the option to increase the 
dose to 900 µg b.i.d. if the patient is not controlled (i.e. 24h-mean UFC levels above the 
upper limit of normal) at earliest after 2 months of treatment provided the 600 µg b.i.d 
dose is well tolerated by the patient. However ongoing patients in the study at the time of 
approval of amendment 3 will continue on their current dose.

[Applicable for countries outside the European Union] 900 µg b.i.d. (twice daily). The 
initial dose for patients with impaired glucose metabolism will be 600 µg b.i.d
Refer to Section 6.2.1 for allowed dose modifications.
After a 21-day screening period, patients who satisfy all the inclusion/exclusion criteria will 
start receiving pasireotide s.c. twice a day. Please, refer to Table 7-1 for a description of the 
screening evaluations required. During the first 24-week period, patients will have a visit on a 
weekly basis up to week 4 and will then be followed on a 4-week basis up to week 24. In the 
second study period, patients will be followed at 12-week intervals until the end of the study.
Patients will be treated until the drug is approved for commercial use and reimbursed in each 
respective country or until 31 December 2015 (until 31 December 2016 for sites in South 
Korea and Brazil), whichever occurs first.
4.2
Timing of interim analyses and design adaptations
No formal interim analysis is planned. However, since the timing of drug approval may differ 
between regions, data from a specific region may be reported when all patients from that 
region have been followed for 28 days after they have either prematurely discontinued 
pasireotide s.c. or after completing treatment as per protocol (i.e. when the study drug is 
approved for commercial use and reimbursed in each respective country or until 31 December 
2015 (until 31 December 2016 for sites in South Korea and Brazil), whichever occurs first).
For regulatory purposes, at time of a regional interim analysis, data from countries where the 
trial is still ongoing may be included. Furthermore, independent of a regional interim analysis 
additional interim analysis may be performed for regulatory or publication purpose.
No design adaptations are planned.
4.3
Definition of end of the study
Patients will be treated until the drug is approved for commercial use and reimbursed in each 
respective country or until 31 December 2015 (until 31 December 2016 for sites in South 
Korea and Brazil), whichever occurs first. Should pasireotide not be approved for commercial 
use and reimbursed in each respective country, Novartis will have a local transition plan in 
order to ensure that all trial patients will still have access to the study medication without any 
 


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delay in their treatment. End of the study will thus be reached once LPLV (28 days after the 
last dose) in the last participating country has occurred.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Table 7-1 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The study population will consist of patients with persistent or recurrent Cushing’s disease or 
patients with de novo Cushing’s disease that are not considered candidates for pituitary 
surgery (poor surgery candidates, surgically unapproachable tumor, patients with no visible 
pituitary tumor, patients who refuse surgery). A confirmed Cushing’s disease diagnosis is 
required.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered enrollment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following 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. (* if IPSS had previously 
been performed without CRH (e.g.with DDAVP), then a central to peripheral pre-
stimulation gradient > 2 is required. If IPSS had not previously been performed, IPSS 
with CRH stimulation is required)
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)
 


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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
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following 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
11. 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 
 


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2 x ULN, serum creatinine >2.0 x ULN, serum bilirubin >1.5 x ULN, serum albumin < 
0.67 x LLN at screening
12. 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
13. 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)
14. 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
15. Known hypersensitivity to somatostatin analogues
16. 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
17. Patients with presence of Hepatitis B surface antigen (HbsAg)
18. Patients with presence of Hepatitis C antibody test (anti-HCV)
6
Treatment
6.1
Investigational treatment, other treatment, supportive treatment
The investigational study drug used in the course of this trial is pasireotide for subcutaneous 
(s.c.) administration.
6.1.1
Dosing regimen
The starting dose will be:

[Applicable for countries in the European Union] 600 µg b.i.d. (twice daily) in all patients 
also including the ones with impaired glucose metabolism with the option to increase the 
dose to 900 µg b.i.d. if the patient is not controlled (i.e. 24h-mean UFC levels above the
upper limit of normal) at earliest after 2 months of treatment provided the 600 µg b.i.d 
dose is well tolerated by the patient. However ongoing patients in the study at the time of 
approval of amendment 3 will continue on their current dose.
 


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
[Applicable for countries outside the European Union] 900 µg b.i.d. (twice daily). The 
initial dose for patients with impaired glucose metabolism will be 600 µg b.i.d
6.1.2
Treatment duration
Patients will be treated until the drug is approved for commercial use and reimbursed in each 
respective country or until 31 December 2015 (until 31 December 2016 for sites in South 
Korea and Brazil),whichever occurs first. Should pasireotide not be approved for commercial 
use and reimbursed in each respective country, Novartis will have a local transition plan in 
order to ensure that all trial patients will still have access to the study medication without any 
delay in their treatment.
6.2
Dose escalation guidelines
[Applicable for countries in the European Union] Refer to corresponding paragraphs in 
Section 6.2.1.
6.2.1
Dose modifications
Uncontrolled disease [Applicable for countries in the European Union]:
If the patient is not controlled with pasireotide 600 µg b.i.d (i.e. 24h-mean UFC levels above 
the upper limit of normal) after 2 months of treatment, the dose will be increased to 900 µg 
b.i.d provided the 600 µg b.i.d dose is well tolerated by the patient. Dose increase will be 
done as soon as UFC results from Visit 7 are available or at the latest at Visit 8.
In case the dose cannot be increased to 900 µg b.i.d after Visit 7 or at the latest at Visit 8 due 
to tolerability issues, the dose should be considered to be increased at subsequent visits 
provided 24h-mean UFC levels are still above the upper limit of normal and safety issues 
have been resolved.
If patients have been controlled with the 600 µg b.i.d dose but are no longer controlled (i.e. 
24h-mean UFC levels above the upper limit of normal) with this dose at any time in the study
after Visit 7, the dose will be increased to 900 µg b.i.d provided the 600 µg b.i.d dose is well 
tolerated by the patient. Dose increase will be done as soon as UFC results are available or at 
the latest at the next visit.
Disease control:
Patients having sustained mean 24h-UFC normalization evidenced by at least 2 consecutive 
normal 24h-mean UFC may have their pasireotide dose reduced, at the discretion of the 
investigator.

Patients receiving 900 µg s.c. b.i.d., will be reduced to receive 600 µg s.c. b.i.d.

Patients receiving 600 µg s.c. b.i.d., will be reduced to receive 300 µg s.c. b.i.d.
Should UFC levels increase above the upper limit of normal after down-titration, the dose 
should be up-titrated to the previous one.
Safety issues:
For patients who are unable to tolerate the protocol specified dose level, guidelines described 
in Table 6-1 have to be followed.
 


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At any time during the study, patients with an early morning (between 8 and 10 am) serum 
cortisol < 3 µg/dl and a mean 24h-UFC measurement < LLN or symptoms suggestive of 
hypoadrenalism (e.g. postural hypotension, nausea, and abdominal pain) in association with a 
mean 24h-UFC measurement < LLN should have their dose reduced by 300 µg b.i.d. Patients 
should return to their previous dose once the tolerability issue resolves.
Any dose changes must be recorded on the Dosage Administration Record.
6.2.1.1
Follow-up for toxicities
Hyperglycemia
Hyperglycemia is known to be associated with the treatment of somatostatin analogues (SSA).
Clinical studies of pasireotide in healthy volunteers and in patients with Cushing’s disease,
acromegaly or carcinoid syndrome have reported transient, asymptomatic increases in fasting
and postprandial glucose levels. Two clinical studies have been conducted ([SOM230B2216]
and [SOM230B2124]) in healthy volunteers to further understand the mechanism of
pasireotide-induced hyperglycemia and to evaluate the potential clinical utility of anti-
diabetes agents in the management of pasireotide-induced hyperglycemia. Data from
([SOM230B2216] study indicate that pasireotide decreases insulin secretion, particularly in
the postprandial period, as well as the GLP-1/GIP secretion. Results from [SOM230B2124]
study suggest that the incretin-based therapies (GLP-1 analogues and DPP-4 inhibitors) may
have the best potential to manage the hyperglycemia associated with pasireotide. Some
patients in [SOM230B2305] required insulin to treat their hyperglycemia.
Monitoring of blood glucose:
The principal investigator is to educate the patient on the signs and symptoms of 
hyperglycemia. In addition to the laboratory evaluation of blood glucose level at the regular 
scheduled visits (Table 7-1), patients are asked to self-monitor their blood glucose using a 
home glucometer provided by Novartis at least 3 times per week for the first month of 
pasireotide treatment. If the patient does NOT have any fasting values above 100mg/dL, 
monitoring can be decreased to at least 2 times per week for months 2 and 3 and 1 time every 
2 weeks for months 4 through 7. If glucose levels remain normal (below 100mg/dL), 
monitoring is at the investigator’s discretion after month 7. If any values are observed above 
100 mg/dL, the guidelines in figure below are to be followed. These guidelines are based on 
the current recommendations from the 2012 ADA and EASD aiming at a glycemic treatment 
goal of FPG <130 mg/dL (<7.2 mmol/L). Appropriate actions such as initiation of anti-
hyperglycemic therapy (and referral to diabetes specialist) are to be taken by the investigator 
as outlined on Figure 6-1. If fasting blood glucose values dictate initiation of anti-
hyperglycemic treatment (i.e., confirmed >130 mg/dL by self-monitoring), a fasting plasma 
glucose sample using the local laboratory is to be collected prior to initiation of anti-
hyperglycemic treatment. If a patient has a dose increase, monitoring for hyperglycemia 
should follow the recommendations for the first month of treatment and continue as presented 
above for subsequent months.
 


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It is recommended that the patients be encouraged to keep a diary for their blood glucose for 
appropriate management throughout the study and present the collected data to their 
physician/diabetes specialist for evaluation. This data will not be collected by the sponsor.
In addition to self-monitoring, fasting plasma glucose and HbA1c will be collected at study 
visits per Table 7-1. Close and frequent monitoring of blood glucose is needed during 
pasireotide treatment. Intervention for hyperglycemia is to be implemented in any patient 
meeting any of the following criteria: FPG > 130 mg/dL or HbA1c ≥ 6.5 %.
Patients with FPG > 160 mg/dL or HbA1c >7.5% despite adjustment of antidiabetic therapy 
should be referred to a diabetes specialist (or earlier per investigator’s judgment).
Figure 6-1
Fasting self-monitoring blood glucose (SMBG) guidelines
QT prolongation:
If at any visit a QTcF>500 msec is observed, triplicate ECGs, each 2-3 min apart need to be 
taken approximately 1 hour after the initial ECG. The mean QTcF from the triplicate ECGs 
will be determined. If the mean QTcF is >500msec, the patient has to discontinue the study 
medication until a cardiologist has re-evaluated the ECG. The re-evaluation is required to be
done as soon as practical but within 7 days of the initial finding of abnormal ECG. If the 
cardiologist confirms a mean QTcF >500msec, the patient will be withdrawn from the study. 
Otherwise and if the cardiologist confirms that at least one ECG shows QTcF >480msec, the 
cardiac assessments described for a confirmed QTcF >480msec are to be followed.
Repeat within the 
next 24 hours
Repeat within the 
next 24 hours
 


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If at any visit a 480msec < QTcF ≤ 500msec is observed for the first time for a patient at a 
given dose level, the following steps are to be taken (as described in Figure 6-2):

A cardiology consultation must be sought as soon as practical but within 7 days of the 
initial finding of abnormal ECG and the cardiologist is to re-evaluate the ECG

If a QTcF >480msec is NOT confirmed, no further action is to be taken

If a QTcF>480msec is confirmed, a cardiologist must perform a thorough 
examination (such as reviewing baseline ECG, concurrent medications and 
performing a cardiovascular examination (including at least a cardiac auscultation) to 
assess the patient for cardiovascular risk factors).

If based upon the assessment by the cardiologist, the investigator considers that 
there is an acute cardiovascular safety risk and that the patient should not 
continue with study medication, the patient is to be discontinued immediately 
(discontinuation criteria to be followed).

