Conditions: Cushings Disease
Keywords: pituitary tumors pasireotide cabergoline combination treatment UFC hormone disorder cortisol adrenocorticotropic hormone Cushing Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 68
Healthy volunteers: no

Brief summary:
The main purpose of this prospective, multicenter, open-label phase II study, was to evaluate the efficacy and safety of pasireotide alone or in combination with cabergoline in patients with Cushing's disease.

Detailed description:
This was an open-label, multi-center, international, non-comparative study with adult patients with confirmed diagnosis of Cushing's disease. Given the fact that CD patients may need a multimodality treatment approach, the trial design aimed to mimic CD treatment by using a medical stepwise approach. Therefore, the whole patient population started treatment with Pasireotide and only in patients within this population who did not achieve biochemical control, cabergoline was added.

The whole patient population had never received pasireotide or had received it in the past (reasons of discontinuation not related to safety).

Core Phase

* Pasireotide naïve patients started pasireotide monotherapy at the dose of 0.6 mg s.c. bid. If at the end of the 8 week treatment period, the biochemical control was not achieved and the 0.6mg bid dose was well tolerated, the pasireotide dose was increased to 0.9mg bid. If the 0.9mg bid dose of pasireotide did not lead to biochemical control, cabergoline was added with a starting dose of 0.5mg qd. If the combination dose of 0.9mg bid of pasireotide plus 0.5mg qd cabergolinedid not achieve biochemical control, the cabergoline dose will be increased to 1.0mg qd.
* Patients who were currently being treated with maximal tolerated doses of pasireotide monotherapy for at least 8 weeks at screening without achieving normal mUFC, entered the study with a combination therapy starting with cabergoline 0.5mg qd.

Extension Phase

• After 35 weeks of treatment in core phase, patients had the option to continue study treatment if pasireotide was not yet approved for commercial use and/or reimbursed - if country reimbursement was applicable - in each respective country, or until 31st December 2017, or once an applicable roll over protocol became available, or whichever occurred first.

Novartis had a local transition plan in order to ensure that all trial patients had access to the study medication without any delay in their treatment

Arms:
arm 1: pasireotide alone or with cabergoline

Interventions: intervention 1: Pasireotide with or without cabergoline
Intervention descriptions: intervention 1: The trial consisted of Pasireotide-untreated patients who started pasireotide 0.6mg twice a day for 8 weeks. If biochemical control was not achieved by the end of the 8 weeks, and the 0.6mg dose is well-tolerated, the dose was increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not achieved, cabergoline was added and patients began combination treatment with cabergoline at the starting dose of 0.5mg once a day for 8 weeks. If biochemical control is still not achieved at the end of the third 8 week period, the dose of cabergoline was increased to 1.0mg once a day. Patients could also immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current maximal tolerated dose of pasireotide. Patients continued with the combination treatment for 8 weeks. If biochemical control was not not achieved by the end of the 8 week period, the dose of cabergoline was increased to 1mg once a day.

Protocol document:
Prot_001.pdf: 
Clinical Development
SOM230 (Pasireotide)
Protocol CSOM230B2411 / NCT01915303
A Phase II trial to assess the efficacy and safety of 
pasireotide s.c. alone or in combination with cabergoline in 
patients with Cushing’s disease
Authors
Document type
Amended Protocol Version
EUDRACT number
2013-002170-49
Version number
04 (Clean)
Development phase
II
Document status
Final
Release date
12-Jul-2017
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 .................................................................................................................2
List of appendices................................................................................................................5
List of figures ......................................................................................................................5
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 4 (12-Jul-2017) ...............................................................................................9
Amendment 3 (25-Jul-2016) .............................................................................................10
Amendment 2 ....................................................................................................................12
Amendment 1 ....................................................................................................................15
Protocol summary:.............................................................................................................18
1
Background........................................................................................................................23
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............23
1.2
Introduction to investigational treatment(s) and other study treatment(s).............24
1.2.1
Overview of Pasireotide........................................................................24
1.2.2
Overview of Cabergoline ......................................................................29
2
Rationale............................................................................................................................30
2.1
Study rationale and purpose...................................................................................30
2.2
Rationale for the study design ...............................................................................31
2.3
Rationale for dose and regimen selection..............................................................32
3
Objectives and endpoints...................................................................................................33
4
Study design ......................................................................................................................35
4.1
Description of study design ...................................................................................35
5
Patient population..............................................................................................................37
5.1
Key inclusion criteria.............................................................................................37
5.2
Exclusion criteria...................................................................................................39
6
Treatment...........................................................................................................................40
6.1
Patient numbering, treatment assignment..............................................................40
6.2
Study treatment......................................................................................................40
6.2.1
Dosing regimen.....................................................................................41
6.2.2
Treatment duration................................................................................42
6.3
Study drug..............................................................................................................42
6.3.1
Supply, preparation and storage............................................................42
6.3.2
Pasireotide.............................................................................................42
6.3.3
Cabergoline ...........................................................................................42


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6.3.4
Study drug compliance..........................................................................42
6.4
Guidelines for dose modifications and titrations...................................................43
6.4.1
Pasireotide and cabergoline dose modification steps............................43
6.5
Special safety.........................................................................................................46
6.5.1
Hyperglycemia ......................................................................................46
6.5.2
Self-monitoring of blood glucose..........................................................46
6.5.3
QT prolongation....................................................................................48
6.5.4
Hepatic Safety Management .................................................................49
6.6
Treatment interruption and treatment discontinuation ..........................................51
6.7
Permitted concomitant therapy requiring caution and/or action............................52
6.7.1
Prohibited concomitant therapy ............................................................53
7
Study flow and visit schedule............................................................................................53
7.1
Study flow and visit schedule................................................................................53
7.1.1
Screening...............................................................................................59
7.1.2
End of treatment, including premature withdrawal and study 
discontinuation visit ..............................................................................60
7.2
Assessment types...................................................................................................61
7.2.1
Efficacy assessments.............................................................................61
7.2.2
Safety and tolerability assessments.......................................................64
8
Safety monitoring and reporting........................................................................................67
8.1
Adverse events.......................................................................................................67
8.1.1
Definitions and reporting ......................................................................67
8.1.2
Adverse events of special interest.........................................................68
8.1.3
Laboratory test abnormalities................................................................68
8.2
Serious adverse events...........................................................................................68
8.2.1
Definitions.............................................................................................68
8.2.2
Reporting...............................................................................................69
8.3
Pregnancies............................................................................................................70
8.4
Warnings and precautions......................................................................................70
8.5
Steering committee................................................................................................70
9
Data collection and management.......................................................................................71
9.1
Data confidentiality ...............................................................................................71
9.2
Site monitoring ......................................................................................................71
9.3
Data collection.......................................................................................................72
9.4
Database management and quality control............................................................72
10 Statistical methods and data analysis ................................................................................73


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10.1
Analysis sets ..........................................................................................................73
10.1.1
Full Analysis Set ...................................................................................73
10.1.2
Safety Set ..............................................................................................73
10.1.3
Per-Protocol Set ....................................................................................73
10.2
Patient demographics/other baseline characteristics .............................................73
10.2.1
Treatments (study treatment, concomitant therapies, compliance).......73
10.2.2
Primary objective ..................................................................................74
10.2.3
Handling of missing values/censoring/discontinuations.......................74
10.2.4
Supportive analyses...............................................................................74
10.3
Secondary objectives .............................................................................................74
10.3.1
Safety objectives ...................................................................................76
78
10.4
Interim analysis......................................................................................................78
10.5
Sample size calculation..........................................................................................79
11 Ethical considerations and administrative procedures ......................................................79
11.1
Regulatory and ethical compliance........................................................................79
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................79
11.3
Informed consent procedures.................................................................................79
11.4
Discontinuation of the study..................................................................................80
11.4.1
Communication and Publication of Clinical Trial Results ...................80
11.5
Study documentation, record keeping and retention of documents.......................81
11.6
Confidentiality of study documents and patient records .......................................82
11.7
Audits and inspections...........................................................................................82
11.8
Financial disclosures..............................................................................................82
12 Protocol adherence ............................................................................................................82
12.1
Amendments to the protocol..................................................................................82
13 References (available upon request)..................................................................................83
14 Appendices ........................................................................................................................85
14.1
Appendix 1 Karnofsky performance status ...........................................................85
14.2
Appendix 2: Cushing’s Syndrome Quality of Life Questionnaire ........................86
14.3
Appendix 3 Patient Report Outcome Questionnaire - SF 12 - v2 .........................90
14.4
Appendix 4: Medications known to be associated with QT interval 
prolongation...........................................................................................................93
14.5
Appendix 5: Ferriman-Gallwey Score...................................................................94


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List of appendices
Appendix 1: Karnofsky Performance Status Scale
Appendix 2: Cushing’s Syndrome Quality of Life Questionnaire
Appendix 3: Patient Report Outcome Questionnaire - SF 12 - v2
Appendix 4: Medications known to be associated with QT interval prolongation
Appendix 5: Ferriman-Gallwey Score
List of figures
Figure 1-1
Pasireotide structural and molecular formula .......................................25
Figure 1-2
Mean (+/- SE) urinary free cortisol (nmol/24h) at time points up to 
Month 12 by randomized dose group (Full analysis set - study 
B2305)...................................................................................................28
Figure 1-3
Cabergoline structure and molecular formular .....................................29
Figure 4-1
Pasireotide-untreated patients at screening...........................................35
Figure 4-2
Patients currently treated with maximal tolerated doses of 
pasireotide monotherapy.......................................................................36
Figure 6-1
Fasting Self-Monitoring Blood Glucose guidelines..............................47
Figure 6-2
QT Prolongation monitoring flow chart................................................49
Figure 6-3
LFT Management Algorithm................................................................51
Figure 14-1
Ferriman-Gallwey Scoring Diagram.....................................................95
List of tables
Table 3-1
Objectives and related endpoints ..........................................................33
Table 6-1
Dose and treatment schedule.................................................................41
Table 6-2
Pasireotide and cabergoline dose modification steps for pasireotide 
un-treated patients.................................................................................44
Table 6-3
Pasireotide and cabergoline dose modification steps for patients 
currently treated with maximal tolerated doses of pasireotide 
monotherapy..........................................................................................46
Table 6-4
Guidelines for treatment of patients experiencing adverse events........52
Table 7-1
Core Phase - Visit evaluation schedule.................................................54
Table 7-2
Extension Phase - Visit evaluation schedule.........................................56
Table 7-3
Extension Phase - Assessment frequencies...........................................58
Table 7-4
Central Laboratory parameters collection plan.....................................58
Table 10-1
Categorical clinical signs ......................................................................76


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List of abbreviations
ACTH
Adrenocorticotropic hormone
ADA
American Diabetes Association
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
b.i.d. (bid or BID)
bis in diem/twice a day
CD
Cushing’s disease
CI
Confidence interval
CMO&PS
Chief Medical Office and Patient Safety
CRF/eCRF
Case Report/Record Form; the term CRF can be applied to either electronic or Paper
CRH
Corticotrophin-releasing hormone
CRO
Contract Research Organization
CSR
Clinical study report
EASD
European Association for the Study of Diabetes
ECG
Electrocardiogram
HAV
Hepatitis A virus
HBc
Hepatitis B core
HbsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
hERG
Human ether-a-go-go-related gene
HRQOL/QoL
Health-related quality of life questionnaires
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IPSS
Inferior petrosal sinus sampling
IRB
Institutional Review Board
IVRS
Interactive Voice Response Systems
IWRS/IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
LDL
Low density lipoprotein
LFT
Liver Function Test
LLN
Lower Limit of Normal
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial SAP documentation
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Cell Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDRD
Modification of Diet in Renal Disease
MRI
Magnetic resonance imaging
mUFC
Mean of urinary free Cortisol
NCI-CTCAE v4.03
National Cancer Institute - Common Toxicity Criteria Adverse Events version 4.03
PHI
Protected Health Information
Plasma ACTH
Plasma Adrenocoticotropic Hormone
PLT
Platelets
PPARγ
Peroxisome Proliferator-Activated Receptor gamma
PPS
Pre Protocol Set
PRO
Patient Reported Outcome


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PT
Prothrombin time
PTT
Partial thromboplastin time
q.d. (qd or QD)
quaque die/once a day
QOL
Quality of life
REB
Research Ethics Board
s.c.
Subcutaneous
SAE
Serious Adverse Event
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which provides evidence of 
preplanned analyses
SmPC (SPC)
Summary of Product Characteristics
SRIFa
Somatostatin Release Inhibiting Factor Analog
SSA
Somatostatin Analog
Sst
Somatostatin receptors
ULN
Upper Limit of Normal
WBC
White blood cells


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
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 tested 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
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Patient Number (Patient 
No. NOVDD)
Subject Number (Subject 
No. NCDS)
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study.
Core phase
The main phase of the study. All patients enrolled to the study will undergo core 
phase.
Extension phase
If pasireotide is not approved for commercial use or reimbursed in a country, the 
respective countries patients will go on to extension phase.
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
Patient number
A number to identify patient. It is 9 – digit number
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
Patient group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points.


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Amendment 4 (12-Jul-2017)
The main objectives of this protocol amendment are as follows:

Participating patients currently have the option to continue study treatment if pasireotide is 
not yet approved for commercial use and/or reimbursed - if country reimbursement is 
applicable - in each respective country, or until 31st December 2017, whichever occurs 
first. At the time of this protocol amendment, pasireotide is not yet approved for 
commercial use and/or reimbursed in several participating countries. In order to continue 
to provide access to treatment for patients in these countries and to collect longer-term 
safety and efficacy data, the maximum duration of the extension phase of the study will be 
extended by two further years, to 31st December 2019. The first results from the interim 
analysis related to the core phase have become available and support the use of the 
combination treatment, justifying the continued use of study medication.
All current procedures and collections will still be done.
The main changes to the protocol and the sections affected are detailed below:

List of Abbreviations section: Multiple abbreviations were updated

Section 4.1, Extension Phase Section was updated to extend the trial until 31Dec2019

Section 6.2.2, Extension Phase Section was updated to extend the trial until 31Dec2019

Section 8.2.2, Reporting section was updated to replace Drug Safety & Epidemiology 
(DS&E) with Chief Medical Office & Patient Safety (CMO&PS)

Section 8.4, Pregnancy section was updated to replace Drug Safety & Epidemiology 
(DS&E) with Chief Medical Office & Patient Safety (CMO&PS)

Multiple grammatical errors corrected throughout
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 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 (25-Jul-2016)
Important note for Spain: The changes noted in Amendment 2 will not be applicable for 
Spain. Spain will follow all protocol procedures from Amendment 1, in addition to the 
applicable changes for Amendment 3 (if approved).
The main objectives of this protocol amendment are as follows:
Participating patients currently have the option to continue study treatment if pasireotide is 
not yet approved for commercial use and/or reimbursed - if country reimbursement is 
applicable - in each respective country, or until 31st December 2016, whichever occurs first. 
At the time of this protocol amendment, pasireotide is not yet approved for commercial use 
and/or reimbursed in several participating countries. In order to continue to provide access to 
treatment for patients in these countries and to collect longer-term safety and efficacy data, the 
maximum duration of the extension phase of the study will be extended by one further year, to 
31 December 2017. All current procedures and collections will still be done.
Also, an analysis of this trial will be performed at the end of the core phase of the study, while 
the analysis related to the overall phase, including the core and the extension phases, will still 
be performed at the end of the extension phase after December 2017.
Based on continuous review of the sections and assessments that pertain to patient safety the 
following sections were updated to align with the current standards for patient safety within 
the pasireotide study program:

Adverse Events of special interest section 8.5.1 was added.

The pregnancy section (Section 8.3) was updated to specify duration of follow-up for
newborn babies.

The Hepatic Safety Management section (Section 6.5.4) was updated to include extra 
safety precautions such as:

The inclusion that if any of the noted criterion is observed, the timing of the sponsor 
notification is changed from 72 to 48 hours.

New wording has been added to this section to describe the SAE terminology to be 
reported if no cause of the Liver Function Test (LFT) abnormalities is identified and 
is considered medically significant.
Lastly, STEP roll over protocol language has been added, in case continued treatment is 
necessary.
The main changes to the protocol and the sections affected are detailed below:

List of Abbreviations section: RAP updated to SAP

Section 4.1, Extension Phase Section was updated to extend the trial until 31Dec2017 and 
STEP roll over protocol language added

Section 6.2.2, Extension Phase Section was updated to extend the trial until 31Dec2017
and STEP roll over protocol language added

Section 6.5.4, Hepatic Safety Management Section was updated with new standard safety 
language


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
Figure 6-3, Figure was updated with a new LFT Management Algorithm

Section 7.2.2.5.3, Liver Function Testing section was updated to state if an abnormal liver 
function criterion is observed; the extra tests should be done within 48 hours, instead of 72 
hours.

Section 8.1.2, Adverse Events of Special Interest section was added

Section 8.3, Pregnancy section was updated to include the follow up for newborn babies,
if applicable

Section 10, was updated to include wording regarding the two separate analyses that will 
be done.

Section 10.3.1.2, Analyzing of Adverse Events of special interest was added

Section 10, 10.3.1.3 and Section 10.3.2, abbreviation RAP changed to SAP (statistical 
analysis plan)

Section 10.4, Interim Analysis section was updated to include wording regarding the 
interim analysis and clinical study reports that will be done after both the core phase and 
the core and extension phase combined.
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 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
The main objectives of this protocol amendment are as follows:
1. To combine Group 1 (pasireotide naïve patients) and Group 2 (patients currently treated 
with maximal tolerated doses of pasireotide monotherapy) into a single cohort of patients. 
Of the 52 patients hitherto enrolled in the study, 50 belong to Group 1 and 2 patients to 
Group 2. The enrolment pattern of the trial indicates that primarily pasireotide-naïve 
patients will be included. Therefore, Groups 1 & 2 will be combined and all patients –
both pasireotide-naïve and the ones currently on maximal tolerated dose but not controlled 
– will enter a 35-week core phase study. All patients will be analyzed in a single cohort. 
The visit evaluation schedule for both core and extension phases will follow the current 
Group 1 schedule.
2. As a consequence of merging the two groups of patients into a single one, the trial primary 
objective and its related endpoints are updated accordingly. The primary objective now 
reads: “To evaluate the overall efficacy of the treatment regimen of pasireotide alone or in 
combination with cabergoline in patients with Cushing’s disease.” The primary endpoint 
now reads: “Proportion of patients who attain mUFC ≤ 1.0xULN at week 35 with 
pasireotide alone or in combination with cabergoline.
3. The enrolment target of the trial will be reduced from 128 to 64 patients. Assuming that 
the proportion of patients who attain a mUFC ≤ 1.0xULN at week 35 will be 34 %, 
derived from a weighted mean of the original assumed response rates for Group 1 (35%) 
and 2 (28%) and assuming that a maximum of 6 out of 64 patients (approx. 10 %) will be 
enrolled in Group 2, a sample size of 64 will result in a precision of the response of 12.8 % 
for the associated two-sided 95% CI considering a drop-out rate of 10%.
4. A significant amount of time would be required to enroll 64 patients to Group 2. In order 
to publish the study results within the originally proposed timeline, it was decided that the 
trial will conclude when the enrolment is reached at 64 patients.
5. As Group 1 and Group 2 will be combined into one single cohort, Group 1 and Group 2 
inclusion criteria will be combined into one single list. No changes will be made to 
exclusion criteria as it is already one single list for both groups.
6. The duration of screening period will be increased from 21 days to 28 days. Current 
experience indicates that it takes about 4 weeks to have the investigation performed for 
study eligibility.
 
8. There are patients who show high sensitivity to pasireotide and whose UFC levels are 
decreased to levels below LLN. These patients require pasireotide to be reduced from the 
starting dose of 0.6 mg bid to 0.3 mg bid; a few of them, despite the dose reduction, 
require further reductions to 0.3 mg qd in order to maintain normal levels of UFC. As such, 
the lowest dose of pasireotide allowed for the trial was changed to 0.3mg qd from 0.3mg 
BID.


