Clinical trial NCT02354508
Conditions: Acromegaly
Keywords: acromegaly GH IGF-1 pasireotide LAR SOM230 first generation somatostatin analogues growth disorder gigantism Pituitary adenoma pituitary gigantism
Sponsor: Novartis Pharmaceuticals
Start date: 2015-03-31; Completion date: 2018-09-27
Enrollment: 123 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase IIIb multicenter, open-label; single arm study to evaluate the efficacy and safety of pasireotide LAR 40 mg and 60 mg in patients with inadequately controlled acromegaly with maximal approved doses of first generation somatostatin analogues. The study will enroll inadequately controlled patients by high doses (maximal approved) of first-generation somatostatin analogues given for at least 3 months. Patients will receive pasireotide LAR 40 mg or 60 mg during the 36 week core study phase. Patients who have completed all visits of core phase and have completed all the assessments at the core phase completion visit can move into the 32-week extension phase. Patients can continue with study treatment until pasireotide LAR is commercially available and reimbursed in their respective country or until the end of the extension phase whichever occurs first.

Detailed description:
This is a phase IIIb multicenter, open-label; single arm study to evaluate the efficacy and safety of pasireotide LAR 40 mg and 60 mg in patients with inadequately controlled acromegaly with maximal doses of first generation somatostatin analogues. The study will enroll inadequately controlled patients by high doses of first-generation somatostatin analogues given for at least 3 months.

Patients will be categorized into two groups. Group 1 consists of patients treated with octreotide LAR 30 mg from countries where octreotide LAR 40mg is approved for the treatment of acromegaly at the time of screening. These patients will start a 3-months run-in phase to receive 40mg octreotide before being considered eligible to enter the core treatment phase. After 3 months of treatment have been completed, and prior to the fourth injection a mean GH and IGF-1 will be assessed. Patients who are achieving biochemical control will be considered a screen failure and they will not qualify for the core phase of the study. They will continue treatment with octreotide LAR 40 mg outside the frame of this study.

Group 2 consists of patients treated with octreotide LAR 30 mg from countries where octreotide 40mg is NOT yet approved at the time of screening. This group also includes patients already treated with octreotide LAR 40 mg or lanreotide ATG 120 mg. Patients should have been treated with the first generation SSAs for at least 3 months prior to screening. Eligible patients can directly enter the core treatment phase of the study. A run-in phase is not required for this patient population.

In the core treatment phase patients will start treatment with pasireotide LAR 40 mg every 4 weeks. At week 12, the mean GH value and IGF-1value will be assessed. Patients who have not achieved biochemical control by week 12 and do not have any tolerability issues with pasireotide LAR 40 mg will have the dose increased to 60 mg. Patients who have achieved biochemical control by week 12 will maintain a dose of pasireotide LAR 40 mg. A mean GH value and IGF-1 value will be assessed every 12 weeks until Visit 777. At weeks 16 and 28, the investigator will be able to adjust the dose based on the achievement of biochemical control and drug tolerability. If tolerability issues occur, the dose can be decreased in 20 mg. Once the tolerability issue resolves, the patients should return to the dose previously received. Patients will be treated for a total of 36 weeks during the core phase. During this period any concomitant medication for the treatment of acromegaly is prohibited. Patients are required to complete a core phase completion visit 4 weeks after the last dose of pasireotide LAR is administered. Patients who discontinue from the core phase are also required to complete the core phase completion visit 4 weeks after receiving the last pasireotide LAR dose.

Patients who have completed all visits of core phase and have completed all the assessments at the core phase completion visit (Visit 777) can move into the extension phase. The core phase completion visit performed at Visit 777, will also be the first visit (Visit 18) of the extension phase. At Visit 18, the patients will receive the same dose of pasireotide LAR that they received at week 32 (Visit 17). At week 40 (Visit 19), the investigator will decide the treatment regimen and the pasireotide LAR dose based on the achievement of biochemical control at Visit 777. Patients achieving biochemical control at the end of the core phase will continue pasireotide LAR monotherapy at the same dose of the core phase. Patients who are uncontrolled at the end of the core phase will continue pasireotide LAR 60 mg and they will be allowed to receive concomitant treatment with medications used to treat acromegaly based on the investigator's clinical judgment. GH and IGF-1 levels will be assessed every 12 weeks until week 72. At weeks 52 and 64, the investigator will be able to adjust the dose of pasireotide LAR and the regimen of the concomitant medication used to acromegaly based on the patients achievement of biochemical control and drug tolerability. Patients will be treated for a total of 32 weeks in the extension phase and receive the last dose of study treatment at week 68 (Visit 26). Patients are required to complete an extension phase completion visit (Visit 778) 4 weeks after the last dose of pasireotide LAR is administered. Patients who prematurely discontinue from the extension phase are also required to complete the extension phase completion visit (Visit 778) 4 weeks after receiving the last dose of pasireotide LAR.

After discontinuation from the study or completion of study treatment either at the core phase or extension phase of the study, all patients will be followed for safety for 12 weeks (84 days) after the last study drug administration. This visit can be performed by phone, a study visit for follow-up is not mandatory.

Arms: arm 1: Patients who qualify for the core phase of the study will be treated with pasireotide LAR 40 mg initially. Patients not achieving biochemical control can be up-titrated to pasireotide LAR 60 mg.
Interventions: intervention 1: Pasireotide LAR
Intervention descriptions: intervention 1: Pasireotide 40 mg and 60 mg. Pasireotide 20 mg which was allowed for dose decrease in case of adverse event.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
Clinical Development 
 
Pasireotide / SOM230 
 
 
Protocol CSOM230C2413 / NCT02354508 
 
A phase IIIb multicenter, open-label, single arm study to 
evaluate the efficacy and safety of pasireotide in patients 
with acromegaly inadequately controlled with first 
generation somatostatin analogues 
 
 
 
Authors 
Document type 
Oncology Clinical Trial Protocol 
EUDRACT number 
2014-002630-31 
Version number 
00 (Original Protocol) 
Development phase 
IIIb 
Document status 
Final 
Release date 
17-Sep-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 appendices ................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Protocol summary .............................................................................................................. 10 
1 
Background........................................................................................................................ 14 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 14 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 15 
1.2.1 
Overview of pasireotide (SOM230) ...................................................... 15 
2 
Rationale ............................................................................................................................ 17 
2.1 
Study rationale and purpose ................................................................................... 17 
2.2 
Rationale for the study design ............................................................................... 18 
2.3 
Rationale for dose and regimen selection .............................................................. 18 
2.4 
Rationale for choice of combination drugs ............................................................ 19 
2.5 
Rationale for choice of comparators drugs ............................................................ 19 
3 
Objectives and endpoints ................................................................................................... 19 
4 
Study design ...................................................................................................................... 22 
4.1 
Description of study design ................................................................................... 22 
4.2 
Timing of interim analyses and design adaptations ............................................... 25 
4.3 
Definition of end of the study ................................................................................ 25 
4.4 
Early study termination .......................................................................................... 25 
5 
Population .......................................................................................................................... 26 
5.1 
Patient population .................................................................................................. 26 
5.2 
Inclusion criteria .................................................................................................... 26 
5.3 
Exclusion criteria ................................................................................................... 26 
6 
Treatment ........................................................................................................................... 28 
6.1 
Study treatment ...................................................................................................... 28 
6.1.1 
Dosing regimen ..................................................................................... 29 
6.1.2 
Ancillary treatments .............................................................................. 30 
6.1.3 
Rescue medication ................................................................................ 30 
6.1.4 
Guidelines for continuation of treatment .............................................. 30 
6.1.5 
Treatment duration ................................................................................ 30 
6.1.6 
Dose escalation guidelines .................................................................... 31 
6.2 
Dose modifications ................................................................................................ 31 
6.2.1 
Dose modification and dose delay ........................................................ 31 


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6.2.2 
Follow-up for toxicities ......................................................................... 32 
6.2.3 
Anticipated risks and safety concerns of the study drug ....................... 39 
6.3 
Concomitant medications ...................................................................................... 39 
6.3.1 
Permitted concomitant therapy ............................................................. 39 
6.3.2 
Prohibited concomitant therapy ............................................................ 40 
6.4 
Patient numbering, treatment assignment or randomization ................................. 40 
6.4.1 
Patient numbering ................................................................................. 40 
6.4.2 
Treatment assignment or randomization ............................................... 40 
6.4.3 
Treatment blinding ................................................................................ 40 
6.5 
Study drug preparation and dispensation ............................................................... 41 
6.5.1 
Study drug packaging and labeling ....................................................... 41 
6.5.2 
Drug supply and storage ........................................................................ 41 
6.5.3 
Study drug compliance and accountability ........................................... 42 
6.5.4 
Disposal and destruction ....................................................................... 42 
7 
Visit schedule and assessments ......................................................................................... 43 
7.1 
Study flow and visit schedule ................................................................................ 43 
7.1.1 
Molecular pre-screening ........................................................................ 51 
7.1.2 
Screening ............................................................................................... 51 
7.1.3 
Run-in period ........................................................................................ 51 
7.1.4 
Treatment period ................................................................................... 51 
7.1.5 
End of treatment visit including study completion and premature 
withdrawal ............................................................................................. 52 
7.1.6 
Follow-up and End of Study visit ............................................................ 54 
7.2 
Assessment types ................................................................................................... 54 
7.2.1 
Efficacy assessments ............................................................................. 54 
7.2.2 
Safety and tolerability assessments ....................................................... 56 
7.2.3 
Pharmacokinetics .................................................................................. 60 
7.2.4 
Resource utilization ............................................................................... 60 
8 
Safety monitoring and reporting ........................................................................................ 60 
8.1 
Adverse events ....................................................................................................... 60 
8.1.1 
Definitions and reporting ...................................................................... 60 
8.1.2 
Laboratory test abnormalities ................................................................ 61 
8.1.3 
Adverse events of special interest ......................................................... 62 
8.2 
Serious adverse events ........................................................................................... 63 
8.2.1 
Definitions ............................................................................................. 63 
8.2.2 
Reporting ............................................................................................... 63 
8.3 
Emergency unblinding of treatment assignment ................................................... 64 
8.4 
Pregnancies. ........................................................................................................... 64 


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8.5 
Warnings and precautions...................................................................................... 65 
8.6 
Data Monitoring Committee .................................................................................. 65 
8.7 
Steering Committee ............................................................................................... 65 
9 
Data collection and management ...................................................................................... 65 
9.1 
Data confidentiality ............................................................................................... 65 
9.2 
Site monitoring ...................................................................................................... 66 
9.3 
Data collection ....................................................................................................... 66 
9.3.1 
ECG data collection .............................................................................. 66 
9.3.2 
IRT data collection ................................................................................ 66 
9.3.3 
Central laboratory data collection ......................................................... 67 
9.4 
Database management and quality control ............................................................ 67 
10 Statistical methods and data analysis ................................................................................ 68 
10.1 
Analysis sets .......................................................................................................... 68 
10.1.1 
Full Analysis Set ................................................................................... 68 
10.1.2 
Safety Set ............................................................................................... 68 
10.1.3 
Per-Protocol Set ..................................................................................... 68 
10.2 
Patient demographics/other baseline characteristics ............................................. 68 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 68 
10.4 
Primary objective ................................................................................................... 68 
10.4.1 
Variable ................................................................................................. 69 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 69 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 69 
10.4.4 
Supporting Analysis of Primary Objective ........................................... 69 
10.5 
Secondary objectives ............................................................................................. 69 
10.5.1 
Secondary objectives- Core phase ........................................................ 70 
10.5.2 
Secondary objectives- Extension phase ................................................ 71 
10.5.3 
Safety objectives ................................................................................... 71 
10.5.4 
Patient-reported outcomes ..................................................................... 73 
10.6 
Interim analysis ...................................................................................................... 74 
10.7 
Sample size calculation.......................................................................................... 74 
10.8 
Power for analysis of key secondary variables ...................................................... 74 
11 Ethical considerations and administrative procedures....................................................... 74 
11.1 
Regulatory and ethical compliance ........................................................................ 74 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 74 
11.3 
Informed consent procedures ................................................................................. 75 
11.4 
Discontinuation of the study .................................................................................. 75 
11.5 
Publication of study protocol and results ............................................................... 75 
11.5.1 
Communication and Publication of Clinical Trial Results .................... 75 