If following the examination by the cardiologist, the investigator considers that 
there is not an acute cardiovascular safety risk and that the patient could continue 
to receive study medication, a 24-hr Holter-ECG is to be recorded as soon as 
practical but within 7 days after the initial finding of abnormal ECG. The Holter 
ECG is to be started 30 minutes prior to an injection of study medication.

The results of the ECGs, cardiac examination, Holter ECG and the 
recommendations by the cardiologist are to be evaluated by the Investigator to 
determine whether the patient should continue in the trial or not (discontinuation 
criteria to be followed)
 


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Figure 6-2
QT Prolongation Monitoring Flow Chart
Perform ECG
QTcF > 500
msec?
Perform triplicate ECGs after 
~1hr, each 2-3 min apart
Interrupt study treatment 
and obtain cardiologist 
consultation on ECG
(≥1 ECG 
with) QTcF 
> 480 msec?
Patient can 
continue/
resume study 
treatment
Mean QTcF 
> 500 msec?
Obtain cardiologist 
consultation on ECG
Cardiologist performs thorough 
examination to assess patient for 
cardiovascular risk factors
Acute 
cardiovascular 
safety risk? / 
Discontinuation 
criteria met?
Patient meets 
discontinuation 
criteria?
Cardiologist 
confirms Mean 
QTcF > 500
msec
Patient is discontinued
Patient can continue / 
resume study treatment
Cardiologist 
confirms (≥1 
ECG with) QTcF 
> 480 msec
Time Period: As soon as practical but within 7 Days of initial QTcF > 480 msec finding
YES
Perform 24-hour Holter ECG 
(Start pre-dose 30 min)
NO
NO
YES
YES
NO
YES
NO
YES
NO
NO
YES
YES
Cardiologist evaluates Holter 
ECG and provides 
recommendation to investigator
Investigator assess cardiologist 
results and recommendations
 


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Hepatic safety management:
If any of the criteria below are observed at any scheduled or unscheduled visit the sponsor 
should be notified immediately upon awareness.

ALT or AST > 3 x ULN and Total Bilirubin ≥2 x ULN

ALT or AST > 5 x ULN and ≤8 x ULN

ALT or AST > 8 x ULN
The following should be performed immediately within 72 hours of awareness of the 
abnormality:

Perform liver-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including OTC meds, inter-current illness, etc)

Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if 
total bilirubin is > 2.0 x ULN), Albumin, PT (INR), ALP, and GGT

Perform hepatitis screen: anti-HAV, IgM (to confirm acute Hepatitis A), HbsAg, Anti-
HBc, anti-HCV (if positive, PCR viral load should be assessed), Anti-HEV, ANA 
antibodies, anti-smooth muscle anti-bodies, CMV and EBV

Perform abdominal ultrasound (liver and biliary tree)
Liver chemistry tests (LFTs) should be monitored every 3-4 days until resolution or return to 
baseline status.
Patients or subjects may need to be discontinued if the abnormal liver function criteria are met 
upon LFT retesting (See discontinuation criteria Section 7.1.3.1). Progress reports of the event 
should be maintained until resolution or stabilization (i.e. no further elevation after 2 
consecutive assessments).
For ALT or AST > 5 x ULN and ≤ 8 x ULN, the following must occur (in addition to the 
safety follow up procedures noted above)

Study medication should be temporarily interrupted and liver chemistry tests monitored 
every 3-4 days until resolution or return to baseline.

If resolution or return to baseline does not occur after 2 weeks, the patient should be 
discontinued.

If ALT or AST return to less than 5 x ULN study drug can be resumed and patient can 
continue study per protocol.

If ALT or AST rises above 5 x ULN anytime after study drug is resumed, then study drug 
should be discontinued immediately.
If any of these criteria are met and deemed an adverse event by the investigator, the event 
must be recorded on the Adverse Event (e) CRF page; if the event is deemed serious by the 
investigator, then proceed with completing the SAE form. In addition, any significant findings 
from the physical examination should be recorded on the Adverse Event (e) CRF page.
 


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Figure 6-3
LFT management algorithm
6.2.2
Treatment interruption and treatment discontinuation
Patients experiencing unacceptable toxicity (AE grade 3 or higher) that the investigator 
considers directly attributable to pasireotide should have their dose reduced or should be 
withdrawn from the study. Table 6-1 should be regarded as a guideline for the treatment of 
patients experiencing Adverse Events which are judged to be drug related. Any deviation 
from these guidelines should be discussed and approved by the sponsor.
Adverse events are described as mild (Grade 1), moderate (Grade 2), severe (Grade 3) or life-
threatening (Grade 4). Guidelines for treatment of patients experiencing adverse events are 
indicated below (Table 6-1).
 


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Table 6-1
Guideline for treatment of patients experiencing adverse events
Patients
Adverse event
Action
All
AE grade ≤ 2 (mild to moderate)
No drug adjustments
AE grade ≥ 3 (severe to life-
threatening) and judged as drug 
related*#
Reduce dose by 300 µg b.i.d.
If AE improves to grade ≤ 2 within 1 week, 
increase dose by 300 µg b.i.d. If AE recurs at 
grade ≥ 3, reduce dose by 300 µg b.i.d. again
and remain at lower dose. If AE does not 
improve to grade ≤ 2 within 1 week on lower 
dose, reduce dose by 300 µg b.i.d. again if 
possible. If AE does not improve to grade ≤ 2 
within 1 week on 300 µg b.i.d., patient is to 
discontinue treatment.
For patients experiencing hyperglycemia, the 
dose should be reduced if the severity grade 3 or 
greater persists despite appropriate 
management.* If the hyperglycemia is 
considered to be life-threatening, the patient 
should be withdrawn regardless of anti-diabetes 
treatment.
* CTCAE v3.0 grades diabetes that is treated with insulin as a grade 3. However, diabetes grade 3 will 
require a study drug dose reduction only in cases of uncontrolled hyperglycemia despite of appropriate 
management.
# No dose reductions are required in case of a QT prolongation but guidelines for QT monitoring and 
discontinuation criteria must be observed.
Note: for hepatic safety management follow Section 6.2.1.1.
If a patient permanently discontinues study treatment, the patients will be considered as 
prematurely discontinued from the study. Patients will have to perform a study phase 
completion evaluation on the day of the last study drug administration (refer to Study Phase 
Completion evaluation in Table 7-1).
Patients must be transitioned to commercial pasireotide within 6 weeks after approval and 
reimbursement in each respective country. Patients who complete the study because they are 
transitioned to commercial pasireotide are considered completed and will have to perform a 
study phase completion evaluation on the day of the last study drug administration (refer to 
Study Phase Completion evaluation in Table 7-1).
Patients who are treated until 31 December 2015 (until 31 December 2016 for sites in South 
Korea and Brazil) will be considered as completed patients. They will have to perform a study 
phase completion evaluation on the day of the last study drug administration (refer to Study 
Phase Completion evaluation in Table 7-1).
6.3
Concomitant medications
All medications, including over the counter medications (OTC), taken prior to the first study 
drug administration and which continue after visit 2 (beginning of the treatment) are to be 
recorded on the Concomitant Medication section of the CRF.
However, investigators should discourage patients from taking any medication during the 
study, with the exception of medications that are required to treat an adverse event.
 


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6.3.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy and blood transfusions) administered during 
the study must be listed on the Concomitant Medications or the Procedures and Significant 
Non-Drug Therapies CRF, respectively.
Diabetic patients must continue their treatment for diabetes throughout the study as indicated
by their physician/diabetes specialist.
6.3.2
Prohibited concomitant therapy
Rosiglitazone and pioglitazone treatment are not permitted during the study as they could 
affect the patient’s ACTH levels.
Further, the use of concomitant medications with known risk of TdP is prohibited and requires 
the discontinuation of the patient prior to starting the respective medication with known risk 
of TdP. The list of updated medications with known risk of TdP can be found at the following 
link: http://crediblemeds.org/
6.4
Patient numbering, treatment assignment and randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available to the investigator. Once assigned, the Subject No. must not 
be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened.
If the patient fails to be assigned to treatment for any reason, the reason will be entered into 
the Screening Disposition page.
6.4.2
Treatment assignment and randomization
Randomization is not applicable in the study.
6.4.3
Treatment blinding
This is an open-label study and blinding is not applicable.
6.5
Study drug supply
6.5.1
Study drug preparation and dispensation
Novartis will supply the investigational drug in 1 ml ampoules containing 900 µg, 600 µg, or 
300 µg pasireotide per 1 ml of solution.
 


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Patients must be able to self-administer the study drug (subcutaneous injections) and are to 
receive instruction from the site staff or investigator on the correct procedures. They should 
be advised to avoid multiple injections at, or near the same site. Ampoules may not be re-
used; a new ampoule should be used for each injection. Patients should be instructed to retain 
and return unused ampoules at their next scheduled visit.
All dosages prescribed to the patient and all dose changes during the study must be recorded 
on the Dosage Administration Record CRF.
6.5.2
Study drug packaging and labeling
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug but no information about the 
patient.
6.5.3
Drug supply and storage
Study treatments must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, pasireotide should be stored according to the 
instructions specified on the drug labels.
6.5.4
Study drug compliance and accountability
6.5.4.1
Study drug compliance
The investigator should instruct the patient to take the study drug exactly as prescribed 
(promote compliance).
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
6.5.4.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability ledger. Drug accountability will be noted by the 
field monitor during site visits and at the completion of the study. Patients will be asked to 
return all unused study treatment and packaging on a regular basis.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
6.5.5
Disposal and destruction
The drug supply can be destroyed at the local Novartis facility, Drug Supply group or third 
party, as appropriate.
 


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column).
 


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Table 7-1
Visit evaluation schedule
Category
Reference 
to Section
Screening
Baseline
Study period
Study 
Phase 
Completion
Study 
Completion
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13, 14,….a
776
777
Study Week
7.1.2.
-3 to 0
0
1
2
3
4
8
12
16
20
24
36
48, 60,… a
Last dose
Last dose + 4
Study days
7.1.2.
-21 to -1
0
7
14
21
28
56
84
112
140
168
252
336, 420, …. a
Last dose
Last dose + 28
Obtain Informed Consent
D
X
Demography
D
7.1.1.2.
X
Inclusion/exclusion criteria
D
X
Complete Inclusion / Exclusion Criteria 
Checklist
X
Relevant medical history/current 
medical conditions
D
X
Physical examination
S
7.2.2.1.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Karnofsky performance status
D
7.2.2.3.
X
X
X
X
X
X
Height
D
7.2.2.1.
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gallbladder Ultrasound
D
7.2.2.6.
X
X
X
X
Xb
X
Hematology, GH, IGF-1
D
7.2.2.4.1, 
7.2.2.4.3.
X
X
X
X
X
X
X
X
Xb
X
Free T4, TSH
D
7.2.2.4.3.
X
X
X
Xb
X
Blood Chemistry (including Total 
proteins, amylase, lipase, total 
cholesterol (TC), LDL-cholesterol, 
triglycerides, sodium, potassium, 
magnesium, urea, serum creatinine, 
creatinine clearance)
D
7.2.2.4.3.
X
X
X
X
X
X
X
X
X
X
LFT (ALT, AST, total bilirubin, 
Albumin, ALP, and GGT)
D
7.2.2.4.3.
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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Category
Reference 
to Section
Screening
Baseline
Study period
Study 
Phase 
Completion
Study 
Completion
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13, 14,….a
776
777
Study Week
7.1.2.
-3 to 0
0
1
2
3
4
8
12
16
20
24
36
48, 60,… a
Last dose
Last dose + 4
Study days
7.1.2.
-21 to -1
0
7
14
21
28
56
84
112
140
168
252
336, 420, …. a
Last dose
Last dose + 28
Coagulation (PT, INR)
D
7.2.2.4.2.
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood Glucose
D
7.2.2.4.3.
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Insulin
D
7.2.2.4.3.
X
X
X
X
X
X
X
X
X
X
X
HbA1C
D
7.2.2.4.3.
X
X
X
X
X
X
X
Vitamin B12
D
7.2.2.4.3.
X
X
X
X
Urinary free cortisol and urine 
creatinine
D
7.2.1.1.1.
X
X
X
X
X
X
X
X
X
X
Serum cortisol
D
7.2.1.1.2.
X
X
X
X
X
X
X
X
X
X
X
Plasma ACTH
D
7.2.1.1.2.
X
X
X
X
X
X
X
X
X
X
X
HbsAg and anti-HCV
D
7.2.2.4.6.
X
Signs and symptoms of Cushing’s 
disease
D
7.2.1.1.3.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cushing’s syndrome HRQoL and 
WPAI-GH questionnaire
D
7.2.1.1.4
7.2.1.1.5.
X
X
X
X
X
X
X
Urinalysis
D
7.2.2.4.4.
X
X
X
X
Xb
X
Serum Pregnancy test
D
7.2.2.4.5.
X
X
X
X
ECG
D
7.2.2.5.1.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
D
8.1.
Continuously
Prior/Concomitant medications
D
6.3.
X
Continuously
Drug administration
D
6.1.
Continuously
Study phase completion record
D
7.1.3.
X
Study completion record
D
7.1.4.
X
 