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The main changes to the protocol and the section affected are detailed below:

In the Protocol Summary table, the following sections were updated to reflect all patients 
to be enrolled to one single group:

Primary Objective(s) and Key Secondary Objective

Secondary Objectives

Study Design

Population

Inclusion Criteria

Other Assessments

Sections 2.2 - Rationale for the study design and 2.3 - Rationale for dose and regimen 
selection were updated to combine Group 1 and Group 2 into one single group.

Section 3 and Table 3-1 Objectives and endpoints were updated. The primary objective 
was updated; the secondary objectives were updated. The patient populations to be 
enrolled to the trial were not changed. The primary and secondary analysis will still be 
performed per patient population, but separately.

Section 4.1 Description of study design was updated to no longer include two groups of 
patients. Pasireotide untreated patients at screening and patients currently treated with 
maximal tolerated doses of pasireotide monotherapy will be enrolled into one single group 
undergoing the same schedule of events.

Section 5 Patient population section was revised to no longer have two separate groups of 
patients.

Section 5.1 Key inclusion criteria section consisted of two separate lists, one for Group 1 
and one for Group 2. The two lists were merged into one inclusion criteria list applicable 
to all patients. No changes were made to the exclusion criteria.

Secton 6.2 Study treatment was reworded to describe one study treatment procedures for 
all patients.

Section 6.2.2 Treatment duration was updated to state that all patients will receive a total 
of 35 week treatment in the core phase. Treatment duration for the extension phase 
remains the same.

Table 6-3 Pasireotide and cabergoline dose modification steps for patients currently 
treated with maximal tolerated doses of pasireotide monotherapy was further clarified.

Section 6.6 Treatment interruption and treatment discontinuation was updated to include 
one single group of patients.

Section 7.1.1 Screening - The screening period was extended from 21 to 28 days.

Tables 7-2 and 7-4 were removed. Tables 7-1 and 7-3 were updated to reflect one single 
group of patients.

Section 7.2.1.1 Mean urinary free cortisol (mUFC) was updated to reflect one single group 
of patients.
 


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
Section 10.1 Analysis sets was updated.

Section 10.2.2 Primary objectives, statistical hypothesis, model and method of analysis 
was updated to re-word the primary objective to no longer having two groups of patients.

Section 10.3 Secondary objectives were updated to no longer having two groups of 
patients.

Section 10.5 Sample size calculation was updated to no longer having two groups of 
patients.

Appendix 5: Ferriman-Gallwey score system descriptions were updated so that they are 
consistently with the diagrams in Figure 14-1.
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 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 1
The main objectives of this protocol amendment are as follows:
1. Per Health Authorities recommendations
1. A urine pregnancy assessment will be performed at every scheduled visit in Core and 
Extension Phases, as a measure of precaution. All pre-menopausal women who are 
not surgically sterile will have a urine dip-stick pregnancy test at every scheduled visit. 
Patients will be required to undergo a serum pregnancy test if a urine dip-stick test is 
positive.
2. To align with the ADR profile of cabergoline and pasireotide as described in the 
approved labels, the following exclusion criteria will be added to the protocol for both 
Group 1 and Group 2 patients:
a. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to 
pasireotide or cabergoline.
b. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer 
or digestive haemorrhage, galactose intolerance, Parkinson’s disease, 
uncontrolled hypertension and Raynaud’s syndrome.
c. Patients with end-stage renal failure and/or hemodialysis
3. An estimated glomerular filtration from serum creatinine will be calculated using the 
traceable Modification of Diet in Renal Disease (MDRD) in order to monitor renal 
function during the study. This calculation will be performed at screening and at the 
end of treatment visits for all patients. In adults, the isotope dilution mass spectrometry 
(IDMS) – traceable Modification of Diet in Renal Disease (MDRD) is considered to 
be an appropriate equation for estimating glomerular filtration rate from serum 
creatinine. Therefore, this approach is considered adequate to monitor renal function 
during the study.
2. The safety monitoring and report section was inadvertently deleted from the original 
protocol prior to finalization. Therefore, it will be added to the protocol.
3. More restrictive requirements regarding contraception were implemented within the 
SOM230 clinical development program based on a new internal pregnancy guidance. 
Pasireotide is not teratogenic but studies in rats and rabbits have shown effects on female 
reproductive parameters: At 10mg/kg/day in rats, the frequency of early/total absorption 
and mal-rotated limbs was increased. At 5mg/kg/day in rabbits, increased absorptions, 
reduced fetal weights and ensuring skeletal variation were observed. As a result, double 
barrier contraception is required for male participants and had been implemented in the 
protocol:

“Male participants in the trial must agree to use a condom during intercourse, and not 
to father a child during the study and for the period of 30 days following stopping of 
the study treatment.”


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4. A criterion to exclude pregnant or nursing (lactating) women will be added to be 
consistent with SOM230 clinical development program standards:

“Pregnant or nursing (lactating) women where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test (> 5mIU/mL).”
5. Cabergoline dosing time was added in Section 6.3.3. In the same section, the protocol also 
clarified that Dostinex, a generic form of Cabergoline, will be used for the trial in 
available participating countries.
6. Two options on how to dispense different dosages of study medication to patients were 
introduced in Section 6.
7. Additional language was added to Section 7 of the protocol to describe the new enrollment 
and eligibility confirmation process.
8. The following administrative errors will be corrected in the original 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 section affected are detailed below:

The following 2 inclusion criteria were left out in the Protocol Summary section for Group 
2 inclusion criteria, they were now added:

Patients currently treated with maximal tolerated doses of pasireotide for at least 8 
weeks at the time of screening but have not achieved biochemical control. These 
patients will enter the study starting combination therapy.

Male or female patients aged 18 years or greater

List of abbreviations section - mUFC abbreviation was updated from “mean of urinary 
frequency control” to “mean of urinary free cortisol”

Figure 4-1 - referenced footnotes above “pasireotide 0.9mg + cabergoline 1.0 mg qd” 
section were deleted.

Figure 4-1 - week numbers were added to the bottom of the graph.

Section 6.1 - Patient numbering, treatment assignment was added.

Section 6.5.3 - referenced Figure 6-3 was changed to 6-2

Weight measured at every scheduled visit was added to Table 7-1 through Table 7-4 to be 
consistent with the protocol text.

Coagulation and Urinalysis time points were updated in Table 7-3 to be consistent with 
time points listed in Table 7-5.

Urinalysis time points were updated in Table 7-4 to be consistent with time points listed in 
Table 7-5.

Tissue archival language was deleted in Section 9.3.

Irrelevant language was deleted from Section 9.4 Database management and quality 
control.

Section 10.2.3 Handling of missing values/censoring/discontinuations was reworded.

Section 10.4 Interim analysis was reworded.


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
Section 11.4 Discontinuation of the study, the last sentence was revised to read: “Specific 
conditions for terminating the study are outlined in Section 7.1.2.1.”

Figure 14-5 - Ferriman-Gallwey Scoring Diagram was changed to Figure 14-1 Ferriman-
Gallwey Scoring Diagram.

Figure 14-1 - Post Authorization Safety Study (PASS) table was deleted.

Appendix 4 reference was updated.
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 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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Protocol summary:
Protocol number
CSOM230B2411
Title
A Phase II trial to assess the efficacy and safety of pasireotide s.c. alone or in 
combination with cabergoline in patients with Cushing’s disease
Brief title
Study of the efficacy and safety of pasireotide s.c. +/- cabergoline in patients with 
Cushing’s disease
Sponsor and 
Clinical Phase
Novartis,
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Cushing’s disease (CD) is a rare debilitating disease. Patients have excessive 
adrenocoticotropic hormone (ACTH) secretion from a benign pituitary adenoma, 
which stimulates the adrenal to produce excess cortisol. The incidence of 
Cushing’s disease ranges from 1-3 patients per million per year. Cushing’s disease 
is associated with severe morbidity and premature mortality. While surgical 
removal of the adenoma is first line therapy for CD, the success rate of surgery is 
between 65-90% for microadenomas (tumors < 1cm) with recurrence rates 
between 10-20% after 10 years. Irradiation of the pituitary is another option but it 
may take many years to be effective and it is curative in only 15-45% of the cases. 
When surgery and/or irradiation fail, or for those patients from whom such 
therapies are not an option, the remaining alternatives are pharmacological 
treatment or bilateral adrenalectomy. Pasireotide is the first pituitary-targeted 
medical treatment approved for patients with Cushing’s disease. Preliminary data 
(Feelders 2010) indicate synergic effect between pasireotide and cabergoline in 
increasing the biochemical control rate in patients. The purpose of this prospective, 
multicenter, open-label study is to evaluate the efficacy and safety of pasireotide 
alone or in combination with cabergoline in patients with Cushing’s disease as 
measured by proportion of patients achieving normal UFC at the end of the study 
period. The study will enroll patients who are pasireotide - untreated at the time of 
screening and patients who are currently on treatment with maximal tolerated 
doses of pasireotide but still with uncontrolled mUFC.
Primary Objective(s) and 
Key Secondary Objective
To evaluate the overall efficacy of the treatment regimen of pasireotide alone or in 
combination with cabergoline in patients with Cushing’s disease.
Secondary Objectives
1. To assess the changes in mUFC from baseline to study end at each scheduled 
visit where UFC is measured
2. To assess overall efficacy of pasireotide alone or in combination with 
cabergoline as measured by normal mUFC levels at each scheduled visit when 
UFC is measured
3. To evaluate overall efficacy of pasireotide alone or in combination with 
cabergoline as measured by controlled and partially controlled mUFC levels at 
each scheduled visit when UFC is measured
4. To evaluate the duration of controlled or partially controlled mUFC
5. To assess the effect on plasma ACTH and serum cortisol
6. To assess the effect on the continuous measures of clinical signs of 
hypercortisolism
7. To assess the effect on the categorical measures of clinical signs of 
hypercortisolism
8. To assess the improvement of health-related quality of life
9. To evaluate the safety profile of pasireotide alone or in combination with 
cabergoline


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Study design
The study consists pasireotide-untreated patients at screening and patients 
currently treated with maximal tolerated doses of pasireotide in two study phases.
Core Phase
Pasireotide-untreated patients at screening - this includes patients who have never 
received pasireotide or patients who have received pasireotide sometime in the 
past but it was not discontinued because of safety - will start pasireotide at 0.6mg 
twice a day for 8 weeks. Should biochemical control not be achieved by week 8 
and the tolerability of the 0.6mg dose be good, the dose of pasireotide will be 
increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not 
achieved with the higher dose of pasireotide, cabergoline at increasing doses will 
be added, starting at 0.5mg once a day, and then increased to 1.0mg once a day. 
Dose adjustments for cabergoline due to safety issues are allowed. Patients will be 
treated for a total of 35 weeks, including three 1-week (+ 3 days) dose titration 
periods at weeks 8, 17 and 26.
Patients currently treated with maximal tolerated doses of pasireotide monotherapy 
for at least 8 weeks - 0.3mg twice a day, 0.6mg twice a day or 0.9mg twice a day 
for at least 8 weeks - but still did not achieve biochemical control will add 
cabergoline 0.5mg once a day at study entry. They will continue the combination 
treatment for 8 weeks. Should biochemical control not be achieved by week 8, the 
dose of cabergoline will be increased to 1.0mg once a day and patients will be 
monitored for another 8 weeks. Dose adjustments for cabergoline due to safety 
issues are allowed. Patients will also be treated for a total of 35 weeks, including 
one 1-week (+ 3 days) dose titration period at week 8.
Extension phase
After 35 weeks of treatment patients have the option to continue study treatment if 
pasireotide is not yet approved for commercial use and/or reimbursed - if country 
reimbursement is applicable - 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. Patients who discontinue or 
complete the extension phase are required to complete a study completion visit 28 
days (+/- 2 days) after last dose is received in the extension phase.
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 study will enroll 
a total of 64 patients:
●
Patients who are not currently treated with pasireotide, i.e., patients who have 
never received pasireotide or have received pasireotide in the past and were not 
discontinued because of safety.
●
Patients who are currently treated with maximal tolerated doses of pasireotide 
monotherapy for at least 8 weeks at screening, without achieving normal mUFC.


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Inclusion criteria
1. Written informed consent obtained prior to any screening procedures
2. Adult patients with confirmed diagnosis of ACTH-dependent Cushing’s disease 
as evidenced by all of the following:
a.
The mean of three 24-hour urine samples collected within 2 weeks > 
1xULN with 2 out of 3 samples >ULN
b.
Morning plasma ACTH within the normal or above normal range
c.
Either Magnetic resonance imaging (MRI) confirmation of pituitary 
adenoma > 6 mm, or inferior petrosal sinus gradient >3 after Corticotrophin-
releasing hormone (CRH) stimulation for those patients with a tumor less than 
or equal to 6 mm*. For patients who have had prior pituitary surgery, 
histopathology confirming an ACTH staining adenoma
d.
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. If 
surgery has been performed and histopathology indicates as ACTH-secreting 
tumor, there is no need for IPSS even for patients with a tumor < 6mm. If 
surgery has not been performed and the tumor is < 6mm, IPSS is required to 
confirm the diagnosis using CRH, or DDAVP if CRH is not available.
3. Patients with de novo Cushing’s disease can be included only if they are not 
considered candidates for pituitary surgery (e.g. poor surgical candidates, 
surgically unapproachable tumors, patients who refuse to have surgical treatment)
4. Male or female patients aged 18 years or greater
5. Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is 
able to care for most of their personal needs)
6. Patients on medical treatment for Cushing’s disease the following washout 
periods must be completed before screening assessments are performed
●
Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
●
Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) 
and Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonists 
(rosiglitazone or pioglitazone): 4 weeks
●
Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks
●
Octreotide (immediate release formulation): 1 week
●
Progesterone receptor antagonist (mifepristone): 4 weeks
7. Patients can be considered to enter the trial if they meet any one of the 
following criteria:
●
They are naïve to pasireotide
●
They have received pasireotide in the past and have been discontinued 
because of lack of efficacy (2 weeks of washout prior to screening for patients 
treated with pasireotide subcutaneously and 12 weeks of washout prior to 
screening for patients treated with pasireotide LAR)
●
Patients who are on maximal tolerated dose but have not achieved 
biochemical control
8. Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, if they are using highly effective methods of contraception 
during dosing and for 30 days after stopping study medication.
9. Male participants in the trial must agree to use a condom during intercourse, 
and not to father a child during the study and for the period of 30 days following 
stopping of the study treatment.


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Exclusion criteria
1. Patients with compression of the optic chiasm causing any visual field defect 
that requires surgical intervention
2. Diabetic patients with poor glycemic control as evidenced by HbA1c >8%
3. Patients with risk factors for torsade de pointes, i.e. patients with a baseline 
QTcF >450 ms in males, and > 460 ms in females. hypokalemia, 
hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT 
syndrome, or concomitant medications known to prolong QT interval.
4. Patients with clinically significant valvular disease.
5. Patients with Cushing’s syndrome due to ectopic ACTH secretion
6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) 
bilateral adrenal hyperplasia
7. Patients who have congestive heart failure (NYHA Class III or IV), unstable 
angina, sustained ventricular tachycardia, clinically significant bradycardia, 
advanced heart block, history of acute MI less than one year prior to study entry or 
clinically significant impairment in cardiovascular function
8. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic 
persistent hepatitis, or patients with ALT/AST > 2 X ULN, serum bilirubin >2.0 X 
ULN
9. Patients with serum creatinine >2.0 X ULN10.
10. Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L
11. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to 
pasireotide or cabergoline
12. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal 
ulcer or digestive hemorrhage, galactose intolerance, Parkinson’s disease, 
uncontrolled hypertension and Raynaud’s syndrome.
13. Pregnant or nursing (lactating) women where pregnancy is defined as the state 
of a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test (> 5 mIU/mL).
14. Patients with end-stage renal failure and/or hemodialysis
Investigational and 
reference therapy
Paireotide: subcutaneous; 0.3mg, 0.6mg and 0.9mg twice a day
Cabergoline: oral; 0.5mg and 1.0mg once a day
Efficacy assessments
●
Mean urinary free cortisol (mUFC)
●
Serum cortisol
●
Late night salivary cortisol
●
Plasma ACTH
●
Clinical signs of hypercortisolism
●
Health-related Quality of Life
Safety assessments
●
Physical examination
●
Vital signs
●
Karnofsky performance status
●
Laboratory evaluations (hematology, clinical chemistry, liver function testing, 
coagulation, urinalysis)
●
Pregnancy and assessments of fertility
●
Gallbladder ultrasound
●
Cardiac assessments
●
Echocardiogram


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Data analysis
The proportion of patients with normalized mUFC at week 35 will be reported along 
with its corresponding asymptotic 95% CI.
The primary endpoint:
Proportion of patients who attain mUFC ≤ 1.0 ULN at week 35 with pasireotide 
alone or in combination with cabergoline
The main secondary endpoints are:
1. Actual and percentage change in mUFC from baseline to study end at each 
scheduled visit when UFC is measured
2. Proportion of patients that attain mUFC ≤ 1.0 x ULN as assessed at each 
scheduled visit when UFC is measured
3. Proportion of patients who attain mUFC ≤ 1.0 x ULN or have at least 50% 
reduction from baseline in mUFC as assessed at each scheduled visit when UFC 
is measured 
Key words
Cushing’s disease, pasireotide, cabergoline, mUFC, ACTH-dependent, pituitary 
adenoma


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Cushing’s disease (CD) is a rare but debilitating disease. Patients have excessive 
adrenocorticotropic hormone (ACTH) secretion from a benign pituitary adenoma, which 
stimulates the adrenal glands to produce excess cortisol. The incidence of Cushing’s disease 
ranges from 1-3 patients per million per year. Cushing’s disease is associated with severe 
morbidity and premature mortality and most commonly affects adults aged 20-50 years of age, 
primary 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 and cortisol hypersecretion due to excessive ACTH secretion. The primary clinical 
signs and symptoms of Cushing’s disease are due to hypercortisolism and include: changes in 
body habitus (moon facies, increased supraclavicular fat pad and dorsicervical hump), 
hirsutism, skin changes (easy bruising, purplish striae, reddening of the cheeks), generalized 
weakness and fatigue, wasting of musculature (particularly proximal muscles), menstrual 
disorders, decreased fertility and/or libido, hypertension, weight gain, decreased insulin 
sensitivity with disorders in glucose metabolism (including impaired glucose tolerance and 
diabetes mellitus), dyslipidemias (including elevated levels of triglycerides and low HDL 
cholesterol), mental disorders ranging from mood and behavior disorders, to depression and 
psychosis, sleep disturbances, osteopenia/osteoporosis, and immunosuppression with 
increased risk for infections. Because of these alterations patients with Cushing’s disease have 
increased morbidity and mortality. Most patients also develop a high set-point for feedback 
inhibition of ACTH secretion by cortisol. Thus some patients may present with
hypercortisolemia, with ACTH levels within normal limits.
Hypercortisolism is also known as Cushing’s syndrome. Cushing’s disease is one from of 
Cushing’s syndrome. There are other disorders that lead to endogenous hypercortisolim. 
These include the ectopic production of ACTH by a tumor outside the pituitary gland and 
excessive secretion of cortisol by an adrenal tumor or adrenal hyperplasia.
The diagnosis of Cushing’s disease requires a multi-step approach. In a patient who presents 
with the medical history and physical examination suggestive of hypercortisolism the first 
step is to confirm the presence of pathologic endogenous hypercortisolism. Several laboratory 
tests and diagnostic techniques are available for the diagnosis of Cushing’s syndrome and 
these include: 24-hour urine free cortisol (UFC) measurements, blood sampling for serum 
cortisol levels, late-night salivary cortisol measurements, the low—dose dexamethasone 
suppression test (LDDST) and a combination of a LDDST with corticotrophin-releasing 
hormone (CRH) stimulation (Arnaldi 1995). The next step is to determine if the 
hypercortisolism is independent (adrenal Cushing’s syndrome) or ACTH dependent (CD or 
ectopic ACTH). If the plasma ACTH level is below the lower limit of normal (suppressed) the 
patient has an ACTH-independent Cushing’s syndrome. If the plasma ACTH level is normal 
or elevated the patient has ACTH-independent Cushing’s syndrome. The third step is to


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distinguish Cushing’s disease from ectopic ACTH. Thus, a confirmation of a pituitary source 
of ACTH secretion is needed. This includes evidence of pituitary tumor > 6mm on MRI scan 
or confirmation by bilateral inferior petrosal sinus sampling (BIPSS) after corticotrophin-
releasing hormone (CRH) stimulation test. In the BIPSS, if the petrsal to peripheral ratio of 
adrenocorticotrophin concentration is greater than or equal to 3.0 after CRH stimulation, a 
diagnosis of Cushing’s disease can be made (Arnaldi 1995).
While surgical removal of the adenoma is first line therapy for CD, the success rate of surgery 
is between 65-90% for microadenomas (tumours < 1 cm) with recurrence rates between 10 to 
20% after 10 years. The surgical cure rate for macroadenomas (>1 cm) is less than 65% and 
recurrence rates as high as 45% (Biller 2008). Surgery is in many cases complicated by 
hypopituitarism, which requires complicated life-long hormonal replacement therapies 
necessary to sustain life.
Irradiation of the pituitary is another treatment 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 very often results in hypopituitarism. Furthermore, there is a 1 to 2% 
risk of development of secondary tumours in the field of radiation over subsequent years 
(Biller 2008).
When surgery and/or irradiation fail, or for those patients for whom such therapies are not an 
option, the remaining alternatives are pharmacological treatment or bilateral adrenalectomy. 
Therefore, for patients who have failed surgery - either with persistent hypercortisolism soon 
after surgery or with recurrent hypercortisolism months or years after surgery - medical 
therapy is an option. A safe and effective targeted medical therapy is highly desirable in this 
patient population. There is an unmet medical need for the treatment of CD as medical 
treatment options are limited.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Pasireotide
Pasireotide is the first pituitary-targeted medical treatment approved for patients with 
Cushing’s disease. It 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
(Figure 1-1):


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Figure 1-1
Pasireotide structural and molecular formula
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 acivity 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 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 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.


