Clinical trial NCT02060383
Conditions: Cushing's Disease Acromegaly
Keywords: Cushing's disease acromegaly pasireotide hyperglycemia
Sponsor: Novartis Pharmaceuticals
Start date: 2014-05-23; Completion date: 2018-03-26
Enrollment: 249 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was designed to investigate the optimal management of hyperglycemia developed during pasireotide treatment in participants with Cushing's disease or Acromegaly, which was not manageable with metformin.

This was a Phase IV, multi-center, randomized, open-label study. Eligible patients started pasireotide subcutaneously (s.c.) for Cushing's disease and pasireotide LAR (long-acting release) for Acromegaly.

Participants being treated with pasireotide s.c or LAR at screening were eligible as long as they met protocol criteria during the screening period. If previously normo-glycemic participants experienced an increase in their fasting blood glucose and met the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to have elevated blood glucose above target on metformin within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks.

Participants who continued to receive clinical benefit after completing the Core Phase could enter an optional Extension Phase if pasireotide was not commercially available in their country or a local access program was not available to provide drug. Patients continued in the Extension Phase until the last participant randomized in the Core Phase completed 16 weeks of treatment post-randomization.

Detailed description:

Arms: arm 1: Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin. arm 2: Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin. arm 3: This arm represents the non-randomized participants: Cushing's Disease (CD) or Acromegaly participants, who received pasireotide s.c. or LAR (long-acting release) respectively, but who were not randomized to the Incretin or Insulin arms.

For the purpose of analysis, this non-randomized arm is further split into 3 groups:

* Baseline insulin group (BL insulin) includes participants who were receiving insulin at study entry
* Oral antidiabetic drugs (OAD) group includes participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment
* No OAD group includes participants who did not receive any anti-diabetic medication during the core phase of the trial
Interventions: intervention 1: Pasireotide s.c. intervention 2: Sitagliptin intervention 3: Liraglutide intervention 4: Insulin intervention 5: Pasireotide LAR intervention 6: Metformin
Intervention descriptions: intervention 1: Administered to Cushing's disease participants. intervention 2: Taken for approximately 16 weeks during the core study phase or until the drug was found not to be effective intervention 3: Participant switched to liraglutide if sitagliptin was found not to be effective. intervention 4: Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required.

Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator.

Note: OAD and No OAD groups within the non-randomized arm did not take Insulin. intervention 5: Administered to Acromegaly participants. intervention 6: If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator.

Note: No OAD group within the non-randomized arm did not take metformin.

Protocol documents:
Prot_000.pdf: 
Clinical Development
Pasireotide, SOM230
Protocol CSOM230B2219 / NCT02060383
A multi-center, randomized, open-label, Phase IV study to 
investigate the management of pasireotide-induced 
hyperglycemia with incretin based therapy or insulin in 
adult patients with Cushing’s disease or acromegaly
Authors
Document type
Amended Protocol Version
EUDRACT number
2012-002916-16
Version number
03 (Clean)
Development phase
IV
Document status
Final
Release date
17-Mar-2017
Property of Novartis
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................................................................................................................6
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 3 (17-Mar-2017) ...........................................................................................11
Amendment 2 (29-Sep-2016)............................................................................................14
Amendment 1 ....................................................................................................................16
Protocol summary:.............................................................................................................19
1
Background........................................................................................................................22
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............22
1.2
Introduction to investigational treatment(s) and other study treatment(s).............23
1.2.1
Overview of pasireotide (SOM230)......................................................23
2
Rationale............................................................................................................................26
2.1
Study rationale and purpose...................................................................................26
2.2
Rationale for the study design ...............................................................................27
2.3
Rationale for dose and regimen selection..............................................................27
3
Objectives and endpoints...................................................................................................28
4
Study design ......................................................................................................................30
4.1
Description of core phase ......................................................................................30
4.1.1
Pre-randomized period..........................................................................31
4.1.2
Randomized period ...............................................................................33
4.1.3
Non-randomized treatment groups (Observational arms).....................34
4.2
Extension phase .....................................................................................................35
4.3
Definition of end of the study................................................................................36
4.4
Early study termination..........................................................................................36
5
Population..........................................................................................................................36
5.1
Patient population..................................................................................................36
5.2
Inclusion criteria ....................................................................................................36
5.3
Exclusion criteria...................................................................................................37
6
Treatment...........................................................................................................................40
6.1
Study treatment......................................................................................................40
6.1.1
Dosing regimen .....................................................................................41
6.1.2
Rescue Therapy.....................................................................................41


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6.1.3
Treatment duration................................................................................41
6.2
Dose modifications ................................................................................................42
6.2.1
Pasireotide dose modification ...............................................................42
6.2.2
Dose modification for anti-diabetic medications ..................................43
6.2.3
Follow-up for toxicities.........................................................................43
6.2.4
Anticipated risks and safety concerns of the study drug.......................48
6.3
Concomitant medications ......................................................................................48
6.3.1
Permitted concomitant therapy .............................................................48
6.3.2
Permitted concomitant therapy requiring caution and/or action...........49
6.3.3
Prohibited concomitant therapy ............................................................49
6.4
Patient numbering, treatment assignment or randomization .................................49
6.4.1
Patient numbering .................................................................................49
6.4.2
Treatment assignment or randomization...............................................50
6.4.3
Treatment blinding................................................................................50
6.5
Study drug preparation and dispensation...............................................................50
6.5.1
Study drug packaging and labeling.......................................................51
6.5.2
Drug supply and storage........................................................................51
6.5.3
Study drug compliance and accountability ...........................................51
6.5.4
Disposal and destruction .......................................................................52
7
Visit schedule and assessments .........................................................................................52
7.1
Study flow and visit schedule................................................................................52
7.1.1
Screening...............................................................................................64
7.1.2
Treatment period ...................................................................................64
7.1.3
End of treatment visit including study completion and premature 
withdrawal.............................................................................................65
7.1.4
Follow-up and End of Study visit .........................................................67
7.2
Assessment types...................................................................................................67
7.2.1
Efficacy assessments.............................................................................67
7.2.2
Clinical benefit assessments..................................................................67
7.2.3
Safety and tolerability assessments.......................................................67
7.2.4
Resource utilization...............................................................................72
7.2.5
Patient reported outcomes.....................................................................72
8
Safety monitoring and reporting........................................................................................72
8.1
Adverse events.......................................................................................................72
8.1.1
Definitions and reporting ......................................................................72
8.1.2
Laboratory test abnormalities................................................................74


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8.1.3
Adverse events of special interest.........................................................74
8.2
Serious adverse events...........................................................................................75
8.2.1
Definitions.............................................................................................75
8.2.2
Reporting...............................................................................................75
8.3
Pregnancies............................................................................................................76
8.4
Warnings and precautions......................................................................................76
8.5
Steering Committee ...............................................................................................77
8.6
Data Monitoring Committee..................................................................................77
9
Data collection and management.......................................................................................77
9.1
Data confidentiality ...............................................................................................77
9.2
Site monitoring ......................................................................................................77
9.3
Data collection.......................................................................................................78
9.4
Database management and quality control............................................................78
10 Statistical methods and data analysis ................................................................................79
10.1
Analysis sets ..........................................................................................................79
10.1.1
Randomized Analysis Set .....................................................................79
10.1.2
Full Analysis Set ...................................................................................79
10.1.3
Safety analysis Set.................................................................................80
10.2
Patient demographics/other baseline characteristics .............................................80
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................80
10.4
Primary objective...................................................................................................80
10.4.1
Variable.................................................................................................81
10.4.2
Statistical hypothesis, model, and method of analysis..........................81
10.4.3
Handling of missing values/censoring/discontinuations.......................81
10.4.4
Supportive analyses...............................................................................81
10.5
Secondary objectives .............................................................................................82
10.5.1
Key secondary objective(s)...................................................................82
10.5.2
Other secondary efficacy objectives .....................................................82
10.5.3
Safety objectives ...................................................................................83
10.5.4
Biomarkers ............................................................................................85
10.5.5
Patient-reported outcomes.....................................................................85
10.6
Exploratory objectives...........................................................................................85
10.7
Interim analysis......................................................................................................85
10.8
Sample size calculation..........................................................................................85
10.9
Power for analysis of key secondary variables......................................................86
11 Ethical considerations and administrative procedures ......................................................86


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11.1
Regulatory and ethical compliance........................................................................86
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................86
11.3
Informed consent procedures.................................................................................86
11.4
Discontinuation of the study..................................................................................87
11.5
Publication of study protocol and results...............................................................87
11.5.1
Communication and Publication of Clinical Trial Results ...................87
11.6
Study documentation, record keeping and retention of documents.......................87
11.7
Confidentiality of study documents and patient records .......................................88
11.8
Audits and inspections...........................................................................................88
11.9
Financial disclosures..............................................................................................88
12 Protocol adherence ............................................................................................................89
12.1
Amendments to the protocol..................................................................................89
13 References (available upon request)..................................................................................90
14 Appendices ........................................................................................................................91
14.1
Appendix 1: Medications known to be associated with QT interval 
prolongation...........................................................................................................91
14.2
Appendix 2: Formula to calculate QTcF ...............................................................92
14.3
Appendix 3: Lifestyle measures in association with anti-diabetic treatments.......93


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List of appendices
Appendix 1: Medications known to be associated with QT interval prolongation
Appendix 2: Formula to calculate QTcF
Appendix 3: Lifestyle measures in association with anti-diabetic treatments
List of figures
Figure 1-1
Mean (+/- SE) Urinary Free Cortisol (nmol/24h) at time points up 
to Month 12 by randomized dose group (Full analysis set - Study 
B2305)...................................................................................................24
Figure 4-1
Treatment Schema.................................................................................33
Figure 6-1
QT Prolongation Safety Management...................................................46
Figure 6-2
LFT management algorithm..................................................................48
List of tables
Table 1-1
Binding profiles for octreotide and pasireotide at hsst1-5 (IC50, 
mol/L)....................................................................................................23
Table 3-1
Objectives and related endpoints ..........................................................29
Table 4-1
Weekly insulin titration schedule..........................................................34
Table 6-1
Dose and treatment schedule.................................................................41
Table 6-2
Dose modification criteria for suspected pasireotide-related adverse 
events.....................................................................................................43
Table 6-3
Packaging and labeling .........................................................................51
Table 6-4
Supply and storage of study treatments ................................................51
Table 7-1
Core Phase Visit Evaluation Schedule..................................................54
Table 7-2
Extension Phase Visit Evaluation Schedule..........................................60
Table 7-3
Central Clinical laboratory parameters collection plan.........................69
Table 7-4
Local ECG collection plan....................................................................72


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List of abbreviations
ACTH
Adrenocorticotropic hormone
ADA
American Diabetes Association
ADME
Absorption Distribution Metabolism Elimination
ADR
Adverse Drug Report
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
Anti-HCV
Hepatitis C antibody
APTT
Activated Partial thromboplastin time
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under the concentration / time curve
b.i.d.
bis in diem/twice a day
BLRM
Bayesian Logistic Regression Model
BUN
Blood urea nitrogen
CABG
Coronary Artery Bypass Graft
CDP
Clinical development plan
CI
Confidence interval
CL/F
The total body clearance of drug from the plasma
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSP
Clinical study protocol
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CVA
Cerebrovascular Accident
d
days
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DS&E
Drug Safety and Epidemiology
E
Extension
EAS
Evaluable Analysis Set
EASD
European Association for the Study of Diabetes
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medical Agency
EOP
End of Phase
EW
Extension Week
FAS
Full Analysis Set
FPG
Fasting Plasma Glucose
GCP
Good Clinical Practice
GEP/NET
Gastroenteropancreatic neuroendocrine tumor
GGT
Gamma-glutamyl transpeptidase
GH
Growth Hormone


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GIP
Gastric inhibitory polypeptide
GLP-1
Glucagon-like peptide-1
h
Hour
HbA1c
Hemoglobin A1c
HbsAg
Hepatitis B surface Antigen
hCG
Human chorionic gonadotropin
HVs
Healthy volunteers
i.m.
Intra-muscular
i.v.
intravenous(ly)
IB
Investigator’ s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGF-1
Insulin-like growth factor 1
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
ITT
Intent to treat
IUD
Intrauterine device
IUS
Intrauterine system
LAR
Long-acting release
LFT
Liver Function Test
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
MI
Myocardial infarction
MTC
Medullary Thyroid Carcinoma
mUFC
Mean Urine Free Cortisol
NAD
No anti-diabetic
NPH
Neutral protamin hagedorn
NRs
Normal Ranges
o.d.
omnia die/once a day
OAD
Oral anti-diabetic
OGTT
Oral glucose tolerance test
p.o.
per os/by mouth/orally
PHI
Protected Health Information
PK
Pharmacokinetic
PPG
Post-Prandial glucose
PR
Pre-randomized
PRL
Prolactin
PT
Prothrombin time
PTT
Partial thromboplastin time
q28d
Every 28-days
R
Randomized
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RAS
Randomized Analysis Set
RBC
Red Blood Cells


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REB
Research Ethics Board
s.c.
Sub-cutaneous
SAE
Serious Adverse Event
SAS
Safety analysis set
SC
Steering committee
SE
Standard error
SEC
Specific Safety Event Categories
SMBG
Self-monitored blood glucose
SmPc
Summary of Product Characteristics
SOP
Standard Operating Procedure
SSA
Somatostatin analogues
SST
Somatostatin receptors
T1/2
Terminal elimination half-life
T4
Thyroxine
TIA
Transient Ischemic Attack
Tmax
Time to reach Cmax
TSH
Thyroid stimulating hormone
UFC
Urine free cortisol
ULN
Upper Limit of Normal
W
Week


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being 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
Medication number
A unique identifier on the label of each study treatment package which is linked 
to one of the treatment groups of a study
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.)
A unique identifying number assigned to each patient/healthy volunteer who 
enrolls in the study
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
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
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 as part of the required study procedures, including placebo and active 
drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this 
case refers to the investigational and non-investigational treatments in 
combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints


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Amendment 3 (17-Mar-2017)
Amendment rationale
1. Clarification regarding the protocol visits included in the 28-day Safety follow-up for 
Cushing’s disease patients receiving pasireotide s.c and the 84-day Safety follow-up for 
acromegaly patients receiving pasireotide LAR as follows:

Eligible patients as per protocol who are transitioning to a roll-over study or local 
access program will not be required to perform the safety follow-up visit (779) as 
patients will continue to be monitored for safety.

Eligible patients as per protocol who are transitioning to commercial drug will be 
required to perform the safety follow-up visit (779).
2. Re-insertion of the missing Figure 6-1 QT Prolongation Safety Management.
3. Allow a ± 3 day visit window for Cushing’s patients. Visit windows for Acromegaly 
patients will remain unchanged as per Table 7-1.
Changes to the protocol sections:
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 underline for insertions.
Section 4.1 Description of core phase, paragraph 7 – revised to “All patients who will not 
continue pasireotide treatment or patients who will transition to commercial drug will have 
the safety follow-up visit after the Core (or Extension) End Of Phase (EOP) visit, which will 
be 28 days after the last pasireotide s.c. dose or 84 days after the last pasireotide LAR dose.”
Section 4.2 Extension phase
Revised paragraph 2: “Both non-randomized patients who reached Visit 6 (Pre-randomized-
W12) - end of pre-randomization phase and randomized patients who reached Visit 14
(Randomized-W14) - end of randomization phase who have completed their Core EOP visit 
will be allowed to continue on to the extension phase of the study if t hey fulfill all of the 
following”

Revised paragraph 3: “Patients who withdraw consent from the core phase (pre-
randomization or randomization phase) cannot participate in the extension phase.”

Added: “Patients who discontinue prematurely from the core phase cannot participate in 
the extension phase”

Added “For all patients, the EOP visit (778) will be performed. However, for patients 
transitioning to a roll-over study or local access program, the Safety follow-up visit (779) 28 
days after the last pasireotide s.c. dose or 84 days after the last pasireotide LAR dose is not 
required. Patients will continue to be monitored for safety while participating in either the 
roll-over study or local access program.
Refer to the eCRF Completion Guidelines for further instructions.”


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Section 6.1.3 Treatment duration – added statement
Revision to paragraph 3:
Patients who are in the extension phase, who continue to receive clinical benefit as assessed 
by the investigator, will have the opportunity to receive pasireotide either commercially if 
available or via a roll-over study or local access program if available in order to continue their 
treatment with pasireotide.
For all patients, the EOP visit (778) will be performed. This includes patients who transition 
to commercial drug, the Safety follow-up visit (779) 28 days after the last pasireotide s.c. dose 
or 84 days after the last pasireotide LAR dose is required.
However, for patients who transition to a roll- over study or local access program, the Safety 
follow-up visit (779) 28 days after the last pasireotide s.c. dose or 84 days after the last 
pasireotide LAR dose is not required. Patients will continue to be monitored for safety while 
participating in either the roll-over study or local access program.
Section 6.2.3.2 QT Prolongation – re-inserted and changed Figure title
Figure 6-1 - QT Prolongation Safety Management was inadvertently deleted in Amendment 2.
Section 7.1 Study flow and visit schedule – added
“± 3-day visit window will be allowed for Cushing’s patients. Visit windows for Acromegaly 
patients will remain unchanged as per Table 7-1”.
Section 7.1.3 End of treatment visit including study completion and premature 
withdrawal – revised end of paragraph 1
“These patients should then return for an End of Study/Follow-up visit as described in Section 
7.1.4 and complete the EOS Visit assessments and Study Completion eCRF. Patients 
continuing pasireotide treatment through a roll-over study or local access program will not 
return for an End of Study/Follow-up visit as their safety will be monitored.
Section 7.1.3 End of treatment visit including study completion and premature 
withdrawal – revised end of paragraph 3
“Patients who discontinue study treatment should be considered withdrawn from the study or 
considered as did not complete the study after the final visit assessments are performed or 
when it is clear that the patient will not return for these assessments.”
Section 7.1.4 Follow-up and End of Study Visit – revised to
“All patients must have safety evaluations and complete the EOS assessments at the EOS visit 
28 days after the last dose of pasireotide s.c or 84 days after the last dose of pasireotide LAR.
Patients continuing pasireotide treatment through a roll-over study or local access program 
will not return for an End of Study/Follow-up visit as their safety will be monitored.”
Refer to the eCRF Completion Guidelines for further instructions.


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IRBs/IECs
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 are non-substantial and do not require 
IRB/IEC approval prior to implementation.


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Amendment 2 (29-Sep-2016)
Rationale
As of 9-Sep-2016, 166 patients have been enrolled (49 patients with Cushing’s disease and 
117 patients with acromegaly). Of the 166 patients enrolled in the trial, out of the planned 79 
patients have been randomized (20 Cushing’s disease and 30 acromegaly).
The rationale of this amendment 2 is to remove the protocol requirement to randomize the 
equal number of patients with Cushing’s disease and Acromegaly (a total of 79 patients).
In protocol amendment 1, the target was to randomize 79 patients (42 in Cushing’s disease 
and 37 in acromegaly) to obtain 68 randomized patients (34 with Cushing’s disease and 34 
with acromegaly, who completed at least 8-week randomized treatment without any rescue 
medication).
Cushing’s disease is a rare disease with a low incidence and prevalence and the recruitment 
of these patients in clinical studies is challenging. In the present study, the availability of this 
patient population has been lower than expected and consequently, more patients with 
acromegaly than patients with Cushing ’ s disease are being screened and ultimately 
randomized. Despite the fact that patients with Cushing’s disease and Acromegaly exhibit 
insulin resistance and metabolic abnormalities secondary to different mechanisms and that the 
severity of hyperglycemia might differ, the effect of pasireotide on glucose metabolism is 
expected to be the same in both populations (i.e. increase of blood glucose levels by 
decreasing insulin and incretin secretion). Therefore, the proportion of randomized patients 
from each disease group is not expected to affect the scientific value of the study.
Additional changes for clarification and corrections are included in this 
amendment:

Since more patients than the originally 133 planned have been enrolled without achieving 
the planned 79 randomized patients, language has been modified to ensure that the number 
of enrolled patients will be based on the actual randomization rate

Added the updated DILI standard language to Section 6.2.3.3 Hepatic safety management.
This language update was made across Oncology Novartis programs

Clarified that all patients are to call the site immediately if results of any single occurrence 
of self-monitored fasting blood glucose is > 250 mg/dL, in order to allow for appropriate 
management of hyperglycemia

Added IWRS/IRT Registration in Table 7-2 Extension Phase Visit Evaluation Schedule

Corrected and removed the PK sample collection which is not applicable in this study 
from Figure 6-2 LFT management algorithm


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Changes to the protocol sections:
1. Protocol summary - Population and Section 5.1 Patient Population:
a.
Removed the need to enroll approximately 133 patients. The total number of enrolled 
patients is defined based on the regular monitoring of the actual randomization rate
b. Removed the need to randomize equal number of Cushing’s disease patients (34) and 
Acromegaly patients (34).
2. Section 4.1.1 Pre-randomized period: Clarified that patients are to report immediately 
results of a single occurrence self-monitored fasting blood glucose > 250 mg/dL
3. Section 6.2.3.3 Hepatic safety management: Updated with the DILI standard language
4. Table 7-2 Extension Phase Visit Evaluation Schedule: Added IWRS/IRT Registration in 
the table
5. Section 10.8 Sample size calculation:
a.
Removed the need to enroll approximately 133 patients. The total number of enrolled 
patients is defined based on the regular monitoring of the actual randomization rate
b. Removed the need is to randomize equal number of Cushing’s disease patients (34) 
and Acromegaly patients (34). This amendment releases this restriction.
c.
Clarified randomized patients who are evaluable
d. Modified the total enrollment which will be based on estimate of the actual 
randomization rate
6. Section 14.2 Appendix 2: Formula to calculate QTcF – added the msec. unit.
Changes will have no significant implications for participants or for the conduct, management 
or scientific value of the study, and can be regarded as “non-substantial” or “administrative”.
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation.
This amendment does require an update of the ICF.


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Amendment 1
As of 23 July 2014, 2 patients have been enrolled on the CSOM230B2219 study.
The main objectives of this protocol amendment are as follows:

Upon Health Authorities request:
1. an additional LFT (Liver Function Test) monitoring at Week 1 for the cohort of 
patients with Cushing’s disease on s.c. formulation of pasireotide is included in line 
with the approved Signifor SmPC (Summary of Product Characteristics)
2. additional ECG (Electrocardiogram) monitoring at Week 1 in line with the approved 
Signifor SmPC for the cohort of patients on the s.c. formulation of pasireotide; and at 
Week 3 in line with the proposed EU SmPC for pasireotide LAR (Long Acting 
Release) in Acromegaly are included
3. in line with the ADR (Adverse Drug Report) profile described in the approved labels 
of anti-diabetic medications used in this study, the following changes are 
implemented:

Exclusion criterion number 13 re-worded to exclude patients with cholelithiasis
and acute and chronic pancreatitis.

A new exclusion criterion for patients with a family history of MTC (Medullary 
Thyroid Carcinoma) or MEN2 (Multiple Endocrine Neoplasia syndrome type 2)
has been added

Exclusion criterion number 18 amended to exclude patients with renal 
dysfunction as defined by local metformin label (E.g., As per SmPC, creatinine 
clearance <60 mL/min)

Additional pancreatic safety monitoring (lipase and amylase) has been added for 
all patients.
4. Patients in Denmark on pasireotide LAR will participate in the overall study (core and 
extension phases) for up to a maximum of 1 year.

To ensure that the patients are followed for at least 5 times the elimination half-life (t1/2) of 
study drug, the safety follow-up monitoring was extended to 84 days in patients receiving 
the pasireotide LAR formulation

To account for gender differences in QTcF as acknowledged by health authorities, the
exclusion criterion at screening was modified to QTcF > 450 ms for males and > 460 ms 
for females.