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11.6 
Study documentation, record keeping and retention of documents ....................... 76 
11.7 
Confidentiality of study documents and patient records ....................................... 77 
11.8 
Audits and inspections ........................................................................................... 77 
11.9 
Financial disclosures .............................................................................................. 77 
12 Protocol adherence ............................................................................................................ 77 
12.1 
Amendments to the protocol .................................................................................. 77 
13 References (available upon request) .................................................................................. 78 
14 Appendices ........................................................................................................................ 80 
14.1 
Appendix 1: Acromegaly Quality of Life Questionnaire ....................................... 80 
14.2 
Appendix 2: Patient Report Outcome Questionnaire EQ-5D5-L .......................... 85 
14.3 
Appendix 3: Concomitant Medications with “known risk of TdP (Torsades de 
pointes)” ................................................................................................................. 87 


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List of appendices 
Appendix 1: Acromegaly Quality of Life Questionnaire 
Appendix 2: Patient Report Outcome Questionnaire EQ-5D5-L 
Appendix 3: Concomitant Medications with “known risk of TdP (Torsades de pointes)” 
 
List of figures 
Figure 4-1 
Flow Chart for Group 1 and Group 2 Patients ...................................... 22 
Figure 4-2 
Study Design; Group 1 .......................................................................... 23 
Figure 4-3 
Study Design; Group 2 .......................................................................... 25 
Figure 6-1 
Group 1: Dose Regimen ........................................................................ 29 
Figure 6-2 
Group 2: Dose Regimen ........................................................................ 30 
Figure 6-3 
QT prolongation flowchart: 480 msec less than QTcF less than or 
equal to 500 msec ......................................................................................... 33 
Figure 6-4 
QT prolongation flowchart; QTcF greater than 500msec ..................... 35 
Figure 6-5 
LFT management algorithm .................................................................. 37 
Figure 6-6 
Fasting SMBG Guidance ...................................................................... 39 
 
List of tables 
Table 1-1 
Binding profiles for octreotide and pasireotide at  hsst1-5  (IC50, 
mol/L) .................................................................................................... 15 
Table 3-1 
Objectives and related endpoints .......................................................... 20 
Table 6-1 
Dose and treatment schedule ................................................................. 29 
Table 6-2 
Guideline for treatment of patients experiencing adverse events .......... 32 
Table 6-3 
Packaging and labeling ......................................................................... 41 
Table 6-4 
Supply and storage of study treatments ................................................. 42 
Table 7-1 
Core Phase Visit evaluation schedule – Group 1 .................................. 44 
Table 7-2 
Core Phase Visit evaluation schedule – Group 2 .................................. 47 
Table 7-3 
Extension Phase Visit evaluation schedule for both Group 1 and 
Group 2 .................................................................................................. 49 
Table 7-4 
Local or Central Clinical Laboratory Parameters Collection Plan ........ 56 
Table 7-5 
Gallbladder Ultrasound Assessment Collection Plan ............................ 58 
Table 7-6 
Central ECG Collection Plan ................................................................ 58 


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List of abbreviations 
AcroQoL 
Acromegaly Quality of Life 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
Anti-HBc 
Anti-Hepatitis B core 
Anti-HCV 
Anti-Hepatitis C Virus 
Anti-HEV 
Anti-Hepatitis E Virus 
APTT 
Partial Thromboplastin Time 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC Class 
Anatomical Therapeutic Chemical Classification System 
ATG 
Autogel 
B-hCG 
β-subunit of hCG gonadotropin 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CPK 
Creatine Phosphokinase 
CPO 
(Novartis) Country Pharma Organization 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DM 
Diabetes Mellitus 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety and Epidemiology 
EBV 
Epstein Barr Virus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GH 
Growth Hormone 
GIP/GLP 
Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 
HbA1C 
Hemoglobin A1c 
Hbs-Ag 
Hepatitis B surface-Antigen 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
HRQoL 
Health Related Quality of Life 
i.m. 
Intramuscular 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF 
Insulin-like Growth Factor 


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IgM 
Immunoglobulin M 
IMS 
Integrated Medical Safety 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
ITT 
Intention To Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LAR 
Long Acting Release 
LDH 
Lactic Dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Testing 
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-CTCAE 
v.4.03 
National Cancer Institute-Common Toxicity Criteria Adverse Event version 4.03 
OGTT 
Oral Glucose Tolerance Test 
PCR 
Polymerase Chain Reaction 
PHI 
Protected Health Information 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PRL 
Prolactin 
PRO 
Patient Reported Outcomes 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin time 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
REB 
Research Ethics Board 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SOP 
Standard Operating Procedure 
SSA 
Somatostatin analogues 
sst 
somatostatin receptor subtype 
TdP 
Torsades de pointes 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit Normal 
γ-GT 
Gamma-Glutamyltransferase 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This also 
includes approved drugs used outside of their indication/approved dosage, or 
that are tested in a fixed combination. Investigational treatment generally does 
not include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment 
Patient Number 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient withdrawal 
Treatment group 
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 


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Protocol summary: 
Protocol number 
CSOMC2413 
Title 
A phase IIIb multicenter, open-label, single arm study to evaluate the efficacy and 
safety of pasireotide in patients with acromegaly inadequately controlled with first 
generation somatostatin analogues 
Brief title 
Study of efficacy and safety of pasireotide LAR in patients with inadequately 
controlled acromegaly 
Sponsor and Clinical 
Phase 
Novartis, Phase lllb 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
To evaluate the efficacy and safety of pasireotide, a second generation 
somatostatin analogue with a broader affinity to sst receptors, in patients with in 
adequately controlled acromegaly after a minimum of 3 months with high doses of 
first generation somatostatin analogues. 
Primary Objective(s) 
Primary Objective 
To evaluate the efficacy of pasireotide LAR in patients with acromegaly who are 
inadequately controlled with currently available somatostatin analogues, as 
measured by the proportion of patients with GH <1µg/L and IGF-1 <ULN at week 
36 overall and by mGH level at screening. 
Supporting Analysis for Primary 
To assess the proportion of patients achieving GH <1µg/L and IGF-1 <ULN at 
week 36 by GH level at screening. 
Secondary Objectives 
Core Phase 
To assess the changes in mean GH from study baseline to week 36. 
To assess the changes in standardized IGF-1 from study baseline to week 36. 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN at 
weeks 12 and 24 overall and by GH level at screening 
To assess the proportion of patients achieving GH <1µg/L at weeks 12, 24 and 36, 
overall and by GH level at screening 
To assess the proportion of patients achieving IGF-1 levels <ULN at weeks 12, 24 
and 36 
To evaluate the tolerability and safety profile of pasireotide LAR 
To evaluate the effect of pasireotide LAR on HRQoL and signs and symptoms of 
acromegaly from baseline to weeks 12, 24 and 36 
Extension Phase 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN overall 
and by GH level at screening at weeks 48, 60 and 72 during the treatment with 
pasireotide LAR monotherapy 
To evaluate the long term tolerability and safety profile of pasireotide LAR 
To evaluate the long term effect of pasireotide LAR on HRQoL and signs and 
symptoms of acromegaly, from baseline and week 36 to week 72 
Study design 
Group 1 – Patients treated with octreotide LAR 30mg from the countries where 
octreotide LAR 40mg is approved for the treatment of acromegaly at the time of 
screening – Patients participate in the run-in phase. 
Run-In phase (Screening to Baseline) 
Patients will start treatment with octreotide LAR 40 mg every 4 weeks. Patients 
who have not achieved biochemical control after 3 injections can be enrolled in the 
study. 
Core Phase (Baseline to week 36) 
Patients will start treatment on pasireotide LAR 40 mg every 4 weeks until week 
32. A mean GH value and IGF-1 value will be assessed every 12 weeks until week 
36. The dose can be adjusted after the evaluation of biochemical control. During 


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the core phase any acromegaly concomitant medication is prohibited. 
Extension Phase (week 36 to week 76) 
Patients will receive the same dose of pasireotide LAR at week 36, which is the  
first dose of study medication in the extension phase. At week 40 the dose can be 
adjusted and acromegaly concomitant medication can be added to the treatment if, 
patients remain uncontrolled. Patients will receive pasireotide LAR 40mg/60mg 
until week 68 for a total of 32 weeks in the extension phase. A mean GH value and 
IGF-1 value will be assessed every 12 weeks until week 72. 
Safety follow-up 
After discontinuation or completion of study treatment, all patients will be followed 
for safety 8 weeks after the last study drug administration. 
Group 2 – Patients treated with octreotide 30 mg from countries where octreotide 
40mg has NOT been approved for the treatment of acromegaly at screening or 
patients treated with octreotide 40mg or lanreotide 120mg - Patients who do not 
have the run-in phase. 
Core Phase (Baseline to week 36) 
Same procedure to be followed as Group1 
Extension Phase (week 36 to week 76) 
Same procedure to be followed as Group1 
Safety follow-up 
Same procedure to be followed as Group1 
Population 
The eligible patient population will consist of inadequately controlled acromegalic 
patients with first generation somatostatin analogues. The study will enroll a total 
number of 112 patients. 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Male and female patients ≥18 years of age 
3. Patients with confirmed diagnosis of inadequately controlled acromegaly as 
evidenced by the following: 
● A mean GH concentration of a 5-point profile over a 2-hour period ≥1 µg/L 
and sex- and age-adjusted IGF-1 >1.3 x ULN 
4. Patients treated with high doses of octreotide LAR (30 mg or 40 mg) or 
lanreotide ATG (120 mg) given as monotherapy for at least 3 months prior to 
screening (Visit 1) 
● Note: Patients currently being treated with octreotide LAR 30mg from 
countries where the 40 mg dose is approved at the time of screening will start a 
run- in phase which they will receive the 3 injections of octreotide LAR 40 mg 
before being evaluated for eligibility for the core phase of the study 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Concomitant treatment with other medications known to reduce GH and or 
IGF-1, other than octreotide LAR or lanreotide ATG, unless it discontinued 3 
months prior to visit 1 (screening) 
2. Patients with compression of the optic chiasm causing any visual field defect 
that requires surgical intervention 
3. Diabetic patients with poor glycaemic control as evidenced by HbA1c >8% at 
visit 1 (screening) 
4. Patients who are hypothyroid and not on adequate replacement therapy 
5. Patients with symptomatic cholelithiasis and acute or chronic pancreatitis 
6. Patients with clinically significant valvular disease 
7. Patients with risk factors for torsade de pointes, i.e. patients with a baseline 
QTcF >450 ms in males, and >460 ms in females 
8. Hypokalaemia, hypomagnesaemia, uncontrolled hypothyroidism, family history 
of long QT syndrome or concomitant medications with known risk of TdP. Drugs 


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with possible risk of TdP should be avoided whenever feasible. 
9. Patients who have congestive heart failure (NYHA Class III or IV), unstable 
angina, sustained ventricular tachycardia, clinically significant bradycardia, 
advanced heart block, history of acute MI less than one year prior to study entry or 
clinically significant impairment in cardiovascular function. 
10. Concomitant disease(s) that could prolong the QT interval such as autonomic 
neuropathy (caused by diabetes or Parkinson’s disease), HIV, cirrhosis, 
uncontrolled hypothyroidism or cardiac failure 
11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic 
persistent hepatitis, or patients with ALT/AST > 2.0 X ULN, serum bilirubin >2.0 X 
ULN 
12. Presence of Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody test 
(anti-HCV) 
13. Patients with serum creatinine >2.0 X ULN 
14. Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L 
15. Patients with the presence of active or suspected acute or chronic uncontrolled 
infection 
16. Patients who have undergone major surgery/surgical therapy for any cause 
within 4 weeks prior to visit 1 (screening) 
17. Patients with active malignant disease within the last five years (with the 
exception of basal cell carcinoma or carcinoma in situ of the cervix) 
18. 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) 
19. History of syncope or family history of idiopathic sudden death 
20. History of immunocompromise, including a positive HIV test result (ELISA and 
Western blot). A HIV test will not be required; however, previous medical history 
will be reviewed 
21. Known hypersensitivity to somatostatin analogues or any other component of 
the pasireotide LAR 
22. Patients who have a history of alcohol or drug abuse in the 6 month period 
prior to receiving pasireotide 
23. Patients who have given a blood donation (of 400 ml or more) within 2 months 
before receiving pasireotide 
24. Patients who have participated in any clinical investigation with an 
investigational drug within 1 month prior to dosing 
25. Patients with any current or prior medical condition that, in the judgment of the 
investigator may interfere with the conduct of the study or the evaluation of the 
study results 
26. 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. 
27. Sexually active males unless they use a condom during intercourse while 
taking drug and for 3 months following last dose of pasireotide 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. 
28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state 
of a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test. 
29. Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and 3 months following the last dose of pasireotide. 
Highly effective contraception methods include: 
● Total abstinence (when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- 
ovulation methods) and withdrawal are not acceptable methods of contraception 
● Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
● Male sterilization (at least 6 months prior to screening). For female subjects 
on the study the vasectomized male partner should be the sole partner for that 