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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 2005), AtT20 cells and human 
corticotroph adenoma cells strongly support this assumption (Hofland 2005, van der Hoek 
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.
1.2.1.1
Non-clinical experience
Preclinical data on binding affinity and functional activity in vitro and efficacy on hormone 
secretion in vivo have been obtained with the s.c. formulation in rats, dogs, mice and monkeys. 
Long-term in vivo studies performed using drug application by osmotic mini-pumps (Bruns 
2002, Weckbecker 2002) have shown not only that the inhibitory effect of pasireotide was 
stronger, but also that there was less response escape (Bruns 2002). Osmotic mini-pumps 
release a drug substance in a constant, predefined way and thus mimic the constant release 
pattern of a LAR formulation. Based on the known efficacy of pasireotide on hormone 
secretion after long-term application, no additional pharmacological experiments with the new 
LAR formulation are considered necessary.
A detailed summary of available preclinical data is provided in the [Investigator’s Brochure].
1.2.1.2
Clinical experience
The pasireotide s.c. formulation has been evaluated in 7 studies with healthy volunteers, 1 
study in patients with hepatic dysfunction, 2 studies with acromegalic patients, 1 study in 
patients with metastatic carcinoid tumors, and 2 studies in patients with Cushing’s disease. A 
detailed summary of the clinical data is provided in the [Investigator’s Brochure].
Single doses of pasireotide s.c. up to 1.5mg q.d. and 0.75mg b.i.d. multiple s.c. doses (7-14 
days) up to 1.5mg q.d., 0.75mg b.i.d. and 2.1mg b.i.d. (up to 5 days), and continuous (7- day) 
s.c. infusion by insulin pump, have been well-tolerated, with mostly mild, transient side 
effects reported. The most commonly reported adverse events (AEs) were GI related as mild 
diarrhea and nausea requiring no treatment or study discontinuation. The frequency of these 
AEs appeared to decrease with time in multiple-dose studies.
An effect of pasireotide on QTcF interval at supra-therapeutic doses of 1.95mg s.c. b.i.d was 
observed in healthy volunteers [CSOM230B2113]. The placebo subtracted QTcF change from 
baseline showed a peak effect at 2-hours post-dose of pasireotide s.c. of 17.5 ms. In vitro 
electrophysiology data from the hERG channel assay revealed no inhibition of the hERG tail 
currents up to 10 µM (10472 ng/mL) and pasireotide did not exert any electrophysiological 
effects on rabbit Purkinje fibers up to the concentration of 30 µM (31416ng/mL). Further, no 
interference with any of the major ion cardiac channels [potassium (KCNQ1 and 
Kv3.4/Kir3.1) sodium (Nav1.5) and calcium (Cav1.2)] was seen at concentrations up to 30 
µM (31.42 µg/ml). A single dose telemetry study in male monkeys, after subcutaneous 


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administration, was performed with doses of up to 2 mg/kg, with no effect on cardiovascular 
function.
Analysis of the clinical database does not indicate that the QT prolonging effect of pasireotide 
translates into an increased risk of arrhythmias (there were no reports of torsades de pointes 
during clinical experience with pasireotide and the incidence of notable QTc outliers of 
interest (new QTcF >480 ms, QTcF > 500ms, and QTcF change from baseline > 60 ms) in the 
overall pasireotide-exposed population was low, ranging from 0.3% to 1.9%. The incidence of 
AEs indicative of arrhythmogenic potential was low, and most cases were confounded by co-
morbidities. There was a single ‘Electrocardiogram QT prolonged’ SAE leading to study drug 
discontinuation (B2305-0771/00003). There was no evidence that the occurrence of AEs 
indicative of arrhythmogenic potential was related to the occurrence of cardiac arrhythmia.
A phase I study [CSOM230B2124] evaluating the effects of 4 classes of antihyperglycemic
agents along with pasireotide for 7 days evaluated the glucose metabolism effects in healthy 
volunteers. Plasma glucose AUC0-4hr values during oral glucose tolerance test were 
increased from baseline by 69% after pasireotide alone, whereas lower increases of 60%, 49%, 
38% and 19% were observed after co-administration of metformin, nateglinide, vildagliptin 
and liraglutide, respectively. Overall, the combination of pasireotide and anti-hyperglycemic 
agents was safe. The most frequent AEs were injection site reaction and GI related (diarrhea 
and nausea).
Data from the proof-of-concept Study [CSOM230B2208] in patients with Cushing’s disease 
showed a reduction in mean urinary free cortisol levels (mUFC). Of the 39 patients enrolled 
on 0.6mg s.c. b.i.d of pasireotide, 29 qualified for the efficacy analysis of mUFC. During the 
initial 15 day treatment period (core study), five of the 29 evaluable patients (17.2%) achieved 
normalization of mUFC, the primary endpoint of this study. Twenty-two patients (75.9%) 
experienced reductions in the mUFC levels by Day 15. Of the 39 patients that received 
pasireotide the most frequent adverse events were diarrhea (51.3%), hyperglycemia (35.9%) 
and nauseas (30.8%).
Subsequently a Phase III Study [CSOM230B2305] evaluated the efficacy and safety of two 
doses of pasireotide s.c. (0.6 and 0.9 mg s.c. b.i.d.) in 162 patients with mostly moderate to 
severe CD by evaluating the normalization of mUFC values at six months of treatment. A 
0.3mg s.c. b.i.d. dose of pasireotide was evaluated as a lower dose and was effective for a 
small number of patients. The study confirmed that pasireotide is effective in the treatment of 
hypercortisolism in CD. At Month 6, 21 of 80 patients (26.3%; 95% CI 16.6%, 35.9%) 
randomized to pasireotide 0.9mg b.i.d. were considered to be responders (i.e. mUFC ≤ ULN, 
with no dose increase). In the 0.6mg b.i.d. dose group, 12 of 82 patients (14.6%; 95% CI 7.0%, 
22.3%) responded. The mUFC decreased in both treatment groups. The mean absolute 
changes from baseline in mUFC were -463.4 and -363.9 nmol/24h respectively for 0.6mg 
b.i.d. and 0.9mg b.i.d. Both doses had similar median percent reductions from Baseline to 
Month 6 in mUFC (approximately 48% for both doses). Robust reductions in mUFC occurred 
relatively quickly, within the first month, and were sustained over the course of Months 6 and 
12 [CSOM230B2305]. Both doses were efficacious in lowering mUFC with the mean mUFC 
values and the median % changes in mUFC from baseline being similar between doses. See 
Figure 1-2 below:


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Figure 1-2
Mean (+/- SE) urinary free cortisol (nmol/24h) at time points up to 
Month 12 by randomized dose group (Full analysis set - study B2305)
Figure 1-2: At least three 24h UFC assays contributed to patient mean results at Months 0 (baseline), 
3, 6 and 12. At least two 24h UFC assays contributed to patient mean results at other time points.
+/-Standard errors are displayed.
— — — is the ULN for the UFC assay (145 nmol/L)
Overall, as mUFC decreased, continuous measures of the signs of Cushing’s disease (e.g. 
blood pressure, weight and serum lipid levels) tended to improve. Both groups demonstrated 
increases in health-related quality of life (HRQL) scores at Months 6 and 12. The mean 
percent changes from baseline in HRQL scores at Month 6 were 31.3% and 73.0%, 
respectively, for the 0.6 and 0.9mg b.i.d. groups. The mean percent changes from baseline in 
HRQL scores at Month 12 showed an additional increase with 38.9% and 91.8%, respectively, 
for the 0.6 and 0.9mg b.i.d. groups.
Patients who had a baseline mUFC between 1.5 to 5 x ULN showed a greater response rate 
than patients with a baseline mUFC > 5x ULN (27.2% vs. 8.2%, respectively). Uncontrolled 
patients (those who did not normalize UFC and had less than 50% reduction from baseline in 
UFC) could be identified early in the treatment course with a high degree of certainty. 
Approximately 90% of patients with uncontrolled mUFC at both Months 1 and 2 were also 
uncontrolled at Months 6 and 12.
Pasireotide was well-tolerated. The majority of AEs were consistent with the known adverse 
drug reactions of Somatostatin Analogs (SSAs). The most common AEs (incidence ≥10%) 
were diarrhea, nausea, abdominal pain, cholelithiasis, hyperglycemia, diabetes mellitus, 
fatigue and glycosylated hemoglobin increased. Hyperglycemia-related AEs appeared to be 
the most significant safety concern in terms of frequency of occurrence as well as overall 
clinical impact (i.e. overall increase in HbA1c of ~1.5% for both dose groups at 6 and 12 
months). Hyperglycemia was managed with the addition or adjustment in oral antidiabetic 
treatment or in some cases the addition of insulin. Patients who had pre-existing diabetes had
a higher degree of hyperglycemia. As expected in successful therapies for hypercortisolism, 
AEs related to cortisol withdrawal (hypocortisolism) were reported in 13 (8.0%) patients, for 
which a dose decrease resulted in effective management of the AE.
Overall, pasireotide demonstrated a favorable benefit/risk profile in Cushing’s disease. 
Importantly, patients that are relatively poor responders to pasireotide can be identified early 


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(i.e. after two months of treatment) with a high degree of certainty, thereby giving the option 
of prompt discontinuation of patients not likely to derive benefit from this drug.
Preliminary data (Feelders 2010) indicate synergic effect between pasireotide and cabergoline
in increasing the biochemical control rate in patients with CD. When cabergoline was added 
to pasireotide in a proof of concept study, UFC normalization increased from 29% to 53%. 
These preliminary data make cabergoline the best partner for pasireotide in increasing 
biochemical control rate.
1.2.2
Overview of Cabergoline
Cabergoline USP is a dopamine receptor agonist. The chemical name for Cabergoline is 1-[(6-
allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea and has the following 
structural formula (Figure 1-3):
Figure 1-3
Cabergoline structure and molecular formular
1.2.2.1
Non-clinical experience
The secretion of prolactin by the anterior pituitary is mainly under hypothalmic inhibitory 
control, likely exerted through release of dopamine by tuberoinfundibular neurons. 
Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. 
Results of in vitro studies demonstrate that Cabergoline exerts a direct inhibitory effect on the 
secretion of prolactin by rat pituitary lactotrophs. Cabergoline decreased serum prolactin 
levels in reserpinized rats. Receptor-binding studies indicate that Cabergoline has low affinity 
for dopamine D1, α1- and α2- adrenergic, and 5-HT1- and 5-HT2-serotonin receptors.


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Like somatostatin receptors, dopamine receptors (DRs) are also expressed in most cell types 
of the anterior pituitary gland. The DR family consists of 5 receptor subtypes that, on the basis 
of functional and pharmacological properties, can be subdivided into D1-like (D1 and D4) and 
D2-like (D2, D3, and D4) receptors. D1-like receptors are preferentially stimulatory, whereas 
D2-like receptors have mainly inhibitory properties (Missale 1998) D2 and, to a lesser extent, 
D4 are the DR subtypes that are expressed in the anterior pituitary gland. The most well-know
action of DR in the regulation of anterior pituitary hormone secretion is the inhibition of 
prolactin secretion. Corticotroph adenomas express predominantly D2 receptors, as 
demonstrated by in situ hybridization studies, RT-PCR, and immunohistochemistry (Pivonello 
2004). In Stefaneanu L et, The expression of D2 in corticotroph adenomas is positively 
correlated to the suppressive effects of cabergoline on urinary free cortisol (UFC) secretion in 
patients with CD (Pivonello 2004). Unlike sst2, but resembling sst5, D2 appears not to be 
negatively regulated by cortisol (de Bruin 2009).
1.2.2.2
Clinical experience
Early studies already showed that short-term treatment with the dopamine agonist 
bromocriptine inhibits ACTH and cortisol levels in 40% of patients with CD, Lamberts SW et 
al., although data on the efficacy of bromocriptine in patients with Cushing’s disease appeared 
equivocal (Miller JW 1993). More recently, Pivonello et al (Pivonello 2004) showed that a 3-
month treatment with cabergoline induced normalization of UFC in 40% of a series of 20 
patients with recurrent or persistent Cushing’s disease. In another study by Godbout et al
(Godbout 2010), it was shown that cabergoline monotherapy was able to normalize UFC in 11 
of 20 patients (37%) after short-term treatment with cabergoline and in 30% of patients with 
CD after long-term cabergoline treatment (at least 2 y, and in some for 5 y; mean dose, 2.1 
mg/wk). However, during the long-term treatment with cabergoline monotherapy, a 
significant number of patients showed a treatment-escape to cabergoline treatment. This effect 
was shown even after several years of treatment in Pivonello R et al. (Pivonello 2004) and 
Godbout A et al (Godbout 2010).
2
Rationale
2.1
Study rationale and purpose
The treatment of patients with CD requires a multimodality approach. One approach is 
represented by medical treatment. Pasireotide, the first pituitary-targeted medical therapy 
approved for patients with CD showed efficacy in a proportion of patients in the registration 
study [SOM230B2305]. Overall results from the pivotal study demonstrated that pasireotide 
has a favorable benefit/risk profile in Cushing’s disease. However, it was noted that some 65% 
and 48% of the patients completed 6- and 12-month treatment, respectively. Apart from the 
very beginning of the study, the main reason for discontinuation was due to insufficient 
therapeutic effect.
Cabergoline is often used in this indication in order to decrease cortisol levels; the literature 
has shown evidence of short-term efficacy but the long-term treatment highlighted treatment 
escapes in many patients. Therefore, combining medical treatment modalities can be 
considered in order to improve patient outcome.


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Taking into consideration that biochemical remission should be rapidly achieved to reverse 
morbidity and mortality, drugs can be combined to control cortisol production within an 
acceptable time frame. If biochemical remission has been accomplished, drug dosage may be 
decreased or one of the used drugs may be withdrawn. Second, combining drugs may allow 
for lower doses with concomitantly less adverse events. Third, combining drugs may have 
potentiating effects on ACTH secretion by corticotroph tumor cells. Because most 
corticotroph adenomas simultaneously express sst5 and D2, it can be anticipated that a 
combination of sst5- and D2-targeting drugs may have additive or synergistic effects on 
ACTH secretion. In vitro data indeed indicate synergism between sst and D2 that might 
increase therapeutic efficacy.
Feelders et al (Feelders 2010) evaluated a medical stepwise approach in the management of 
17 patients with Cushing’s disease. The results of this study indicate synergic effect between 
pasireotide s.c. and cabergoline in increasing the biochemical control rate in patients with CD. 
Seventeen patients with Cushing’s disease were started on pasireotide 0.1 mg tid for 2 weeks 
and the dose of pasireotide was increased to 0.25 mg tid should mUFC be elevated at the end 
of the 2-week period. After one month treatment, cabergoline at the dose 1.5 mg every other 
day was added to pasireotide in the patients who did not achieve biochemical control on 
pasireotide monotherapy. When cabergoline was added to pasireotide, UFC normalization 
increased from 29% to 53%. The improvement in cortisol secretion was accompanied by 
ameliorations in the classical features of Cushing’s disease. The safety profile of the 
combination is consistent with the ones of the two single compounds. These preliminary data 
make cabergoline the best partner for pasireotide in increasing biochemical control rate.
The purpose of this prospective, multicenter, open-label phase II study, is to evaluate the
efficacy and safety of pasireotide alone or in combination with cabergoline in patients with 
Cushing’s disease as measured by the proportion of patients achieving normal UFC at the end 
of the study period. The study will enroll patients who are pasireotide-untreated at the time of 
screening and patients who are currently on treatment with maximal tolerated doses of 
pasireotide but still with uncontrolled mUFC.
2.2
Rationale for the study design
This is an open-label, multi-center international non-comparative study with adult patients 
with confirmed diagnosis of Cushing’s disease. The study will consist of patients who have 
never received pasireotide or patients who have received pasireotide sometimes in the past but 
was discontinued for reasons not related to safety. The study will also enroll pasireotide-
treated patients who at the time of screening have not achieved biochemical control despite 
maximal tolerated doses of pasireotide for at least 8 weeks.
Pasireotide naïve patients will start pasireotide monotherapy at the dose of 0.6 mg s.c. bid. If 
at the end of the 8 week treatment period, the biochemical control is not achieved and the 
0.6mg bid dose is well tolerated, the pasireotide dose will be increased to 0.9mg bid. If the 
0.9mg bid dose of pasireotide does not lead to biochemical control, cabergoline will be added 
with a starting dose of 0.5mg qd. If the combination dose of 0.9mg bid of pasireotide plus 
0.5mg qd cabergoline does not achieve biochemical control, the cabergoline dose will be 
increased to 1.0mg qd.


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Patients who are currently treated with maximal tolerated doses of pasireotide monotherapy 
for at least 8 weeks at screening without achieving normal mUFC will enter the study with
combination therapy with cabergoline. Cabergoline starting dose will be 0.5mg qd.
The stepwise approach implemented in the trial is consistent with clinical practice where 
patients are first started on monotherapy and, if necessary, combinations are considered.
2.3
Rationale for dose and regimen selection
Pasireotide naïve patients or patients who have received pasireotide sometime in the past but 
was discontinued for reasons not related to safety, will start pasireotide dose of 0.6 mg bid 
with the possibility of increase to 0.9 mg bid. In case of safety issues, the dose of the 
medication can be decreased from 0.6 mg bid to 0.3 mg bid or from 0.9 mg bid to 0.6 mg bid, 
respectively. The doses used in the study are the ones currently approved by Health 
Authorities.
Patients currently treated with pasireotide at 0.3mg bid, 0.6mg bid or 0.9mg bid, whichever 
the maximal tolerated dose they have reached, will start with combination treatment of 
pasireotide plus 0.5mg of cabergoline qd. The dose of cabergoline is consistent with the one 
used in the studies published by Pivonello (Pivonello 2004) and by Feelders (Feelders 2010). 
The daily schedule selected in the trial has the objective to increase patient’s compliance with 
the treatment. Furthermore, when higher doses of cabergoline are required, such as in 
acromegaly, a daily schedule is always chosen. Higher doses than the one used in the current 
trial are not expected to provide further benefit.