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Category
Reference 
to Section
Screening
Baseline
Study period
Study 
Phase 
Completion
Study 
Completion
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13, 14,….a
776
777
Study Week
7.1.2.
-3 to 0
0
1
2
3
4
8
12
16
20
24
36
48, 60,… a
Last dose
Last dose + 4
Study days
7.1.2.
-21 to -1
0
7
14
21
28
56
84
112
140
168
252
336, 420, …. a
Last dose
Last dose + 28
a One visit every 12 weeks/84 days until patients are transitioned to commercial pasireotide or until 31 December 2015 (until 31 December 2016 for sites in South Korea 
and Brazil), whichever comes first
b To be done every 24 weeks after visit 13
D
Data/assessments to be entered in the database
S
Data/assessments that remain in source documents only, not to be recorded on CRF
 


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7.1.1
Screening
After the informed consent is obtained, screening evaluations will be performed to assess 
eligibility for study entry prior to administration of any study drug (Week -3 to 0).
Informed consent must be obtained before starting the washout periods for the drugs indicated 
in the protocol. The washout period for the drugs indicated in the inclusion criteria need to be 
completed before urine, blood and saliva collections at screening are started.
Enrollment and eligibility confirmation
In order to determine and confirm the eligibility of the patient, when all screening procedures 
are complete, a key eligibility checklist must be completed manually by the investigator or 
designee prior to receiving the first dose.  After the eligibility has been checked and the 
patient is confirmed as eligible for the trial, the patient can then be enrolled into the trial.  This 
checklist must be submitted to the sponsor for approval prior to study enrollment.
7.1.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered 
on the Screening Log Page. The demographic information, must also be completed for Screen 
Failure patients. No other data will be entered into the clinical database for patients who are 
screen failures, unless the patient experienced a Serious Adverse Event during the Screening 
Phase (see Section 8 for SAE reporting details).
7.1.1.2
Patient demographics and other baseline characteristics
Standard demographic information and medical history will be collected at visit 1. Cushing’s 
disease history and DM history together with the medication/treatment used will be collected.
7.1.2
Treatment period
Patients will be treated until the drug is approved for commercial use and reimbursed in each 
respective country or until 31 December 2015 (until 31 December 2016 for sites in South 
Korea and Brazil), whichever occurs first.
Patients who are transitioned to commercial pasireotide s.c. will be considered as completed 
as per protocol requirements (refer to Section 6.1.2).
All visits should be performed on the indicated days. Should this not be possible, the 
following visit windows apply: +/- 2 days from visit 3 to 11 and +/- 5 days from visit 12 
onwards. The Study Phase Completion visit has to be performed on the day of the last study 
drug administration (+ 5 days). The Study Completion visit has to be performed 28 days (+/- 5
days) after the patient received the last pasireotide s.c. dose.
7.1.3
Study phase completion visit, including premature withdrawal and 
study discontinuation visit
Patients who permanently discontinue the study drug should be considered prematurely 
discontinued from the study Patients will have to perform a study phase completion 
 


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evaluation on the day of the last study drug administration (refer to Study Phase Completion 
evaluation in Table 7-1).
If a withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Phase Completion CRF page. If patients refuse to return for 
these visits or are unable to do so, every effort should be made to contact them.
Patients who complete the study because they are transitioned to commercial pasireotide or 
patients who are treated until 31 December 2015 (until 31 December 2016 for sites in South 
Korea and Brazil) will have to perform a study phase completion evaluation on the day of the 
last study drug administration (refer to Study Phase Completion evaluation in Table 7-1). A 
Study Phase Completion CRF page has to be completed.
7.1.3.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time.
Patients must be withdrawn from the study if any of the following occurs:

Patients experiencing unacceptable drug-related toxicity (as described in Table 6-1)

Uncontrolled diabetes mellitus (DM), consistently high capillary glucose values in excess 
of 275 mg/dL (15.5 mmol/L), FPG ≥ 240 mg/dL (13.3 mmol/L) or HbA1c value ≥ 10 % 
despite prior appropriate management and prior dose adjustment of the study drug,

Patients experiencing adverse events in QTc:

a confirmed QTcF > 480msec and discontinuation recommended by a cardiologist, or

Mean QTcF > 500msec measured by triplicate ECGs and confirmed by a cardiologist

Significant arrhythmia findings from Holter monitoring such as:
1. Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms
of hemodynamic compromise
2. Sustained ventricular tachycardia (>30 sec) irrespective of symptoms
3. Recurrent non-sustained VT (≥ 3 beats) during any 24-hour monitoring period
4. Torsades de Pointes (TdP)
5. Cardiac arrest
6. Pause >5 seconds
7. Second or third degree AV block

New occurrence of clinically significant/symptomatic bradycardia, or

Increased risk of QT prolongation by use of medications with known risk of TdP, or

Hypokalemia (<3.5 mmol/L) or hypomagnesaemia (<0.5 mmol/L) confirmed by 
repeat testing that is either a new finding or accompanied by vomiting or diarrhea and 
not corrected by treatment.

Evidence of hypoadrenalism: defined as an early morning (between 8 and 10 am) serum 
cortisol < 3 µg/dL and a mean 24h-UFC measurement < LLN or symptoms suggestive of 
 


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hypoadrenalism (e.g. postural hypotension, nausea, and abdominal pain) in association 
with a mean 24h-UFC measurement < LLN, which persist after drug dose adjustment

Lack of efficacy: consistently elevated mean 24h-UFC level and lack of clinical benefit
after ≥3 months treatment

Pregnancy

Patient experiencing

ALT or AST > 3 x ULN and Total Bilirubin ≥2 x ULN and ALP < 2 x ULN

ALT or AST > 5 x ULN and ≤8 x ULN persistent for more than 2 weeks

ALT or AST > 8 x ULN
If any of those 3 discontinuation criteria are met, study medication should be discontinued 
immediately. In addition, proper safety follow-up management should be performed as 
outlined in
Section 6.2.1.1. Re-challenge of study medication is prohibited once 
discontinuation criteria are met.
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Completion CRF page. Patients may be withdrawn from the 
study prematurely for one of the following reasons:

Adverse event(s)

Abnormal laboratory value(s)

Abnormal test procedure result(s)

Protocol violation

Subject withdrew consent

Lost to follow-up

Administrative problems

Death
7.1.4
Follow up period
All patients must have a safety evaluation during the Study Completion visit, 28 days after the 
last dose of study treatment.
A Study Completion CRF page should be completed giving the date and reason for stopping 
the study treatment.
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
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7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Secondary parameters
7.2.1.1.1 Mean 24-hour urinary free cortisol (UFC)
Screening urinary free cortisol will be measured in three 24-hour urine specimens collected 
during the screening period (24-h urine collections will have to be performed within the first 8 
to 10 days of the screening period so that to have 24h-UFC results available before visit 2). 
The 24h-UFC concentration results from these three samples will be averaged to obtain the 
baseline urinary free cortisol level. During the study, mean 24h-UFC will be determined at 4-
week intervals until week 24. At week 4, 8, 16 and 20, mean 24h-UFC will be 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, will be determined. After week 24, the mean 24h-
UFC will be 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). For 
each sample, the first urine of the day will be discarded, all subsequent urine has to be 
collected in the specimen container, including the last urine of the 24-hr period. The urine 
sample will be checked for volume and creatinine will be measured from the urine sample by 
the central laboratory.
UFC will be determined by LC/MS/MS. The normal ranges will be determined by the central 
laboratory’s own reference range. All samples, including screening samples, will be analyzed 
by a central laboratory. Procedures for sample collection, handling, storage and transportation 
will be provided in detail to the sites by the central laboratory.
7.2.1.1.2 Serum cortisol and plasma ACTH
A predose blood draw for plasma ACTH and serum cortisol assessment will be taken. Blood 
samplings will be done as indicated in Table 7-1. Procedures for sample drawing, handling, 
storage and transportation will be provided by the central laboratory.
7.2.1.1.3 Clinical signs and symptoms
The following clinical signs and symptoms will be assessed:
Manual blood pressure
Sitting and standing blood pressure will be recorded at every indicated visit. The arm in which 
the highest sitting pressures are found at screening will be the arm used for all subsequent 
readings throughout the study. If there is a discrepancy between the arms regarding the 
highest systolic and diastolic value, the arm with the highest mean blood pressure will be used 
according to the following formula: mean BP=DBP + (SBP - DBP)/3. All attempts should 
be made to have the same individual obtain blood pressure readings from each individual 
patient at each visit at the same time of the day with the same equipment.
 


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Arterial blood pressure determinations will be made in accordance with the (1988 AHA 
Committee Report) on blood pressure determination (Circulation 88: 2460-2467, 1993). With 
the arm supported at the level of the heart, systolic pressure will be recorded when the initial 
sound is heard (Phase I of the Korotkoff sound); diastolic pressure will be recorded at the 
disappearance of the sound (Phase V of the Korotkoff sound). At each study visit, after having 
the patient in a sitting position for five minutes, systolic/diastolic blood pressure will be 
measured three times. The repeat measurements are to be made at one- to two-minute 
intervals. No up-and-down rounding is allowed. The mean of all three sitting measurements is 
decisive for study specific procedures.
Weight
Body weight will be measured at every indicated visit using a calibrated balance. The balance 
should be placed on a hard flat surface, and checked for zero balance before each 
measurement. The patient should stand unassisted, in the center of the platform, and be asked 
to look straight ahead, standing relaxed but still. The patient should wear light underclothing 
and/or a paper examining gown and paper slippers. Shoes and socks should not be worn.
Body mass index (BMI)
BMI will be derived from the height and weight measurements.
Waist circumference
Waist circumference will be measured at all indicated visits. Patients should remove clothing 
from around the waist to ensure the measuring tape is correctly positioned. Using a cosmetic 
pencil, make a mark at the “natural waist” midway between the palpated iliac crest and the 
palpated lowest rib margin in the left and right mid-axillary lines. Place the non-stretchable 
tape evenly around the natural waist covering the left and right natural-waist marks. The 
measurement scale should face outward, and there should be no twists in the tape. Ensure that 
the tape is just touching the skin but not compressing the soft tissue. Instruct patients to stand 
erect with abdomen relaxed, arms at sides, feet together, and weight divided equally over both 
legs.
Facial rubor, hirsutism, striae, bruising and supraclavicular and dorsal fat pad
These signs and symptoms will be evaluated by the investigator as per visit evaluation
schedule (refer to Table 7-1). For assessment of hirsutism, the Ferriman-Gallway score, a 
method of evaluating and quantifying hirsutism in women, will be used. Female patients will 
be asked not to shave during 3 weeks prior to corresponding visits if possible.
Muscle strength
To test proximal muscle strength patients should be placed in a low seated position (for 
instance on an examination room stool). They should be asked to extend the arms in front of 
them. From this seated position patients will be asked to stand up. Patients will be evaluated 
using the following scale:

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
2.- able to stand only by using arms as assistance

