Conditions: Acromegaly Pituitary Gigantism
Keywords: SOM230 Pasireotide acromegaly Phase II growth disorder gigantism Pituitary adenoma pituitary gigantism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 33
Healthy volunteers: no

Brief summary:
To evaluate efficacy, safety, pharmacokinetics and pharmacodynamics of pasireotide LAR in Japanese patients with active acromegaly or pituitary gigantism. Primary objective was to assess the total-group efficacy of pasireotide LAR on the reduction of mean GH levels to \< 2.5 µg/L and the normalization of insulin-like growth factor-1 (IGF-1) at 3 months of study treatment.

Detailed description:

Arms:
arm 1: Enrolled patients were randomized to 20mg pasireotide LAR. arm 2: Enrolled patients were randomized to 40mg pasireotide LAR. arm 3: Enrolled patients were randomized to 60mg pasireotide LAR.

Interventions: intervention 1: Pasireotide LAR
Intervention descriptions: intervention 1: Intramuscular administration of pasireotide LAR was repeated every month (1 month = 28 days) for 12 months in core phase. It was permitted to increase the dose up to 60 mg in a patient showing the following biochemical test results after 3 and 6 months of study treatment: mean GH levels ≥2.5 µg/L and/or IGF-1 \> ULN. In the event of any problem with tolerability, it was permitted to reduce the next lower dosage level at any time.

Protocol document:
Prot_001.pdf: 
Clinical Development 
Pasireotide LAR / SOM230 LAR 
Oncology Clinical Trial Protocol CSOM230C1202 / NCT01673646
A multicenter, open-label, randomized, phase II study to 
evaluate efficacy, safety, pharmacokinetics and 
pharmacodynamics of pasireotide LAR in Japanese 
patients with active acromegaly or pituitary gigantism 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Version number 
03 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
11-Jul-2014
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ............................................................................................................. 2 
List of tables ................................................................................................................... 5 
List of figures .................................................................................................................. 6 
List of abbreviations ........................................................................................................ 7 
Glossary of terms .......................................................................................................... 10 
Amendment 3................................................................................................................ 11 
Amendment 2................................................................................................................ 12 
Amendment 1................................................................................................................ 15 
Protocol summary: ........................................................................................................ 16 
1 
Background ................................................................................................................... 19 
1.1 
Overview of acromegaly and pituitary gigantism pathogenesis, epidemiology 
and current treatment ......................................................................................... 19 
1.2 
Introduction to investigational study treatment(s) and other study treatment(s)... 21 
1.2.1 
Overview of pasireotide (SOM230) ................................................... 21 
2 
Rationale ....................................................................................................................... 27 
2.1 
Study rationale and purpose ............................................................................... 27 
2.2 
Rationale for the study design ............................................................................ 27 
2.3 
Rationale for dose and regimen selection ........................................................... 28 
2.4 
Rationale for choice of combination drugs ......................................................... 28 
2.5 
Rationale for choice of comparators drugs ......................................................... 28 
3 
Objectives and endpoints ............................................................................................... 28 
4 
Study design ................................................................................................................. 32 
4.1 
Description of study design ................................................................................ 32 
4.2 
Timing of interim analyses and design adaptations ............................................. 33 
4.3 
Definition of end of the study............................................................................. 33 
4.4 
Early study termination ...................................................................................... 33 
5 
Population ..................................................................................................................... 33 
5.1 
Patient population .............................................................................................. 33 
5.2 
Inclusion criteria ................................................................................................ 33 
5.3 
Exclusion criteria ............................................................................................... 34 
6 
Study treatment ............................................................................................................. 36 
6.1 
Study treatment .................................................................................................. 36 
6.1.1 
Dosing regimen.................................................................................. 36 
6.1.2 
Ancillary treatments ........................................................................... 36 
6.1.3 
Rescue medication ............................................................................. 36 


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6.1.4 
Guidelines for continuation of treatment ............................................ 36 
6.1.5 
Treatment duration ............................................................................. 36 
6.2 
Dose escalation guidelines ................................................................................. 36 
6.3 
Dose modifications ............................................................................................ 37 
6.3.1 
Dose modification and dose delay ...................................................... 37 
6.3.2 
Follow-up for toxicities ...................................................................... 38 
6.3.3 
Anticipated risks and safety concerns of the study drug ...................... 39 
6.4 
Concomitant medications ................................................................................... 46 
6.4.1 
Permitted concomitant therapy ........................................................... 46 
6.4.2 
Permitted concomitant therapy requiring caution and/or action .......... 46 
6.4.3 
Prohibited concomitant therapy .......................................................... 46 
6.5 
Patient numbering, treatment assignment or randomization ................................ 47 
6.5.1 
Patient numbering .............................................................................. 47 
6.5.2 
Treatment assignment or randomization ............................................. 47 
6.5.3 
Treatment blinding ............................................................................. 48 
6.6 
Study drug preparation and dispensation ............................................................ 48 
6.6.1 
Study drug packaging and labeling ..................................................... 48 
6.6.2 
Drug supply and storage..................................................................... 48 
6.6.3 
Study drug compliance and accountability ......................................... 48 
6.6.4 
Disposal and destruction .................................................................... 49 
7 
Visit schedule and assessments...................................................................................... 49 
7.1 
Study flow and visit schedule ............................................................................. 49 
7.1.1 
Screening ........................................................................................... 55 
7.1.2 
Treatment period ................................................................................ 56 
7.1.3 
End of treatment visit including study completion and premature 
withdrawal ......................................................................................... 56 
7.1.4 
Follow up period ................................................................................ 58 
7.2 
Assessment types ............................................................................................... 58 
7.2.1 
Efficacy assessments .......................................................................... 58 
7.2.2 
Safety and tolerability assessments..................................................... 59 
7.2.3 
Pharmacokinetics ............................................................................... 62 
 
 64 
7.2.5 
Other assessments .............................................................................. 64 
8 
Safety monitoring and reporting .................................................................................... 64 
8.1 
Adverse events................................................................................................... 64 
8.1.1 
Definitions and reporting ................................................................... 64 


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8.1.2 
Laboratory test abnormalities ............................................................. 66 
8.1.3 
Adverse events of special interest (optional) ...................................... 66 
8.2 
Serious adverse events ....................................................................................... 66 
8.2.1 
Definitions ......................................................................................... 66 
8.2.2 
Reporting ........................................................................................... 67 
8.3 
Pregnancies........................................................................................................ 68 
8.4 
Warnings and precautions .................................................................................. 68 
9 
Data collection and management ................................................................................... 69 
9.1 
Data confidentiality............................................................................................ 69 
9.2 
Site monitoring .................................................................................................. 69 
9.3 
Data collection ................................................................................................... 70 
9.4 
Database management and quality control ......................................................... 70 
10 Statistical methods and data analysis ............................................................................. 71 
10.1 
Analysis sets ...................................................................................................... 71 
10.1.1 
Full Analysis Set ................................................................................ 71 
10.1.2 
Safety Set........................................................................................... 71 
10.1.3 
Per-Protocol Set ................................................................................. 71 
10.1.4 
Dose-determining analysis set ............................................................ 71 
10.1.5 
Pharmacokinetic analysis set .............................................................. 71 
10.2 
Patient demographics/other baseline characteristics ........................................... 71 
10.3 
Study treatments (study treatment, concomitant therapies, compliance) ............. 72 
10.4 
Primary objective ............................................................................................... 72 
10.4.1 
Variable ............................................................................................. 72 
10.4.2 
Statistical hypothesis, model, and method of analysis ......................... 72 
10.4.3 
Handling of missing values/censoring/discontinuations ...................... 72 
10.4.4 
Supportive analyses ........................................................................... 72 
10.5 
Secondary objectives ......................................................................................... 73 
10.5.1 
Key secondary objective(s) ................................................................ 73 
10.5.2 
Other secondary efficacy objectives ................................................... 74 
10.5.3 
Safety objectives ................................................................................ 74 
10.5.4 
Pharmacokinetics ............................................................................... 76 
10.5.5 
Biomarkers ........................................................................................ 77 
10.5.6 
Resource utilization ........................................................................... 77 
10.5.7 
Patient-reported outcomes .................................................................. 77 
 78 
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10.7 
Interim analysis ................................................................................................. 78 
10.8 
Sample size calculation ...................................................................................... 79 
10.9 
Power for analysis of key secondary variables ................................................... 79 
11 Ethical considerations and administrative procedures .................................................... 79 
11.1 
Regulatory and ethical compliance ..................................................................... 79 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 80 
11.3 
Informed consent procedures ............................................................................. 80 
11.4 
Discontinuation of the study .............................................................................. 80 
11.5 
Publication of study protocol and results ............................................................ 81 
11.6 
Study documentation, record keeping and retention of documents...................... 81 
11.7 
Confidentiality of study documents and patient records ...................................... 82 
11.8 
Audits and inspections ....................................................................................... 82 
11.9 
Financial disclosures .......................................................................................... 82 
12 Protocol adherence ........................................................................................................ 82 
12.1 
Amendments to the protocol .............................................................................. 82 
13 References (available upon request) .............................................................................. 83 
14 Appendices ................................................................................................................... 85 
Appendix 1: Instructions for use .................................................................................... 85 
Appendix 2: Medications known to be associated with QT interval prolongation .......... 87 
 
List of tables 
Table 1-1 
Binding profile for octreotide and pasireotide at hsst1-5 (IC50, M) ..... 22 
Table 1-2 
Summary of PK parameters for pasireotide LAR single dose of 10-
60 mg in Japanese healthy volunteers (PK set) in study 
CSOM230G1101 ............................................................................... 25 
Table 3-1 
Objectives and related endpoints ........................................................ 29 
Table 6-1 
Dose titration steps for pasireotide LAR ............................................. 38 
Table 6-2 
Guideline for treatment of patients experiencing adverse events ......... 38 
Table 6-3 
Guideline for treatment of patients experiencing adverse events in 
QTcF ................................................................................................. 38 
Table 6-4 
Treatment assignment numbering....................................................... 47 
Table 7-1 
Visit evaluation schedule (core phase)................................................ 50 
Table 7-2 
Extension Visit evaluation schedule ................................................... 53 
Table 7-3 
Blood sampling schedule ................................................................... 55 
Table 7-4 
Clinical laboratory parameters collection plan .................................... 60 


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Table 7-5 
Blood sampling for PK assessment .................................................... 63 
Table 10-1 
Primary and secondary variables for core phase ................................. 73 
Table 10-2 
Primary and secondary variables for core phase ................................. 73 
Table 10-3 
Pharmacokinetic parameters for LAR formulations ............................ 76 
List of figures 
Figure 1-1 
Pasireotide pamoate structural formulae ............................................. 21 
Figure 1-2 
Plasma concentration versus time profiles after a single i.m. 
administration of pasireotide LAR n Japanese healthy volunteers 
(PK set) (n=8 each dose cohort) in study CSOM230G1101 ................ 25 
Figure 4-1 
Study design ...................................................................................... 32 
Figure 6-1 
Fasting self-monitoring blood glucose guidelines ............................... 40 
Figure 6-2 
QT prolongation monitoring flow chart .............................................. 43 
Figure 6-3 
LFT management algorithm ............................................................... 45 
 


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List of abbreviations 
ACTH 
Adrenocorticotropic Hormone 
ADA 
American Diabetes Association 
AE 
Adverse Event 
Alb 
Albumin 
ALP 
alkaline phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANA 
Anti-nuclear antibody 
APTT 
Partial thromboplastin time 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical therapeutic chemical 
AUC 
area under the drug plasma (serum/blood) concentration-time curve 
AUCinf 
area under the drug plasma (serum/blood) concentration-time curve (time 0 to infinity) 
AUClast 
area under the drug plasma (serum/blood) concentration-time curve (time 0 to the last 
measurable concentration sampling time) 
b.i.d. 
bis in diem/twice a day 
BMI 
body mass index 
BUN 
Blood urea nitrogen 
Cmax 
maximal drug plasma (serum/blood) concentration 
CMH 
Cochran-Mantel-Haenszel 
CMV 
Cytomegalovirus 
CPK 
Creatine phosphokinase 
CRF 
Case Report/Record Form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
Ctrough 
trough drug plasma (serum/blood) concentration 
CV 
Coefficient of variation 
DM 
Diabetes Mellitus 
DPP-4 
dipeptidyl peptidase-IV 
DS&E 
Drug safety and Epidemiology 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practices 
GEP/NET 
Gastroenteropancratic neuroendocrine tumor 
GGT 
Gamma-glutamyltransferase 
GH 
Growth Hormone 
GI 
Gastrointestinal 
GIP 
glucose dependent insulinotropic polypeptide, also known as gastric inhibitory polypeptide 
GLP-1 
glucagon-like peptide-1 
HAV 
Hepatitis A virus 
HbA1c 
hemoglobin A1c 
HBc 
Hepatitis B core 


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HBsAg 
Hepatitis B surface antigen 
hCG-β 
Human chorionic gonadotropin, β-subunit 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HEV 
Hepatitis E virus 
Hgb 
hemoglobin 
hsst 
Human somatostatin subtype receptor 
i.m. 
intramuscular 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like Growth Factor-1 
IgM 
Immunoglobulin M 
IRB 
Institutional Review Board 
LAR 
Long Acting Release 
LDH 
Lactic dehydrogenase 
LDL 
Low density lipoprotein 
LFT 
Liver function test(s) 
LLN 
Lower limit normal 
MAP 
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCI-CTC 
National Cancer Institute-common toxicity criteria 
NYHA 
New York Heart Association 
OGTT 
Oral Glucose Tolerance Test 
PAS 
Pharmacokinetic analysis set 
PHI 
Protected health information 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PLT 
Platelet count 
PPS 
Per protocol set 
PRL 
Prolactin 
PT 
Prothrombin time 
q.d. 
Once a day 
QOL 
Quality of life 
RAP 
The report and analysis plan 
RBC 
Red blood cell counts (erythrocyte counts) 
REB 
Research Ethics Board 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 
SD 
Standard deviation 
SEC 
Safety event categories 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SSA 
Somatostatin analogues 
SST 
Somatostatin 
SSTR 
Somatostatin Receptor 


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T4 
Thyroxine 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit Normal 
VT 
Ventricular Tachycardia 
WBC 
White blood cell counts (leukocyte counts) 
WHO 
World Health Organization 
 


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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.” 
Patient Number  
A unique identifying number assigned to each patient 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. 
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 study treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the patient 
(subject) as part of the required study procedures, including placebo and active drug 
run-ins. 
In specific examples, it is important to judge investigational study treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational study 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 
Amendment rationale 
As of May 31 2014, patient enrollment has been completed and 33 patients have been 
randomized in this trial. 
The purpose of this amendment is to update Table 7-2 to clarify what assessments need to be 
performed in patients that remain in the study for more than 2 years of treatment. 
This amendment will introduce the following change to the study protocol: 
Update Table 7-2 to clarify assessments beyond 2 years of treatment 
The protocol allows patients to continue study drug until it becomes commercially available 
or until pasireotide LAR development program is discontinued. No information regarding the 
assessments to be performed in patients in the study beyond 2 years of treatment had been 
included in the Visit schedule. Table 7-2 has been updated to include pregnancy assessment 
and collection of adverse events for patients in the study beyond 2 years of treatment. 
Changes to the protocol 
• Change to Table 7-2: Table 7-2 “Extension Visit evaluation schedule” has been updated 
for patients who continue the study treatment beyond 2 years. 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Amendment 2 
Amendment rationale 
As of Aug 31, 2013, 8 patients have been randomized to receive treatment in this trial.  
Additional insights gained from recent analysis of pasiretide s.c. data and feedback received 
from study investigators resulted in amending or clarifying sections within the study protocol 
with the aim to facilitate recruitment. This amendment will introduce the following changes to 
the study protocol: 
1. Allow patients previously or current treated with GH receptor antagonists to be enrolled 
2. Reduce the exclusion period after radiotherapy from ten years to three years 
3. Reduce the study visit 
4. Provide guidance for blood glucose monitoring and management of hyperglycemia 
5. Provide more updated pregnancy guidelines 
6. Introduce changes to the biomarker analysis 
The rationale for these changes is presented below: 
Include Patients who have been treated with GH receptor antagonists during 
the last 8 weeks prior to Visit 1:  
In clinical practice, many patients who have inadequately controlled acromegaly or pituitary 
gigantism have been treated with the combination therapy of GH receptor antagonists and 
somatostatin analogues (SSA). The objective of the combination therapy is that GH receptor 
antagonist normalizes IGF-1 and SSA controls GH value. The results of SOM230C2305 
shows that pasireotide LAR is more effective than SSA (octreotide LAR) in IGF-1 control 
rate. Pasireotide LAR has the potential to normalize IGF-1 and control GH in patients who 
have been treated with GH receptor antagonists. Therefore, patients who have been treated 
with GH antagonists can be enrolled in CSOM230C1202. 
Reduce the exclusion period after radiotherapy from ten years to three years 
In case of conventional fractionated radiotherapy, the mean time to remission after 
conventional RT is about 10 years. Recently, stereotactic radiotherapy is utilized and this type 
of radiotherapy, it takes about 3 years to gain GH and IGF-1 normalization.  
Change of the visit schedule: 
The enrollment of patients in this trial is quite slow and one of the causes for the slow 
enrollment is the high frequency of study visits to the investigational site. Non-critical PK and 
PD sampling has been removed to decrease the patient burden. 
Management of Hyperglycemia:  
The management of hyperglycemia has been expanded. This is done to reinforce glycemic 
goals of treatment per current ADA and EASD guidelines and to emphasize the need to 
initiate anti-hyperglycemic treatment accordingly when needed. 


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Update to Pregnancy Guidelines:  
Considering pasireotide LAR half-life of 15.74 days, this amendment mandates female or 
male patients to continue preventive pregnancy procedures (i.e. use of oral contraception, use 
of condoms respectively) for three months post last pasireotide LAR dose (instead of two 
months). In addition follow up of a newborn of a patient or a partner who becomes pregnant 
during the study has been added (3months post-delivery). 
Biomarkers analysis: 
• Based on the experiences in other pasireotide studies, the few paraffin embedded tissue 
samples obtained will be used to determine the expression of SSTR1-5 receptors by 
immunohistochemistry (IHC) method and not by PCR method. Therefore mentioning of 
the PCR methodology was deleted. 
• The small number of tissue samples obtained is too low for adequate analysis of Gs alpha 
mutation and that has therefore been deleted. 
• In addition, determination of Ki67 would be most valuable in a study in which tumor 
biopsies from pre- and post-treatment would be available. As pituitary samples from 
patients cannot and will not be determined after treatment and only very few samples may 
be obtained from historical samples in this trial, the analysis of the expected few cases is 
not meaningful and will be deleted. 
Clarification/Inconsistencies: 
Clarification was provided through edited text and inconsistent language was corrected 
throughout the protocol.  
• The exclusion criterion 15 was corrected to clarify the exclusion of patients that have 
either chronic or active hepatitis B or C. 
• The footnote for AE Table 6-2 was revised to refer to the specific management for QT 
prolongation and LFT increases provided in anticipated risks and safety concerns of the 
study drug Section 6.3.3. 
• The criterion listed for patient withdrawal based on capillary glucose values in excess of 
275 mg/dL (15.5 mmol/L) which was erroneously added previously has been removed. 
(Section 7.1.3.1) 
Changes to the protocol 
• Changes to the Table of contents: current page numbers and changes to section headings. 
• Change to Protocol Summary: Changes in the main body of the protocol (see bullet points 
below) are also implemented in the relevant sections of the protocol synopsis.  
• Changes to Section 5.3: 
• Exclusion criteria 1: Changed 3rd bullet to be able to enroll patient who have been 
treated with GH antagonists. 
• Exclusion criteria 7: Reduced the exclusion period after radiotherapy from ten years 
to three years prior to visit 1. 


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• Exclusion criteria 15: Removed “and” and replaced it with “or” for the type of 
chronic viral hepatitis. 
• Exclusion criteria 20: Extended the contraception period after the last dose from 2 
months to 3 months  
• Change to Figure 6-1: Modified Figure 6-1 by adding “obtain fasting plasma glucose” 
• Change to Table 6-2: Footnote corrected to “For the management of QT prolongation and 
LFT increases refer to specific instructions provided in Section 6.3.3 Anticipated risks and 
safety concerns of the study drug (Figure 6-2 and Figure 6-3)”. 
• Changes to Section 6.3.3: Sub-heading and information was added to reflect guidance on 
the monitoring of blood glucose 
• Changes to Section 6.4.1: Extended the contraception period after the last dose from 2 
months to 3 months. 
• Change to Table7-1: Removed the visit number 3, 4 and 7. 
• Change to Table7-3: Removed the descriptions of day 2, 15 and 43. 
• Change to Table7-5: Removed the visit number 3,4 and 7 
• Change to Section 7.2.4: Deletion of the PCR methodology and analysis of Ki67 and Gs 
alpha mutation. 
• Change to Section 8.3: Added language related to follow up of a newborn of a patient or a 
partner who becomes pregnant during the study (3months post-delivery).  
• Change to Section 10.6.1: Added description of “Different Analysis may be applied for 
patients before and after Amendment 2”. 
IRB/IEC/REB Approval  
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Amendment 1 
Amendment rationale 
As of July 15, 2012 study CSOM230C1202 has not been initiated at any study center and no 
patients has received study drug in the trial. 
The purpose of this amendment is to revise the randomization number and to make the 
editorial changes throughout the protocol. 
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. 
• Changes to Section 1.1: Clarified disease 
• Changes to the List of abbreviations: Deleted LOCF 
• Change to Section 5.2: Added dopamine agonists to Inclusion 3b to consist with the 
definition of prior medications 
• Changes to Section 6.4.3: Clarified the criteria 
• Changes to Section 6.5.2.1 and Table 6-4: Revised the randomization numbers for either 
with prior medication or without prior medication 
• Changes to Table 7-1 and Table 7-2: Added pituitary gigantism to History of acromegaly, 
Prior therapy for acromegaly and Symptom of Acromegaly where applicable 
• Changes to Section 7.1.1.3: Clarified disease 
• Changes to Section 7.2.1.4: Clarified disease 
• Changes to Section 8.2.2: Corrected to remove language ‘in English’ regarding to 
completing SAE report form 
• Changes to Section 11.2: Corrected the language that follow the Japanese regulation. 
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. 