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3
Objectives and endpoints
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.2.2
1. To evaluate the overall efficacy of the treatment 
regimen of pasireotide alone or in combination with 
cabergoline in patients with Cushing’s disease
1. Proportion of patients who attain mUFC <1.0xULN at week 35 with 
pasireotide alone or in combination with cabergoline
Secondary
Refer to Section 10.3
1. To assess the changes in mUFC from baseline to study 
end at each scheduled visit where UFC is measured 
1. Actual and percentage change in mUFC from baseline to study end at each 
scheduled visit when UFC is measured
2. To assess overall efficacy of pasireotide alone or in 
combination with cabergoline as measured by normal 
mUFC levels at each scheduled visit when UFC is 
measured
2. Proportion of patients that attain mUFC ≤ 1.0xULN as assessed at each 
scheduled visit when UFC is measured
3. To evaluate overall efficacy of pasireotide alone or in 
combination with cabergoline as measured by controlled 
and partially controlled mUFC levels at each scheduled 
visit when UFC is measured
3. Proportion of patients who attain mUFC ≤ 1.0xULN or have at least 50% 
reduction from baseline in mUFC as assessed at each scheduled visit when 
UFC is measured
4. To evaluate the duration of controlled or partially 
controlled mUFC response
4. Duration of controlled or partially controlled response is defined as the 
period starting from the date of patient’s first normalization (mUFC ≤ 1.0xULN) 
or at least 50% reduction from baseline up to the date when the patient’s 
mUFC > 1.0xULN and the reduction from baseline falls to less than 50% from 
the first time
5. To assess the effect on plasma ACTH and serum 
cortisol
5. Change from baseline in plasma ACTH and serum cortisol over time
6. To assess the effect on the continuous measures of 
clinical symptoms of hypercortisolism
6. Actual and percentage change from baseline in clinical symptoms over 
time: blood pressure, body mass index, waist circumference, fasting serum 
lipid profile, and weight
7. To assess the effect on the categorical measures of 
clinical signs of hypercortisolism
7. Shift from baseline in clinical signs over time: facial rubor, fat pads, 
hirsutism, striae (via photographs) and muscle strength


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Objective
Endpoint
Analysis
8. To assess the improvement of health-related quality of 
life 
8. Change from baseline in standardized scores, as measured by the 
Cushing’s QOL and SF-12v2 over time 
9. To evaluate the safety profile of pasireotide alone or in 
combination with cabergoline 
9. Toxicity will be assessed using the National Cancer Institute-Common 
Toxicology Criteria Adverse Events version 4.03 (NCI-CTCAE v4.03) and for 
laboratory assessments that include biochemistry, hematology, urinalysis; 
special safety assessments that include the regular monitoring and recording 
of blood glucose, insulin, HbA1c, GH and IGF-1, thyroid and liver function 
tests, gallbladder examinations and ECGs. Concomitant 
medications/Significant nondrug therapies will be assessed from study 
enrollment until the safety follow-up visit.
Other secondary
Not applicable


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4
Study design
4.1
Description of study design
Core Phase
Pasireotide-untreated patients at screening - this includes patients who have never received 
pasireotide or patients who have received pasireotide sometime in the past but it was not 
discontinued because of safety - will start on pasireotide at 0.6mg twice a day for 8 weeks. 
Should biochemical control not be achieved by week 8 and the tolerability of the 0.6mg dose 
is good, the dose of pasireotide will be increased to 0.9mg twice a day for another 8 weeks. If 
biochemical control is not achieved with the higher dose of pasireotide, cabergoline at 
increasing doses will be added, starting at 0.5mg once a day, and then increased to 1.0mg 
once a day. Dose adjustments for cabergoline due to safety issues are allowed. Patients will be 
treated for a total of 35 weeks, including three 1-week (+ 3 days) dose titration periods at 
weeks 8, 17 and 26. For details on dose titration, please refer to Dose Modification and 
Titration Guidelines section. Stepwise treatment schema is outlined in Figure 4-1 Pasireotide-
untreated patients at screening below:
Figure 4-1
Pasireotide-untreated patients at screening
1. Patients not achieving normal UFC at the end of each treatment period will have the dose 
of the medication up-titrated to the next level
2. Patients must receive at least 8-week study treatment at each dose level in order to be 
titrated up to the next dose level, if biochemical control is not achieved
3. Patients that cannot have the dose up-titrated to 0.9mg because of safety reasons e.g. 
increased blood glucose levels will be treated with the combination pasireotide 0.6 mg and 
cabergoline at increasing doses. Patients who cannot tolerate 0.6mg bid will have the dose 
down-titrated to 0.3mg bid
Patients currently treated with maximal tolerated doses of pasireotide monotherapy for at least 
8 weeks - 0.3mg twice a day, 0.6mg twice a day or 0.9mg twice a day for at least 8 weeks -
but still did not achieve biochemical control will add cabergoline 0.5mg once a day at study 
entry. They will continue the combination treatment for 8 weeks. Should biochemical control 


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not be achieved by week 8, the dose of cabergoline will be increased to 1mg once a day and 
patients will be monitored for another 8 weeks. Dose adjustments for cabergoline due to 
safety issues are allowed. These patients will also be treated for a total of 35 weeks including 
one 1-week (+ 3 days) dose titration period at week 8. For details on dose titration, please 
refer to Dose Modification and Titration Guidelines section. Stepwise treatment schema is 
outlined in Figure 4-2. Patients currently treated with maximal tolerated doses of pasireotide 
monotherapy below:
Figure 4-2
Patients currently treated with maximal tolerated doses of pasireotide 
monotherapy
1. Patients not achieving normal UFC at the end of each treatment period will have the dose 
of the medication up-titrated to the next level
2. Patients must receive at least 8-week of pasireotide 0.3/0.6/0.9mg bid + cabergoine 0.5mg 
qd in order to be titrated up to the next dose level, if biochemical control is not achieved
The total duration of the core phase will be 43 weeks (4 weeks of screening period, 35 weeks 
of study treatment + study completion visit occurring within 4 weeks of last dose). All 
patients not continuing into the extension phase will have a study completion visit 28 days 
(+/- 2 days) after last dose is received in the core phase.
Extension phase
After 35 weeks of treatment in core phase, patients have the option to continue study 
treatment if pasireotide is not yet approved for commercial use and/or reimbursed - if country 
reimbursement is applicable - in each respective country, or until 31st December 2019, or once 
an applicable roll over protocol becomes available, or whichever occurs first. 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. Patients who come off the extension 
phase are required to complete a study completion visit 28 days (+/- 2 days) after last dose is 
received in the extension phase.


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5
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 study will enroll a total of 64 patients.
The study population consists of patients who have never received pasireotide or patients who 
have received pasireotide sometime in the past but it was not discontinued because of safety. 
These patients will start pasireotide monotherapy at 0.6mg bid. In addition, patients who are 
currently treated with maximal tolerated doses of pasireotide monotherapy for at least 8 weeks 
at screening but with elevated mUFC will enter the study with combination treatment of 
pasireotide at 0.3mg bid, 0.6mg bid, or 0.9mg bid, whichever the maximal tolerated dose they 
have reached, plus 0.5mg of cabergoline qd.
5.1
Key inclusion criteria
1. Written informed consent obtained prior to any screening procedures.
2. Adult patients with confirmed diagnosis of ACTH-dependent Cushing’s disease as 
evidenced by all of the following:
a. The mean of three 24-hour urine samples collected within 2 weeks > 1xULN with 2 
out of 3 samples >ULN
b. Morning plasma ACTH within the normal or above normal range
c. Either MRI confirmation of pituitary adenoma > 6 mm, or inferior petrosal sinus 
gradient >3 after CRH stimulation for those patients with a tumor less than or equal to 
6 mm*. For patients who have had prior pituitary surgery, histopathology confirming 
an ACTH staining adenoma
d. *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. If surgery has 
been performed and histopathology indicates as ACTH-secreting tumor, there is no 
need for IPSS even for patients with a tumor < 6mm. If surgery has not been 
performed and the tumor is < 6mm, IPSS is required to confirm the diagnosis using
CRH, or DDAVP if CRH is not available.
3. Patients with de novo Cushing’s disease can be included only if they are not considered 
candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable 
tumors, patients who refuse to have surgical treatment)
4. Male or female patients aged 18 years or greater
5. Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care 
for most of their personal needs)


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6. Patients on medical treatment for Cushing’s disease the following washout periods must 
be completed before screening assessments are performed

Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week

Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ 
agonists (rosiglitazone or pioglitazone): 4 weeks

Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks

Octreotide (immediate release formulation): 1 week

Progesterone receptor antagonist (mifepristone): 4 weeks
7. Patients can be considered to enter the trial if they meet any one of the following criteria:

They are naïve to pasireotide

They have received pasireotide in the past and have been discontinued because of lack 
of efficacy (2 weeks of washout prior to screening for patients treated with pasireotide 
subcutaneously and 12 weeks of washout prior to screening for patients treated with 
pasireotide LAR)

Patients who are on maximal tolerated dose but have not achieved biochemical 
control
8. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, if they are using highly effective methods of contraception during 
dosing and for 30 days after stopping study medication. Highly effective contraception 
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject.

Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.
9. Male participants in the trial must agree to use a condom during intercourse, and not to 
father a child during the study and for the period of 30 days following stopping of the 
study treatment.


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5.2
Exclusion criteria
Patients must not meet any of the following exclusion criteria at screening:
1. Patients with compression of the optic chiasm causing any visual field defect that requires 
surgical intervention
2. Diabetic patients with poor glycemic control as evidenced by HbA1c >8%
3. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >450 
ms in males, and > 460 ms in females. hypokalemia, hypomagnesaemia, uncontrolled 
hypothyroidism, family history of long QT syndrome, or concomitant medications known 
to prolong QT interval
4. Patients with clinically significant valvular disease
5. Patients with Cushing’s syndrome due to ectopic ACTH secretion
6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral 
adrenal hyperplasia
7. Patients who have a known inherited syndrome as the cause for hormone over-secretion 
(i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
8. Patients who are hypothyroid and not on adequate replacement therapy
9. Patients with symptomatic cholelithiasis
10. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, 
history of acute MI less than one year prior to study entry or clinically significant 
impairment in cardiovascular function
11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent 
hepatitis, or patients with ALT/AST > 2 X ULN, serum bilirubin >2.0 X ULN
12. Patients with serum creatinine >2.0 X ULN
13. Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L
14. Patients who have a history of alcohol or drug abuse in the 6 month period prior to 
receiving pasireotide
15. Patients who have participated in any clinical investigation with an investigational drug 
within 1 month prior to dosing
16. Patients with active malignant disease within the last five years (with the exception of 
basal cell carcinoma or carcinoma in situ of the cervix)
17. Patients with the presence of active or suspected acute or chronic uncontrolled infection
18. 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
19. Patients with presence of Hepatitis B surface antigen (HbsAg)
20. Patients with presence of Hepatitis C antibody test (anti-HCV)
21. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide 
or cabergoline
22. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or 
digestive hemorrhage, galactose intolerance, Parkinson’s disease, uncontrolled 
hypertension and Raynaud’s syndrome.


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23. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 5 mIU/mL).
24. Patients with end-stage renal failure and/or hemodialysis
6
Treatment
6.1
Patient numbering, treatment assignment
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 Number is a 9-digit 
number 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
6.2
Study treatment
Patients who are not treated with pasireotide at the time of screening or have never been 
treated with pasireotide in the past will start pasireotide 0.6mg twice a day for 8 weeks. If 
biochemical control is not achieved by the end of 8 weeks, and the 0.6mg dose is well-
tolerated, the dose of pasireotide will be increased to 0.9mg twice a day for another 8 weeks. 
If biochemical control is not achieved with the higher dose of pasireotide, cabergoline will be 
added and patients will begin combination treatment with cabergoline at the starting dose of
0.5mg qd for 8 weeks. If biochemical control is still not achieved at the end of the third 8-
week treatment period, the dose of cabergoline will be further increased to cabergoline at 
1.0mg qd for another 8 weeks.
Patients that cannot have the dose up-titrated to 0.9mg bid because of safety reasons, for 
example, significantly increased blood glucose levels, will be treated with combination 
pasireotide 0.6mg bid and cabergoline at increasing doses. Patients who cannot tolerate 
pasireotide 0.6mg bid will have the dose down-titrated to 0.3mg bid and begin combination 
treatment with cabergoline at increasing doses should pasireotide 0.3mg bid monotherapy not 
be able to lead to normal mUFC. If a patient shows high sensitivity to pasireotide 0.6 mg bid 
resulting in cortisol values <LLN and/or signs/symptoms consistent with the diagnosis of 
hypocortisolism, the dose of pasireotide can be decreased to 0.3 mg bid. Despite the dose 
reduction, some patients may still present with cortisol values <LLN and/or signs/symptoms 
consistent with hypocortisolism; in this case the dose of pasireotide can be further reduced to 
0.3 mg qd in order to achieve and maintain normal cortisol levels. Please refer to Dose 
modifications and titration guidelines Section 6.4 of the protocol for more details.


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At weeks 8, 17 and 26, patients will continue to receive their current dose until their UFC
results are available, at which time, a decision will be made on whether to maintain the 
current dose or titrate up to the next level.
Patients who are currently treated with maximal tolerated doses of pasireotide monotherapy at 
0.3mg, 0.6mg or 0.9mg twice a day for at least 8 weeks, but still with elevated UFC will 
immediately start the combination treatment by adding cabergoline 0.5mg once a day to their 
current pasireotide dose at study entry. Patients will continue with the combination treatment 
for 8 weeks. If biochemical control is not achieved by the end of the 8 weeks, the dose of 
cabergoline will be increased to 1mg once a day. At week 8, patients will continue to receive 
their starting combination dose until their UFC results are available, at which time, a decision 
will be made on whether to maintain the current dose or titrate up to the next combination 
dose.
All patients will be treated for a total of 35 weeks in the core phase.
The possible monotherapy or combination treatment regimens are as follows:
1. Monotherapy: pasireotide 0.3mg twice a day
2. Monotherapy: pasireotide 0.6mg twice a day
3. Monotherapy: pasireotide 0.9mg twice a day
4. Combination: pasireotide 0.3mg twice a day + cabergoline 0.5mg once a day
5. Combination: pasireotide 0.3mg twice a day + cabergoline 1.0mg once a day
6. Combination: pasireotide 0.6mg twice a day + cabergoline 0.5mg once a day
7. Combination: pasireotide 0.6mg twice a day + cabergoline 1.0mg once a day
8. Combination: pasireotide 0.9mg twice a day + cabergoline 0.5mg once a day
9. Combination: pasireotide 0.9mg twice a day + cabergoline 1.0mg once a day
10. Monotherapy: pasireotide 0.3mg once a day*
* This dosage should only be applied if a patient shows high sensitivity to pasireotide 0,6 mg 
bid resulting in cortisol values <LLN and/or signs/symptoms consistent with the diagnosis of 
hypocortisolism, the dose of pasireotide can be decreased to 0.3 mg bid. Despite the dose 
reduction, some patients may still present with cortisol values <LLN and/or signs/symptoms 
consistent with hypocortisolism; in this case the dose of pasireotide can be further reduced to 
0.3 mg qd in order to achieve and maintain normal cortisol levels.
6.2.1
Dosing regimen
For dose and treatment schedule, please see Table 6-1 below.
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Pasireotide
Subcutaneous
0.3mg, 0.6mg, and 0.9mg
Twice a day
Cabergoline
Oral
0.5mg or 1.0mg
Once a day


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6.2.2
Treatment duration
Core phase
All patients will receive a total of 35-week treatment.
Extension phase
After up to 35 weeks of treatment, patients have the option to continue study treatment if 
pasireotide is not approved for commercial use and/or reimbursed in each respective country, 
if country reimbursement is applicable. Patients can continue with study treatment on 
extension phase until pasireotide is approved for commercial use and reimbursed in their
respective country, or until 31st December, 2019, or once an applicable roll over protocol 
becomes available, or whichever occurs first.
6.3
Study drug
6.3.1
Supply, preparation and storage
6.3.2
Pasireotide
Please refer to pasireotide Package Insert and Summary of Product Characteristics (SmPC) for 
preparation and storage. Pasireotide will be supplied by Novartis if it is not available in the 
respective country.
6.3.3
Cabergoline
Cabergoline is in the form of 0.5mg tablet. Cabergoline should be taken in the evening after a 
full meal. Dostinex, a generic form of cabergoline, will be used in the trial. If Dostinex is not 
available in a participating country, a different type of generic form will be used. For storage 
conditions, please refer to cabergoline Package Insert and SmPC. Cabergoline will be 
supplied by Novartis.
6.3.4
Study drug compliance
Patients must be able to self-administer the study drug, pasireotide (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 will 
not be reused; a new ampoule should be used for each injection. Patients should be instructed 
to retain and return unused ampoules at their next scheduled visit.
Patients will self-administer pasireotide subcutaneously twice a day 12 hours apart. It is 
advised to take the study medication at the same time every day at around 10:00 in the 
morning and 10:00 in the evening.
For patients who are unable to tolerate the protocol specified dosing schedule, dose 
adjustments are permitted to keep the patient on study drug. Please refer to the Dose 
Modification and Titration Guidelines section.


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The investigator should instruct the patient to take the study drug exactly as described. All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record Case Report Form (CRF).
Patient should phone the investigator if he/she experiences an adverse event and their next 
study visit is not yet due. If dose delay or modification is required due to the adverse event, 
the investigator should document in the medical record the telephone conversation regarding 
the dose delay or modification.
6.4
Guidelines for dose modifications and titrations
6.4.1
Pasireotide and cabergoline dose modification steps
Pasireotide untreated patients: will begin their treatment with pasireotide 0.6mg twice a day 
monotherapy for 8 weeks. If biochemical control is not achieved by the end of the 8-week 
period, and the 0.6mg dose is well tolerated, the dose of pasireotide will be increased to 0.9mg 
twice a day for another 8 weeks. If biochemical control is still not achieved at 0.9mg twice a 
day and the dose is well tolerated, the combination treatment of pasireotide 0.9mg twice a day 
plus cabergoline 0.5mg once a day will be given for another 8 weeks. If biochemical control is 
not yet achieved either during or at the end of the 8-week period, cabergoline dose will be 
increased to 1.0mg once a day.
If a patient shows high sensitivity to pasireotide 0.6mg bid resulting in cortisol values <LLN 
and/or signs/symptoms consistent with the diagnosis of hypocortisolism, the dose of 
pasireotide can be decreased to 0.3mg bid. Despite the dose reduction, some patients may still 
present with cortisol values <LLN and/or signs/symptoms consistent with hypocortisolism; in 
this case the dose of pasireotide can be further reduced to 0.3 mg qd in order to achieve and 
maintain normal cortisol levels.
If the 0.9mg twice a day dose is not tolerated and biochemical control is not achieved, patient 
will begin combination treatment of pasireotide at 0.6mg twice a day plus cabergoline at 
0.5mg once a day for 8 weeks. If during or at the end of the 8-week period, the biochemical 
control is not achieved, the combination dose will be increased to pasireotide at 0.6mg twice a 
day plus cabergoline at 1.0mg once a day for 8 weeks. The patient will continue with the 
highest combination dose of 0.6mg pasireotide twice a day plus 1.0mg cabergoline once a day, 
or 0.9mg pasireotide twice a day plus 1.0mg of cabergoline once a day for 8 weeks. The total 
duration of treatment is 35 weeks. (see Table 6-2)
If patient does not tolerate 0.6mg twice a day, the dose of pasireotide should be decreased to 
0.3mg twice a day. If pasireotide 0.3mg twice a day does not lead to biochemical control after 
at least 8 weeks of treatment, combination with cabergoline as described above can be 
initiated (see Table 6-2).
If patient cannot increase from 0.6mg twice a day to 0.9mg twice a day due to safety, and is 
not yet biochemically controlled, combination with cabergoline 0.5mg qd can be initiated 
right away with pasireotide at 0.6mg twice a day (see Table 6-2).
If patient is being escalated to 0.9mg twice a day, but cannot tolerate the dose, dose should be 
reduced to 0.6mg twice a day. If the latter dose does not lead to biochemical control, 
combination with cabergoline as described above can be initiated (see Table 6-2).