To clarify the washout period for other SSAs, 8 weeks washout for octreotide LAR and 
lanreotide autogel was specified

Wash-out period for previous exposure to pasireotide s.c. has been updated to 1 week to 
minimize unnecessary interruption of pasireotide based on the 16-hour half-life of 
pasireotide s.c.

The suggested insulin titration schedule has been updated to align with the study defined 
glycemic control (mean 3-consecutive daily SMBG <126 mg/dL).

Clarifications have been included and minor discrepancies have been fixed throughout the 
protocol.


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Please refer to the following section for further details about the amendment.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 4.1, Section 6.1.3, Section 7.1.3, Section 7.1.4, Section 8.1.1, Section 8.2.2, 
Section 10.5.3, Figure 4-1, Table 7-1 and Table 7-2: extended the safety follow-up 
monitoring of patients receiving the LAR formulation to 84 days

Section 4.1 and Section 4.2: maximum overall study duration for patients in Denmark on 
pasireotide LAR was added.

Section 4.1.1 and Section 6.2.3.1: clarified language for self-monitored blood glucose 
review

Section 4.1.1: added and clarified language for creatinine clearance and metformin 
treatment

Section 4.1.2: Suggested weekly insulin titration schedule has been updated

Section 5.2: previous exposure to pasireotide wash-out period has been updated

Section 5.2: Inclusion criterion has been added to consider patients treated with insulin for 
an acute medical need.

Section 5.3: clarifications were made to exclusion criteria # 2, #13 and #18 based on the 
safety profile of the study drug and the anti-diabetic treatment

Section 5.3: exclusion criterion has been added for known family history of MTC or 
multiple endocrine neoplasia syndrome type 2 (MEN2)

Section 5.3: exclusion criterion #14 has been updated based on gender

Section 6.2.2.1: Metformin dose modification based on renal function added

Section 6.3.3: Added wash out period for other medical therapies for Cushing’s disease or 
acromegaly

Section 6.5.3.3: Clarified language related to anti-diabetic treatment

Section 6.5.3.3: Added information for anti-diabetic treatment according to local 
regulations

Table 7-1: table has been updated to correct inconsistencies and visits, PR-Week 1 (401) 
and PR- Week 3 (402) have been added to align with the approved label for pasireotide s.c. 
and proposed label for pasireotide LAR

Section 7.1.3.1: criteria for premature patient withdrawal has been updated with pancreas 
related discontinuation criteria

Table 7-3: table has been updated to include lipase and amylase as additional tests

Section 7.2.3.4.2: Added clarification regarding creatinine clearance

Section 7.2.3.4.4: Self-monitored blood glucose language clarified

Section 7.2.3.4.9: Tests related to pancreas function added

Section 7.2.3.5: Gallbladder ultrasound tests updated to meet pasireotide s.c. and 
pasireotide LAR study specific criteria


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
Table 7-4: ECG tests updated to meet pasireotide s.c. and pasireotide LAR study specific 
criteria

Section 8.6: Clarified that there is no DMC for the study

Section 9.4: randomization and data dispensation information by IRT system included

Section 10: Timing of final CSR has been updated

Section 10.1: Definition of FAS & SAS have been clarified

Section 10.3: Analysis sets for treatment exposure amended from FAS to SAS.

Section 10.5.3.1: Analysis set and grouping for the analyses listings and tables information 
has been updated.
IRB/IEC Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
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 
protocol amendment.


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Protocol summary:
Protocol number
CSOM230B2219
Title
A multi-center, randomized, open-label, Phase IV study to investigate the 
management of pasireotide-induced hyperglycemia with incretin based therapy or 
insulin in adult patients with Cushing’s disease or acromegaly.
Brief title
An open-label study to investigate the management of pasireotide-induced 
hyperglycemia with incretin based therapy or insulin in adults patients with Cushing’s 
disease or acromegaly
Sponsor and
Clinical Phase
Novartis
Phase IV study
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Hyperglycemia was a frequently observed adverse event in the pasireotide clinical 
studies in both patients with Cushing’s disease and acromegaly. The purpose of this 
trial is to investigate the optimal management of pasireotide-induced hyperglycemia 
in these patients.
Primary Objective
To evaluate the effect of treatment with incretin based therapy vs. insulin on the 16-
week glycemic control in patients with Cushing’s disease or acromegaly who develop 
or worsen hyperglycemia on pasireotide, and cannot be controlled by metformin 
alone or other background anti-diabetic treatments.
Secondary Objectives
Objective 1: To evaluate the overall effect of anti-diabetic intervention on glycemic 
control in patients with Cushing’s disease or acromegaly.
Objective 2: To evaluate the sustainability of glycemic control in the incretin based 
therapy arm and the insulin arm in Cushing’s disease patients treated with 
pasireotide s.c. and acromegaly patients treated with pasireotide LAR.
Objective 3: To evaluate the safety and tolerability of pasireotide in combination with
anti-diabetic treatments.
Study design
This is a Phase IV, multi-center, randomized, open-label study. Eligible patients will 
start pasireotide s.c. for Cushing’s disease and pasireotide LAR for acromegaly. 
Patients currently treated at screening visit with pasireotide s.c. or LAR are eligible if 
they have an elevated FPG > ULN or a diagnosis of diabetes (FPG ≥ 126 mg/dL on 
two occasions or HbA1c ≥ 6.5% or a random plasma glucose ≥ 200 mg/dL with 
classic symptoms of hyperglycemia (polydipsia, polyphagia and polyuria)) during 
screening period. If previously normo-glycemic patients experience increases in their 
fasting blood glucose based on pre-defined glycemic criteria while on pasireotide, 
they will start anti-diabetic treatment using metformin. If they continue to experience 
increases in their fasting blood glucose within the first 16 weeks, they will be 
randomized in a 1:1 ratio to receive treatment with incretin based therapy (sitagliptin 
followed by liraglutide) or insulin for 16 weeks.
Population
The eligible patient population will consist of adult Cushing’s disease and acromegaly 
patients. The study targets to have 68 randomized evaluable patients. The total 
number of patients will be based on the actual randomization rate which will be 
monitored regularly.


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Key Inclusion criteria
Cushing’s disease population
●
Adult patients (age ≥ 18 y) with confirmed diagnosis of Cushing’s disease 
(persistent/recurrent or de Novo patients who are not considered candidates for 
pituitary surgery).
Acromegaly population
●
Adult patients (age ≥ 18 y) with confirmed diagnosis of acromegaly. De Novo
patients (with no prior pituitary surgery) can be included if they are not considered 
candidates for pituitary surgery or have refused surgery.
Patients being treated at screening visit with pasireotide should have an elevated 
FPG > ULN or a diagnosis of diabetes during screening period.
Key Exclusion criteria
●
Patients who are receiving other medical therapies for Cushing’s disease or 
acromegaly. All other medical therapies for Cushing’s disease or acromegaly have to 
be discontinued at least 5 times the half-life of the respective preparation before 
study entry (start of pasireotide).
●
Patients who require surgical intervention
●
Patients receiving DPP-4 inhibitors or GLP-1 receptor agonists within 4 weeks 
prior to study entry
●
HbA1c > 10 % at screening
●
Known hypersensitivity to somatostatin analogues
●
History of liver disease
●
Cholelithiasis or acute or chronic pancreatitis
●
Cardiac or repolarization abnormality
●
Life-threatening autoimmune disorders
●
Patients who have clinical symptoms of hypothyroidism
●
Inadequate bone marrow function
Investigational and 
reference therapy
Pasireotide s.c. for Cushing’s disease, Pasireotide LAR for acromegaly.
Anti-diabetic medications: Metformin, Sitagliptin, Liraglutide, Insulin
Efficacy assessments
Primary efficacy parameter:
Primary efficacy variable is defined as the change in HbA1c (unit in %) from 
randomization to the subsequent scheduled visit after 16 weeks on randomization in 
incretin based therapy arm and insulin arm. For patients who require rescue 
treatment, the last HbA1c assessment before rescue treatment will be used for 
primary efficacy analysis.
Supportive efficacy parameter:
Supportive efficacy parameter is the same as primary efficacy parameter except that 
patients taking rescue treatment before the time of assessing the primary endpoint 
will follow ITT rule, i.e., HbA1c assessment on Core End of Phase (EOP) in each 
randomized arm will be utilized for analysis regardless of rescue treatment use.
Secondary efficacy parameters:
●
Change in HbA1c and FPG from baseline to Core EOP
●
Proportion of patients with an increase in HbA1c ≤ 0.3%
●
Change in HbA1c and FPG from randomization overtime
●
Proportion of patients that received anti-diabetic rescue treatment
Safety assessments
●
Adverse Events
●
Laboratory evaluations
●
Cardiac assessments (ECG)
●
Vital Signs
●
Hypoglycemia events
●
Thyroid function tests
●
Gall bladder ultrasound


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Other assessments
None
Data analysis
There is no formal hypothesis testing planned in this study. An estimate of the mean 
difference of the change from randomization in HbA1c between the two randomized 
arms will be reported along with 95% confidence interval (CI). Patients will be 
stratified by their disease and baseline glycemic status. Variance estimation will be 
based on analysis of variance (ANOVA) model using the two stratification factors 
(disease and glycemic status at baseline) as well as their anti-diabetic treatment as 
fixed effects. Patients who are randomized to either incretin based therapy or insulin 
will be used for primary analysis.
For the secondary objectives, categorical variables will be summarized via the 
number and proportion of patients. Continuous variables will be summarized using 
relevant descriptive statistics, such as number of patients with measurements, mean, 
standard deviation, median, minimum, and maximum.
Key words
Cushing’s disease, acromegaly, somatostatin, pasireotide, hyperglycemia, incretin 
based therapy, DPP4 inhibitor, GLP-1 receptor agonist, insulin


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Cushing’s disease and acromegaly are both rare but debilitating diseases. Patients with 
Cushing’s disease have excessive adrenocorticotropic hormone (ACTH) secretion from a 
benign pituitary adenoma, which stimulates the adrenal glands to produce excess cortisol. The 
hypercortisolemia results in a debilitating condition that affects multiple organ systems. The 
morbidity includes increased blood pressure, dyslipidemia, insulin resistance, weight gain 
with central obesity, moon facies, accumulation of fat pad in the supraclavicular and 
dorsicervical area, osteopenia and osteoporosis, immunosuppression and mental disorders 
ranging from mood changes to depression and psychosis (Pivonello 2008). 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, primarily females.
Acromegaly is characterized by chronic hypersecretion of GH (growth hormone), which, in 
over 95% of patients, is caused by a GH-secreting pituitary adenoma. The clinical 
manifestations of acromegaly are due to the peripheral actions of the GH excess and elevated 
IGF-1 concentrations and/or local tumor mass effect. It is estimated that about 3 out of every 
million people develop acromegaly each year and that 40 to 60 out of every mi llion people 
suffer from the disease at any one time (Melmed et al 1998).
Surgical removal of the adenoma is the first line therapy for Cushing’s disease. However, the 
success rate of surgery is between 65-90% for microadenomas (tumors < 1 cm) with 
recurrence rates between 10 - 20% after 10 years. 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 (Biller et al 2008).
Treatment modalities for acromegaly include surgery, drug treatment or radiotherapy. 
Transphenoidal surgery is currently the most frequently recommended treatment; however the 
surgical effectiveness varies depending on expertise in pituitary surgery, both the size and 
extension of the anatomic mass, and the preoperative levels of GH. Radiation therapy has 
been used both as a primary treatment and combined with surgery or drugs. It is usually 
reserved for patients who have tumor remaining after surgery, for patients who are not good 
candidates for surgery because of other health problems; and for patients who do not respond 
adequately to surgery and medication. Radiation therapy causes a gradual loss of production 
of other pituitary hormones with time which can result in the undesired effect of 
panhypopituitarism. Loss of vision and brain injury, which have been reported, can be 
complications from radiation treatment (Wass et al 2001). Currently the medical treatment 
options for acromegaly include somatostatin analogues (SSAs), growth hormone antagonists 
and dopamine agonists. SSAs have been proven to be safe, well-tolerated and effective and 
are the medical treatment of choice for acromegalic patients. The currently marketed SSAs are 
octreotide (Sandostatin®) and lanreotide (Somatuline®). Octreotide has been available for over 
15 years and is considered the world-wide gold standard medical treatment for acromegaly.


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Pasireotide is a SSA, recently approved in Europe and in the US as a subcutaneous (s.c.) 
formulation under the trade name Signifor® for the treatment of adult patients with Cushing’s 
disease for whom surgery is not an option or for whom surgery has failed. Pasireotide is also 
being developed as a long-acting depot formulation (LAR) for the treatment of acromegaly. A 
phase III study to assess the safety and efficacy of pasireotide LAR vs octreotide LAR in 
acromegaly was recently completed. The results from this study show that pasireotide LAR is 
effective and superior to octreotide in treating acromegaly patients. [CSOM230C2305]
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of pasireotide (SOM230)
Pasireotide (SOM230) is a cyclohexapeptide, SSA with the following chemical name: (2-
Aminoethyl)carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-
benzyloxybenzyl)-14-(1H-indol-3ylmethyl)-4,7,10,13,16,19-hexaoxo-17-
phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadeen-2-yl 
ester, 
di[(S)-
2aminosuccinic acid] salt. Like natural somatostatin and other SSAs, pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors (sst.). Somatostatin is an 
endogenous peptide that modulates a number of exocrine and endocrine secretions. There are 
five known somatostatin receptors: sst1, 2, 3, 4 and 5 as outlined in Table 1-1. When 
compared to octreotide, pasireotide has a binding affinity which is 30-40 times greater for sst1 
and sst5, 5 times greater for sst3, and a comparable affinity for sst2 (Schmid and Brueggen 
2012). Somatostatin receptors are expressed in different tissues under normal physiological 
conditions as well as in many solid tumors, especially in neuroendocrine tumors where 
hormones are excessively secreted, e.g. acromegaly, gastroenteropancreatic neuroendocrine 
tumor (GEP/NET) and Cushing’s disease (Freda 2002, Oberg et al 2004 and Van der Hoek et 
al 2005). A detailed summary of available preclinical data is provided in the [Investigator’s 
Brochure].
Table 1-1
Binding profiles for octreotide and pasireotide at hsst1-5 (IC50, mol/L)
Compound
sst1
sst2
sst3
sst4
sst5
Octreotide acetate (SMS995)
2.8x10-7
3.8x10-10
7.1x10-9
>10-6
6.3x10-9
Pasireotide (SOM230)
9.3x10-9
1.0x10-9
1.5x10-9
>10-6
1.6x10-10
Ratio of IC50:octreotide 
acetate/pasireotide 
(SMS995/SOM230)
30
0.4
5
--
39
1.2.1.1
Clinical experience
1.2.1.1.1 Pasireotide s.c.
The pasireotide s.c. formulation has been evaluated in a total of 19 studies: 11 studies with 
healthy volunteers, 1 study in patients with varying degrees of hepatic dysfunction, 3 studies 
with acromegalic patients, 1 study in patients with metastatic carcinoid tumors, and 3 studies 
in patients with Cushing’s disease. A detailed summary of the clinical data (including safety 
and PK) is provided in the [Investigator’s Brochure].


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Pasireotide s.c. has demonstrated linear and time-independent pharmacokinetics (PK) in 
healthy volunteers and patient populations following single- and multiple-dose regiments. The 
Tmax was observed to occur within 15-30 minutes. The PK exposures to pasireotide in 
acromegaly patients were comparable to healthy volunteers. However, the PK exposures to 
pasireotide in carcinoid syndrome patients and Cushing’s disease patients were approximately 
2- to 3-fold and 1.4-fold higher relative to healthy volunteers, respectively. The therapeutic 
doses for Cushing’s disease are 600 µg b.i.d. and 900 µg b.i.d. observed from phase II and III 
studies. [CSOM230B2201, CSOM230B2202, CSOM230B2208, CSOM230B2305]. More 
detailed description of PK results can be found in the [Investigator’s Brochure].
The efficacy of pasireotide s.c. in Cushing’s disease is based mainly on the pivotal phase III 
study CSOM230B2305. The primary objective was to assess the efficacy in terms of response 
to pasireotide 600 and 900 µg b.i.d. in patients with Cushing’s disease as measured by 
normalization of urine free cortisol (UFC) after 6 months of treatment and whose dose was 
not increased prior to Month 6.
At Month 6, a total of 12 (15%) of 82 patients in the 600 µg b.i.d. group and 21 (26%) of 
80 patients in the 900 µg b.i.d. group achieved mean UFC (mUFC) ≤ ULN. At Month 6, the 
proportion of patients who were partially controlled (i.e. had a ≥50% reduction in UFC but 
did not achieve mUFC ≤ ULN) was 18.3% and 12.5%, respectively, for the 600 and 900 µg 
b.i.d. groups. Robust reductions in mUFC occurred relatively quickly, within the first month, 
and were sustained over the course of Months 6 and 12 (Figure 1-1).
Figure 1-1
Mean (+/- SE) Urinary Free Cortisol (nmol/24h) at time points up to 
Month 12 by randomized dose group (Full analysis set - Study B2305)
nmol/24h
100
300
500
700
900
1100
1300
1500
Month
0
3
6
9
12
Pasireotide 900 ug bid
Pasireotide 600 ug bid


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In the pivotal Cushing’s disease study [CSOM230B2305], the subcutaneous formulation of 
pasireotide was well tolerated and the safety profile was generally comparable between the 
two dose groups. The majority of the AEs reported are consistent with the known adverse 
drug reactions of SSAs. Most patients (98.1%) experienced at least one AE up to data cut-off 
and most patients (95.7%) had at least one AE suspected by the investigator to be study drug 
related. By preferred term, the most frequent (> 15% of patients) AEs overall were diarrhea, 
nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue and diabetes mellitus. 
These gastrointestinal AEs (in general) were transient, and did not result in discontinuation of 
pasireotide. Patients with Cushing’s disease have a known predisposition for hyperglycemia, 
which was also observed in this study. Elevated glucose was the most frequently reported 
Grade 3 laboratory abnormality (23.2% of patients). Grade 1, Grade 2 and Grade 4 elevated 
glucose was observed in 26.0 %, 24.0 % and 0 % of patients respectively. More detailed 
safety data can be found in the [Investigator’s Brochure].
1.2.1.1.2 Pasireotide LAR
The pasireotide LAR has been evaluated in a total of 11 studies: 4 studies in healthy 
volunteers, 4 studies in both patients with acromegaly and patients with carcinoid disease, 1 
study in acromegaly patients and 2 studies in patients with metastatic carcinoid tumors. A 
detailed summary of the clinical data (including safety and PK) is provided in the 
[Investigator’s Brochure].
Pasireotide LAR demonstrated favorable PK profile for extended release in healthy volunteers 
and patients. PK steady state was achieved following 3 monthly (q28d) intra-muscular (i.m.) 
injections of pasireotide LAR in a study with both acromegaly and carcinoid patients. PK 
exposures of trough concentrations were approximately dose-proportional. CL/F of the LAR 
formulation was comparable to CL/F of the s.c. formulation (4.3-9.0 L/h). T1/2 for the LAR 
formulation was approximately 16 days, suitable for monthly dosing. The relative 
bioavailability of the LAR formulation to the s.c. formulation was complete, ranging from 106% 
to 148%. PK exposures in acromegaly patients were comparable to those in healthy volunteers. 
PK exposures in carcinoid patients were 2-fold higher than in healthy volunteers.
The efficacy of pasireotide LAR in acromegaly patients is based on CSOM230C2305, the 
phase III study to assess the safety and efficacy of pasireotide LAR vs octreotide LAR in 
patients with active acromegaly. In this study, pasireotide LAR was shown to be significantly 
superior to octreotide LAR for the treatment of acromegaly in medically naïve patients in 
terms of biochemical control (GH < 2.5 μg/L and normalization of IGF-1 levels) (31.3% vs. 
19.2%; p-value 0.007), providing higher response rate in both de novo patients and in patients 
with prior pituitary surgery (25.7% vs. 17.3% in de novo patients; 39.4% vs. 21.8% in post -
surgical patients). Pasireotide LAR was as effective as octreotide LAR in reducing tumor 
volume, improving acromegaly symptoms and ring size, and quality of life 
[CSOM230C2305].
In the registration study, CSOM230C2305, most patients experienced at least one AE during 
the core phase of the study. The most frequent event in patients who received pasireotide LAR 
was diarrhea. By preferred term, AEs that were more frequent (at least 5% difference) in the 
pasireotide than the octreotide group were all related to glucose metabolism: hyperglycemia, 


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diabetes mellitus, blood glucose increased, and type 2 diabetes mellitus. Grade 1 elevated 
glucose as a lab abnormality was observed in 69.6%, Grade 2 in 16.6%, Grade 3 in 9.7% and 
Grade 4 in 0.6% of patients in the pasireotide group in the study [CSOM230C2305].
2
Rationale
2.1
Study rationale and purpose
Hyperglycemia was a frequently observed adverse event in the pasireotide clinical studies. 
This study is a post-approval commitment to health authorities to evaluate the effect of 
incretin based anti-diabetic agents compared to insulin in patients with Cushing’s disease 
treated with pasireotide s.c. or with acromegaly treated with pasireotide LAR. Acromegaly 
patients are included given that the issue of pasireotide-induced hyperglycemia is not limited 
to Cushing's disease patients. The purpose of this trial is to investigate the optimal 
management of pasireotide-induced hyperglycemia in patients with Cushing’s disease or 
acromegaly.
Mechanistic data in healthy volunteers (HVs) indicate that the hyperglycemia associated with 
pasireotide is due to decreases in insulin secretion (with relatively small inhibition of 
glucagon) and decreases in incretin hormone GLP-1 and GIP secretion [CSOM230B2216].
A follow-up study [CSOM230B2124] in HVs corroborate that the underlying mechanisms of 
hyperglycemia following pasireotide s.c. treatment in humans are mainly due to decreased 
insulin secretion and reduced GLP-1 and GIP incretin secretion with no changes in hepatic or 
peripheral insulin sensitivity. In this study pasireotide 600 µg b.i.d. was either administered 
alone or with one of 4 different classes of antihyperglycemic drugs (biguanide [metformin], 
insulin secretagogue [nateglinide], DPP-4 inhibitor [vildagliptin], and GLP-1 analog 
[liraglutide]) for 7 days. On Day 7, plasma glucose AUC post-OGTT increased with 
pasireotide alone. This effect was reduced by 13%, 29%, 45% and 72% with co-
administration of metformin, nateglinide, vildagliptin and liraglutide, respectively.
Similarly, compared with pasireotide alone, insulin levels were increased by a mean of 71% 
and 34% when pasireotide was co-administered with vildagliptin and liraglutide, respectively; 
only minimal increases were seen after co-administration with metformin (6%) and 
nateglinide (3%).
These results suggest that incretin based therapies (i.e. GLP-1 analogs and DPP-4 inhibitors) 
would be most useful in the management of pasireotide-induced hyperglycemia. In view of 
the pre-existing insulin resistance in patients with Cushing’s disease, combination therapy 
with a biguanide (e.g. metformin) and an incretin enhancer may also be appropriate to treat 
pasireotide-induced hyperglycemia [CSOM230B2124].
However, the optimal management of pasireotide-induced hyperglycemia in patients is not 
known.
This study is designed to provide guidance on the optimal treatment algorithm with specific 
focus on incretin based therapy [i.e., sitagliptin (first DPP-4 inhibitor approved, available in 
US and EU) followed by liraglutide (long acting GLP-1 receptor agonist available in EU and 
US)] vs. insulin. In patients who are anti-diabetic treatment naïve, initiation of anti-diabetic 