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subject. 
● Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception 
or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository 
In case of use of oral contraception women should have been stable on the same 
pill for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
Investigational and 
reference therapy 
pasireotide LAR 40mg and 60mg, octreotide LAR 40mg 
Efficacy assessments 
● A 5-point GH 
● IGF1 
● Acromegaly symptoms 
● Health-related Quality of Life 
Safety assessments 
● Physical examination 
● Vital signs 
● Laboratory evaluations (hematology, clinical chemistry, liver function testing, 
coagulation, urinalysis) 
● Pregnancy 
● Gallbladder ultrasound 
● Cardiac assessments 
Other assessments 
NA 
Data analysis 
The primary variable is the proportion of patients who achieved GH < 1µg/L and 
IGF-1 < ULN at week 36. This proportion will be provided along with its asymptotic 
(or exact, depending on the sample size) 95% CI. Secondary objectives which are 
measured by proportions will be similarly reported. Descriptive summaries of actual 
and percentage change in GH, actual and percentage change in standardized IGF- 
1, from study baseline to week 36 values will be provided. Change in standardized 
scores as measured by HRQoL and signs and symptoms of acromegaly from 
baseline and week 36 to week 72 will be provided. 
Key words 
acromegaly, pasireotide LAR, octreotide LAR, 5-point GH, IGF-1 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Acromegaly is a rare growth disorder characterized by a clinical syndrome resulting primarily 
from the effects of excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on 
various organ systems. Acromegaly is caused by a GH-secreting pituitary adenoma in more 
than 90% of patients. The prevalence of acromegaly is estimated to be 40 to 70 cases per 
million, with an annual incidence of 3 to 4 new cases per million (Holdaway and Rajasoorya 
1999). However, recent studies suggest that pituitary adenomas may be more prevalent than 
previously thought, and that the prevalence of acromegaly may be well over 100 cases per 
million (Rosario 2011, Daly et al 2006). 
The clinical manifestations of acromegaly are due to the peripheral actions of the GH excess 
and elevated IGF-1 concentrations and/or local tumor mass effect. The symptoms and signs of 
acromegaly can be divided 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 (Becker et al 2000). 
The therapeutic goals in acromegaly are to reduce mortality to the expected age and sex 
adjusted rates by using treatments that remove the tumor mass and/or control its growth and 
restore GH secretion and action to normal. In the past, the biochemical goals of therapy were 
to reduce the circulating IGF-1 levels to normal for age and sex and to reduce serum GH 
concentrations to <2.5 µg/L (mean GH concentration of a 5-point profile within a 2-hour time 
period) or to less than 1 µg/L after an oral glucose load (Giustina et al 2000). Current 
guidelines recommend GH levels <1 µg/L and normalization of IGF-1 as biochemical goals of 
therapy (Melmed et al 2010). 
Treatment modalities for acromegaly include surgery, radiotherapy or treatment with drugs. 
Surgery: transphenoidal surgery is the most frequently recommended treatment however 
surgical effectiveness varies depending on expertise in pituitary surgery, on the size and 
extension of the anatomic mass, and the preoperative levels of GH. 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 throughout their lifespan 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 medications. 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 drugs in rare cases as primary treatment. It is usually reserved for  patients 
who have tumor remaining after surgery, for patients who are not good candidates for surgery 


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because of other health problems; and for patients who do not respond adequately to surgery 
and medication. This treatment generally lowers GH levels over a 2-year timeframe, although 
late effects can occur in some cases. Radiation therapy causes a gradual loss of production of 
other pituitary hormones with time which can result in the undesired effect of 
panhypopituitarism. Loss of vision and brain injury, which have been reported, can be 
complications from radiation treatment. 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: the medical treatment options for acromegaly include somatostatin 
analogues, growth hormone antagonists and dopamine agonists. 
Somatostatin analogues have proven to be safe, well-tolerated and effective and are the 
medical treatment of choice for patients with acromegaly. The currently marketed 
somatostatin analogues are octreotide (Sandostatin®) and lanreotide (Somatuline®). Octreotide 
has been available for over 20 years and is considered the world-wide gold standard medical 
treatment for acromegaly. Other medical treatment options are growth hormone antagonists 
and dopamine agonists. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of pasireotide (SOM230) 
Pasireotide (SOM230) is a cyclohexapeptide, SSA with the following chemical name: (2- 
Aminoethyl)carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4- 
benzyloxybenzyl)-14-(1H-indol-3ylmethyl)-4,7,10,13,16,19-hexaoxo-17- 
phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadeen-2-yl 
ester, 
di[(S)- 
2aminosuccinic acid] salt. Like natural somatostatin and other SSAs, pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors (sst.). Somatostatin is an 
endogenous peptide that modulates a number of exocrine and endocrine secretions. There are 
five known somatostatin receptors: sst1, 2, 3, 4 and 5 as outlined in Table 1-1. When 
compared to octreotide, pasireotide has a binding affinity which is 30-40 times greater for sst1 
and sst5, 5 times greater for sst3, and a comparable affinity for sst2 (Schmid and Brueggen 
2012). Somatostatin receptors are expressed in different tissues under normal physiological 
conditions as well as in many solid tumors, especially in neuroendocrine tumors where 
hormones are excessively secreted, e.g. acromegaly, gastroenteropancreatic neuroendocrine 
tumor (GEP/NET) and Cushing’s disease (Freda 2002, Oberg et al 2004 and Van der Hoek et 
al 2005). A detailed summary of available preclinical data is provided in the current 
[Investigator’s Brochure]. 
Table 1-1 
Binding profiles for octreotide and pasireotide at hsst1-5 (IC50, mol/L) 
 
Compound 
sst1 
sst2 
sst3 
sst4 
sst5 
Octreotide acetate (SMS995) 
2.8x10-7 
3.8x10-10 
7.1x10-9 
>10-6 
6.3x10-9 
Pasireotide (SOM230) 
9.3x10-9 
1.0x10-9 
1.5x10-9 
>10-6 
1.6x10-10 
Ratio of IC50:octreotide 
acetate/pasireotide 
(SMS995/SOM230) 
30 
0.4 
5 
-- 
39 


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1.2.1.1 
Non-clinical experience 
Preclinical data on binding affinity and functional activity in vitro and efficacy on hormone 
secretion in vivo have been obtained with the s.c. formulation in rats, dogs, mice and monkeys. 
Long-term in vivo studies performed using drug application by osmotic mini-pumps (Bruns 
2002, Weckbecker 2002) have shown not only that the inhibitory effect of pasireotide was 
stronger, but also that there was less response escape (Bruns 2002) and (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. 
A detailed summary of available preclinical data is provided in the current [Investigator’s 
Brochure]. 
1.2.1.2 
Clinical experience 
The clinical development program for pasireotide has focused on endocrine-related 
pathologies. Two formulations of pasireotide are currently in development: an immediate 
release formulation for subcutaneous (s.c.) injection and a long-acting release (LAR) 
formulation for i.m. injection. These formulations have been characterized by Phase 1 studies 
in healthy volunteers, and Phase 1 - 3 studies in patients with acromegaly, Cushing’s disease, 
and gastroenteropancreatic neuroendocrine tumors. 
The pasireotide s.c. formulation (Signifor®) is currently approved in more than 50 countries 
worldwide for the treatment of Cushing’s disease. 
The efficacy and safety of pasireotide LAR in acromegaly are primarily derived from two 
large, randomized Phase 3 studies comparing pasireotide LAR with active controls 
(superiority design): 
• Study [SOM230C2305] compared pasireotide LAR with octreotide LAR in medically 
naïve patients with active acromegaly. In this study, pasireotide LAR was shown to be 
significantly superior to octreotide LAR for the treatment of acromegaly in medically 
naïve patients in terms of biochemical control (GH < 2.5 µg/L and normalization of IGF-1 
levels) (31.3% vs. 19.2%; p-value 0.007), providing higher response rate in both de novo 
patients and in patients with prior pituitary surgery (25.7% vs. 17.3% in de novo patients; 
39.4% vs. 21.8% in post-surgical patients). Pasireotide LAR was as effective as octreotide 
LAR in reducing tumor volume, improving acromegaly symptoms and ring size, and 
quality of life [CSOM230C2305]. 
• Study [SOM230C2402] compared double-blind pasireotide LAR 40 mg and pasireotide 
LAR 60 mg with open-label octreotide LAR or lanreotide ATG– active control - in 
patients with inadequately controlled acromegaly. This study showed that both pasireotide 
LAR doses (40 mg and 60 mg) are superior to active control (octreotide LAR 30 mg or 
lanreotide ATG 120 mg). The proportion of responders at Week 24 was significantly 
higher with pasireotide LAR 40 mg (15.4%, 95% CI 7.63, 26.48) and pasireotide LAR 60 
mg (20.0%, 95% CI 11.10, 31.77) than in patients who continued their previous treatment 
(0%) (p=0.0006 and <0.0001 for pasireotide LAR 40 mg and 60 mg, respectively). Both 
pasireotide doses were superior to active control in normalizing IGF-1 levels and in 


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reducing GH to <2.5 µg/L. The proportion of patients with a reduction of GH to <2.5 µg/L 
at Week 24 was highest in the pasireotide LAR 60 mg arm (43.1%), followed by the 
pasireotide LAR 40 mg arm (35.4%), and the active control arm (13.2%) The proportion 
of patients who achieved normalization of IGF-1 at Week 24 (key secondary efficacy 
variable) was significantly higher in both pasireotide arms (24.6% and 26.2% responders) 
compared to the active control arm (zero responders) 
The safety of pasireotide has been well characterized in 491 patients with acromegaly (419 
patients using the LAR formulation, and 72 patients using the s.c. formulation). In addition, 
pasireotide s.c. and LAR formulations have been used in over 750 other subjects including 
healthy volunteer and special safety studies. The safety findings in patients with acromegaly 
are in line with expected pharmacodynamic effects of pasireotide, based on both preclinical 
and clinical experience, and are consistent with the known side effects of approved SSAs 
(with the exception of an increased incidence and magnitude of hyperglycemia) 
A detailed summary of the clinical data (including safety and PK) is provided in the current 
[Investigator’s Brochure]. 
 
2 
Rationale 
2.1 
Study rationale and purpose 
Pasireotide (SOM230) is a second generation SSA with a higher affinity to a greater number 
of somatostatin receptors compared to octreotide and lanreotide, which results in improved 
efficacy in acromegaly. Pituitary GH-secreting tumors primarily express SSTR2 and 5 (and to 
a lesser extent SSTR1 and 3). The currently available SSAs octreotide and lanreotide have 
high affinity for SSTR2, and low affinity for the remaining receptor subtypes. Although 
SSTR2 is considered the pivotal receptor subtype for regulation of GH secretion, its 
expression is variable and this may at least in part explain resistance or partial response to 
octreotide or lanreotide therapy observed in some patients. Recent data suggest that 
approximately 50% of the patients are not biochemically controlled with currently available 
SSAs (Carmichael et. all 2014). In a recently completed phase III study in medically naive 
acromegalic patients, the largest in this population, 19% of patients treated with octreotide 
LAR achieved biochemical control after one year of treatment. 
Results of clinical studies currently available with pasireotide indicate that it is a safe and 
effective treatment in patients with acromegaly. The purpose of this study is to evaluate the 
efficacy and safety of pasireotide LAR, in patients with acromegaly who are inadequately 
controlled after a minimum of 3 months with maximal approved doses of first generation 
somatostatin analogues (octreotide LAR 30 mg or 40 mg– depending on the country - or 
lanreotide ATG 120mg). The recently completed SOM230C2402 study in biochemically 
uncontrolled patients after at least 6 months of treatment with high doses of octreotide LAR or 
lanreotide ATG showed that no further benefit was achieved when this therapy was continued 
with patients achieving neither biochemical control nor normal IGF-1. Therefore, an earlier 
treatment change to pasireotide LAR might be beneficial for these patients. 
In addition, a new consensus has been reached on the definition of controlled acromegaly: 
GH<1.0 µg/L in association with normal IGF-I levels (Giustina et al 2014). Therefore, the 