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If combination pasireotide and cabergoline 0.5mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 0.5mg every other day. If 0.5mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 6-2).
If combination pasireotide and cabergoline 1.0mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 1.0mg every other day. If 1.0mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 6-2).
The minimum treatment of any regimen is 8 weeks. Patients losing biochemical control at any 
time point after the 8 week period will have the dose of the study mediation increased 
immediately to the next level provided that the dose is well tolerated.
For patients whose starting dose is 0.6mg pasireotide twice a day monotherapy, at weeks 9, 18 
and 27, before patient’s UFC results are available, the investigator may select one of the 
following two options to dispense study medication to the patient for the next 5-9 weeks of 
treatment:
Option 1: The investigator dispenses study medication at the current dose, plus study 
medication at the next dose level at the end of week 8, 13, 17, 22, 26, or 31 visits. When 
patient’s UFC results are available, the investigator should phone the patient to inform 
him/her to either remain at the current dose or titrate up to the next monotherapy dose level or
start the combination therapy.
Option 2: The investigator dispenses study medication at the current dose at the end of week 8, 
13, 17, 22, 26 or 31 visits. When patient’s UFC results are available and shown that his/her 
biochemical is not controlled, the investigator schedules a visit for patient to come to the 
clinic and pick up study medication at the next monotherapy dose level or start the 
combination therapy.
The dosing decision should be properly documented in the medical record and dose 
administration CRF page.
Table 6-2
Pasireotide and cabergoline dose modification steps for pasireotide 
un-treated patients
Pasireotide: pasi 
Cabergoline: cabe
Starting dose 
level
Dose 
modification
level - 1
Dose 
modification
level - 2
Dose 
modification
level - 3
Dose 
medication 
level - 4
Modification # 1
0.6mg bid pasia
0.3mg bid pasib
0.3mg bid pasi + 
0.5mg cabe qdb
0.3mg bid pasi + 
1.0mg cabe qd
Modification # 2
0.6mg bid pasib
0.9mg bid pasib
0.9mg bid pasi + 
0.5mg qd cabeb
0.9mg bid pasi + 
1.0mg qd cabe
Modification # 3
0.6mg bid pasib
0.9mg bid pasia
0.6mg bid pasib
0.6mg bid pasi + 
0.5mg cabe qdb
0.6mg bid 
pasi + 1.0mg 
cabe qd
Modification # 4
0.6mg bid pasic
0.6mg bid pasi + 
0.5mg qd cabeb
0.6mg bid pasi + 
1.0mg cabe qd
Modification # 5
0.9mg bid pasiab
0.6mg bid pasi + 
0.5mg qd cabeb
0.6mg bid pasi + 
1.0mg qd cabe


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Pasireotide: pasi 
Cabergoline: cabe
Starting dose 
level
Dose 
modification
level - 1
Dose 
modification
level - 2
Dose 
modification
level - 3
Dose 
medication 
level - 4
Modification # 6
0.3, 0.6 or 
0.9mg bid pasi + 
0.5mg qd cabea
0.3, 0.6 or 
0.9mg bid pasi + 
0.5mg every 
other day cabeab
Discontinuation 
if no clinical 
benefit
Modification # 7
0.3, 0.6 or 
0.9mg bid pasi + 
1.0mg qd cabea
0.3, 0.6 or 0.9 
mg bid pasi + 
1.0mg every 
other day cabeab
Discontinuation 
if no clinical 
benefit
a Dose modification is initiated if the current dose is not tolerated
b Dose modification is initiated if biochemical control is not achieved
c Dose cannot be increased to the next level due to toxicity but biochemical control is not achieved
Patients currently treated with maximal tolerated doses of pasireotide monotherapy: 
0.3mg bid, 0.6mg bid or 0.9mg bid, for at least 8 weeks but did not achieve biochemical 
control will begin their combination treatment of pasireotide at 0.3mg, 0.6mg or 0.9mg bid 
plus 0.5mg of cabergoline once a day at study entry. They will continue the treatment for 8 
weeks. If biochemical control is not achieved at the end of the 8-week period, the dose of 
cabergoline will be increased to 1.0mg once a day and continue with the combination 
treatment for the remainder of 26 weeks.
If combination pasireotide and cabergoline 0.5mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 0.5mg every other day. If 0.5mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 6-3).
If combination pasireotide and cabergoline 1.0mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 1.0mg every other day. If 1.0mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 6-3).
The minimum treatment of any regimen is 8 weeks. Patients losing biochemical control at any 
time point after the 8-week treatment period at the starting combination dose will have the 
dose of the study mediation increased immediately to the next level provided that the dose is 
well tolerated (see Table 6-3).
At week 9, before patient’s UFC results are available, the investigator may select one of the 
following two options to dispense study medication to the patient for the next 26 weeks of 
treatment:
Option 1: The investigator dispenses study medication at the current dose, plus study 
medication at the next dose level at the end of week 8 visit. When patient’s UFC results are 
available, the investigator should phone the patient to inform him/her to either remain at the 
current dose or titrate up to the next combination dose level.
Option 2: The investigator dispenses study medication at the current dose at the end of week 8 
visit. When patient’s UFC results are available and shown that his/her biochemical is not 
controlled, the investigator schedules a visit for patient to come to the clinic and pick up study 
medication at the next combination dose level.


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Table 6-3
Pasireotide and cabergoline dose modification steps for patients 
currently treated with maximal tolerated doses of pasireotide 
monotherapy
Pasireotide: pasi 
Cabergoline: cabe
Starting dose level
Dose modification
level - 1
Dose modification
level - 2
Modification # 1
0.3, 0.6 or 0.9mg bid pasi 
+ 0.5mg qd cabea
0.3, 0.6 or 0.9mg bid pasi + 
0.5mg every other day cabea
Discontinuation if no clinical 
benefit
Modification # 2
0.3, 0.6 or 0.9mg bid pasi 
+ 0.5mg qd cabeb
0.3, 0.6 or 0.9mg bid pasi + 
1.0mg qd cabea
Modification # 3
0.3, 0.6 or 0.9mg bid pasi 
+ 1.0mg qd cabea
0.3, 0.6 or 0.9 mg bid pasi + 
1.0mg every other day cabea
0.3, 0.6 or 0.9mg bid pasi + 
0.5mg qd cabe
a Dose modification is initiated if the current dose is not tolerated
b Dose modification is initiated if biochemical control is not achieved
6.5
Special safety
6.5.1
Hyperglycemia
Hyperglycemia is known to be associated with the treatment of somatostatin analogues.  
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.
6.5.2
Self-monitoring of blood glucose
The principal investigator is to educate the patient on the signs and symptoms of 
hyperglycemia. Patients must monitor their fasting blood glucose by finger stick at home at 
least 3 times per week for the first 4-week treatment with pasireotide or when the dose of 
pasireotide is increased. If a patient does not have any fasting values above 100mg/dL, 
monitoring can be decreased to at least 2 times per week from week 4 to week 12 and 1 time 
every week for the rest of the study. If glucose values remain normal (below 100mg/dL), 
monitoring is at the investigator’s discretion during the extension phase (where it is 
applicable). If any values are observed above 100mg/dL, the guidelines in Figure 6-1 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 < 130mg/dL (<7.2mmol/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 > 130mg/dL 
by self-monitoring), a fasting plasma glucose sample using the central laboratory is to be 


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collected prior to initiation of anti-hyperglycemic treatment; however, treatment may be 
initiated using local laboratory results.
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. These 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 to Table 7-4. 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 > 130mg/dL or HbA1c ≥ 6.5%.
Patients with FPG > 160mg/dL or HbA1c > 7.5% despite adjustment of antidiabetic therapy 
should be referred to a diabetes specialist (or earlier per investigator’s judgment).
As outlined in Table 6-4 patients with grade 3 hyperglycemia (FPG value > 250mg/dL; >13.9 
mmol/L) at any point in the study should have the dose of pasireotide decreased. Patients who 
in spite of appropriate therapeutic interventions and despite dose reduction of study drug 
develop uncontrolled diabetes mellitus and/or consistently high blood glucose values: FPG ≥ 
240mg/fdL (13.3 mmol/L) or HbA1c value ≥ 10% will require study treatment 
discontinuation.
Figure 6-1
Fasting Self-Monitoring Blood Glucose guidelines


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6.5.3
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.
If at any visit a 480 msec > QTcF ≤ 500 msec 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 HolterECG 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
6.5.4
Hepatic Safety Management
Patients who develop increased transaminase and/or total bilirubin (> 2.0 x ULN) levels,
should be monitored with a second liver function evaluation for confirmation. If confirmed, 
liver function should be frequently monitored until values return to pre-treatment levels.
If any of the criteria below are observed at any scheduled or unscheduled visit the sponsor 
should be notified immediately and the Hepatic Safety evaluation, described below, should be 
performed preferably within 48- hours of awareness of the abnormality:


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Patient experiencing

ALT or AST > 3 x ULN and total bilirubin ≥ 2 x ULN

ALT or AST > 5 x ULN

total bilirubin > 2.0 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 function 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 function tests (LFTs) should be monitored every 3-4 days until resolution or return to 
baseline status.
Patients should be managed according to the LFT algorithm Figure 6-3. Patients may need to 
be discontinued if the abnormal liver function criteria are met upon LFT retesting (See 
discontinuation criteria Section 7.1.2.1). Progress reports of the event should be maintained 
until resolution or stabilization (i.e. no further elevation after 2 consecutive assessments).
If any of these criteria are met and not confirmed by repeat testing, and the event is considered 
to be an adverse event by the investigator, the event must be recorded on the Adverse Event 
eCRF 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 eCRF page.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant”, thus, meet the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.


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Figure 6-3
LFT Management Algorithm
6.6
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 6-4 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.
If patients permanently discontinued from study treatment without completing the full 35 
weeks of treatment in the core phase, the patients will be considered as prematurely 
discontinued from the study.
All patients must have a safety evaluation 28 days after the last dose of study treatment. 
Patients who do not complete study completions visit will be documented as a protocol 
deviation. This applies also to patients who discontinue the trial due to withdrawal of consent 
unless they do not consent to such a visit. Patients lost to follow up should be recorded as 
such on the CRF.


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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 6-4).
Table 6-4
Guidelines 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 
pasireotide-related 
Reduce dose of by 0.3mg bid. If AE improves to grade ≤ 2 within 1 
week, increase dose by 0.3mg bid. If AE recurs at grade ≥ 3, reduce 
dose by 0.3mg bid again and remain at lower dose. If AE does not 
improve to grade ≤ 2 within 1 week on lower dose, reduce dose by 
0.3mg bid again if possible. If AE does not improve to grade ≤ 2 
within 1 week on 0.3mg bid patient should be discontinued from 
study treatment
AE grade ≥ 3 (severe to life-
threatening) and judged as 
cabergoline-related
Reduce dose from daily schedule to every other day schedule. If AE 
improves to grade ≤ 2 within 1 week, increase dose to daily 
schedule. If AE recurs at grade ≥ 3, reduce dose every other day 
schedule again and remain at that schedule. If AE does not improve 
to grade ≤ 2 within 1 week on the every other day schedule, patient 
should be discontinued from study treatment
All patients
For patients experiencing hyperglycemia, the dose should be 
reduced if severity grade 3 or greater persists despite appropriate 
management. If the hyperglycemia is considered to be life-
threatening, the patient should be withdrawn from study treatment 
regardless of anti-diabetes treatment
AE grade 3 – All patients
NCI-CTCAE v4.03 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 
appropriate management. Patients who despite appropriate 
therapeutic interventions and dose reduction of study drug, develop 
uncontrolled diabetes and/or consistently high blood glucose 
values: FPG ≥ 240mg/fdL (13.3 mmol/L) or HbA1c value ≥ 10% will 
require study treatment discontinuation
Hypocortisolsim
If a patient shows high sensitivity to pasireotide 0,6 mg bid resulting 
in cortisol values <LLN and/or signs/symptoms consistent with the 
diagnosis of hypocortisolism, the dose of pasireotide can be 
decreased to 0.3 mg bid. Despite the dose reduction, some patients 
may still present with cortisol values <LLN and/or signs/symptoms 
consistent with hypocortisolism; in this case the dose of pasireotide 
can be further reduced to 0.3 mg qd in order to achieve and 
maintain normal cortisol levels.
No dose reductions are required in case of a QT prolongation but guidelines for QT monitoring and 
discontinuation criteria outlined in Section 6.5.3
6.7
Permitted concomitant therapy requiring caution and/or action
Patient must be told to notify the investigational site about any new medications he/she takes 
after the start of the study drug, as well as any changes in the dose of any medication the 
patient was taking prior to or during the study. 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. If oral contraception is 


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used, the patient must have been practicing this method of birth control for at least three 
months prior to enrollment and must agree to continue the oral conceptive throughout the 
course of the study and for 30 days after the last dose of study drug.
6.7.1
Prohibited concomitant therapy
PRARγ agonists (rosiglitazone or pioglitazone) treatment is not permitted during the study as 
it could affect patient’s ACTH levels. Treatment with prednisolone is prohibited as this 
interferes with the UFC detection. Use of the medications listed in below that requires a 
washout are also prohibited during the study.
Further, the use of concomitant medications with a known risk for QT prolongation is 
prohibited and requires the discontinuation of the patient from the study prior to starting the 
respective QT prolonging medication. Please refer to Appendix 4 for guidance regarding 
medications which pose a known risk for QT prolongation.
Patients on medical treatment for Cushing’s disease the following washout periods must be 
completed before screening assessments are performed:
1. Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
2. Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ 
agonists (rosiglitazone or pioglitazone): 4 weeks
3. Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks
4. Octreotide (immediate release formulation): 1 week
5. Progesterone receptor antagonist (mifepristone): 4 weeks
6. Pasireotide s.c.: 2 weeks
7. Pasireotide LAR: 12 weeks
7
Study flow and visit schedule
7.1
Study flow and visit schedule
Table 7-1 to Table 7-4 list all of the assessments and indicate with an “x” where visits are 
performed. All data obtained from these assessments are recorded in the eCRF.


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Table 7-1
Core Phase - Visit evaluation schedule
Category
Protocol 
Section
Screening
Baseline 
(first 
dose)
Study Period
End of 
Treatment 
Visit (last 
dose)
Study 
Completion 
Visit ( Last 
dose + 28 
days)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
777
779
Study Week
-3 to 0
0
1
2
4
8
13
17
22
26
31
35
Obtain Informed Consent
D
7.1.1
x
Patient history
Demography
D
7.1.1.2
x
Inclusion/exclusion criteria
D
5.1 / 5.2
x
Relevant medical history/current medical 
conditions
D
7.1.1.2
x
Prior/concomitant medications
D
7.1.1.2
Continuous
Physical examination
7.2.2.1
x
x
x
x
x
x
x
x
x
x
x
x
Karnofsky performance status
D
7.2.2.4
x
x
x
x
Height and weight
D
7.2.2.3
x
Vital signs (including weight)
D
7.2.2.2
x
x
x
x
x
x
x
x
x
x
x
x
Signs and symptoms of Cushing’s disease
D
7.2.1.5
7.2.1.6
x
x
x
x
x
x
x
x
x
x
x
Cushing QOL and SF-12v2 HRQoL 
questionnaires
D
7.2.1.7
x
x
x
Laboratory assessments
Hematology, GH, IGF-1
D
7.2.2.5.1
x
x
x
x
x
x
Free T4, TSH
D
7.2.2.5.5
x
x
x
Clinical Chemistry 
D
7.2.2.5.2
x
x
x
x
x
x
x
MDRD creatinine clearance
D 
7.2.2.5.2
x
x
LFT
D
7.2.2.5.3
x
x
x
x
x
x
x
x
x
x
x
Coagulation (PT, INR)
D
7.2.2.5.4
x
x
x
x
x
x
x


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Category
Protocol 
Section
Screening
Baseline 
(first 
dose)
Study Period
End of 
Treatment 
Visit (last 
dose)
Study 
Completion 
Visit ( Last 
dose + 28 
days)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
777
779
Study Week
-3 to 0
0
1
2
4
8
13
17
22
26
31
35
Fasting Blood Glucose
D
7.2.2.5.2
x
x
x
x
x
x
x
x
x
x
x
HbA1c
D
7.2.2.5.2
x
x
x
x
x
Midnight salivary cortisol
D
7.2.1.3
x
x
x
x
x
x
x
x
x
Urinary free cortisol and urine creatinine
D
7.2.1.1
x
x
x
x
x
x
x
x
x
Serum cortisol
D
7.2.1.2
x
x
x
x
x
x
x
x
x
x
Plasma ACTH
D
7.2.1.4
x
x
x
x
x
x
x
x
x
x
HbsAg and anti-HCV
D
7.2.2.5.3
x
Urinalysis
D
7.2.2.5.6
x
x
x
x
x
Pregnancy Test
D
7.2.2.5.7
x
x
x
x
x
x
x
x
x
x
x
x
Imaging/Other assessments
ECG (pasireotide pre-dose)
D
7.2.2.5.9
x
x
x
x
x
x
x
x
x
x
x
x
Echocardiogram
D
7.2.2.5.10
x
x
Gallbladder Ultrasound
D
7.2.2.5.8
x
x
x
Safety
Adverse events
D
10.3.1.2
Continuous
Drug administration
D
6
Continuous


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Table 7-2
Extension Phase - Visit evaluation schedule
Category
Protocol 
Section
Study Period
End of 
Treatment 
Visit (last 
dose)
Study 
Completion 
Visit ( Last 
dose + 28 
days)
Visit Number
13
14
15
16
17
18
19
20
21
22, 23….
778
779
Study Week
43
51
59
67
75
83
91
99
107
115, 123…
Last dose
Physical examination
7.2.2.1
x
x
x
x
x
x
x
x
x
x
Vital signs (including weight)
D
7.2.2.2
x
x
x
x
x
x
x
x
x
x
Signs and symptoms of Cushing’s disease
D
7.2.1.5
7.2.1.6
x
x
x
x
x
x
x
x
x
x
x
Prior/concomitant medications
D
7.1.1.2
Continuous
Laboratory assessments
Hematology, GH, IGF-1
D
7.2.2.5.1
x
x
x
x
x
x
Free T4, TSH
D
7.2.2.5.5
x
x
x
x
x
Clinical Chemistry
D
7.2.2.5.2
x
x
x
x
x
x
MDRD creatinine clearance
D
7.2.2.5.2
x
LFT
D
7.2.2.5.3
x
x
x
x
x
x
x
x
x
x
x
Coagulation (PT, INR)
D
7.2.2.5.4
x
x
x
x
x
x
Fasting Blood Glucose
D
7.2.2.5.2
x
x
x
x
x
x
x
x
x
x
x
HbA1c
D
7.2.2.5.2
x
x
x
x
x
x
Midnight salivary cortisol
D
7.2.1.3
x
x
x
x
x
x
x
x
x
x
x
Urinary free cortisol and urine creatinine
D
7.2.1.1
x
x
x
x
x
x
x
x
x
x
x
Serum cortisol
D
7.2.1.2
x
x
x
x
x
x
x
x
x
x
x
Plasma ACTH
D
7.2.1.4
x
x
x
x
x
x
x
x
x
x
x
Urinalysis
D
7.2.2.5.6
x
x
x
x
x
x
Pregnancy Test 
D
7.2.2.5.7
x
x
x
x
x
x
x
x
x
x
x


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Category
Protocol 
Section
Study Period
End of 
Treatment 
Visit (last 
dose)
Study 
Completion 
Visit ( Last 
dose + 28 
days)
Visit Number
13
14
15
16
17
18
19
20
21
22, 23….
778
779
Study Week
43
51
59
67
75
83
91
99
107
115, 123…
Last dose
Imaging/Other assessments
ECG (pasireotide pre-dose)
D
7.2.2.5.9
x
x
x
x
x
x
x
x
x
x
x
Echocardiogram
D
7.2.2.5.10
x
x
x
x
x
Gallbladder Ultrasound
D
7.2.2.5.8
x
x
x
x
x
Safety
Adverse events
D
10.3.1.2
Continuous
Drug administration
D
6
Continuous
Please refer to Table 7-3 for extension phase assessment frequencies.