1.- able to stand after several efforts without using arms as assistance

0.- able to stand easily with arms extended
7.2.1.1.4 Quality of Life
A Cushing's syndrome HRQoL questionnaire (CushingQOL, Webb et al 2008) will be used in 
this study to monitor patients' HRQoL. This questionnaire will be completed by the patient as 
per visit evaluation schedule (refer to Table 7-1).
7.2.1.1.5 Work Productivity and Activity Impairment – General Health Questionnaire
The Work Productivity and Activity Impairment – General Health (WPAI-GH) questionnaire 
will be used in this study to assess patient-reported quantitative assessment of the amount of 
absenteeism, presenteeism, and daily activity impairment attributable to their disease. This 
questionnaire will be completed by the patient as per visit evaluation schedule (refer to Table 
7-1).
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing the evaluations described below and the collection of
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.
7.2.2.1
Physical examination, height
A complete physical examination will be performed by the investigator at every visit. Height 
will be recorded at visit 1 only.
Information about the physical examination findings will be presented in the source 
documentation at the study site. Significant findings that were present prior to the signing of 
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Conditions page on the patient’s CRF. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event page of the patient’s CRF.
If, at visit 2, the complete physical examination occurred within the last 4 days of the baseline 
visit, it does not have to be repeated at baseline.
7.2.2.2
Vital signs
Blood pressure, body temperature and heart rate will be measured at every visit and recorded 
in the CRF.
7.2.2.3
Performance status
The Karnofsky performance scale index will be used to evaluate the performance status of the 
patients and assessed at visits indicated in Table 7-1.
7.2.2.4
Laboratory evaluations
The following laboratory evaluations will be performed during the study:
7.2.2.4.1 Hematology
Hematology assessment will include: hemoglobin, hematocrit, red blood cell count, platelets, 
total white blood cell count (WBC) absolute & differential including neutrophils, 
lymphocytes, monocytes, eosiniphils, basophils.
7.2.2.4.2 Coagulation
The prothrombin time (PT) will be reported in seconds and as international normalized ratio 
(INR).
7.2.2.4.3 Clinical chemistry
The following tests will be performed at each scheduled visit as indicated in Table 7-1: total 
proteins, amylase, lipase, total cholesterol (TC), LDL-cholesterol, triglycerides, sodium, 
potassium, magnesium, urea, serum creatinine, creatinine clearance, thyroid function test (free 
T4 and TSH), fasting blood glucose, fasting insulin, glycosylated hemoglobin (HbA1C), and 
assessment of Vitamin B12, GH and IGF-1.
Liver function tests (LFT)
LFT will be performed at each scheduled visit as indicated in Table 7-1 and will include ALT, 
AST, total bilirubin, albumin, ALP, and GGT.
7.2.2.4.4 Urinalysis
A urinalysis test (specific gravity, pH, glucose, proteins, bilirubin, ketones, leucocytes, and 
blood) is required as per Table 7-1.
7.2.2.4.5 Pregnancy test
For women of childbearing potential, a serum pregnancy test (β-HCG) will be performed as 
indicated in Table 7-1. During treatment, an additional test will be performed if menses are 
 


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delayed for more than 7 days. In case of pregnancy, patients must be withdrawn from the 
study.
7.2.2.4.6 Serology
Hepatitis B surface antigen (HbsAg) as well as Hepatitis C antibody (anti-HCV) test will be 
performed at screening.
7.2.2.5
Cardiac assessments
7.2.2.5.1 Electrocardiogram (ECG)
A 12-lead ECG will be performed at the sites, in lying position, at all indicated visits as per 
Table 7-1.
All ECGs should include all 12 standard leads and a Lead II rhythm strip of at least a 10-
second duration. The ECGs will be evaluated locally.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG CRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History CRF page. Clinically significant findings 
must be discussed with the Medical Monitor prior to enrolling the patient in the study. New or 
worsened clinically significant findings occurring after informed consent must be recorded on 
the Adverse Events CRF page. In case of confirmed QTcF> 480msec, a Holter ECG will be 
required for patients continuing in the study (described in Section 6.2.1.1).
7.2.2.6
Gallbladder ultrasound
A gallbladder ultrasound will be performed at the sites at visits indicated in Table 7-1. The 
results will be recorded in the CRF.
 


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. Abnormal laboratory values or test results occurring 
after informed consent constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy (e.g., hematologic 
abnormality that requires transfusion or hematological stem cell support), or require changes 
in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF under the signs, symptoms or diagnosis associated with them. Conditions that 
were already present at the time of informed consent should be recorded in the Medical 
History CRF.
Adverse event monitoring and reporting will be continued for at least 28 days following the 
last dose of study treatment.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
 


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used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected through a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:
1. The severity grade (grade 1-4)
2. Its relationship to the study drug (suspected/not suspected)
3. Its duration (start and end dates or if continuing at final exam)
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization)
5. Whether it is serious, where a serious adverse event (SAE) is defined as per Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be
required by the protocol and is still, by definition, an adverse event.
 


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8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Protocol exempt SAEs: SAEs specifically defined in the protocol and where there has 
been a clear agreement with regulators not to collect these SAEs in the safety database, 
provided the information is collected elsewhere. For example, this may include serious 
adverse events that are also a primary outcome measure, such as mortality, survival rate or 
number of flares of the condition being studied.
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 28 days after the patient has stopped study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after this 28 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report Form in 
English, and send the completed, signed form by fax within 24 hours to the oncology Novartis 
Drug Safety and Epidemiology (DS&E) department.
 


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The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or withdrew from 
study participation.
In addition, for Pasireotide s.c the following events are of special interest for targeted follow-
up and should be notified to Novartis DS&E in the same manner as a SAE.

Arrhythmogenic

Bradycardia

Coagulation

Constipation

Convulsions

Diabetes insipidus

Diarrhoea

Gallbladder and biliary related AEs

GI bleeding

Growth hormone deficiency

Hyperglycemia

Hypocalcemia

Hypocortisolism

Hypotension

Hypothyroidism

Injection site reaction

Liver safety

Low blood cell

Nausea

Pancreatitis

QT-prolongation

Rhabdomyolysis
8.3
Emergency unblinding of treatment assignment
Not applicable.
 


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8.4
Pregnancies
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
No Data monitoring Committee will be established in this study.
8.7
Steering Committee
No Steering Committee will be established in this study.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period.
 


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The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
The designated investigator staff will enter the data required by the protocol into the 
Electronic Case Report Forms (eCRF). The eCRFs have been built using fully validated 
secure web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site 
staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs and, allow modification or 
verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data in CRFs is complete, 
accurate, and that entry and updates are performed in a timely manner.
 


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9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
The results of laboratory/Biomarker samples processed centrally will be sent electronically to 
Novartis (or a designated CRO) for inclusion in the clinical database.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After this action has been completed and the data has been verified to be complete and 
accurate, the database will be declared locked. Authorization is required prior to making any 
database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development.
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site.
10
Statistical methods and data analysis
Data will be analyzed by Novartis and/or a designated CRO. It is planned that the data from 
all centers that participate in this protocol will be used. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation.
Final analyses will be performed when all patients have been followed for 28 days after they 
have either prematurely discontinued pasireotide s.c. or after completing treatment as per 
protocol (i.e. when the study drug is approved for commercial use and reimbursed in each 
respective country or until 31 December 2015 (until 31 December 2016 for sites in South 
Korea and Brazil), whichever occurs first).
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of 
pasireotide s.c.
 


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10.1.2
Safety Set
The safety set includes all patients who received at least one dose of pasireotide s.c. and had 
at least one post-baseline safety assessment.
Please note: the statement that a patient had no adverse events (on the Adverse Event CRF) 
constitutes a safety assessment.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively for the FAS. Categorical data will be presented as frequencies and percentages. 
For continuous data, the mean, standard deviation, median, minimum, and maximum will be 
presented.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
Descriptive statistics will be used to summarize the mean daily dose and duration of 
pasireotide s.c. The actual and planned doses administered and reason for dose change will be 
listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by ATC class and preferred term.
These analyses will be performed on the safety set.
10.4
Primary objective
Refer to Section 3.
10.4.1
Variable
The primary variable is the proportion of patients having a drug-related adverse event that was 
recorded as grade 3 or 4, or as a serious adverse event.
The analysis of the primary variable is described in Section 10.5.2.2.
10.4.2
Statistical hypothesis, model, and method of analysis
No statistical hypotheses are being tested in this study.
10.4.3
Handling of missing values/censoring/discontinuations
Not applicable. All attempts will be made to ensure that the database contains full information 
for all safety data.
10.4.4
Supportive analyses
Not applicable.
10.5
Secondary objectives
Refer to Section 3.
 


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10.5.1
Secondary efficacy variables
The secondary efficacy analysis will be performed on the FAS. Unless noted otherwise, 
missing values will not be imputed in these analyses. The parameters assessed at screening 
and not at baseline are to be considered as baseline.
10.5.1.1 Normalization of mean 24h-UFC at Week 12, 24 and 48
The number and percentage with corresponding exact two-sided 95% CI of patients achieving 
normalization of mean 24h-UFC (i.e. mean 24h-UFC ≤ 1.0xULN) at Week 12, 24 and 48
(separately) will be presented.
If Week 24 mean 24h-UFC is missing then it will be imputed by the last available mean 24h-
UFC of at least two samples between and including Week 12 and Week 24, and if Week 48 
mean 24h-UFC is missing then it will be imputed by the last available mean 24h-UFC of at 
least two samples between and including Week 12and Week 48. Summaries with and without 
imputing missing Week 24 and Week 48 mean 24h-UFC will be presented.
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments.
10.5.1.2 Reduction of mean 24h-UFC ≥50% from baseline to Week 12, 24 and 
48
The number and percentage with corresponding exact two-sided 95% CI of patients achieving 
a reduction of mean 24h-UFC ≥ 50% from baseline to Week 12, 24 and 48 (separately) will 
be presented.
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments.
10.5.1.3 Change from baseline in mean 24h-UFC to Week 12, 24 and 48
Descriptive summaries of actual and percentage change with corresponding two-sided 95% 
CIs in mean 24h-UFC from baseline to Week 12, 24 and 48 will be provided.
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments.
10.5.1.4 Changes from baseline in GH and IGF-I to Week 12, 24 and 48
Descriptive summaries of actual and percentage change in mean GH and IGF-1 values from 
baseline to Week 12, 24 and 48 will be provided.
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments.
10.5.1.5 Clinical signs and symptoms
The following clinical signs of Cushing’s disease will be assessed by descriptive summaries 
of the change in systolic BP (standing and sitting), diastolic BP (standing and sitting), BMI, 
waist circumference and weight from baseline to each post-baseline visit. In addition, the 
proportion of patients satisfying the clinically relevant thresholds specified in the following 
 


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table will be calculated along with the exact two-sided 95% CIs at each scheduled post-
baseline assessment.
Clinical signs
Unit, Scale
Clinically relevant threshold (at 
any timepoint)
Standing Systolic BP
mmHg
≤ 140 mmHg
Sitting Systolic BP
mmHg, mean of 3 assessments
mean of 3 assessments ≤ 140 
mmHg
Standing Diastolic BP
mmHg
≤ 90 mmHg
Sitting Diastolic BP
mmHg, mean of 3 assessments
mean of 3 assessments ≤ 90 
mmHg
BMI
kg/m2, Class levels: < 25.0, 25.0 to < 
30.0, ≥ 30.0
% of patients reducing by at least 
one class level
Waist circumference
cm
Reduction of ≥ 5%
Reducing of ≥ 10%
Weight
Kg
Reducing of ≥ 5%
The following clinical signs and symptoms of Cushing’s disease will be assessed by 
descriptive summaries of changes and shifts from baseline to each scheduled post-baseline 
assessment. The clinical signs and symptoms that will be analyzed and the corresponding 
methods of analyses are provided in the following table.
Clinical signs and 
symptoms
Scale
Analyses methods
Facial Rubor 
(redness)
0=none, 1=mild, 2=moderate, 3=severe
Investigator interpretation,
Counts & shifts from baseline.
Hirsutism 
(Ferriman-Gallway 
scoring)
0=minimum, 36=maximum
Scoring in females only
Investigator interpretation,
Ferriman-Gallway score,
Actual and % change from baseline
Supraclavicular fat 
pads
0=none, 1=mild, 2=moderate, 3=severe
Investigator interpretation,
Counts & shifts from baseline.
Dorsal fat pads
0=none, 1=mild, 2=moderate, 3=severe
Investigator interpretation,
Counts & shifts from baseline.
Muscle strength
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
Direct observation of ability to stand 
unaided.
Counts & shifts from baseline.
Striae
0=none, 1=mild, 2=moderate, 3=severe
Investigator interpretation,
Counts & shifts from baseline.
Bruising
0=none, 1=mild, 2=moderate, 3=severe
Investigator interpretation,
Count s & shifts from baseline.
 