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Protocol summary: 
Protocol number 
CSOM230C1202 
Title 
A multicenter, open-label, randomized, phase II study to evaluate efficacy, safety, 
pharmacokinetics and pharmacodynamics of pasireotide LAR in Japanese patients with 
active acromegaly or pituitary gigantism 
Brief title 
Evaluate Efficacy and Safety of pasireotide LAR in patients with active acromegaly 
Sponsor and Clinical 
Phase 
Novartis, Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
Pasireotide LAR was tested in patients with acromegaly in phase I patient study 
[CSOM230C2110]. Patients in this study received once every 28 days doses of 20, 40 
or 60 mg pasireotide LAR, given as an i.m. depot intragluteal injection for a period of 3 
months. 
The response rate, the proportion of patients with a reduction of 5-point mean GH levels 
to <2.5 µg/L and normalization of IGF-1 to within normal limits (age and sex related), at 
3 months of study treatment was 30% in the 20 mg group, 41.7% in the 40 mg group, 
and 38.5% in the 60 mg group. 
The phase 3 study [CSOM230C2305] demonstrated Pasireotide LAR was superior in 
efficacy [i.e. GH levels to <2.5 µg/L and normalization of IGF-1 to within normal limits 
(age and sex related)] to octreotide LAR for patients with medication naive active 
acromegaly. Pasireotide LAR appeared to have a similar safety profile relative to 
octreotide LAR, except for hyperglycemia (Section 1.2.1.2). Pasireotide LAR was 
generally tolerated in Japanese healthy volunteers from the tested doses (10-60 mg) 
[CSOM230G1101]. And the safety profile in Japanese healthy volunteers was similar to 
that in Western healthy volunteers [CSOM230C2101]. 
Basically, acromegaly and pituitary gigantism are identical diseases. Pituitary gigantism 
is also caused by a GH-secreting pituitary adenoma. According to the guidance of 
diagnosis and treatment for these diseases, major symptoms of pituitary gigantism are 
almost same as acromegaly and treatment strategy is same as acromegaly. Therefore 
it is expected that pasireotide has efficacy for not only acromegaly but also pituitary 
gigantism.  
The purpose of [CSOM230C1202] is to evaluate the efficacy, safety, pharmacokinetics 
and pharmacodynamics of pasireotide LAR in Japanese patients with acromegaly and 
pituitary gigantism. 
Primary Objective(s) 
and Key Secondary 
Objective 
Primary objective: Assess the total-group efficacy of pasireotide LAR on the reduction 
of mean GH levels to < 2.5 µg/L and the normalization of IGF-1 at 3 months of study 
treatment 
Key Secondary Objective: 
● Assess the effect of each starting dose pasireotide LAR on the reduction of mean 
GH levels to < 2.5 µg/L and the normalization of IGF-1 at 3 months of study treatment 
● Assess the PK and PK/PD of pasireotide LAR 20 mg, 40 mg and 60 mg 
● Assess the tolerability and safety profile of pasireotide LAR at 3 months and during 
and after the 12- month study treatment Assess the effect of pasireotide LAR on the 
reduction of mean GH levels to < 2.5 µg/L at 3 months of study treatment 
● Assess the effect of pasireotide LAR on the normalization of IGF-1 at 3 months of 
study treatment 


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Secondary Objectives 
Core phase 
Objective 1: Assess the effect of pasireotide LAR on the reduction of mean GH levels to 
< 2.5 µg/L and the normalization of IGF-1 at 6, 9 and 12 months of study treatment 
Objective 2: Assess the effect of pasireotide LAR on the reduction of mean GH levels to 
< 2.5 µg/L at 6, 9and 12 months of study treatment 
Objective 3: Assess the effect of pasireotide LAR on the normalization of IGF-1 at 6, 9 
and 12 months of study treatment 
Objective 4: Assess the effect of pasireotide LAR on the change of tumor volume at 
6and 12 months of study treatment 
Objective 5: Assess the effect of pasireotide LAR on the change of mean GH level from 
baseline 
Objective 6: Assess the effect of pasireotide LAR on the symptoms of acromegaly, 
specifically: ring size, headache, fatigue, perspiration, paresthesias, osteoarthralgia 
Objective 7: Assess the effect of pasireotide LAR on the change of prolactin (PRL) level 
from baseline 
Extension phase 
Objective 1: Assess the effect of pasireotide LAR as long term study treatment on the 
proportion of patients with a reduction of mean GH level to < 2.5 µg/L and normalization 
of IGF-1 at 18 and 24 months of study treatment 
Objective 2: Assess the effect of pasireotide LAR as long term study treatment on the 
reduction of mean GH levels to < 2.5 µg/L at 18 and 24 months of study treatment 
Objective 3: Assess the effect of pasireotide LAR as long term study treatment on the 
normalization of IGF-1 at 18 and 24 months of study treatment 
Objective 4: Assess the effect of pasireotide LAR as long term study treatment on the 
change of mean GH levels from baseline 
Objective 5: Assess the safety and tolerability of pasireotide LAR in extension phase 
Objective 6: Assess the total-group safety and tolerability of pasireotide LAR as long 
term study treatment 
Study design 
A multicenter, open-label, randomized study. This study consists of two phases, core 
phase and extension phase. Patients will be treated with SOM230 LAR for 12 months in 
the core phase. The patients will be randomized to one of 3 doses (20mg, 40mg or 
60mg). 
Population 
Adult (at least 18 years of age), male and female patients, with medication naive 
acromegaly and pituitary gigantism or inadequately controlled acromegaly and pituitary 
gigantism with current medications. 30 patients will be enrolled. 
Inclusion criteria 
1. Written informed consent obtained prior to any screening procedures 
2. Male or female patients of at least 18 years of age 
3. Patients with active acromegaly or pituitary gigantism following a or b 
 
a. Patients with medication naïve acromegaly or pituitary gigantism demonstrated 
by:  
 
 
● a lack of suppression of GH nadir to <1 µg/L after an oral tolerance test with 75 
g of glucose (OGTT) (not applicable for diabetic patients) or a mean GH concentration 
of a 5-point profile within a 2 hour time period of > 5 µg/L 
 
 
● elevated circulating IGF-1 concentration (age and sex related) 
 
 
● Patients who have undergone one or more pituitary surgeries, but have not 
been treated medically or de-novo patients presenting a visible pituitary adenoma on 
MRI and who refuse pituitary surgery or for whom pituitary surgery is contraindicated 
 
b. Patients with inadequately controlled acromegaly or pituitary gigantism as defined 
by a mean GH concentration of a 5- point profile over a 2-hour period > 2.5 µg/L and 
age and sex related IGF-1 > 1.3 x upper limit of laboratory normal (ULN), even if 
acromegaly have been treated for at least 12 weeks with somatostatin analogues or 
dopamine agonist 
4. Patients with a known history or new diagnosis of impaired fasting glucose or 
diabetes mellitus may be included, however blood glucose and antidiabetic treatment 
must be monitored closely throughout the trial and adjusted as necessary 


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Key exclusion criteria 
● For patients with inadequately controlled acromegaly or pituitary gigantism with 
current medication. 
 
● 
Patients who have been treated with dopamine agonists during the last 8 
weeks prior to visit 1 (screening). 
 
● 
Patients who have been treated with long -acting somatostatine analogues 
during the last 4 weeks prior to visit 1 (screening). 
 
● 
Patients who have been treated with GH antagonists during the last 8 weeks 
prior to visit1 (screening). Such patients must have been treated with long -acting 
somatostatine analogues or dopamine agonists monotherapy continuously for a 
minimum of 12 weeks prior to starting GH receptor antagonists therapy and they should 
have been inadequately controlled on monotherapy. 
● Diabetic patients whose blood glucose is poorly controlled as evidenced by 
HbA1c >8% 
● Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, ventricular fibrillation, clinically significant 
bradycardia, advanced heart block or a history of acute myocardial infarction within the 
six months preceding enrollment 
● Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF > 
470 ms, hypokalemia, hypomagnesemia, hypocalcemia, family history of long QT 
syndrome, or patients receiving a concomitant medication known to prolong QT interval.
● Patients with history of liver disease such as cirrhosis, chronic active hepatitis B or 
C, or patients with ALT or AST more than 2 x ULN, baseline total bilirubin > 1.5 x ULN 
● Presence of Hepatitis B surface antigen (HbsAg) 
● Presence of Hepatitis C antibody (anti-HCV) 
● Female patients who are pregnant or lactating, or are of childbearing potential 
Investigational and 
reference therapy 
Pasireotide 
Efficacy assessments 
Growth Hormone (GH) 
glucagon-like peptide-1(IGF-1) 
Tumor volume 
Symptoms of acromegaly or pituitary gigantism 
Prolactin  
Safety assessments 
Adverse Events  
Laboratory assessments 
special safety assessments  
● thyroid 
● liver function tests, 
● gallbladder examinations  
● ECGs 
Other assessments 
Pharmacokinetic(PK) 
Pharmacodynamic(PD) 
Biomarker 
Data analysis 
Primary endpoint 
The overall response rate at 3 months of study treatment along with the corresponding 
exact 90% confidence interval will be provided. The primary analysis will be performed 
on the FAS.  
Key Secondary endpoint 
The response rate at 3 months of study treatment along with the corresponding exact 
95% confidence interval will be provided by dose level at randomization study 
treatment. 
Sample size calculation 
The planned sample size of 30 is determined based on the accuracy of estimated 
overall response rate at the end of 3 months.  
Under these assumptions, the sample size of 30 can demonstrate that the lower limit of 
the exact two-sided 90% CI for the overall response rate is not less than the clinically 
required minimum response rate. 
Key words 
Pasireotide, acromegaly, Phase II 


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1 
Background 
1.1 
Overview of acromegaly and pituitary gigantism pathogenesis, 
epidemiology and current treatment 
Acromegaly and pituitary gigantism are diseases both resulting from excessive secretion of 
growth hormone (GH) and manifested by characteristic clinical symptoms including 
enlargement of hands and feet, facial features, as well as metabolic disorders. These 
symptoms not only disturb daily lives of the patients but also seriously deteriorate their 
quality of life (QOL). These two diseases are basically common in etiology and study 
treatment approaches, although distinction is made by the time of disease onset in relation to 
the closure of the epiphyseal plate: the condition occurring after the closure is called 
acromegaly, and the condition occurring before the closure is called pituitary gigantism. GH 
is secreted from the GH secreting cells located in the pituitary anterior lobe, and is responsible 
for enhancement of bone growth, muscle growth, and control of metabolism. Chronic 
hypersecretion of GH often leads to heart diseases and cerebrovascular accidents and, if not 
properly treated, would approximately double or triple the mortality as compared with the 
general population (Sherlock et al. 2010) and shorten the life expectation by approximately 10 
years (Rajasoorya et al 1994). It is estimated that about 3 out of every million people develop 
acromegaly each year and that 40 to 60 out of every million people suffer from the disease at 
any one time (Melmed et al 1998). According to the 5-year national survey for the period 
from 1988 to 1992 conducted by the MHW specified disease survey research group for 
diencephalohypophysial dysfunction (1993), patients with acromegaly amounted to 815 (392 
males and 423 females) and those with pituitary gigantism amounted to 28 (21 males and 7 
females). The same group (Saito et al 1991) reported that as of 1989 the estimated average 
age at disease onset for acromegaly was 35.9 years and the average age at the first diagnosis 
of acromegaly was 44.5 years, whereas those for pituitary gigantism were 12.6 years and 23.4 
years, respectively. In the report, neither prevalence nor incidence of acromegaly per general 
population in Japan was calculated. 
An eleven-year survey for the period from 1995 to 2005 in Miyazaki Prefecture conducted by 
Katakami et al (2006) estimated the prevalence of acromegaly at 84.6 cases per million people, 
and the incidence at 5.3 new cases per million annually (Japan Intractable Diseases 
Information Center 2009). 
The clinical symptoms of acromegaly and pituitary gigantism are due to the peripheral actions 
of the GH excess and elevated insulin-like growth factor 1(IGF-1) concentrations and/or local 
tumor mass effect. The symptoms and signs of acromegaly can be classified into 3 categories: 
physical changes due to excessive amounts of GH and IGF-1, metabolic effects of excessive 
amounts of GH, and local effects of the pituitary tumor (Baumann 2001). 


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The therapeutic goals in acromegaly are to reduce mortality to the expected age and sex 
related rates by using treatments that remove the tumor mass or control its growth and restore 
GH secretion and action to normal. The biochemical goals of therapy are to reduce the 
circulating IGF-1 levels to normal for age and sex and to reduce serum GH concentrations to 
< 2.5µg/L (mean GH concentration of a 5-point profile within a 2-hour time period) or to less 
than 1µg/L after an oral glucose load (Giustina et al 2000). The epidemiological data suggests 
that the reduction of mean GH levels to < 2.5µg/l improves the mortality rate of acromegalic 
patients to a level close to that of the general population (Kauppinen-Makelin et al 2005). 
Treatment modalities for acromegaly and pituitary gigantism include surgery, drug treatment 
and radiotherapy. 
Surgery: 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. Surgery is most 
successful in patients with blood GH levels below 40 µg/L before the operation and with 
pituitary tumors no larger than 10 mm in diameter (microadenomas). Approximately 80% of 
patients with microadenomas and substantially < 50% of patients with macroadenomas can be 
effectively treated with surgery. Even when surgery is successful and hormone levels return to 
normal, patients must be carefully monitored for years for possible recurrence. More 
commonly, hormone levels may improve, but do not return completely to normal. When 
patients do not achieve normalization of GH and IGF-1 with surgery they require additional 
treatment, usually with medication. In addition to the normal risks associated with any surgery, 
transphenoidal surgery may also result in complications such as cerebrospinal fluid leaks, 
meningitis, or damage to the surrounding normal pituitary tissue, thus requiring lifelong 
pituitary hormone replacement. 
Radiotherapy: Radiation therapy has been used both as a primary treatment and combined 
with surgery or medications. Radiotherapy is considered as the treatment choice 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. This treatment generally lowers GH levels for more than 2 year timeframe, 
although late effects can occur in some cases. Radiation therapy leads to 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. Radiotherapy is not advised as primary treatment, 
because it may take several years before it is fully effective, and because of its possible 
complications (Wass et al 2001). 
Medical treatment: Currently the medical treatment options for acromegaly include 
somatostatin analogues, growth hormone antagonists and dopamine agonists. 
Somatostatin analogues (SSA) 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®, Sandostatin®LAR®) and lanreotide (Somatuline®, not commercially 
available in Japan). Octreotide has been available for more than 15 years and is considered the 
world-wide gold standard medical treatment for acromegaly. Other medical treatment options 
are growth hormone antagonists and dopamine agonists. 


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1.2 
Introduction to investigational study treatment(s) and other 
study treatment(s) 
1.2.1 
Overview of pasireotide (SOM230) 
Pasireotide (SOM230), a new chemical entity, is an injectable somatostatin analogue. It is a 
novel cyclohexapeptide containing the amino acids lysine, tryptophane, phenylglycine, 
aminoethylcarbamoyl-hydroxyproline, phenylalanine and O-benzyltyrosine, with the 
following structural formulae (Figure 1-1): 
Figure 1-1 
Pasireotide pamoate structural formulae 
N
H
O
N
O
O
N
H
N
H
N
H
N
H
N
H
O
O
O
O
NH2
O
NH
O
N
H2
OH
OH
OH
O
OH
O
 
Pasireotide (SOM230) contains the structural elements [(2-aminoethyl) amino carbonyl oxy]-
L-proline, phenylglycine and tyrosine (benzyl). Like natural somatostatin and other 
somatostatin analogues (SSA), pasireotide exerts its pharmacological activity via binding to 
somatostatin receptors (SSTR). There are five known somatostatin receptors: SSTR1, 2, 3, 4 
and 5. Somatostatin receptors are expressed in different tissues under normal physiological 
conditions. Somatostatin analogues activate these receptors with different potencies 
(Schmid and Schoeffter 2004) and this activation results in a reduced cellular activity and 
inhibition of hormone secretion. Somatostatin receptors are strongly expressed in many solid 
tumors, especially in neuroendocrine tumors where hormones are excessively secreted (e.g. 
acromegaly (Freda 2002), GEP/NET tumors (Oberg 2004) and Cushing’s disease 
(Van der Hoek et al 2005)). 
The SSA currently approved for use in the clinic (octreotide and lanreotide: non commercially 
available in Japan) have a high affinity to the sst subtype 2 (sst2), with moderate or no affinity 
to the remaining subtypes. Pasireotide exhibits a unique binding profile with high affinity 
binding to four of the five known human somatostatin receptors (SSTR1, 2, 3 and 5). 
Compared to octreotide, pasireotide has a binding affinity which is 30-40 times greater for 
sst1 and sst5 receptors, 5 times greater for sst3 receptors and a comparable affinity for sst2 
receptors (see Table 1-1). A detailed summary of available preclinical data is provided in the 
[Investigator’s Brochure]. 


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Table 1-1 
Binding profile for octreotide and pasireotide at hsst1-5 (IC50, M) 
Compound 
sst 1 
sst2 
sst3 
sst4 
sst5 
octreotide acetate 
(SMS 201-995) 
2.8x10-7 
3.8x10-10 
7.1x10-9 
>10-6 
6.3x10-9 
Pasireotide 
(SDZ 227-230) 
9.3x10-9 
1.0x10-9 
1.5x10-9 
>10-6 
1.6x10-10 
Ratio of IC50: 
octreotide acetate/ 
pasireotide 
SMS/SOM230 
30 
0.4 
5 
-- 
40 
1.2.1.1 
Non-clinical experience 
Preclinical data on binding affinity and functional activity in vitro and efficacy on hormone 
secretion in vivo have been obtained with the s.c. formulation in rats, dogs, mice and monkeys. 
Long-term in vivo studies performed using drug application by osmotic mini-pumps 
(Bruns 2002, Weckbecker 2002) have shown not only that the inhibitory effect of pasireotide 
was stronger, but also that there was less response escape (Bruns et al 2002), 
(Schmid and Silva 2005). Osmotic mini-pumps release a drug substance in a constant, 
predefined way and thus mimic the constant release pattern of a LAR formulation. Based on 
the known efficacy of pasireotide on hormone secretion after long-term application, no 
additional pharmacological experiments with the new LAR formulation are considered 
necessary. 
The PK of pasireotide s.c. in rats and monkeys showed rapid absorption, low clearance, a high 
volume of distribution, and a half-life (t1/2) suitable for a b.i.d. dosing regimen. The PK of 
pasireotide LAR in rabbits demonstrated a controlled-release profile suitable for monthly 
(every 28 days) dosing regimen. In rats, pasireotide was mainly distributed in the liver, kidney, 
cartilage, lymph nodes and spleen, it was highly metabolically stable, and was found 
predominantly eliminated as an unchanged form in feces. 
A detailed summary of available preclinical data is provided in the Investigator’s Brochure. 
1.2.1.2 
Clinical experience 
Pasireotide s.c. 
Single doses of pasireotide s.c. up to 1500 µg q.d. and multiple s.c. doses up to 1500 µg 
q.d.,750 µg b.i.d., and 2100 µg b.i.d., and continuous (7-day) s.c. infusion by a pump, have 
been well tolerated by healthy volunteers and patients with acromegaly, metastatic carcinoid 
tumor, or Cushing’s disease. The most common adverse events (AEs) were gastrointestinal, 
predominantly mild diarrhea, nausea, and abdominal pain. These effects were seen at all doses, 
but occurred more frequently at higher doses in all studies. The frequency of the 
gastrointestinal events appeared to decrease with time in multiple-dose studies. A number of 
subjects also reported mild to moderate headaches. Generally events were mild, transient, and 
only occasionally caused patients to discontinue treatment. 