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treatment will be based on a confirmed diagnosis of diabetes. The definition of diabetes will 
be in accordance with the American Diabetes Association (ADA) guidelines: FPG ≥ 
126 mg/dL on two occasions or HbA1c ≥ 6.5% or a random plasma glucose ≥ 200 mg/dL 
with classic symptoms of hyperglycemia (polydipsia, polyphagia and polyuria) ( ADA 2013). 
Consistent with ADA and EASD (European Association for the Study of Diabetes) treatment 
guidelines, metformin will be used as first line therapy. If additional glycemic control is 
needed, patients will be randomized to the incretin based therapy (sitagliptin followed by 
liraglutide) or insulin. Patients not adequately controlled by the incretin based treatment will 
receive rescue therapy with insulin.
The study aims to demonstrate that pasireotide-induced hyperglycemia can be effectively and 
safely managed in majority of patients, including those with diabetes at start of pasireotide 
treatment.
2.2
Rationale for the study design
This study is designed to evaluate the safety and efficacy of intensive hyperglycemia 
management in patients treated with pasireotide. Patients will be evaluated at baseline and 
throughout the study by a diabetologist or endocrinologist. The purpose of intensive glucose 
control is for the patient to reach the glycemic levels recommended by the ADA’s standard of 
care (Nathan et al 2006, ADA 2013). These glycemic goals are: fasting plasma glucose (FPG) 
70 to 130 mg/dL, post-prandial glucose (PPG) < 180 mg/dL and HbA1c < 7%. The ADA 
standard of care for glycemic goals are in accordance with the EASD standards of care for 
glycemic goals. In accordance with the ADA-EASD treatment guidelines, metformin will be 
used as first line therapy in this study. Patients needing additional glycemic control wil l be 
randomized to the incretin based therapy (sitagliptin followed by liraglutide) or insulin arms. 
The rationale for using incretin based therapy in this study is based on data from a HV study 
that suggests that it would be useful in the management of pasireotide-induced hyperglycemia 
[CSOM230B2124]. The primary efficacy variable in this study [CSOM230B2219] is the 
change in HbA1c from randomization to approximately 16 weeks post-randomization in the 
incretin based therapy arm and the insulin arm. Study baseline for other statistical analyses 
will be at the initiation of pasireotide in the study.
2.3
Rationale for dose and regimen selection
Pasireotide s.c.
The doses used in this study are in line with the approved label in countries where pasireotide 
s.c is currently marketed. Patients with Cushing’s disease in this study will start with a 
pasireotide initial dose of 600 μg b.i.d by s.c. injection. Eight weeks (2 months) after the start 
of pasireotide s.c., patients should be evaluated for clinical benefit. After 8 weeks, Cushing’s 
patients who experience a significant reduction in UFC levels should continue to receive 
pasireotide for as long as benefit is derived. Dose up-titrations to 900 µg s.c. b.i.d after 8 
weeks of study treatment will be allowed based on response to treatment, as long as the 
600 μg b.i.d dose is well tolerated by the patient and glucose is controlled as recommended by 
ADA-EASD guidelines. Dose reduction (decrements of 300 μg b.i.d recommended) or 
discontinuation from the study may occur at any time for safety reasons if this is in the best 


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interest of the patient. Dose increase and dose reduction is to be based on investigator 
assessment of risk and benefit for the patient.
Pasireotide LAR
The pasireotide dose for acromegaly patients is based on the study [CSOM230C2305]. It was 
a multi-center, randomized, blinded study to assess the safety and efficacy of pasireotide LAR 
vs. octreotide LAR in patients with active acromegaly. The results of the study showed that 
40 mg/28 days pasireotide LAR is superior to 20 mg/28 days octreotide LAR in achieving 
biochemical control in acromegaly, suppression of GH levels to < 2.5 μg/L and normalization 
of IGF-1 [CSOM230C2305]. Patients with acromegaly in this study will start with 
40 mg/28days pasireotide LAR.
Based on data from the CSOM230C2305 study, patients should be evaluated for clinical 
benefit 3 months (84 days) after the start of pasireotide LAR i.m. therapy. A dose increase to 
60 mg/28days will be permitted after 12-weeks of pasireotide LAR treatment if adequate 
levels of GH and IGF-1 are not observed with the 40 mg dose (no reduction of mean GH level 
to < 2.5 µg/L and no normalization of IGF-1 to within normal limits (age and sex related)).
Management of suspected adverse reactions may require temporary dose reduction of 
pasireotide LAR. Dose reduction by decrements of 20 mg/28 days is recommended. Dose 
increase and dose reduction is to be based on investigator assessment of risk and benefit for 
the patient.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate the effect of treatment with incretin based therapy vs. 
insulin on the 16-week glycemic control in patients with Cushing’s 
disease or acromegaly who develop or worsen hyperglycemia on 
pasireotide, and cannot be controlled by metformin alone or other 
background anti-diabetic treatments
Change in HbA1c from randomization to approximately 16 weeks in 
the incretin based therapy arm and insulin arm
Secondary
Refer to Section 10.5
To evaluate the overall effect of anti-diabetic intervention on glycemic 
control in patients with Cushing’s disease or acromegaly 
Change in HbA1c and FPG from baseline to Core EOP (End of 
Phase) in patients who received pasireotide by treatment group
To evaluate the sustainability of glycemic control in the incretin based 
therapy arm and the insulin arm in Cushing’s disease patients treated 
with pasireotide s.c. and acromegaly patients treated with pasireotide 
LAR
Proportion of patients with ≤ 0.3% HbA1c increase from baseline to 
Core EOP per randomized arm
Change in HbA1c and FPG from randomization over time and to 
Core EOP (only for FPG) per randomized arm
Proportion of patients who required anti-diabetic rescue therapy with 
insulin per randomized arm
To evaluate the safety and tolerability of pasireotide in combination with
anti-diabetic treatments 
Toxicity will be assessed using NCI-CTC criteria version 4.03 for 
adverse events.
Incidence of hypoglycemia events (# of episodes, # of patients)
Clinical chemistry, hematology, urinalysis assessments
ECGs
Special safety assessments: Thyroid function tests, pancreatic safety 
tests (for anti-diabetic treatments) and gallbladder examinations


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4
Study design
4.1
Description of core phase
This is a Phase IV, multicenter, randomized open-label study to investigate the optimal 
management of pasireotide-induced hyperglycemia in patients with Cushing’s disease or 
acromegaly. Eligible patients will start pasireotide s.c. for Cushing’s disease and pasireotide 
LAR for acromegaly (See Section 6.1). If they experience increases in their fasting blood 
glucose as described below, they will start anti-diabetic treatment using metformin. If they 
continue to experience increases in their fasting blood glucose within the first 16 weeks based 
on pre-defined glycemic criteria, they will be randomized in a 1:1 ratio to receive treatment 
with incretin based therapy (sitagliptin followed by liraglutide) or insulin for approximately 
16 weeks as described below. The effect on glycemic control will be evaluated up to 32 weeks.
To ensure a similar distribution of patients expected to develop mild/moderate/severe 
hyperglycemia in both treatment arms, randomization will be stratified according to the levels 
of the following two factors:

Disease:
a. Cushing’s disease
b. Acromegaly

Glycemic status at baseline:
a. HbA1c < 7 %
b. HbA1c ≥ 7%
Patients who are not randomized by Week 16 (of pre-randomized period) will have their Core 
End of Phase (EOP) visit on Week 16. Patients who are randomized will have their Core EOP 
visit 16 weeks post-randomization.
Patients who continue to receive clinical benefit will have the option to continue on the 
extension phase if pasireotide is not commercially available or a local access program is not 
available and they meet the criteria described in Section 4.2.
The total duration of the core study treatment will be a maximum of 32 weeks (Up to 16 
weeks of pre-randomized period + 16 weeks of randomized period). Patients who are not 
continuing into the extension phase, the last injection of pasireotide s.c. on study will be 1 day 
prior to Core EOP visit and the last injection of pasireotide LAR on study will be 4 weeks 
prior to Core EOP visit.
Patients in Denmark on pasireotide LAR will participate in the overall study (core phase + 
extension phase) for up to a maximum of 1 year.
All patients who will not continue pasireotide treatment or patients who will transition to 
commercial drug will  have the safety follow-up visit after the Core (or Extension) End of 
Phase (EOP) visit, which will be 28 days after the last pasireotide s.c. dose or 84 days after 
the last pasireotide LAR dose.


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4.1.1
Pre-randomized period
All patients will measure their fasting blood glucose with a glucometer at home daily after 
study enrollment. At each scheduled visit, the study investigator will review the patient’s 
fasting self-monitored blood glucose (SMBG) values. After their baseline visit, patients will 
also be instructed to call the site on a weekly basis between visits during the core phase of the 
study for the investigator to review their SMBG values. Patient will return to the site as soon 
as possible if the SMBG is elevated and meets the criteria below.
Anti-diabetic treatment naïve patients at study entry
1. If the average fasting SMBG is ≥126 mg/dL on 3 consecutive days, the patient needs to 
return to the site as soon as possible for FPG to confirm diabetes.
2. If the patient meets the criteria for diabetes (FPG ≥ 126 mg/dL on two occasions or 
HbA1c ≥ 6.5% or a random plasma glucose ≥ 200 mg/dL with classic symptoms of 
hyperglycemia [polydipsia, polyphagia and polyuria]) then the patient should be started on 
metformin 1000 mg/day (twice daily). In patients that cannot tolerate metformin or that 
have a contraindication to metformin, the patient should be randomized immediately to 
either the incretin based therapy arm or insulin arm.
3. Metformin dose is to be increased incrementally according to the approved package insert 
at the discretion of study investigator and patient tolerability.
4. If the average fasting SMBG is ≥126 mg/dL on 3 consecutive days at maximum tolerated 
and stable dose of metformin for not more than 8 weeks, patients will be randomized to 
either the incretin based therapy arm or insulin arm. Patients will continue metformin at 
the same dose as at the time of randomization if they continue to tolerate it. The dose of 
metformin can be reduced at any time based on investigator’s judgment for hypoglycemia. 
Dose of metformin should not be increased after randomization.
Patients on metformin at study entry

AND treated with maximum tolerated and stable dose of metformin: Patients will continue 
metformin as long as they tolerate it and they have not met the elevated SMBG criteria. If 
the average fasting SMBG is ≥126 mg/dL on 3 consecutive days during pre-randomized 
period, the patient needs to return to the site as soon as possible to be randomized.

AND treated with sub-maximal tolerated dose of metformin: Patients will continue 
metformin as long as they tolerate it and have not met the elevated SMBG criteria. If the 
average fasting SMBG is ≥126 mg/dL on 3 consecutive days, the patients’ metformin 
dose needs to be titrated weekly to a maximum tolerated dose (per local approved package 
insert). Patients with average fasting SMBG ≥ 126 mg/dL on 3 consecutive days on 
maximal tolerated and stable dose of metformin for not more than 8 weeks should be 
randomized immediately.


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Patients on other allowed oral anti-diabetic agents (OAD) at study entry

AND can tolerate metformin and have no contraindication to metformin should start on 
metformin after study enrollment. The starting dose of metformin will be based on 
investigator’s judgment. Metformin dose is to be increased incrementally according to the 
approved package insert at the discretion of study investigator and patient tolerability. 
Patients may continue their OADs at the discretion of the study investigator. If the average 
fasting SMBG is ≥126 mg/dL on 3 consecutive days on maximal tolerated and stable dose 
of metformin for not more than 8 weeks, the patient needs to be randomized immediately.

AND cannot tolerate metformin or have a contraindication to metformin can continue on 
their OADs. Prior to meeting the elevated SMBG criteria patients should continue their 
OADs as long as they tolerate it. Dose modifications can be made according to approved 
package insert at the discretion of study investigator and patient tolerability. If the average 
fasting SMBG is ≥126 mg/dL on 3 consecutive days during the pre-randomized period, 
the patient needs to be randomized immediately. Dose of the OAD should not be increased 
after randomization. The dose of OAD may be decreased at any time based on investigator 
judgment for hypoglycemia.
Patients on insulin at study entry

These patients are not eligible for randomization. They will be followed in a 16-week 
observational arm to evaluate the effect of pasireotide on blood glucose levels. Patients 
being treated with a stable dose of insulin (basal with or without prandial insulin) may 
continue their current dose of insulin (basal with or without prandial insulin). The insulin 
dose is to be adjusted based on the investigator’s discretion to achieve a mean fasting 
SMBG <126 mg/dl and to prevent hypoglycemia. The dose of insulin may be down-
titrated at any point at the discretion of the investigator to prevent hypoglycemia. These 
patients will end the core phase of the study at the end of the 16-week pre-randomized 
period.
All patients will be instructed to call the site immediately if results of any single occurrence 
self-monitored fasting blood glucose are > 250 mg/dL for appropriate management of 
hyperglycemia. Please see Section 6.2.3.1.1.
If at any time during the study the patient experiences hypoglycemia, anti-diabetic treatment 
is to be modified at the discretion of the study investigator. Patients are to be educated on the 
symptoms and management of hypoglycemia. Please see Section 6.2.3.1.2.
If at any time during the pre-randomization period, the patient develops renal failure or renal 
dysfunction (creatinine clearance < 60 mL/min or as defined in the local label), metformin 
should be discontinued and patient can be randomized. Patient can continue on other allowed 
OADs based upon investigator judgment and in compliance with local prescribing guidelines.
Figure 4-1 shows the general study treatment and anti-diabetic treatment schema.


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Figure 4-1
Treatment Schema
4.1.2
Randomized period
4.1.2.1
Incretin based therapy arm
Patients randomized to the incretin based arm will start with sitagliptin and will continue 
metformin and/or other prior anti-diabetic agents at the discretion of the investigator and at 
the same dose if they continue to tolerate it. The dose of sitagliptin will be adjusted based on 
patients renal function status as measured by creatinine clearance consistent with the approved 
package insert. See Section 6.2.2.1 for details. The dose of metformin or other prior anti-
diabetic therapy should not be increased after randomization. The dose of metformin or other
prior anti-diabetic agent may be decreased at any time based on the investigator’s judgment 
for hypoglycemia.
If the average of fasting SMBG values of 3 consecutive days is ≥126 mg/dL while on stable 
dose of sitagliptin for at least 6 weeks, sitagliptin will be stopped by the investigator and 
patients will be switched to liraglutide. Patients may be switched to liraglutide earlier if the 
average fasting SMBG value on 3 consecutive days is >160 mg/dL. In this event, patients will 
be instructed to return to the site for an FPG determined by central lab. If FPG value > 
160 mg/dL, then the patient will be switched to liraglutide prior to the 6 week dose 
stabilization period.


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After completion of at least 6 week dose stabilization period with liraglutide, patients with 
fasting SMBG values on 3 consecutive days ≥ 126 mg/dL will be instructed to return to the 
site for an HbA1c determined by central lab. If HbA1C value >7%, then the patient will be 
eligible for rescue therapy with addition of insulin. Please see Section 6.1.2 for details on 
rescue therapy.
Patients may be started on rescue therapy with insulin before the 6-week dose stabilization 
period with liraglutide if the average fasting SMBG value on 3 consecutive days
is >160 mg/dL. In this event, patients will be instructed to return to the site for an FPG 
determined by central lab. If the FPG >160 mg/dL, then the patient will be started on rescue 
therapy.
4.1.2.2
Insulin arm
Patients randomized to the insulin arm may start with once daily dose of basal insulin, either 
insulin NPH (insulin isophane) or insulin glargine or insulin detemir administered at bedtime. 
The suggested starting dose of insulin is 10 IU/day administered at bedtime with weekly 
titration to achieve mean 3-consecutive daily SMBG <126 mg/dL. Suggested weekly insulin 
titration schedule may be as described in Table 4-1.
Table 4-1
Weekly insulin titration schedule
Mean of self-monitored FPG values from preceding 3 days
Increase of insulin dosage (IU/day)
≥ 180 mg/dL (10.0 mmol/L)
6
≥ 140 – <180 mg/dL (7.8 – 10.0 mmol/L)
4
≥ 126 – <140 mg/dL (6.7 – 7.8 mmol/L)
2
The dose of basal insulin may be down-titrated at any point during the randomization period 
at the discretion of the investigator to prevent hypoglycemia. Addition or treatment with 
prandial insulin (such as insulin regular or lispro or aspart or glulisine) may be ins tituted at 
any time based on investigator discretion to achieve optimal glucose control.
Patients will continue metformin at the same dose as at the time of randomization if they 
continue to tolerate it. The dose of metformin can be reduced at any time bas ed on 
investigator judgment for hypoglycemia. Dose of metformin should not be increased after 
randomization.
Patients receiving insulin at baseline will not be randomized (observational arm) and treated 
as described in Section 4.1.3.
4.1.3
Non-randomized treatment groups (Observational arms)
Patients who do not develop pasireotide-induced hyperglycemia or worsen their 
hyperglycemia as specified in Section 4.1.1 within 16 weeks of study entry or they enter the 
study on insulin will be categorized to one of the following observational groups in the final 
analysis:

No anti-diabetic treatment group

Oral anti-diabetic (OAD) group

Baseline insulin group


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For additional details, please see Section 10.3.
These patients will end the core phase of the study at the end of the 16 -week pre-randomized 
period. Patients who continue to receive clinical benefit will have the option to continue on 
the extension phase if pasireotide is not commercially available or a local access program is 
not available and they meet the criteria described in Section 4.2.
4.2
Extension phase
The purpose of the extension phase is to provide pasireotide to patients if it is not 
commercially available in their country or a local access program is not available to obtain the 
drug. However, no anti-diabetic medications will be provided by the sponsor during the 
extension phase unless required by local regulations. Use of anti-diabetic medications during 
the extension phase will be at the discretion of the study investigator and based on patient’s 
tolerability.
Both non-randomized patients who reached Visit 6 (Pre-randomized-W12) - end of pre-
randomization phase and randomized patients who reached Visit 14 (Randomized-W14) - end 
of randomization phase who have completed their Core EOP visit will be allowed to continue 
on to the extension phase of the study if they fulfill all of the following:

the investigator believes the patient is getting significant clinical benefit from treatment 
with pasireotide

for female patients of child bearing potential: the patient agrees to continue to use 
contraception detailed in Section 5.3 throughout the course of the extension phase, and for 
1 month following last dose of s.c. or 3 months following last dose of LAR formulation. If 
oral contraception has been practiced throughout the trial, the patient must continue the 
oral contraceptive throughout the course of the extension phase, and for 1 month 
following last dose of s.c. or 3 months following last dose of LAR formulation.

for male patients: the patient agrees to continue to use condoms throughout the course of 
the extension phase, and for 1 month following last dose of s.c. or 3 months following last 
dose of LAR formulation.
Patients who withdraw consent from the core phase (pre-randomization or randomization 
phase) cannot participate in the extension phase.
Patients who discontinue prematurely from the core phase cannot participate in the extension 
phase.
The patients can continue on the extension phase until the last patient randomized in the core 
study completes treatment for 16 weeks post-randomization, or when pasireotide is available 
commercially in their country or when a local access program is available in their country. 
Patients in Denmark on pasireotide LAR will participate in the overall study (core phase + 
extension phase) for up to a maximum of 1 year. At the end of the extension phase, all
patients will complete their Extension EOP visit. If the patients continue to receive clinical 
benefit as assessed by the investigator, they will have the opportunity to receive pasireotide 
either commercially if available or via a roll-over study or a local access program if available 
in order to continue their treatment with pasireotide.


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For all patients, the EOP visit (778) will be performed. However, for patients transitioning to 
a roll-over study or local access program, the Safety follow-up visit (779) 28 days after the 
last pasireotide s.c. dose or 84 days after the last pasireotide LAR dose is not required.
Patients will continue to be monitored for safety while participating in either the roll-over 
study or local access program.
Refer to the eCRF Completion Guidelines for further instructions.
4.3
Definition of end of the study
Completion of the study as a whole will occur when last patient last visit is completed or 
when all patients have completed their end of study (EOS)/ follow-up visit as per Table 7-1
(core phase) and Table 7-2 (extension phase) or have discontinued early.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.3.1 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The eligible patient population will consist of adult Cushing’s disease and acromegaly 
patients. The study targets to have 68 randomized evaluable patients. The total number of 
enrolled patients required to reach the targeted sample size will be based on the estimate of 
the actual randomization rate which will be monitored regularly.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Cushing’s disease population
1. Adult patients (age ≥ 18y) with confirmed diagnosis of Cushing’s disease 
(persistent/recurrent or de Novo patients who are not considered candidates for pituitary 
surgery).
2. Patients currently treated at screening visit with pasireotide s.c. should have an elevated 
FPG > ULN or a diagnosis of diabetes (FPG ≥ 126 mg/dL on two occasions or HbA1c ≥ 
6.5% or a random plasma glucose ≥ 200 mg/dL with classic symptoms of hyperglycemia 
(polydipsia, polyphagia and polyuria)) during screening period.


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3. Previous exposure to pasireotide is allowed. In case pasireotide s.c. was discontinued 
before screening a wash-out period of at least 1 week before study entry (start of 
pasireotide) has to be followed.
Acromegaly population
4. Adult patients (age ≥ 18 y) with confirmed diagnosis of acromegaly. De Novo patients 
(with no prior pituitary surgery) can be included if they are not considered candidates for 
pituitary surgery or have refused surgery.
5. Patients currently treated at screening visit with pasireotide LAR should have elevated 
FPG > ULN or a diagnosis of diabetes (FPG ≥ 126 mg/dL on two occasions or HbA1c ≥ 
6.5% or a random plasma glucose ≥ 200 mg/dL with classic symptoms of hyperglycemia 
(polydipsia, polyphagia and polyuria)) during screening period.
6. Previous exposure to pasireotide is allowed. In case pasireotide LAR was discontinued 
before screening a wash-out period of at least 3 months before study entry (start of 
pasireotide) has to be followed.
Inclusion criteria for both Cushing’s disease and acromegaly population
7. Patients with either Type 1 or Type 2 diabetes currently being treated with insulin (basal 
insulin with or without prandial insulin) are eligible for study entry. However, these 
patients will be treated in the non-randomized observational arm.
8. Patients with Type 2 diabetes being treated with anti-diabetic agents (including metformin) 
other than incretin based therapies are eligible for study entry and randomization.
9. Written informed consent must be obtained prior to any study related procedure.
10. If patients were treated with insulin only for an acute medical need and insulin was 
discontinued after that, then a wash-out period of at least 48 hours before study entry (start 
of pasireotide) has to be followed. These patients will be eligible for randomization.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
Cushing’s disease population
1. Patients who are receiving other medical therapies for Cushing’s disease. All other 
medical therapies for Cushing’s disease have to be discontinued at least 5 times the half-
life of the respective preparation before study entry (start of pasireotide).
Acromegaly population
2. Patients who are receiving other medical therapies for acromegaly and not compliant with 
the following rules:

other medical therapies for acromegaly have to be discontinued at least 5 times the 
elimination half-life (t1/2) of the respective preparation before study entry (start of 
pasireotide);

other SSAs (octreotide, lanreotide) have to be discontinued at least 5 times the 
elimination half-life of the respective formulation before study entry (8 weeks 
washout for octreotide LAR and lanreotide autogel);


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
Dopamine agonists (bromocriptine, cabergoline) or pegvisomant (INN) will only be 
accepted provided the dose regimen is stable from at least 4 weeks before study entry 
and throughout the study.
Exclusion criteria for both Cushing’s disease and acromegaly population
3. Patients who require surgical intervention
4. Patients receiving DPP-4 inhibitors or GLP-1 receptor agonists within 4 weeks prior to 
study entry
5. HbA1c >10% at screening
6. Patients with life-threatening diabetic ketoacidosis or diabetic hyperosmolar coma
7. Any major surgery/surgical therapy for any cause within 4 weeks of signing the informed 
consent (patients must recover from the surgery and be in good clinical condition before 
entering the study).
8. Participation in any clinical protocol and/or receiving an investigational drug within 4 
weeks prior to dosing or longer (a minimal wash out of 5 t1/2 of the investigational drug is 
mandatory and local regulation should be followed).
9. Known hypersensitivity to somatostatin analogues.
10. Patients who are hypothyroid and have clinical symptoms of hypothyroidism despite
adequate replacement therapy
11. Life-threatening autoimmune disorders
12. History of liver disease, such as severe hepatic impairment (Child-Pugh C, cirrhosis, or 
chronic active hepatitis B or C [presence of hepatitis B surface antigen (HbsAg) or 
hepatitis C antibody (anti-HCV)]).
13. Cholelithiasis acute or chronic pancreatitis.
14. Cardiac or repolarization abnormality, including any of the following:

Screening QTcF>450 ms for males and >460 ms for females (See Appendix 2)

History of syncope, family history of idiopathic sudden death, family history of 
congenital long QT syndrome or diagnosis of congenital long QT syndrome.