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10.5.2
Safety objectives
10.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication,
2. On-treatment period: from day of first dose of study medication to 28 days after last dose 
of study medication
3. Post-treatment period: starting at 29 days after last dose of study medication
10.5.2.2 Adverse events (AEs)
The definition of an adverse event for this study can be found in Section 8.1.
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre and post-treatment period will be flagged.
For the primary objective of the study, the number and percentage of patients having any 
drug-related adverse event that was recorded as a grade 3 or 4, or as a serious adverse event 
will be summarized by system organ class and/or preferred term, severity (based on CTCAE 
grades), type of adverse event and relation to study treatment.
In addition, the incidence of treatment-emergent adverse events (new or worsening from 
baseline) will be summarized by system organ class and/or preferred term, severity (based on 
CTCAE grades), type of adverse event and relation to study treatment. Deaths will be listed 
and summarized by cause of death.
10.5.2.3 Laboratory abnormalities
The summaries will include all laboratory assessments collected no later than 28 days after 
study treatment discontinuation. All laboratory data will be listed and those collected later 
than 28 days after study treatment discontinuation will be flagged in the listings.
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0, the study’s biostatistics and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-
missing values not graded as 1 or higher. Grade 5 will not be used. In the unlikely case when 
a laboratory normal range overlaps into the higher (i.e. non-zero) CTC grade, the laboratory 
value will still be taken as within normal limits and assigned a CTC grade of zero.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.The following summaries 
will be produced for the laboratory data (by laboratory parameter):

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value,
 


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
For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high classification to compare baseline to the worst on-treatment value,

Shift tables of fasting glucose and related biochemical parameters using the ADA (2010) 
or similar low/normal/high classifications to compare baseline to the worst and last on-
treatment value.
The following listings will be produced for the laboratory data:

Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges,

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
10.5.2.4 Other safety data
Vital signs
The parameters collected are: height (cm), weight (kg), body temperature (°C), heart rate 
(beats per minute), systolic and diastolic blood pressure (mmHg).
The criteria for clinically notable abnormalities are defined as follows:
Clinically notable elevated values

Systolic BP: 180 mmHg and an increase 20 mmHg from baseline

Diastolic BP: 105 mmHg and an increase 15 mmHg from baseline.

Body temperature: 39.1°C

Weight: Increase from baseline of 10%

Heart rate: 120 bpm with increase from baseline of 15 bpm
Clinically notable below normal values

Systolic BP: 90 mmHg and a decrease 20 mmHg from baseline

Diastolic BP: 50 mmHg and a decrease 15 mmHg from baseline

Body temperature: 35°C

Weight: decrease from baseline of 10%

Heart rate: 50 bpm with decrease from baseline of 15 bpm
The following summaries will be produced for each vital sign parameter:

Summary statistic for change from baseline to the worst post-baseline value (in both 
directions, i.e. from baseline to highest post baseline and from baseline to lowest post-
baseline value),

Number and percentage of patients with at least one post-baseline vital sign abnormality 
(in both directions, i.e. both elevated and below normal values).
 


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All vital sign assessments will be listed by vital sign parameter. Clinically notable values will 
be flagged on listings.
10.5.3
Resource utilization
Not applicable
10.5.4
Patient-reported outcomes
Cushing’s syndrome HRQoL questionnaire
A 12-item Cushing’s syndrome HRQoL questionnaire (CushingQoL) is implemented in this 
trial. Raw summative scores are calculated and standardized on a by-patient and visit basis.
Patients who completed 9 or more items at an assessment are considered evaluable for that 
visit. Standardized scores and their changes from baseline to each scheduled post-baseline 
assessment will be descriptively summarized.
Work Productivity and Activity Impairment-General Health (WPAI-GH) 
questionnaire
The WPAI-GH yields four types of scores:
1. Absenteeism (work time missed)
2. Presenteesism (impairment at work / reduced on-the-job effectiveness)
3. Work productivity loss (overall work impairment / absenteeism plus presenteeism)
4. Activity Impairment
WPAI-GH scores are based on 1-item (presenteeism, activity impairment), 2-items 
(absenteeism) and multiple items (overall work productivity); a score will not be calculated if 
there is a missing response to the corresponding item. For example, an analysis of 
absenteeism would include only those subjects with responses to hours missed and to hours 
worked.
WPAI-GH scores and their changes from baseline to each scheduled post-baseline assessment 
will be descriptively summarized.
 


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10.7
Interim analysis
No formal interim analysis is planned. However, since the timing of drug approval may differ 
between regions, data from a specific region may be reported when all patients from that 
region have been followed for 28 days after they have either prematurely discontinued 
pasireotide s.c. or after completing treatment as per protocol (i.e. when the study drug is 
approved for commercial use and reimbursed in each respective country or until 31 December 
2015 (until 31 December 2016 for sites in South Korea and Brazil), whichever occurs first).
For regulatory purposes, at time of a regional interim analysis, data from countries where the 
trial is still ongoing maybe included. Furthermore, independent of a regional interim analysis 
additional interim analysis may be performed for regulatory purpose or publication purpose 
and details will be specified in the study’s analysis plan.
10.8
Sample size calculation
No sample size calculation was performed. The planned sample size of approximately 200
patients was chosen based on the expected accrual rates and planned duration of the trial. The 
actual sample size may differ from this planned numbers.
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required.
 


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. The date when a subject’s Informed Consent was actually obtained will be 
captured in their CRFs.
Novartis will provide investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy was to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. Different publications 
of the data are planned. Regional and/or country population analysis and publication will be 
allowed after the analysis and presentation of the multinational (or global) population is 
performed.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
 


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and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study CRF is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the CRFs and all other required reports. Data reported on the CRF, that 
are derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. All data requested on the CRF must be recorded. Any 
missing data must be explained. For electronic CRFs an audit trail will be maintained by the 
system. The investigator/institution should maintain the trial documents as specified in 
Essential Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required 
by applicable regulations and/or guidelines. The investigator/institution should take measures 
to prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who is directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
 


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12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days.
 


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13
References (available upon request)
Adams EF, Lei T, Buchfelder M, et al. (1995). Biochemical characteristics of human pituitary 
somatotropinomas with and without gsp mutations: in vitro cell culture studies. J Clin 
Endocrinol Metab.; Jul;80(7):2077-81.
Ballarè E, Persani L, Lania AG, et al. (2001). Mutation of somatostatin receptor type 5 in an 
acromegalic patient resistant to somatostatin analog treatment. J Clin Endocrinol Metab.; 
Aug;86(8):3809-14.
Barlier A, Gunz G, Zamora AJ, et al. (1998). Pronostic and therapeutic consequences of Gs 
alpha mutations in somatotroph adenomas. J Clin Endocrinol Metab.; May;83(5):1604-10.
Bertherat J, Chanson P, Dewailly D, et al. (1993). Somatostatin receptors, adenylate cyclase 
activity, and growth hormone (GH) response to octreotide in GH-secreting adenomas. J Clin 
Endocrinol Metab.; Dec;77(6):1577-83.
Bochicchio D, Losa M, Buchfelder M, et al. (1995). Factors influencing the immediate and 
late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by 
the European Cushing’s disease Survey Group. J Clin Endocrinol Metab; 80: 3114.
Boscaro M, Ludlam WH, Atkinson B, et al. (2009). Treatment of Pituitary-Dependent 
Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide 
(SOM230): A Multicenter, Phase II Trial. J Clin Endocrinol Metab.; Jan;94(1):115-22.
Corbetta S, Ballaré E, Mantovani G, et al. (2001). Somatostatin receptor subtype 2 and 5 in 
human GH-secreting pituitary adenomas: analysis of gene sequence and mRNA expression. 
Eur J Clin Invest.; Mar;31(3):208-14.
Daly AF, et al. (2006). High prevalence of pituitray adenoma. A cross-sectional study in the 
province of Liege, Belgium. J Clin Endocrinol Metab; 91: 4769-4775.
Filopanti M, Ronchi C, Ballarè E, et al. (2005). Analysis of somatostatin receptors 2 and 5 
polymorphisms in patients with acromegaly. J Clin Endocrinol Metab.; Aug;90(8):4824-8. 
Epub 2005 May 24.
Fougner SL, Borota OC, Berg JP, et al. (2008). The clinical response to somatostatin 
analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression 
of the adenoma. Clin Endocrinol (Oxf).; Mar;68(3):458-65. Epub 2007 Oct 17.
Freda PU (2002). Somatostatin analogs in acromegaly. J Clin Endocrinol Metab;7:3013-3018.
Hofland LJ, van der Hoek J, Feelders R, et al. (2005). The multi-ligand somatostatin analogue 
SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin 
receptor type 5. European Journal of Endocrinology; Vol. 152(4). 645-654.
Hosoi E, Yokogoshi Y, Hosoi E, et al. (1993). Analysis of the Gs alpha gene in growth 
hormone-secreting pituitary adenomas by the polymerase chain reaction-direct sequencing 
method using paraffin-embedded tissues. Acta Endocrinol (Copenh); Oct;129(4):301-6.
 


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Lamberts SW, Uitterlinden P, Klijn JM (1989). The effect of the long-acting somatostatin 
analogue SMS 201-995 on ACTH secretion in Nelson's syndrome and Cushing's disease. Acta 
Endocrinol (Copenhagen); 6:760-766.
Landis CA, Harsh G, Lyons J, et al. (1990). Clinical characteristics of acromegalic patients 
whose pituitary tumors contain mutant Gs protein. J Clin Endocrinol Metab; Dec;71(6):1416-
20.
Landis CA, Masters SB, Spada A, et al. (1989). GTPase inhibiting mutations activate the 
alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature; 
Aug;31:340(6236):692-6.
Lindholm J, et al. (2001). Incidence and late prognosis of cushing’s syndrome: a population-
based study. J Clin Endocrinol Metab, 86:117-123.
Miller JW, Crapo L (1993). The medical treatment of Cushing’s syndrome. Endocr Rev; 14: 
443-58.
Nathan DM, Buse JB, Davidson MB, et al. (2009). Medical management of hyperglycemia in 
type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a 
consensus statement of the American Diabetes Association and the European Association for 
the Study of Diabetes. Diabetologia; 52: 17–30 and Diabetes Care 2009; 32: 193–203.
Newell-Price J, Trainer P, Besser GM, et al. (1998). The diagnosis and differential diagnosis 
of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev; 19(5): 647-72.
Nieman LK (2002). Medical therapy of Cushing’s disease. Pituitary; 5:, 77.
Oberg K (2004). Treatment of neuroendocrine tumours of the gastrointestinal tract. Oncologia 
(Madrid); 27(4): 57-61.
Oldfield EH, Doppman JL, Nieman LK, et al. (1991). Petrosal sinus sampling with and 
without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. 
N Engl J Med; 325 (13): 897-90.
Orth DN (1995). Cushing’s Syndrome. NEJM; 332: 791.
Perloff D, Grim C, Flack J, et al. (1993). AHA Medical/Scientific statement. Human blood 
pressure determination by sphygmomanometry. Circulation, 88: 2460- 2467.
Schmid HA, Schoeffter P (2004). Functional Activity of the Multiligand Analog SOM230 at 
Human Recombinant Somatostatin Receptor Subtypes Supports Its Usefulness in 
Neuroendocrine Tumors. Neuroendocrinology; 80(1): 47-50.
Silva AP, Schoeffter P, Weckbecker G, et al. (2005). Regulation of CRH-induced secretion of 
ACTH and corticosterone by SOM230 in rats. European Journal of Neuroendocrinology; 153: 
1-5.
Sonino N, Zielezny M, Fava GA, et al. (1996). Risk factors and long-term outcome in 
pituitary-dependent Cushing’s disease: a single centre audit. Clin Endocrinol (Oxf); 56: 25.
Stalla GK, Brockmeier SJ, Renner U, et al. (1994). Octreotide exerts different effects in vivo 
and in vitro in Cushing's disease. Eur J Endocrinol; 2:125-131.
 