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Pasireotide s.c. has been studied in phase II studies at doses of up to 900 µg b.i.d. in 
acromegalic patients, 1200 µg b.i.d. in patients with CD and patients with carcinoid tumors, 
with pasireotide s.c. study treatment periods of 4 years, 4.8 years and 1.6 years respectively. 
For all indications the most frequently reported AEs have been gastrointestinal, predominantly 
diarrhea, nausea and abdominal pain. Generally these events were mild, transient, and only 
occasionally caused patients to discontinue study treatment. Pasireotide s.c. has also been 
evaluated in a Phase III study [CSOM230B2305] in patients with CD. Pasireotide s.c. was 
well-tolerated. The majority of AEs were consistent with the known adverse drug reactions of 
SSAs. The most common AEs (incidence ≥10%) were diarrhea, nausea, abdominal pain, 
cholelithiasis, hyperglycemia, diabetes mellitus, fatigue and glycosylated hemoglobin 
increased. Hyperglycemia-related AEs appeared to be the most significant safety concern in 
terms of frequency of occurrence as well as overall clinical impact (i.e. overall increase in 
HbA1c of ~1.5% for both dose groups at 6 and 12 months). Hyperglycemia was managed 
with the addition or adjustment in oral antidiabetic treatment or in some cases the addition of 
insulin. 
Hyperglycemia was also observed across all indications. Blood glucose increases tended to 
occur with increasing dose, and appeared to be more notable in patients who had a history of 
hyperglycemia or diabetes mellitus prior to receiving pasireotide s.c.. However, 
hyperglycemia in these patients was responsive to appropriate diabetic management such as 
adjustments in oral antidiabetic treatment, or in some cases the addition of insulin. 
There were 3 healthy volunteers who had biochemical changes meeting Hy’s Law criteria (i.e. 
ALT > 3 x ULN with concurrent total bilirubin >2 x ULN, without increases in alkaline 
phosphatase and no other cause(s) identified for the abnormal findings). One subject received 
pasireotide 600 µg bid s.c. for 7 days, while the second subject received pasireotide 1950 µg 
bid s.c. for 5 days. The third subject (pasireotide 600 µg bid s.c. for 7 days) had ALT and total 
bilirubin increases that met the criteria for Hy’s Law but the alkaline phosphatase was not 
assessed and the subject received a potentially confounding concomitant medication. ALT 
values for all 3 subjects were greater than 3 x ULN but < 4 x ULN and total bilirubin values 
were < 4 x ULN. All 3 cases were asymptomatic, presented within 10 days after initial 
pasireotide s.c. administration, and were reversible with discontinuation of pasireotide s.c.. 
None of the cases were reported as adverse events and the subjects completed the respective 
studies per protocol. Liver function tests will be monitored during this clinical trial. 
Pasireotide’s effect on QT prolongation was demonstrated by two thorough QT (TQT) studies 
[SOM230B2113] and [SOM230B2125]. The second TQT study [SOM230B2125] was 
designed to evaluate the effect of pasireotide on cardiac intervals using an individualized 
correction method to account for the known bradycardic effect of pasireotide. It was 
conducted as a follow-up to Study [SOM230B2113], which showed that pasireotide at the 
Maximum Tolerated Dose (MTD) of 1950 µg b.i.d dose induced prolongation of QTcF, 
whereas no relevant effect on QTcB was observed. The second TQT study confirmed an 
effect of pasireotide on QTcI of pasireotide at both the 600 µg bid and the 1950 µg bid dose. 
The maximal placebo-subtracted change from baseline in QTcI was seen at 2 hours post dose, 
at which time the mean (90% CI) difference was 13.19 ms (11.38; 15.01) for pasireotide 600 
µg bid, and 16.12 ms (14.30; 17.95) for pasireotide 1950 µg b.i.d. Both pasireotide doses 
decreased heart rate, with a maximal difference to placebo observed at 1 hour for pasireotide 


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600 µg b.i.d (-10.39 bpm), and at 0.5 hours for pasireotide 1950 µg bid (-14.91 bpm). There 
were no subjects with QTcI or QTcF values that were increased more than 60 ms from 
baseline, or that exceeded 500 ms on Day 5, the last day of study treatment. Detailed 
information of the results of these two TQT studies can be found in the [Investigator’s 
Brochure]. 
Pasireotide long acting release (LAR) formulation 
A long acting formulation of pasireotide (pasireotide LAR) has been developed to reduce the 
number of injections from twice a day to once a month in order to enhance convenience and 
potentially provide a better efficacy profile with a smoother PK profile minimizing fluctuation 
from Cmax and Cmin. 
Pasireotide LAR in healthy volunteers 
Data from a Western healthy volunteer study [CSOM230C2101] which assessed single i.m. 
doses of pasireotide LAR up to 60 mg (N=5 per cohort for 40 mg and 60 mg) showed that 
pasireotide LAR was well-tolerated, and the adverse events (AEs) were comparable with 
those from octreotide LAR (a long acting release formulation of octreotide). Diarrhea was the 
most common adverse event which was sometimes associated with abdominal pain and/or 
flatulence. The gastrointestinal events were mild or moderate in severity. About half of the 
subjects reported transient mild injection site pain. An increase in fasting blood glucose 
accompanied by a decrease in fasting blood insulin (and a small decrease in glucagon levels) 
was observed with the injection of the LAR formulations. Post-prandially, in the LAR 
formulations there was a marked increase in post-prandial glucose. These changes tended to 
normalize over time. 
Pharmacokinetics (PK) of pasireotide LAR was assessed in healthy volunteers following a 
single i.m. injection of 40 mg [CSOM230C2101] or 60 mg [CSOM230C2101] 
[CSOM230C2111]. The PK exposures of pasireotide was dose-proportional with Cmax of the 
extended release phase as 9.6 ± 5.1 ng/mL and 15.8 ± 3.3 ng/mL for the 40 and 60 mg doses, 
respectively [CSOM230C2101]. Multiple-dose PK simulation suggest that this LAR 
formulation is suitable for monthly (q 28 d) dosing and steady state reaches after three 
injections. 
Further details and data available from the healthy volunteer study [CSOM230C2101] are 
described in the pasireotide LAR Investigator’s Brochure. 
Phase I study [CSOM230G1101] is an open-label, single center, dose escalation study to 
assess the safety, tolerability and PK of single dose of pasireotide LAR in Japanese healthy 
volunteers. A total of 32 subjects were enrolled, 8 in each of four cohorts. Each cohort 
received a single dose at 10 mg, 20 mg, 40 mg or 60 mg per subject. The PK analysis 
demonstrated that exposure of pasireotide (Cmax,p1, Cmax,p2, AUClast and AUCinf) 
increased in a dose-proportional manner (see Figure 1-2 and Table 1-2). No SAE was reported. 
Most frequently reported adverse events were blood glucose increased (18/32 subjects, 56.3%; 
1/8 at 10 mg, 3/8 at 20 mg, 8/8 at 40 mg and 6/8 at 60 mg) and diarrhea (14/32 subjects, 
43.8%; 1/8 at 20 mg, 5/8 at 40 mg and 8/8 at 60 mg). Single dose of pasireotide LAR up to 60 
mg was in general tolerated among Japanese healthy volunteers. 


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Figure 1-2 
Plasma concentration versus time profiles after a single i.m. 
administration of pasireotide LAR n Japanese healthy volunteers (PK 
set) (n=8 each dose cohort) in study CSOM230G1101 
 
Table 1-2 
Summary of PK parameters for pasireotide LAR single dose of 10-60 
mg in Japanese healthy volunteers (PK set) in study CSOM230G1101 
 
10 mg 
N=8 
20 mg 
N=8 
40 mg 
N=8 
60 mg 
N=8 
Tmax,p1 (hr) 
Median 
10.00 
12.00 
10.00 
12.00 
Min-Max 
6.0-12.0 
10.0-24.0 
8.0-24.0 
10.0-24.0 
Cmax,p1 (ng/mL) 
Mean (SD) 
1.703 (0.3740) 
3.110 (1.6296) 
10.551 (4.0629) 
9.726 (4.3778) 
Tmax,p2 (hr) 
Median 
408.0 
456.0 
480.0 
504.0 
Min-Max 
336-480 
336-528 
384-576 
240-576 
Cmax,p2 (ng/mL) 
Mean (SD) 
4.370 (1.0687) 
8.194 (1.6885) 
19.825 (10.3789) 
29.013 (8.9550) 
AUClast (ng·hr/mL) 
Mean (SD) 
1858.9 (246.49) 
3848.0 (1086.89) 
9968.9 (4737.60) 
12840.8 (1349.46) 


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10 mg 
N=8 
20 mg 
N=8 
40 mg 
N=8 
60 mg 
N=8 
AUCinf (ng·hr/mL) 
Mean (SD) 
1953.1 (271.92) 
4069.3 (1183.95) 
10258.7 (4843.78) 
13394.8 (1467.57) 
T1/2 (hr) 
Mean (SD) 
290.6 (61.84) 
442.9 (253.81) 
341.3 (111.13) 
378.3 (198.59) 
CL/F (L/hr) 
Mean (SD) 
5.204 (0.6900) 
5.240 (1.3024) 
4.468 (1.5157) 
4.526 (0.4883) 
Vz/F (L) 
Mean (SD) 
2167.0 (462.82) 
3292.8 (1738.48) 
2199.1 (1016.81) 
2404.5 (1084.35) 
MRTlast (hr) 
Mean (SD) 
483.1 (42.60) 
518.1 (57.39) 
500.1 (22.44) 
543.7 (61.04) 
MRTinf (hr) 
Mean (SD) 
557.1 (50.12) 
617.1 (108.30) 
549.9 (38.80) 
617.2 (88.24) 
Pasireotide LAR in acromegaly patients 
Pasireotide 
LAR 
was 
evaluated 
in 
a 
patient 
study 
[CSOM230C2110]. 
Study 
[CSOM230C2110] is a multicenter, open-label, randomized study designed to evaluate the 
pharmacokinetics, safety and tolerability of monthly doses (dosing every 28 days) of 20, 40, 
and 60 mg pasireotide LAR in patients with acromegaly. Thirty-five acromegaly patients have 
been enrolled (approximately 10 patients per dose cohort per indication). Preliminary safety 
data on three months of study treatment reflect a similar safety profile to that observed with 
pasireotide s.c. Overall, 24 of the 35 patients with acromegaly (68.6%) who received at least 
one dose of LAR study treatment experienced at least one AE including 7/10 patients in the 
pasireotide LAR 20 mg group, 7/12 patients in the pasireotide LAR 40 mg group and 10/13 
patients in the pasireotide LAR 60 mg group. The most commonly affected primary SOCs 
were Gastrointestinal disorders (13/35 patients; primarily diarrhea), Infections & infestations 
(12/35 patients; primarily nasopharyngitis), Metabolism & nutrition disorders (9/35 patients; 
primarily hyperglycemia followed by diabetes mellitus) and Investigations (6/35 patients; 
primarily blood glucose increased and blood insulin decreased). PK exposures were 
approximately dose proportional. PK steady state was achieved following 3 injections. PK 
exposures to pasireotide at steady state in acromegalic patients were comparable to the 
simulated PK exposures at steady state in healthy volunteers. Further details and data 
available from the acromegaly patients study [CSOM230C2110] are described in the 
[pasireotide LAR Investigator’s Brochure]. 
Preliminary data from the Phase III study [CSOM230C2305] assessed the efficacy and safety 
of pasireotide LAR vs. octreotide LAR in patients with active medication naïve acromegaly. 
Patients randomized into 40mg pasireotide LAR and 20mg octreotide LAR. Then dose 
titration was allowed up and down for efficacy and safety reason, respectively. The primary 
efficacy variable was the proportion of patients with a reduction of mean GH levels to < 
2.5µg/L and the normalization of IGF-1 to within normal limits (age and sex related) at 12 
months. A two-sided Cochran-Mantel-Haenszel (CMH) test (adjusting for randomization 
stratification factor) showed a statistical significant result favoring pasireotide LAR (p-value 
= 0.005). Odds ratio along with 95% confidence interval was 1.992 (1.222, 3.247), response 
rates and their corresponding confidence intervals were 31.4% (24.5%, 38.7%) and 19.2% 


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(13.8%, 25.7%) for pasireotide LAR and octreotide LAR, respectively. The response rate at 3 
was same as that at 6 months, it was 30.1%. The most frequent AEs were diarrhoea (38.2% 
and 45.0%), cholelithiasis (25.8% and 37.2%), headache (18.0% and 26.1%), abdominal pain 
(17.4% and 22.2%), alopecia (18.0% and 19.4%), hyperglycaemia (28.1% and 8.3%), nausea 
(12.9% and 21.7%), and nasopharyngitis (15.7% and 15.6%) for pasireortide LAR and 
octreotide LAR. Among the most frequent AEs (>5%), grade 3 or 4 AEs exceeding 2% were 
hyperglycaemia (2.8% and 0.6%) and diabetes mellitus (5.6% and 0%). 
2 
Rationale 
2.1 
Study rationale and purpose 
Pasireotide LAR was tested in patients with acromegaly in phase I patient study 
[CSOM230C2110]. The response rate, the proportion of patients with a reduction of 5-point 
mean GH levels to <2.5 µg/L and normalization of IGF-1 to within normal limits (age and sex 
related), at 3 months of study treatment was 30% in the 20 mg group, 41.7% in the 40 mg 
group, and 38.5% in the 60 mg group. 
The phase 3 study CSOM230C2305 demonstrated Pasireotide LAR was superior in efficacy 
(i.e. GH levels to <2.5 µg/L and normalization of IGF-1 to within normal limits (age and sex 
related)) to octreotide LAR for patients with medication naive active acromegaly. Pasireotide 
LAR appeared to have a similar safety profile relative to octreotide LAR, except for 
hyperglycemia (Section 1.2.1.2). Pasireotide LAR was generally tolerated in Japanese healthy 
volunteers from the tested doses (10-60 mg) [CSOM230G1101]. The safety profile in 
Japanese healthy volunteers was similar to that in Western healthy volunteers 
[CSOM230C2101]. 
Pituitary gigantism patients are included in the target population. Basically, acromegaly and 
pituitary gigantism are identical diseases. Pituitary gigantism is also caused by a GH-secreting 
pituitary adenoma. According to the guidance of diagnosis and treatment for these diseases, 
major symptoms of pituitary gigantism are almost the same as acromegaly and the treatment 
strategy is the same as that for acromegaly. Therefore it is expected that pasireotide has 
efficacy for not only acromegaly but also for pituitary gigantism. The difference between 
acromegaly and pituitary gigantism from a diagnostic perspective is age at onset. Pituitary 
gigantism occurs before closing epiphyseal growth plates. However, pituitary gigantism 
diagnosed in childhood is very rare case. Average age of the initial visit is 23.4 years old. 
Therefore it is appropriate to include the patient who is at least 18 years of age. 
The purpose of [CSOM230C1202] is to evaluate the efficacy, safety, PK and 
pharmacodynamics of pasireotide LAR in Japanese patients with acromegaly and pituitary 
gigantism. 
2.2 
Rationale for the study design 
This study is a multi-center, open label, randomized phase II study in Japan evaluating the 
efficacy, safety, PK and pharmacodynamics of pasireotide LAR in patients with active 
acromegaly and pituitary gigantism. 


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With reference to the design of [CSOM230C2110] in western patients with acromegaly, the 
starting doses of this study will be fixed at 20 mg, 40 mg, and 60 mg during the first 3 months. 
The response rate is defined as the proportion of responders (responder defined as the 
reduction of mean GH levels to < 2.5 µg/L and normalization of IGF-1 to within normal 
limits). The response rates at 20 mg, 40mg and 60mg in [CSOM230C2110] were comparable 
(30% at 20mg, 41.7% at 40mg, and 38.5% at 60mg). According to [CSOM230C2305], early 
response was observed at 3 months. And the response rate at 3 months was almost same as 
that at 6 and 12 months. After 3 months study treatment, the efficacy of pasireotide LAR in 
overall population will be assessed. As in the case of [CSOM230C2305], it is permitted to 
increase the dose (up to 60 mg) after the first 3 months of study treatment if biochemical 
parameters show a mean GH level ≥ 2.5 µg/L and/or IGF-1 > ULN (age and sex related). In 
the event of any problem with tolerability, it is permitted to reduce the dose down to 20 mg at 
any time. Core and extension treatment periods were set with reference to [CSOM230C2305]. 
2.3 
Rationale for dose and regimen selection 
Pasireotide LAR doses (20mg, 40mg and 60mg) selected for evaluation in this study were 
based on evaluation of PK, pharmacodynamics, efficacy and safety/tolerability data from 
patients (acromegaly, carcinoid disease) treated with pasireotide LAR ([CSOM230C2110]) 
and Japanese healthy volunteers treated with pasireotide LAR ([CSOM230G1101]). 
2.4 
Rationale for choice of combination drugs 
Not applicable. 
2.5 
Rationale for choice of comparators drugs 
Not applicable. 
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 
Assess the total-group efficacy of pasireotide LAR on the reduction 
of mean GH levels to < 2.5 µg/L and the normalization of IGF-1 at 3 
months of study treatment 
Proportion of patients with a reduction of mean GH levels to < 2.5 µg/L 
and the normalization of IGF-1 to within normal limits (age and sex 
related) at 3 months across all doses 
Key secondary 
Refer to Section 10.5.1 
Assess the effect of each starting dose pasireotide LAR on the 
reduction of mean GH levels to < 2.5 µg/L and the normalization of 
IGF-1 at 3 months of study treatment 
Proportion of patients with a reduction of mean GH levels to < 2.5 µg/L 
and the normalization of IGF-1 to within normal limits (age and sex 
related) at 3 months in each starting dose 
Assess the PK and PK/PD of pasireotide LAR 20 mg, 40 mg and 60 
mg 
PK: Ctrough, Cmax, 3rd inj, accumulation ratio (AR) 
PD: GH, IGF-1 
Safety: blood glucose (BG), HbA1c, ECG, liver function test (LFT) 
Assess the tolerability and safety profile of pasireotide LAR at 3 
months and during and after the 12- month study treatment 
Toxicity will be assessed using the National Cancer Institute-Common 
Toxicology Criteria (NCI-CTC) grading scale for Adverse Events and for 
laboratory assessments that include biochemistry, hematology, 
urinalysis; special safety assessments that include the regular 
monitoring and recording of blood glucose, HbA1c, thyroid and liver 
function tests, gallbladder examinations and ECGs.  
Assess the effect of pasireotide LAR on the reduction of mean GH 
levels to < 2.5 µg/L at 3 months of study treatment 
Proportion of patients with a reduction of mean GH levels to < 2.5 µg/L 
at 3 months 
Assess the effect of pasireotide LAR on the normalization of IGF-1 
at 3 months of study treatment 
Proportion of patients with the normalization of IGF-1 to within normal 
limits (age and sex related) at 3 months 
This document (090095a8858c5ecf in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI.
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Objective 
Endpoint 
Analysis 
Other secondary (Core phase) 
Refer to Section 10.5.2 
Assess the effect of pasireotide LAR on the reduction of mean GH 
levels to < 2.5 µg/L and the normalization of IGF-1 at 6, 9 and 12 
months of study treatment 
Proportion of patients with a reduction of mean GH levels to < 2.5 µg/L 
and the normalization of IGF-1 to within normal limits (age and sex 
related) at 6, 9 and 12 months 
 
Assess the effect of pasireotide LAR on the reduction of mean GH 
levels to < 2.5 µg/L at 6, 9and 12 months of study treatment 
Proportion of patients with a reduction of mean GH levels to < 2.5 µg/L 
at 6, 9 and 12 months 
Assess the effect of pasireotide LAR on the normalization of IGF-1 
at 6, 9 and 12 months of study treatment 
Proportion of patients with the normalization of IGF-1 to within normal 
limits (age and sex related) at 6, 9 and 12 months 
Assess the effect of pasireotide LAR on the change of tumor volume 
at 6and 12 months of study treatment 
Change of tumor volume from baseline at 6 and 12 months 
Assess the effect of pasireotide LAR on the change of mean GH 
level from baseline 
Change of mean GH levels from baseline 
Assess the effect of pasireotide LAR on the symptoms of 
acromegaly, specifically: ring size, headache, fatigue, perspiration, 
paresthesias, osteoarthralgia 
Change of clinical signs from baseline: ring size, headache, fatigue, 
perspiration, paresthesias, osteoarthralgia 
Assess the effect of pasireotide LAR on the cahge of prolactin (PRL) 
level from baseline 
Change PRL level from baseline 
Other secondary (Extension phase) 
Assess the effect of pasireotide LAR as long term study treatment 
on the proportion of patients with a reduction of mean GH level to < 
2.5 µg/L and normalization of IGF-1 at 18 and 24 months of study 
treatment 
Proportion of patients with a reduction of mean GH levels to < 2.5 µg/L 
and the normalization of IGF-1 to within normal limits (age and sex 
related) a18 and 24 months of study treatment  
Assess the effect of pasireotide LAR as long term study treatment 
on the reduction of mean GH levels to < 2.5 µg/L at 18 and 24 
months of study treatment 
Proportion of patients with a reduction of mean GH levels to < 2.5µg/L 
at 18 and 24 months of study treatment 
Assess the effect of pasireotide LAR as long term study treatment 
on the normalization of IGF-1 at 18 and 24 months of study 
treatment 
Proportion of patients with the normalization of IGF-1 to within normal 
limits (age and sex related) at 18 and 24 months of study treatment 


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Objective 
Endpoint 
Analysis 
Assess the effect of pasireotide LAR as long term study treatment 
on the change of mean GH levels from baseline 
Change of mean GH levels from baseline in extension phase 
Assess the safety and tolerability of pasireotide LAR in extension 
phase  
Toxicity in extension phase will be assessed using the National Cancer 
Institute-Common Toxicology Criteria (NCI-CTC) grading scale for 
Adverse Events  
Assess the total-group safety and tolerability of pasireotide LAR as 
long term study treatment 
Toxicity in total-group study treatment will be assessed using the 
National Cancer Institute-Common Toxicology Criteria (NCI-CTC) 
grading scale for Adverse Events and for laboratory assessments that 
include biochemistry, hematology, urinalysis; special safety 
assessments that include the regular monitoring and recording of blood 
glucose, HbA1c, thyroid and liver function tests, gallbladder 
examinations and ECGs. 


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4 
Study design 
4.1 
Description of study design 
A total of 30 eligible patients will be enrolled. The enrolled patients will be randomized to 
one of 3 doses of pasireotide LAR (20 mg, 40 mg, or 60 mg) in a ratio of 1:1:1. 
Randomization will be stratified by prior medications (e.g. somatostatin analogues, dopamine 
agonists or GH receptor antagonists), (yes or no). Intramuscular administration of pasireotide 
LAR will be repeated every month (1 month = 28 days) for 12 months in core phase. It is 
permitted to increase the dose up to 60 mg in a patient showing the following biochemical test 
results after 3 and 6 months of study treatment: mean GH levels ≥2.5 µg/L and/or IGF-1 > 
ULN (age and sex related). In the event of any problem with tolerability, it is permitted to 
reduce the next lower dosage level at any time. After 3 months of study treatment, the primary 
endpoint (proportion of patients with a reduction of mean GH levels to <2.5 µg/L and 
normalization of IGF-1 to within normal limits) will be evaluated.  
Patients with a reduction of mean GH levels to <2.5 µg/L and normalization of IGF-1 at the 
end of the 12-month study treatment will be enrolled in an extension phase of study treatment. 
Patients with a mean GH level ≥ 2.5 µg/L and/or IGF-1 > ULN at the end of the 12- month 
study treatment may be enrolled in an extension phase of study treatment if the extended 
study treatment is thought to be clinically beneficial for them by the investigator. Patients will 
receive pasireotide LAR in the extension phase until unacceptable toxicity appears or until the 
medication is commercially available or until the pasireotide LAR development program is 
discontinued whichever comes first. 
Patients, who participate in the extension phase, will receive a 13th injection of the pasireotide 
LAR, the Visit 779 (Study completion) will be their last visit. 
Figure 4-1 
Study design 
 


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4.2 
Timing of interim analyses and design adaptations 
Not applicable 
4.3 
Definition of end of the study 
Completion of the study as a whole (last patient last visit) will occur after all patients have 
completed all assessments as per Table 7-1 and Table 7-2 (core and 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 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 Japanese patients, with active acromegaly 
or pituitary gigantism. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered study treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent obtained prior to any screening procedures 
2. Male or female patients of at least 18 years of age 
3. Patients with active acromegaly or pituitary gigantism following a or b 
a. Patients with medication naïve acromegaly or pituitary gigantism demonstrated by:  
• a lack of suppression of GH nadir to <1 µg/L after an oral tolerance test with 75 g 
of glucose (OGTT) (not applicable for diabetic patients) or a mean GH 
concentration of a 5-point profile within a 2 hour time period of > 5 µg/L 
• elevated circulating IGF-1 concentration (age and sex related) 
• Patients who have undergone one or more pituitary surgeries, but have not been 
treated medically or de-novo patients presenting a visible pituitary adenoma on 
MRI and who refuse pituitary surgery or for whom pituitary surgery is 
contraindicated 