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new study will enrol patients that satisfy the new criteria of uncontrolled acromegaly – 
GH≥1.0 µg/L and IGF-I>1.3xULN - and it will provide data not only in the patients with a 
GH>2.5 µg/L but also, for the first time, in the patients with a GH level between 1.0 and 2.5 
µg/L that are known to represent a large group of patients with inadequately controlled 
acromegaly. 
2.2 
Rationale for the study design 
The study is an open-label, single-arm; multi-centre international study to evaluate the safety 
and the efficacy of pasireotide LAR in patient with inadequately controlled acromegaly after a 
minimum of 3 months with high doses of the first generation somatostatin analogues. 
A single-arm, open-label study design was chosen since the objective of this study is to obtain 
further data of the efficacy and safety of pasireotide LAR in patients with acromegaly, but not 
as confirmation of efficacy. Efficacy of pasireotide in patients not controlled with other 
somatostatin analogues was already demonstrated in Study C2402, a double-blinded 
controlled study, in which patients randomized to the active control (octreotide LAR 30mg or 
lanreotide ATG 120mg) did not achieve biochemical control with further treatment whereas 
patients randomly allocated to pasireotide LAR 40 mg or 60 mg were able to achieve 
biochemical control for the very first time. Additionally, the natural history of the disease is 
well understood and placebo effects on efficacy evaluations are negligible. 
The primary objective of the study was chosen based on the new published criteria for 
diagnosis and management of acromegaly (Giustina et al 2014). Elevated GH and IGF-1 
levels are predictors of mortality, and lowering GH and normalizing IGF-1 results in mortality 
rates similar to those expected in the general population. The definition of a safe GH level  
was updated, due to the new more sensitive and specific assays. This new guideline 
recommends reducing GH to levels as close to normal as possible. According to this 
consensus document optimal disease control is now defined as IGF-1 level in the age-adjusted 
normal range and a GH level less than 1.0 µg/L. This data will complement the results 
obtained in study C2402, where patients achieving the previous definition of biochemical 
control (i.e. GH levels <2.5µg/L and normalization of IGF-1) were reported. 
2.3 
Rationale for dose and regimen selection 
The pasireotide LAR dose for acromegaly patients is based on the study CSOM230C2305. It 
was a multi-center, randomized, blinded study to assess the safety and efficacy of pasireotide 
LAR vs. octreotide LAR in patients with active acromegaly. The results of the study 
demonstrated that pasireotide LAR 40 mg every 28 days is superior to octreotide LAR 20 mg 
every 28 days in providing biochemical control in patients with medically naïve acromegaly 
i.e., suppression of GH levels to < 2.5 µg/L and normalization of IGF-1 [CSOM230C2305]. 
Patients enrolled in this study will start with pasireotide LAR 40 mg every 28days. 
Study [CSOM230C2402] demonstrated that both doses of pasireotide LAR 40mg and 60 mg 
are efficacious in patients inadequately controlled on octreotide LAR and lanreotide ATG. 
Based on these data, patients should be evaluated for clinical benefit 3 months (84 days) after 
the start of pasireotide LAR 40 mg (i.m.) therapy. A dose increase to 60 mg every 28 days 
will be mandated after 12 weeks of pasireotide LAR treatment if adequate levels of GH and 


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IGF-1 are not observed with the 40 mg dose (no reduction of mean GH level to < 1.0µg/L and 
no decrease of IGF-1 to within normal limits (age and sex related) and provided there are no 
safety concerns. 
Management of suspected adverse reactions may require temporary dose reduction of 
pasireotide LAR. Dose reduction by decrements of 20 mg every 28 days is recommended. 
Dose increase and dose reduction is to be based on investigator’s assessment of risk and 
benefit for the patient. 
In the case of octreotide LAR, in order to be enrolled in the study, patients should have been 
treated with 30 or 40 mg for at least three months and not achieved biochemical control. 
Octreotide LAR 30mg has been approved and available for over 20 years: octreotide LAR 
40mg is not approved/available in all countries. Patients enrolled in countries where the 40mg 
dose is approved, must be treated with this dose prior to enrollment or during the run-in phase 
of the study. 
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 
To evaluate the efficacy of pasireotide LAR in patients 
with acromegaly who are inadequately controlled with 
maximal approved doses of currently available 
somatostatin analogues, as measured by the 
proportion of patients with GH <1µg/L and IGF-1 <ULN 
at week 36 
Proportion of patients who achieved GH <1µg/L and 
IGF-1 <ULN at week 36. 
 
 
Supporting Analysis for Primary 
Refer to Section 10.4.4 
To assess the proportion of patients achieving GH 
<1µg/L and IGF-1 <ULN at week 36 by GH level at 
screening. 
Proportion of patients who achieved GH <1µg/L and 
IGF-1 <ULN at week 36 in patients having GH level at 
screening between 1 µg/L and 2.5 µg/L, and in 
patients having GH level at screening >2.5 µg/L 
 
 
Secondary- core phase 
Refer to Section 10.5.1 
To assess the changes in mean GH from study 
baseline to week 36 
To assess the changes in standardized IGF-1 from 
study baseline to week 36 
To assess the proportion of patients achieving GH <1 
µg/L and IGF-1 <ULN at weeks 12 and 24 overall and 
by GH level at screening 
To assess the proportion of patients achieving GH 
<1µg/L at weeks 12, 24 and 36, overall and by GH 
level at screening 
To assess the proportion of patients achieving IGF-1 
levels <ULN at weeks 12, 24 and 36 
To evaluate the tolerability and safety profile of 
pasireotide LAR 
Changes in mean GH from study baseline to week 36. 
 
Changes in standardized IGF-1 from study baseline to 
week 36. 
Proportion of patients who achieved GH <1µg/L and 
IGF-1 <ULN at week 12 and 24 overall and by GH 
level at screening. 
Proportion of patients who achieved GH <1µg/L at 
week 12, 24 and 36 overall and by GH level at 
screening. 
Proportion of patients who achieved IGF-1 <ULN at 
week 12, 24 and 36. 
Toxicity will be assessed using the National Cancer 
Institute-Common Toxicology Criteria Adverse Events 
version 4 (NCI-CTCAE v.4.03) and for laboratory 
assessments that include biochemistry, hematology, 
urinalysis; special safety assessments that include the 
regular monitoring and recording of blood glucose, 
  
insulin, HbA1c, GH and IGF-1, thyroid and liver 
 


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Objective 
Endpoint 
Analysis 
function tests, gallbladder examinations and ECGs. 
Concomitant medications/Significant nondrug 
therapies will be assessed from study enrollment until 
the safety follow-up. 
 
To evaluate the effect of pasireotide LAR on HRQoL 
and signs and symptoms of acromegaly from baseline 
to weeks 12, 24 and 36 
Change in scores as measured by AcroQoL, EQ-5D- 
5L and signs and symptoms of acromegaly from 
baseline to weeks 12, 24 and 36 
 
 
Secondary – extension phase 
Refer to Section 10.5.2 
To assess the proportion of patients achieving IGF-1 
<ULN at weeks 48, 60 and 72 
To assess the proportion of patients achieving GH <1 
µg/L and IGF-1 <ULN at weeks 48, 60 and 72 by 
treatment with pasireotide LAR alone or with 
concomitant medications used to treat acromegaly 
To assess the proportion of patients achieving GH <1 
µg/L at weeks 48, 60 and 72 by treatment with 
pasireotide LAR alone or with concomitant 
medications used to treat acromegaly 
To evaluate the long term tolerability and safety profile 
of pasireotide LAR 
 
 
 
 
 
 
 
To evaluate the long term effect of pasireotide LAR on 
HRQoL and signs and symptoms of acromegaly, from 
baseline and week 36 to week 72 
Proportion of patients who achieved IGF-1 <ULN at 
weeks 48, 60 and 72 
Proportion of patients who achieved GH <1 µg/L and 
IGF-1 <ULN at weeks 48, 60 and 72 by treatment with 
pasireotide LAR alone or with concomitant 
medications used to treat acromegaly 
Proportion of patients who achieved GH <1 µg/L at 
weeks 48, 60 and 72 by treatment with pasireotide 
LAR alone or with concomitant medications used to 
treat acromegaly 
Toxicity will be assessed using the National Cancer 
Institute-Common Toxicology Criteria Adverse Events 
version 4 (NCI-CTCAE v.4.03) and for laboratory 
assessments that include biochemistry, hematology, 
urinalysis; special safety assessments that include the 
regular monitoring and recording of blood glucose, 
insulin, HbA1c, GH and IGF-1, thyroid and liver 
function tests, gallbladder examinations and ECGs. 
Concomitant medications/Significant nondrug 
therapies will be assessed from study enrollment until 
the safety follow-up. 
Change in scores as measured by AcroQoL, EQ-5D- 
5L and signs and symptoms of acromegaly from 
baseline to week 72 and from week 36 to week 72. 
 


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4 
Study design 
4.1 
Description of study design 
This is a phase IIIb multicenter, open-label; single arm study to evaluate the efficacy and 
safety of pasireotide LAR 40 mg and 60 mg in patients with inadequately controlled 
acromegaly with maximal doses of first generation somatostatin analogues. The study will 
enroll inadequately controlled patients by high doses of first-generation somatostatin 
analogues given for at least 3 months. 
Figure 4-1 
Flow Chart for Group 1 and Group 2 Patients 
 
Group 1 – It consists of patients treated with octreotide LAR 30 mg from countries where 
octreotide LAR 40mg is approved for the treatment of acromegaly at the time of screening – 
These patients will start a run-in phase to receive 40mg octreotide before being considered 
eligible to enter the core treatment phase. 


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 Pts treated with octreotide 
30mg from the countries 
where octreotide 40mg has 
been approved at the 
screening 
 
Figure 4-2 
Study Design; Group 1 
 
Screening 
Core 
*Extension 
FU 
 
*Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 
Run-In phase (Screening to Baseline) 
Patients treated with octreotide LAR 30 mg who meet all inclusion criteria and no exclusion 
criteria will start treatment with octreotide LAR 40 mg in the run-in phase. Patients must have 
been treated with octreotide LAR 30 mg for at least three months before the screening visit. 
Patients will start treatment in the run-in phase and will receive octreotide LAR 40 mg every 4 
weeks for 3 months. A mean GH value and IGF-1 value will be assessed after the third 
injection. 
Patients who are achieving biochemical control will be considered screening failure and they 
will not qualify for the core phase of the study. They will continue treatment with octreotide 
LAR 40 mg outside the frame of this study. 
Core Phase (Baseline to Visit 777) 
Patients treated with octreotide LAR 40 mg in the run-in phase that meet all inclusion criteria 
and no exclusion criteria will be enrolled in the core phase of the study. The evaluation at the 
last visit of the run-in phase must be used for the eligibility assessment. Patients will start 
treatment with pasireotide LAR 40 mg every 4 weeks. At week 12, the mean GH value and 
IGF-1value will be assessed. Patients who have not achieved biochemical control by week 12 
and do not have any tolerability issues with pasireotide LAR 40 mg will have the dose 
increased to 60 mg. Patients who have achieved biochemical control by week 12 will maintain 
a dose of pasireotide LAR 40 mg. A mean GH value and IGF-1 value will be assessed every 
12 weeks until Visit 777. At weeks 16 and 28, the investigator will be able to adjust the dose 
based on the achievement of biochemical control and drug tolerability. If tolerability issues 
occur, the dose can be decreased in 20 mg. Once the tolerability issue resolves, the patients 
should return to the dose previously received. Patients will be treated for a total of 36 weeks 
during the core phase. During this period any concomitant medication for the treatment of 
acromegaly is prohibited. Patients are required to complete a core phase completion visit 4 
weeks after the last dose of pasireotide LAR is administered. Patients who discontinue from 
Safety follow up 
pasireotide 40mg or 
60mg 
pasireotide 
40mg or 
60mg 
pasireotide 
40mg 
Run-In 
octreoti 
de 40mg 
Screening 


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the core phase are also required to complete the core phase completion visit 4 weeks after 
receiving the last pasireotide LAR dose. 
Extension Phase (Visit 18 to Visit 778) 
Patients who have completed all visits of core phase and have completed all the assessments 
at the core phase completion visit (= Visit 777) can move into the extension phase. The core 
phase completion visit performed at Visit 777, will also be the first visit (= Visit 18) of the 
extension phase. At Visit 18, the patients will receive the same dose of pasireotide LAR that 
they received at week 32 (= Visit 17). At week 40 (= Visit 19), the investigator will decide the 
treatment regimen and the pasireotide dose based on the achievement of biochemical control 
at Visit 777. Patients achieving biochemical control at the end of the core phase will continue 
pasireotide LAR monotherapy at the same dose of the core phase. Patients who are 
uncontrolled at the end of the core phase will continue pasireotide LAR 60 mg and they will 
be allowed to receive concomitant treatment with medications used to treat acromegaly based 
on the investigator’s clinical judgment. GH and IGF-1 levels will be assessed every 12 weeks 
until week 72. At weeks 52 and 64, the investigator will be able to adjust the dose of 
pasireotide LAR and the regimen of the concomitant medication used to acromegaly based on 
the patients achievement of biochemical control and drug tolerability. Patients will be treated 
for a total of 32 weeks in the extension phase and receive the last dose of study treatment at 
week 68 (= Visit 26). Patients are required to complete an extension phase completion visit 4 
weeks after the last dose of pasireotide LAR is administered. Patients who prematurely 
discontinue from the extension phase are also required to complete the extension phase 
completion visit 4 weeks after receiving the last dose of pasireotide LAR 
Safety follow-up 
After discontinuation from the study or completion of study treatment either at the core phase 
or extension phase of the study, all patients will be followed for safety for 8 weeks after the 
last study drug administration. This visit can be performed by phone, a study visit for follow- 
up is not mandatory. 
Group 2 – It consists of patients treated with octreotide LAR 30 mg from countries where 
octreotide 40mg is NOT yet approved at the time of screening. This group also include 
patients already treated with octreotide LAR 40 mg or lanreotide ATG 120 mg. Patients 
should have been treated with the first generation SSAs for at least 3 months prior to 
screening. Eligible patients can directly enter the core treatment phase of the study. –A run-in 
phase is not required for this patient population. 