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Table 7-3
Extension Phase - Assessment frequencies
Assessment
Frequency
Gallbladder
Every 6 months (24 weeks)
Hematology
Every 4 months (16 weeks)
GH and IGF-1
Every 4 months (16 weeks)
Free T4 and TSH
Every 6 months (24 weeks)
Blood chemistry
Every 4 months (16 weeks)
LFT
Every 2 months (8 weeks)
Coagulation
Every 4 months (16 weeks)
Fasting blood glucose
Every 2 months (8 weeks)
HbA1C
Every 4 months (16 weeks)
Midnight salivary cortisol
Every 2 months (8 weeks)
Urinary free cortisol and urine creatinine
Every 2 months (8 weeks)
Serum cortisol
Every 2 months (8 weeks)
Plasma ACTH
Every 2 months (8 weeks)
Signs and symptoms of Cushing’s disease
Every 2 months (8 weeks)
Urinalysis
Every 4 months (16 weeks)
Pregnancy test
At every scheduled visit 
ECG
Every 2 months (8 weeks)
Echocardiogram
Every 6 months (24 weeks)
Table 7-4
Central Laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH (Mean Corpuscular Hemoglobin), MCHC (Mean Cell 
Hemoglobin Concentration), MCV (Mean Corpuscular Volume), Platelets, Red blood cells, 
White blood cells, RBC Morphology with Differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), GGT, Calcium, Urine Creatinine, 
Creatine kinase, amylase, lipase, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total 
Cholesterol, LDL- cholesterol, HDL-cholesterol, Total Protein, Triglycerides, Blood Urea 
Nitrogen (BUN) or Urea, Uric Acid, magnesium, sodium, potassium, serum creatinine, fasting 
blood glucose and glycosylated hemoglobin (HbA1C). Estimated glomerular filtration rate 
from serum creatinine at screening and end of treatment only
Urine collection
24 hour urinary collections for mUFC
Coagulation
International normalized ratio [INR]) and Prothrombin time (PT)
Additional 
hormones
Midnight salivary cortisol, Urine free cortisol (UFC), Insulin-like growth factor 1 (IGF-1), GH, 
Free T4, and TSH, serum cortisol, Plasma ACTH
Pregnancy and 
assessments of 
fertility
All pre-menopausal women who are not surgically sterile will undergo a urine dip-stick -
pregnancy test at visits indicated in Table 7-1 through Table 7-4. The patient will be required 
to undergo a serum β-hCG pregnancy test if the urine dip-stick pregnancy test is positive. A 
positive serum pregnancy test requires immediate interruption of study treatment until the 
assessment is confirmed. If positive, the patient must be discontinued from the study.


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7.1.1
Screening
The informed consent must be signed prior to ANY screening procedure being performed. 
Screening visit (Visit 1) should occur within 28 days prior to the baseline visit (Visit 2). The 
site should enter the Interactive Web Response System (IWRS ) when a patient signs the 
informed consent and begins his/her screening. Patients that do not meet eligibility criteria are 
allowed to be rescreened and should use the same patient ID number. Rescreening should be 
documented in the source files.
If the following procedures meet all entry criteria at the original screening they do not have to 
be repeated for patients who rescreen within 60 days from the first day of the initial screening: 
vital signs, MRI, and gallbladder ultrasound. Any of these assessments that are abnormal and 
all other assessments not listed here are to be repeated.
7.1.1.1
Enrollment and eligibility confirmation
In order to determine and confirm the eligibility of the patient, when all screening procedures 
are completed, a key eligibility checklist must be completed in IWRS 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 for the trial.
7.1.1.2
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 screen fail will be entered on the appropriate 
CRF page. Screen failed patient’s demographic information will still be recorded on the 
Demography CRF page. No other data will be entered into the clinical database for screen 
failed patients. Screening assessments of 24 hour urine free cortisol and late night salivary 
cortisol for patients who are screen failures will be collected by the central laboratory for 
analysis but no CRF page is to be completed. IWRS must be notified within 2 days of the 
screen fail.
7.1.1.3
Patient demographics and other baseline characteristics
Standard demographic information and medical history will be collected. Cushing’s disease 
history and diabetes history together with the medication/treatment used will also be collected. 
Other baseline assessments will be collected as per Table 7-1 and Table 7-2.
7.1.1.4
Treatment period – core phase
The Study period in the core phase of the study is 35 weeks. Study visits are at week 1, week 
2, week 4, week 8, week 13, week 17, week 22, week 26 week 31 and week 35. All visits 
should be performed within the indicated week (+/- 1 day).


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7.1.2
End of treatment, including premature withdrawal and study 
discontinuation visit
Patients who discontinue study treatment before visit 777 in the core phase and visit 778 in 
the extension phase, should be scheduled for a visit as soon as possible, at which time all of 
the assessments listed for the EOT visit will be performed (Table 7-1 and Table 7-2). An End 
of Treatment Phase Disposition CRF page should be completed, giving the date and reason 
for stopping the study treatment. At a minimum, all patients who discontinue study treatment, 
including those who refuse to return for a final visit, will be contacted for safety evaluations 
during the 28 days following the last dose of study treatment.
If a study 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 End of Treatment Discontinuation CRF page. The investigator must 
contact IVRS to register the patient’s discontinuation.
For criteria for premature withdrawal refer to Section 7.1.2.1.
7.1.2.1
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:
1. Patients experiencing unacceptable drug-related toxicity (as described in Table 6-1)
2. 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,
3. 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:
a. Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms 
of hemodynamic compromise
b. Sustained ventricular tachycardia (>30 sec) irrespective of symptoms
c. Recurrent non-sustained VT (≥ 3 beats) during any 24-hour monitoring period
d. Torsades de Pointes (TdP)
e. Cardiac arrest
f.
Pause >5 seconds
g. Second or third degree AV block

New occurrence of clinically significant/symptomatic bradycardia, or

Increased risk of QT prolongation by use of QT prolonging medication, or

Hypokalemia (<3.5 mmol/L) or hypomagnesaemia (<0.7 mmol/L) confirmed by 
repeat testing that is either a new finding or accompanied by vomiting or diarrhea and 
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
Evidence of hypoadrenalism: defined as an early morning (between 8 and 10 am) 
serum cortisol < 3 µg/dL and a UFC measurement < LLN or symptoms suggestive of 
hypoadrenalism (e.g. postural hypotension, nausea, and abdominal pain) in 
association with a UFC measurement < LLN, which persist after drug dose 
adjustment

Lack of efficacy: consistently elevated UFC level and lack of clinical benefit after ≥3 
months treatment

Pregnancy

Patient experiencing
a. ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN
b. ALT or AST > 5 x ULN ≤ 8 x ULN persistent for more than 2 weeks
c. 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 outline in Section 6.5.4. 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:
1. Adverse event(s)
2. Abnormal laboratory value(s)
3. Abnormal test procedure result(s)
4. Protocol violation
5. Subject withdrew consent
6. Lost to follow-up
7. Administrative problems
8. Death
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Mean urinary free cortisol (mUFC)
The primary efficacy parameter will be the proportion of patients who attain mUFC ≤ 1.0 
ULN at week 35 with pasireotide alone or in combination with cabergoline.
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 
(baseline visit). 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 interval in the core phase and at 8 week interval in the extension phase. 


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In the core phase of the study, patients at weeks 4, 8, 13, 17, 22, 26, 31 and 35, mean 24h-
UFC will be determined from two 24-hour urine collections collected on two consecutive 
days occurring before the visit. In the extension phase of the study, patients’ 24h-UFC will be 
determined at 8 week interval, at weeks 43, 51, 59, 67, 75 and so on. The 24h-UFC will 
continue to be determined from two 24-hour urine collections collected from two consecutive 
days occurring before the visit in the extension phase until patient is discontinued from 
treatment.
7.2.1.2
Serum cortisol
A pre-dose blood draw for an 8 am fasting serum cortisol measurement will be taken at visits 
indicated in Table 7-1 and Table 7-2. Procedures for sample drawing, handling, storage and 
transportation will be provided by the central laboratory.
7.2.1.3
Late night salivary cortisol
Late night salivary cortisol will be determined at visits indicated in Table 7-1 and Table 7-2.
Patients should be given instructions and supplies for use at home. In order to correlate the 
salivary and urinary cortisol results, a single salivary sample per evening is to be collected on 
the same evenings as the first 2 of the 3 twenty-four hour urinary collections for UFC for a 
total of 2 salivary samples as indicated in Table 7-1 and Table 7-2. One sample per evening is 
to be taken at 11 PM (23:00) with a +/- 1 hour window. All efforts should be made to have the 
samples taken at the same time throughout the study. Samples are to be collected by the site at 
the same time as the UFC samples as described in Table 7-1 and Table 7-2.
7.2.1.4
Plasma ACTH
A pre-dose blood draw for plasma ACTH sampling will be taken at visits indicated in Table 
7-1 and Table 7-2. Procedures for sample drawing, handling, storage and transportation will 
be provided by the central laboratory.
7.2.1.5
Continuous measures of clinical symptoms of hypercortisolism
The following clinical 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.
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 


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the patient in a sitting position for five minutes, systolic/diastolic blood pressure will be 
measured three times. The systolic/diastolic blood pressure will then be measured in a 
standing position three times. The repeat measurements are to be made at least at 5-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 visits indicated in Table 7-1
and Table 7-2. 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.
7.2.1.6
Categorical measures of clinical signs of hypercortisolism
The results of all the following assessments will be recorded in the CRF.
The following symptoms will be evaluated using photographs taken at visits in the core and 
extension phases as indicated in Table 7-1 and Table 7-2:
Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, 
one frontal and one lateral from the shoulders up will be taken to assess facial plethora, 
supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with 
patient in standing position will be taken to assess striae, and hirsutism. The photographs must 
be assessed by a qualified physician at the site, who is blinded to the dose given to the patient 
and to the time point at which the photographs were taken. Consisting with confidentiality 
requirements these will not be published without explicit written permission by the patient.
For further assessment of hirsutism, the Ferriman-Gallywey score (see Appendix 5), a method 
of evaluating and quantifying hirsutism in women, will be used. Female patients will be asked 
not to shave or use any methods of hair removal during the 3 weeks prior to corresponding 
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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:
3. - completely unable to stand
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
7.2.1.7
Health-related quality of life (HRQOL)
The health-related quality of life will be assessed for patients using the Cushing QoL and SF-
12v2 General Health Survey (see Appendix 2 and Appendix 3), a patient-reported outcome 
instrument specific to patients with Cushing's syndrome. The questionnaires will be 
completed at visits indicated in Table 7-1 and Table 7-2.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing Physical examination, karnofsky performance status, 
vital signs, Laboratory assessments (hematology, chemistry, including LFTs, coagulation, 
urinalysis, hormone assessments, fasting blood glucose, HbA1C, GH and IGF-1), gallbladder 
ultrasound, and ECG as well as collecting of the adverse events at every visit.
7.2.2.1
Physical examination
A complete physical examination will be performed by the investigator at screening visits 
indicated in Table 7-1 and Table 7-2. An abbreviated physical examination will be performed 
at the subsequent visits indicated Table 7-1 and Table 7-2. 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 informed consent must be 
included in the Relevant Medical History/Current Medical 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.
7.2.2.2
Vital signs
Blood pressure, body temperature and heart rate will be measured visits indicated in Table 7-1
and Table 7-2 and recorded in the appropriate CRF.
7.2.2.3
Height and weight
Height in centimeters (cm) and weight to the nearest 0.1 kilogram [kg] are to be collected at 
visits indicated in Table 7-1 and Table 7-2 and recorded in the appropriate CRF.


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7.2.2.4
Karnofsky performance status
The Karnofsky performance scale index (see Appendix 1) will be used to evaluate the 
performance status of the patients at visits indicated in Table 7-1 and Table 7-2.
7.2.2.5
Laboratory evaluations
Central laboratories will be used for the analysis of all laboratory evaluations. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are to be 
provided to investigators in the [Laboratory Manual].
7.2.2.5.1 Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White blood cells, 
RBC Morphology with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils)
7.2.2.5.2 Clinical chemistry
GGT, calcium, urine creatinine, creatine kinase, amylase, lipase, total cholesterol, LDL-
cholesterol, HDL-cholesterol, total protein, triglycerides, blood urea nitrogen (BUN) or urea, 
uric acid, magnesium, sodium, potassium, serum creatinine, estimated glomerular filtration 
rate from serum creatinine (at screening and end of treatment only), fasting blood glucose and 
glycosylated hemoglobin (HbA1C).
The following Modification of Diet in Renal Disease (MDRD) will be used for creatinine 
clearance calculation:
MDRD (GFR) (ml/min/1.73m2) = 175 * PD93 power -1.154 * Age power - 0.203 * Race * 
Sex Where PD93 = Serum Creatinine (mg/dL), Race = 1.212 for Black & 1.000 for other, Sex 
= 1.00 for males and 0.742 for females.
SI Results MDRD (GFR) (ml/min/1.73m2) = 175 * (PD9S3/88.4) power -1.154 * Age power 
- 0.203 * Race * Sex Where PD9S3 = Serum Creatinine (UMOL/L), Race = 1.212 for Black 
& 1.000 for other, Sex = 1.00 for males and 0.742 for females.
7.2.2.5.3 Liver function testing
Presence of HbsAg and Anti-HCV are to be assessed during screening. Liver function tests 
(LFTs) will be measured: ALT, AST, total bilirubin, direct bilirubin, indirect bilirubin, 
Albumin, ALP and GGT. If at any visit abnormal liver function criteria as described in the 
inclusion and exclusion section are met, the following should be performed immediately 
within 48 hours of awareness of the abnormality. Liver function tests (LFTs) should be 
monitored every 3-4 days until resolution or return to baseline status. Please refer to Section 
6.5.4 Hepatic Safety Management.
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.


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7.2.2.5.4 Coagulation
PT and INR will be measured at visits indicated in Table 7-1 and Table 7-2.
7.2.2.5.5 Additional hormones
Midnight salivary cortisol, Urine free cortisol (UFC), Insulin-like growth factor 1 (IGF-1), 
GH, Free T4, and TSH, serum cortisol, Plasma ACTH
7.2.2.5.6 Urinalysis
A urinalysis test (specific gravity, pH, glucose, proteins, bilirubin, ketones, leucocytes, color, 
nitrite and blood) will be analyzed at visits indicated in Table 7-1 and Table 7-2. The 24 hour 
urinary collections used for mUFC will also be used to collect urine volume, and urinary 
creatinine.
7.2.2.5.7 Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have a urine dip-stick 
pregnancy test at visits indicated in Table 7-1 and Table 7-2. A serum β-hCG pregnancy test 
must be performed if the urine dip-stick pregnancy test is positive. A positive serum 
pregnancy test requires immediate interruption of study treatment until the assessment is 
confirmed. If positive, the patient must be discontinued from the study.
7.2.2.5.8 Gallbladder ultrasound
A gallbladder ultrasound will be performed at the sites at visits indicated in Table 7-1 and
Table 7-2 and the results will be recorded in the CRF.
7.2.2.5.9 Cardiac assessments
Electrocardiogram (ECG)
A 12-lead ECG and a rhythm strip will be performed at the sites at visits indicated in Table 7-
1 and Table 7-2. 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 performed on the machine(s) provided for 
the study by the central reader and are sent to the central reader for evaluation. To ensure 
consistency throughout all participating sites, the ECGs should be performed and processed 
following the guidelines from the central reading facility, which will be distributed to the sites. 
A Holter ECG will be required in case of a confirmed QTcF > 480msec (described in Section 
6.5.3).
7.2.2.5.10
Echocardiogram
An echocardiogram will be performed at the visits indicated in Table 7-1 and Table 7-2.


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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. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 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 4.03. 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 
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 duration (start and end dates or Ongoing at End of Study)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse even (SAE) is defined as in 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 


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necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
All adverse events, regardless of the severity, should be reported. This will also include any
adverse events that meet the definition of special interest.
8.1.2
Adverse events of special interest
Adverse events of special interest consist of AEs for which there is a specific interest in 
connection with pasireotide treatment (i.e. where pasireotide may influence a common 
mechanism of action responsible for triggering them). The adverse events of special interest 
may require reporting additional information and completion of the event-specific checklists 
and/or questionnaires.
Targeted follow-up may be required for the following: hypocortisolism/cortisol withdrawal 
syndrome, hyperglycemia, and QTc interval prolongation.
8.1.3
Laboratory test abnormalities
8.1.3.1
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 in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
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 
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
Requires inpatient hospitalization or prolongation of existing hospitalization

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

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

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 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 30 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 tothe Novartis Chief 
Medical Office and Patient Safety (CMO&PS).
Detailed instructions regarding the SAE submission process and requirements for signatures 
are to be found 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.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Chief Medical Office and Patient Safety (CMO&PS)department associate may 


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urgently require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN), to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.
8.3
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 Chief Medical Office and Patient Safety 
(CMO&PS)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.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
A newborn of a patient (or a partner of a patient) who becomes pregnant during the study 
within 1 month of the last pasireotide s.c. dose, should be followed for 3 months post-delivery 
(from Day 0 to Month 3 of life).
8.4
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 Investigator Brochure 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.
8.5
Steering committee
The steering committee will be established that will provide guidance for the analysis and the 
conduct of the study. It will consist of at least an independent medical expert in Cushing’s 
disease, one study investigator and one Novartis physician. The roles and responsibilities of 
the Steering Committee will be defined in the Steering Committee Charter.


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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 follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
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 
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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 entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
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 and prior medications 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.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
The investigator or designee should register a patient into the IVR and IWR system when a 
patient is screened, enrolled and discontinued from the study treatment. The IVR and IWR 
system will prompt the investigator to answer a few key inclusion/exclusion. When patient is 
discontinued from the study treatment, the status of study completion must be registered into 
the IVR and IWR system.
The occurrence of any protocol violations will be determined. After these actions have 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.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.


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10
Statistical methods and data analysis
This is a phase II exploratory study to assess the efficacy and safety of pasireotide s.c. alone 
and in combination with cabergoline in patients with Cushing’s disease.
The data will be analyzed by Novartis and/or designed CRO. It is planned that the data from 
all centers that participate in this protocol will be used.
Two separate analyses will be made one related to the core phase and one related to the 
overall phase, including the core and the extension phases.
Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, 25th quantile, median, 75th quantile and maximum. Categorical variables will be 
summarized by absolute and relative frequencies.
Unless otherwise stated, baseline assessment refers to the last assessment prior to the patient’s 
first study drug dose recorded after the signing of the informed consent.
In addition to the statistical methods outlined, further details and any additional exploratory 
analyses that may be performed will be described in the Statistical Analysis Plan (SAP).
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who received at 
least one dose of the study drug and had no major protocol violations. The protocol deviations 
criteria will be defined prior to database lock.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be summarized descriptively for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
10.2.1
Treatments (study treatment, concomitant therapies, compliance)
Descriptive statistics will be used to summarize the dose intensity and duration of drug 
exposure. 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.


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These analyses will be performed on the safety set.
10.2.2
Primary objective
To evaluate the overall efficacy of the treatment regimen of pasireotide alone or in 
combination with cabergoline in patients with Cushing’s disease with the proportion of 
patients who attain mUFC ≤ 1.0 ULN at week 35.
10.2.2.1 Statistical hypothesis, model, and method of analysis
The trial is exploratory in nature and no formal hypothesis testing is planned.