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b. Patients with inadequately controlled acromegaly or pituitary gigantism as defined by 
a mean GH concentration of a 5- point profile over a 2-hour period > 2.5 µg/L and 
age and sex related IGF-1 > 1.3 x upper limit of laboratory normal (ULN), even if 
acromegaly have been treated for at least 12 weeks with somatostatin analogues or 
dopamine agonist 
4. Patients with a known history or new diagnosis of impaired fasting glucose or diabetes 
mellitus may be included, however blood glucose and antidiabetic treatment must be 
monitored closely throughout the trial and adjusted as necessary (see Section 6.3.3) 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. For patients with inadequately controlled acromegaly or pituitary gigantism with current 
medication. 
• Patients who have been treated with dopamine agonists during the last 8 weeks prior 
to visit 1 (screening). 
• Patients who have been treated with long -acting somatostatine analogues during the 
last 4 weeks prior to visit 1 (screening). 
• Patients who have been treated with GH receptor antagonists during the last 8 weeks 
prior to visit 1 (screening). Such patients must have been treated with long -acting 
somatostatine analogues or dopamine agonists monotherapy continuously for a 
minimum of 12 weeks prior to starting GH receptor antagonists therapy and they 
should have been inadequately controlled on monotherapy. 
2. Patients who have received pasireotide (SOM 230) prior to enrollment 
3. Patients with compression of the optic chiasm causing any visual field defect for whom 
surgical intervention is indicated. 
4. Patients who require a surgical intervention for relief of any sign or symptom associated 
with tumor compression 
5. Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks 
of visit 1 
6. Patients who have received radiotherapy (except for pituitary irradiation) for any reason in 
the 4 weeks prior to visit 1 must have recovered from any side effect of radiotherapy 
7. Patients who have received pituitary irradiation within the last three years prior to visit 1 
8. Patients who are hypothyroid and not adequately treated with stable doses of thyroid 
hormone replacement therapy 
9. Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1c >8% 
10. Patients with symptomatic cholelithiasis 
11. Patients with abnormal coagulation (PT and/or APTT elevated by 30% above normal 
limits) or patients receiving anticoagulants that affect PT (prothrombin time) or APTT 
(activated partial thromboplastin time) 
12. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, 
advanced heart block or a history of acute myocardial infarction within the six months 
preceding enrollment 


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13. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF > 470 
ms, hypokalemia, hypomagnesemia, hypocalcemia, family history of long QT syndrome, 
or patients receiving a concomitant medication known to prolong QT interval. 
14. Patients with confirmed central hypothyroidism, central hypoadrenalism and diabetes 
insipidus, unless they are adequately treated with stable doses of hormone replacement 
therapy for a minimum of three months prior to study entry (first dose of study 
medication). Patients with confirmed central hypogonadism unless they are adequately 
treated with stable doses of hormone replacement therapy for a minimum of three months 
prior to study entry (first dose of study medication) except in cases where hormones 
replacement therapy is not indicated. 
15. Patients with history of liver disease such as cirrhosis, chronic active hepatitis B or C, or 
patients with ALT or AST more than 2 x ULN, baseline total bilirubin > 1.5 x ULN 
16. Presence of Hepatitis B surface antigen (HbsAg) 
17. Presence of Hepatitis C antibody (anti-HCV) 
18. Patients with WBC <3 x 109/L; Hgb < 90 % LLN; PLT <100 x 109/L 
19. Patients who have any current or prior medical condition that may interfere with the 
conduct of the study or the evaluation of its results in the opinion of the Investigator  
20. Female patients who are pregnant or lactating, or are of childbearing potential (defined as 
all women physiologically capable of becoming pregnant) and not practicing an effective 
method of contraception/birth control. Female patients of child bearing potential and 
sexually active males must use a condom during intercourse while taking the drug and for 
3 months after the last dose of study drug 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. Effective contraception methods include: 
• Use of oral, injected or implanted hormonal methods of contraception 
• Placement of an intrauterine device or intrauterine system 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 
• Total abstinence 
• Patient sterilization (male or female) 
21. Patients who have a history of alcohol or drug abuse in the 12 month period prior to 
receiving pasireotide LAR 
22. Patients who have given a blood donation (of 400 ml or more) within 2 months before 
receiving pasireotide LAR 
23. Patients who have participated in any clinical investigation with an investigational drug 
within 1 month before receiving pasireotide LAR 
24. Known hypersensitivity to somatostatin analogues or any components of the LAR 
formulation 
25. Patients with active malignant disease within the last five years (with the exception of 
basal cell carcinoma or carcinoma in situ of the cervix) 
26. Patients with the presence of active or suspected acute or chronic uncontrolled infection 


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27. Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will be unable to complete the entire study 
28. Known gallbladder or bile duct disease, acute or chronic pancreatitis 
6 
Study treatment 
6.1 
Study treatment 
Investigational study treatment: pasireotide LAR i.m. 
6.1.1 
Dosing regimen 
Patient will receive one of three pasireotide LAR i.m. doses of 20, 40, or 60 mg. 
Intramuscular administration of pasireotide LAR will be repeated every month (1 month = 28 
days) for 12 months in core phase. It is permitted to increase the dose up to 60 mg in a patient 
showing the following biochemical test results after 3 and 6 months of study treatment: mean 
GH levels ≥2.5 µg/L and/or IGF-1 > ULN (age and sex related). In the event of any problem 
with tolerability, it is permitted to reduce next lower dosage level at any time. 
6.1.2 
Ancillary treatments 
Not applicable. 
6.1.3 
Rescue medication 
Not applicable. 
6.1.4 
Guidelines for continuation of treatment 
Patients may continue treatment provided no tolerability issues are present (See Section 6.3) 
and criteria for discontinuation are not met (see Section 7.1.3). 
6.1.5 
Treatment duration 
Patients will be treated for 12 months in the core phase of the study and will have the option 
to continue study treatment for 12 more months in the extension phase of the study. 
6.2 
Dose escalation guidelines 
Not applicable. 


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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
Dose up-titration 
Dose increases is permitted after the first three months of treatment (steady-state reached) if 
biochemical parameters show a mean GH level ≥ 2.5 µg/L and/or IGF-1 > ULN (age and sex 
related) and there are no tolerability issues (see Table 6-1). Patients on the 20 mg arm with a 
mean GH level ≥ 2.5 µg/L and/or IGF-1 > ULN (age and sex related) after the Month 2.75 
(Visit 11) GH and IGF-1 assessment will have their dose increased to 40 mg at Month 3 (Visit 
12), if there are no tolerability issues. Patients on the 40 mg arm with a mean GH level ≥ 2.5 
µg/L and/or IGF-1 > ULN (age and sex related) after the Month 2.75 (Visit 11) GH and IGF-1 
assessment will have their dose increased to 60 mg at Month 3 (Visit 12), if there are no 
tolerability issues. At Month 7 (Visit 16), patients receiving 20 mg and 40 mg doses with 
mean GH level ≥ 2.5 µg/L and/or IGF-1 > ULN (age and sex related) after the Month 6 (Visit 
15) GH and IGF-1 assessment will have their dose increased to 40 mg and 60 mg, 
respectively, if there are no tolerability issues. Patients receiving the 60 mg dose at Month 3, 6 
or 9 with a mean GH level ≥ 2.5 µg/L and IGF-1 > ULN (age and sex related) will be 
discontinued from the study unless clinical benefit has been observed as per the investigator’s 
judgment. 
Patients that have a mean GH level < 2.5 µg/L and IGF-1 ≤ULN (age and sex related) on 
current therapy after Month 3 and/or Month 6 will be kept on their current dose. 
After Month 12, the timing of the dose adjustments will be based on GH and IGF-1 values, at 
the investigators discretion but must include duration of at least 3 months on a current dose 
prior to up-titration and no tolerability issues are present. Patients receiving the 60 mg dose 
after Month 12 with a mean GH level ≥ 2.5 µg/L and IGF-1 > ULN (age and sex related) will 
be discontinued from the study unless clinical benefit has been observed as per the 
investigator’s judgment. 
Dose down-titration 
Dose reduction is due to lack of tolerability (refer to Table 6-2 and Table 6-3) will be allowed 
as one dose level reduction at a time (i.e. from 60 mg to 40 mg or from 40 mg to 20 mg) If 
tolerability issue is resolved, increase dose to that prior to the dose reduction unless 
investigator opinion to remain on current dose. 
These changes must be recorded on the Dosage Administration Record CRF. 
Dose interruption 
If a patients requires a dose interruption of >28 days from the intended day of the next 
scheduled dose (>56 days from the previous dose), then the patient must be discontinued from 
the study. 


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Table 6-1 
Dose titration steps for pasireotide LAR 
 
Dose level 0 
Dose level 1 
Dose level 2 
Dose increase 
SOM230 LAR 
60 mg 
Not applicable 1 
Not applicable 1 
SOM230 LAR 
40 mg 
60 mg 
Not applicable 1 
SOM230 LAR 
20 mg 
40 mg 
60 mg 
Dose reduction 
SOM230 LAR 
60 mg 
40 mg 
20 mg 
SOM230 LAR 
40 mg 
20 mg 
Not applicable 2 
SOM230 LAR 
20 mg 
Not applicable 2 
Not applicable 2 
1 Dose increase above 60 mg is prohibited. 
2 Dose reduction below 20mg is prohibited .Dose reduction should be based on the worst toxicity demonstrated at 
the last dose. 
Table 6-2 
Guideline for treatment of patients experiencing adverse events 
Adverse event 
Action 
AE CTC grade ≤ 2 
No drug adjustments 
AE CTC grade ≥ 3 and 
assessed as study drug related 
Reduce pasireotide LAR i.m. dose from 
60 mg to 40mg 
40 mg to 20mg 
20 mg - discontinue 
If AE improves to grade ≤ 2 before the next administration, increase dose to 
that prior to the dose reduction unless investigator opinion is to remain on 
current dose.  
If the dose is increased and the AE recurs at CTC grade ≥ 3, the dose should 
be reduced again and the patient should stay on this lower dose and no further 
dose titrations are allowed. 
If AE does not improve to grade ≤ 2 on the minimum dose the patient will be 
withdrawn. 
For the management of QT prolongation and LFT increases refer to specific instructions provided in Special 
Safety in Section 6.3.3 (Figure 6-2 and Figure 6-3). 
Table 6-3 
Guideline for treatment of patients experiencing adverse events in 
QTcF 
Adverse event 
Action 
CTC grade 1 
(QTcF ≤ 470 msec) 
No study drug adjustments 
CTC grade 2 
(470 < QTcF ≤ 500 msec) 
No study drug adjustments 
Patient is to be referred to a cardiologist for evaluation and appropriate 
management. 
Patient can remain in the study (unless discontinuation is recommended by 
cardiologist) 
CTC grade ≥ 3 
(QTcF > 500 msec) 
Dose is interrupted until a cardiologist consult obtained. 
If QTcF >500 is confirmed by cardiologist, the patient is to be discontinue 
See Section 6.3.3 for further guidance on QTcF adverse events 
6.3.2 
Follow-up for toxicities 
Refer to Table 6-2, Table 6-3 and Section 6.3.3. 


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6.3.3 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria, 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 abnormal are provided below. Refer to preclinical toxicity and or 
clinical data found in the [Investigator’s Brochure]. 
6.3.3.1 
Hyperglycemia 
Hyperglycemia is known to be associated with the treatment of somatostatin analogues (SSA). 
Clinical studies of pasireotide in healthy volunteers and in patients with Cushing’s disease, 
acromegaly or carcinoid syndrome have reported transient, asymptomatic increases in fasting 
and postprandial glucose levels. Two clinical studies have been conducted ([SOM230B2216] 
and [SOM230B2124]) in healthy volunteers to further understand the mechanism of 
pasireotide-induced hyperglycemia and to evaluate the potential clinical utility of anti-
diabetes agents in the management of pasireotide-induced hyperglycemia. Data from 
([SOM230B2216] study indicate that pasireotide decreases insulin secretion, particularly in 
the postprandial period, as well as the GLP-1/GIP secretion. Results from [SOM230B2124] 
study suggest that the incretin-based therapies (GLP-1 analogues and DPP-4 inhibitors) may 
have the best potential to manage the hyperglycemia associated with pasireotide. 
Monitoring of blood glucose 
Close and frequent monitoring of blood glucose is needed during pasireotide treatment. The 
principal investigator is to educate the patient on the signs and symptoms of hyperglycemia. 
Patients must monitor their fasting blood glucose by fingerstick at home at least 3 times per 
week for the first month of pasireotide LAR treatment. If a patient does NOT have any fasting 
values above 100 mg/dL, monitoring can be decreased to at least 2 times per week for months 
2 and 3 and 1 time every 2 weeks for 4 months through 6 months. If glucose values remain 
normal (lower than or equal to 100 mg/dL), monitoring is at the investigator’s discretion after 
6 months. If any values are observed above 100 mg/dL, the guidelines in Figure 6-1 are to be 
followed. These guidelines are based on the current recommendations from the 2012 
American Diabetes Association and European Association for the Study of Diabetes aiming at 
a glycemic treatment goal of FPG <130 mg/dL (<7.2 mmol/L). Appropriate actions such as 
initiation of anti-hyperglycemic therapy (and referral to diabetes specialist) are to be taken by 
the investigator as outlined on Figure 6-1. If fasting blood glucose values dictate initiation of 
anti-hyperglycemic treatment (i.e., confirmed >130 mg/dL by self-monitoring), a fasting 
plasma glucose sample using the local laboratory is to be collected prior to initiation of anti-
hyperglycemic treatment. If a patient has a dose increase, monitoring for hyperglycemia 
should follow the recommendations for the first month of treatment and continue as presented 
above for subsequent months. 
It is recommended that the patients be encouraged to keep a diary for their blood glucose for 
appropriate management throughout the study and present the collected data to their 
physician/diabetes specialist for evaluation. This data will not be collected by the sponsor. 


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In addition to self-monitoring, fasting plasma glucose and HbA1c will be collected at study 
visits per Table 7-1 and Table 7-2. Intervention for hyperglycemia is to be implemented in 
any patient meeting any of the following criteria: FPG > 130 mg/dL or HbA1c ≥ 6.5 %. 
Patients with FPG > 160 mg/dL or HbA1c >7.5% despite adjustment of antidiabetic therapy 
should be referred to a diabetes specialist (or earlier per investigator’s judgment). 
As outlined in Table 6-2, patients with grade 3 hyperglycemia (FPG value >250 mg/dL; >13.9 
mmol/L) at any point in the study should have the dose of pasireotide decreased.Patients who 
in spite of appropriate therapeutic interventions and despite dose reduction of study drug 
develop uncontrolled diabetes mellitus and/or consistently high blood glucose values: FPG ≥ 
240 mg/fdL (13.3 mmol/L) or HbA1c value ≥ 10 % will require study treatment 
discontinuation as outlined in Section 7.1.3.1. 
Figure 6-1 
Fasting self-monitoring blood glucose guidelines 
 
6.3.3.2 
QT-related cardiology consultation / Holter monitoring 
All patients will be asked to return on Day 22 for an ECG recording and PK sampling. 
If at any visit a QTcF > 500 msec is observed, triplicate ECGs, each 2-3 minutes apart, need 
to be taken approximately 1 hour after the initial ECG. The mean QTcF from the triplicate 
ECGs will be determined. If the mean QTcF is > 500 msec, the patient has to postpone study 
treatment until a cardiologist has re-evaluated the ECG (this can be done by the central 
cardiologist). The re-evaluation needs to be done as soon as practical but within 7 days of the 


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initial abnormal ECG. If the cardiologist confirms a mean QTcF > 500 msec, the patient must 
be discontinued from the study. Otherwise and if the cardiologist confirms that at least one 
ECG shows a QTcF > 470msec, the cardiac assessments described for a confirmed QTcF > 
470 msec needs to be followed. 
If at Day 22 a QTcF / mean QTcF > 470 msec but ≤ 500 msec is observed for the first time for 
a patient at a given dose level, the following steps need to be taken (please also refer to Figure 
6-2): 
A cardiology consultation must be sought as soon as practical but within 7 days of the initial 
abnormal ECG and prior to the next pasireotide LAR injection. The cardiologist must re-
evaluate the ECG: 
• If a QTcF > 470 msec is NOT confirmed, no further action needs to be taken. 
• If a QTcF > 470 msec is confirmed, a cardiologist must perform a thorough examination 
(such as reviewing baseline ECG, concurrent medications and performing a cardiovascular 
examination, including at least a cardiac auscultation) to assess the patient for 
cardiovascular risk factors. 
• If based upon the assessment by the cardiologist, the investigator considers that there is an 
acute cardiovascular safety risk and that the patient should not continue with study 
medication, the patient needs to be discontinued immediately (discontinuation criteria to 
be followed as described in Section 7.1.3). 
• If following the examination by the cardiologist, the investigator considers that there 
is no acute cardiovascular safety risk and that the patient could continue to receive 
study medication, a 24hr Holter ECG must be recorded at the next pasireotide LAR 
injection. The Holter-ECG must be started 30 min prior to an injection of study 
medication and a pre-dose PK sample will be taken. 
If at any visit at trough level (28 days after the previous dose) a QTcF/mean QTcF > 470 msec 
but ≤ 500msec is observed for the first time for a patient at a given dose level, the following 
steps need to be taken (please also refer to Figure 6-2): 
A cardiology consultation must be sought as soon as practical but within 7 days of the initial 
abnormal ECG and prior to the next pasireotide LAR injection. The cardiologist must re-
evaluate the ECG. 
• If a QTcF > 470msec is NOT confirmed, no further action needs to be taken. 
• If a QTcF > 470msec is confirmed, a cardiologist must perform a thorough examination 
(such as reviewing baseline ECG, concurrent medications and performing a cardiovascular 
examination, including at least a cardiac auscultation) to assess the patient for 
cardiovascular risk factors. 
• If based upon the assessment by the cardiologist, the investigator considers that there is an 
acute cardiovascular safety risk and that the patient should not continue with study 
medication, the patient needs to be discontinued immediately (discontinuation criteria to 
be followed). 


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• If following the examination by the cardiologist, the investigator considers that there is not 
an acute cardiovascular safety risk and that the patient could continue to receive study 
medication, a 24hr Holter ECG must be recorded and evaluated prior to the next injection 
of pasireotide LAR and a trough PK sample will be taken. The pasireotide LAR injection 
must be postponed with a maximal permissible delay of 7 days until the Holter-ECG 
results are available. If the outcome of the cardiac evaluation is that the patient may 
receive a further dose of pasireotide LAR, then a second 24hr Holter-ECG must be done 
on the day of the injection and a pre-dose PK sample must be taken. This Holter ECG 
should be started 30min prior to the injection. 
The results of the ECGs, cardiac examination, Holter-ECGs and the recommendation by the 
cardiologist must be evaluated by the investigator to determine whether the patient should 
continue in the study or not (discontinuation criteria to be followed as described in Section 
7.1.3). 


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Figure 6-2 
QT prolongation monitoring flow chart 
Time Period:  As soon as practical but within 7 Days of initial QTcF > 470 msec finding.
 


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6.3.3.3 
Hepatic safety management 
If any of the criteria below are observed at any scheduled or unscheduled visit the sponsor 
should be notified immediately upon awareness.  
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN  
• ALT or AST > 5 x ULN and ≤ 8 x ULN  
• ALT or AST > 8 x ULN 
The following should be performed immediately within 72 hours of awareness of the above 
abnormality: 
• Perform liver-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including OTC meds, inter-current illness, etc) 
• Liver chemistry tests: ALT, AST, total bilirubin (fractionated to direct/indirect if total 
bilirubin is >2.0 x ULN), Alb, PT (INR), ALP, and GGT 
• Perform hepatitis screen: anti-HAV, IgM (to confirm acute Hepatitis A), HBsAg, Anti-
HBc, anti-HCV (if positive, PCR viral load should be assessed), Anti-HEV, ANA 
antibodies, anti-smooth muscle anti-bodies, CMV and EBV 
• Perform abdominal ultrasound (liver and biliary tree) 
• Collect PK sample and record the dose level and the dosing time for the last dose the 
patient has taken prior to PK sampling 
Liver chemistry tests (LFTs) should be monitored every 3-4 days until resolution or return to 
baseline status. 
Patients or subjects may need to be discontinued if the abnormal liver function criteria are met 
upon LFT retesting (See criteria for premature withdrawal criteria Section 7.1.3.1). Progress 
reports of the event should be maintained until resolution or stabilization (i.e. no further 
elevation after 2 consecutive assessments). 
For ALT or AST > 5 x ULN and ≤ 8 x ULN, the following must occur (in addition to the 
safety follow up procedures noted above) 
• Study medication should be temporarily interrupted and liver chemistry tests monitored 
every 3-4 days until resolution or return to baseline. 
• If resolution or return to baseline does not occur after 2 weeks, the patient should be 
discontinued.  
• If ALT or AST (or both if ALT and AST were elevated) return to less than 5 x ULN study 
drug can be resumed and patient can continue study per protocol. 
• If ALT or AST rises above 5 x ULN any time after study drug is resumed, then study drug 
should be discontinued immediately. 
If any of these criteria are met and deemed an adverse event by the investigator, the event 
must be recorded on the Adverse Event (e) CRF page; if the event is deemed serious by the 
investigator, then proceed with completing the SAE form. In addition, any significant findings 
from the physical examination should be recorded on the Adverse Event (e) CRF page. 


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Figure 6-3 
LFT management algorithm 
 


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6.4 
Concomitant medications 
6.4.1 
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. As well as any changes in the dose of any medication 
the patient was taking prior to or during the study. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered during the study must be listed on the Concomitant 
Medications/Significant Non-Drug Therapies CRF. Note: Concomitant medications 
information will not be collected for the patients who continue the study treatment beyond 2 
years (See Table 7-2). Diabetic patients must continue their treatment for diabetes throughout 
the study as indicated. If oral contraception is used, the patient must have been practicing this 
method of birth control for at least two months prior to enrollment and must agree to continue 
the oral contraceptive throughout the course of the study and for three months after the last 
dose of study drug. 
6.4.2 
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. 
6.4.3 
Prohibited concomitant therapy 
For patients with medication naïve acromegaly or pituitary gigantism the single dose of short 
acting octreotide or short-acting dopamine agonists should not be administered within 3 days 
prior to Visit2 (baseline). In case of a single dose of short-acting octreotide, the dose should 
not be used to predict the response to the octreotide treatment. 
The use of the following treatments is prohibited after start of study. 
• Other investigational drug or therapy. 
• Medication known to affect GH or IGF-1 concentration should not be taken during this 
study. 
The use of concomitant medications with a known risk for QT prolongation is prohibited and 
requires the discontinuation of the patient from the study prior to starting the respective QT 
prolonging medication. Please refer to Appendix 2 for guidance regarding medications which 
pose a known risk for QT prolongation. 