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Figure 4-3 
Study Design; Group 2 
 
Screening 
Core 
*Extension 
FU 
 
* Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 
Core Phase (Baseline to Visit 777) 
Please refer to the core phase for Group 1. 
Extension Phase (Visit 18 to Visit 778) 
Please refer to the extension phase for Group 1. 
Safety follow-up 
Please refer to Safety follow-up for Group 1. 
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 will occur when all patients have completed their study 
completion visit and the follow up visit as per Table 7-1 and Table  7-2 (core phase)  and 
Table 7-3 (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 7.1.5 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. 
 Pts treated with 
octreotide 30mg from 
the countries where 
octreotide 40mg has 
NOT been approved 
at the screening 
 Pts treated with 
octreotide 40mg 
 Pts treated with 
lanreotide 120mg 
pasireotide 
40mg 
pasireotide 
40mg or 
60mg 
pasireotide 40mg or 
60mg 
Safety follow up 
Screening 


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5 
Population 
5.1 
Patient population 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Male and female patients ≥ 18 years of age 
3. Patients with confirmed diagnosis of inadequately controlled acromegaly as evidenced by 
the following: 
• A mean GH concentration of a 5-point profile over a 2-hour period ≥ 1 µg/L and sex- 
and age-adjusted IGF-1 >1.3 x ULN 
4. Patients treated with high dose of octreotide LAR (30 mg or 40 mg) or lanreotide ATG 
(120 mg) given as monotherapy for at least 3 months prior to screening (Visit 1) 
• Note: Patients currently being treated with octreotide LAR 30 mg from countries 
where the octreotide LAR 40 mg dose is approved at the time of screening will start a 
run- in phase in which they will receive the 3 injections of octreotide LAR 40 mg 
before being evaluated for eligibility for the core phase of the study 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Concomitant treatment with other medications known to reduce GH and or IGF-1, other 
than octreotide LAR or lanreotide ATG, unless discontinued 3 months prior to visit 1 
(screening) 
2. Patients with compression of the optic chiasm causing any visual field defect that requires 
surgical intervention 
3. Diabetic patients with poor glycaemic control as evidenced by HbA1c >8% at Visit 1 for 
Group 2 and at both Visit 1 and Visit 5 for Group 1 
4. Patients who are hypothyroid and not on adequate replacement therapy 
5. Patients with symptomatic cholelithiasis and acute or chronic pancreatitis 
6. Patients with clinically significant valvular disease 
7. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >450 
ms in males, and >460 ms in females 
8. Hypokalaemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long 
QT syndrome or concomitant medications with known risk of Torsades de pointes (TdP). 
Drugs with posible risk of TdP should be avoided whenever feasible. 
9. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, 
history of acute MI less than one year prior to study entry or clinically significant 
impairment in cardiovascular function 


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10. Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy 
(caused by diabetes or Parkinson’s disease), HIV, cirrhosis, uncontrolled hypothyroidism 
or cardiac failure 
11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent 
hepatitis, or patients with ALT/AST > 2.0 X ULN, serum bilirubin >2.0 X ULN 
12. Presence of Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody test (anti-HCV) 
13. Patients with serum creatinine >2.0 X ULN 
14. Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L 
15. Patients with the presence of active or suspected acute or chronic uncontrolled infection 
16. Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks 
prior to visit 1 (screening) 
17. Patients with active malignant disease within the last five years (with the exception of 
basal cell carcinoma or carcinoma in situ of the cervix) 
18. 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) 
19. History of syncope or family history of idiopathic sudden death 
20. History of immunocompromise, including a positive HIV test result (ELISA and Western 
blot). A HIV test will not be required; however, previous medical history will be reviewed 
21. Known hypersensitivity to somatostatin analogues or any other component of the 
pasireotide LAR 
22. Patients who have a history of alcohol or drug abuse in the 6 month period prior to 
receiving pasireotide 
23. Patients who have given a blood donation (of 400 ml or more) within 2 months before 
receiving pasireotide 
24. Patients who have participated in any clinical investigation with an investigational drug 
within 1 month prior to dosing 
25. Patients with any current or prior medical condition that, in the judgment of the 
investigator may interfere with the conduct of the study or the evaluation of the study 
results 
26. 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 
27. Sexually active males unless they use a condom during intercourse while taking drug and 
for 3 months following last dose of pasireotide 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. 
28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test 
29. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and 3 months following last dose of pasireotide. Highly effective 
contraception methods include: 


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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject 
• Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential. 
 
6 
Treatment 
6.1 
Study treatment 
Pasireotide LAR 40 mg or 60 mg will be administered as intra-muscular (i.m.) injections  
every 4 weeks for the core and the extension phases of the study. Patients will begin their 
treatment with pasireotide LAR 40mg every 4 weeks. Dose down-titrations are permitted for 
patients who do not tolerate the protocol-specified dosing schedule. These dose adjustments 
are permitted in order to allow the patient to continue the study treatment. If tolerability issues 
occur, the dose is permitted to decrease by 20 mg. Please refer to Section 6.2.1 for further 
instructions of dose adjustments. Octreotide LAR 40mg will be administered as intra- 
muscular injections every 4 weeks for the run-in phase if it applies. Dose up-titration of 
pasireotide LAR to 60mg will be allowed after 12weeks of treatment (i.e. after 3 injections) in 
patients who do not achieve adequate biochemical control and the 40mg is well tolerated. 
Prior to dose escalation it is recommended that glucose homeostasis is adequately controlled 
and that patients with HbA1c >8% should not have the dose of the pasireotide LAR increased 
to 60 mg. 


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6.1.1 
Dosing regimen 
Table 6-1 
Dose and treatment schedule 
Pharmaceutical form and 
 
 
 
Frequency and/or 
Study treatments 
route of administration 
Dose 
Regimen 
 
 
pasireotide 
intra-muscular 
20mg, 40mg, 60 mg 
every 4 weeks 
octreotide 
intra-muscular 
40mg 
every 4 weeks 
Group 1 – Dosing Regimen 
Figure 6-1 
Group 1: Dose Regimen 
 
* Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 


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Group 2 – Dosing Regimen 
Figure 6-2 
Group 2: Dose Regimen 
 
* Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 
6.1.2 
Ancillary treatments 
Not applicable. 
6.1.3 
Rescue medication 
Not applicable. 
6.1.4 
Guidelines for continuation of treatment 
For guidelines for continuation of treatment, refer to Section 6.2 Dosing modification. 
6.1.5 
Treatment duration 
Run-in Phase (Group 1 only) 
Patients in this group will receive octreotide LAR 40 mg for 16 weeks in total. After the third 
injection, biochemical control will be assessed for the eligibility criteria. 
Core phase 
Patients will continue to receive pasireotide LAR 40 mg or 60 mg until week 36, when all 
assessments will be done(=Visit 18), receiving the last injection for the core phase at week 32 
(=Visit17). 


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Extension phase 
At the end of the core phase, patients will have the option to continue study treatment with 
pasireotide LAR until week 68 (=Visit 26). Patients who are not biochemically controlled 
during the extension will be allowed to receive concomitant treatment with medications used 
to treat acromegaly. 
Patients can continue with study treatment until pasireotide LAR is commercially available 
and reimbursed in their respective country or until 68 weeks whichever occurs first. If 
pasireotide LAR is not commercially available and reimbursed and the patient is  still 
receiving clinical benefit at 68 weeks as assessed by the investigator, the patient will have the 
opportunity to receive pasireotide LAR via a roll over study or a local access program if 
available. 
6.1.6 
Dose escalation guidelines 
Not applicable. 
6.2 
Dose modifications 
6.2.1 
Dose modification and dose delay 
Patients will begin their treatment with pasireotide LAR 40 mg every 4 weeks. Dose up- 
titration of pasireotide LAR to 60 mg will be allowed after 12 weeks of treatment (i.e. after 3 
injections) in patients who do not achieve adequate biochemical control and the 40 mg is well 
tolerated. Prior to dose escalation it is recommended that glucose homeostasis is adequately 
controlled and that patients with HbA1c >8% should not have the dose of the pasireotide LAR 
increased to 60 mg. 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. If tolerability issues 
occur, the dose is permitted to decrease by 20 mg. Once the tolerability issue resolves, the 
dose should be returned to the one prior to  the  dose  reduction.  For  guidance  refer  to  
Table 6-2. 


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Table 6-2 
Guideline for treatment of patients experiencing adverse events 
LAR 
treatment 
Adverse event 
Action 
Pasireotide LAR i.m. 
AE CTC grade ≤ 2 
No drug adjustments 
AE CTC grade ≥ 3 and 
assessed as study drug related 
Reduce pasireotide LAR i.m. dose by 
20 mg 
If the AE improves to grade ≤ 2 before the next 
administration, increase dose back to the prior dose. 
If the dose is increased and the AE recurs at a grade 
≥ 3, the dose should be reduced again. The patient 
should stay on this lower dose if clinical benefits are 
maintained. No further dose titrations are allowed. 
If the AE does not improve to grade ≤ 2, the dose is 
to be reduced further if clinical benefits are 
maintained. If the AE does not improve to grade ≤ 2 
on the minimum study dose, the treatment should be 
stopped. The patient should be discontinued and 
followed up for safety. 
 
For the management of hyperglycemia, QT prolongation and LFT increases refer to specific instructions provided 
  in Section 6.2.2.3, Section 6.2.2.1, and Section 6.2.2.2. 
 
In case of over-efficacy (i.e. IGF-1 levels below the LLN), the dose can be reduced based on 
the investigator’s judgment. 
These changes must be recorded on the Dosage Administration Record CRF. 
6.2.2 
Follow-up for toxicities 
6.2.2.1 
QT-prolongation 
The results of the ECGs, cardiac examination and any recommendation provided by the 
cardiologist must be evaluated by the investigator to determine whether the patient should 
continue in the trial or not (discontinuation criteria to be followed). 
6.2.2.1.1 480 msec < QTcF ≤ 500 msec 
If at any visit a 480 msec < QTcF ≤ 500 msec is observed for a first time for a patient at a 
given dose level, the following steps need to be taken (refer to Figure 6-3): 
A cardiology consultation must be sought as soon as practical but within 7 days of the initial 
finding of abnormal ECG and the cardiologist must re-evaluate the ECG. The study treatment 
will be postponed until a cardiologist has re-evaluated the ECG. 
• If a QTcF > 480 msec is NOT confirmed, no further action needs to be taken. 
• If a QTcF > 480 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). 