Sustained or clinically significant cardiac arrhythmias.

Risk factors for Torsade de Pointes such as hypokalemia, hypocalcemia and 
hypomagnesemia (unless corrected with adequate ongoing supplementation prior to 
and during study), cardiac failure, clinically significant/symptomatic bradycardia, or 
AV block > I.

Concomitant disease(s) that could prolong QT interval such as autonomic neuropathy 
(caused by diabetes, or Parkinson's disease), HIV, cirrhosis.

Concomitant medication(s) known to prolong the QT interval (see Appendix 1).

Any of the following within 6 months prior to starting study treatment: myocardial 
infarction (MI), angina pectoris, Coronary Artery Bypass Graft (CABG), 
Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA)
15. History of HIV infection, including a positive HIV test result (Elisa and Western blot). An 
HIV test is not required; however, previous medical history should be reviewed.
16. Screening ALT or AST > 2x ULN


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17. Screening total bilirubin > 1.5x ULN
18. Renal dysfunction as defined by local metformin label (E.g., As per SmPC, creatinine 
clearance <60 mL/min; As per US package insert, serum creatinine >1.5 mg/dL 
(males), >1.4 mg/dL (females)) at screening.
19. Inadequate bone marrow function:

WBC < 2.5 x 109/L

Absolute Neutrophil Count (ANC) < 1.5 x 109/L

Platelets < 100 x 109/L

Hemoglobin < 9 g/dL
20. Abnormal coagulation function (PT and PTT elevated by 30% above normal limits, or 
INR ≥1.3 except for patients on anti-coagulant therapy. Patients on anticoagulant therapy 
must be stable for at least 1 month prior to study entry).
21. Any known contraindication to DPP-4 inhibitor, GLP-1 receptor agonists or insulin,
including but not limited to:

Known family history of medullary thyroid cancer (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN2)
22. History of, or current alcohol misuse/abuse within the past 12 months.
23. Potentially unreliable or vulnerable individuals (e.g. person kept in detention) and those 
judged by the investigator to be unsuitable for the study are excluded from enrollment in 
the study.
24. 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.
25. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 1 month following last dose of s.c. or 3 months following last dose 
of LAR formulation. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. 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 patients on the 
study the vasectomized male partner should be the sole partner for that patient.


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
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.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
26. Sexually active males unless they use a condom during intercourse while taking drug and 
for 1 month following last dose of s.c. or 3 months following last dose of LAR 
formulation and should not father a child in this period. A condom is required to be used 
also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
27. Any current or prior medical condition (including clinically significant abnormal 
laboratory values) that can interfere with the conduct of the study or the evaluation of its 
results in the opinion of the investigator or the sponsor’s medical monitor.
6
Treatment
6.1
Study treatment
Pasireotide

Cushing’s disease: Pasireotide (SOM230) s.c. injection: 300 - 900 µg b.i.d.; Starting dose 
= 600 µg b.i.d.

Acromegaly: Pasireotide (SOM230) i.m. LAR: 20 – 60 mg every 28 days; Starting dose = 
40 mg q28d
Anti-diabetic treatment

Metformin at individual doses starting from 1000 mg/day to maximum dose according to 
the approved package insert and depending on the patient tolerability

Sitagliptin 50 or 100 mg administered orally once a day

Liraglutide administered s.c. once a day according to package insert

Insulin administered s.c. according to package insert


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6.1.1
Dosing regimen
Patients with Cushing’s disease will receive pasireotide 600µg s.c. b.i.d. at study entry. 
Patients with acromegaly will receive pasireotide LAR 40 mg i.m. once/28days at study entry.
Table 6-1
Dose and treatment schedule
Treatment
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Study drug
Pasireotide s.c.
Subcutaneous injection
300 or 600 or 900 µg
Twice daily
Pasireotide LAR
Intramuscular injection
20 or 40 or 60 mg
Once/28 days
Anti-diabetic treatment
Metformin
Oral
As per local package 
insert
Twice daily
Sitagliptin
Oral
50 or 100 mg based upon 
renal function
Once daily
Liraglutide
Subcutaneous injection
As per local package 
insert
Once daily
Insulin
Subcutaneous injection
investigator discretion 
As per package insert
6.1.2
Rescue Therapy
For incretin-based therapy arm, rescue therapy will be instituted if the average of fasting 
SMBG values of 3 consecutive days is >160 mg/dL and FPG > 160 mg/dL by central lab 
during the randomized treatment period before dose stabilization for liraglutide is achieved. In 
addition, rescue therapy will be instituted if the average of fasting SMBG values of 3 
consecutive days is ≥126 mg/dL and HbA1C > 7% by central lab after at least 6-week dose 
stabilization period with liraglutide is achieved. Patients receiving liraglutide in combination 
with or without metformin, with or without other OADs will be started on insulin. The dose of 
insulin and the type of insulin used (e.g. basal with or without prandial insulin) will be left to 
the discretion of the investigator. In addition, the decision to continue baseline therapy with 
either metformin and/or liraglutide will also be left to the investigator’s discretion and the 
local prescribing guidelines.
6.1.3
Treatment duration
Pasireotide treatment duration in the core phase of the study will be:

Up to 32 weeks for randomized patients (≤16 weeks pre-randomized period + 16 weeks 
post-randomization) dependent on when randomization occurs.

16 weeks for patients who do not randomize (observational arms).
Both the above group of patients will have the option to continue treatment on the extension 
phase of the study until the last patient randomized completes 16 weeks of treatment post-
randomization, or when pasireotide is available commercially in their country or when a local 
access program is available.
Patients who will not continue pasireotide treatment (i.e. discontinued study treatment early in 
the core or extension phase, or complete core phase and do not move into the extension phase) 


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or patients who complete the extension phase will have a safety follow-up visit (779) 28 days 
after the last pasireotide s.c. dose or 84 days after the last pasireotide LAR dose.
Patients who are in the extension phase, who continue to receive clinical benefit as assessed 
by the investigator, will have the opportunity to receive pasireotide either commercially if 
available or via a roll-over study or local access program if available in order to continue their 
treatment with pasireotide.
For all patients, the EOP visit (778) will be performed. This includes patients who transition 
to commercial drug, the Safety follow-up visit (779) 28 days after the last pasireotide s.c. dose 
or 84 days after the last pasireotide LAR dose is required.
However, for patients who transition to a roll- over study or local access program, the Safety 
follow-up visit (779) 28 days after the last pasireotide s.c. dose or 84 days after the last 
pasireotide LAR dose is not required. Patients will continue to be monitored for safety while 
participating in either the roll-over study or local access program.
6.2
Dose modifications
6.2.1
Pasireotide dose modification
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following
guidelines need to be applied:
After 8 weeks, Cushing’s disease patients who experience a significant reduction in UFC 
levels as determined by site locally should continue to receive pasireotide at 600 µg s.c. b.i.d 
for as long as benefit is derived. A dose increase to 900 μg b.i.d after 8 weeks of treatment 
may be considered based on response to treatment, as long as the 600 μg b.i.d dose is well 
tolerated by the patient and glucose is controlled. Patients who have not responded to 
pasireotide after 8 weeks of treatment should be considered for discontinuation. At any time
during the study the pasireotide dose may be reduced to 300 µg b.i.d fo r safety or tolerability 
reasons. Dose may be increased to 600 or 900 µg b.i.d if tolerability issues have resolved per 
investigator’s discretion.
Dose up-titration of pasireotide LAR to 60 mg i.m. once/28 days after 12 weeks of treatment 
will be allowed in patients who do not achieve adequate levels of GH and IGF-1 (no reduction 
of mean GH level to <2.5 µg/L and no normalization of IGF-1 to within normal limits (age 
and sex related)) as determined locally. A dose reduction to 20 mg will be permitted in case of 
tolerability issues, but the patient may return to the 40 mg dose once tolerability issues are 
resolved.
Patients with an average fasting SMBG value of > 300 mg/dL for 3 consecutive days, who 
have been compliant with anti-diabetic medication and who do not have any co-morbidities 
influencing glucose metabolism, are to have a reduction of pasireotide dose. Dose reduction 
by decrements of 300 μg b.i.d for pasireotide s.c. and 20 mg/28days for pasireotide LAR is 
recommended. If the patients continue to have an average fasting SMBG values > 300 mg/dL 
for 3 consecutive days in spite of optimal anti-diabetic therapy, then pasireotide will be 
discontinued and a core EOP visit will be performed. The decision to discontinue is to be 
based on an assessment of risk and benefit by the investigator.


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Dose should also be modified for adverse events that are suspected to be pasireotide-related as 
described in Table 6-2.
Any dose change must be recorded on the respective Dosage Administration Record CRF.
Table 6-2
Dose modification criteria for suspected pasireotide-related adverse 
events
Adverse event
Action
CTCAE grade ≤ 2
No drug adjustments
CTCAE grade ≥ 3 and 
assessed as study drug 
related
Reduce pasireotide to the next dose level.
If the AE improves to grade ≤ 2 before the next administration, increase dose back 
to the prior dose. If the dose is increased and the AE recurs at a grade ≥ 3, the 
dose should be reduced again. The patient should stay on this lower dose and no 
further dose titrations are allowed.
If the AE does not improve to grade ≤ 2, the dose is to be reduced further. If the AE 
does not improve to grade ≤ 2 on the minimum study dose, the treatment should be 
stopped. The patient should be discontinued and followed up for safety.
For the management of hyperglycemia, QT prolongation, and LFT increases refer to specific instructions provided 
in Section 6.2.3.1, Section 6.2.3.2 and Section 6.2.3.3.
6.2.2
Dose modification for anti-diabetic medications
Doses for anti-diabetic medications (metformin, sitagliptin, liraglutide) should be modified as 
per local prescribing label. Any dose change must be recorded on the respective Dosage 
Administration Record CRF during the core phase.
6.2.2.1
Metformin dose modification
If at any time during the study, the patient develops renal failure or renal dysfunction 
(creatinine clearance < 60 mL/min or as defined in the local label), metformin should be 
discontinued. Patient can continue on other allowed OADs based upon investigator judgment
and in compliance with local prescribing guidelines. Patients in the pre-randomized period are 
eligible for randomization.
6.2.2.2
Sitagliptin dose modification
For patients with renal insufficiency sitagliptin dose should be modified as per local 
prescribing label.
Any dose change must be recorded on the respective Dosage Administration Record CRF
during the core phase.
6.2.3
Follow-up for toxicities
6.2.3.1
Glucose monitoring
All patients need to be educated on the signs and symptoms of hyperglycemia and 
hypoglycemia. Patients must monitor their fasting blood glucose with a glucometer at home, 
and the blood glucose values will be captured in a diary. They should present the collected 
data to their study investigator for evaluation and for appropriate management during the core 
phase of the study. After their baseline visit, patients need to be instructed to call the site on a 


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weekly basis between visits during the core phase of the study for the investigator to review 
their SMBG values.
6.2.3.1.1 Hyperglycemia
The following process needs to be followed if the SMBG value is found to be elevated:
If the average fasting SMBG value is ≥126 mg/dL on 3 consecutive days:
During pre-randomized period
a.
In anti-diabetic treatment naïve patients at study entry, patient need to be instructed to call 
the site to schedule a visit as soon as possible for parameters of glycemic control (FPG, 
HbA1C or random plasma glucose) at the central lab to confirm diabetes. If patients meet 
the criteria for diabetes, then anti-diabetic treatment should be initiated as soon as possible 
using metformin as described in Section 4.1.1.
b. Patients with the diagnosis of Type 2 diabetes entering the trial on the maximum tolerated 
dose of metformin OR metformin intolerant patients OR patients that have a 
contraindication for metformin OR patients being treated with other allowed OAD 
medications needs to be instructed to call the site to schedule a visit as soon as possible
and be randomized immediately.
c.
Patients with the diagnosis of Type 2 diabetes entering the trial on a sub-maximal dose of 
metformin need to have the dose of metformin titrated at weekly intervals to the maximal 
tolerated dose and follow the other steps as described in Section 4.1.1.
During randomized period
a.
Patients on a stable dose of sitagliptin (adjusted for renal function) for at least 6 weeks, 
should stop sitagliptin and switched to liraglutide.
b. Patients past their 6-week dose stabilization period with liraglutide need to be instructed to 
call the site to schedule a visit as soon as possible for an HbA1c. If HbA1c>7%, then they 
should be started on rescue therapy with insulin. Please see Section 6.1.2 for details on 
rescue therapy. If patients are not on a stable dose of liraglutide for at least 6 weeks, then 
liraglutide dose should be adjusted according to the approved package insert.
If the average fasting SMBG value is >160 mg/dL on 3 consecutive days:
During pre-randomized period
a.
In anti-diabetic treatment naïve patients at study entry, patients need to be instructed to 
call the site to schedule a visit as soon as possible for parameters of glycemic control 
(FPG, HbA1C or random plasma glucose) at the central lab to confirm diabetes. If patients 
meet the criteria for diabetes, then anti-diabetic treatment should be initiated using 
metformin as described in Section 4.1.1.
During randomized period
a.
Patients on sitagliptin during the 6-week dose stabilization period need to be instructed to 
call the site to schedule a visit as soon as possible for a FPG level at the central lab. If the 
FPG>160 mg/dL then patients should be switched to liraglutide.


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b. Patients on liraglutide (during or after the 6-week dose stabilization period) need to be 
instructed to call the site to schedule a visit as soon as possible for a FPG level at the 
central lab. If the FPG>160 mg/dL then patients should be started on rescue therapy with 
insulin. Please see Section 6.1.2 for details on rescue therapy.
If at any time the fasting SMBG is > 250 mg/dL:
a.
Patients need to be instructed to call the site immediately for appropriate management of 
hyperglycemia. If the patients have an average fasting SMBG > 300 mg/dL on 3 
consecutive days, they need to be instructed to return to the site as soon as possible for 
pasireotide dose reduction or study discontinuation (see Section 6.2.1).
6.2.3.1.2 Hypoglycemia
Hypoglycemia should be reported as an AE following the CTCAE version 4.03.
Patients who experience recurrent episodes of hypoglycemia in the absence of known 
precipitating factors may be eligible for dose reduction or adjustment in the dose of their anti-
hyperglycemic therapy based on the investigator's clinical judgment.
Patients should not be discontinued from any treatment phase based on single episodes of 
hypoglycemia or symptoms of hypoglycemia unless clinically indicated.
6.2.3.2
QT-prolongation
If at any visit QTcF > 500 ms is observed, triplicate ECGs, each 2-3 minutes apart, need to be 
collected approximately 1 hour after the initial ECG. The mean QTcF from the triplicate 
ECGs should be determined. If mean QTcF > 500 ms, study treatment should be interrupted 
until a cardiologist has re-evaluated the ECG (this can be done by the central cardiologist if 
the trial has one). Patient reassessment should be performed as early as possible but within 7 
days of the initial abnormal ECG by a cardiologist for cardiovascular risk factors and a 
decision regarding study continuation.
If mean QTcF > 480 ms / ≤ 500 ms is observed, the repeat ECG assessment must be 
performed as soon as practical but within 7 days of the initial abnormal ECG. The following 
steps must be taken (Figure 6-1):

If a QTcF > 480 ms / ≤ 500 ms is confirmed and QTcF change from pretreatment exceeds 
60 ms, cardiology consultation must be sought as soon as practical (within 7 days) for 
ECG re-evaluation and clinical assessment for cardiovascular risk factors and a decision 
regarding study continuation.

If a QTcF > 480 ms / ≤ 500 ms is confirmed and QTcF change from pretreatment < 60 ms, 
more frequent ECG follow-up is advised.


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Figure 6-1
QT Prolongation Safety Management
6.2.3.3
Hepatic safety management
Patients who develop increased transaminase levels should be monitored with a second liver 
function evaluation to confirm the finding. If the finding is confirmed, the patient should be 
followed with frequent liver function monitoring 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 upon awareness and the hepatic safety follow up should be 
performed within 72 hours of awareness of the abnormality:

ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN

ALT or AST > 5 x ULN and ≤8 x ULN

ALT or AST > 8 x ULN
Hepatic Safety Follow up including follow-up on potential Drug-induced Liver injury cases 
(DILI):


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
Perform liver-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including over-the-counter medications, inter-current 
illness, etc.)

Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if 
total bilirubin is > 2.0 x ULN), Albumin, creatine kinase, PT (INR), ALP, and GGT. 
These tests should be monitored every 3-4 days until resolution or return to baseline status.

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)
Patients should be managed according to the LFT algorithm Figure 6-2. Patients may need to 
be discontinued if the abnormal liver function criteria are met upon LFT retesting (see 
discontinuation criteria Section 7.1.3.1). Progress reports of the event should be maintained 
until resolution or stabilization (the latter defined as no further elevation after 2 consecutive 
assessments).
If any of these criteria are met and deemed an AE by the investigator, the event must be
recorded on the Adverse Event eCRF page; if the event is deemed serious by the investigator, 
then the SAE form should be completed. In addition, any significant findings from the 
physical examination should be recorded on the Adverse Event eCRF page.
For identification of potential Drug–induced Liver Injury (DILI), medical review by Novartis 
and the participating investigator needs to ensure that liver tests elevations are not caused by 
cholestasis, defined as ALP elevation >2.0 X ULN with R value (ALT/ALP in X ULN) <2. If 
confirmed, these patients should be immediately discontinued from the study drug treatment 
and repeat LFTs as soon as possible, preferably within 48 hours from the awareness of the 
abnormal results.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, without 
cholestasis, with no other alternative cause for LFT abnormalities identified should be 
considered as “medically significant”, thus, met 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 6-2
LFT management algorithm
6.2.4
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria and specific Dose Limiting Toxicity (DLT) definitions, as well 
as specific dose modification and stopping rules are included in this protocol. Recommended 
guidelines for prophylactic or supportive treatment for expected toxicities, including 
management of study-drug induced adverse events, i.e., hyperglycemia, QT prolongation and 
LFT increases are provided in Section 6.2.3. Refer to preclinical toxicity and or clinical data
found in the [Investigator’s Brochure].
6.3
Concomitant medications
6.3.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. Any changes in the dose of any medication the patient 
was taking prior to or during the study have to be notified as well. 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/Significant non-drug therapies eCRF.


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Any anti-diabetic medications that the patient takes during the study must be listed on the 
Concomitant medications/Significant non-drug therapies for Diabetes
CRF.
If oral 
contraception is 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 contraceptive 
throughout the course of the study and for one month after pasireotide s.c. last dose or for 3 
months after pasireotide LAR last dose.
6.3.2
Permitted concomitant therapy requiring caution and/or action
Investigators should discourage patients from taking any medication during the study, with 
the exception of medications that are required to treat an adverse event.
6.3.3
Prohibited concomitant therapy
The use of concomitant medication known to prolong QT interval is prohibited. In case a 
patient needs to take QT prolonging drug, it will require study drug discontinuation prior to
starting QT prolonging medication. Please see Appendix 1 for further guidance on QT 
prolonging medication.
The following washouts are to be followed prior to study entry (start of pasireotide) and the 
use of these drugs during the study is prohibited:

All other medical therapies or other SSAs (octreotide, lanreotide) for Cushing’s disease or 
acromegaly have to be discontinued at least 5 times the half-life of the respective 
preparation (8 weeks washout for octreotide LAR and lanreotide autogel)

Dopamine agonists (bromocriptine, cabergoline) or pegvisomant (INN) will only be 
accepted provided the dose regimen is stable from at least 4 weeks before study entry and 
throughout the study.

DPP-4 inhibitors or GLP-1 receptor agonists have to be discontinued for at least 4 weeks
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient 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 Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
patient number suffixed to it, so that each patient is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Patient No. available to the investigator.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 
not be reused for any other patient and the Patient No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be enrolled or start treatment for any 
reason, the reason will be entered into the Screening Log.
IRT must be notified within 2 days that the patient was not enrolled.


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6.4.2
Treatment assignment or randomization
Patients will be assigned to either the incretin based therapy arm or the insulin arm in a 1:1 
ratio if they meet the SMBG criteria during the pre-randomized period as specified in Section 
4.1.1.
Randomization will be stratified by the following factors:

Disease:
a.
Cushing’s disease
b. Acromegaly

Glycemic status at baseline:
a.
HbA1c < 7 %
b. HbA1c ≥ 7%
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms.
All patients who fulfill randomization criteria will be randomized via IRT to one of the 
treatment arms. The investigator or his/her delegate will call or log on to the IRT and confirm 
that the patient fulfills all the randomization criteria. The IRT will assign a randomization 
number to the patient, which will be used to link the patient to a treatment arm. The 
randomization number will not be communicated to the caller.
6.4.3
Treatment blinding
Investigators, patients and the sponsor will have full knowledge of the treatment.
6.5
Study drug preparation and dispensation
Detailed instructions on the use of pasireotide solution for s.c. injection and pasireotide LAR 
for i.m. injection are provided in the pharmacy manual.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized sit e 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
Pasireotide s.c will be provided as solution for injection in individual one-point-cut 1 mL 
ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution.
Pasireotide LAR will be provided as microparticles powder in vials containing nominally 20, 
40 and 60 mg of Pasireotide (as free base) and solvent for suspension for injection in ampules 
for the reconstitution of the LAR microparticles.


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6.5.1
Study drug packaging and labeling
Pasireotide s.c. will be provided in ampules and will be self-injected by the patients. 
Pasireotide LAR will be provided as powder for suspension in vials and solution for 
suspension (“vehicle”) will be provided in ampules. Pasireotide LAR will be injected by a 
health care provider at the site.
The study medication packaging for globally supplied pasireotide has a 2-part label. 
Investigator staff will identify the study treatment package(s) to dispense to the patient. 
Investigator staff will add the patient number on the label. Immediately before dispensing the 
package, Investigator staff will detach the outer part of the label from the packaging and affix 
it to the source document (Drug Label Form) for that patient’s unique patient number. When 
medication is supplied locally, label will comply with local requirements.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug but no information about the 
patient.
Table 6-3
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
Pasireotide s.c.
Solution for subcutaneous injection in ampoule
Labeled as ‘SOM230’ (twice daily)
Pasireotide LAR
Microparticle powder for suspension in vial
Solution for suspension (vehicle) in ampoule or 
pre-filled syringe
Labeled as ‘SOM230’ LAR 
(once/28days)
Labeled as ‘solvent’ (once/28days)
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the [Investigator’s Brochure].
Table 6-4
Supply and storage of study treatments
Study treatments
Supply
Storage
Pasireotide s.c.
Centrally or locally supplied by Novartis
Refer to study treatment label
Pasireotide LAR
Centrally or locally supplied by Novartis
Refer to study treatment label
6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
Study drug compliance will be assessed by the Dosage Administration Record. All 
information is to be noted in the Dosage Administration Record.
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.5.3.3
Handling of other study treatment
The following anti-diabetic treatments have to be monitored specifically:

Metformin

Sitagliptin

Liraglutide

Insulin
Details are described in the monitoring plan.
All the above anti-diabetic medications will be supplied locally during the core phase of the 
study. These medications will not be provided by the sponsor during the extension phase of 
the study unless required by local regulations.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation.
No CRF will be used as a source document. The table indicates which assessments produce 
data to be entered into the database (D) or remain in source documents only (S) (“Category” 
column).
± 3-day visit window will be allowed for Cushing’s patients. Visit windows for Acromegaly 
patients will remain unchanged as per Table 7-1.
Patients on pasireotide s.c. will have an additional visit at Week 1 (Visit 401) during pre-
randomized period to perform liver function test and ECG monitoring. Patients on pasireotide 


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
LAR will have an additional visit at Week 3 (Visit 402) during the pre-randomized period to 
perform ECG monitoring.
Patients who are not randomized by Week 16 (of pre-randomized period) will complete all 
assessments for Core EOP (Visit 777) on Week 16 (4 weeks from PR-W12).
Patients will complete all assessments for the randomization visit (Visit 7) on the day of 
randomization. After their randomization they will follow the visit schedule for randomized 
treatment period. Randomized patients will complete all assessments for Core EOP (Visit 777) 
approximately 16 weeks post-randomization.
During the course of the study:

The dose of pasireotide (s.c or LAR) is to be administered after all assessments have been 
completed on the day of the visit.