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6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
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.  
Only the assigned patient number should be entered in the field labeled “Patient number on 
the EDC data entry screen (e.g. enter ‘1’, ‘2’, etc.). Once assigned, the patient number must 
not be reused for any other patient and the patient number for that individual must not be 
changed, even if the patient is re-screened. 
6.5.2 
Treatment assignment or randomization 
6.5.2.1 
Randomization number 
If the patient is deemed eligible for the study and will commence dosing, a randomization 
number will be assigned. Once assigned to a subject, a randomization number will not be 
reused. 
Patients who have prior medications will be assigned randomization numbers 
 and 
patients who don’t have prior medications will be assigned randomization numbers 
 
Table 6-4 
Treatment assignment numbering 
 
With prior medication 
Without prior medication 
Randomization numbers 
 
 
Patients will be assigned to one of the 3 treatment arms (Section 4.1 and Section 6.1) in a ratio 
of 1:1:1. 
Randomization will be stratified by prior medications (i.e. somatostatine analogue and 
dopamine agonist) (yes or no). 
Randomization will be performed using the following procedure to ensure that treatment 
assignment is unbiased. Random permuted blocks scheme will be used for this study. 
A randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of treatment 
groups to randomization numbers in the specified ratio. The randomization list will be 
reviewed by a Biostatistics Quality Assurance Group and locked by them after approval. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be assigned the 
lowest available number on the randomization list. 


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6.5.3 
Treatment blinding 
This is an open-label study. However, in order to minimize the potential impact of treatment 
knowledge, treatment allocation, dose information and PK data will not be accessed by 
sponsor except data manager and CRA until it will be locked for the primary analysis. The 
investigators and patients have full knowledge of the treatment allocation. 
6.6 
Study drug preparation and dispensation 
Novartis supplies pasireotide LAR to the investigational sites as 20 mg and 40mg vials. All 
dosages given to the patient and all dose changes during the study must be recorded on the 
Dosage Administration Record CRF. 
Instructions for Use can be found in Appendix 1. 
6.6.1 
Study drug packaging and labeling 
Pasireotide LAR will be provided as powder for suspension in vials and solution for 
suspension (“vehicle”) will be provided in ampoules. Medication labels will be in the local 
language and comply with the legal requirements of Japan. They will include storage 
conditions for the drug (For details, see study drug handling procedure which is provided by 
Novartis) 
6.6.2 
Drug supply and storage 
Study treatments must be received by a 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, pasireotide LAR should be stored 
according to the instructions specified on the study drug handling procedure. 
For any further information on the formulation, storage and handling of SOM230, please 
consult the investigators brochure. 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
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. 
6.6.3.2 
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.  
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. 


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6.6.3.3 
Handling of other study treatment 
Not applicable. 
6.6.4 
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 and Table 7-2 list all of the assessments and indicate with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. The table indicates which assessments produce data to be 
entered into the database (D) or remain in source documents only (S) (“Category” column). 
The blood sampling schedule at each visit for PK and GH are shown in Table 7-3. Patients are 
to fast overnight for at least 8 hours prior to all blood samples being taken. 
No CRF will be used as a source document. 


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Table 7-1 
Visit evaluation schedule (core phase) 
 
Category 
Reference 
Screening 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of study 
treatment 
Core phase D 
Study 
completion 
Visit number 
 
 
1 
2
3
4
5
6
7
8
9 
10
11
12
13,14
15
16,17
18
19,20 
777 
779 
Study day 
 
 
-28 
to -1
1
2
15
22
29
43
50
57 
71
78
85 113, 141 169 197, 225 253
281, 309
337 
56 days 
following 
the last 
dose 
Month (1 month = 28 days)  
 
 
0
 
 
0.75
1
 
1.75
2 
2.5 2.75 3
4,5 
6
7,8 
9 
10,11 
12 
14 
pasireotide LAR Injection A 
D 
6.1 
 
1
 
 
 
2
 
 
3 
 
 
4
5,6 
7
8,9 
10
11,12 
 
 
Informed Consent 
D 
11.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
S/D 5.2, 5.3 
X 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant Medical history 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of acromegaly or 
pituitary gigantism 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior therapy for acromegaly 
or pituitary gigantism 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tumour Sample 
D 
7.2.4.1 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
S 
7.2.2.1 
X 
X
 
 
X
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.2 
X 
X
 
 
X
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
Height 
D 
7.2.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3 
X 
X
 
 
X
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
MRI 
D 
7.2.1.3 
X 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
X 
 
ECG 
D 
7.2.2.5.1
X 
X
 
 
X
X
 
 
X 
 
X
X
X 
X
X 
X 
X 
X 
X 
Gallbladder ultrasound 
D 
7.2.2.4.10
X 
 
 
 
 
 
 
 
 
 
 
X
 
X
 
X 
 
X 
 
Hematology 
D 
7.2.2.4.1
X 
X
 
 
X
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 


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Category 
Reference 
Screening 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of study 
treatment 
Core phase D 
Study 
completion 
Visit number 
 
 
1 
2
3
4
5
6
7
8
9 
10
11
12
13,14
15
16,17
18
19,20 
777 
779 
Study day 
 
 
-28 
to -1
1
2
15
22
29
43
50
57 
71
78
85 113, 141 169 197, 225 253
281, 309
337 
56 days 
following 
the last 
dose 
Month (1 month = 28 days)  
 
 
0
 
 
0.75
1
 
1.75
2 
2.5 2.75 3
4,5 
6
7,8 
9 
10,11 
12 
14 
Coagulation Parameters (PT 
and APTT) 
D 
7.2.2.4.2
X 
X
 
 
X
X
 
X
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
HbA1c 
D 
7.2.2.4.3
X 
X
 
 
 
 
 
 
 
 
 
X
 
X
 
X 
 
X 
X 
Biochemistry (Including 
LFTs) 
D 
7.2.2.4.3
X 
X
 
 
X
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
Fasting blood glucose 
D 
7.2.2.4.3
X 
X
 
 
X
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
Fasting serum cortisol 
D 
7.2.2.4.5
 
X
 
 
 
 
 
 
 
 
 
X
 
X
 
X 
 
X 
X 
Plasma ACTH 
D 
7.2.2.4.6
 
X
 
 
 
 
 
 
 
 
 
X
 
X
 
X 
 
X 
X 
Urinalysis 
D 
7.2.2.4.8
X 
X
 
 
 
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
Symptoms of Acromegaly or 
pituitary gigantism 
D 
7.2.1.4. 
 
X
 
 
 
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
 
Pregnancy test 
D 
7.2.2.4.9
X 
X
 
 
 
X
 
 
X 
 
 
X
X 
X
X 
X 
X 
X 
X 
PK Blood collection 
D 
7.2.3. 
 
X
 
 
X
X
 
 
X 
X 
X
X
X 
X
X 
X 
X 
X 
 
Efficacy 
assessme
nts 
GH profile 
D 
7.2.1.1. 
X 
X
 
 
 
 
 
 
 
 
X
X
 
X
 
X 
 
X 
 
PRL 
D 
7.2.1.5. 
X 
X
 
 
 
 
 
 
 
 
 
X
 
X
 
X 
 
X 
 
IGF-1 
D 
7.2.1.2. 
X 
X
 
 
 
 
 
 
 
 
X
X
 
X
 
X 
 
X 
 
GH suppression 
post OGTT B 
D 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
assessme
nt 
GH 
D 
7.2.3 
 
X
 
 
X
X
 
 
X 
X 
X
X
X 
X
 
 
 
 
 
IGF-1 
D 
7.2.3 
 
XC
 
 
X
X
 
 
X 
X 
XC
XC
X 
XC
 
 
 
 
 


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Category 
Reference 
Screening 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of study 
treatment 
Core phase D 
Study 
completion 
Visit number 
 
 
1 
2
3
4
5
6
7
8
9 
10
11
12
13,14
15
16,17
18
19,20 
777 
779 
Study day 
 
 
-28 
to -1
1
2
15
22
29
43
50
57 
71
78
85 113, 141 169 197, 225 253
281, 309
337 
56 days 
following 
the last 
dose 
Month (1 month = 28 days)  
 
 
0
 
 
0.75
1
 
1.75
2 
2.5 2.75 3
4,5 
6
7,8 
9 
10,11 
12 
14 
Free T4, TSH 
D 
7.2.2.4.7
X 
X
 
 
 
 
 
 
 
 
 
X
 
X
 
X 
 
X 
X 
Liver function test 
D 
7.2.2.4.4
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
HBsAg and AntiHCV 
D 
7.2.2.4.4
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study completion data 
D 
7.1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse events 
D 
8.1, 8.3. 
C O N T I N U O U S 
Concomitant med 
D 
6.4. 
C O N T I N U O U S 
Comments 
D 
 
C O N T I N U O U S 
A. pasireotide LAR injection and study visits every 28 days +/- 2 days. 
B Patients’ GH nadir within 2 hours after an oral glucose load with 75 g of glucose (OGTT) will be measured. The scheduled time points are at t0, oral glucose, t30, t60, 
t90, t120 (except for diabetic patients). 
C Blood sampling of IGF-1 for PD assessment combines with efficacy assessment. 
D For patients accepting to continue in the extension phase, at 12 months, a 13th injection of the same study treatment received in the core phase will be administered. 
Patients continuing the study treatment with pasireotide LAR in the extension phase will have the option of receiving pasireotide therapy as long as they do not fulfill any of 
the study discontinuation criteria or until pasireotide LAR is commercially available or until the pasireotide LAR development program is discontinued (whichever comes 
first). 
Visit 21 and Visit 777 are on the same day for patients willing to continue in the extension phase. 


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Table 7-2 
Extension Visit evaluation schedule 
 
Category 
Reference 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of study 
treatment for 
Ext 
Study 
completion 
Visit number 
 
 
21
22
23
24
25
26
27 
28
29
30
31
32
33 
34 and 
following 
visits 
778 
779 
Study day 
 
 
337
365
393
421
449
477
505 533
561
589
617
645
673
701, 729, 
757, 813…
 
56 days 
following 
the last 
dose 
Month 
(1 month = 28 days) 
 
 
12
13
14
15
16
17
18 
19
20
21
22
23
24 
25- 
 
 
pasireotide LAR Injection A 
D 
6.1 
13
14
15
16
17
18
19 
20
21
22
23
24
25 
26- 
 
 
Physical Examination 
S 
7.2.2.1 
 
X
X
X
X
X
X 
X
X
X
X
X
X 
 
X 
X 
Vital signs 
D 
7.2.2.2 
 
X
X
X
X
X
X 
X
X
X
X
X
X 
 
X 
X 
Weight 
D 
7.2.2.3 
 
X
X
X
X
X
X 
X
X
X
X
X
X 
 
X 
X 
ECG 
D 
7.2.2.5.1 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Gallbladder ultrasound 
D 
7.2.2.4.10 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
 
Hematology 
D 
7.2.2.4.1 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Coagulation Parameters (PT 
and APTT) 
D 
7.2.2.4.2 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
HbA1c 
D 
7.2.2.4.3 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Biochemistry 
D 
7.2.2.4.3 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Fasting blood glucose 
D 
7.2.2.4.3 
 
X
X
X
X
X
X 
X
X
X
X
X
X 
 
X 
X 
Fasting serum cortisol 
D 
7.2.2.4.5 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Plasma ACTH 
D 
7.2.2.4.6 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Urinalysis 
D 
7.2.2.4.8 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Pregnancy test 
D/S 
7.2.2.4.9 
 
X
X
X
X
X
X 
X
X
X
X
X
X 
X 
X 
X 


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Category 
Reference 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of study 
treatment for 
Ext 
Study 
completion 
Visit number 
 
 
21
22
23
24
25
26
27 
28
29
30
31
32
33 
34 and 
following 
visits 
778 
779 
Study day 
 
 
337
365
393
421
449
477
505 533
561
589
617
645
673
701, 729, 
757, 813…
 
56 days 
following 
the last 
dose 
Month 
(1 month = 28 days) 
 
 
12
13
14
15
16
17
18 
19
20
21
22
23
24 
25- 
 
 
Symptoms of Acromegaly or 
pituitary gigantism 
D 
7.2.1.4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Efficacy 
assessments
GH profile 
D 
7.2.1.1 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
PRL 
D 
7.2.1.5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
IGF-1 
D 
7.2.1.2 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Free T4, TSH 
D 
7.2.2.4.7 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Liver function test 
D 
7.2.2.4.4 
 
 
 
X
 
 
X 
 
 
X
 
 
X 
 
X 
X 
Study completion data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X* 
X* 
Adverse events 
D 
8.1, 8.3 
C O N T I N U O U S * 
Concomitant med 
D 
6.4 
C O N T I N U O U S (up to 24 months) 
Comments 
D 
 
C O N T I N U O U S * 
A. pasireotide LAR injection and study visits every 28 days +/- 2 days study treatment 


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Table 7-3 
Blood sampling schedule 
 
-120 
min 
-90 
min 
-60 
min 
-30 
min 
0 
min 
120 
min 
PK (Day 1, ) 
 
 
 
 
X 
X 
PK (except for Day 1) 
 
 
 
 
X 
 
GH (Day 1, 85) 
X 
X 
X 
X 
X 
X 
GH (Scr, Day 78,169, 253, 337) 
X 
X 
X 
X 
X 
 
GH (Day 22, 29, 57, 71, 113, 141) 
 
 
 
 
X 
 
7.1.1 
Screening 
Screening examination (Visit 1) is to include the procedures found in Table 7-1 and should 
occur within 28 days prior to baseline. The informed consent must be signed prior to ANY 
screening procedure being performed. Patients that do not meet eligibility criteria are allowed 
to be rescreened. The rescreening should be documented in the source files. If the following 
procedures meet all inclusion and exclusion criteria at the original screening they do not have 
to be repeated for patients who rescreen within 60 days of baseline (Day 1): vital signs, MRI, 
and gallbladder ultrasound. Any of these assessments that are abnormal and all other 
assessments not listed here are to be repeated. 
7.1.1.1 
Eligibility screening 
Manual process: Patient eligibility will be checked by the Registration center once all 
screening procedures are completed. The eligibility check form will be sent from the site to 
the Registration center either via fax or email for evaluation. Upon confirmation of eligibility, 
the Registration center will return the signed eligibility check form and inform assigned 
treatment arm to the site. Please refer and comply with detailed guidelines in the registration 
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 Demography, Informed consent eCRF pages must be completed 
for Screen failure patients. No other data will be entered into the clinical database for patients 
who are screen failures. Please refer to Section 8.2.2 for guidelines on SAE reporting 
requirements. 
7.1.1.3 
Patient demographics and other baseline characteristics 
Standard demographic information and medical history will be collected. Acromegaly or 
pituitary gigantism history and diabetes history together with the medication/treatment used 
will also be collected. Other baseline assessments will be collected as per Table 7-1. 


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7.1.2 
Treatment period 
The treatment period in the core phase of the study will be 12 months. Patients will have 
monthly visits with some visits more frequently (see Table 7-1). All visits should be 
performed on the indicated days. In cases where this is not possible, the following visit 
windows apply: +/- 2 days for visits 4-20 and 777, -2/+7 days for the 778, 779 and extension 
phase. Efforts should be made to have pasireotide LAR administration occurring as indicated 
in Table 7-1 and Table 7-2 at approximately the same time of day at each occurrence. 
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 visit 33 (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 visit 777 / 778 will 
be performed (Table 7-1 and Table 7-2). An End of Treatment eCRF page should be 
completed, giving the date and reason for stopping the study treatment. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations (visit 779) during 56 days 
following the last dose of study treatment. 
Patients who discontinue study treatment should be considered withdrawn from 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 End of Treatment eCRF page. The investigator must inform the 
premature withdrawal to Novartis. 
For criteria for premature withdrawal refer to Section 7.1.3.1. 
End of treatment visit and Study completion visit for patients treated for more 
than 2 years (after Visit 33)  
If a patient discontinues after 2 years of treatment (after Visit 33), only the assessments with 
an asterisk in Table 7-2 need to be performed on visit 778 and visit 779. 
7.1.3.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following 
occur: 
• Adverse event(s) [including abnormal laboratory value(s) and abnormal test procedure 
result(s)] 
• Protocol deviation (including but not limited to, new therapy for acromegaly, and 
discovery of patient ineligibility) 
• Patient withdrew consent 


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• Lost to follow-up 
• Administrative problems 
• Death 
• Disease progression 
• Pregnancy 
• Treatment duration completed as per protocol 
The investigator must also inform the premature withdrawal to Novartis, if this occurs during 
the core period. 
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation: 
• Patients experiencing unacceptable toxicity, as described in Table 6-2, Table 6-3. 
• Patients unable to tolerate the lowest dose (20 mg) as per Section 6.3. 
• Patients with > 28 consecutive days of treatment interruption (either due to tolerability, 
investigator decision or patient compliance) 
• Uncontrolled diabetes mellitus, consistently high glucose values FPG ≥ 240 mg/dL (13.3 
mmol/L) or HbA1c value ≥ 10 % despite prior appropriate management and prior dose 
adjustment of the study drug, 
• Patients experiencing adverse events in QTc: 
• a confirmed QTcF >470msec and discontinuation recommended by a cardiologist, or 
• Mean QTcF > 500 msec measured by triplicate ECGs 
• Significant arrhythmia findings from Holter monitoring such as: 
1. Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms 
of hemodynamic compromise 
2. Sustained ventricular tachycardia (>30 sec) irrespective of symptoms 
3. Recurrent non-sustained ventricular tachycardia (≥ 3 beats) during any 24-hour 
monitoring period 
4. Torsades de Pointes 
5. Cardiac arrest 
6. Pause >5 seconds 
7. Second or third degree AV block 
• New occurrence of clinically significant/symptomatic bradycardia, or 
• Increased risk of QT prolongat 
• ion by use of QT prolonging medication, or 
• Hypokalemia (<3.5 mmol/L) or hypomagnesaemia (<0.7 mmol/L) confirmed by 
repeat testing that is either a new finding or accompanied by vomiting or diarrhea and 
not corrected by treatment. 
• Patients experiencing the abnormal hepatic criteria below:  
• 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 


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• ALT or AST > 8 x ULN 
• Lack of efficacy: during the core phase treatment period, patients with GH level > 2.5ug/L 
and/or IGF-1 > ULN (age and sex related) be discontinued from the study unless clinical 
benefit has been observed as per the investigator’s judgment. 
Patients who withdraw prematurely from the core phase cannot participate in the extension 
phase. 
7.1.4 
Follow up period 
All patients must have safety evaluations for 56 days after the last dose of study treatment. 
Patients lost to follow up should be recorded as such on the eCRF. 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 should be followed 
up as detailed in Section 6.3.3. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
7.2.1.1 
GH (5-point mean GH level) 
Patients’ 5-point mean GH level will be assessed from a 2-hour profile after one hour at rest at 
the hospital before pasireotide LAR injection (for details please refer to Table 7-1 and Table 
7-2). The scheduled time points for blood sampling are t-120, t-90, t-60, t-30 and t-0 (pre-dose 
with respect to pasireotide LAR injection). All the GH 2 hour profiles should be taken at the 
same time (morning at around 8-10 am). The samples for GH will be analyzed by the central 
laboratory, 
. Please refer to the 
 manual 
for processing details. This manual will be provided by 
. 
7.2.1.2 
IGF-1 
Patient’s total IGF-1 levels will be assessed with one pre-dose sample at the same visits as GH 
(for details please refer to Table 7-1 and Table 7-2). T0 is defined as time point immediately 
pre-dose with respect to pasireotide LAR injection. The samples for IGF-1 will be analyzed 
by the central laboratory, 
. Please refer to the 
 
 
 for processing details. This manual will be provided by 
 
. 
7.2.1.3 
MRI 
An MRI of the pituitary will be performed at visits indicated in Table 7-1. MRI will not be 
performed during Extension phase. For de-novo patients an adenoma must be visible on 
screening MRI. The MRIs will be sent for evaluation by a central reader. To ensure 
consistency throughout all participating sites, the MRIs should be performed and processed 
following the guidelines from the central reader facility, which will be distributed to the sites 
before study start. 


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7.2.1.4 
Symptoms of acromegaly or pituitary gigantism 
The investigator will measure the patient’s ring size using the gauge at visits indicated in 
Table 7-1 and Table 7-2. Ring size will be measured at the fourth digit of the non-dominant 
hand. In the case a patient has a fourth digit size exceeding the highest size; the fifth digit of 
that hand will be used for initial and follow-up investigation. The investigator will also ask the 
patient to score the following symptoms of acromegaly or pituitary gigantism: headache, 
fatigue, perspiration, paresthesia, osteoarthralgia according to a five-point score scale 
(0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe) 
7.2.1.5 
Prolactin (PRL) 
PRL levels will be assessed at visits indicated in Table 7-1 and Table 7-2. T0 is defined as 
time point immediately pre-dose with respect to pasireotide LAR injection. The samples for 
PRL will be analyzed by the central laboratory, 
. Please refer to the 
 
 
 for processing details. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing hematology (including coagulation parameters), 
Biochemistry (including fasting blood glucose, glycosylated hemoglobin, LFTs), fasting 
serum cortisol, plasma ACTH, liver and thyroid function tests, urinalysis, injection site 
reactions, physical examinations including vital signs, gallbladder ultrasound, ECGs and body 
weight as well as collecting of the adverse events at every visit. For details on AE collection 
and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A complete physical examination will be performed by the investigator at visits indicated in 
Table 7-1 and Table 7-2. 
Information about the physical examination findings will be presented in the source 
documentation at the study site. Significant findings that were present prior to the signing of 
informed consent must be included in the Relevant Medical History/Current Medical 
Conditions page on the patient’s eCRF. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event page of the patient’s eCRF. 
7.2.2.2 
Vital signs 
Blood pressure, heart rate and body temperature will be assessed at visits indicated in Table 7-
1 and Table 7-2 and recorded in the eCRF. Blood pressure and heart rate are to be taken after 
the patient has been in a supine position for 3 minutes. 
7.2.2.3 
Height and weight 
Height in centimeters (cm) and weight to the nearest 0.1 kilogram (kg) are to be collected are 
to occur at visits indicated in Table 7-1 and Table 7-2 and recorded in the appropriate eCRF. 