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• If following the examination by the cardiologist, the investigator considers that there 
is no acute cardiovascular safety risk the patient could continue to receive study 
medication. 
Figure 6-3 
QT prolongation flowchart: 480 msec less than QTcF less than or 
equal to 500 msec 
 


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6.2.2.1.2 QTcF > 500msec 
If at any visit a QTcF > 500msec is observed, the following steps need to be taken (refer to 
Figure 6-4): 
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 > 500msec, the patient has to postpone study treatment until a cardiologist has re-evaluated 
the ECG. The re-evaluation needs to be done as soon as practical but within 7 days of the 
initial finding of abnormal ECG. 
• If the cardiologist confirms a mean QTcF > 500msec, the patient has to be withdrawn 
from the study. 
• Otherwise and if the cardiologist confirms that at least one ECG shows a QTcF > 480msec, 
the cardiac assessments described for a confirmed QTcF > 480msec need to be followed. 


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Figure 6-4 
QT prolongation flowchart; QTcF greater than 500msec 
 


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6.2.2.2 
Hepatic Safety management 
Patients who develop increased transaminase levels should be monitored with a second liver 
function evaluation to confirm the finding. If the finding is confirmed, the patient should be 
followed with frequent liver function monitoring until values return to pre-treatment levels. 
If any of the criteria below are observed at any scheduled or unscheduled visit the sponsor 
should be notified immediately upon awareness and the hepatic safety follow up should be 
performed within 72 hours of awareness of the abnormality: 
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN 
• ALT or AST > 5 x ULN and ≤ 8 x ULN 
• ALT or AST > 8 x ULN 
Hepatic Safety Follow up: 
• Perform liver-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including over-the-counter medications, inter-current 
illness, etc.) 
• Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if 
total bilirubin is > 2.0 x ULN), Albumin, PT (INR), ALP, and GGT. These tests should be 
monitored every 3-4 days until resolution or return to baseline status. 
• Perform hepatitis screen: anti-HAV, IgM (to confirm acute hepatitis A), HbsAg, Anti-HBc, 
anti-HCV (if positive, PCR viral load should be assessed), Anti-HEV, ANA antibodies, 
anti-smooth muscle anti-bodies, CMV and EBV 
• Perform abdominal ultrasound (liver and biliary tree) 
Patients should be managed according to the LFT algorithm Figure 6-5 Patients may need to 
be discontinued if the abnormal liver function criteria are met  upon LFT retesting or 
immediately discontinued without LFT retesting in the case of ALT or AST > 8 times the 
upper limit of normal (see discontinuation criteria Section 7.1.5.1). Progress reports of the 
event should be maintained until resolution or return to baseline status. 
If any of these criteria are met and deemed an AE by the investigator, the event must be 
recorded on the Adverse Event CRF page; if the event is deemed serious by the investigator, 
then the SAE form should be completed. In addition, any clinically significant findings from 
the physical examination should be recorded on the Adverse Event CRF page. 


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Figure 6-5 
LFT management algorithm 
6.2.2.3 
Hyperglycemia 
Hyperglycemia is known to be associated with the treatment of somatostatin analogues (SSA). 
Clinical studies of pasireotide in healthy volunteers and in patients with Cushing’s disease, 
acromegaly or carcinoid syndrome have reported transient, asymptomatic increases in fasting 
and postprandial glucose levels. Two clinical studies have been conducted [SOM230B2216] 
and [SOM230B2124] in healthy volunteers to further understand the mechanism of 
pasireotide-induced hyperglycemia and to evaluate the potential clinical utility of anti- 
diabetes agents in the management of pasireotide-induced hyperglycemia. Data from 
[SOM230B2216] study indicate that pasireotide decreases insulin secretion, particularly in the 
postprandial period, as well as the GLP-1/GIP secretion. Results from [SOM230B2124] study 
suggest that the incretin-based therapies (GLP-1 analogues and DPP-4 inhibitors) may have 
the best potential to manage the hyperglycemia associated with pasireotide. Some patients in 
[SOM230B2305], [SOM230C2305] and the [SOM230C2402] trials required insulin to treat 
their hyperglycemia. 
Prior to dose escalation it is recommended that glucose homeostasis is adequately controlled 
and that patients with HbA1c >8% should not have the dose of the pasireotide LAR increased 
to 60 mg. 


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6.2.2.3.1 Self-monitoring of blood glucose 
The principal investigator is to educate the patient on the signs and symptoms of 
hyperglycemia. Patients must monitor their fasting blood glucose by finger stick at home at 
least 3 times per week for the first 4-week treatment with pasireotide or when the dose of 
pasireotide is increased. If a patient does not have any fasting values above 100mg/dL, 
monitoring can be decreased to at least 2 times per week from week 4 to week 12 and 1 time 
every week for the rest of the study. If glucose values remain normal (below 100mg/dL), 
monitoring is at the investigator’s discretion during the extension phase (where it is 
applicable). If any values are observed above 100mg/dL, the guidelines in Figure 6-6 are to be 
followed. These guidelines are based on the current recommendations from the 2012 ADA 
and EASD aiming at a glycemic treatment goal of FPG < 130mg/dL (<7.2mmol/L). 
Appropriate actions such as initiation of anti-hyperglycemic therapy (and referral to diabetes 
specialist) are to be taken by the investigator as outlined on Figure 6-6. If fasting blood 
glucose values dictate initiation of anti-hyperglycemic treatment (i.e. confirmed > 130mg/dL 
by self-monitoring), a fasting plasma glucose sample using the central laboratory is to be 
collected prior to initiation of anti-hyperglycemic treatment; however, treatment may be 
initiated using local laboratory results. 
It is recommended that the patients be encouraged to keep a diary for their blood glucose for 
appropriate management throughout the study and present the collected data to their 
physician/diabetes specialist for evaluation. These data will not be collected by the sponsor. 
In addition to self-monitoring, fasting plasma glucose and HbA1c will be collected at study 
visits per Table 7-1 to Table 7-3. Close and frequent monitoring of blood glucose is needed 
during pasireotide treatment. Intervention for hyperglycemia is to be implemented in any 
patient meeting any of the following criteria: FPG > 130mg/dL or HbA1c ≥ 6.5%. 
Patients with FPG > 160mg/dL or HbA1c > 7.5% despite adjustment of antidiabetic therapy 
should be referred to a diabetes specialist (or earlier per investigator’s judgment). 
As outlined in Table 6-2, patients with grade 3 hyperglycemia (FPG value > 250mg/dL; >13.9 
mmol/L) at any point in the study should have the dose of pasireotide decreased. Patients who 
in spite of appropriate therapeutic interventions and despite dose reduction of study drug 
develop uncontrolled diabetes mellitus and/or consistently high blood glucose values: FPG ≥ 
240mg/fdL (13.3 mmol/L) or HbA1c value ≥ 10% will require study treatment 
discontinuation. 


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Figure 6-6 
Fasting SMBG Guidance 
 
 
6.2.3 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Refer to Section 7.1.5 for details. 
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced adverse events, i.e., hyperglycemia, QT 
prolongation and LFT increases are provided in Section 6.2.2. Refer to preclinical toxicity and 
or clinical data found in the current [Investigator’s Brochure]. 
6.3 
Concomitant medications 
6.3.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. 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 
and Significant Non-Drug Therapies CRF. 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 three months prior to enrollment and 
must agree to continue the oral conceptive throughout the course of the study and for 12 
weeks after the last dose of study drug. 
Repeat within the 
next 24 hours 
Repeat within the 
next 24 hours 


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6.3.1.1 
Permitted concomitant therapy requiring caution and/or action 
Acromegaly concomitant therapy is allowed only during the extension period for patients who 
do not achieve biochemical control. 
Otherwise, investigators should discourage patients from taking any medication during the 
study, with the exception of medications that are required to treat an adverse event. 
6.3.2 
Prohibited concomitant therapy 
The use of concomitant medication with a known risk of TdP is prohibited. In case a patient 
needs to take medication with a known risk of TdP, it will require study drug discontinuation 
prior to starting the medication. Please see Appendix 3 for further guidance on medication 
with a known risk to TdP. 
The following washouts are to be followed prior to screening 
1. Dopamine agonists (bromocriptine, cabergoline) or pegvisomant (INN); 12 weeks 
2. Pasireotide s.c.: 12 weeks 
3. Pasireotide LAR: 12 weeks 
6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject Number (Subject No.) consists 
of the Center Number (Center No.) (As assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form the patient is assigned to the next 
sequential Subject No. available to the investigator. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be 
changed, even if the patient is re-screened. If the patient fails to be randomized or start 
treatment for any reason, the reason will be entered into the Screening Log. IRT must be 
notified within 2 days that the patient was not enrolled. 
6.4.2 
Treatment assignment or randomization 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be assigned to 
pasireotide LAR 40 mg treatment arm. The investigator or his/her delegate will call or log on 
to the IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT 
will assign a patient number to the patient, which will be used to link the patient to a treatment 
arm and will specify a unique medication number but only for the pasireotide LAR treatment. 
6.4.3 
Treatment blinding 
Not applicable. 


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6.5 
Study drug preparation and dispensation 
Detailed instructions on the use of pasireotide LAR for i.m. injection and octreotide LAR 
40mg are provided in the pharmacy manual. 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
Pasireotide LAR will be provided as microparticles powder in vials containing nominally 20, 
40 and 60 mg of Pasireotide (as free base) and solvent for suspension for injection in ampules 
for the reconstitution of the LAR microparticles. 
Octreotide LAR 40 mg will be locally supplied to the site. 
6.5.1 
Study drug packaging and labeling 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms and a [specific visit or 
dose/dose level]. Responsible site personnel will identify the study treatment package(s) to 
dispense to the patient by using the IRT and obtaining the medication number(s). Site 
personnel will add the patient number on the label. Immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that patient’s unique patient 
number. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient. 
Table 6-3 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
 
Pasireotide LAR 
Microparticle powder for suspension 
in vial 
Solution for suspension (vehicle) in 
ampoule or pre-filled syringe 
Labeled as ‘SOM230’ LAR (once/28days) 
Labeled as ‘SOM230 Solvent’ (once/28days) 
Octreotide LAR 
Octreotide LAR sourced locally 
Octreotide LAR sourced locally 
6.5.2 
Drug supply and storage 
Study drugs must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study drugs should be stored 
according to the instructions specified on the drug labels and in the current [Investigator’s 
Brochure]. 


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Table 6-4 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
 
Pasireotide LAR 
Centrally or locally supplied by 
Novartis 
Refer to study treatment label 
Octreotide LAR 
Octreotide LAR sourced locally 
Refer to the label 
6.5.3 
Study drug compliance and accountability 
6.5.3.1 
Study drug compliance 
Study drug compliance will be assessed by the Dosage Administration Record. All 
information is to be noted in the Dosage Administration Record. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
6.5.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
6.5.3.3 
Handling of other study treatment 
Not applicable. 
6.5.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 


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7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 to Table 7-3 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. No CRF except Quality of Life Questionnaire will be used as 
a source document. 
For all dosing visits, there is a general ± 2 day window on assessments to take into account 
scheduling over public holidays. For all safety visits (visit without dosing), there is a general 
± 1 day window on assessments to take into account scheduling over public holidays. 
Patients who discontinue treatment early must perform an end of core/extension phase visit 28 
± 2 days from the last dose. 