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Table 7-1
Core Phase Visit Evaluation Schedule
Category
Protocol Section
Screening
Baseline
Pre-Randomized(PR) Period
Randomized(R) Treatment Period
Core EOP/
Early 
discontinuation
End of Study/ 
Follow-up
Randomiza-
tion
Visit Number
1
2
401
3
402
4
5
6
7
8
9
10
11
12
13
14
777
779
Study Day
-21 
to 
-1
PR
1
PR 
8
PR
15
PR
22
PR2
9
PR
57
PR
85
R
1
R1
5
R
29
R
43
R
57
R
71
R
85
R
99
28 days 
from last 
s.c dose/
84 days
from last 
LAR dose
Study Week (W)
PR
-
W0
PR-
W1
PR-
W2
PR-
W3
PR-
W4
PR
-
W8
PR-
W1
2
R-
W
0
R-
W2
R-
W
4
R-
W
6
R-
W8
R-
W
10
R-
W1
2
R-
W14
PR-
W16
/ R-
W16
Obtain Informed 
Consent
S
5.2
X
IWRS/IRT 
Registration
D
7.1.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography
D
7.1.1.3
X
Inclusion/exclusio
n criteria
D
5.2 / 5.3
X
Relevant medical 
history/current 
medical 
conditions
D
7.1.1.3
X


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Category
Protocol Section
Screening
Baseline
Pre-Randomized(PR) Period
Randomized(R) Treatment Period
Core EOP/
Early 
discontinuation
End of Study/ 
Follow-up
Randomiza-
tion
Visit Number
1
2
401
3
402
4
5
6
7
8
9
10
11
12
13
14
777
779
Study Day
-21 
to 
-1
PR
1
PR 
8
PR
15
PR
22
PR2
9
PR
57
PR
85
R
1
R1
5
R
29
R
43
R
57
R
71
R
85
R
99
28 days 
from last 
s.c dose/
84 days
from last 
LAR dose
Study Week (W)
PR
-
W0
PR-
W1
PR-
W2
PR-
W3
PR-
W4
PR
-
W8
PR-
W1
2
R-
W
0
R-
W2
R-
W
4
R-
W
6
R-
W8
R-
W
10
R-
W1
2
R-
W14
PR-
W16
/ R-
W16
Prior Diabetes 
History
D
7.1.1.3
X
Concomitant 
Medications
D
6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination
S
7.2.3.1
X
X
X
X
X
X
X
X
X
X
X
Height
D
7.2.3.3
X
Vital signs 
(Weight, Supine 
BP, Pulse, 
Temperature) 
D
7.2.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c [Also to be 
collected prior to 
starting rescue 
therapy]
D
7.2.3.4.4
X
X
X
X
X
X
X
X
X
X
X


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Category
Protocol Section
Screening
Baseline
Pre-Randomized(PR) Period
Randomized(R) Treatment Period
Core EOP/
Early 
discontinuation
End of Study/ 
Follow-up
Randomiza-
tion
Visit Number
1
2
401
3
402
4
5
6
7
8
9
10
11
12
13
14
777
779
Study Day
-21 
to 
-1
PR
1
PR 
8
PR
15
PR
22
PR2
9
PR
57
PR
85
R
1
R1
5
R
29
R
43
R
57
R
71
R
85
R
99
28 days 
from last 
s.c dose/
84 days
from last 
LAR dose
Study Week (W)
PR
-
W0
PR-
W1
PR-
W2
PR-
W3
PR-
W4
PR
-
W8
PR-
W1
2
R-
W
0
R-
W2
R-
W
4
R-
W
6
R-
W8
R-
W
10
R-
W1
2
R-
W14
PR-
W16
/ R-
W16
FPG [Also to be 
collected prior to 
starting rescue 
therapy]
D
7.2.3.4.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Insulin 
(Serum)
D
7.2.3.4.4
X
X
X
X
X
X
Glucagon
D
7.2.3.4.4
X
X
X
X
X
X
Self-monitored 
blood glucose 
(SMBG)
D
7.2.3.4.4
At Home Daily
Hematology 
D
7.2.3.4.1
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
D
7.2.3.4.2
X
X
X 
(s.c.
only
)
X
X
X
X
X
X
X
X
X
X


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Category
Protocol Section
Screening
Baseline
Pre-Randomized(PR) Period
Randomized(R) Treatment Period
Core EOP/
Early 
discontinuation
End of Study/ 
Follow-up
Randomiza-
tion
Visit Number
1
2
401
3
402
4
5
6
7
8
9
10
11
12
13
14
777
779
Study Day
-21 
to 
-1
PR
1
PR 
8
PR
15
PR
22
PR2
9
PR
57
PR
85
R
1
R1
5
R
29
R
43
R
57
R
71
R
85
R
99
28 days 
from last 
s.c dose/
84 days
from last 
LAR dose
Study Week (W)
PR
-
W0
PR-
W1
PR-
W2
PR-
W3
PR-
W4
PR
-
W8
PR-
W1
2
R-
W
0
R-
W2
R-
W
4
R-
W
6
R-
W8
R-
W
10
R-
W1
2
R-
W14
PR-
W16
/ R-
W16
Amylase and 
lipase
D
7.2.3.4.2
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
(Dipstick)
D
7.2.3.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.3.4.5
X
X
X
X
X
X
X
X
Hepatitis B and C 
tests
D
7.2.3.4.8
X
Serum Pregnancy 
test
D
7.2.3.4.1
0
X
Urine Pregnancy 
test
D
7.2.3.4.1
0
X
X
X
X
X
X
X
X
Free T4, TSH
D
7.2.3.4.6
X
X
X
GLP-1, GIP
D
7.2.3.4.7
X
X
X
X
GH, IGF-1
D
7.2.3.4.7
X
X
X
X
Serum Cortisol
D
7.2.3.4.7
X
X
X
X
Plasma ACTH
D
7.2.3.4.7
X
X
X
X


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Category
Protocol Section
Screening
Baseline
Pre-Randomized(PR) Period
Randomized(R) Treatment Period
Core EOP/
Early 
discontinuation
End of Study/ 
Follow-up
Randomiza-
tion
Visit Number
1
2
401
3
402
4
5
6
7
8
9
10
11
12
13
14
777
779
Study Day
-21 
to 
-1
PR
1
PR 
8
PR
15
PR
22
PR2
9
PR
57
PR
85
R
1
R1
5
R
29
R
43
R
57
R
71
R
85
R
99
28 days 
from last 
s.c dose/
84 days
from last 
LAR dose
Study Week (W)
PR
-
W0
PR-
W1
PR-
W2
PR-
W3
PR-
W4
PR
-
W8
PR-
W1
2
R-
W
0
R-
W2
R-
W
4
R-
W
6
R-
W8
R-
W
10
R-
W1
2
R-
W14
PR-
W16
/ R-
W16
ECG (12 lead)
D
7.2.3.6.1
X
X
X 
(s.c. 
only
)
X
(LAR
only)
X
X
X
X
X
Gall-bladder 
Ultrasound
D
7.2.3.5
X
X
Adverse Events
D
8.1
Continuous
Study Drug 
(pasireotide s.c.) 
administration 
record for patients 
with Cushing’s 
disease (daily 
b.i.d dosing) [Last 
dose is one day 
prior to Core EOP 
visit]
D
6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Category
Protocol Section
Screening
Baseline
Pre-Randomized(PR) Period
Randomized(R) Treatment Period
Core EOP/
Early 
discontinuation
End of Study/ 
Follow-up
Randomiza-
tion
Visit Number
1
2
401
3
402
4
5
6
7
8
9
10
11
12
13
14
777
779
Study Day
-21 
to 
-1
PR
1
PR 
8
PR
15
PR
22
PR2
9
PR
57
PR
85
R
1
R1
5
R
29
R
43
R
57
R
71
R
85
R
99
28 days 
from last 
s.c dose/
84 days
from last 
LAR dose
Study Week (W)
PR
-
W0
PR-
W1
PR-
W2
PR-
W3
PR-
W4
PR
-
W8
PR-
W1
2
R-
W
0
R-
W2
R-
W
4
R-
W
6
R-
W8
R-
W
10
R-
W1
2
R-
W14
PR-
W16
/ R-
W16
Study Drug 
(pasireotide LAR) 
administration for 
patients with 
acromegaly 
(once/28 days) 
[Last dose is 1 
month prior to 
core EOP visit]
D
6.1
X
X
X
X
X
(administer every 3-4 weeks from prior dose)
Anti-Diabetic Drug 
Administration 
Record
D
4.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Phase 
Completion
D
7.1.3
X
Study Completion
D
7.1.4
X


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Table 7-2
Extension Phase Visit Evaluation Schedule
Category
Protocol Section
Start of Extension
Annual Visits during Extension(E)
Extension EOP 
End of Study/ 
Follow-up
Visit 
Number
15
16/
30/..
17/
31/..
18/
32/..
19/
33/..
20/
34/..
21/
35/..
22/
36/..
23/
37/..
24/
38/..
25/
39/..
26/
40/..
27/
41/..
28/
42/..
29/
43/..
77
8
779
Study Day
E1
E29/
421/.
.
E57/
449/.
.
E85/
477/.
.
E113
/
505/.
.
E141
/
533/.
.
E169
/
561/.
.
E197
/
589/.
.
E225
/
617/.
.
E253/
E645/.
.
E281
/
673/.
.
E309
/
701/.
.
E337
/
729/.
.
E365
/
757/.
.
E393
/
785/.
.
28 
days 
from 
last 
s.c 
dose/
84 
days
from 
last 
LAR 
dose
Study Week 
(W)
EW
0
EW4
/
60/..
EW
8/
64/..
EW 
12/
68/..
EW
16/
72/..
EW
20/
76/..
EW
24/
80/..
EW
28/
84/..
EW
32/
88/..
EW
36/
92/..
EW
40/
96/..
EW
44/
100/.
.
EW
48/
104/.
.
EW
52/
108/.
.
EW 
56/
112/.
.
IWRS/IRT 
Registration
D
7.1.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
D
6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination
S
7.2.3.1
X
X
X
X
X
X
X
X
X
Vital signs 
(Weight, 
Supine BP, 
Pulse, 
Temperature
)
D
7.2.3.2
7.2.3.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c 
D
7.2.3.4.4
X
X
X
X
X
X
X
X
X


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Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Category
Protocol Section
Start of Extension
Annual Visits during Extension(E)
Extension EOP 
End of Study/ 
Follow-up
Visit 
Number
15
16/
30/..
17/
31/..
18/
32/..
19/
33/..
20/
34/..
21/
35/..
22/
36/..
23/
37/..
24/
38/..
25/
39/..
26/
40/..
27/
41/..
28/
42/..
29/
43/..
77
8
779
Study Day
E1
E29/
421/.
.
E57/
449/.
.
E85/
477/.
.
E113
/
505/.
.
E141
/
533/.
.
E169
/
561/.
.
E197
/
589/.
.
E225
/
617/.
.
E253/
E645/.
.
E281
/
673/.
.
E309
/
701/.
.
E337
/
729/.
.
E365
/
757/.
.
E393
/
785/.
.
28 
days 
from 
last 
s.c 
dose/
84 
days
from 
last 
LAR 
dose
Study Week 
(W)
EW
0
EW4
/
60/..
EW
8/
64/..
EW 
12/
68/..
EW
16/
72/..
EW
20/
76/..
EW
24/
80/..
EW
28/
84/..
EW
32/
88/..
EW
36/
92/..
EW
40/
96/..
EW
44/
100/.
.
EW
48/
104/.
.
EW
52/
108/.
.
EW 
56/
112/.
.
FPG
D
7.2.3.4.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
D
7.2.3.4.1
X
X
X
X
X
X
X
X
X
Clinical 
Chemistry 
D
7.2.3.4.2
X
X
X
X
X
X
X
X
X
Urinalysis 
(dipstick)
D
7.2.3.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine 
pregnancy 
test
D
7.2.3.4.1
0
X
X
X
X
Gall-bladder 
Ultrasound
D
7.2.3.5
X
Adverse 
Events
D
8.1
Continuous


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Page 62
Amended Protocol Version 03 (Clean)
Protocol No. CSOM230B2219
Category
Protocol Section
Start of Extension
Annual Visits during Extension(E)
Extension EOP 
End of Study/ 
Follow-up
Visit 
Number
15
16/
30/..
17/
31/..
18/
32/..
19/
33/..
20/
34/..
21/
35/..
22/
36/..
23/
37/..
24/
38/..
25/
39/..
26/
40/..
27/
41/..
28/
42/..
29/
43/..
77
8
779
Study Day
E1
E29/
421/.
.
E57/
449/.
.
E85/
477/.
.
E113
/
505/.
.
E141
/
533/.
.
E169
/
561/.
.
E197
/
589/.
.
E225
/
617/.
.
E253/
E645/.
.
E281
/
673/.
.
E309
/
701/.
.
E337
/
729/.
.
E365
/
757/.
.
E393
/
785/.
.
28 
days 
from 
last 
s.c 
dose/
84 
days
from 
last 
LAR 
dose
Study Week 
(W)
EW
0
EW4
/
60/..
EW
8/
64/..
EW 
12/
68/..
EW
16/
72/..
EW
20/
76/..
EW
24/
80/..
EW
28/
84/..
EW
32/
88/..
EW
36/
92/..
EW
40/
96/..
EW
44/
100/.
.
EW
48/
104/.
.
EW
52/
108/.
.
EW 
56/
112/.
.
Study Drug 
(pasireotide 
s.c.) 
administratio
n record for 
patients with 
Cushing’s 
disease 
(daily b.i.d 
dosing) 
D
6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Category
Protocol Section
Start of Extension
Annual Visits during Extension(E)
Extension EOP 
End of Study/ 
Follow-up
Visit 
Number
15
16/
30/..
17/
31/..
18/
32/..
19/
33/..
20/
34/..
21/
35/..
22/
36/..
23/
37/..
24/
38/..
25/
39/..
26/
40/..
27/
41/..
28/
42/..
29/
43/..
77
8
779
Study Day
E1
E29/
421/.
.
E57/
449/.
.
E85/
477/.
.
E113
/
505/.
.
E141
/
533/.
.
E169
/
561/.
.
E197
/
589/.
.
E225
/
617/.
.
E253/
E645/.
.
E281
/
673/.
.
E309
/
701/.
.
E337
/
729/.
.
E365
/
757/.
.
E393
/
785/.
.
28 
days 
from 
last 
s.c 
dose/
84 
days
from 
last 
LAR 
dose
Study Week 
(W)
EW
0
EW4
/
60/..
EW
8/
64/..
EW 
12/
68/..
EW
16/
72/..
EW
20/
76/..
EW
24/
80/..
EW
28/
84/..
EW
32/
88/..
EW
36/
92/..
EW
40/
96/..
EW
44/
100/.
.
EW
48/
104/.
.
EW
52/
108/.
.
EW 
56/
112/.
.
Study Drug 
(pasireotide 
LAR) 
administratio
n for patients 
with 
acromegaly 
(once/28 
days)
D
6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Phase 
Completion
D
7.1.3
X
Study 
Completion
D
7.1.4
X


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7.1.1
Screening
The informed consent form must be signed prior to ANY screening procedure being 
performed. Once the patient has consented to participate in the study he/she will be screened 
for eligibility at Visit 1. Informed consent must be signed and dated prior to any study related 
procedure at Visit 1. During the screening period the inclusion and exclusion criteria will be 
assessed. The screening period for this study is a maximum of 21 days (3 weeks) to allow 
sufficient time for laboratory and procedural assessments prior to study drug administration. 
Patients that do not meet eligibility criteria are allowed to be rescreened once more and should 
keep the same patient ID number. The rescreening should be documented in the source files. 
All assessments are to be repeated when patients are rescreened.
7.1.1.1
Eligibility screening
Following registration in IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
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 not being started on treatment will be entered on 
the Screening Log Page. The demographic information must be completed for Screen failure 
patients. No other data will be entered into the clinical database for patients who are screen 
failures.
7.1.1.3
Patient demographics and other baseline characteristics
Standard demographic information and medical history will be collected. Diabetes history 
together with the medication/treatment used will also be collected. Other baseline assessments 
will be collected as per Table 7-1.
7.1.2
Treatment period
The treatment period in the core phase of the study will be up to 32 weeks. Patients that are 
randomized within 16 weeks of study entry will continue in the core phase for 16 weeks post-
randomization. Patients that are not randomized complete their core phase at pre-randomized 
period Week 16 (PR-W16). Both group of patients will have the option to continue 
pasireotide treatment in the extension phase of the study until the last patient randomized 
completes 16 weeks of treatment post-randomization, or when pasireotide is available 
commercially or when a local access program is available.
Pre-randomized period
The pre-randomized period can be up to 16 weeks. Eligible patients will start pasireotide s.c. 
for Cushing’s disease and pasireotide LAR for acromegaly. If they experience increases in 
their fasting blood glucose, they will start anti-diabetic treatment using metformin. If they 
continue to experience increases in their fasting blood glucose within the first 16 weeks, they 


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will be randomized. During the pre-randomized period, patients will have visits every two 
weeks in the first month and then monthly visits (see Table 7-1).
Randomized period
Patients are randomized in a 1:1 ratio to receive treatment with incretin based therapy 
(sitagliptin followed by liraglutide) or insulin for approximately 16 weeks. During the 
randomized period, patients will have visits every two weeks (see Table 7-1).
7.1.3
End of treatment visit including study completion and premature 
withdrawal
Patients who discontinue study treatment before visit 777 (if patient is in the core phase of the 
study) or 778 (if patient is in the extension phase of the study), should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the Core EOP or Extension 
EOP visit will be performed (Table 7-1 and Table 7-2). A Study Phase Completion CRF page 
should be completed, giving the date and reason for stopping the study treatment. These 
patients should then return for an End of Study/Follow-up visit as described in Section 7.1.4
and complete the EOS Visit assessments and Study Completion eCRF. Patients continuing 
pasireotide treatment through a roll-over study or local access program will not return for an 
End of Study/Follow-up visit as their safety will be monitored.
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 either 28 days following the 
last dose of s.c treatment for Cushing’s patients or 84 days following the last dose of LAR 
treatment for acromegaly patients.
Patients who discontinue study treatment should be considered withdrawn from the study or 
considered as did not complete the study after the final visit assessments are performed or 
when it is clear that the patient will not return for these assessments.
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 Study Phase Completion CRF page and Study Completion CRF page.
If a patient discontinues study treatment, but continues on to the end of treatment and final 
end of study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments. At that time, the reason for study completion 
should be recorded on the Study Completion CRF page.
If using IRT, the Investigator must contact the IRT to register the patient’s discontinuation.
End of phase/Premature withdrawal visit is not considered as the end of the study.
7.1.3.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be discontinued from it at the discretion 
of the investigator at any time. Patients may be withdrawn from the study if any of the 
following occur:


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
Adverse event(s)[including abnormal laboratory values(s) and abnormal test procedures 
results(s)]

Patient withdrew consent

Lost to follow-up

Death

Pregnancy
In addition to the general withdrawal criteria, the study specific criteria below also require 
immediate study drug discontinuation. Proper safety follow-up management should be 
performed as outlined in Section 6.2.3.1, Section 6.2.3.2 and Section 6.2.3.3. Re-challenge of 
study medication is prohibited once discontinuation criteria are met.
Hepatic-related discontinuation criteria

Jaundice or other signs of clinically significant liver dysfunction

ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN

ALT or AST > 5 x ULN and ≤ 8 x ULN persistent for more than 2 weeks

ALT or AST > 8 x ULN
Following discontinuation of treatment with pasireotide, patients should be monitored until 
resolution. Treatment should not be restarted.
QT related discontinuation criteria

Confirmed QTcF > 500 ms and discontinuation recommended by a cardiologist

Clinically significant arrhythmias including:
1. Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms of 
hemodynamic compromise.
2. Sustained ventricular tachycardia (VT > 30 s) irrespective of symptoms.
3. Recurrent non-sustained VT (≥ 3 beats) during any 24-hour monitoring period.
4. Clinically significant brady-arrhythmia or third degree AV block.
5. Need to use QT prolonging medication.
Hyperglycemia related discontinuation criteria

Uncontrolled diabetes mellitus (DM), consistently high glucose values with average of 
fasting SMBG values of 3 consecutive days > 300 mg/dL or HbA1c value ≥ 10 % despite 
prior appropriate anti-diabetic management and prior dose adjustment of the pasireotide.
Pancreas-related discontinuation criteria
If clinical diagnosis of pancreatitis is suspected, as per investigator’s discretion, then patient 
should be discontinued from the study.
The investigator must also notify the IRT of the premature withdrawal, if this occurs during 
the core period.


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7.1.4
Follow-up and End of Study visit
All patients must have safety evaluations and complete the EOS assessments at the EOS visit 
28 days after the last dose of pasireotide s.c or 84 days after the last dose of pasireotide LAR. 
Patients continuing pasireotide treatment through a roll-over study or local access program 
will not return for an End of Study/Follow-up visit as their safety will be monitored.
Refer to the eCRF Completion Guidelines for further instructions.
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. Patients that meet the requirements for follow up of abnormal LFTs at the end of study 
visit should be followed up as detailed in Section 6.2.3.3.
7.2
Assessment types
7.2.1
Efficacy assessments
There are no efficacy assessments for pasireotide in this study. Clinical benefit with 
pasireotide should be evaluated as described in Section 7.2.2.
Change in HbA1c from the time of randomization to approximately 16 weeks post-
randomization between incretin based therapy arm and insulin arm will be assessed to 
determine the efficacy of anti-diabetic therapy on pasireotide-induced hyperglycemia. Change 
in HbA1c and FPG from baseline to Core EOP in patients who received pasireotide by 
treatment group will also be assessed. Please see Section 7.2.3.4.4 for details.
7.2.2
Clinical benefit assessments
Clinical benefit should be evaluated 8 weeks after the start of pasireotide s.c. and 12 weeks 
after the start of pasireotide LAR to determine if pasireotide dose modification is needed. 
Please refer to Section 6.2.1. Clinical benefit can also be evaluated any time afterwards at 
investigator’s discretion.
mUFC levels for patients with Cushing’s disease and GH and IGF-1 levels for patients with 
acromegaly should be determined by site locally. These evaluations should be part of the 
source documentation at the site.
7.2.3
Safety and tolerability assessments
Safety will be monitored by assessing laboratory assessments, ECGs, imaging for gallstones, 
vital signs and physical examinations as well as collecting of adverse events at every visit. For 
details on AE collection and reporting, refer to Section 8.1.
7.2.3.1
Physical examination
A complete physical exam must be performed by the investigator at visits indicated below and 
in Table 7-1 and Table 7-2. These examinations will be performed according to the standards 
at each institution.