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7.2.2.4 
Laboratory evaluations 
Central laboratories will be used for the analysis of serum cortisol and ACTH evaluations. 
Details on the collections, shipment of samples and reporting of results by the central 
laboratory are to be provided to investigators in the [Laboratory Manual]. 
Patients are to fast overnight for 8 hours prior to all blood samples being taken. Water is 
allowed during this time. The blood samples are to be taken before pasireotide LAR i.m. 
injection. Laboratory samples for hematology and blood chemistry will be analyzed locally. 
Table 7-4 
Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology (Local) 
Hematocrit, Hemoglobin, Red blood cells, Platelets, White blood cells, WBC Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Chemistry (Local) 
Albumin, Alkaline phosphatase (ALP), Total Bilirubin, ALT (SGPT), AST (SGOT), GGT, 
Calcium, Chloride, Magnesium, Potassium, Sodium, Creatinine, Creatine kinase, Total 
Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea Nitrogen (BUN), Uric 
Acid, LDH, Inorganic phosphorus, Lipase and α-amylase, Fasting blood glucose, 
Glycosylated hemoglobin (HbA1c),  
If the total bilirubin concentration is increased above 2.0 times x ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. 
Urinalysis (Local) 
Dipstick (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, pH, Protein, Specific 
Gravity) 
Coagulation (Local) 
Prothrombin time (PT), Activated partial thromboplastin time (APTT) 
Thyroid (Local) 
T4 [free], TSH 
Hepatitis markers 
(Local) 
Anti HAV IgM, HbsAg, HbcAb, anti HCV(if positive, PCR viral load should be assessed), 
Anti HEV, ANA antibodies, Anti smooth muscle anti-bodies, CMV and EBV 
Additional tests 
(Central) 
GH (Growth Hormone), Insulin-like growth factor 1 (IGF-1), Prolactin, Cortisol, ACTH 
7.2.2.4.1 Hematology 
Hematology will be assessed locally at the site at visits indicated in Table 7-1 and Table 7-2. 
Hematology will include: WBC count with differential, hemoglobin, hematocrit, RBC count 
and platelet count. 
7.2.2.4.2 Coagulation 
PT and activated partial thromboplastin time (APTT) will be assessed locally at the site at 
visits indicated in Table 7-1 and Table 7-2. 
7.2.2.4.3 Biochemistry 
Fasting biochemistry (including fasting blood glucose) will be assessed locally at the site at 
visits indicated in Table 7-1 and Table 7-2. 
Albumin, Alkaline phosphatase (ALP), Total Bilirubin, ALT (SGPT), AST (SGOT), GGT, 
Calcium, Chloride, Magnesium, Potassium, Sodium, Creatinine, Creatine kinase, Total 
Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea Nitrogen (BUN), Uric Acid, 
LDH, Inorganic phosphorus, Lipase and α-amylase, Fasting blood glucose, Glycosylated 
hemoglobin (HbA1c),  


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If the total bilirubin concentration is increased above 2.0 times x ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. 
7.2.2.4.4 Liver function testing 
Presence of HBsAg and AntiHCV are to be assessed during screening.  
At Visit 8 (Day 50) a full chemistry panel is not required and only the following Liver 
chemistry tests (LFTs) will be measured: ALT, AST, total bilirubin, direct bilirubin, indirect 
bilirubin, Alb, ALP and GGT.  
If at any visit abnormal liver function criteria as described in Section 6.3.3 are met, the 
following should be performed immediately within 72 hours of awareness of the abnormality: 
• Liver chemistry tests: ALT, AST, total bilirubin (fractionated to direct/indirect if total 
bilirubin is > 2.0 x ULN), Alb, PT (INR), ALP, and GGT 
• Perform hepatitis screen: anti-HAV, IgM (to confirm acute Hepatitis A), HBsAg, Anti-
HBc, anti-HCV (if positive, PCR viral load should be assessed), Anti-HEV, ANA 
antibodies, anti-smooth muscle antibodies, CMV and EBV 
Liver chemistry tests (LFTs) should be monitored every 3-4 days until resolution or return to 
baseline status. 
7.2.2.4.5 Serum cortisol 
One pre-dose sample for fasting serum cortisol will be taken early in the morning at visits 
indicated in Table 7-1 and Table 7-2 and assessed at the central laboratory. 
It is strongly recommended to take the sample for fasting serum cortisol between 7 and 9 am 
as this is the peak time for the cortisol secretion. 
7.2.2.4.6 ACTH 
A pre-dose blood draw for plasma ACTH sampling will be taken at visits indicated in Table 
7-1 and Table 7-2 and assessed at the central laboratory. 
7.2.2.4.7 Thyroid function tests 
Free T4 and TSH will be assessed at visits indicated in Table 7-1 and Table 7-2. These tests 
will be performed and assessed locally at the site. 
7.2.2.4.8 Urinalysis 
Specific gravity, pH, semi-quantitative “dipstick” evaluation of glucose, protein, bilirubin, 
ketones, leukocytes and blood will be assessed at visits indicated in Table 7-1 and Table 7-2. 


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7.2.2.4.9 Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum hCG-β pregnancy 
test at visits indicated in Table 7-1 and Table 7-2. Note: Up to Visit 33, serum pregnancy test 
will be done and after Visit 33, serum or urine pregnancy test will be done and this data 
remain in source documents only. A positive serum or urine pregnancy test requires 
immediate interruption of study treatment until the assessment is confirmed. If positive, the 
patient must be discontinued from the study. 
7.2.2.4.10 
Gallbladder ultrasound 
A gallbladder ultrasound will be performed at the sites at visits indicated in Table 7-1 and 
Table 7-2 and the results will be recorded in the eCRF. 
7.2.2.5 
Cardiac assessments 
7.2.2.5.1 Electrocardiogram (ECG) 
A 12-lead ECG and a rhythm strip will be performed in supine position at the sites at visits 
indicated in Table 7-1 and Table 7-2. 
All ECGs should include all 12 standard leads and a Lead II rhythm strip of at least a 10-
second duration. The ECGs will be performed on the machine(s) provided for the study by the 
central reader and are sent to the central reader for evaluation. To ensure consistency 
throughout all participating sites, the ECGs should be performed and processed following the 
guidelines from the central reading facility, which will be distributed to the sites. 
A Holter ECG will be required in case of a confirmed QTcF > 470 msec (Section 6.3.3). 
7.2.2.6 
Tolerability 
In addition to general safety data, information on dose reductions will be collected. 
7.2.3 
Pharmacokinetics 
To assess the pharmacokinetic profile of pasireotide administered as LAR, blood samples will 
be collected at the predefined time points (Table 7-5) and plasma concentration of pasireotide 
will be measured. The time of blood collection will be recorded on the PK blood collection 
eCRF page. 
Descriptive statistics and graphical depiction (mean and individual) for pasireotide plasma 
concentrations during the course of treatment will be performed. 
 
 
 


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Table 7-5 
Blood sampling for PK assessment 
Sample 
Volume 
(mL) 
Visit 
Week 
Day 
PK Collection 
number 
Sample 
number 
Scheduled time 
(hr) 
Blood 
2.5 
2 
0 
1 
1 
1 
0 (pre-dose) 
Blood 
2.5 
2 
0 
1 
1 
2 
2 
Blood 
2.5 
5 
3 
22 
1 
6 
504 
Blood 
2.5 
6 
4 
29 
2 
7 
672/0 (pre-dose)1 
Blood 
2.5 
9 
8 
57 
3 
9 
672/0 (pre-dose)1 
Blood 
2.5 
10 
10 
71 
3 
10 
336 
Blood 
2.5 
11 
11 
78 
3 
11 
504 
Blood 
2.5 
12 
12 
85 
3, 4 
12 
672/0 (pre-dose)1 
Blood 
2.5 
13 
16 
113 
5 
13 
0 (pre-dose) 
Blood 
2.5 
14 
20 
141 
6 
14 
0 (pre-dose) 
Blood 
2.5 
15 
24 
169 
7 
15 
0 (pre-dose) 
Blood 
2.5 
16 
28 
197 
8 
16 
0 (pre-dose) 
Blood 
2.5 
17 
32 
225 
9 
17 
0 (pre-dose) 
Blood 
2.5 
18 
36 
253 
10 
18 
0 (pre-dose) 
Blood 
2.5 
19 
40 
281 
11 
19 
0 (pre-dose) 
Blood 
2.5 
20 
44 
309 
12 
20 
0 (pre-dose) 
Blood 
2.5 
777 
48 
337 
12 
21 
6722 
Blood 
2.5 
NA 
NA 
NA 
NA 
10013 
Unscheduled 
1 : These samples are treated as samples for 672 hours post dose and pre-dose samples as well. 
2 : The sample must be obtained before pasireotide LAR administration if the subject is enrolled in the extension 
phase 
3 : Unscheduled blood samples must be uniquely and sequentially numbered from 1001, eq., 1001, 1002… 
7.2.3.1 
Pharmacokinetic blood sample collection and handling 
All blood samples will be taken by either direct venipuncture or indwelling cannula inserted 
in a forearm vein. 2.5 mL of blood will be collected into an EDTA tube to yield 1mL of 
plasma for analysis of pasireotide plasma concentration. Immediately after blood is drawn 
into EDTA tubes, they should be inverted gently several times to ensure the mixing of tube 
contents. Prolonged exposure to the rubber stopper should be avoided. The tube should be 
placed upright in tube rack surrounded by ice until centrifugation. Within 20 minutes after 
blood collection, the sample should be centrifuged between 3 and 5ºC for 10 minutes at 
approximately 1000 x g. Immediately after centrifugation, 1.0 mL plasma should be 
transferred to a polypropylene screw cap tube immersed in dry ice. The storage temperature 
for PK samples should be at or below -20°C. 
PK samples will be taken in the case of a confirmed QTcF > 470msec (described in Section 
6.3.3.2). 
If at any visit abnormal liver function criteria as described in Section 6.3.3 are met, the 
following should be performed within 72 hours of awareness of the abnormality: 
• Collect PK sample and record the dose level and the dosing time for the last dose the 
patient has taken prior to PK sampling 


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The time of blood collection will be recorded on the PK blood collection eCRF page (e.g. the 
actual date/time of blood samples will recorded relative to the dose). 
7.2.3.2 
Analytical method 
Pasireotide plasma concentrations will be measured using a validated radio-immunoassay 
(RIA) with a lower limit of quantification (LLOQ) of at least 0.15 ng/mL (150 pg/mL). 
PK samples will be shipped to Atlanbio for bioanalysis. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
7.2.5 
Other assessments 
No additional tests will be performed on patients entered into this study. 
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 eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Relevant Medical History/Current Medical Conditions eCRF. Adverse event 
monitoring should be continued for at least 56 days following the last dose of study treatment. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0 If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected in the End of Treatment or End of Study eCRF page. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) 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 
(subject) 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) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued) 
5. Whether medication or therapy taken (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 eCRF. However the 
elevation of GH, IGF-1 and PRL values should not be reported as an adverse event. 
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 (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 eCRF. 
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 (optional) 
Adverse events of special interest include but may not be limited to AE’s related to the 
following preferred terms: arrhythmogenic potential, bradycardia, coagulation, constipation, 
diabetes insipidus, diarrhoea, gall bladder and biliary, GI bleeding, GH deficiency, 
hyperglycemia, hypocalcemia, hypocortisolism, hypotension, hypothyroidism, injection site 
reaction, liver safety, low blood cells, nausea, pancreatitis, QT prolongation, and 
rhabdomyoloysis. 
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 SOM230 treatment (i.e. where SOM230 
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 
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 


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• 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 
• Protocol exempt SAEs: Add any additional SAEs specifically defined by the protocol and 
where there has been a clear agreement with regulators not to collect these SAEs in the 
safety database, provided the information is collected elsewhere. For example, this may 
include serious adverse events that are also a primary outcome measure, such as mortality, 
survival rate or number of flares of the condition being studied. 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 56 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 56 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; 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, and send the completed, signed form by fax within 24 hours to the oncology Novartis 
Drug Safety and Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. 


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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 Drug Safety and Epidemiology (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. The follow up period for a newborn of a patient or 
a partner who becomes pregnant during the study and up to 3 months post last pasireotide 
LAR dose, is 3months. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
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. 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 


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9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 
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 eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, 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 eCRFs 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 eCRF 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 
eCRFs are performed according to the study-specific monitoring plan. 


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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. 
All central labs including pharmacokinetic (PK) and Biomarker (tissue) samples drawn during 
the course of the study will be collected from the investigator sites and analyzed by Novartis 
or a central lab contracted by Novartis. The site staff designated by the investigator will enter 
the information required by the protocol onto the PK and Biomarker sample collection eCRFs, 
respectively, as well as the designated CRO’s requisition form. One copy of the requisition 
form will be forwarded to the central lab along with the corresponding samples with required 
information (including study number, patient ID, etc.) and one copy will be retained by the 
site. 
ECG tracings and radiological scans will be transferred to a central reader. 
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) for the following: biomarkers, PK, central radiology and 
ECGs. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 


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10 
Statistical methods and data analysis 
In this study, the results will be reported several times. The first report is planned when the 
last patient completes 3 months assessment. The result of the primary endpoint will be 
summarized. On emerging safety concerns observed during the early study period, the second 
report may be planned when the last patient completes 6 months assessment. The subsequent 
report is planned when the last available patient completes 12 months assessment. An 
additional report will be prepared after all patients end study treatment. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the study treatment they have been assigned to during the randomization 
procedure. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment they actually received. 
A precise definition of “actually received” will be added in the RAP. 
10.1.3 
Per-Protocol Set 
 The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS without any major 
protocol deviation and who received at least one dose of study treatment.  
Any protocol deviations leading to exclusion from the PPS will be detailed in the validation 
and planning (VAP) Module 3. 
10.1.4 
Dose-determining analysis set 
Not applicable 
10.1.5 
Pharmacokinetic analysis set 
 The pharmacokinetic analysis set (PAS) consists of FAS who have evaluable 
pharmacokinetic concentration data. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (e.g. age, sex) will be summarized descriptively by 
study treatment group for the FAS. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, 25th and 75th percentiles, 
minimum and maximum will be presented. 


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10.3 
Study treatments (study treatment, concomitant therapies, 
compliance) 
The number of study drug administration will be summarized by dose levels and total-group 
for Safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by dose level study treatment and total-group for the 
Safety Set. 
10.4 
Primary objective 
The primary objective is to assess the efficacy of pasireotide LAR on the reduction of mean 
GH levels to < 2.5µg/L and the normalization of IGF-1 at 3months of study treatment. 
10.4.1 
Variable 
The primary variable is the total-group response rate defined as the proportion of patients with 
the reduction of mean GH levels to < 2.5µg/L and the normalization of IGF-1 at 3 months of 
study treatment.  
10.4.2 
Statistical hypothesis, model, and method of analysis 
The total-group response rate at 3 months of study treatment along with the corresponding 
Clopper-Pearson exact two-sided 90% confidence interval will be provided. The primary 
analysis will be performed on the FAS.  
10.4.3 
Handling of missing values/censoring/discontinuations 
If the GH and/or IGF-1 samples are taken after 35 days from the date of any LAR injection, 
the values of GH and/or IGF-1 at the corresponding visit will be treated as missing. In 
addition, if a patient has less than 3 samples for the assessment of 5-point mean GH levels 
from the 2-hour profile, the mean GH levels will be considered as missing. 
The patients with missing values of mean GH levels and/or IGF-1 at 3 months of study 
treatment or who discontinue prior to the assessment at 3 months of study treatment will be 
considered as non-responders.  
10.4.4 
Supportive analyses 
The primary analysis will also be repeated on the PPS. 
As subgroup analysis, the primary analysis will also be repeated by prior medication (i.e., 
somatostatine analogue and dopamine agonist) (yes or no) on the FAS if the number of 
patients in the subgroup is large enough. 
The total-group response rate at 3 months of study treatment along with the corresponding 
Clopper-Pearson exact 95% confidence interval will be provided on the FAS and PPS.  


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10.5 
Secondary objectives 
All secondary efficacy endpoints will be based on the FAS. All secondary endpoints measured 
up to 3 months of study treatment will be summarized by dose level at randomization study 
treatment and total-group. All secondary endpoints measured after 3 months of study 
treatment will be summarized by total-group only. 
10.5.1 
Key secondary objective(s) 
Table 10-1 shows the primary, key secondary and secondary variables for core phase by time 
point. Table 10-2 shows the secondary variables for extension phase by time point. For the 
detailed key secondary objectives and secondary objectives, please refer to Table 3-1. 
For other key secondary objectives, please refer to Section 10.5.3 (safety and tolerability) and 
Section 10.5.4 (PK). 
Table 10-1 
Primary and secondary variables for core phase 
Variables 
3M 
6M 
9M 
12M 
Proportion of patients with the reduction 
of mean GH levels to < 2.5µg/L and the 
normalization of IGF-1 
P (total-group)
KS (by dose 
level) 
S (total-group) 
S (total-group) 
S (total-group) 
Proportion of patients with the reduction 
of mean GH levels to < 2.5µg/L 
KS (total-group 
and by dose 
group) 
S (total-group) 
S (total-group) 
S (total-group) 
Proportion of patients with the 
normalization of IGF-1 
KS (total-group 
and by dose 
group) 
S (total-group) 
S (total-group) 
S (total-group) 
Change of tumor volume from baseline 
 
S 
 
S 
Change of mean GH level from baseline 
S 
Symptoms of acromegaly 
S 
Change of PRL level from baseline 
S 
P: primary endpoint, KS: key secondary endpoint, S: secondary endpoint 
Table 10-2 
Primary and secondary variables for core phase 
Variables 
15M 
18M 
21M 
24M 
Proportion of patients with the reduction of 
mean GH levels to < 2.5µg/L and the 
normalization of IGF-1 
 
S 
 
S 
Proportion of patients with the reduction of 
mean GH levels to < 2.5µg/L 
 
S 
 
S 
Proportion of patients with the 
normalization of IGF-1 
 
S 
 
S 
Change of mean GH level from baseline 
S 
S: secondary endpoint 
The response rate at 3 months of study treatment along with the corresponding exact 95% 
confidence interval will be provided by dose level at randomization study treatment. 


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For patients with the reduction of mean GH levels to < 2.5 µg/L and patients with the 
normalization of IGF-1 at 3 months of study treatment, total-group proportions of patients 
along with the corresponding Clopper-Pearson exact two-sided 95% confidence interval will 
be provided. The same analyses will be performed by dose level at randomization study 
treatment. 
10.5.2 
Other secondary efficacy objectives 
10.5.2.1 Other secondary efficacy analyses for core phase 
For patients with the reduction of mean GH levels to < 2.5µg/L and normalization of IGF-1, 
patients with the reduction of mean GH levels to < 2.5 µg/L and patients with the 
normalization of IGF-1 at 6, 9 and 12 months of study treatment, total-group proportions 
along with the corresponding Clopper-Pearson exact two-sided 95% confidence interval will 
be provided. 
Changes of tumor volume at 6 and 12 months of study treatment from baseline will be 
summarized. 
Changes of mean GH level from baseline will be summarized. 
Changes of ring size from baseline will be summarized. The shift tables from baseline to the 
most extreme post-baseline value will also be presented for acromegaly symptoms other than 
ring size (headache, fatigue, perspiration, paresthesias, and osteoarthralgia). 
Changes of PRL level from baseline will be summarized.  
10.5.2.2 Other secondary efficacy objectives for extension phase 
For patients with the reduction of mean GH levels to < 2.5 µg/L and normalization of IGF-1, 
patients with the reduction of mean GH levels to < 2.5 µg/L and patients with the 
normalization of IGF-1 at 18 and 24 months of study treatment, total-group proportions along 
with the corresponding Clopper-Pearson exact two-sided 95% confidence interval will be 
provided. 
Changes of mean GH level from baseline will be summarized. 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented 
appropriately.  
For each safety variables to be summarized by summary tables, followings will be provided: 
1. Summary table by dose level for variables measured up to 3 months of study treatment 
2. Summary table for overall patients for variables measured after 3 months of study 
treatment 
For each safety variables to be summarized by shift tables, followings will be provided: 


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1. Shift table by dose level to compare baseline to the worst value(s) measured up to 3 
months of study treatment 
2. Shift table for overall patients to compare baseline to the worst value(s) of all post-
baseline values 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-study treatment period: from day of patient’s informed consent to the day before first 
dose of study medication 
2. on-study treatment period: from day of first dose of study medication to 56 days after last 
dose of study medication 
3. post-study treatment period: starting at day 57 after last dose of study medication. 
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-study treatment period, the study treatment-emergent AEs. However, all 
safety data (including those from the pre and post-study treatment periods) will be listed and 
those collected during the pre-study treatment and post-study treatment period are to be 
flagged. 
The incidence of study treatment-emergent adverse events (new or worsening from baseline) 
will be summarized by system organ class, preferred term, severity (based on CTCAE grades), 
type of adverse event and relation to study treatment. Deaths reportable as SAEs and non-fatal 
serious adverse events 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. 
The incidence of study treatment-emergent adverse events (new or worsening from baseline) 
occurred in core phase and extension phase will be summarized separately by system organ 
class, preferred term, severity (based on CTCAE grades), type of adverse event and relation to 
study treatment. 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 (see NCI 2006), the study’s biometrics and statistical reporting team 
will grade laboratory data accordingly. For laboratory tests covered by CTCAE, a Grade 0 
will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. 
In cases differentials count, the lower limits of normal ranges used in CTCAE definition have 
to be replaced by a clinical meaningful limit expressed in absolute counts. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 


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The following summaries will be generated by dose level or total-group for hematology, 
biochemistry and urinary laboratory tests: 
• frequency table for newly occurring on-study treatment grades 3 or 4 
• shift tables using CTCAE grades to compare baseline to the worst on-study 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-study 
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. 
10.5.3.4 Other safety data 
ECG 
• shift table baseline to worst on-study treatment result 
• listing of ECG evaluations for all patients with at least one abnormality 
Vital signs 
Definitions of notably abnormal results have to part of the MAP, CSP and/or RAP. 
• shift table baseline to worst on-study treatment result 
• listing of vital signs for all patients with at least one notably abnormal result 
Gallbladder Ultrasound 
Gallbladder data at each visit will be listed. 
10.5.3.5 Tolerability 
Tolerability will be studied in terms of dose reductions or drug interruption due to an AE. 
10.5.4 
Pharmacokinetics 
PAS will be used in all pharmacokinetic data analysis and summary statistics. 
Pharmacokinetic variables 
The following PK parameters (Table 10-3) will be determined using non-compartmental 
method. 
Table 10-3 
Pharmacokinetic parameters for LAR formulations 
i.m. LAR dose 
Ctrough day28 
The trough level concentration on day 28 post each injection of LAR, expressed as Ctrough 
day28, 1st inj, Ctrough day28, 2nd inj, Ctrough day28, 3rd inj etc. 
Cmax,3rd inj 
The maximum concentration post the 3rd injection of LAR 
AR 
The accumulation ratio calculated as a ratio of [Ctrough day28,3rd inj / Ctrough day28,1st inj] 


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Descriptive statistics of pasireotide plasma concentrations will be provided by each time point 
and dose. Descriptive statistics of PK parameters will be provided by dose. Descriptive 
statistics will include arithmetic and geometric mean, median, SD, and CV, geometric CV, 
minimum and maximum. Zero concentrations will not be included in the geometric mean 
calculation. The concentration data and the PK parameters obtained after dose 
increase/reduction will be summarized separately. 
The effect of patient demographics (e.g. age, body weight, BMI and gender) on PK will be 
explored, if applicable. 
Statistical methods for pharmacokinetic analyses: 
The relationship between the dose and the PK parameters (Ctroughday28,3rd inj,) will be explored 
by the following linear model on the log scale: 
ln(PK parameters) = intercept + slope*ln(Dose) + error. 
In this model, the dose-exposure relationship is mainly characterized by the slope parameter: a 
value lower/higher than 1 indicates an under/over proportional dose-exposure relationship. 
The point estimate and associated 90% CI for the slope parameter will be provided for each 
PK parameters. Point estimates and the corresponding 90% CIs for the PK ratios of 40 mg 
versus 20 mg and 60 mg versus 20 mg will be presented on the original scale. 
10.5.4.1 Data handling principles 
Plasma concentrations of pasireotide will be expressed in ng/mL. All concentrations below 
the limit of quantitation or missing data will be reported as such in the concentration data 
listings. Concentrations below the limit of quantitation will be treated as zero in summary 
statistics. 
10.5.5 
Biomarkers 
10.5.5.1 Outline of the data analysis 
Not applicable. 
10.5.5.2 Data handling principles 
Not applicable. 
10.5.5.3 Data analysis principles 
Not applicable. 
10.5.6 
Resource utilization 
Not applicable. 
10.5.7 
Patient-reported outcomes 
Not applicable. 