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Section 
Run-In 
completion / 
on 
 
 
Table 7-1 
Core Phase Visit evaluation schedule – Group 1 
 
Category 
Protocol 
Screening 
Run-In 
Baseline 
Core phase 
discontinuati 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-20 
-16 
- 
12 
-8 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Obtain Informed Consent 
D 
7.1.2 
x 
IRT Registration 
D 
7.1.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient history 
Demography 
D 
7.1.2.3 
x 
Inclusion/exclusion 
criteria 
D 
5.2/5.3 
x 
x 
Relevant medical 
history/current medical 
conditions 
D 
7.1.2.3 
x 
Prior/concomitant 
medications 
D 
7.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
History of acromegaly 
D 
7.1.2.3 
x 
Physical examination 
S 
7.2.2.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
D 
7.2.2.3 
x 
x 
Weight 
D 
7.2.2.3 
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 
x 
x 
x 
x 
Symptoms of 
acromegaly 
D 
7.2.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Category 
Protocol 
Section 
Screening 
Run-In 
Run-In 
Baseline 
Core phase 
completion / 
discontinuati 
on 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-20 
-16 
- 
12 
-8 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1 
x 
x 
x 
x 
x 
Chemistry (except LFT) 
D 
7.2.2.4.2 
x 
x 
x 
x 
x 
LFT (ALT, AST, T-bil, 
Alb,ALP,γ-GT) 
D 
7.2.2.4.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hepatitis (Hbs-Ag, anti- 
HCV) 
D 
7.2.2.4.4 
x 
Coagulation APTT/PTT 
D 
7.2.2.4.5 
x 
x 
x 
x 
x 
Coagulation PT( INR) 
D 
7.2.2.4.5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
5-point GH and IGF-1 
D 
7.2.1.1.1/7.2.1.1.2 
x 
x 
x 
x 
x 
Fasting blood glucose 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
oGTT 
D 
7.2.2.4.6 
x 
x 
PlasmaACTH/ FreeT4, 
TSH/ Cortisol 
D 
7.2.2.4.7 
x 
x 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.8 
x 
x 
x 
x 
x 
Pregnancy test urine 
D 
7.2.2.4.9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test Serum 
D 
7.2.2.4.9 
x 
Serum 
pregnancy test 
is required 
when urine 
pregnancy test 
is positive. 
x 
x 
Serum pregnancy test is required when urine pregnancy test 
is positive. 
x 


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Category 
Protocol 
Section 
Screening 
Run-In 
Run-In 
Baseline 
Core phase 
completion / 
discontinuati 
on 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-20 
-16 
- 
12 
-8 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Imaging 
ECG 
D 
7.2.2.6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gallbladder Ultrasound 
D 
7.2.2.5 
x 
x 
x 
x 
x 
Safety 
Adverse Event 
D 
8.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient reported Outcomes 
AcroQOL/EQ-5D5-L 
D 
7.2.1.2.2 
x 
x 
x 
x 
Study Drug administration 
Octreotide LAR 40mg 
x 
x 
x 
x 
Pasireotide LAR 40mg or 
60mg 
D 
6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Phase 
Completion 
D 
7.1.4 
x 


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Table 7-2 
Core Phase Visit evaluation schedule – Group 2 
 
Category 
Protocol 
Section 
Screening 
Baseline 
Core phase 
completion 
/discontinuat 
ion 
Visit Number 
1 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Obtain Informed Consent 
D 
7.1.2 
x 
IRT Registration 
D 
7.1.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient history 
Demography 
D 
7.1.2.3 
x 
Inclusion/exclusion criteria 
D 
5.2/5.3 
x 
Relevant medical 
history/current medical 
conditions 
D 
7.1.2.3 
x 
Prior/concomitant medications 
D 
7.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
History of acromegaly 
D 
7.1.2.3 
x 
Physical examination 
S 
7.2.2.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
D 
7.2.2.3 
x 
x 
Weight 
D 
7.2.2.3 
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 
Symptoms of acromegaly 
D 
7.2.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1 
x 
x 
x 
x 
Chemistry (except LFT) 
D 
7.2.2.4.2 
x 
x 
x 
x 
LFT (ALT, AST, T-bil, 
Alb,ALP,γ-GT) 
D 
7.2.2.4.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hepatitis (Hbs-Ag, anti-HCV) 
D 
7.2.2.4.4 
x 


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Category 
Protocol 
Section 
Screening 
Baseline 
Core phase 
completion 
/discontinuat 
ion 
Visit Number 
1 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Coagulation APTT/PTT 
D 
7.2.2.4.5 
x 
x 
x 
x 
Coagulation PT( INR) 
D 
7.2.2.4.5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
5-point GH and IGF-1 
D 
7.2.1.1.1/7.2.1.1.2 
x 
x 
x 
x 
Fasting blood glucose 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c 
D 
7.2.2.4.6 
x 
x 
x 
x 
oGTT 
D 
7.2.2.4.6 
x 
x 
PlasmaACTH/ FreeT4, TSH/ 
Cortisol 
D 
7.2.2.4.7 
x 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.8 
x 
x 
x 
x 
Pregnancy test urine 
D 
7.2.2.4.9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test Serum 
D 
7.2.2.4.9 
x 
x 
Serum pregnancy test is required when urine pregnancy test is positive. 
x 
Imaging 
ECG 
D 
7.2.2.6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gallbladder Ultrasound 
D 
7.2.2.5 
x 
x 
x 
x 
Safety 
Adverse Event 
D 
8.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient reported Outcomes 
AcroQOL/EQ-5D5-L 
D 
7.2.1.2.2 
x 
x 
x 
x 
Study Drug administration 
Pasireotide LAR 40mg or 60mg 
D 
6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Phase Completion 
D 
7.1.4 
x 


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Table 7-3 
Extension Phase Visit evaluation schedule for both Group 1 and Group 2 
 
Category 
Protocol 
Section 
Extension 
phase 
completion / 
discontinua 
tion 
Safety 
Follow Up 
Study 
Evaluation 
Completion 
Visit Number 
18 
19 
20 
21 
22 
23 
24 
25 
26 
778 
779 
Study Week 
36 
40 
44 
48 
52 
56 
60 
64 
68 
8 weeks after 
last study 
drug 
administration 
IRT Registration 
D 
7.1.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient history 
concomitant medications 
D 
7.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
S 
7.2.2.1 
x 
x 
x 
Height 
D 
7.2.2.3 
x 
Weight 
D 
7.2.2.3 
x 
x 
x 
Vital signs 
D 
7.2.2.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Symptoms of acromegaly 
D 
7.2.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1 
x 
x 
x 
Clinical Chemistry (except 
LFT) 
D 
7.2.2.4.2 
x 
x 
x 
LFT (ALT, AST, T-bil, 
Alb,ALP,γ-GT) 
D 
7.2.2.4.3 
x 
x 
x 
Coagulation (APTT,PTT 
and PT(INR)) 
D 
7.2.2.4.5 
x 
x 
x 
5-point GH and IGF-1 
D 
7.2.1.1.1/7.2.1.1.2 
x 
x 
x 
Fasting blood glucose 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c 
D 
7.2.2.4.6 
x 
x 
x 
oGTT 
D 
7.2.2.4.6 
x 


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Category 
Protocol 
Section 
Extension 
phase 
completion / 
discontinua 
tion 
Safety 
Follow Up 
Study 
Evaluation 
Completion 
Visit Number 
18 
19 
20 
21 
22 
23 
24 
25 
26 
778 
779 
Study Week 
36 
40 
44 
48 
52 
56 
60 
64 
68 
8 weeks after 
last study 
drug 
administration 
PlasmaACTH/ FreeT4, 
TSH/ Serum Cortisol 
D 
7.2.2.4.7 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.8 
x 
x 
x 
Pregnancy test (urine) 
D 
7.2.2.4.9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (serum) 
D 
7.2.2.4.9 
Serum pregnancy test is required when urine pregnancy test 
is positive. 
x 
Imaging 
ECG 
D 
7.2.2.6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gallbladder Ultrasound 
D 
7.2.2.5 
x 
x 
Safety 
Adverse Event 
D 
8.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient reported Outcomes 
AcroQOL/EQ-5D5-L 
D 
7.2.1.2.2 
x 
Study Drug administration 
Pasireotide LAR 40mg or 
60mg 
D 
6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Phase completion 
D 
7.1.4 
x 
Study Evaluation 
Completion 
x 


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7.1.1 
Molecular pre-screening 
Not applicable 
7.1.2 
Screening 
The informed consent must be signed prior to ANY screening procedure being performed.  
The site should enter the IRT when a patient signs the informed consent and begins his/her 
screening. Patients that do not meet eligibility criteria are allowed to be rescreened and should 
use the same patient number. Rescreening should be documented in the source files. Should 
the cause of screening failure be normal GH and/or IGF-1, patients can be rescreened once 
these parameters go beyond the control level, provided that at least a 3-month treatment with 
maximal doses of first generation SSAs has been given to the patient. 
7.1.2.1 
Eligibility screening 
Following registration in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. For Group 1 patients, patient eligibility will be checked 
again at the end of the run-in period prior to the baseline. The eligibility check will be 
embedded in the IRT system. Please refer and comply with detailed guidelines in the IRT 
Manual. 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign the informed consent, but fail to be started on study treatment for any 
reason will be considered a screen failure. The reason for not being started on treatment will 
be entered on the applicable Screening Failure CRF pages. If the patient fails to be enrolled, 
the IRT must be notified within 2 days of the screen fail that the patient was not enrolled. 
7.1.2.3 
Patient demographics and other baseline characteristics 
Standard demographic information and medical history will be collected. History of 
acromegaly, prior medications for acromegaly, AIP mutation and information on MRIs 
performed as standard of care will also be collected. Other baseline assessments will be 
collected as per Table 7-1 and Table 7-2. 
7.1.3 
Run-in period 
If a patient is considered as a Group 1, the run-in phase is required. Patients will be treated 
with octreotide LAR 40 mg for 16 weeks. The eligibility will be re-assessed after 3 injections 
of octreotide LAR 40 mg. 
7.1.4 
Treatment period 
Core Phase 
Patients will be treated with pasireotide LAR until week 36, receiving the last core injection at 
week 32, unless they discontinue from the study treatment due to any reason. The core phase 
completion visit is required at week 36. The safety follow up assessment is also required 56 
days after the last study drug administration. 


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For details of assessments refer to Table 7-1 and Table 7-2. 
Extension Phase 
Patients will be treated with pasireotide LAR until 68 weeks, unless they discontinue from the 
study treatment due to any reason. Starting from week 40, acromegaly concomitant therapy is 
allowed for patients who do not achieve the biomedical control. The extension phase 
completion visit is required at week 72. The safety follow up assessment is also required 56 
days after the last study drug administration. 
For details of assessments refer to Table 7-3. 
7.1.5 
End of treatment visit including study completion and premature 
withdrawal 
Patients who discontinue study treatment before visit 777 (week 36) in the core phase and  
visit 778 (week 72) in the extension phase, should be scheduled for a visit as soon as possible 
to have all assessments listed for the 777 or 778 visits performed (Table 7-1 to Table 7-3). A 
Study Completion CRF page should be completed, giving the date and reason for stopping the 
study treatment. At a minimum, all patients who discontinue study treatment, including those 
who refuse to return for a final visit, will be contacted for safety evaluations during the 56 
days following the last dose of study treatment. 
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Completion CRF page. Patients may be withdrawn from the 
study prematurely for one of the following reasons: 
• Adverse event(s) 
• Abnormal laboratory value(s) 
• Abnormal test procedure result(s) 
• Unsatisfactory therapeutic effect 
• Protocol violation 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Death 
The investigator must contact IRT to register the patient’s discontinuation. 
For criteria for premature withdrawal refer to Section 7.1.5.1. 


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7.1.5.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be discontinued from it at the discretion 
of the investigator at any time. Patients may be withdrawn from the study if any of the 
following occur: 
• Adverse event (s) including abnormal laboratory values (s) and abnormal test procedures 
results (s) 
• Patient withdrew consent 
• Protocol deviation 
• Physician decision 
• Administrative problems 
Patients must be withdrawn from the study in case of: 
• Pregnancy 
• Lost to follow up 
• Death 
In addition to the general withdrawal criteria, the study specific criteria below also require 
immediate study drug discontinuation. The safety follow-up management should be 
performed as outlined in Section 6.2.2. Re-challenge of study medication is prohibited once 
discontinuation criteria are met. 
Hepatic-related discontinuation criteria 
• Jaundice or other signs of clinically significant liver dysfunction 
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN 
• ALT or AST > 5 x ULN ≤ 8 x ULN persistent for more than 2 weeks 
• ALT or AST > 8 x ULN 
QT related discontinuation criteria 
Patients experiencing adverse events in QTc: 
• QTcF > 500 msec, if confirmed by a cardiologist. 
• QTcF > 480 msec, if the investigator determines it is no longer safe for the patient to 
continue in the study, based on ECGs, cardiac examination and recommendation from a 
cardiologist. 
• Clinically significant arrhythmias including: 
• Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms of 
hemodynamic compromise. 
• Sustained ventricular tachycardia (>30 s) irrespective of symptoms. 
• Clinically significant brady-arrhythmia or third degree AV block. 
• Need to use QT prolonging medication with known risks factors for torsade de pointes. 