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Swearingen B, Biller B, Barker FG, et al. (1999). Long-term Mortality after Transsphenoidal 
surgery for Cushing Disease. Ann Intern Med; 130:821.
Taboada GF, Luque RM, Bastos W, et al. (2007). Quantitative analysis of somatostatin 
receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning 
pituitary adenomas. Eur J Endocrinol.; Jan;156(1):65-74.
Taboada GF, Luque RM, Neto LV, et al. (2008). Quantitative analysis of somatostatin 
receptor subtypes (1-5) gene expression levels in somatotropinomas and correlation to in vivo 
hormonal and tumor volume responses to treatment with octreotide LAR. Eur J Endocrinol.; 
Mar;158(3):295-303.
Van der Hoek J, Lamberts SWJ, Hofland LJ (2005a). The role of somatostatin analogs in 
Cushing's disease. Pituitary; 7(4): 257-264.
Van der Hoek J, Waaijers M, van Koetsveld PM, et al. (2005b). Distinct functional properties 
of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH 
release by corticotroph tumor cells. American Journal of Physiology, Endocrine and 
Metabolism; 289(2):E278-87.
Webb SM, Badia X, Barahona MJ, et al. (2008). Evaluation of health-related quality of life in 
patients with Cushing’s syndrome with a new questionnaire. Eur. J. Endocrinol., 158(5):623-
30.
Yang IM, Woo JT, Kim SW, et al. (1995). Characteristics of acromegalic patients with a good
response to octreotide, a somatostatin analogue. Clin Endocrinol (Oxf).; Mar;42(3):295-301.
 

SAP_000.pdf: 
Clinical Development 
SOM230 (Pasireotide) 
CSOM230B2406 / NCT01582061
An open-label, multi-center, expanded access study of 
pasireotide s.c. in patients with Cushing’s disease 
(Seascape) 
RAP Module 3 – Detailed Statistical Methodology 
 
 
Document type: 
RAP Documentation-Amendment 2 
Document status: 
 Final 
Release date: 
 10 March 2017 
Number of pages: 
23 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 7 
2 
Study design and treatment ................................................................................................. 7 
3 
Objectives ............................................................................................................................ 7 
3.1 
Primary .................................................................................................................... 7 
3.2 
Secondary ................................................................................................................ 7 
 8 
4 
Definitions and general methodology ................................................................................. 8 
4.1 
Study drug start and end date................................................................................... 8 
4.2 
Study day ................................................................................................................. 8 
4.3 
Baseline definition ................................................................................................... 8 
4.4 
Visit windows .......................................................................................................... 9 
4.5 
Study completion status (end of study) ................................................................. 10 
4.6 
Analysis sets .......................................................................................................... 10 
4.6.1 
Full analysis set ..................................................................................... 10 
4.6.2 
Safety set ............................................................................................... 10 
4.7 
Subgroups .............................................................................................................. 10 
4.8 
Study drug exposure .............................................................................................. 10 
4.9 
Calculation of change ............................................................................................ 11 
4.10 
Dose calculations ................................................................................................... 11 
4.10.1 
Sample size calculation ......................................................................... 12 
4.11 
Analyses ................................................................................................................. 12 
4.11.1 
Interim report ........................................................................................ 12 
4.11.2 
Final analysis ......................................................................................... 12 
4.12 
Methods for calculating confidence intervals (CI) ................................................ 12 
5 
Statistical methods and data analysis ................................................................................ 13 
5.1 
Primary objective ................................................................................................... 13 
5.1.1 
Primary variable .................................................................................... 13 
5.2 
Secondary objectives ............................................................................................. 13 
5.2.1 
Efficacy objectives ................................................................................ 13 
17 
5.3 
Safety analyses ....................................................................................................... 18 
5.3.1 
Analysis set and grouping for the analyses ........................................... 18 
5.3.2 
Adverse events ...................................................................................... 18 
5.3.3 
Laboratory abnormalities ...................................................................... 20 


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5.3.4 
Vital signs.............................................................................................. 20 
5.3.5 
Other safety data ................................................................................... 21 
5.4 
Patient demographics/other baseline characteristics ............................................. 22 
5.4.1 
Protocol deviations ................................................................................ 22 
5.5 
Concomitant therapies ........................................................................................... 22 
5.6 
Study medication ................................................................................................... 22 
 
 
 
 
6 
Subgroup analyses ............................................................................................................. 22 
7 
Data handling conventions ................................................................................................ 23 
8 
Adverse Events of Special Interest (MedDRA v 19.0) ..................................................... 23 
9 
References ......................................................................................................................... 23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1-1 
List of abbreviations 
 
 
 
ADA 
American Diabetes Association 
b.i.d.  
bis in diem / twice a day 
BMI 
Body Mass Index 
 
 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSR 
Clinical Study Report 
 
 
ECG 
Electrocardiogram 
GH 
Growth Hormones 
HRQOL 
Health-related quality of life 
IGF-1 
Insulin like Growth Factor 1 
 
 
QOL 
Quality of Life 
RAP 
Report and Analysis Plan 
SAE 
Serious Adverse Event 
s.c. 
Sub-cutaneous 
UFC 
Urinary free cortisol 
ULN 
Upper limit normal 
WPAI-GH 
Work Productivity and Activity Impairment-General Health 
 
 


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Table 1-2 
Document History – Changes compared to previous version of RAP 
module 3. 
Version 
Date 
Changes 
2.0 
11-Nov-2011 
Initial version 
2.1 
13-June-2012 
Biomarker section modified: Hscores for Immunohistochemistry 
added  
Incorporation of changes made after Protocol amendment 3 
Objectives and Endpoints 
    As a consequence of extending the study duration, objectives and 
endpoints have been updated to include an additional time point for 
analysis at week 48. 
Description of Study Design 
   This section has been updated to reflect the changes of the 
starting dose in the European Union and the change of study 
duration. 
Subgroup analysis 
In this section an additional analysis by starting dose has been  
added. 
 
(Adding week 48, starting dose) 
2.2 
22-July-2012 
Revision after 2nd RAP II meeting (visit windows, dose calculation, 
biomarker section) 
3.0 
26-Sep-2012 
Final version, Amendment 1 
Revision after LF review 
Mean daily dose grouping has been added. 
Section 4.4 Visit window has been added.  
Section 4.9 Calculation of changes has been added. 
Section 4.10 Dose calculations has been added  
Section 4.12.1.2 CI for continuous variable has been added. 
 
3.1 
26- Oct -2012 
Removed “Normally Distributed” from section 4.12.1.2 
3.2 
29-Sep-2016 
Draft version , Amendment 2 
Added Mean 24h-UFC calculation section: the mean UFC 
calculation at week 12,24and 48 will be based on the last two or 
three samples collected before the visit , instead of considering only 
three samples  
Update sample size calculation  
Added the publication purposes in the interim analysis  
Removed biomarker data analysis due to the fact that the vendor 
never analyzed the data collected for only 7 patients due to Novartis 
decision 
3.3 
10-Mar-2017 
Final version , Amendment 2  
  
  


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1 
Introduction 
The RAP document describes the planned statistical analyses for the clinical study report  for 
study SOM230B2406 in the treatment of Cushing’s disease. SAS® version 9.4 (SAS Institute 
Inc., Cary, NC, USA) or later will be used for all analyses. Any changes made to this statistical 
plan after the clinical database lock will be documented separately. 
Even written before database lock, this document is using past tense in order to simplify the 
CSR writing. 
2 
Study design and treatment 
This study is an open-label, uncontrolled, single-arm, multi-center, multi-national expanded 
access study of pasireotide sub-cutaneous administered twice a day in patients with persistent 
or recurrent Cushing’s disease or with de novo Cushing’s disease that are not considered 
candidates for pituitary surgery (confirmed Cushing’s disease). 
The starting dose depends on the location of the site: 
For sites located in the European Union: the starting dose is 600 μg b.i.d. . However, patients 
already enrolled in the study at the time of the approval of the amendment 3 are to 
continue on their current assigned dose. 
For site located outside the European Union: the starting dose is 900 μg b.i.d. in all patients 
except for those with impaired glucose metabolism for whom the starting dose is 600 μg 
b.i.d. 
After a 21-day screening period, patients who satisfied all the inclusion/exclusion criteria 
started receiving pasireotide. During the first 24-week period, patients had a visit on a weekly 
basis up to week 4 and then on a 4-week basis. In the second study period, i.e. after the 24 week 
visit, visits are taking place on 12-week intervals until the end of the study.  
Patients remained in the study until pasireotide is approved for commercial use and reimbursed 
in each respective country or until 31 December -2015 (until 31 December 2016 for sites in 
South Korea and Brazil), whichever occurred first. 
3 
Objectives 
3.1 
Primary 
The primary objective is to document the safety of pasireotide s.c. in patients with Cushing’s 
disease. 
3.2 
Secondary 
The secondary objectives are: 
• To document the efficacy of pasireotide s.c. in normalizing mean 24h-UFC at Week 
12, 24 and 48, separately, 
• To document the efficacy of pasireotide s.c. in achieving at least 50% reduction of 
mean 24h-UFC from baseline at Week 12, 24 and 48, separately, 


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• To document the changes in clinical signs and symptoms, 
• To document the changes in patient-reported outcome questionnaires (CushingQoL 
and WPAI-GH), 
• To document the effects of pasireotide s.c. on the GH/IGF-1 axis. 
• To document the overall safety and tolerability of pasireotide s.c. in patients with CD 
 
4 
Definitions and general methodology 
4.1 
Study drug start and end date 
Study drug start date is defined as the first date when a non-zero dose of study drug was 
administered and recorded on the Drug Administration Record (DAR) CRF page.  
Similarly, study drug end date is defined as the last date when a non-zero dose of study drug 
was administered and recorded on the DAR CRF page of the study. 
4.2 
Study day 
Study day is defined to be the number of calendar date from study drug start to any event 
date.  
For events that occurred on or after study drug start date (e.g. lab samples, AEs), study day 
is computed using following formula: 
 Study day = (event date – study drug start date) + 1 day 
For events prior to study drug start date (e.g. time of diagnosis), study day is computed using 
following formula:  
 Study day = (event date – study drug start date)  
Note that study drug start date is study day 1 and the day before study drug start date is 
study day -1, therefore there is no study day 0. Unless stated otherwise, one month is defined 
as a 28 days period.  
4.3 
Baseline definition 
For efficacy and safety evaluations, baseline assessment is defined as the last available value 
(or assessment) prior to study drug start date. If for a given parameter, a patient had no value 


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(or assessment) prior to study drug start date, baseline will be considered missing for that 
efficacy and/or safety evaluation.  
4.4 
Visit windows 
It is anticipated that some assessments could be done outside the protocol planned visit 
windows, for that purpose a computed Visit windows schedule is defined. 
Visits after the date of first dose are scheduled weekly for the first 4 weeks and then monthly 
from study day 28 (visit number 6) to study day 168 (visit number 11). Thereafter every 12 
weeks/84 days. 
Table 4-1 
Visit windows 
Study visit 
Week 
Visit 
window 
Visit 
window 
Start* 
Visit 
window 
Mid-point* 
Visit 
window 
End* 
Visit 
window 
Duration 
 
1 (Screening) 
-1 
-1 
-21 
0 
-1 
21 
2 (Baseline) 
0 
0 
0 
0 
0 
1 
3 
1 
1 
1 
7 
11 
7 
4 
2 
2 
12 
14 
18 
7 
5 
3 
3 
19 
21 
25 
7 
6 
4 
4 
26 
28 
32 
7 
7 
8 
5 
33 
56 
70 
28 
8 
12 
6 
71 
84 
98 
28 
9 
16 
7 
99 
112 
126 
28 
10 
20 
8 
127 
140 
154 
28 
11 
24 
9 
155 
168 
182 
28 
12 
36 
10 
183 
252 
294 
84 
13 
48 
11 
295 
336 
378 
84 
14 
60 
12 
379 
420 
462 
84 
15 
72 
13 
463 
504 
546 
84 
16 
84 
14 
547 
588 
630 
84 
17 
96 
15 
631 
672 
714 
84 
18 
108 
16 
715 
756 
798 
84 
19 
120 
17 
799 
840 
882 
84 
20 
132 
18 
883 
924 
966 
84 
21 
144 
19 
967 
1008 
1050 
84 
22 
156 
20 
1051 
1092 
1134 
84 
Note: * study day 
 
For summary statistics (tables) for all laboratory data assessment visits are processed as 
follows: 
1. Unscheduled visits are used.  