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10.7 
Interim analysis 
No interim analysis is planned for this study. 


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10.8 
Sample size calculation 
The planned sample size of 30 is determined based on the accuracy of estimated total-group 
response rate at the end of 3 months. 
The response rate is the proportion of responders, where responders are defined as patients 
with the reduction of mean GH levels to < 2.5 µg/L and normalization of IGF-1. The response 
rates at 20 mg, 40mg and 60mg in [CSOM230C2110] were comparable (30% at 20mg, 41.7% 
at 40mg, and 38.5% at 60mg). Furthermore, the dose of pasireotide LAR will be adjusted 
according to efficacy and safety. It is considered, therefore, that the efficacy of pasireotide 
LAR can be evaluated more appropriately based on the response rate of all groups combined. 
In this study, based on the results from CSOM230C2110, the expected total-group response 
rate will be at least 30%. 
In [CSOM230C2305], patients inadequately controlled with 12 month octreotide LAR study 
treatment were crossed over to pasireotide LAR. The response rate at 3 months after crossover 
was 17.3% (two-sided 95% CI: [9.8%, 27.3%]). Since a large number of patients who enroll 
to this study are assumed to be inadequately controlled with octreotide LAR treatment, a 
clinically meaningful minimum response rate is set as 10% based on the lower limit of two-
sided 95% CI, 9.8%. 
The expected drop out rate is 10% based on [CSOM230C2305]. The patients with missing 
values of mean GH levels or IGF-1 at the assessment at 3 months of study treatment or who 
discontinue prior to the assessment at 3 months of study treatment will be considered as non-
responders. 
Under these assumptions, the expected total-group response rate adjusted by the expected 
drop out rate is 27%. The sample size of 30 can demonstrate that the lower limit of the 
Clopper-Pearson exact two-sided 90% CI for the total-group response rate is not less than the 
clinically meaningful response rate, 10%. 
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. 


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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. Documentation (written and dated approval 
or favorable opinion) that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis before study initiation. Prior to study start, the 
investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. The date when a subject’s Informed Consent was actually obtained will be 
captured in their eCRFs. 
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. 
Additional consent form 
Not applicable. 
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. 


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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. 
11.6 
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) 
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 (eCRF) 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 eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
eCRF should be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. For electronic eCRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper eCRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 


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11.7 
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. 
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 (2012). Standards of medical care in diabetes. Diabetes Care; 
35 (Suppl 1); S11-63. 
Baumann G (2001) Section A Adenohypophysis Chapter 12 Growth hormone and its 
disorders. Principles and practice of endocrinology and metabolism, 129-45 
Bruns C, Lewis I, Briner U, et al (2002)] SOM230: a novel somatostatin peptidomimetic with 
broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique 
antisecretory profile. Eur J Endocrinol 146, 707-16. 
Freda P (2002) Somatostatin analogs in acromegaly. J Clin Endocrinol Metab; 87(7):3013-
3018. 
Giustina A, Barkan A, Casanueva FF, et al (2000) Criteria for cure of acromegaly: a 
consensus statement. J Clin Endocrinol Metab; 85:526-529. 
Japan Intractable Diseases Information Center (2009) Acromegaly (Internet) Available from: 
http://www.nanbyou.or.jp/entry/287. 
Katakami H, Ishikawa E, Hidaka H, et al. (2006) 7 Incidence and prevalence of acromegaly 
and gigantism: Survey in Miyazaki Prefecture (population of 1 million). Japan. J. 
Endocrine. ;82(1):100. 
Kauppinen-Makelin R, Sane T, Reumanen A, et al (2005)] A Nationwide survey of mortality 
in acromegaly. J Clin Endocrinol Metab; 90(7):4081-4086. 
Melmed S, Jackson I, Kleinberg D, et al (1998) Current treatment guidelines for acromegaly. 
J Clin Endocrinol Metab; 83(8):2646-2652. 
Oberg K (2004)] Treatment of neuroendocrine tumours of the gastrointestinal tract. Oncologia 
(Madrid); 27(4):57-61. 
Rajasoorya C, Holdaway IM, Wrightson P, et al. (1994)] Determinants of clinical outcome 
and survival in acromegaly. Clin Endocrinol (Oxf); 41:95-102. 
Saito S, Yokokoshi H, and Shimizu N (1991) Report on long-term prognosis of the 
diencephalohypophysial dysfunction. Japan. J. Endocrine. 67: 263-76 
Schmid HA and Schoeffter P (2004) Functional activity of the multiligand analog SOM230 at 
human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine 
tumors. Neuroendocrinology; 80 Suppl 1:47-50. 
Schmid HA and Silva AP (2005) Short term and long term effects of octreotide and SOM230 
on GH, IGF-1, ACTH, corticosterone and ghrelin in rats. Journal of Endocrinological 
Investigation, 28 (Suppl.11), 28-35. 
Sherlock M, Ayuk J, Tomlinson JW, et al. (2010) Mortality in patients with pituitary disease. 
Endocrine Reviews; 31(3):301-42. 
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 corticotroph tumor cells. American Journal of Physiology, Endocrine and 
Metabolism; 289(2):278-87. 


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


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14 
Appendices 
Appendix 1: Instructions for use 
1 Procedure for pasireotide LAR 20 mg dosage strength 
For preparation of the microparticle powder suspension for injection, the standard vehicle for 
microparticles has to be taken to reconstitute the suspension in the 6R vials. 
• Take one (1) drug product vial with the following label 
Project name: pasireotide LAR 
Form: MPVI 
Dosage: 20 MG/VIAL 
• Remove the transparent flip-off cap from the vial. 
• Take one vehicle ampoule and break off the upper part. 
• Withdraw the content of the vehicle ampoule with the 18 G (min 50 mm length) needle 
and e.g. a 3 ml syringe. 
• Remove air bubbles by pushing the piston and adjust the volume to 2 ml. 
• Inject 2 ml of vehicle into the vial containing the powder (20mg). 
• Shake the vial up and down at least 30 seconds in order to get a homogenous suspension. 
• Withdraw the whole volume of suspension from the vial with the same 18 G (min 50 mm 
length) needle and e.g. a 3 ml syringe. 
• Change the needle with a new 20 G needle for i.m. injection. 
• Remove air bubbles by pushing the piston. 
• Immediately, inject the whole volume of suspension intra-muscularly to the patient. 
2 Procedure for pasireotide LAR 40 mg dosage strength 
For preparation of the microparticle powder suspension for injection, the standard vehicle for 
microparticles has to be taken to reconstitute the suspension in the 6R vials. 
• Take one (1) drug product vial with the following label 
Project name: pasireotide LAR 
Form: MPVI 
Dosage: 40 MG/VIAL 
• Remove the transparent flip-off cap from the vial. 
• Take one vehicle ampoule and break off the upper part. 
• Withdraw the content of the vehicle ampoule with 18 G (min 50 mm length) needle and 
the e.g. a 3 ml syringe. 
• Remove air bubbles by pushing the piston and adjust the volume to 2 ml. 
• Inject 2 ml of vehicle into the vial containing the powder (40 mg). 
• Shake the vial up and down at least 30 seconds in order to get a homogenous suspension. 
• Withdraw the whole volume of suspension from the vial with the same 18 G (min 50 mm 
length) needle and the e.g. a 3 ml syringe. 


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• Change the needle with a new 20 G needle for i.m. injection 
• Remove air bubbles by pushing the piston. 
• Immediately, inject the whole volume of suspension intra-muscularly to the patient. 
3 Procedure for pasireotide LAR 60 mg dosage strength 
For preparation of the microparticle powder suspension for injection, the standard vehicle for 
microparticles has to be used to reconstitute the suspension in the 6R vials. 
• Take one (1) drug product vials with the following label 
Project name: pasireotide LAR 
Form: MPVI 
Dosage: 20 MG/VIAL 
• Take one (1) additional drug product vial with the following label 
Project name: pasireotide LAR 
Form: MPVI 
Dosage: 40 MG/VIAL 
• Remove the transparent flip-off cap from the vials. 
• Take one vehicle ampoule and break off the upper part. 
• Withdraw the content of the vehicle ampoule with the 18 G (min 50 mm length) needle 
and the 3 ml syringe. 
• Remove air bubbles by pushing the piston and adjust the volume to 2 ml. 
• Inject 2 ml of vehicle into the first vial containing the powder (20mg). 
• Shake the vial up and down for 30 seconds in order to get a homogenous suspension. 
• Withdraw the whole volume of suspension from the vial with the 18 G (min 50 mm 
length) needle and the 3 ml syringe. 
• Inject the whole volume of suspension into the second vial (40mg) 
• Shake the vial up and down at least 30 seconds in order to get a homogenous suspension. 
• Withdraw the whole volume of suspension from the vial with the 18 G (min 50 mm 
length) needle and e.g. a 3 ml syringe. 
• Change the needle with a new 20 G needle i.m. injection 
• Remove air bubbles by pushing the piston. 
• Immediately, inject the whole volume of suspension intra-muscularly to the patient 


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Appendix 2: 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. 
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 
Brand Name 
Class 
Bepridil 
Vascor® 
Anti-anginal / heart pain 
Amiodarone 
Cordarone® 
Anti-arrhythmic / abnormal heart rhythm 
Amiodarone 
Pacerone® 
Anti-arrhythmic / abnormal heart rhythm 
Disopyramide 
Norpace® 
Anti-arrhythmic / abnormal heart rhythm 
Dofetilide 
Tikosyn® 
Anti-arrhythmic / abnormal heart rhythm 
Ibutilide 
Corvert® 
Anti-arrhythmic / abnormal heart rhythm 
Procainamide 
Pronestyl® 
Anti-arrhythmic / abnormal heart rhythm 
Procainamide 
Procan® 
Anti-arrhythmic / abnormal heart rhythm 
Quinidine 
Cardioquin® 
Anti-arrhythmic / abnormal heart rhythm 
Quinidine 
Quinaglute® 
Anti-arrhythmic / abnormal heart rhythm 
Sotalol 
Betapace® 
Anti-arrhythmic / abnormal heart rhythm 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial infection 
Sparfloxacin 
Zagam® 
Antibiotic / bacterial infection 
Erythromycin 
Erythrocin® 
Antibiotic;GI stimulant / bacterial infection; increase GI motility 
Erythromycin 
E.E.S.® 
Antibiotic;GI stimulant / bacterial infection; increase GI motility 
Arsenic trioxide 
Trisenox® 
Anti-cancer / Leukemia 
Astemizole 
Hismanal® 
Antihistamine / Allergic rhinitis 
Terfenadine 
Seldane® 
Antihistamine / Allergic rhinitis 
Pentamidine 
Pentam® 
Anti-infective / pneumocystis pneumonia 
Pentamidine 
NebuPent® 
Anti-infective / pneumocystis pneumonia 
Probucol 
Lorelco® 
Antilipemic / Hypercholesterolemia 
Chloroquine 
Aralen® 
Anti-malarial / malaria infection 
Halofantrine 
Halfan® 
Anti-malarial / malaria infection 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Mesoridazine 
Serentil® 
Anti-psychotic / schizophrenia 
Thioridazine 
Mellaril® 
Anti-psychotic / schizophrenia 
Haloperidol 
Haldol® 
Anti-psychotic / schizophrenia, agitation 
Pimozide 
Orap® 
Anti-psychotic / Tourette's tics 
Chlorpromazine 
Thorazine® 
Anti-psychotic/ Anti-emetic / schizophrenia/ nausea 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Levomethadyl 
Orlaam® 
Opiate agonist / pain control, narcotic dependence 
Methadone 
Dolophine® 
Opiate agonist / pain control, narcotic dependence 
Methadone 
Methadose® 
Opiate agonist / pain control, narcotic dependence 
Droperidol 
Inapsine® 
Sedative;Anti-nausea / anesthesia adjunct, nausea 
Reference: qtdrugs.org/medical-pros/drug-lists/drug-lists.cfm 

SAP_000.pdf: 
Clinical Development
Pasireotide LAR / SOM230 LAR
CSOM230C1202 / NCT01673646
A multicenter, open-label, randomized, phase II study to evaluate 
efficacy, safety, pharmacokinetics and pharmacodynamics of pasireotide 
LAR in Japanese patients with active acromegaly or pituitary gigantism
RAP Module 3 – Detailed Statistical Methodology for final 
CSR
Author:
Document type:
RAP Documentation
Document status:
Amendment 1.0
Release date:
25-Jan-2017
Number of pages:
20
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
Document History – Changes compared to previous version of RAP module 3. ...............4
1
Introduction .........................................................................................................................5
2
Study design ........................................................................................................................5
3
Objectives............................................................................................................................6
4
Definitions and general methodology .................................................................................8
4.1
Definitions ...............................................................................................................8
4.1.1
Study drug and study treatment...............................................................8
4.1.2
Date of first administration of study drug...............................................8
4.1.3
Date of last administration of study drug................................................8
4.1.4
Study day.................................................................................................8
4.1.5
Baseline...................................................................................................9
4.1.6
On-treatment assessment/event...............................................................9
4.1.7
Month......................................................................................................9
4.1.8
Standardized IGF-1.................................................................................9
4.1.9
Handling of missing values/censoring/discontinuations.........................9
4.1.10
Evaluation time window .........................................................................9
4.2
Data included in the analyses ................................................................................10
4.3
Analysis sets ..........................................................................................................10
5
Statistical methods used in reporting.................................................................................11
5.1
General presentation of descriptive summaries.....................................................11
5.2
Protocol deviation summaries................................................................................11
5.3
Patient disposition..................................................................................................11
5.4
Demographics........................................................................................................11
5.5
Medical history and current medical conditions....................................................12
5.6
Prior therapies........................................................................................................12
5.7
Study medication ...................................................................................................12
5.8
Concomitant therapy..............................................................................................12
5.9
Efficacy evaluation................................................................................................12
5.9.1
Primary analysis....................................................................................12
5.9.2
Secondary analyses ...............................................................................13
5.10
Safety evaluation ...................................................................................................14
5.10.1
Adverse events (AEs)............................................................................14
5.10.2
Laboratory data .....................................................................................16
5.10.3
ECG.......................................................................................................17


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5.10.4
Vital signs..............................................................................................18
5.10.5
Gallbladder ultrasound..........................................................................18
5.11
Pharmacokinetics evaluation .................................................................................18
18
18
19
6
Interim analysis .................................................................................................................19
7
Sample size calculation .....................................................................................................19
8
Changes from planned analysis in the protocol and Month 12 CSR.................................19


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Document History – Changes compared to previous version of RAP
module 3.
Version
Date
Changes
1.0
13-Jul- 2016
Initial version of RAP Module 3 for final CSR
Amendment 
1.0
See title page
1. Some previously reported baseline characteristic data 
have been changed and summary will be re-generated:

Medical history and current medication conditions 
in section 5.5

Prior medication in section 5.6.
2. Section 5.10.2.1 liver function parameters are newly 
inserted.
3. Safety disclosure section with two tables related to 
adverse events (non-serious AE and death due to SAE)
are added in order to comply with legal requirements 
pertinent to the disclosure of study results (Section 
5.10.1)


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1
Introduction
This document describes the detailed statistical methodology of the Report Analysis Plan 
(RAP) of Study SOM230C1202 required for reporting the results of final clinical study report 
(CSR). 
The first analysis, for the purpose of the First Interpretable Results (FIR) only, was conducted 
when the last patient completed the Month 3 assessment with data cut-off date on 31-Jul-2014. 
The second analysis was conducted, when the last patient completed the Month 12 
assessments (with data cut-off date on 2-Apr-2015), and the results were reported in an 
interim CSR dated 01-Jul-2015. Details on the final analysis are provided in the Section 4.2
for final CSR. For completeness a short description of prior analysis is provided in the same 
section.
Data will be analyzed by Novartis personnel or a designated third party. This RAP contains 
relevant statistical considerations for the final analysis which will contain cumulative data 
generated from first patient first visit (FPFV) to last patient last visit (LPLV) until all patients 
have withdrawn study. Further supportive statistical information will be provided in the 
[Appendix 16.1.9 of the CSR].
2
Study design
A total of 33 eligible patients were enrolled and randomized to one of 3 doses of pasireotide 
LAR (20 mg, 40 mg, or 60 mg) in a ratio of 1:1:1. Randomization was stratified by prior 
medications (e.g. somatostatin analogues or dopamine agonists), (yes or no). Intramuscular 
administration of pasireotide LAR has been repeated every month (1 month = 28 days) for 12 
months in core phase. It is permitted to increase the dose up to 60 mg in a patient showing the 
following biochemical test results after 3 and 6 months of study treatment: mean GH levels 
≥2.5 µg/L and/or IGF-1 > ULN (age and sex related). In the event of any problem with 
tolerability, it is permitted to reduce the next lower dosage level at any time. After 3 months 
of study treatment, the primary endpoint (proportion of patients with a reduction of mean GH 
levels to <2.5 µg/L and normalization of IGF-1 to within normal limits) will be evaluated. 
Patients with a reduction of mean GH levels to <2.5 µg/L and normalization of IGF-1 at the 
end of the 12-month study treatment will be enrolled in an extension phase of study treatment. 
Patients with a mean GH level ≥  2.5 µg/L and/or IGF-1 > ULN at the end of the 12- month 
study treatment may be enrolled in an extension phase of study treatment if the extended 
study treatment is thought to be clinically beneficial for them by the investigator. Patients will 
receive pasireotide LAR in the extension phase until unacceptable toxicity appears or until the 
medication is commercially available or until the pasireotide LAR development program is 
discontinued whichever comes first.


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Figure 2-1 Study design
3
Objectives
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Primary
Assess the total-group efficacy of pasireotide 
LAR on the reduction of mean GH levels to < 
2.5 µg/L and the normalization of IGF-1 at 3 
months of study treatment
Proportion of patients with a reduction of mean 
GH levels to < 2.5 µg/L and the normalization of 
IGF-1 to within normal limits (age and sex 
related) at 3 months across all doses
Key secondary
Assess the effect  of each starting dose 
pasireotide LAR on the reduction of mean GH 
levels to < 2.5 µg/L and the normalization of 
IGF-1 at 3 months of study treatment
Proportion of patients with a reduction of mean 
GH levels to < 2.5 µg/L and the normalization of 
IGF-1 to within normal limits (age and sex 
related) at 3 months in each starting dose
Assess the PK and PK/PD  of pasireotide LAR 
20 mg, 40 mg and 60 mg
PK: Ctrough, Cmax, 3rd inj, accumulation ratio (AR)
PD: GH, IGF-1
Assess the tolerability and safety profile of 
pasireotide LAR at 3 months and during and 
after the 12- month study treatment
Toxicity will be assessed using the National 
Cancer Institute-Common Toxicology Criteria 
(NCI-CTC) grading scale for Adverse Events 
and for laboratory assessments that include 
biochemistry and hematology; special safety 
assessments that include the regular monitoring 
and recording of blood glucose, HbA1c, thyroid 
and liver function tests, gallbladder 
examinations and ECGs. 
Assess the effect of pasireotide LAR on the 
reduction of mean GH levels  to < 2.5 µg/L at 3 
months of study treatment
Proportion of patients with a reduction of mean 
GH levels to < 2.5 µg/L at 3 months


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Objective
Endpoint
Assess the effect of pasireotide LAR on the 
normalization of IGF-1 at 3 months of study 
treatment
Proportion of patients with the normalization of 
IGF-1 to within normal limits (age and sex 
related) at 3 months
Other secondary (Core phase)
Assess the effect of pasireotide LAR on the 
reduction of mean GH levels to < 2.5 µg/L and 
the normalization of IGF-1 at 6, 9 and 12 months 
of study treatment
Proportion of patients with a reduction of mean 
GH levels to < 2.5 µg/L and the normalization of 
IGF-1 to within normal limits (age and sex 
related) at 6, 9 and 12 months
Assess the effect of pasireotide LAR on the 
reduction of mean GH levels to < 2.5 µg/L at 6, 
9and 12 months of study treatment
Proportion of patients with a reduction of mean 
GH levels to < 2.5 µg/L at 6, 9 and 12 months
Assess the effect of pasireotide LAR on the 
normalization of IGF-1 at 6, 9 and 12 months of 
study treatment
Proportion of patients with the normalization of 
IGF-1 to within normal limits (age and sex 
related) at 6, 9 and 12 months
Assess the effect of pasireotide LAR on the 
change of tumor volume at 6and 12 months of 
study treatment
Change of tumor volume from baseline at 6 and 
12 months
Assess the effect of pasireotide LAR on the 
change of mean GH level from baseline
Change of mean GH levels from baseline
Assess the effect of pasireotide LAR on the 
symptoms of acromegaly, specifically: ring size, 
headache, fatigue, perspiration, paresthesias, 
osteoarthralgia
Change of clinical signs from baseline: ring size, 
headache, fatigue, perspiration, paresthesias, 
osteoarthralgia
Assess the effect of pasireotide LAR on the 
change of prolactin (PRL) level from baseline
Change PRL level from baseline
Other secondary (Extension phase)
Assess the effect of pasireotide LAR as long 
term study treatment on the proportion of 
patients with a reduction of mean GH level to < 
2.5 μg/L and normalization of IGF-1 at 18 and 
24 months of study treatment
Proportion of patients with a reduction of mean 
GH levels to < 2.5 µg/L and the normalization of 
IGF-1 to within normal limits (age and sex 
related) a18 and 24 months of study treatment 
Assess the effect of pasireotide LAR as long 
term study treatment on the reduction of mean 
GH levels to < 2.5 µg/L at 18 and 24 months of 
study treatment
Proportion of patients with a reduction of mean 
GH levels to < 2.5µg/L at 18 and 24 months of 
study treatment
Assess the effect of pasireotide LAR as long 
term study treatment on the normalization of 
IGF-1 at 18 and 24 months of study treatment
Proportion of patients with the normalization of 
IGF-1 to within normal limits (age and sex 
related) at 18 and 24 months of study treatment
Assess the effect of pasireotide LAR as long 
term study treatment on the change of mean GH 
levels from baseline
Change of mean GH levels from baseline in 
extension phase
Assess the safety and tolerability of pasireotide 
LAR in extension phase 
Toxicity in extension phase will be assessed 
using the National Cancer Institute-Common 
Toxicology Criteria (NCI-CTC) grading scale for
Adverse Events 
Assess the total-group safety and tolerability of 
pasireotide LAR as long term study treatment
Toxicity in total-group study treatment will be 
assessed using the National Cancer Institute-
Common Toxicology Criteria (NCI-CTC) grading 


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Objective
Endpoint
scale for Adverse Events and for laboratory 
assessments that include biochemistry, 
hematology, urinalysis; special safety 
assessments that include the regular monitoring 
and recording of blood glucose, HbA1c, thyroid 
and liver function tests, gallbladder 
examinations and ECGs.
4
Definitions and general methodology
4.1
Definitions
4.1.1
Study drug and study treatment
Study drug will refer to SOM230 (pasireotide) LAR.
4.1.2
Date of first administration of study drug
The date of first administration of study drug will be derived as the first date when a nonzero 
dose of study drug is administered and recorded on the dose administration record (DAR) 
page of the electronic case report form (eCRF). For the sake of simplicity, the date of first 
administration of study drug will also be referred as start date of study drug.
4.1.3
Date of last administration of study drug
The date of last administration of study drug will be defined as the last date when a nonzero 
dose of study drug is administered and recorded on DAR page of the eCRF. This date will 
also be referred as last date of study drug.
4.1.4
Study day
The study day for all assessments (i.e. efficacy, safety) will be calculated as the difference 
between the date of the event (i.e. visit date, onset date of an event, assessment date) and the 
first date of study drug plus 1. For patients who got randomized but never dosed, study day is 
calculated as the difference between the date of event and the date of randomization plus 1.
For any assessment or event such as baseline disease characteristics or medical history that is 
supposed to occur prior to the start of study drug, the study day will be negative and 
calculated as the difference between the date of the event and the first date of study drug.
The study day will be displayed in the data listings.