The proportion of patients with normalized mUFC at week 35 will be reported along with 
its corresponding asymptotic 95% CI.
10.2.3
Handling of missing values/censoring/discontinuations
Patients missing mUFC at week 35, the last available mUFC assessment at or after week 31 
will be carried forward as the week 35 mUFC assessment. However, if any patient discontinue 
between week 31 and week 35, then the patient’s week-31 assessment will not be carried 
forward for week 35, and the week 35 mUFC assessment will be considered as non-response. 
Any patient who discontinue before week 31 will be considered as non-responder.
Sensitivity analyses may be performed using different methods for handling missing mUFC 
data to assess the robustness of the primary efficacy analysis. Details will be presented in the 
analysis plan.
10.2.4
Supportive analyses
An additional analysis on the primary efficacy variable will also be performed using the PPS 
and the same handling of missing values as described above.
The primary efficacy endpoint at week 35 will be summarized by baseline mUFC categories.

1 x ULN < baseline mUFC ≤ 2.0 x ULN

2 x ULN < baseline mUFC ≤ 5.0 x ULN

5.0 x ULN
10.3
Secondary objectives
The secondary efficacy analysis will be performed on the FAS.
Assess the changes in mUFC from baseline to study end at each scheduled visit where 
UFC is measured.
Descriptive summary statistics of actual and percentage change in mean 24h-UFC from 
baseline to each scheduled visit where UFC is measured will be provided along with 
corresponding two-sided 95% CIs.
Assess overall efficacy of pasireotide alone or in combination with cabergoline as 
measured by normal mUFC levels at each scheduled visit.


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Proportion of patients with normalized mUFC (i.e. mUFC ≤ 1.0xULN) at each scheduled visit 
will be reported along with its corresponding 95% CI.
Evaluate the overall efficacy of pasireotide alone or in combination with cabergoline as 
measured by controlled and partially controlled mUFC levels at each scheduled visit 
when mUFC is measured.
Proportion of patients who attained mUFC ≤ 1.0 X ULN (controlled) or have at least 50% 
reduction (partially controlled) at each scheduled visit will be reported along with its 
corresponding 95% CI.
Evaluate the duration of controlled or partially controlled mUFC response.
Duration of controlled or partially controlled response is defined as the period starting from 
the date of patient’s first normalization (mUFC ≤ 1.0xULN) or at least 50% reduction from 
baseline up to the date when the patient’s mUFC > 1.0xULN and the reduction from baseline 
falls to less than 50% for the first time. Patients without a loss of response will be censored at 
their last available mean UFC assessment date. The median and 95% confidence interval (CI)
of duration of response will be derived from Kaplan-Meier curve and will be presented.
Assess the effect on plasma ACTH and serum cortisol.
Plasma ACTH and serum cortisol concentrations will be summarized using descriptive 
statistics at each scheduled visit. Actual and percent changes from baseline at each scheduled 
post baseline visit will also be presented along with 95% CIs. Mean serum cortisol and plasma 
ACTH results over time will be presented graphically.
Assess the effect of continuous measures of clinical symptoms of hypercortisolism.
Actual and percentage change from baseline in the following clinical symptoms of Cushing’s 
disease (blood pressure, body mass index, waist circumference, fasting serum lipid profile and 
weight) will be assessed over time using descriptive statistics.
Assess the effect on the categorical measures of clinical signs of hypercortisolism.
Change in clinical signs of Cushing’s disease: facial rubor, supraclavicular and dorsal fat pads, 
hirsutism, striae and muscle strength will be assessed using shift tables. Two assessors blinded 
to the visit number will score each qualitative endpoint (facial rubor, hirsutism, 
supraclavicular and dorsal fat pads and striae) by review of duplicated photographs. The 
investigator will adjudicate non-agreeing assessments. Table 10-1 below describes scales and 
endpoint definitions for each of these assessments. For each clinical sign, descriptive 
summary statistics will be presented.


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Table 10-1
Categorical clinical signs
Clinical Symptom
Scale
Tool/Endpoint
Facial Rubor(redness)
0=none, 1=mild, 
2=moderate,3=severe
Photographic interpretation, Count & percent shifts from 
baseline
Supraclavicular and 
dorsal fat pads
0=none, 1=mild, 
2=moderate,3=severe
Photographic interpretation, Count & percent shifts from 
baseline
Hirsutism
Sum area scores to total 
body score,
Photographic interpretation, Descriptive % change from 
baseline
Striae
0=none, 1=mild, 
2=moderate,3=severe
Photographic interpretation, Count & percent shifts from 
baseline
Muscle strength
0= minimum, 3= maximum
Direct observation of ability to stand unaided. 
Descriptive % change from baseline
Assess the improvement of health-related quality of life.
Descriptive statistics, including mean, median, standard deviation, minimum and maximum, 
will be presented to describe actual standardized scores and changes from baseline. Graphical 
display(s) of descriptive results will be produced.
10.3.1
Safety objectives
10.3.1.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. Key safety analyses will be presented for 
patients who receive pasireotide in combination with cabergoline after they started receiving 
the combination therapy.
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 day 28+1 after last dose of study medication.
10.3.1.2 Adverse events (AEs)
Summary tables for adverse events (AEs) have to 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-treatment and post-treatment period are to be flagged.
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 NCI-CTCAE 
v4.03 grades), type of adverse event, relation to study treatment. Similar summaries will also 
be produced for treatment-emergent AEs of special interest. The number and percentage of 
patients with at least one treatment-emergent Adverse Event of Special Interest will be 
reported.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment regimen.


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Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s).
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported.
10.3.1.3 Laboratory abnormalities
For laboratory tests covered by the National Cancer Institute - Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0, the study’s biostatistical and reporting team will 
grade laboratory data accordingly. For laboratory tests covered by CTCAE, NCI-CTCAE 
v4.03 a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by NCI-CTCAE v4.03, results will be 
graded by the low/normal/high classifications based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:

shift tables using NCI–CTCAE v.4 grades to compare baseline to the worst on-treatment 
value

for laboratory tests where NCI-CTCAE v4.03 grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.

listing of all laboratory data with values flagged to show the corresponding NCI-CTCAE 
v4.03 grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the MAP and/or SAP.
10.3.1.4 Other safety data
ECG
ECG data will be summarized with:

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs
Vital signs (supine BP, HR & temperature) reporting of results will include:

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.


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Karnofsky performance status
Results will be summarized by visit using counts and percentages of

patients in each performance status category.
Gallbladder Ultrasound
Gallbladder data at each visit will be summarized and listed.
10.3.1.5 Tolerability
Tolerability will be studied in terms of dose reduction or drug interruption due to an AE.
 
 
 
10.3.1.7 Patient-reported outcomes
The health-related quality of life will be assessed for patients using the Cushing QoL, a 
Cushing’s disease specific validated scale, and SF-12L, a generic QOL scale. These patient-
reported outcome (PRO) measures are included as secondary endpoint in order to assess the 
beneficial clinical consequences of pasireotide LAR on disease specific and general QOL. 
Changes from baseline in the above outcomes measurements will be compared. PRO analysis 
of study data will be conducted on the subset of patients with all measurements. This analysis 
will utilize the previously defined Minimal Important Difference  for Cushing QoL as well as 
correlations between Cushing QoL and SF-12 and both PRO instruments with UFC response 
and signs and symptoms of disease.
10.4
Interim analysis
No formal interim analysis is planned for this study. If Novartis publishes interim data, details 
will be specified in the study’s analysis plan. Interim analysis may be performed for 
regulatory purposes if deemed necessary.


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However, an analysis of this trial will be performed at the end of the core phase, while the 
final analysis related to the overall phase, including the core and the extension phases, will be 
performed at the end of the extension phase after December 2019.
10.5
Sample size calculation
The sample size was designed for the estimate of the proportions of patients with a 
normalized mUFC at week 35 in patients who are pasireotide untreated at screening or 
patients treated with pasireotide at screening but still with uncontrolled mUFC.
With a sample size of 64 patients and assuming that the proportion of patients who attain a 
mUFC ≤ 1.0xULN at week 35 will be 34 %, derived from a weighted mean of the original 
assumed response rates for Group 1 (35%) and 2 (28%) and assuming that a maximum of 6
out of 64 patients (approx. 10 %) will be enrolled in Group 2, the precision of the response 
will be 12.8 % for the associated two-sided 95% CI considering a drop-out rate of 10%.
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. 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.
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.
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 to investigators, in a separate document, 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 


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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 were 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 
7.1.2.1.
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.
11.4.1
Communication and Publication of Clinical Trial Results
Novartis is committed to upholding the highest ethical standards for reporting the results of 
medical research, including the timely communication and publication of clinical trials results, 
whatever their outcome.
Novartis complies with the authorship guidelines of the International Committee of Medical 
Journal Editors (ICMJE) uniform requirements for manuscripts submitted to biomedical 
journals and other specific guidelines of the journal or congress to which the document will be 
submitted. These guidelines apply to any clinical trial publication including but not limited to 
manuscripts, abstracts, posters, and oral presentations. For more information regarding the 
ICMJE 
guidelines, 
visit 
http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html.
Accordingly, all authors must have:

Contributed substantially to the study concept, design and/or conduct of the study or to the 
acquisition, analysis, and interpretation of the data AND

Drafted or critically revised the proposed clinical publication for important intellectual 
content AND

Approved the final proposed clinical publication for submission AND

Have intimate knowledge of trial implementation/analysis
Substantial contribution for primary publication is defined as having active and ongoing 
participation in the study. Study steering committee members must have significant 
involvement to study concept, design, and data interpretation and patient recruitment. Each 
steering committee member must have attended the majority of the steering committee 
meetings and recruited patients into the trial from his/her own center to be included as an 


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author. Study investigators must have significant contribution to patient recruitment based on 
number of eligible patients upon study entry and data quality.
11.5
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) 
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 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. Any change or correction to a paper CRF should be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. For electronic 
CRFs an audit trail will be maintained by the system. The investigator should retain records of 
the changes and corrections to paper CRFs.
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.


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11.6
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.
11.7
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.8
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
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 at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Arnaldi G, Angeli A, Atkinston AB, 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
Biller BMK, Grossman AB, Steward PM, et al (2008) Treatment of adrenocorticotropin-
dependent Cushing’s Syndrome: a consensus statement. J Clin Endocrinol metab; 93(7): 
2454-62.
Bruns C, Lewis I, Briner U, et al (2002). SOM230: a novel somatostatin peptidomimetic with 
broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique 
antisecretory profile. Eur J Endocrinol; 146(5):707-16
de Bruin C, Feelders RA, Waaijers AM, et al (2009) Differential regulation of human 
dopamine D2 and somatostatinreceptor subtype expression by glucocorticoids in vitro. J Mol 
Endocrinol;42:47–56
Feelders RA, de Bruin C, Pereira AM, et al (2010) Pasireotide alone or with cabergoline and 
ketoconazole in Cushing’s disease. N Engl J Med; 362(19):1846-8.
Freda, P.U., 2002. Somatostatin analogs in acromegaly. The Journal of Clinical 
Endocrinology & Metabolism, 87(7), pp.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. Eur J of 
Endocrinol;152(4)/ 645-654.
Godbout A, Manavela M, Danilowicz K, et al (2010) Cabergoline monotherapy in the long-
term treatment of Cushing's disease. Eur J Endocrinol;163:709–716
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.
Miller JW, Crapo L (1993) The medical treatment of Cushing's syndrome. Endocr 
Rev;14:443–458
Missale C, Nash SR, Robinson SW, et al (1998). Dopamine receptors: from structure to 
function. Physiol Rev; 78:189–225
Oberg K. (2004) Treatment of neuroendocrine tumors of the gastrointestinal tract. Oncologia
(Madrid; 27(4): 57-61.
Pivonello R, Ferone D, de Herder WW, et al (2004) Dopamine receptor expression and 
function in corticotroph pituitary tumors. J Clin Endocrinol Metab; 89:2452–2462
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.
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.
Van der Hoek J. Lamberts SWJ. Hofland LJ (2005a) The role of somatostatin analogs in
Cushing's disease. Pituitary; 7(4): 257-264.


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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.
Weckbecker G, Briner U, Lewis I, et al (2002). SOM230: a new somatostatin peptidomimetic 
with potent inhibitory effects on the growth hormone/insulin—like growth factor-I axis in rats, 
primates, and dogs. Endcrinology; Oct; 143(10):4123-30


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14
Appendices
14.1
Appendix 1 Karnofsky performance status


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14.2
Appendix 2: Cushing’s Syndrome Quality of Life Questionnaire


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14.3
Appendix 3 Patient Report Outcome Questionnaire - SF 12 - v2


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14.4
Appendix 4: Medications known to be associated with QT
interval prolongation
The following link contains a list of drugs generally recognized to have a possible association 
with QT prolongation:
https://www.crediblemeds.org/index.php/login/dlcheck


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14.5
Appendix 5: Ferriman-Gallwey Score
The Ferriman-Gallwey scoring system is used to score the degree of excess male pattern body 
hair in females. A score is to be assigned for each body location pictured below (upper lip, 
chin, chest, upper abdomen, lower abdomen, arms, thighs, upper back and lower back) and 
then added together to get the total score (see Figure 14-1). The definition of each grade is 
listed here:
4. - extensive terminal hair growth
3. - moderate terminal hair growth
2. - mild terminal hair growth
1. - no excessive terminal hair growth
0. - absence of terminal hair growth


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Figure 14-1
Ferriman-Gallwey Scoring Diagram

SAP_000.pdf: 
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Confidential
SAP – Core/Extension
27-OCT-2019
SOM230/ 2411
1
Clinical Development
Pasireotide/SOM230B
CSOM230B2411 / NCT01915303
A Phase II trial to assess the efficacy and safety of 
pasireotide s.c. alone or in combination with cabergoline in 
patients with Cushing’s disease
  Statistical Analysis Plan (SAP)
Author(s):
, Trial Statistician;
 
Document type:
SAP Documentation
Document status
Final – Addendum
Release date:
27-OCT-2019
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP – Core/Extension                                                     27-OCT-2019
SOM230/ 2411
2
Document History – Changes compared to previous version.
date
Time 
point
Reason for 
update
Outcome 
for update
Section and title impacted
7/05/2019
Before 
Dry 
run
Creation 
for final 
version
Initial version
08/30/2019
Prior to
final 
DBL
Creation of
amendment
v1.0
For section 
8.2.6 new 
wording was 
added.
For section 
6.4.1.1.2 and 
6.4.2.1.1 
modification 
was done.
Analysis of 
AESI was 
changed.
Section 8.2.6, added: However, per 
protocol amendment 2, group 2 
patients time window and study 
period based on VIS eCRF will be re-
mapped into time window of group 1 
and end their core phase at week 35, 
according to the window schema in 
_bookmark18 Table 8-1. All efficacy 
and safety analysis will be using the 
time window newly defined.
Section 6.4.1.1.2 and  6.4.2.1.1 
added >8 to 17  weeks, >17 to 35 weeks
Section 6.6.1.
10/27/2019
Post-
DBL
Creation of 
addendum: 
Karnofsky 
performance 
status 
analysis 
description 
was missed 
although  it 
was 
included in 
the protocol.
Karnofsky 
performance 
status
analysis is 
added.
Section  6.6.6.


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3
Table of contents
1
Objectives ............................................................................................................................5
2
Studies considered ...............................................................................................................5
3
Data source ..........................................................................................................................5
4
Cut-off date..........................................................................................................................5
5
Patient population ................................................................................................................5
5.1
Full analysis set........................................................................................................5
5.2
Safety set..................................................................................................................5
5.3
Per-protocol set ........................................................................................................6
6
Analyses related to already existing outputs........................................................................6
6.1
Treatment regimen...................................................................................................6
6.2
Patient disposition....................................................................................................6
6.3
Patient demographics and other characteristics - Core and Extension phase............6
6.3.1
Medical history - Core phase...................................................................7
6.4
Treatments (study drug, other concomitant therapies).............................................7
6.4.1
Extent of exposure of cabergoline...........................................................7
6.4.2
Extent of exposure of pasireotide s.c. alone or in combination with 
cabergoline ..............................................................................................8
6.5
Efficacy evaluation ..................................................................................................9
6.5.1
Primary efficacy evaluation for core and extension phase......................9
6.5.2
Secondary efficacy evaluation.................................................................9
Assess the changes in mUFC from baseline to study end at each scheduled 
visit where UFC is measured – Core and extension phase....................10
Assess overall efficacy of pasireotide alone or in combination with 
cabergoline as measured by controlled and partially controlled 
mUFC levels at each scheduled visit  until the final cut-off date..........10
Evaluate the duration of controlled or partially controlled mUFC response –
Core and extension phase......................................................................11
Assess the effect on plasma ACTH and serum cortisol - Core and extension 
phase......................................................................................................11
Assess the effect of continuous measures of clinical symptoms of 
hypercortisolism - Core and extension phase........................................11
Assess the effect on the categorical measures of clinical signs of 
hypercortisolism - Core and extension phase........................................11
6.6
Safety parameters and analysis ..............................................................................11
6.6.1
Adverse events (AE)..............................................................................12
6.6.2
Laboratory evaluation............................................................................13
All the lab analysis over core and extension phase  will be based on safety set. 
Study baseline will be used in analysis. ................................................13


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6.6.3
Vital signs and weight for core and extension phase ............................15
6.6.4
ECG.......................................................................................................16
6.6.5
Gallbladder ultrasound ..........................................................................17
6.6.6
Karnofsky performance status...............................................................17


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1
Objectives
This analysis is intended to provide a combined final analysis plan for the core and extension 
phase of the study. The details of previously performed analysis are described in the document  
CSOM230B2411_Statistical Analysis Plan_Core phase publication, final version dated 27 
March 2017 [4]. This SAP first adapts protocol amendment 2 to combine group 1 (Pasireotide
not currently treated) and group 2 (Pasireotide currently treated) into one cohort in most 
efficacy and safety analysis.
2
Studies considered
Core and extension phase data of the CSOM230B2411 study will be used to perform the 
analysis. 
3
Data source
All analysis will be based on the derived datasets with the following details:
// GPSII\CSOM230B\CSOM230B2411\csr_2\analysis_data
4
Cut-off date 
The cut-off date for this analysis is the final cut-off date for extension phase, 30-Jun-2019
(LPLV).
5
Patient population
5.1
Full analysis set
The Full Analysis Set (FAS): comprises all patients to whom study treatment has been assigned
at core phase, including all group 1 and group 2 subjects. FAS will be used in analysis for the 
core phase.
Extension Full analysis set (Extension FAS): a subset of FAS, included patients to whom
study treatment has been assigned in extension phase, including all group 1 and group 2 subjects.
Extension FAS will be used to summarized data from week 43 to final cutoff week data, unless 
it is specified, EXTENSION FAS and will be used to combine the core and extension phase 
data for some analyses.
5.2
Safety set
Safety set: includes all patients who received at least one dose of study medication defined 
in the core and extension study phase. 
The safety set will be used to combine the core and extension phase data for all safety
analyses and summaries over the visit window with available data. Core phase data will be 


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summarized from baseline to week 35 at end of the core phase. Extension phase data will be 
summarized from week 43 to last cutoff week for patients enrolled into extension phase.
5.3
Per-protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who received at
least one dose of the study drug and had no major protocol violations. The protocol deviations 
criteria will be defined prior to database lock in VAP 3 and in section 2.3.2 of [4]. Protocol 
deviations will be reported for core and extension phase in table and listings.
6
Analyses related to already existing outputs
6.1
Treatment regimen
The following labels for treatment regimens will be used in generating tables and figures where 
is applicable:

Pasireotide s.c alone

Pasireotide s.c. in combination with cabergoline
6.2
Patient disposition
Frequency distributions will be used to summarize the patient disposition at the time of 
analysis and associated reasons for discontinuation of study medication and study using 
EXTENSION FAS for the  Extension phase. The following will be tabulated for the 
extension phase:
•
Number (%) of patients who are still on-treatment at final cutoff 
date (based on the absence of the ‘Study Phase Completion - Extension 
study’ page);
•
Number (%) of patients who discontinued treatment (based on completion of the 
‘Study Phase Completion – extension Phase’ page with date of discontinuation and 
reason of discontinuation/ ‘Subject Status’ entered);
•
Primary reasons for treatment discontinuation Extension phase (based on 
discontinuation reasons entered under ‘Subject Status’ in the ‘Study Phase 
Completion – Extension study’ page).
6.3
Patient demographics and other characteristics - Core and 
Extension phase
Demographic data (such as age, sex, race, ethnicity,  height,  and  weight),  disease  
characteristics, and other baseline characteristics will be summarized descriptively using 
the FAS and EXTENSION FAS.
All data collected at baseline such as the history of Cushing's disease (time since 
diagnosis in months, status of disease, prior pituitary surgery/irradiation, time since prior 


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pituitary irradiation, duration of prior treatment with pasireotide, baseline symptoms, 
mean UFC at baseline), will be summarized using descriptive statistics and will be listed 
as required.
For group 2, the duration of prior treatment with pasireotide (in months) will be 
summarized with descriptive statistics, as continuous variable and by category 
( >12 months or missing).
6.3.1
Medical history - Core phase
Medical history and ongoing conditions will be summarized and listed for all patients. 
Separate summaries will be presented for ongoing and historical medical conditions. 
The summaries will be presented by primary system organ class and preferred term. 
Medical history/current medical conditions are coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology using the latest version available 
(Version. 22.0) prior to clinical database lock.
6.4
Treatments (study drug, other concomitant therapies)
6.4.1
Extent of exposure of cabergoline
All study medication data will be summarized using the safety set.
6.4.1.1
Dose intensity and exposure - Core and extension phase
Duration of exposure will be summarized by appropriate descriptive statistics. The 
following definitions will be used:
Treatment start date: defined as the first date at which a non-zero dose of 
cabergoline is administered during the study and recorded on the Dosage 
Administration Record (DAR) eCRF over core and extension phase for safety set.
6.4.1.1.1 Core and extension phase
Treatment end date (extension phase): defined as the last date at which a non-zero 
dose of cabergoline was administered and recorded on the DAR eCRF for patients 
who discontinue before the final cutoff date of the extension phase or who complete 
the extension phase with the final cutoff date recorded on the VIS eCRF.  
Duration of exposure (core and extension phase): will be calculated as the number 
of days from the treatment start date to the treatment end date above, including days 
with interruptions.
duration of exposure for extension phase = treatment end date (final cutoff date) –
treatment start date + 1.