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2. Unless stated otherwise, the closest assessment to the mid-point of each visit-
window is considered.  
3. In case 2 or more assessments are reported on the same day, or have the same 
distance from the mid-point, i.e. 2 days before, 2 days after, then the mean will be 
taken. 
With regard to mean 24h-UFC, the above rules do not apply as per protocol there are 
particular definitions, see section 5.2.1 for further details. 
All lab assessments are listed. 
4.5 
Study completion status (end of study) 
A patient has completed the study after he/she has been followed for 28 days: 
1. After having either prematurely discontinued pasireotide s.c.  
2. Or, after completing treatment as per protocol (i.e. when the study drug is approved for 
commercial use and reimbursed in each respective country or until 31 December 2015 
and until 31 December 2016 for sites in South Korea and Brazil, whichever occurs first).  
4.6 
Analysis sets 
4.6.1 
Full analysis set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose of 
pasireotide s.c. 
4.6.2 
Safety set 
The safety set includes all patients who received at least one dose of pasireotide s.c. and had 
at least one post-baseline safety assessment amongst the following parameters: adverse 
events, laboratory assessments, vital signs, and ECG. 
Please note: the statement that a patient had no adverse events (on the Adverse Event CRF) 
constitutes a safety assessment. 
4.7 
Subgroups 
Subgroups are based on characteristics measured before study inclusion. Subgroup analyses 
are described in Section 6. 
4.8 
Study drug exposure 
Duration of exposure (in weeks) will be calculated as  
 Duration of exposure = (study drug end date – study drug start date +1) / 7 days 
The exposure duration includes periods of temporary interruption for any reason. 


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4.9 
Calculation of change 
Baseline value is the value collected during the baseline assessment as per the specific 
definition applying to the parameter, e.g. lab value  
Absolute change from baseline is the absolute difference between value a time point t 
(post-baseline) and value at baseline assessment, it is calculated as:  
 Absolute change from baseline = post-baseline value – baseline value 
Relative change from baseline, or Percentage change from baseline, is calculated as: 
 Relative change from baseline (%) = (absolute change / baseline value) × 100 
4.10 
Dose calculations 
Total daily dose  
The total daily dose is the sum of the evening and morning dose: 
                 Total daily dose (μg / day) = morning dose (μg) + evening dose (μg) 
Cumulative dose  
The cumulative dose (μg) is defined as the total dose administered to a patient over the 
whole study period. 
Cumulative dose (μg) = ∑ (morning dosei + evening dosei) 
Where i is the day and morning and evening doses are being expressed in μg. 
Mean daily dose  
Mean daily dose or dose intensity (DI) is defined as: 
DI (μg/day) = Cumulative dose (μg) / Duration of exposure (days). 
For patients who did not take any drug the mean daily dose is by definition equal to zero.  
Similarly, a 4-week mean daily dose will be computed over a 4-week period in order to 
allow exploratory analyses on the impact of the dose on clinical safety (adverse events). 
Mean daily dose grouping 
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. 
• 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day 
Note: As mean daily dose groups are based on the actual exposure to the treatment, i.e. not 
considering days without any study drug administration, reflecting an actual dosing rather 
than the intended one. That is, 0 dose days are not considered for mean daily dose grouping. 


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4.10.1 
Sample size calculation 
No sample size calculation was performed. The planned sample size of approximately 200 
patients was chosen based on the expected accrual rates and the planned duration of the 
trial. The actual sample size may differ from this planned number. 
4.11 
Analyses 
4.11.1 
Interim report 
It was anticipated that the timing of drug approvals would differ between regions leading to 
different study completion amongst the different regions (e.g. EU and non-EU sites). 
Therefore, data from a specific region may have to be reported when all patients from that 
region have completed the trial. 
The primary reason for those analyses are to address health authorities’ needs and/or 
requests, for this reason, data from other regions may be considered in the analysis planned 
for one region even if the study is still ongoing. . Furthermore, independent of a regional 
interim analysis additional interim analysis may be performed for regulatory purpose or 
publication purpose and details will be specified in the study’s analysis plan. 
Note that this is not a formal interim analysis and does not affect any statistical tests as no 
hypothesis testing is planned. 
4.11.2 
Final analysis  
The final analysis will be performed when all patients have completed the study. 
4.12 
Methods for calculating confidence intervals (CI) 
4.12.1.1 CI for proportions 
Two-sided 95% confidence intervals for proportions will be calculated on the exact method. 
Confidence intervals will be obtained using Clopper-Pearson confidence intervals (Clopper 
and Pearson 1934). 
4.12.1.2 CI for continuous variables 
Two sided 95%Confidence Interval for continuous variable will be based on the t-
distribution. The respective N, Mean and Standard error are outputted in to a data-step and 
then the TINV function is used to calculate the Confidence Interval as follows: 
 
PROC MEANS DATA=test NOPRINT ; 
VAR age ; 
OUTPUT OUT=xxtmp N=n MEAN=mean STDERR=stderr ; 
RUN ; 
 
DATA xxtmp1 ;  SET xxtmp ; 
lo = mean - ( TINV ( 0.95 , n-1 ) * stderr ) ; 
hi = mean + ( TINV ( 0.95 , n-1 ) * stderr ) ; 
RUN ; 


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5 
Statistical methods and data analysis 
Categorical data will be presented as frequencies and percentages. For continuous data, 
mean, standard deviation, median, minimum, and maximum will be presented. 
A missing category for categorical data will be presented where applicable. Unless 
otherwise noted, percentages will be based on the number of patients in the relevant 
population or subgroup. 
Whenever possible, minimum and maximum will be presented to the same precision as the 
raw data. Mean and median will be presented to one more decimal place and standard 
deviation to two more decimal places.  
Unless noted otherwise, no imputation for missing data will be performed. 
5.1 
Primary objective 
The primary objective is to document safety of pasireotide s.c. in patients with Cushing’s 
disease (see Section 3). 
5.1.1 
Primary variable 
The primary variable is the proportion of patients having a drug-related adverse event that 
was recorded as grade 3 or 4, or as a serious adverse event (see Section on Adverse events 
as to how the primary variable will be analyzed). 
The analysis will be performed on the Safety set. 
5.2 
Secondary objectives 
5.2.1 
Efficacy objectives 
These analyses will be performed on the FAS. 
Mean 24h-UFC calculation  
Screening urinary free cortisol will be measured in two or three 24-hour urine specimens 
collected during the screening period. The 24h-UFC concentration results from these two 
or three samples will be averaged to obtain the baseline UFC level. During the study, mean 
24h-UFC will be determined at 4-week intervals until week 24. At week 4, 8, 16 and 20, 
mean 24h-UFC will be 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 will 
be determined from two or three 24-hour urine collections, collected over the week before 
the visit. After week 24, the mean 24h-UFC will be 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).  
 


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Normalization of mean 24h-UFC at Week 12, 24 and 48 
The endpoint associated with this objective is the proportion of patients achieving 
normalization of the mean 24h-UFC (UFC normalization), i.e. the mean 24h-UFC is ≤ 1.0 
× ULN.  
The number and percentage with corresponding two-sided 95% CI of patients achieving 
normalization of mean UFC mean 24h-UFC will be presented at Week 12, 24 and 48 
(separately). 
Note, the mean 24h-UFC is determined from two or three 24h-urine collections collected 
over the week before the visit.  
Mean 24h-UFC imputation 
If Week 24 mean 24h-UFC is missing then it will be imputed by the last available mean 
24h-UFC values of at least two samples between and including Week 12 and Week 24. If 
Week 48 mean 24h-UFC is missing then it will be imputed by the last available mean 24h-
UFC values of at least two samples between and including Week 12 and Week 48.  
Summaries with and without imputing missing Week 24 and Week 48 mean 24h-UFC will 
be presented. 
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments. 
Reduction of mean 24h-UFC ≥ 50% from baseline to Week 12, 24 and 48 
The number and percentage with corresponding two-sided 95% CI of patients achieving a 
reduction of mean 24h-UFC ≥ 50% from baseline to Week 12, 24 and 48 (separately) will 
be presented. 
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments. 
In addition, descriptive summaries of actual and percentage change in mean 24h-UFC from 
baseline to Week 12, 24 and 48 and all other scheduled post-baseline assessments will be 
provided. 
Changes from baseline to Week 12, 24 and 48 in clinical signs and 
symptoms  
The following clinical signs (Table 5-1) of Cushing’s disease will be assessed by descriptive 
summaries of the change in systolic BP (standing and sitting), diastolic BP (standing and 
sitting), BMI, waist circumference and weight from baseline to each post-baseline visit. In 
addition, the proportion of patients satisfying the clinically relevant thresholds specified in 
the following table will be calculated along with the exact two-sided 95% CIs at each 
scheduled post-baseline assessment. 


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Table 5-1 
Clinical Signs 
Clinical Sign 
 
Unit, Scale 
Clinically relevant threshold (at any 
time point) 
Standing Systolic BP 
mmHg 
≤ 140 mmHg 
Sitting Systolic BP 
mmHg, mean of 3 assessments 
mean of 3 assessments ≤ 140 mmHg 
Standing Diastolic BP 
mmHg 
≤ 90 mmHg 
Sitting Diastolic BP 
mmHg, mean of 3 assessments 
mean of 3 assessments ≤ 90 mmHg 
BMI 
kg/m2, Class levels:  
< 25.0, 25.0 to < 30.0,  ≥ 30.0  
% of patients reducing by at least one 
class level 
Waist circumference 
cm  
Reduction of ≥ 5% 
Reduction of ≥ 10% 
Weight 
Kg 
Reduction of ≥ 5% 
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments. 
The following clinical signs and symptoms (Table 5-2) of Cushing’s disease will be 
assessed by descriptive summaries of changes (or shifts) from baseline to each scheduled 
post-baseline assessment. The corresponding method of analysis for each clinical sign and 
symptom are provided in the table. 
Table 5-2 
Clinical Signs and Symptoms 
Clinical signs and 
symptoms 
Scale 
Analyses Methods 
Facial Rubor 
(redness) 
0=none, 1=mild, 2=moderate, 3=severe 
Investigator interpretation, 
Counts & shifts from baseline. 
Hirsutism (Ferriman-
Gallway scoring) 
0=minimum, 36=maximum 
Scoring in females only 
Investigator interpretation, 
Ferriman-Gallway score,  
Actual and % change from baseline 
Supraclavicular fat 
pads 
0=none, 1=mild, 2=moderate, 3=severe 
Investigator interpretation, 
Counts & shifts from baseline. 
Dorsal fat pads 
0=none, 1=mild, 2=moderate, 3=severe 
Investigator interpretation, 
Counts & shifts from baseline.  
Muscle strength 
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 
Direct observation of ability to stand 
unaided. 
Counts & shifts from baseline. 
Striae 
0=none, 1=mild, 2=moderate, 3=severe 
Investigator interpretation, 
Counts & shifts from baseline. 
Bruising 
0=none, 1=mild, 2=moderate, 3=severe 
Investigator interpretation, 
Count s & shifts from baseline. 
Similar analyses as defined above will also be performed at all other scheduled post-baseline 
assessments. 