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4.1.5
Baseline
The baseline will be the last pre-treatment evaluation result within 28 days of the start date of 
study drug. 
4.1.6
On-treatment assessment/event
Safety summaries and selected summaries of deaths will be presented using only on-treatment 
assessments/events.
For patients who discontinue study drug, on-treatment assessment/event will be any 
assessment/event obtained in the time interval between start date of study drug and last date of 
study drug + 56 days.
4.1.7
Month
A month will be calculated as 28 days. If duration in months has to be reported, duration in 
days will be divided by 28.
4.1.8
Standardized IGF-1
IGF-1 normal range is age and gender dependent. When pooling all the data for analyses, 
unless otherwise specified, the standardized IGF-1 will be used. The standardized IGF-1 is 
defined as:
Standardized IGF-1 = IGF-1 value / ULN,
where ULN is the upper limit of the normal range.
4.1.9
Handling of missing values/censoring/discontinuations
If the GH and/or IGF-1 samples are taken after 35 days (=28 + 7 days) from the date of LAR 
injection, the values if GH and/or IGF-1 at the corresponding visit will be treated as missing.
In addition, if a patient has less than 3 samples for the assessment of 5-point mean GH levels 
from the 2-hour profile, the mean GH levels will be considered as missing.
The patients with missing values of mean GH levels and/or IGF-1 at 3 months of study 
treatment or who discontinue prior to the assessment at 3 months of study treatment will be 
considered as non-responders.
4.1.10
Evaluation time window
GH and IGF-1 measurements taken within 35 days after the date of LAR injection are allowed 
and the last values of 5-point mean GH and IGF-1 within window will be used as the value of 
the corresponding month. For assessments beyond 3 months of study treatment, the ongoing 
patients will be counted in the denominator of calculation of response rate, if they have 
reached at each visit (e.g. Assessments collected at end of the study treatment of Core Phase 
will be treated at those at 12 months of study treatment as long as those were collected within 
the time window specified in the above). Discontinued patients are included in the 
denominator of calculation of response rate in the core phase and are included at a visit to 
which a patient reached in the extension phase.


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MRI collected within +/- 35 days from the date of visit is allowed. For corresponding visit, the 
patient will be counted at a specific visit if they have reached at each visit.
4.2
Data included in the analyses
The first interpretable result (FIR) was generated when the last patient completed 3 months 
assessment with data cut-off on 31-Jul-2014. Primary CSR, which contained results of 
primary and key secondary analyses, was generated when the last patient completed the 12
months assessment with data cut-off on 2-Apr-2015. 
The final analysis will be performed after all patients discontinued the study or study drug has 
been available on the market, and cumulative data will be reported in a final CSR. For the 
final analysis, only data through 24 months of study treatment and data at end of study 
treatment visit will be summarized, except for study disposition and adverse events/serious 
adverse events, as only minimal data will be collected beyond 24 months of study treatment.
Study disposition and adverse events/serious adverse events data beyond 24 months will be 
summarized in addition to listings.
For efficacy endpoints, all primary and key secondary analyses were already reported in 12 
month CSR. Updates of other secondary endpoints will be provided in the final CSR.
If an event continues until the end, then the event will be considered continuing and not 
having documented end date. This approach applies, in particular, to adverse event and 
concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
If it is required to impute an end date to be able to perform a specific analysis, (e.g. end date 
after the cut-off date) the data cut-off date will be imputed as the end date (to allow for 
calculation of treatment exposure duration for instance).
4.3
Analysis sets
Full analysis set (FAS) comprises of all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed 
according to the study treatment they have been assigned to during the randomization 
procedure.
Safety set includes all patients who received at least one dose of study treatment. Patients will 
be analyzed according to the study treatment according to the treatment they first received.
The rules for patient classification in the analysis sets (FAS and safety) are described hereafter:
Table 4-1
Patient classification rule
Analysis set
Protocol deviations that cause patients to be excluded from analysis and 
corresponding deviation codes from VAP Module 3
FAS
No written informed consent prior to any procedure (deviation code = I01)
Safety set
No written informed consent prior to any procedure (deviation code = I01)


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The per-protocol set (PPS) and pharmacokinetic analysis set (PAS) discussed on the study 
protocol, will not be used for the final analysis since there is no pharmacokinetic analysis nor 
PPS analysis performed and all of them were already reported in [the 12 month CSR].
Although there is no PPS involved, all protocol deviations will be finalized before database 
lock and reported in the listing.
Analyses of efficacy endpoints will be based on the FAS. Safety analyses will be performed 
based on the safety set. 
5
Statistical methods used in reporting
5.1
General presentation of descriptive summaries
Categorical data (e.g. gender, race, etc.) will be summarized by frequency count and 
percentages. Percentages will be calculated using the number of patients in the relevant 
population or subgroup as the denominator.
Continuous data (e.g. age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum and maximum).
Data through 24 months of study treatment and at end of study treatment will be summarized 
except for study disposition, drug administration record and adverse events/serious adverse 
events.  For study disposition, drug administration record and adverse events/serious adverse 
events, all data even beyond 24 months of study treatment will be summarized and listed.
All data will be listed appropriately.
5.2
Protocol deviation summaries
The number and percentage of patients in the FAS with any protocol deviation will be 
tabulated by the deviation category (as specified in the VAP Module 3).
5.3
Patient disposition
The FAS will be used for the following analyses.
Number of patients who are randomized and treated will be presented.
Number of patients who are still on-treatment, complete and discontinue at core phase will be 
presented. Primary reason for discontinuation at core phase will be summarized.
Number of patients who are still on-treatment, complete and discontinue at extension phase 
will be presented. Primary reason for discontinuation at extension phase will be summarized.
Number of patients who are beyond 24 months of study treatment and discontinue will be 
presented. Primary reason for discontinuation at extension phase will be summarized.
5.4
Demographics
Summary of demographics characteristics were reported in [the 12 months CSR] and not 
applicable in this document. 


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5.5
Medical history and current medical conditions
Due to few data changes since data cut-off for the analysis of [the 12months CSR], relevant 
medical history and current medical conditions will be summarized again by primary system 
organ class, preferred term, randomized dose level and overall for the FAS, although these 
were reported previously in [the 12 months CSR].
5.6
Prior therapies
Summaries of prior radiotherapy and surgery were reported in [the 12 months CSR] and not 
applicable in this document.
Due to few data changes since data cut-off for the analysis of [the 12months CSR], prior 
medication will be summarized again by WHO drug reference list, randomized dose level and 
overall for the FAS, although these were reported previously in [the 12 months CSR].
5.7
Study medication
The following analyses will be conducted by study phase for the safety set. 
The durations of exposure to the study drug and the number of injections received will be 
summarized. Duration of exposure is calculated as 
Duration of exposure = min (last date of study drug + 27, date of death) – first date of study 
drug + 1
Number of patients with dose reduction and dose increase will be presented.
5.8
Concomitant therapy
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized by ATC class, preferred term, phase and overall for the safety 
set.
5.9
Efficacy evaluation
5.9.1
Primary analysis
Primary variable
The primary variable is the total-group response rate defined as the proportion of patients with 
the reduction of mean GH levels to < 2.5 µg/L and the normalization of IGF-1 at 3 months of 
study treatment. This has already been reported in [the 12 month CSR].
Please see the Section 4.1.9 about how to handle missing values and discontinuations.
Primary analysis
The total-group response rate at 3 months of study treatment along with the corresponding 
Clopper-Pearson exact two-sided 90% confidence interval was reported in [the 12 months 
CSR ]and not applicable in this document. 


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5.9.2
Secondary analyses
The FAS will be used for the following analyses.
5.9.2.1
Key secondary analyses
The response rate for patients with the reduction of mean GH levels to < 2.5 µg/L and the 
normalization of IGF-1 at 3 months of study treatment along with the corresponding exact 
95% confidence interval as well as respective response rate with mean GH and IGF-1 were 
reported in [the 12 months CSR ]and not applicable in this document. 
5.9.2.2
Other secondary analyses
Other secondary analyses for core phase
Most secondary objectives were reported in [the 12 months CSR] and not applicable in this 
document. The below analyses, which were previously performed, will be repeated with 
updated data for the final analysis (most likely at 18 months and 24 months of study 
treatment).
Proportions of overall patients with the reduction of mean GH levels to < 2.5 ug/L and 
normalization of IGF-1 will be updated along with subgroup analysis of SSA uncontrolled 
status, while SSA uncontrolled population is defined as patients who were pre-treated with 
SSA for >= 12 weeks and patients who were pre-treated with SSA for < 12 weeks or were not 
pre-treated with SSA are considered as others. Proportions of patients with the reduction of 
mean GH level to < 2.5 ug/L by visit and with normalization of IGF-1 by visit will be updated 
along with subgroup analysis of SSA uncontrolled status, respectively.
Bar charts for all total group response rate, proportion of patients with reduction of mean GH 
level to < 2.5 ug/L and proportion of patients with normalization of IGF-1 will be repeated by 
visit for updated data.
Total group response rate with over responder by visit will be also updated where over 
responder is defined as a patient with reduction of mean GH levels to <2.5 ug/L and IGF-1 
reached lower than lower limit normal. This summary will be updated with SSA uncontrolled 
status subgroups as well.
Changes from baseline in mean GH and in normalization of IGF-1 will be updated by visit 
and SSA uncontrolled status, respectively, in addition to change from baseline in ring size and 
PRL.  
Plots of individual patient absolute value of mean GH and IGF-1 will be re-ran as well.
Changes of tumor volume at 6 and 12 months of study treatment from baseline were reported 
in [the 12 month CSR] and not applicable in this document. The summary will be repeated by 
subgroup of categorical longest diameter with 10 mm cut-off in the final analysis. Changes 
and percent changes will be plotted along with the longest diameter as well.


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5.10
Safety evaluation
For all safety analyses, the safety set will be used. All analysis through Month 3 was 
reported in [the 12 month CSR] and not applicable in this document.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-study treatment period: from day of patient’s informed consent to the day before the 
first dose of study medication 
2. On-study treatment period: from the day of first dose of study medication to 56 days after 
last dose of study medication
3. Post-study treatment period: starting at 57 days after last dose of study medication
5.10.1
Adverse events (AEs)
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The last version at the time of database lock will be used.
AEs will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0. If CTCAE grading does not exist for an adverse event, grades 1-4 
corresponding to the severity of mild, moderate, severe, and life-threatening will be used. 
CTCAE grade 5 (death) will not be used in this study; rather this information will be collected 
on the “Study phase completion – core study”, “Study phase completion – extension study” or 
“Study completion” eCRF pages.
Summary tables for AEs have to include only AEs that started or worsened during the on-
study treatment period, the study treatment-emergent AEs. However, all AE data (including 
those from the pre and post-study treatment periods) will be listed and those collected during 
the pre and post-study treatment are to be flagged. Serious AEs, AEs leading to study drug 
discontinuation, AEs requiring dose adjustment or interruption and death will be listed.
Grouping of adverse events of special interest
Specific groupings of adverse events of special interest will be considered and the number of 
patients with at least one event in each grouping will be reported. Such groups consist of 
adverse events for which there is a specific clinical interest in connection with SOM230 
treatment (i.e. where SOM230 may influence a common mechanism of action responsible for 
triggering them) or adverse events which are similar in nature (although not identical) within 
project defined group. The specific groupings of AEs as defined in the latest documentation 
available prior to database lock 
 
will be used.
AE summaries using all available data
The following AE summaries will be provided by phase (core/extension) using all data up to 
data cut-off:


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
AEs, regardless of study drug relationship, by primary system organ class and preferred 
term

AEs, regardless of study drug relationship, by preferred term 

AEs suspected to be related to the study drug by primary system organ class and preferred 
term

AEs, regardless of study drug relationship, by primary system organ class, preferred term 
and maximum CTCAE grade

AEs suspected to be related to the study drug by primary system organ class, preferred 
term and maximum CTCAE grade

On-treatment deaths by primary system organ class and preferred term

Serious AEs (SAEs), regardless of study drug relationship, by primary system organ class, 
preferred term and maximum CTCAE grade

AEs leading to study discontinuation, regardless of study drug relationship, by primary 
system organ class, preferred term and CTCAE grade

AEs requiring dose adjustment or study drug interruption, regardless of study drug 
relationship, by primary system organ class, preferred term and maximum CTCAE grade

AEs requiring significant additional therapy, regardless of study drug relationship, by 
primary system organ class, preferred term and maximum CTCAE grade

AEs of special interest, regardless of study drug relationship, by category and preferred 
term

AEs of special interest suspected to be related to the study drug by category and preferred 
term

AEs of special interest leading to study discontinuation, regardless of study drug 
relationship, by category and preferred term 
Study disclosure
For the legal requirements of ClinicalTrials.gov, two required tables on on-treatment adverse 
events which are not serious adverse events and on on-treatment serious adverse events and 
SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.


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The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
5.10.2
Laboratory data
For laboratory test covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0, the study’s biometrics and statistical reporting team will grade 
laboratory data accordingly. Grade 5 will not be used.
In cases differentials count, the lower limits of normal ranges used in CTCAE definition have 
to be replaced by a clinical meaningful limit expressed in absolute counts.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
Patients with laboratory abnormalities of CTC grade 3 or 4 will be listed. All laboratory data 
with values flagged to show the corresponding CTCAE grades and the classifications relative 
to the laboratory normal ranges will be listed.
For analyses performed by core baseline diabetic status, the core diabetic status is defined as 
follow:

Diabetic: patients taking any antidiabetic medication, or with history of diabetic 
medication or HbA1c≥6.5% or FPG ≥126 mg/dL

Pre-diabetic: patients not qualifying as diabetic and with FPG≥100 mg/dL and < 126 
mg/dL or HbA1c≥5.7% and <6.5%

Normal glucose tolerance: patients not qualifying as diabetic or pre-diabetic and with 
FPG< 100 mg/dL and/ or HbA1c<5.7%.
Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges.
Laboratory summaries using all available data
The following summaries using all available data will be generated by phase (core/extension):

For hematology, biochemistry and urinary laboratory tests where CTCAE grades are 
defined, shift tables using CTCAE grades to compare baseline to the worst post-baseline 
value

For hematology, biochemistry and urinary laboratory tests where CTCAE grades are not 
defined, shift tables using the low/normal/high/high and low/missing classification to 
compare baseline to the worst post-baseline value

For fasting serum cortisol and plasma ACTH, shift tables using the low/normal/high/high 
and low/missing classification to compare baseline to the worst post-baseline value will be 
generated.

For fasting blood glucose and HbA1c, shift tables using the ADA (2010) to compare 
baseline to the last available value


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
For fasting blood glucose and HbA1c, shift tables using the ADA (2010) to compare 
baseline to the last available value by baseline diabetic status

For fasting blood glucose and HbA1c, summary of change from baseline over time

For fasting blood glucose and HbA1c, summary of changes at the last value from baseline 
by baseline diabetic status
5.10.2.1 Liver function parameters
Liver function parameters of interest are total bilirubin (TBIL), ALT, AST and alkaline 
phosphates (ALP). The number (%) of subjects with worst post-baseline values will be 
summarized:

ALT or AST > 3xULN

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL >2xULN

ALT or AST > 3xULN & TBL >2xULN & ALP < 2xULN
Potential Hy’s Law events are defined as those subjects with concurrent occurrence of AST or 
ALT > 3xULN and TBL > 2xULN and ALP < 2xULN in the same assessment sample during 
the on-treatment period. Further medical review has to be conducted to assess potential 
confounding factor such as, liver metastases, liver function at baseline etc.
For more details and adaptation of above summary, please refer to the Oncology Hepatic 
Safety guidance.
5.10.3
ECG
A newly occurring ECG abnormality is defined as notable ECG abnormality at post-baseline 
but not at baseline. Clinically notable ECG abnormality is defined in Table 5-1. The 
percentage is calculated based on patients with both baseline and post-baseline evaluations. A 
patient with multiple occurrences of a newly occurring abnormality is counted only once for 
each abnormality.
The patients with newly occurring ECG abnormalities will be listed and the corresponding 
values will be flagged in the listing.
ECG summaries using all available data
The following summaries using all available data will be generated by phase (core/extension):

For QTcF, QTcB and QT, shift tables to compare baseline to the worst post-baseline value

The number of patients and percentage of patients with newly occurring ECG changes


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Table 5-1
Clinically notable ECG abnormalities
ECG value
Notable ECG abnormality
QT, QTcB, QTcF
New > 450
[ms]
New > 480
New > 500
Increase from baseline > 30
Increase from baseline > 60
PR [ms]
Increase from baseline > 25% and > 200
QRS [ms]
Increase from baseline > 25% and > 110
HR [bpm]
Decrease from baseline > 25% and < 50
Increase from baseline > 25% and > 100
5.10.4
Vital signs
Patients with clinically notable vital sign abnormalities will be listed and the corresponding 
values will be flagged in the listing.
Vital signs summaries using all available data

For systolic BP, diastolic BP and pulse rate, shift tables using the high/normal/low/(high 
and low) classification defined in Table 5-2 will be produced to compare baseline to the 
worst post-baseline value by phase (core/extension).
Table 5-2
Clinically notable vital signs
Vital sign
High
Low
Systolic BP
[mmHg]
≥ 160 with increase from baseline of ≥ 
20
≤ 90 with decrease from baseline of ≥ 
20
Diastolic BP
[mmHg]
≥ 100 with increase from baseline of ≥ 
15
≤ 50 with decrease from baseline of ≥ 
15
Pulse rate [bpm]
≥ 120 with increase from baseline of ≥ 
15 
≤ 50 with decrease from baseline of ≥ 
15
5.10.5
Gallbladder ultrasound
Gallbladder data at each visit will be listed.
5.11
Pharmacokinetics evaluation
Pharmacokinetic data were reported in [the 12 month CSR] and not applicable in the final 
analysis.


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6
Interim analysis
No interim analysis was planned for this study which required considerations on multiplicity.
However there are multiple analyses were performed with updated data. Please see Section 
4.2 for further details.
7
Sample size calculation
The planned sample size of 30 was determined based on the accuracy of estimated total-group 
response rate at the end of 3 months of treatment.
The response rate is the proportion of responders, where responders are defined as patients 
with the reduction of mean GH levels to < 2.5 µg/L and normalization of IGF-1. The response 
rates at 20 mg, 40mg and 60mg in Study SOM230C2110 were comparable (30% at 20mg, 
41.7% at 40mg, and 38.5% at 60mg). Furthermore, the dose of pasireotide LAR will be 
adjusted according to efficacy and safety. It is considered, therefore, that the efficacy of 
pasireotide LAR can be evaluated more appropriately based on the response rate of all groups 
combined. In this study, based on the results from Study SOM230C2110, the expected total-
group response rate will be at least 30%.
In Study SOM230C2305, patients inadequately controlled with 12 month octreotide LAR 
study treatment were crossed over to pasireotide LAR. The response rate at 3 months after 
crossover was 17.3% (two-sided 95% CI: [9.8%, 27.3%]). Since a large number of patients 
who enroll to this study are assumed to be inadequately controlled with octreotide LAR 
treatment, a clinically meaningful minimum response rate is set as 10% based on the lower 
limit of two-sided 95% CI, 9.8%.
The expected drop out rate is 10% based on the results from Study SOM230C2305. The 
patients with missing values of mean GH levels or IGF-1 at the assessment at 3 months of 
study treatment or who discontinue prior to the assessment at 3 months of study treatment will 
be considered as non-responders.
Under these assumptions, the expected total-group response rate adjusted by the expected 
drop out rate is 27%. The sample size of 30 can demonstrate that the lower limit of the 
Clopper-Pearson exact two-sided 90% CI for the total-group response rate is not less than the 
clinically meaningful response rate, 10%.
8
Changes from planned analysis in the protocol and Month 
12 CSR
Comparing with the analysis for 12 months of study treatment CSR, the following analyses 
was added for final analysis (Table 8-1).


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Table 8-1
List of changes from planned analysis 
No.
Items
When
Note
1
Disposition table including patients who continue 
treatment beyond 24 months.
RAP for final CSR (See 
title page)
New
2
Concomitant medication by phase 
RAP for final CSR (See 
title page)
New
3
Tumor volume by categorical longest diameter
RAP for final CSR (See 
title page)
New
4
Tumor volume listing with longest/shortest diameters
RAP for final CSR (See 
title page)
New