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Physical Examinations will be performed on the scheduled visits. More frequent examinations 
may be performed at the investigator’s discretion, if medically indicated. The physical 
examination comprises a total body examination (general appearance, skin, neck, including 
thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and
nervous system).
Information about the physical examination must be present in the source documentation at 
the study site. Body weight and height will be recorded on the eCRF page for vital signs. 
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 
eCRF. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the patient’s eCRF.
7.2.3.2
Vital signs
Vital signs (supine blood pressure, pulse rate and body temperature) will be performed by the 
investigator at all visits as indicated in Table 7-1 and Table 7-2 and recorded in the 
appropriate eCRFs. More frequent examinations may be performed at the investigator’s 
discretion, if medically indicated.
7.2.3.3
Height and weight
Height in centimeters (cm) and weight to the nearest 0.1 kilogram [kg] (in indoor clothing, but 
without shoes) are to be collected at visits indicated in Table 7-1 and recorded in the 
appropriate eCRF.

Height will be measured at screening only

Weight will be measured at every visit during the core and extension phase of the study
7.2.3.4
Laboratory evaluations
Central laboratories will be used for the analysis of all laboratory evaluations except 
urinalysis and urine pregnancy test. Details on the collections, shipment of samples and 
reporting of results by the central laboratory will be provided to investigators in the 
[Laboratory Manual].
Urinalysis and urine pregnancy test will be performed by dipstick locally. The dipsticks will 
be provided to the sites by the central lab.


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Table 7-3
Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
RBC, Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, WBC including 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Clinical Chemistry
Albumin, Total Protein, Alkaline phosphatase, GGT, ALT, AST, Total Bilirubin, 
direct Bilirubin, indirect Bilirubin, Bicarbonate, Sodium, Potassium, Calcium, 
Chloride, Creatine kinase, Total Cholesterol, LDL, HDL, Triglycerides, 
Creatinine, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Hyperglycemia related tests
HbA1c, fasting plasma glucose, fasting insulin, glucagon
Coagulation
Prothrombin time (PT), International normalized ratio (INR), Activated partial 
thromboplastin time (APTT)
Thyroid
Free T4, TSH
Additional tests
IGF-1, GH, GLP-1, GIP, serum cortisol, plasma ACTH.
Screening only: Serum pregnancy test, Hepatitis B and C tests (HbsAg, anti-
HCV).
Hepatic safety follow-up: Hepatitis A (anti-HAV, IgM), Anti-HBc, anti-HCV (if 
positive, PCR viral load will be assessed), Anti-HEV, ANA antibodies, anti-
smooth muscle anti-bodies, CMV and EBV
Pancreatic safety: Lipase and Amylase
7.2.3.4.1 Hematology
Hemoglobin, hematocrit, WBC with differential, RBC, MCV, MCH, MCHC and platelet 
count will be measured at visits indicated in Table 7-1 and Table 7-2.
7.2.3.4.2 Clinical chemistry
Albumin, total protein, alkaline phosphatase, GGT, ALT (GPT), AST (GOT), total bilirubin,
direct bilirubin, indirect bilirubin, bicarbonate, sodium, potassium, calcium, chloride, Creatine
Kinase, total cholesterol, LDL, HDL, Triglycerides, Creatinine, Blood Urea Nitrogen (BUN) 
or Urea, Uric Acid will be measured at visits indicated in Table 7-1 and Table 7-2.
Investigator should calculate creatinine clearance at each visit to assess if dose modification 
or discontinuation is required for pasireotide and/or anti-diabetic medications. (Please see 
Section 6.2.2.1 and Section 6.2.2.2) Creatinine clearance calculation will be recorded in the 
source document and will not be captured in the eCRF.
7.2.3.4.3 Urinalysis
Urinalysis includes dipstick analysis (glucose, bilirubin, ketone, specific gravity, blood, pH, 
protein and leukocyte esterase). Urinalysis will be analyzed locally at visits indicated in Table 
7-1 and Table 7-2.
7.2.3.4.4 Hyperglycemia related tests
HbA1c, fasting plasma glucose, fasting insulin and glucagon will be measured at visits 
indicated in Table 7-1 and Table 7-2.
FPG and/or HbA1c will also be measured at unscheduled visits for the following reasons:


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
To confirm diagnosis of diabetes in anti-diabetic treatment naïve patients prior to initiating 
anti-diabetic treatment.

To confirm an FPG > 160 mg/dl during the 6-week dose stabilization period prior to 
switching from sitagliptin to liraglutide

To confirm an FPG > 160 mg/dl during the 6-week dose stabilization period prior to 
switching from liraglutide to rescue therapy.

To confirm an HbA1c > 7% in patients after the 6-week dose stabilization period on 
liraglutide prior to starting rescue therapy.
FPG and HbA1c should be measured prior to starting rescue therapy as well.
Please refer to Section 4.1 for guidance on anti-diabetic treatment management.
Self-monitored blood glucose
All patients will measure their fasting blood glucose with a glucometer at home daily after 
study enrollment. The patients will be instructed to record the glucose values in their glycemia
diary. At each scheduled visit, the study investigator will review the patient’s fasting self-
monitored blood glucose (SMBG) values. After their baseline visit, patients will also be 
instructed to call the site on a weekly basis between visits during the core phase of the study 
for the investigator to review their SMBG values. Highest and lowest SMBG values since the 
last visit and the last 3 fasting SMBG values prior to the visit will be recorded in the eCRF.
7.2.3.4.5 Coagulation
Prothrombin time (PT),
International normalized
ratio (INR), and activated partial 
thromboplastin time (APTT) will be performed at visits indicated in Table 7-1 and Table 7-2.
7.2.3.4.6 Thyroid
Free T4 and TSH will be measured at visits indicated in Table 7-1 and Table 7-2.
7.2.3.4.7 Hormones
IGF-1, GH, GLP-1, GIP, serum cortisol and plasma ACTH will be measured at visits 
indicated in Table 7-1 and Table 7-2.
7.2.3.4.8 Liver function testing
Presence of HbsAg and Anti-HCV are to be assessed during screening.
If at any visit abnormal liver function criteria as described in Section 6.2.3.3 are met, a hepatic 
safety follow-up as described in Section 6.2.3.3 should be performed immediately within 72 
hours of awareness of the abnormality.
7.2.3.4.9 Pancreas function testing
Serum lipase and amylase will be measured at visits indicated in Table 7-1 and Table 7-2.


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7.2.3.4.10
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have a serum B-hCG 
pregnancy test at screening visit and urine pregnancy test at visits indicated in Table 7-1 and 
Table 7-2. A positive pregnancy test requires immediate interruption of study treatment until 
the assessment is confirmed. If positive, the patient must be discontinued from the study.
7.2.3.5
Gallbladder ultrasound
A gallbladder ultrasound will be performed at the sites at screening visit, and core EOP visit 
(777). Additionally, a gallbladder ultrasound will be performed every 12 months during the 
Extension Phase. The results will be recorded in the eCRF.
7.2.3.6
Cardiac assessments
7.2.3.6.1 Electrocardiogram (ECG)
Standard 12 lead ECGs will be performed locally at the sites at visits during the core phase as 
indicated in Table 7-1 and Table 7-4. If the ECG machine at your site does not automatically 
provide QTcF then use the formula in Appendix 2 to calculate it.
If at any visit QTcF >500 ms is observed, all the procedures for QT-prolongation described in 
Section 6.2.3.2 should be followed.
ECGs will be obtained after the patient has been supine and resting for at least 10 minutes 
prior to each time point indicated. All ECGs should be recorded with the patient in the same 
physical position.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG eCRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History eCRF page. Clinically significant findings 
must be discussed with Novartis prior to enrolling the patient in the study. New or worsened 
clinically significant findings occurring after informed consent must be recorded on the
Adverse Events eCRF page.


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Table 7-4
Local ECG collection plan
CORE
Week
Day
Time
ECG Type
CORE PHASE:
Screening
-21 to -1
Anytime
12 lead
PR-W0
PR1
Pre-dose
12 Lead
PR-W1
(pasireotide s.c. only)
PR8
Pre-dose
12 Lead
PR-W3
(pasireotide LAR only)
PR22
Pre-dose
12 Lead
R-W0
R1
Pre-dose
12 Lead
R-W4
R29
Pre-dose
12 Lead
R-W8
R57
Pre-dose
12 Lead
R-W12
R85
Pre-dose
12 Lead
Core EOP
Anytime
12 Lead
Unscheduled sample
Anytime
12 Lead
7.2.3.7
Tolerability
In addition to general safety data, information on dose reductions will be collected.
7.2.3.8
Other assessments
No additional tests will be performed on patients entered into this study.
7.2.4
Resource utilization
Not applicable.
7.2.5
Patient reported outcomes
Not applicable.
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).


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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 28 days after the last pasireotide s.c. dose or 84 days after the last 
pasireotide LAR dose. 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 though a Death 
form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(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 
(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 (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
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 event (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 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.


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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an adverse event in their own right (CTCAE grade ≥3; 
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.
8.1.3
Adverse events of special interest
Based on the knowledge of the SSA drug class and experience gained during the clinical 
development of pasireotide, two areas of risks associated with pasireotide treatment have been 
identified: risks which are known SSA class effects, and risks which were observed mainly in 
pre-clinical studies. The risks identified as class effects of SSAs are the following: QT-
prolongation, bradycardia, hyperglycemia, cholelithiasis, hematological abnormalities, 
abnormal liver functions, injection site reactions, gastrointestinal disorders, pancreatitis, and 
hypothyroidism. Risks which were mainly seen in pre-clinical studies are coagulation 
abnormalities, hypotension, hypocalcaemia, and gastrointestinal erosions/bleedings. In 
addition, hypocortisolism/cortisol withdrawal syndrome is an identified risk for patients with 
Cushing’s disease treated with pasireotide.
Based on these identified risks, several categories of AEs of special interest were defined. 
These categories consist of AEs where pasireotide may influence a common mechanism of 
action responsible for triggering them, or that are similar in nature (although not identical).
8.1.3.1
Definitions and reporting
Groupings of adverse event of special interest will be considered and the number of patients 
with at least one event in each grouping will be reported. Such groups consist of 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) or 
adverse event that are very similar although not identical. The groups will be defined
according to criteria described in MedDRA.


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8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

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 at least 1 month for those patients who 
discontinued pasireotide s.c and at least 84 days for those patients who discontinued 
pasireotide LAR must be reported to Novartis within 24 hour of learning of its occurrence.
Any SAEs experienced after this 28 days period for pasireotide s.c. and 84 days for 
pasireotide LAR (or 5 half-lives, whichever is longer) 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; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.


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The telephone and telefax number of the contact persons in the local department of DS&E, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, 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 DS&E department associate may 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 occurring while the patient is 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 Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis DS&E Department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to 
the study treatment any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
Pregnancy outcomes must 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.
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 (or within 3 months of the last pasireotide LAR 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 
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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 (SC) will be established comprising investigators participating in the 
trial, i.e. not being members of the DMC (Data Monitoring Committee) and Novartis 
representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in a Steering Committee charter.
8.6
Data Monitoring Committee
There is no DMC for the study.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect 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.
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 


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completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), 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
For studies using eCRFs, 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).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 


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system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). 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 and the treatment codes will be unblinded and 
made available for data analysis. 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.
10
Statistical methods and data analysis
The study will be analyzed when all treated patients have completed or discontinued the study 
and the final CSR will be produced. Additional interim CSR may be performed at the end of 
the core phase as needed.
Novartis or designated CRO will analyze all data using the SAS System for data analysis V8.0 
or higher. Any data analyses carried out independently by an investigator should be submitted 
to Novartis before publication or presentation.
The data from all centers participating in the trial will be combined, so that an adequate 
number of patients will be available for analysis. The statistical analysis methods described in 
this section will focus on the analysis of the data in the core study. Similar methods will be 
applied to the analyses in the extension phase as appropriate.
10.1
Analysis sets
10.1.1
Randomized Analysis Set
The Randomized Analysis Set (RAS) comprises all patients who received at least one dose of 
pasireotide and have been assigned to either incretin based therapy or insulin by 
randomization. According to the ITT principle, patients will be analyzed according to the 
treatment they have been assigned to during the randomization procedure. RAS will be used 
for the primary analysis and some secondary analyses.
10.1.2
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who receive at least one dose of 
pasireotide. The anti-diabetic treatment group will follow the Intent-To-Treat (ITT) principle.


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10.1.3
Safety analysis Set
The Safety Analysis Set (SAS) includes all patients who received at least one dose of 
pasireotide and had at least one post-baseline safety assessment. SAS will be used for safety 
summaries. Randomized patients within SAS will be analyzed according to the anti-diabetic 
study treatment first received.
Please note: the statement that a patient had no adverse events (on the Adverse Event CRF) 
constitutes a safety assessment. Patients who have received at least one dose of study drug but 
who have no post-treatment safety data of any kind would be excluded from the SAS.
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, minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The patients will be grouped into five mutually exclusive treatment groups based on the anti-
diabetic treatment received:
1. Incretin based therapy group
2. Insulin group
3. Baseline insulin group - includes patients who receive insulin at baseline and thus not 
randomized.
4. Oral anti-diabetic (OAD) treatment group - patients who developed hyperglycemia that 
can be controlled by metformin or their background anti-diabetic treatment and thus are 
not randomized
5. No anti-diabetic treatment (NAD) group - includes patients who do not receive any anti-
diabetic treatment during the core phase of the study.
The NAD group, baseline insulin group, and OAD group are the three observational arms that 
will be treated for 16 weeks during the core phase. The core treatment period of the two 
randomized arms, i.e., incretin based therapy group and insulin group, is varied and can be up 
to 32 weeks depending on when patients get randomized.
Treatment exposure will be summarized descriptively using SAS by disease and treatment 
groups.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized using SAS.
10.4
Primary objective
The primary objective is to evaluate the effect of initial treatment with incretin based therapy 
vs. insulin on glycemic control in patients with Cushing’s disease or acromegaly who develop 
or worsen hyperglycemia on pasireotide, and cannot be controlled by metformin alone or 


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other background anti-diabetic treatments. The primary endpoint will be assessed at the Core 
EOP.
10.4.1
Variable
The primary variable is defined as the change from randomization in HbA1c (unit in %) at the 
time of assessing primary endpoint in incretin based therapy arm and insulin arm. For patients 
who require rescue treatment, the last HbA1c assessment before rescue treatment will be used 
for primary efficacy analysis.
10.4.2
Statistical hypothesis, model, and method of analysis
There is no formal hypothesis testing planned in this study. An estimate of the mean 
difference of the change from randomization in HbA1c between the two randomized arms 
will be reported along with 95% confidence interval (CI). Patients will be stratified by their 
disease and baseline glycemic status. Variance estimation will be based on the following 
analysis of variance (ANOVA) model using the two stratification factors as well as treatment 
as fixed effects. RAS will be used for primary analysis:
Change from baseline in HbA1c = Baseline glycemic status + Disease + Treatment + Error
Disease:
a. Cushing’s disease
b. Acromegaly
Glycemic status at baseline:
a. HbA1c < 7 %
b. HbA1c ≥ 7%
Treatment:
a. Incretin based therapy group
b. Insulin group
10.4.3
Handling of missing values/censoring/discontinuations
For patients who discontinued the study or require rescue treatment before the time of 
assessing primary endpoint, the last HbA1c assessment collected 8 weeks after randomization 
will be carried forward for primary efficacy analysis. If the patient discontinued the study or 
used rescue treatment within 8 weeks after randomization, it will be considered missing for 
primary analysis.
10.4.4
Supportive analyses
Mean difference of change from randomization to the time of assessing the primary endpoint 
between two randomized arms, as well as the corresponding 95% confidence interval will be 
analyzed by ANOVA with disease state and baseline glycemic status as fixed effects. Patients 
taking rescue treatment before the time of assessing the primary endpoint will follow ITT rule, 
i.e., HbA1c assessment on Core EOP in each randomized arm will be utilized for analysis 
regardless of rescue treatment use. RAS will be used for supportive analysis. Subgroup 
analysis by disease and baseline HbA1c level may be performed.


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In addition, the primary efficacy variable will be analyzed by analysis of covariance 
(ANCOVA) model with treatment and disease as classification variables and baseline HbA1c 
as the covariate. The least squares mean (“adjusted mean”) of change from randomization for 
each treatment group and its standard error (SE), the difference between two treatment groups 
and the associated two-sided 95% CI for the difference will be obtained from the following 
ANCOVA model.
Change from baseline in HbA1c = intercept + Baseline HbA1c + Disease + Treatment + Error
Disease:
a. Cushing’s disease
b. Acromegaly
Treatment:
a. Incretin based therapy group
b. Insulin group
10.5
Secondary objectives
The secondary objectives are to assess the overall effect of anti-diabetic intervention on the 
glycemic control, as well as the sustainability of glycemic control in the insulin arm and the 
incretin based therapy arm in patients with Cushing’s disease or acromegaly. Safety and 
tolerability of pasireotide and anti-diabetic treatments will also be evaluated.
10.5.1
Key secondary objective(s)
Not applicable.
10.5.2
Other secondary efficacy objectives
10.5.2.1 Change in HbA1c and FPG to EOP
The change in HbA1c and FPG from baseline to the core EOP in patients who received 
pasireotide (FAS) will be summarized by treatment group using descriptive statistics. 95% 
confidence intervals will be provided for the changes from baseline.
10.5.2.2 Proportion of patients with an increase in HbA1c less than or equal 0.3%
The proportion of patients with an increase from baseline in HbA1c ≤ 0.3% at Core EOP will 
be summarized for each randomized arm. The corresponding 95% confidence interval will be 
estimated by exact method.
10.5.2.3 Change in HbA1c and FPG overtime
The change in HbA1c and FPG from randomization overtime and to the core EOP (only for 
FPG) will be summarized for each randomized arm. Descriptive statistics as well as 95% 
confidence intervals will be provided for the changes from baseline. Graphical presentation 
will also be used for change from randomization overtime in HbA1c and FPG.


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10.5.2.4 Proportion received anti-diabetic rescue therapy
The proportion of patients who received anti-diabetic rescue therapy in incretin based therapy 
will be summarized. The corresponding 95% confidence interval will be estimated by exact 
method.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
SAS will be used for safety analysis including both pre-randomized period and randomized 
treatment period. Randomized patients within SAS will be used to summarize main safety 
output during the randomized treatment period. All listings and tables will be presented by
disease state when using SAS unless otherwise specified, safety outputs on randomized 
patients will be presented by disease state and by randomized arms. 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 pasireotide s.c., and 84 days after last dose of pasireotide LAR, or the follow-up visit, 
whichever comes later. On-treatment period can be further divided into pre-randomized 
period and randomized treatment period as depicted in the visit evaluation schedule in 
Table 7-1.
3. Post-treatment period: starting at 28+1 days after last dose of pasireotide s.c., and 84 days
+ 1 day after last dose of pasireotide LAR, or the follow-up visit + 1 days whichever 
comes later.
10.5.3.2 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 Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 grades), type of AE, and 
relation to study treatment.
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type 
of adverse event.
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. In this study, SEC refers to AE of special interest.


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10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered by 
CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded as 
low/normal/high based on laboratory normal ranges (NRs).
The following by-treatment summaries will be generated separately for hematology, clinical 
chemistry and urinary laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4 (see below for details)

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(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 CTCAE 
grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, might be 
specified in the RAP (Report and Analysis Plan).
10.5.3.4 Other safety data
ECG

Data from ECG will be listed, notable values will be flagged, and any information 
collected will be listed as appropriate.

Summary statistics will be provided at baseline and scheduled post-baseline time points 
for ECG variables PR, QRS, QT/QTcF interval and ventricular rate. Shift table from 
baseline to worst on-treatment result and summary statistics of changes from baseline will 
also be provided.

Number and percentage of patients with clinically notable QT/QTcF interval values will 
be summarized.
Vital signs
Definitions of notably abnormal results have to part of the Clinical Development Plan (CDP), 
Master Analysis Plan (MAP), Clinical Study Protocol (CSP) and Report and Analysis Plan 
(RAP).

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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Hypoglycemia events
The number of treatment emergent hypoglycemia events, as well as the number of patients 
with hypoglycemia events will be summarized using SAS by treatment group. Hypoglycemia 
events will be defined based on CTCAE grade.
Thyroid function tests
Change from baseline to different time points for thyroid function tests will be summarized 
along with corresponding descriptive statistics.
Gallbladder examinations
Shift table of baseline to worst on-treatment result for gallbladder examinations will be 
provided.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.4
Biomarkers
Not applicable.
10.5.5
Patient-reported outcomes
Not applicable.
10.6
Exploratory objectives
Not applicable.
10.7
Interim analysis
Not applicable.
10.8
Sample size calculation
There is no formal hypothesis testing planned in this study.
A total sample size of 68 randomized evaluable patients (in 1:1 allocation ratio to incretin 
based therapy and insulin) with at least 8 weeks of randomized treatment without any rescue 
anti-diabetic medication is required. In order to reach 68 randomized evaluable patients, 
approximately 79 patients will be randomized based on current drop-out/rescue rate prior to 
Week 8 (i.e., patients without 8 weeks of randomized treatment or took rescue medication 
prior to Week 8). The total number of enrolled patients will be based on the actual 
randomization (which occurs within 16 weeks after patients are enrolled) rate which will be 
monitored regularly.
The sample size was calculated to ensure that the half-width of the 95% confidence interval 
around the mean difference of the change from randomization to Week 16 (the subsequent 
scheduled visit after 16 weeks in randomization) in HbA1c (%) will be approximately 0.5%. 


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The calculation was performed using R version 3.00 and based on a standard deviation of 
1.03%, which was consistent with the results from the CSOM230B2305 phase III trial.
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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 patient’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 
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.


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11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.5.1
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/index.html#author.
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 
author. Study investigators must have significant contribution to patient recruitment based on 
number of eligible patients upon study entry and data quality.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 


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and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (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.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.


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12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC 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)
American Diabetes Association (2013). Standards of medical care in diabetes - 2013. Diabetes 
Care; 36 (Suppl 1);S11-66.
Biller BMK, Grossman AB, Stewart PM, et al (2008). Treatment of adrenocorticotropin 
independent Cushing’s Syndrome: a consensus statement. J Clin Endocrinol Metab; 
93(7):2454-62.
Freda P (2002) Somatostatin Analogs in Acromegaly. Journal of Clinical Endocrinology & 
Metabolism; 87(7):3013-8.
Melmed S, Jackson I, Kleinberg D, et al (1998) Current treatment guidelines for acromegaly. 
J Clin Endocrinol Metab; 83(8):2646-52.
Nathan DM, Buse JB, Davidson MB, et al (2008) Management of hyperglycemia in type 2 
diabetes: A consensus algorithm for the initiation and adjustment of therapy; Diabetes Care; 
31(1):173-5.
Oberg K, Kvols L, Caplin M et al (2004). Consensus report on the use of somatostatin analogs 
for the management of neuroendocrine tumors of the gastroenteropancreatic system. Annals 
of Oncology; 15(6):966-73.
Pivonello R, De Martino MC, De Leo M, et al (2008). Cushing’s Syndrome. Endocrinol. 
Metab Clin N Am; 37:135-49.
Schmid HA, Brueggen J (2012). Effects of somatostatin analogs on glucose homeostasis in 
rats. J Endocrinol; 212(1):49-60.
Van der Hoek, J, Waaijers M, Van Koetsveld PM, et al (2005). Distinct functional properties 
of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH 
release by coritcotroph tumor cells. Am J Phsyiol Endocrinol Metab; 289:E278-87.
Wass J, Lamberts S, Melmed S (2001). Long-term treatment strategies for acromegaly. In: 
Wass J (eds). Handbook of Acromegaly. BioScientifica, Bristol; 7:79-83.