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Changes from baseline to Week 12  ,24 and 48  in Cushing Quality of Life 
scores 
A 12-item Cushing’s syndrome HRQoL questionnaire (CushingQoL, cf. Webb et al 2008) 
is implemented in this trial. Patients who completed 9 or more items at a visit are considered 
evaluable for that visit. 
The list of questions includes the following and are answered using a categorical variable 
ranging from 1 to 5 (see Table 5-3): 
1. I have trouble sleeping (I wake up during the night; it takes me a long time to get to 
sleep, etc.) 
2. I have pain that keeps me from leading a normal life 
3. My wounds take a long time to heal 
4. I bruise easily 
5. I am more irritable, I have sudden mood swings and angry outbursts 
6. I have less self-conﬁdence, I feel more insecure 
7. I’m worried about the changes in my physical appearance due to my illness 
8. I feel less like going out or seeing relatives or friends 
9. I have had to give up my social or leisure activities due to my illness 
10. My illness affects my everyday activities such as working or studying 
11. It’s difﬁcult for me to remember things 
12. I’m worried about my health in the future 
 
Table 5-3 
HRQoL ratings 
Answers to HRQoL questions 
Rating 
‘Always’ or ‘Very much’ 
1 
‘Often’ or  ‘Quite a bit’ 
2 
‘Sometimes’ or ‘Somewhat’ 
3 
‘Rarely’ or ‘Very little’ 
4 
‘Never’ or ‘Not at all’ 
5 
 
Standardized scores and their changes from baseline to Week 12, 24 and 48 will be 
descriptively summarized. 
The standardized scores are 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, the greater the impact on HRQoL.  
2. Obtain standardized score, Y, for a single patient 
a. 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. 


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Similar analyses as defined above will also be performed at all other scheduled post-
baseline assessments. 
Changes from baseline to Week 12 , 24 and 48 in WPAI-GH scores 
The WPAI-GH questionnaire is to assess work productivity and activity impairment. 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes, as follows (see Reilly 2002): 
Questions: 
1 = currently employed 
2 = hours missed due to health problems 
3 = hours missed other reasons 
4 = hours actually worked 
5 = degree health affected productivity while working 
6 = degree health affected regular activities 
Scores (multiply scores by 100 to express in percentages): 
Percent work time missed due to health: Q2/(Q2+Q4) 
Percent impairment while working due to health: Q5/10 
Percent overall work impairment due to health: 
Q2/(Q2 + Q4)+[(1 – Q2/(Q2 + Q4)) ∙ (Q5/10)] 
Percent activity impairment due to health: Q6/10 
Descriptive summaries of actual and percentage change in mean scores from 
baseline to Week 12, 24 and 48 will be provided. Similar analyses will also be 
performed at all other scheduled post-baseline assessments. 
Changes from baseline in GH and IGF-I to Week 12, 24 and 48 
Descriptive summaries of the absolute and relative change from baseline of GH and IGF-at 
Week 12, 24 and 48 will be provided.  
Similar analyses will also be performed at all other scheduled post-baseline assessments. 


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5.3 
Safety analyses 
5.3.1 
Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication, 
2. On-treatment period: from day of first dose of study medication to 28 days after last 
dose of study medication, 
3. Post-treatment period: starting at 29 days after last dose of study medication. 
5.3.2 
Adverse events 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. However, all safety data (including those 
from the pre and post-treatment periods) will be listed and those collected during the pre and 
post-treatment period will be flagged. 
For the primary objective of the study, the number and percentage of patients having any drug-
related adverse event that was recorded as grade 3 or 4, or as a serious adverse event will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
and type of adverse event. 
In addition, the incidence of treatment-emergent adverse events (new or worsening from 
baseline) will be summarized by system organ class and/or preferred term, severity (based on 
CTCAE grades), type of adverse event and relation to study treatment. Deaths will be listed and 
summarized by cause of death. 
The following adverse event summaries will be provided: 
• Adverse events, suspected to be study drug related that was recorded as grade 3 or 4, or as 
a serious adverse event, by primary system organ class and/or preferred term and severity 
(based on CTCAE grades), 


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• Adverse events, regardless of study drug relationship, by primary system organ class and 
preferred term, 
• Adverse events, suspected to be study drug related, by primary system organ class and 
preferred term, 
• CTC grade 3 or 4 adverse events, regardless of study drug relationship, by primary system 
organ class and preferred term, 
• CTC grade 3 or 4 adverse events, suspected to be study drug related, by primary system 
organ class and preferred term, 
• Adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by primary system organ class and preferred term, 
• Deaths by primary system organ class and preferred term, 
• SAEs, regardless of study drug relationship, by primary system organ class and preferred 
term, 
• SAEs, suspected to be study drug related, by primary system organ class and preferred 
term, 
• SAEs leading to study drug discontinuation, regardless of study drug relationship, by 
primary system organ class and preferred term. 
 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment-
emergent adverse events which are not serious adverse events with an incidence greater than 
2% and on treatment-emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
5.3.2.1 
Grouping of adverse events of special interest 
Specific groupings of adverse events of special interest will be considered and the number of 
patients with at least one event in each grouping will be reported. Such groups consist of adverse 
events for which there is a specific clinical interest in connection with pasireotide treatment (i.e. 
where pasireotide may influence a common mechanism of action responsible for triggering 
them) or adverse events which are similar in nature (although not identical) within project 
defined group. The specific groupings of AEs will be used and documented in CSR. For more 
detail please refer section 8.  


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The following adverse event summary will be produced: 
• Adverse events of special interest, regardless of study drug relationship, by category, 
preferred term and maximum CTC grade. 
5.3.3 
Laboratory abnormalities 
The summaries will include all laboratory assessments collected no later than 28 days after 
study treatment discontinuation. All laboratory data will be listed and those collected later than 
28 days after study treatment discontinuation will be flagged in the listings. 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0, the study’s biostatistics and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-
missing values not graded as 1 or higher. Grade 5 will not be used. In the unlikely case when a 
local laboratory normal range overlaps into the higher (i.e. non-zero) CTC grade, the laboratory 
value will still be taken as within normal limits and assigned a CTC grade of zero. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
Concentrations below the limit of quantification will not be presented in summary statistics. 
The following summaries will be produced for the laboratory data (by laboratory parameter) 
• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value, 
• For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high classification to compare baseline to the worst on-treatment value, 
• Shift tables of fasting glucose and related biochemical parameters using the ADA (2010) 
or similar low/normal/high classifications to compare baseline to the worst and last on-
treatment value. 
The following listings will be produced for the laboratory data: 
• Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges, 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
5.3.4 
Vital signs 
The parameters collected are: height (cm), weight (kg), body temperature (°C), pulse (beats per 
minute, bpm), systolic and diastolic blood pressure (mmHg). 
The criteria for clinically notable abnormalities are defined as follows: 
Clinically notable elevated values 
• Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline 
• Body temperature: ≥ 39.1°C 
• Weight: Increase from baseline of ≥ 10% 


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• Pulse: ≥ 120 bpm with increase from baseline of ≥ 15 bpm 
Clinically notable below normal values 
• Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline 
• Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline 
• Body temperature: ≤ 35°C 
• Weight: decrease from baseline of ≥ 10% 
• Pulse: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm 
The following summaries will be produced for each vital sign parameter: 
• Summary statistic for change from baseline to the worst post-baseline value (in both 
directions, i.e. from baseline to highest post baseline and from baseline to lowest post-
baseline value), 
• Number and percentage of patients with at least one post-baseline vital sign abnormality 
(in both directions, i.e. both elevated and below normal values). 
All vital sign assessments will be listed by vital sign parameter. Clinically notable values will 
be flagged on listings. 
5.3.5 
Other safety data 
5.3.5.1 
ECG  
The following analyses will be performed for HR, PR, QT intervals and QRS duration, 
ventricular rate, QTcB (Bazett’s formula) and QTcF (Fridericia’s formula): 
• Summary statistics at baseline and all scheduled post-baseline time points, 
• Summary statistics of changes from baseline at each scheduled post-baseline time point, 
• Listing of ECG data (scheduled and unscheduled visits). 
Number (%) of patients with a notable QT interval, based on both QTcB and QTcF, and newly 
occurring qualitative ECG abnormalities will be summarized at all scheduled post-baseline time 
points. A newly occurring ECG abnormality is defined as an abnormal post-baseline finding 
that was not present at baseline. 
Notable criteria for QTcB/QTcF include: 
• > 450 ms at any post-baseline scheduled time point and ≤ 450 ms at baseline, 
• > 480 ms at any post-baseline scheduled time point and ≤ 480 ms at baseline, 
• > 500 ms at any post-baseline scheduled time point and ≤ 500 ms at baseline, 
• An increase from baseline > 30 ms at any post-baseline scheduled time point, 
• An increase from baseline > 60 ms at any post-baseline scheduled time point. 
A patient with multiple occurrences of a notable QT interval or a newly occurring ECG 
abnormality is counted only once in that category. 
Patients with notable QT interval values and newly occurring qualitative ECG abnormalities 
will be flagged in the listings. 


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5.3.5.2 
Gallbladder Ultrasound 
Gallbladder data at each visit will be summarized and listed by treatment group. Shifts from 
baseline to last on-treatment (post-baseline) value will be presented for each evaluation. 
5.4 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively for the FAS. 
5.4.1 
Protocol deviations 
The number and percentage of patients with any relevant protocol deviation will be tabulated. 
All relevant protocol deviations will be listed. Protocol deviation criteria are specified in the 
Validation and Planning (VAP) document. 
5.5 
Concomitant therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by ATC class and preferred term. These analyses will be 
performed on the safety set. 
5.6 
Study medication 
Descriptive statistics will be used to summarize the mean daily dose and duration of exposure 
to pasireotide s.c for all patients and by mean daily dose group (see section 4.8). The actual and 
planned doses administered and reason for dose change will be listed. These analyses will be 
performed on the safety set. 


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7 
Data handling conventions 
Date imputation for AEs and concomitant medications will be imputed according to Novartis 
conventions described in [RAP Module 8]. 
Vital sign Study Completion CMP, ECG and laboratory assessment will be imputed in 
associating visit date from Visit-based event date imputation (AVIS) (See RAP Module 8). 
As describe in the RAP Module 8, any event which has a partial date and requires imputing but 
has no specific imputation rule, is imputed as follows: 
- if the day and month is missing, it will be replaced by 1st of July 
- if only the day is missing it will be replaced by the 1st of that month. Partial dates will 
remain partial in the data listings. 
8 
Adverse Events of Special Interest (MedDRA v 19.0) 
 
Adverse events of special interest will use MedDRA v 19.0 or the latest version available at a 
time of data base lock. The current version of grouping of adverse event is present in an attached 
spreadsheet. The latest version of this spreadsheet will be used at the time of database lock.  
  
SOM230_AESI_Med
DRA 19.0_22Apr2016 
The adverse events of special interest list for SOM230 based on MedDRA version 19.1 is 
available on CREDI: 
 
/CREDI 
Projects/S/SOM230C/Administrative 
files/CIS 
(Clinical 
Information 
Sciences)/Biostatistics - SOM230_AESI_MedDRA 19.1_21Nov2016.xls 
https://webedi02.eu.novartis.net:8443/webEDI02_non_SSO/drl/objectId/090095a88a122b51 
9 
References 
American Diabetes Association, (2010), ‘Diagnosis and Classification of Diabetes Mellitus’, 
Diabetes Care, 33, Supplement 1, S62-S69. 
Webb, SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, 
Rivonello R, Stalla G, Lamberts SWJ, Glusman JE, (2008), ‘Evaluation of health-related quality 
of life in patients with Cushing’s syndrome with a new questionnaire’, European Journal of 
Endocrinology, 15, 623-630. 
Clopper, C. J., and Pearson, E. S. (1934), ‘The Use of Confidence or Fiducial Limits Illustrated 
in the Case of the Binomial’, Biometrika 26, 404–413.  
Reilly, M. “www.reillyassociates.net” ©2002 Margaret Reilly Associates, Inc., October 19, 
2011, “http://www.reillyassociates.net/WPAI_Scoring.html”.