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6.4.1.1.2 Dose exposure and intensity
Dose intensity of cabergoline will be calculated for each patient as total cumulative 
dose at the time of last administration divided by the duration of exposure.
Duration of exposure and dose intensity while in the study will be summarized with 
descriptive statistics over the core phase. A frequency table will show the number 
and percentage of patients per duration of exposure category: fore core phase
category (<=8 weeks, >8 to 17  weeks, >17 to 35 weeks, >35 to 40 weeks). For core 
and extension phase: (<=8 weeks, >8 to 17 weeks, 17-35 weeks, >35 to 43 
weeks, >43 to 98 weeks, >98 to 153 weeks, >153 to 208 weeks, >208 to 263 (up to 
final week)).
6.4.2
Extent of exposure of pasireotide s.c. alone or in combination with 
cabergoline
6.4.2.1
Dose intensity and exposure - Core and extension phase
All study medication data will be summarized using the safety set.
Duration of exposure will be summarized by appropriate descriptive statistics. The 
following definitions will be used:
Treatment start date: defined as the first date at which a non -zero dose of 
pasireotide s.c. alone or in combination with cabergoline,  administered during the 
study and recorded on the Dosage Administration Record (DAR) eCRF.
Treatment end date (extension phase): defined as the last date at which a non-zero 
dose of pasireotide was administered and recorded on the DAR eCRF for patients 
who discontinued before the last cutoff date of the extension phase or who complete 
the extension phase with the final cutoff date recorded on the VIS eCRF.  
Duration of exposure (core and extension phase): will be calculated as the 
number of days from the treatment start date to the treatment end date above, 
including days with interruptions.
duration of exposure = treatment end date (extension phase) – treatment start date + 1
6.4.2.1.1 Dose exposure and intensity
Dose intensity of pasireotide s.c. alone or in combination with cabergoline will be 
calculated for each patient as total cumulative dose at the time of last administration 
divided by the duration of exposure.
Duration of exposure and dose intensity while in the study will be summarized with 
descriptive statistics over the core phase. A frequency table will show the number 
and percentage of patients per duration of exposure category: core phase category 
(<=8 weeks, >8 to 17  weeks, >17 to 35 weeks, >35 to 40 weeks). For core and 


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extension phase:(<=8 weeks, >8 to 17 weeks, 17-35 weeks, >35 to 43 weeks, >43 to 
98 weeks, >98 to 153 weeks, >153 to 208 weeks, >208 to 263 (up to final weeks)).
6.5
Efficacy evaluation
6.5.1
Primary efficacy evaluation for core and extension phase
The primary efficacy endpoints are:
•
Proportion with corresponding asymptotic 95% CI of patients who attain mean 
of urinary free cortisol (mUFC) ≤ 1.0 x ULN at date-cutoff date with pasireotide alone 
or in combination with cabergoline for FAS and Extension FAS set.
Handling of missing value/censoring/discontinuation is described in Section 8.3.2.
A responder is a patient who has mUFC ≤ ULN.
Last observation carried forward (LOCF) methodology will be used for mUFC 
assessment for the core phase. The primary efficacy at end of core phase date (week 35) 
and cut-off of the extension phase will be summarized by baseline mUFC categories. 
The primary efficacy endpoint will be summarized within each of the three mUFC levels 
at baseline:
• 1 x ULN < baseline mUFC ≤ 2.0 x ULN
• 2 x ULN < baseline mUFC ≤ 5.0 x ULN
• baseline mUFC >5.0 x ULN
These analyses will be performed on FAS and EXTENSION FAS.
6.5.2
Secondary efficacy evaluation
The secondary efficacy endpoints will be summarized for the  FAS and EXTENSION FAS
for parameters from baseline measurements over core phase to week 35 and extension 
phase from week 43 to final cutoff date at each scheduled assessment:
1. Actual and percentage change in mUFC from baseline to each 
scheduled visit when UFC is measured until the final cut-off date
2. Proportion of patients with normalized mUFC (i.e mUFC ≤ 1.0xULN) as assessed 
at each scheduled visit when UFC is measured until the final cut-off date
3. Proportion of patients, at each visit, who attained mUFC ≤ 1.0xULN (controlled) or 
have at least 50% reduction (partially controlled) from baseline in mUFC as assessed at 


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each scheduled visit when UFC is measured until the final cut-off date
4. Duration of controlled or partially controlled response is defined as the period 
starting from the date of patient’s first normalization (mUFC ≤ 1.0xULN) or at least 50% 
reduction from baseline up to the date when the patient’s mUFC > 1.0xULN and the 
reduction from baseline falls to less than 50% from the first time until the final cut-off 
date
5. Actual and percentage changes from baseline, at each scheduled post baseline visit, 
in plasma ACTH and serum cortisol over visit time window until the final cut-off date
6. Actual and percentage change from baseline over visit time window in clinical 
symptoms of Cushing’s disease: blood pressure, body mass index, waist circumference, 
fasting serum lipid profile, and weight until the final cut-off date
7. Change from baseline in clinical signs of Cushing’s disease: facial until the final cut-
off date
8. Rubor, supraventricular and dorsal fat pads, hirsutism, striae (via photographs) and 
muscle strength until the cut-off date
9. Change from baseline in standardized scores, as measured by the 
Cushing’s QOL and SF-12v2 over time until the final cut-off date
10. Toxicity assessed by using the National Cancer Institute-Common Toxicology 
Criteria Adverse Events version 4.0 (NCI-CTCAE v.4) and for laboratory assessments 
(biochemistry, hematology, urinalysis); special safety assessments (regular monitoring 
and recording of blood glucose, insulin, HbA1c, GH and IGF-1, thyroid and liver 
function 
tests, 
 
gallbladder 
examinations 
and 
ECGs). 
Concomitant 
medications/Significant non-drug therapies will be assessed from study enrollment until 
the final safety date cutoff visit.
Assess the changes in mUFC from baseline to study end at each scheduled visit where 
UFC is measured – Core and extension phase 
Descriptive summaries of actual and percentage change in mean 24h-UFC from baseline
to each scheduled visit where UFC is measured will be provided
along with 
corresponding two-sided 95% CIs.
Assess overall efficacy of pasireotide alone or in combination with cabergoline as 
measured by controlled and partially controlled mUFC levels at each scheduled visit
until the final cut-off date
Proportion patients with normalized mUFC (i.e. mUFC ≤ 1.0xULN) at each scheduled 
visit will be reported along with its corresponding 95% CI until the final cut-off date
Proportion of patients who attained mUFC ≤ 1.0 X ULN (controlled) or have at least 
50% reduction (partially controlled) at each scheduled visit will be reported along with 
its corresponding 95% CI. If mUFC is missing, no imputation will be done.


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Evaluate the duration of controlled or partially controlled mUFC response – Core 
and extension phase 
Duration of controlled or partially controlled response is defined as the period starting 
from the date of patient’s first normalization (mUFC ≤ 1.0xULN) or at least 50% 
reduction from baseline up to the date when the patient’s mUFC > 1.0xULN and the 
reduction from baseline falls to less than 50% for the first time. Patients without a loss 
of response will be censored at their last available mean UFC assessment date (during 
the core phase). The median and 95% confidence interval of duration of response will 
be derived from Kaplan-Meier method.
Assess the effect on plasma ACTH and serum cortisol - Core and extension phase
Plasma ACTH and serum cortisol concentrations will be summarized using descriptive 
statistics at scheduled visit window for core and extension phase. Actual and percent 
changes from baseline at each scheduled post baseline visit will also be presented along 
with 95% CIs. Mean serum cortisol and plasma ACTH results over time will be 
presented graphically.
Assess the effect of continuous measures of clinical symptoms of hypercortisolism 
- Core and extension phase
Actual and percentage change from baseline in the following clinical symptoms of 
Cushing’s disease (blood pressure, body mass index, waist circumference, fasting serum 
lipid profile and weight) will be assessed over time window using descriptive statistics.
Fasting serum lipid profile includes four basic parameters: total cholesterol, HDL 
cholesterol, LDL cholesterol and total protein.
Assess the effect on the categorical measures of clinical signs of hypercortisolism -
Core and extension phase
Change in clinical signs of Cushing’s disease: facial rubor, supraclavicular and dorsal 
fat pads, hirsutism, striae and muscle strength will be assessed by descriptively 
summarizing changes and shifts from baseline to each timepoint. Two assessors blinded 
to the visit number will score each qualitative endpoint (facial rubor, hirsutism, 
supraclavicular and dorsal fat pads and striae) by review of duplicated photographs. The 
investigator will adjudicate non-agreeing assessments. Table 2-2 [4] describes scales 
and endpoint definitions for each of these assessments. For each clinical sign, descriptive 
summary statistics will be presented.
6.6
Safety parameters and analysis


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Safety and tolerability assessments include AEs, vital signs (blood pressure, heart 
rate, body temperature), blood glucose (fasting plasma glucose, Hemoglobin A1c), 
hormones (IGF -1, TSH/free T4), liver enzymes (AST, ALT, alkaline phosphatase, 
γGT, total bilirubin), hematology, electrolytes, gallbladder ultrasound and ECGs.
All the safety analysis will be over core and extension phase combined based on 
safety set. 
6.6.1
Adverse events (AE)
All adverse events and the cause of death, as recorded on the completion CRF pages, 
will be coded using the latest available version of the MedDRA coding dictionary 
that provides the system organ class (SOC) and preferred term (PT) information.
AEs will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.
The CTC/severity grade will not be imputed if missing. CTC grade 5 (death) will 
not be used in this study.
The incidence of treatment-emergent AEs, during the core phase and during the 
overall on- treatment period, will be summarized by system organ class (SOC), 
preferred term (PT) and severity (based on NCI-CTCAE v.4 grades), type of adverse 
event, relation to study treatment.
A patient with multiple occurrences of an AE will be counted only once in the 
respective AE category
The following selection of treatment-emergent AEs will be listed and summarized for 
safety set from study start to final cut-off date  for safety set:

AEs regardless of study drug relationship

AEs suspected to be study drug-related

SAEs regardless of study drug relationship

AEs leading to study drug discontinuation, regardless of study drug relationship

AEs leading to study drug discontinuation, suspected to be study drug-related

AEs requiring dose adjustment or study-drug interruption, regardless of 
study drug relationship

AEs requiring additional therapy, regardless of study drug relationship

AEs excluding SAEs

Adverse events of special interest by type


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Specific groupings of AEs of special interest will be considered and the number of 
patients with at least one event in each grouping ("category") will be reported. Such 
groups consist of AEs 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 AEs which are similar in nature (although 
not identical) within  safety set. The specific groupings of AEs as defined in the latest 
documentation 
available 
prior 
to 
database 
lock 
(in 
[[Cabinets/CREDI 
Projects/S/SOM230B/Integrated Medical Safety/Safety Profiling and Signal 
detection/Signal detection]]).
The following table will be produced:

AEs of special interest by type (any AE, AE suspected to be drug-related, 
SAE, AE leading to discontinuation, AE requiring dose adjustment), PT and 
maximum Common Terminology Criteria (CTC) grade.
6.6.2
Laboratory evaluation
For laboratory data assessments, data from all sources (central and local laboratories) 
will be combined. All laboratory assessments will be listed and those collected 
outside of the on- treatment period will be flagged in the listings. All laboratory 
values will be converted into SI units.
All the lab analysis over core and extension phase  will be based on safety set. Study 
baseline will be used in analysis.
Laboratory data will be classified into CTC grades according to the NCI Common 
Terminology Criteria for Adverse Events CTCAE) v4.03. A severity grade of 0 will 
be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be 
used.
For some laboratory tests, CTC grades are defined in two directions (low and high, 
e.g. for potassium: hypokalemia and hyperkalemia). The two directions will be 
analyzed separately.
The following summaries will be produced for the laboratory data (by laboratory 
parameter and direction of abnormality, as applicable) over core (baseline to week 
35) and extension phase (from week 43 to final cutoff) for safety set:

Shift tables using CTC grades to compare baseline to the worst post-baseline
value.

For laboratory test where NCI-CTCTAE v4.03 grades are not defined, shift 
tables using the low/normal/high/ (low and high) classification will be 
produced/used to compare baseline to the worst on-treatment value.

Listing of all laboratory data with values flagged to show the corresponding 
NCI - CTCAE v4.03 grades and the classifications relatives to the laboratory 


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normal ranges.
Patients with laboratory values outside the normal range will be listed and flagged 
to show the corresponding CTC grades and the classifications relative to the 
laboratory reference ranges. In addition, laboratory values of patients with laboratory 
abnormalities of CTC grade 3 or 4 will be presented in separate listings.
Liver function tests (LFTs) of interest are total bilirubin (TBILI), ALT, AST and 
ALP. LFTs will be summarized over core and extension phase based on safety set:

Shift tables of baseline vs. worst post-baseline on-treatment values for the
categories:
o
TBILI ≤ 2xULN, TBILI > 2xULN and missing TBILI
o
ALT ≤ 3xULN, ALT > 3xULN and missing ALT
o
AST ≤ 3xULN, AST > 3xULN and missing AST
o
ALT or AST ≤ 3xULN, ALT or AST > 3xULN and missing ALT or
AST
o
ALP <2xULN, ALP ≥ 2xULN and missing ALP

Frequency counts and percentages of patients with worst post -baseline on-
treatment values in the categories:
o
ALT > 3xULN, ALT > 5xULN, ALT > 10xULN, ALT > 20xULN
o
AST > 3xULN, AST > 5xULN, AST > 10xULN, AST > 20xULN
o
AST or ALT > 3xULN, AST or ALT > 5xULN, AST or ALT > 
10xULN, AST or ALT > 20xULN
o
TBILI > 2xULN
o
Concurrent ALT > 3xULN and TBILI > 2xULN
o
Concurrent AST > 3xULN and TBILI > 2xULN
o
Concurrent AST or ALT > 3xULN and TBILI > 2xULN
o
Concurrent AST or ALT > 3xULN and TBILI > 2xULN and ALP <
2xULN
o
Concurrent AST or ALT > 3xULN and TBILI > 2xULN and ALP ≥
2xULN
Concurrent measurements are those occurring on the same date.


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In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a 
post-baseline TBILI > 2xULN, ALT> 3xULN or AST > 3xULN will be provided.
Renal Disease (MDRD) will be summarized over core and extension phase based 
on safety set:

Shift tables of baseline vs. worst post-baseline on-treatment values

Frequency counts and percentages of patients with worst post-baseline on-
treatment values
The minimum of all the post baseline assessments is the worst value for MDRD.
For calcium, the corrected calcium will be used for analysis. Corrected calcium will 
be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL 
by multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by 
dividing by 0.2495. For calculation of laboratory CTC grades 0 and 1, the normal 
range for derived corrected calcium is set to the same limits (in mg/dL) as for 
calcium.
6.6.3
Vital signs and weight for core and extension phase
Vital signs (body temperature, sitting pulse, sitting blood pressure), weight and waist 
circumference will be summarized and listed. Patients with clinically notable vital 
sign values will be flagged in the listing.
Vital sign analysis will be summarized over core (baseline to week 35) and extension 
phase (week 43 to final cutoff) based on safety set. Study baseline will be used in 
analysis.
The criteria for clinically notable abnormalities are defined as follows:

Systolic BP: 180 mmHg and an increase 20 mmHg from baseline
90 mmHg and a decrease 20 mmHg from baseline

Diastolic BP: 105 mmHg and an increase 15 mmHg frombaseline
50 mmHg and a decrease 15 mmHg from baseline

Pulse rate:
120 bpm with increase from baseline of 15 bpm
50 bpm with decrease from baseline of 15 bpm

Body temperature: 39.1°C


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35°C

Weight:
Increase from baseline of 10%
decrease from baseline of 10%
The following summaries will be produced for each vital sign parameter:

Number (%) of patients with clinically notable abnormalities in Vital signs 
at any post- baseline time point

Summary statistic for change from baseline to each post-baseline time points.
Baseline = last value prior to or on the first dose during the study. After baseline, 
the value closest to the target day (i.e. visit window mid - point) is analyzed if a 
patient had more than one value within a time window.
6.6.4
ECG
ECG  analysis will be summarized over core (baseline to week 35) and extension (week 
43 to final cutoff) phase based on safety set. Study baseline will be used in analysis.
The following analyses will be performed for RR, 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 until 
final  cut-off date in extension phase

Summary statistics of changes from baseline at each scheduled post-baseline time
point until final cut-off date  in extension phase

Listing of ECG data (scheduled and unscheduled visits)
Number (%) of patients with a notable QT interval, based on both QTcB and QTcF 
will be summarized for extension phase on -treatment period separately. ECG shift 
table based on notable values will be summarized. Notable criteria for QTcB/QTcF 
include:

>450 ms at any post-baseline time point and ≤ 450 ms at baseline,

>480 ms at any post-baseline time point and ≤ 480 ms at baseline,

>500 ms at any post-baseline time point and ≤ 500 ms at baseline,

An increase from baseline > 30 ms at any post-baseline time point ,

An increase from baseline > 60 ms at any post-baseline time point.
Patients with notable QT interval values and newly occurring qualitative ECG 
abnormalities will be flagged in the listings.


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6.6.5
Gallbladder ultrasound
The findings of the gallbladder imaging (presence of gallstones, presence of sludge, 
dilatation of ductal system) will be summarized at each visit using frequency tables
for safety set over core and extension phase.
6.6.6
Karnofsky performance status
The Karnofsky performance status will be summarized at available visits
mentioned in Table 7-1 of protocol by performance status category using counts 
and percentages.


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