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14
Appendices
14.1
Appendix 1: Medications known to be associated with QT 
interval prolongation
The following list of drugs is generally recognized to have a possible association with QT 
prolongation. This list is not considered to be all inclusive and any questions regarding the QT 
prolongation potential should be discussed with the Novartis Medical Monitor.
The current list of these drugs can be found on:
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm
Drugs that are generally accepted by the QTdrugs.org Advisory Board of the Arizona CERT 
to have a risk of causing torsade de pointes are listed below.
Generic Name
Class
Bepridil
Anti-anginal / heart pain
Amiodarone
Anti-arrhythmic / abnormal heart rhythm
Azithromycin
Antibiotic
Disopyramide
Anti-arrhythmic / abnormal heart rhythm
Dofetilide
Anti-arrhythmic / abnormal heart rhythm
Ibutilide
Anti-arrhythmic / abnormal heart rhythm
Procainamide
Anti-arrhythmic / abnormal heart rhythm
Quinidine
Anti-arrhythmic / abnormal heart rhythm
Sotalol
Anti-arrhythmic / abnormal heart rhythm
Clarithromycin
Antibiotic / bacterial infection
Sparfloxacin
Antibiotic / bacterial infection
Erythromycin
Antibiotic;GI stimulant / bacterial infection; increase GI motility
Arsenic trioxide
Anti-cancer / Leukemia
Astemizole
Antihistamine / Allergic rhinitis
Terfenadine
Antihistamine / Allergic rhinitis
Pentamidine
Anti-infective / pneumocystis pneumonia
Probucol
Antilipemic / Hypercholesterolemia
Chloroquine
Anti-malarial / malaria infection
Halofantrine
Anti-malarial / malaria infection
Domperidone
Anti-nausea / nausea
Mesoridazine
Anti-psychotic / schizophrenia
Thioridazine
Anti-psychotic / schizophrenia
Haloperidol
Anti-psychotic / schizophrenia, agitation
Pimozide
Anti-psychotic / Tourette's tics
Chlorpromazine
Anti-psychotic/ Anti-emetic / schizophrenia/ nausea
Cisapride
GI stimulant / heartburn
Levomethadyl
Opiate agonist / pain control, narcotic dependence
Methadone
Opiate agonist / pain control, narcotic dependence
Droperidol
Sedative;Anti-nausea / anesthesia adjunct, nausea


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14.2
Appendix 2: Formula to calculate QTcF
If the ECG machine at your site does not automatically provide QTcF then use the following 
formula to calculate it.
QTcF = QTInterval / (RRInterval) 1/3 in msec.
Use the QTInterval and RRInterval provided by the ECG machine.
All calculations should be part of the source documentation in the patients’ files.


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14.3
Appendix 3: Lifestyle measures in association with anti-diabetic 
treatments
Lifestyle recommendations from the ADA (ADA 2013)
You have the power to improve and protect your health. With proper nutrition and physical 
activity and by making good lifestyle choices (like not smoking), you can feel better, stronger, 
and healthier, and can lower your risk of diseases such as cancer, diabetes, heart disease and 
stroke.
What is a Healthy Weight?
There's an easy way to find out if your current weight puts you at risk for developing serious 
diseases. Go to www.diabetes.org/bmi and take the Body Mass Index (BMI) test. The results 
will help you decide if you need to be concerned about your weight.
The Better You Eat, the Better You Feel
Here are some basic guidelines to help you and your family make healthier food decisions.

Eat lots of vegetables and fruits.

Choose whole grain foods over processed grain products. Try brown rice instead of white. 
Substitute whole wheat bread for white.

Eat fish 2 - 3 times a week.

Select leaner cuts of meat like those that end in "loin."

Remove the skin from chicken and turkey.

Eat non-fat dairy

Drink water and calorie-free non-carbonated beverages.

Use liquid oils for cooking instead of solid fats.

Cut back on high calorie snacks like chips, cookies, cakes, and regular ice cream. Look for 
baked chips and reduced calorie snacks. Or have a piece of fruit instead.

Watch your portion sizes. Even too much "healthy" food can cause weight gain.
Another resource that you might find valuable is the American Diabetes Association's online 
nutrition tool, My Food Advisor. Here you can find recipes, compare foods, search for 
healthier alternatives and calculate calories, carbohydrates and other nutrients for a meal, a 
recipe or a whole day of food.
Tips:

Compare labels of similar foods, then choose the one with smaller amounts of saturated fat, 
cholesterol and sodium.

Adults should eat less than 2400 mg. of sodium per day. If you have high blood pressure, 
you should aim for even less.

Try adding herbs and spices in your cooking to take the place of salt for enhancing flavor.
To learn more about comparing foods and making healthier choices, go to 
www.diabetes.org/myfoodadvisor.


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A Little Physical Activity Goes a Long Way
Anything that gets you up and moving is good for you. Here's what it can do:

Reduce your risk of developing type 2 diabetes

Reduce your risk of heart disease and stroke

Lower blood pressure and cholesterol

Reduce blood glucose (sugar) levels if you have diabetes, which can reduce your risk of 
developing diabetes-related complications

Relieve stress

Help you lose weight

Give you more energy

Help you sleep better

Build stronger bones and muscles
You don't need to go to a gym, play sports or use fancy equipment. Of course, you should talk 
to your doctor before starting any exercise regimen.
If You Have Diabetes
Eating healthy and staying active are even more important if you have diabetes. Well-
balanced meals can help keep your glucose (sugar) level as close to normal as possible.
Being active also helps you lower your blood glucose. If you increase your level of physical 
activity, you may be able to take less insulin or diabetes pills. If you're very inactive, have 
heart disease or a history of foot ulcers, consult your doctor about safe exercise for you.
Check your blood glucose before exercising. If it's under 100 mg/dl, eat some fruit, crackers 
or have a glass of milk or juice. Check it again after exercising to learn how your blood 
glucose reacts to exercise. Bring a snack if you'll be active for a few hours.

SAP_001.pdf: 
Clinical Development
Pasireotide, SOM230
CSOM230B2219 / NCT02060383 
A multi-center, randomized, open-label, Phase IV study to 
investigate the management of pasireotide-induced 
hyperglycemia with incretin based therapy or insulin in 
adult patients with Cushing’s disease or acromegaly
Statistical Analysis Plan (SAP)
Author:
 Trial Statistician
Document type:
SAP Documentation
Document status:
Final 1.0 Amendment 2
Release date:
25-Jun-2018
Number of pages:
27
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CSOM230B2219
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted 
(Current)
15-
Aug-
2014
Prior 
to DB 
lock
Creation 
of 
final version
N/A - First version
NA
07-
Feb-
2018
Prior 
to DB 
lock
Creation of 
amendment 
1
Change from RAP 
module 3 to new SAP 
template.
Update of sample size 
section following 
protocol amendment 2 
which removed the 
protocol requirement to 
randomize the equal 
number of patients with 
Cushing’s disease and 
Acromegaly.
Clarification that 
reported but unreliable 
serum creatinine values 
(due to technical 
malfunction) are 
excluded from summary 
tables.
Addition of AE language 
for safety disclosure at 
CT.gov / EudraCT.
Addition of location of 
PTs for AEs of special 
interest.
Updated pasireotide
nomenclature from 
pasireotide LAR to 
pasireotide long-acting
Addition of diabetic 
status definition, and 
analysis of change in 
this status during the 
study
Addition of analysis of 
change in HbA1c 
categories
Throughout the SAP, the sections from 
the previous RAP M3 have been mapped
to the relevant section in the SAP 
template.
In Section 3.1, sample size was updated 
in line with protocol amendment 2.
Section 2.8.3
Section 2.8.2.4
Section 2.8.2.5
Various sections
Section 2.1.1.6 & Section 2.7.6
Section 2.7.5
25-Jun-
2018
Prior 
to DB 
lock
Creation of 
amendment 
2
Update of diabetic status 
definition to be aligned 
with protocol
Rewording of supportive 
analysis for the primary
Addition of potential 
subgroup analysis by 
Section 2.1.1.6
Section 2.5.4
Section 2.7


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SAP Amendment 2
CSOM230B2219
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted 
(Current)
disease for secondary 
efficacy objectives
Correction of reference 
to Sections in Table 1-1
Section 1.3


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SAP Amendment 2
CSOM230B2219
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Protocol amendments...............................................................................................7
1.2
Study design.............................................................................................................8
1.3
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................15
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Patient disposition.................................................................................16
2.3.2
Demography and baseline disease characteristics.................................17
2.3.3
Medical history and current medical conditions ...................................17
2.3.4
Protocol deviations (PDs) .....................................................................17
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................18
2.4.1
Exposure to Study Treatment................................................................18
2.4.2
Concomitant medication .......................................................................18
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................18
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.5.4
Supportive analyses...............................................................................19
2.6
Analysis of the key secondary objective ...............................................................20
2.7
Analysis of secondary efficacy objective(s)..........................................................20
2.7.1
Change in HbA1c and FPG to EOP......................................................20
2.7.2
Proportion of patients with an increase in HbA1c less than or equal 
0.3% ......................................................................................................20
2.7.3
Change in HbA1c and FPG overtime....................................................20
2.7.4
Proportion received anti-diabetic rescue therapy..................................20
2.7.5
Change in HbA1c category...................................................................20
2.7.6
Change in diabetic status.......................................................................21
3
Safety analyses ..................................................................................................................21
3.1.1
Analysis set and grouping for safety analysis.......................................21
3.1.2
Adverse events (AEs)............................................................................21


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3.1.3
Laboratory data .....................................................................................24
3.1.4
Other safety data ...................................................................................24
3.2
PD and PK/PD analyses.........................................................................................26
3.3
Patient-reported outcomes .....................................................................................26
3.4
Biomarkers.............................................................................................................26
3.5
Other Exploratory analyses....................................................................................26
3.6
Interim analysis......................................................................................................26
4
Sample size calculation .....................................................................................................26
4.1
Primary analysis.....................................................................................................26
5
Change to protocol specified analyses ..............................................................................26
5.1
Imputation rules.....................................................................................................27


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CSOM230B2219
List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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CSOM230B2219
1
Introduction
This document describes the detailed statistical methodology to be used in analyzing the data 
collected consequent to study CSOM230B2219 in patients with Cushing’s disease or 
acromegaly. 
The study will be analyzed when all treated patients have completed the study or discontinued 
earlier, and the final CSR will be produced. 
The data from all centers participating in the trial will be combined, so that an adequate number 
of patients will be available for analysis. The statistical analysis methods described in this SAP 
will focus on the analysis of the data in the core study. Similar methods will be applied to the 
analyses in the extension phase as appropriate.
All decisions regarding final analysis, as defined in the SAP document, have been made prior 
to database lock of the study data.
1.1
Protocol amendments
At the time of finalization of this document the original study protocol had undergone three
amendments, as summarized below.
Amendment 1, 08-Aug-2014
Amendment 1 amended visit schedule by adding Week 1 in pasireotide s.c. for ECG and liver 
function test, and adding Week 3 in pasireotide long-acting for ECG per health authorities 
request. The inclusion/exclusion criteria are modified in line with adverse drug report profile or 
to account for gender difference. In addition, the safety follow-up of pasireotide long-acting 
was updated to 84 days instead of 56 days to ensure 5 times elimination half-life. Wash out 
periods of other SSAs and previous exposure to pasireotide was updated. 
Amendment 2, 29-Sep-2016
As of 9-Sep-2016, 166 patients have been enrolled (49 patients with Cushing’s disease and 117 
patients with acromegaly). Of the 166 patients enrolled in the trial, out of the planned 79 patients 
have been randomized (20 Cushing’s disease and 30 acromegaly).
The rationale of this amendment 2 is to remove the protocol requirement to randomize the equal 
number of patients with Cushing’s disease and Acromegaly (a total of 79 patients).
In protocol amendment 1, the target was to randomize 79 patients (42 in Cushing’s disease and 
37 in acromegaly) to obtain 68 randomized patients (34 with Cushing’s disease and 34 with 
acromegaly, who completed at least 8-week randomized treatment without any rescue 
medication).
Cushing’s disease is a rare disease with a low incidence and prevalence and the recruitment of 
these patients in clinical studies is challenging. In the present study, the availability of this 
patient population has been lower than expected and consequently, more patients with 
acromegaly than patients with Cushing’s disease are being screened and ultimately randomized. 
Despite the fact that patients with Cushing’s disease and Acromegaly exhibit insulin resistance 
and metabolic abnormalities secondary to different mechanisms and that the severity of 


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SAP Amendment 2
CSOM230B2219
hyperglycemia might differ, the effect of pasireotide on glucose metabolism is expected to be 
the same in both populations (i.e. increase of blood glucose levels by decreasing insulin and 
incretin secretion). Therefore, the proportion of randomized patients from each disease group 
is not expected to affect the scientific value of the study.
Amendment 3, 17-Mar-2017
Clarification regarding the protocol visits included in the 28-day Safety follow-up for Cushing’s 
disease patients receiving pasireotide s.c and the 84-day Safety follow-up for acromegaly 
patients receiving pasireotide long-acting as follows:

Eligible patients as per protocol who are transitioning to a roll-over study or local access 
program will not be required to perform the safety follow-up visit (779) as patients will 
continue to be monitored for safety.

Eligible patients as per protocol who are transitioning to commercial drug will be 
required to perform the safety follow-up visit (779).

Re-insertion of the missing Figure 6-1 QT Prolongation Safety Management.

Allow a ± 3 day visit window for Cushing’s patients. Visit windows for Acromegaly 
patients will remain unchanged as per Table 7-1.
1.2
Study design
This is a Phase IV, multi-center, randomized, open-label study. Eligible patients will start 
pasireotide s.c. for Cushing’s disease and pasireotide long-acting for acromegaly. 
Patients currently treated at screening visit with pasireotide s.c. or LAR are eligible if they have 
an elevated FPG > ULN or a diagnosis of diabetes (FPG ≥ 126 mg/dL on two occasions or 
HbA1c ≥ 6.5% or a random plasma glucose ≥ 200 mg/dL with classic symptoms of 
hyperglycemia (polydipsia, polyphagia and polyuria)) during screening period. For patients 
naive to pasireotide, if previously normo-glycemic patients experience increases in their fasting 
blood glucose based on pre-defined glycemic criteria while on pasireotide, they will start anti-
diabetic treatment using metformin. If they continue to experience increases in their fasting 
blood glucose within the first 16 weeks, they will be randomized in a 1:1 ratio to receive 
treatment with incretin based therapy (sitagliptin followed by liraglutide) or insulin for 
approximately 16 weeks. The effect on glycemic control will be evaluated up to 32 weeks.
To ensure a similar distribution of patients expected to develop mild/moderate/severe 
hyperglycemia in both treatment arms, randomization will be stratified according to the levels 
of the following two factors:

Disease:
a. Cushing’s disease
b. Acromegaly 

Glycemic status at baseline:
a. HbA1c < 7 % 
b. HbA1c ≥ 7%


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Patients who are not randomized by Week 16 (of pre-randomized period) will have their Core 
End of Phase (EOP) visit on Week 16. Patients who are randomized will have their Core EOP 
visit 16 weeks post-randomization. 
The total duration of the core study treatment will be a maximum of 32 weeks. Forpatients who 
do not continue into the extension phase, the last injection of pasireotide s.c. on study will be 1 
day prior to Core EOP visit and the last injection of pasireotide long-acting on study will be 4 
weeks prior to Core EOP visit. 
All patients who will not continue pasireotide treatment must have safety follow-up evaluations 
after the Core (or Extension) EOP visit, which will be 84 days after the last dose of pasireotide 
long-acting treatment and 28 days after pasireotide s.c. treatment.
Data Cutoff for Analyses
Patients who discontinue study drug (pasireotide s.c. or pasireotide long-acting) will be 
considered withdrawn from the study after the final visit assessments and the final safety follow-
up visit are performed or when it is clear that the patient will not return for final visit 
assessments and/or final safety follow-up visit. The CSR will be generated after all patients 
have completed the study or discontinued earlier. The results within the CSR will be split to 
show results for the core phase only, then then also for the overall study (core and extension 
combined). For the two randomized arms, the core phase results will be split into the pre-
randomized and randomized treatment periods as necessary.
Figure 1-1
Study design schema


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1.3
Study objectives and endpoints
The study objectives and related endpoints as specified in the protocol are given in Table 1-1.
Table 1-1
Study objectives
Objective
Endpoint
Analysis
Primary
Refer to Section
To evaluate the effect of treatment with 
incretin based therapy vs. insulin on the 
16-week glycemic control in patients 
with Cushing’s disease or acromegaly 
who develop or worsen hyperglycemia 
on pasireotide, and cannot be controlled 
by metformin alone or other background 
anti-diabetic treatments
Change in HbA1c from randomization 
to approximately 16 weeks in the 
incretin based therapy arm and insulin 
arm
2.5
Secondary
Refer to Section
To evaluate the overall effect of anti-
diabetic intervention on glycemic control 
in patients with Cushing’s disease or 
acromegaly
- Change in HbA1c and FPG from 
baseline to Core EOP (End of Phase) 
in patients who received pasireotide by 
treatment group
2.71
To evaluate the sustainability of 
glycemic control in the incretin based 
therapy arm and the insulin arm in 
Cushing’s disease patients treated with 
pasireotide s.c. and acromegaly 
patients treated with pasireotide long-
acting
- Proportion of patients with ≤ 0.3% 
HbA1c increase from baseline to Core 
EOP per randomized arm
- Change in HbA1c and FPG from 
randomization over time and to Core 
EOP (only for FPG) per randomized 
arm
- Proportion of patients who required 
anti-diabetic rescue therapy with 
insulin per randomized arm
- Proportion of patients with HbA1c at 
the end of the core and extension 
phases in the following categories:

HbA1c < 6.5%

6.5% ≥HbA1c < 7%

HbA1c ≥7%
- Change in diabetic status during the 
core and extension phases (diabetic 
status is defined in section 2.1.1.6)
2.7.2
2.7.3
2.7.4
2.7.5
2.7.6
To evaluate the safety and tolerability of 
pasireotide in combination with anti-
diabetic treatments
- Toxicity will be assessed using NCI-
CTC criteria version 4.03 for adverse 
events.
- Incidence of hypoglycemia events (# 
of episodes, # of patients)
- Clinical chemistry, hematology, 
urinalysis assessments
- ECGs 
3.1.2
3.1.4.2
3.1.3
3.1.4.1


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Objective
Endpoint
Analysis
- Special safety assessments: Thyroid 
function tests, pancreatic safety tests 
(for anti-diabetic treatments) and 
gallbladder examinations
3.1.4.3
3.1.4.4


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2
Statistical methods
2.1
Data analysis general information
The primary and final analysis will be performed by Novartis. SAS version 9.4 or later will be 
used to perform all data analyses and to generate tables, figures and listings.
2.1.1
General definitions
Patients with Cushing’s disease will take pasireotide s.c., and patients with acromegaly will 
take pasireotide long-acting. Herein, study drug is used to reference pasireotide across this 
document.
In addition, for the purpose of analysis, the patients will be grouped into randomized patients, 
and non-randomized patients group, forming a total of five mutually-exclusive treatment groups 
based on the anti-diabetic treatment received: 
Randomized treatment groups
1. Incretin based therapy group
2. Insulin group
Non-randomized treatment groups
3. Baseline insulin group - includes patients who receive insulin at baseline and thus not 
randomized. 
4. Oral anti-diabetic (OAD) treatment group - patients who developed hyperglycemia that 
can be controlled by metformin or their background anti-diabetic treatment and thus not 
randomized 
5. No anti-diabetic treatment (NAD) group - includes patients who do not receive any anti-
diabetic treatment during the core phase of the study and thus not randomized. 
The NAD group, baseline insulin group, and OAD group are the three non-randomized groups 
that will be treated for 16 weeks during the core phase. The core treatment period of the two 
randomized arms, i.e., incretin based therapy group and insulin group, is varied and can be up 
to 32 weeks depending on when patients get randomized.
2.1.1.1
Study day
Study day 1 is the date of first administration of study drug.
The study day for an event that occurs prior to study day 1 will be calculated as (date of event 
– date of first administration of study drug).
The study day for an event that occurs on or after study day 1 will be calculated as (date of 
event – date of first administration of study drug) + 1.
2.1.1.2
Baseline
For efficacy and safety evaluations, the last available pre-dose assessment is taken as “baseline” 
assessment. If several measurements are taken on the same day, the last one prior dose is used 
as measurement of that day.


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2.1.1.3
Visit number
The time point (Day/Week) associated with an assessment, will be determined by the visit 
number assigned to the corresponding assessment in the database. The mappings of visit 
numbers to time points in the core study and the extension phases are provided in Table 2-1 and
Table2-2. 
Table 2-1
Visit number during the core phase
Core phase visit 
Day/Week
Clarifying notes
Visit 1
Day -21 to Day -1
Screening
Visit 2
Day 1/PRW0
Baseline
Visit 401
Day 8/PRW1
Pre-randomization period
Visit 3
Day 15/PRW2
Pre-randomization period
Visit 402
Day 22/PRW3
Pre-randomization period
Visit 4
Day 29/PRW4
Pre-randomization period
Visit 5
Day 57/ PRW8
Pre-randomization period
Visit 6
Day 85/ PRW12
Pre-randomization period
Visit 7
R-Day1/RW0
Randomization period
Visit 8
R-Day15/RW2
Randomization period
Visit 9
R-Day29/RW4
Randomization period
Visit 10
R-Day43/RW6
Randomization period
Visit 11
R-Day57/RW8
Randomization period
Visit 12
R-Day71/RW10
Randomization period
Visit 13
R-Day85/RW12
Randomization period
Visit 14
R-Day99/RW14
Randomization period
Visit 777
R-Day113/RW16
End of treatment in core phase
Visit 779
28 days after last s.c. 
dose or 84 days after last 
LAR dose
End of study/Follow-up
Table 2-2
Visit number during the extension phase
Extension phase visit 
Day/Week
Clarifying notes
Visit 15
E-Day 1/EW0
Long term extension
Visit 16
E-Day 29/EW4
Long term extension
Visit 17
E-Day 57/EW8
Long term extension


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Extension phase visit 
Day/Week
Clarifying notes
Visit 15
E-Day 1/EW0
Long term extension
Visit 18
E-Day 85/EW12
Long term extension
Visit 19
E-Day 113/EW16
Long term extension
Visit 20
E-Day 141/EW20
Long term extension
Visit 21
E-Day 169/EW24
Long term extension
Visit 22
E-Day 197/EW28
Long term extension
Visit 23
E-Day 225/EW32
Long term extension
Visit 24
E-Day 253/EW36
Long term extension
Visit 25
E-Day 281/EW40
Long term extension
Visit 26
E-Day 309/EW44
Long term extension
Visit 27
E-Day 337/EW48
Long term extension
Visit 28
E-Day 365/EW52
Long term extension
Visit 29
E-Day 393/EW56
Long term extension
…
…
Long term extension
Visit 778
…
End of treatment in extension phase
Visit 779
28 days after last s.c. 
dose or 84 days after 
last LAR dose
End of study
Unlike the above visits that are scheduled to occur after a fixed number of days have elapsed 
since Day 1, the Visits 777 (End-of-Treatment in core phase) and 778 (End-of-Treatment in 
extension phase) are scheduled when the patient either completes the respective study phase or 
decides (or is mandated by the protocol) to prematurely discontinue from the study. 
If such a visit happens neither too soon nor too late after the actual last scheduled visit, then it 
will be mapped to the next scheduled visit that would have occurred had the patient continued 
in the study. Otherwise, the early discontinuation visit will be mapped to an unscheduled visit.
The 777/778 visit will be considered to have occurred neither too soon nor too late after the 
actual last scheduled visit if number of days between the two visits is
1. at least half of the planned gap between the patient’s actual last scheduled visit and the 
next scheduled visit and
2. at most the total of
a. the planned gap between the patient’s actual last scheduled visit and the next 
scheduled visit (that would have occurred if the patient had not discontinued)  
b. half of the planned gap between the patient’s next two scheduled visits (that would 
have occurred if the patient had not discontinued).


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If the number of days between the 777/778 visit and last scheduled visit (last scheduled visit 
+1) is less than the range specified above, then the 777/778 visit will be mapped to an 
unscheduled visit of the last scheduled visit (last scheduled visit +1); if it’s more than the range, 
then it will be mapped to an unscheduled visit of the last scheduled visit + 1 (last scheduled 
visit+2). 
Further, if a patient continued into the extension phase, then we set Visit 777 in the core phase 
to Visit 14 without checking the days-in-between. Visit 779 will not be mapped.
2.1.1.4
Conversion of duration in days to duration in months/years
Duration in months = 12 * (Duration in days)/365.25
Duration in years = (Duration in days)/365.25
2.1.1.5
Method for calculating confidence interval
Two-sided 95% confidence intervals for proportions will be calculated using the exact 
(Clopper-Pearson) method, unless stated otherwise.
Two-sided 95% confidence intervals for change and percentage change from baseline will 
assume normally distributed data and will be calculated using the t-distribution.
2.1.1.6
Diabetic status
Patients will be assigned a diabetic status at baseline, and at subseuqent visits during the study.
Diabetic status is defined as one of

Diabetic: Patients taking antidiabetic medication, or prior history of DM, or HbA1c>= 
6.5%, or at two different visits FPG>= 126 mg/dL

Pre-diabetic: Patients not qualifying as diabetic and with 100 mg/dL <=FPG and/ or 5.7% 
<=HbA1c< 6.5%

Normal glucose tolerance: Patients not qualifying as diabetic or pre-diabetic and with 
FPG< 100 mg/dL and/ or HbA1c< 5.7%
Patients classified as diabetic will stay in that category for the rest of the study.
2.2
Analysis sets
Randomized analysis set
The Randomized Analysis Set (RAS) comprises all patients who received at least one dose of 
pasireotide and have been assigned to either incretin based therapy or insulin by randomization. 
According to the ITT principle, patients will be analyzed according to the treatment they have 
been assigned to during the randomization procedure. RAS will be used for the primary analysis 
and some secondary analyses. 


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Full analysis set
The Full Analysis Set (FAS) comprises all patients who receive at least one dose of pasireotide. 
The anti-diabetic treatment group will follow the Intent-To-Treat (ITT) principle. RAS is a 
subgroup of FAS.
Safety analysis set
The Safety Analysis Set (SAS) includes all patients who received at least one dose of pasireotide 
and had at least one post-baseline safety assessment. SAS will be used for safety summaries. 
Randomized patients within SAS will be analyzed according to the anti-diabetic study treatment 
first received.
The statement that a patient had no adverse events (on the Adverse Event CRF) constitutes a 
safety assessment. Patients who have received at least one dose of study drug but who have no 
post-treatment safety data of any kind would be excluded from the SAS.
The analysis sets used for various analyses are summarized in the following table
RAS
FAS
SAS
Patient Disposition
X
Protocol Deviation
X
Demography and baseline disease 
characteristics
X
Medical History
X
Prior Medication
X
Concomitant Medications
X
Exposure to study medication
X
Primary efficacy analyses
X
Other efficacy analyses
X
X
Safety analyses
X
2.3
Patient disposition, demographics and other baseline 
characteristics
Frequency distributions or summary statistics of data pertaining to subject disposition, 
demographics, baseline characteristics, medical history, prior medications and protocol 
deviations will be tabulated and displayed for all enrolled patients. 
2.3.1
Patient disposition
Patient disposition will be summarized using the FAS by disease and the 5 treatment groups, 
i.e., incretin based therapy, insulin, and the three non-randomized treatment groups. Counts of 
the following items will be included in disposition summaries. Patients who are ongoing in the 
extension phase will also be summarized.


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
Patients treated

Treatment ongoing*

End of treatment

Primary reason for end of treatment in the core phase** 

Patients completed core phase 

Patients did not enter extension phase

Entered extension phase 

Completed extension phase

Discontinued in extension, with reasons for discontinuation
* ongoing is only summarized at the time of the data cut-off, if applicable
** core phase is 16 weeks for non-randomized patients, and up to 32 weeks for randomized 
patients
2.3.2
Demography and baseline disease characteristics
Summary statistics will be provided for demographics, and baseline characteristics using FAS
by disease and the 5 treatment groups, i.e., incretin based therapy, insulin, and the three non-
randomized treatment groups. Categorical data will be presented by frequencies and 
percentages. Continuous data will be summarized by mean, standard deviation, minimum, 
median, and maximum. All data for background and demographic variables, as well as medical 
history, current medical conditions, results of lab screens, and any other relevant information 
will also be presented in listing.
2.3.3
Medical history and current medical conditions
Relevant medical history and current medical conditions will be summarized and listed by 
disease and the 5 treatment groups, i.e., incretin based therapy, insulin, and the three non-
randomized treatment groups. The summary will be presented for FAS by primary system organ 
class (SOC) and preferred term (PT).
2.3.4
Protocol deviations (PDs)
Protocol deviation criteria are specified in the Validation and Planning (VAP) document 
Module 3. The number and percentage of FAS patients with protocol deviations will be 
provided for PDs by the end of the study.
All protocol deviations up to data cutoff will be listed by disease and 3 treatment groups, i.e., 
incretin based therapy, insulin, and non-randomized treatment group.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Exposure to Study Treatment
The duration of exposure to the study drug will be summarized by descriptive statistics using 
the SAS. Exposure will be summarized for pasireotide s.c., pasireotide long-acting, metformin, 
insulin, sitagliptin, and liraglutide.  Exposure to pasireotide will be summarized for all patients. 
Exposure to metformin will be summarized by the randomized treatment groups (incretin based 
therapy and insulin), and for the three non-randomized groups. Exposure to all other anti-
diabetic medications will be summarized by the two randomized groups.
Duration of exposure of daily dose for those medications that are administered daily (i.e. all 
anti-diabetic medication and pasireotide s.c.) is calculated as   
Duration of exposure (months) = (min (last date of study medication, date of death, date 
of data cut-off) – first date of study medication + 1)/(365.25/12)
Duration of exposure of pasireotide long-acting is calculated as   
Duration of exposure (months) = (min (last date of study medication + 27, date of death, 
date of data cut-off) – first date of study medication + 1)/ (365.25/12)
2.4.2
Concomitant medication
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized and listed by disease and 5 treatment groups (incretin based 
therapy, insulin, and the 3 non-randomized treatment groups) according to the Anatomical 
Therapeutic Chemical (ATC) classification system and preferred term by means of frequency 
counts and percentages using the SAS. 
2.5
Analysis of the primary objective
The primary objective is to evaluate the effect of initial treatment with incretin based therapy 
vs. insulin on glycemic control in patients with Cushing’s disease or acromegaly who develop 
or worsen hyperglycemia on pasireotide, and cannot be controlled by metformin alone or other 
background anti-diabetic treatments. The primary endpoint will be assessed at the Core EOP. 
2.5.1
Primary endpoint
The primary variable is defined as the change from randomization in HbA1c (unit in %) at the 
time of assessing primary endpoint in the incretin based therapy arm and insulin arm. For 
patients who require rescue treatment, the last HbA1c assessment prior to rescue treatment will 
be used for primary efficacy analysis. 
2.5.2
Statistical hypothesis, model, and method of analysis
There is no formal hypothesis testing planned in this study. An estimate of the mean difference 
of the change from randomization in HbA1c between the two randomized arms will be reported 
along with 95% confidence interval (CI). Patients will be stratified by their disease and baseline 


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glycemic status. Variance estimation will be based on the following analysis of variance 
(ANOVA) model using the two stratification factors as well as treatment as fixed effects. RAS 
will be used for primary analysis:
Change from baseline in HbA1c = Baseline glycemic status + Disease + Treatment + Error 
Disease:
a. Cushing’s disease
b. Acromegaly 
Glycemic status at baseline:
a. HbA1c < 7 % 
b. HbA1c ≥ 7%
Treatment:
a. Incretin based therapy group
b. Insulin group
2.5.3
Handling of missing values/censoring/discontinuations
For patients who discontinued the study or require rescue treatment before the time of assessing 
primary endpoint, the last HbA1c assessment collected 8 weeks after randomization (and prior 
to or on the date of start of rescue treatment) will be carried forward for primary efficacy 
analysis. If the patient discontinued the study or used rescue treatment within 8 weeks after 
randomization, it will be considered missing for primary analysis.
2.5.4
Supportive analyses
As a supportive analysis, the ANOVA for the primary analysis will be repeated. Following ITT 
principle, the last available HbA1c assessment during core in each randomized arm will be 
utilized for analysis regardless of time of early discontinuation or rescue treatment use.
RAS will be used for supportive analysis. Subgroup analysis by disease and baseline HbA1c 
level may be performed.
In addition, the primary efficacy variable will be analyzed by analysis of covariance (ANCOVA) 
model with treatment and disease as classification variables and baseline HbA1c as the 
covariate. The least squares mean (“adjusted mean”) of change from randomization for each 
treatment group and its standard error (SE), the difference between two treatment groups and 
the associated two-sided 95% CI for the difference will be obtained from the following 
ANCOVA model.
Change from baseline in HbA1c = intercept + Baseline HbA1c + Disease + Treatment + Error
Disease:
a. Cushing’s disease
b. Acromegaly 
Treatment:
a. Incretin based therapy group
b. Insulin group


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2.6
Analysis of the key secondary objective
There is no key secondary objective in this study.
2.7
Analysis of secondary efficacy objective(s)
The secondary objectives are to assess the overall effect of anti-diabetic intervention on the 
glycemic control, as well as the sustainability of glycemic control in the insulin arm and the 
incretin based therapy arm in patients with Cushing’s disease or acromegaly. Subgroup analysis
by disease may be performed for change in HbA1c and FGP over time.
2.7.1
Change in HbA1c and FPG to EOP
The change in HbA1c and FPG from baseline to the core EOP in patients who received 
pasireotide (FAS) will be summarized by treatment group (incretin based therapy, insulin, and
the three non-randomized treatment groups) using descriptive statistics. 95% confidence 
intervals will be provided for the changes from baseline.
2.7.2
Proportion of patients with an increase in HbA1c less than or equal 
0.3%
The proportion of patients with an increase from baseline in HbA1c ≤ 0.3% at Core EOP will 
be summarized for each randomized arm. The corresponding 95% confidence interval will be 
estimated by exact method.
2.7.3
Change in HbA1c and FPG overtime
The change in HbA1c and FPG from randomization overtime and to the core EOP (only for 
FPG) will be summarized for each randomized arm. Descriptive statistics as well as 95% 
confidence intervals will be provided for the changes from baseline. Graphical presentation will 
also be used for change from randomization overtime in HbA1c and FPG.
2.7.4
Proportion received anti-diabetic rescue therapy
The proportion of patients who received anti-diabetic rescue therapy in the incretin based 
therapy randomized arm will be summarized. The corresponding 95% confidence interval will 
be estimated by exact method.
2.7.5
Change in HbA1c category
The change in category of HbA1c until the end of the core and extension phases will be 
summarized by treatment group (incretin based therapy, insulin, and the three non-randomized 
treatment groups) using shift tables. The categories used will be
•
HbA1c < 6.5%
•
6.5% ≥ HbA1c < 7%
•
HbA1c ≥ 7%


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2.7.6
Change in diabetic status
The change in diabetic status until the end of the core and extension phases will be summarized 
for the three non-randomized treatment groups using shift tables. Diabetic status is defined in 
section 2.1.1.6.
3
Safety analyses
The assessment of safety will be based on the frequency of adverse events (AEs), laboratory 
values that fall outside the pre-determined ranges, vital signs, as well as ECG, hypoglycemia 
events, thyroid function test and gallbladder examinations data. 
3.1.1
Analysis set and grouping for safety analysis
SAS will be used for safety analysis including both pre-randomized period and randomized 
treatment period. The 5 distinct groups (the 2 randomized treatment arms and the 3 non-
randomized groups) will be used to summarize the safety findings, unless otherwise specified. 
Disease status (Cushing’s disease or acromegaly) will also be used to summarize some safety 
results as appropriate.
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 pasireotide s.c., and 84 days after last dose of pasireotide long-acting, or the follow-up 
visit, whichever comes later. On-treatment period can be further divided into pre-
randomized period and randomized treatment period as depicted in the visit evaluation 
schedule in [Table 10-1] of the protocol.
3. Post-treatment period: starting at 28+1 days after last dose of pasireotide s.c., and 84+1 
days after last dose of pasireotide long-acting, or the follow-up visit + 1 days whichever 
comes later.
3.1.2
Adverse events (AEs)
All information obtained on AEs will be displayed by patient.
The number and percentage of subjects with AEs will be tabulated by SOC and PT. A subject 
with multiple adverse events within a body system is only counted once towards the total of 
this body system if no change in severity.
3.1.2.1
Coding of AEs
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
3.1.2.2
Grading of AEs
AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (http://ctep.cancer.gov/forms/CTCAEv4.pdf). 


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The CTCAE represents a comprehensive grading system for reporting acute and late effects of 
cancer treatments. CTCAE v4.03 is graded by definition a 5-point scale generally 
corresponding to clinical severity (mild, moderate, severe, life-threatening, and death). This 
grading system inherently places a value on the importance of an event although there is not 
necessarily proportionality among grades (a Grade 2 is not necessarily twice as bad as a Grade 
1). 
For adverse events for which CTCAE grades are not available, grades 1 – 4 corresponding to 
the severity of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) 
is not used in this study. Information regarding death will be collected in the “Study Phase 
Completion Evaluation” CRF pages. 
3.1.2.3
General rules for AE reporting
AE summaries will include all AEs starting on or after study day 1 (i.e. on or after the day of 
the first administration of study drug) and ending no later than 28 days after last study treatment 
for pasireotide s.c. and 84 days for pasireotide long-acting or the follow-up visit, whichever is 
later. All AEs before data cutoff date will be listed, including those that start before study day 
1. AEs starting prior to study day 1 will be identifiable based on the AE start date displayed in 
the listings. 
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, and having at least one AE in each body system/primary SOC and for each PT using 
the most current MedDRA coding available prior to database lock. A subject with multiple 
occurrences of an AE will be counted only once in the AE category.
Separate AE summaries will be presented by primary SOC, PT, and maximum CTCAE grade. 
A patient with multiple CTCAE grades for an AE will be summarized under the maximum 
CTCAE grade recorded for the event. In the summaries presented by grade, all AEs will be 
pooled regardless of whether they are CTCAE gradable or not. AEs with missing CTCAE grade 
will be summarized under “missing”.
Any information collected (e.g. CTCAE grades, relationship to study drug, action taken etc.) 
will be listed as appropriate.
3.1.2.4
AE summaries
Summary tables for 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 AEs (new or worsening from baseline) will be 
summarized by SOC and or PT, severity (based on CTCAE version 4.03 grades), type of AE, 
and relation to study treatment.
The following AE summaries will be produced:

Adverse events, regardless of study drug relationship, by primary system organ class and 
preferred term 


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
Adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and maximum CTCAE grade

Adverse events, regardless of study drug relationship, by preferred term

Adverse events, regardless of study drug relationship, by preferred term and maximum 
CTCAE grade

Deaths, by primary system organ class, and preferred term 

Adverse events, with suspected relationship to study drug, by primary system organ class, 
preferred term 

Adverse events, with suspected study drug relationship, by primary system organ class, 
preferred term and maximum CTCAE grade

Adverse events, with suspected relationship to study drug, by preferred term

Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term

Serious adverse events, with suspected relationship to study drug, by preferred term

Adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by primary system organ class and preferred term 

Adverse events leading to study drug discontinuation, with suspected relationship to study 
drug, by primary system organ class and preferred term 

Adverse events requiring dose adjustment or study-drug interruption, regardless of study 
drug relationship, by primary system organ class and preferred term 

Adverse events of special interest, regardless of study drug relationship, by group name,
severity, and preferred term
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 5%
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
3.1.2.5
Adverse events of special interest / grouping of AEs
Groupings of AEs of special interest consist of adverse events for which there is a specific 
clinical interest in connection with pasireotide treatment (i.e. where pasireotide may influence 
a common mechanism of action responsible for triggering them) or adverse events which are 
similar in nature (although not identical).
An Excel file with the exact composition of the adverse events groupings is available in the 
CREDI folder “/CREDI Projects/S/SOM230C/Administrative files/CIS (Clinical Information 
Sciences)/Biostatistics/” which is to be used to map reported adverse events to the adverse 
events groupings. This file is updated periodically based on review of accumulating trial data. 
The number of patients with at least one event in each category and each preferred term within 
category will be reported, and AEs of special interest will also be listed.


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3.1.3
Laboratory data
For analyzing laboratory results, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments up to data cut-off date. All 
laboratory assessments will be listed. Results will be reported for each visit at which collected 
in the core, extension, and safety follow-up phases through the last study visit.
Biochemistry, hematology, and urine laboratory data will be presented using

shift tables using CTC grades (if available), otherwise by normal ranges, to compare 
baseline to the most extreme post-baseline

listings flagging values with CTC grades (i.e. greater than 0), and outside of the normal 
ranges otherwise
All laboratory values will be converted into SI units and the severity grade derived using NCI 
CTCAE v4.03. Glucose will be presented as mg/dL and will be assessed using the ADA criteria 
2010. Insulin may also be presented by US unit.
The following summaries will be produced for the laboratory data (by laboratory parameter):

Number and percentage of patients with worst post-baseline CTC grade (regardless of the 
baseline status). Each patient will be counted only for the worst grade observed post-
baseline

Number and percentage of patients meeting categorical liver function test criteria, 
including Hy’s Law criteria for liver injury (ALT or AST > 3 x ULN and TBIL >= 2 x 
ULN and ALP < 2 x ULN). Each patient will be counted only for the worst grade 
observed post-baseline
The following listings will be produced for the laboratory data:

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges

Listing of notable laboratory abnormalities (i.e. CTC grade 3 or 4 laboratory toxicities).
Laboratory samples that are reported as unreliable (e.g. due to technical malfunction) will be 
excluded from summary tables. All reported laboratory data will be listed and unreliable values 
flagged.
3.1.4
Other safety data
3.1.4.1
ECG
Fridericia’s formula (QTcF) will be used to calculate the heart rate-corrected QT interval (ms) 
on the heart rate (HR bpm) and QT (ms) as follows:
QTcF (ms) = QT / (RR)1/3
The derivation will be used when QTcF is missing. All ECG data (heart rate (bpm), PR interval 
(ms), QT interval (ms), QRS duration (ms), QTcB interval (ms)) will be listed by patient and 
visit/time. Abnormalities will be flagged. Summary statistics will be provided at baseline and 
scheduled post-baseline time points for ECG variables PR, QRS, QT/QTcF interval and 
ventricular rate. Shift table from baseline to worst on-treatment result and summary statistics of 


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changes from baseline will also be provided. Number and percentage of patients with clinically 
notable QT/QTcF interval values will be summarized.
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
provided by visit/time for the above parameters. Descriptive statistics will be provided for 
change from baseline to different time points in heart rate, PR interval, QT interval, QRS 
duration, and QTcF interval. Shift table based on notable values will be provided for ECGs.
The notable criteria for PR is

Increase > 25% compared to baseline to a post-baseline value > 200 ms
The notable criteria for QRS is

Increase > 25% compared to baseline to a post-baseline value > 110 ms
The notable criteria for HR are 

Increase > 25% compared to baseline to a post-baseline value > 100 bpm

Decrease > 25% compared to baseline to a post-baseline value < 50 bpm
The notable criteria for QT and QTcF are

an increase from baseline > 30 ms at any post-baseline

an increase from baseline > 60 ms at any post-baseline
All vital signs data (height (cm), weight (kg), body temperature (°C), supine pulse rate (bpm), 
and systolic/diastolic blood pressure (mmHg)) will be listed by patient and visit/time, and 
abnormalities will be flagged on listing. Shift table based on notable value will be provided for 
vital signs. 
The criteria for clinically notable abnormalities are defined as follows:
Clinically notable elevated values

Systolic BP: 180 mmHg and an increase 20 mmHg from baseline

Diastolic BP: 105 mmHg and an increase 15 mmHg from baseline.

Supine pulse: 120 bpm with increase from baseline 15 bpm
Clinically notable below normal values

Systolic BP: 90 mmHg and a decrease 20 mmHg from baseline

Diastolic BP: 50 mmHg and a decrease 15 mmHg from baseline

Supine pulse: 50 bpm with decrease from baseline 15 bpm
3.1.4.2
Hypoglycemia events
The number of treatment emergent hypoglycemia events, as well as the number of patients with 
hypoglycemia events will be summarized for SAS by disease and 5 treatment groups. 
Hypoglycemia events will be defined based on CTCAE grade.
3.1.4.3
Thyroid function tests 
Change from baseline to different time points for thyroid function tests including Free T4 and 
TSH will be summarized along with corresponding descriptive statistics. 


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3.1.4.4
Gallbladder examinations
Shift table of baseline to worst on-treatment result for gallbladder examinations will be provided.
3.2
PD and PK/PD analyses
Not applicable
3.3
Patient-reported outcomes
Not applicable
3.4
Biomarkers
Not applicable
3.5
Other Exploratory analyses
Not applicable
3.6
Interim analysis
Not applicable
4
Sample size calculation
4.1
Primary analysis
There is no formal hypothesis testing planned in this study.
A total sample size of 68 randomized evaluable patients (in 1:1 allocation ratio to incretin based 
therapy and insulin) with at least 8 weeks of randomized treatment without any rescue anti-
diabetic medication is required. In order to reach 68 randomized evaluable patients, 
approximately 79 patients will be randomized based on current drop-out/rescue rate prior to 
Week 8 (i.e., patients without 8 weeks of randomized treatment or took rescue medication prior 
to Week 8). The total number of enrolled patients will be based on the actual randomization 
(which occurs within 16 weeks after patients are enrolled) rate which will be monitored 
regularly.
The sample size was calculated to ensure that the half-width of the 95% confidence interval 
around the mean difference of the change from randomization to Week 16 (the subsequent 
scheduled visit after 16 weeks in randomization) in HbA1c (%) will be approximately 0.5%. 
The calculation was performed using R version 3.00 and based on a standard deviation of 1.03%, 
which was consistent with the results from the CSOM230B2305 phase III trial.
5
Change to protocol specified analyses
Two additional secondary efficacy objectives have been added to the table of study objectives 
in section 1.3, with the details given in the newly added sections 2.7.5 and 2.7.6. These two 
analyses have been added to allow more detailed description of the glycemic control in study 
patients.Appendix


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5.1
Imputation rules
Partial dates will remain partial in the data listing. For the purpose of analysis, the following 
imputation rules will be used to impute the partial dates: if the day and month is missing, it will 
be replaced by 30th June (to be used only for prior events, e.g. medical history); if only the day 
is missing it will be replaced by the 15th of that month. For the dates known to be within the trial
period, if this imputation make the date later then the trial completion date, use the trial 
completion date; if the imputed date is earlier then the first medication date, use the first 
medication date.
The imputation of partial date for AE and concomitant medication will follow Novartis standard 
rules (See Programming Datasets Specifications (PDS) for details).