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Hyperglycemia related discontinuation criteria 
• Uncontrolled diabetes mellitus (DM), consistently high capillary glucose values in excess 
of 275 mg/dL (15.5 mmol/L), FPG ≥ 240 mg/dL (13.3 mmol/L) or HbA1c value ≥ 10 % 
despite prior appropriate management and prior dose adjustment of the study drug 
The investigator must also notify the IRT of the premature withdrawal, if this occurs during 
the core period. Patients who withdraw prematurely from the core phase cannot participate in 
the extension phase. 
7.1.6 
Follow-up and End of Study visit 
All patients must have safety evaluations and complete the safety follow up assessments at the 
56 days after the last dose of pasireotide LAR. 
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, 
etc. Patients that meet the requirements for follow up of abnormal LFTs at the end of study 
visit should be followed up as detailed in Section.6.2.2.2. 
7.2 
Assessment types 
 
7.2.1.1.1 GH (5-point mean GH level) 
A 5-point mean GH will be assessed from a 2-hour profile after one hour at rest at the hospital 
and prior to the study drug administration at week -20 (Group1 only), week -4, week 12, 24, 
36 in the core phase and at week 48, 60, 72 in the extension phase. 
The 5-point mean GH profile is to be done within a 2-hour time period prior to glucose intake 
when an oGTT is required. 
All GH 2-hour profiles should be taken at the same time in the morning. The samples for GH 
will be analyzed by the central laboratory. Please refer to the central laboratory’s [Clinical 
Trial Laboratory Manual] for processing details. 
7.2.1.1.2 IGF-1 
Total IGF-1 levels will be assessed at the same visits as GH with one pre-dose sample which 
is week -20 (Group1 only), week -4, week 12, 24, 36 in the core phase and at week 48, 60, 72 
in the extension phase. Blood sampling for IGF-1 will be done prior to the study drug 
administration and glucose intake for oGTT when applicable. This sample must be taken 
together with the first sample of the GH profile. The samples for IGF-1 will be analyzed by 
the central laboratory. Please refer to the laboratory’s [Clinical Trial Laboratory Manual] for 
processing details. 
7.2.1 
Efficacy assessments 


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7.2.1.2 
Secondary efficacy assessments 
7.2.1.2.1 GH and IGF-1: 
Both values in combination or alone will be used to assess secondary efficacy parameters at 
week 12, 24 and 36 in the core phase and at week 48, 60 and 72 in the extension phase. 
7.2.1.2.2 Health-Related Quality of Life (HRQoL) 
Patient Reported Outcomes Assessment: 
HRQoL will be assessed at baseline, week 12, 24, visit 777(core phase completion) and at  
visit 778 (extension phase completion) using the AcroQoL, an acromegaly-specific quality of 
life instrument. The AcroQol instrument is comprised of 22 questions divided into two scales: 
one evaluating physical aspects (8 items) and the other that addresses psychological aspects 
(14 items). The psychological scale can also be further divided into subscale that evaluates 
physical appearance and the other subscale focused on the impact of the disease on personal 
relationships of the patient (7 items each). Each of the questions has a 5-item Likert scale. The 
instrument was developed with input from both physicians and patients to assess those 
dimensions of health-related quality of life most relevant and bothersome to patients with this 
disease. It has been found to be a valid, reliable instrument, that is sensitive to changes in the 
concepts being measured (Badia et al 2004). 
Health Status: 
Health status will be measured at baseline and weeks 12, 24, visit 777 and visit 778 using the 
EQ-5D-5L, a valid and reliable instrument for measuring general health status. The EQ-5D- 
5L consists of 2 pages – the descriptive system and the EQ visual analogue scale (EQ VAS) 
(Herdman M et al 2011) The descriptive system comprises 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS 
records the respondent’s self-rated health on a 20 cm vertical, visual analogue scale with 
endpoints labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’ 
Laboratory evaluations. 
7.2.1.2.3 Symptoms of acromegaly 
Symptom of acromegaly are to be collected at visits indicated in Table 7-1 to Table 7-3 and 
appropriate CRFs. Ring size will be measured with a gauge using 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 measurement  will  
be provided on a scale of 1-15 including half sizes. The investigator will also ask the patient  
to score the following symptoms of acromegaly: headache, fatigue, perspiration, paresthesias, 
osteoarthralgia according to a five-point score scale (0=absent, 1=mild, 2=moderate, 3=severe, 
4=very severe). 


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7.2.2 
Safety and tolerability assessments 
7.2.2.1 
Physical examination 
A complete physical examination must be performed by the investigator at visits indicated in 
Table 7-1 to Table 7-3. The examinations will be performed according to the standards at each 
institution. 
Information about the physical examination must be present 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 Medical History/Current Medical Condition page on the patient’s CRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the patient’s CRF. 
7.2.2.2 
Vital signs 
Vital signs (supine blood pressure, supine pulse rate and body temperature) will be performed 
by the investigator at all visits as indicated in Table 7-1 to Table 7-3 and appropriate CRFs. 
7.2.2.3 
Height and weight 
Height in centimeters and weight to the nearest 0.1 kilogram (in indoor clothing, but without 
shoes) are to be collected at visits indicated in Table 7-1 to Table 7-3 and appropriate CRFs. 
7.2.2.4 
Laboratory evaluations 
Central laboratories will be used for the analysis of all laboratory evaluations except  
urinalysis and urine pregnancy test. Details on the collections, shipment of samples and 
reporting of results by the central laboratories will be provided to investigators in the 
[Laboratory Manual]. 
Urinalysis and urine pregnancy test will be performed by dipstick locally. The dipsticks will 
be provided to the sites by the central laboratory. 
Table 7-4 
Local or Central Clinical Laboratory Parameters Collection Plan 
 
Test Category 
Test Name 
Hematology (central) 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC Morphology 
with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Clinical Chemistry 
(central) 
Bicarbonate, Calcium, Chloride, Creatinine, Creatine Kinase, Total Cholesterol, LDL, 
HDL, Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, α- 
amylase, Lipase, Lactic Dehydrogenase (LDH), Magnesium, Sodium, Potassium, 
Prolactin, 
LFT (central) 
ALT, AST, Total bilirubin, (total bilirubin should be differentiated into direct and indirect 
reacting bilirubin if total bilirubin is increased > 2.0ULN), Albumin, ALP and GGT 
Hepatic Screening 
(central) 
HbsAg , AntiHCV 
Hyperglycemia 
related test (central) 
Fasting Blood Glucose, Glycosylated Hemoglobin (HbA1C), oGTT (insulin and plasma 
glucose) 
Coagulation (central) 
Prothrombin time (PT) or International normalized ratio (INR), Partial thromboplastin time 
(PTT), Activated partial thromboplastin time (APTT) 


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Test Category 
Test Name 
Thyroid and 
hormones (central) 
T4 [free], TSH, Plasma Adrenocorticotropic Hormone (ACTH), Fasting Serum Cortisol, 
Urinalysis (local) 
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
pH, Protein, Specific Gravity) 
Additional tests 
(central) 
Insulin-like growth factor 1 (IGF-1), Growth Hormone (GH) 
Pregnancy Test 
Urine (dipstick) and serum B-hCG 
 
7.2.2.4.1 Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC Morphology  
with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) are to be 
collected at visits indicated in Table 7-1 to Table 7-3. 
7.2.2.4.2 Clinical Chemistry 
Bicarbonate, Calcium, Chloride, Creatinine, Creatine Kinase, Total Cholesterol, LDL, HDL, 
Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, α-amylase, 
Lipase, Lactic Dehydrogenase (LDH), Magnesium, Sodium, Potassium, Prolactin are to be 
collected at visits indicated in Table 7-1 to Table 7-3. 
7.2.2.4.3 Liver function testing (LFT) 
ALT, AST, Total bilirubin, (total bilirubin should be differentiated into direct and indirect 
reacting bilirubin if total bilirubin is increased > 2.0ULN), Albumin, ALP and GGT are to be 
collected at visits indicated in Table 7-1 to Table 7-3. 
7.2.2.4.4 Hepatic Screening 
HbsAg, AntiHCV are to be collected at visit 1. 
7.2.2.4.5 Coagulation 
Prothrombin time (PT) or International normalized ratio (INR), Partial thromboplastin time 
(PTT), Activated partial thromboplastin time (APTT) are to be collected at visits indicated in 
Table 7-1 to Table 7-3. 
7.2.2.4.6 Hyperglycemia related test 
Fasting Blood Glucose, Glycosylated Hemoglobin (HbA1C), oGTT (insulin and plasma 
glucose) are to be collected at visits indicated in Table 7-1 to Table 7-3. Diabetic patients are 
not required to perform oGTT. If the patient discontinues from the study, the oGTT at visit 
777/778 can be performed based on the judgment of the investigator. 
7.2.2.4.7 Thyroid and hormones 
T4 (free), TSH, ACTH, Fasting Serum Cortisol are to be collected at  visits  indicated  in 
Table 7-1 to Table 7-3. 


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7.2.2.4.8 Urinalysis 
Dipstick measurements for Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, pH, 
Protein, Specific Gravity are to be collected at visits indicated in Table 7-1 to Table 7-3. 
7.2.2.4.9 Pregnancy 
All pre-menopausal women who are not surgically sterile will have a serum B-hCG  
pregnancy test at screening, baseline and end of treatment (visit 777 and visit 778) and urine 
pregnancy test at visits indicated in Table 7-1 to Table 7-3 
A positive pregnancy test by urine is required an immediate serum B-hCG pregnancy test. 
A positive pregnancy test requires immediate interruption of study treatment until the 
assessment is confirmed. If positive, the patient must discontinued from the study. 
7.2.2.5 
Gallbladder ultrasound 
Table 7-5 
Gallbladder Ultrasound Assessment Collection Plan 
Group 1 
 
Procedure 
Screening/Run-in/Baseline 
During Treatment/Follow-up 
Gallbladder Ultrasound 
Mandated (Week -20 and Week -4) 
Week 12, 24, Visit 777 (core 
phase) 
Week 60, Visit 778 (extension 
phase) 
Group 2 
 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Gallbladder Ultrasound 
Mandated (Week -4) 
Week 12, 24, Visit 777(core 
phase) 
Week 60, Visit 778 (extension 
phase) 
A gallbladder ultrasound will be performed at the sites at visits indicated in Table 7-1 to Table 
7-3. The results will be recorded in the CRFs. 
7.2.2.6 
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG) 
Table 7-6 
Central ECG Collection Plan 
Group 1 
 
Week 
Time 
ECG Type 
-20 (Screening Run-In) 
Pre-dose 
12 Lead 
-4 (Run-in) 
Pre-dose 
12 Lead 
0 (Baseline) 
Pre-dose 
12 Lead 
3 
At any time during the visit 
12 Lead 
4 
Pre-dose 
12 Lead 


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Week 
Time 
ECG Type 
7 
At any time during the visit 
12 Lead 
8 
Pre-dose 
12 Lead 
11 
At any time during the visit 
12 Lead 
12 
Pre-dose 
12 Lead 
Every 4 weeks until Visit 
777 (core phase), until 
week Visit 778 (extension 
phase) 
Pre-dose 
12 Lead 
Unscheduled visit 
As clinically indicated 
12 Lead 
 
Group 2 
 
Week 
Time 
ECG Type 
-4 (Screening) 
Pre-dose 
12 Lead 
0 (Baseline) 
Pre-dose 
12 Lead 
3 
At any time during the visit 
12 Lead 
4 
Pre-dose 
12 Lead 
7 
At any time during the visit 
12 Lead 
8 
Pre-dose 
12 Lead 
11 
At any time during the visit 
12 Lead 
12 
Pre-dose 
12 Lead 
Every 4 weeks until Visit 
777 (core phase), until 
Visit 778 (extension 
phase) 
Pre-dose 
12 Lead 
Unscheduled visit 
As clinically indicated 
12 Lead 
Standard 12 lead ECGs will be performed at the sites at visits  indicated  in Table  7-1  to 
Table 7-3. 
If at any visit QTcF >480 msec is observed, all the procedures for QT-prolongation described 
in Section 6.2.2.1 should be followed. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG CRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History CRF. Clinically significant findings must 
be discussed with Novartis prior to enrolling the patient in the study. New or worsened 
clinically significant findings occurring after informed consent must be recorded on the 
Adverse Events CRF. 
Each ECG should be taken prior to the study drug administration. At the discontinuation 
(including the core phase completion visit for patients who do not participate in the extension 
phase) or the extension phase completion visit, the ECG should be taken prior to the 
commercial drug administration. 


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7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
Not applicable. 
7.2.2.6.3 Cardiac enzymes 
Not applicable. 
7.2.2.7 
Tolerability 
In addition to general safety data, information on dose changes will be collected. 
7.2.3 
Pharmacokinetics 
Not applicable 
7.2.3.1 
Other assessments 
No additional tests will be performed on patients entered into this study. 
7.2.4 
Resource utilization 
Not applicable 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Except for screening failures, adverse events that begin or worsen after informed consent 
should be recorded in the Adverse Events CRF. Conditions that were already present at the 
time of informed consent should be recorded in the Relevant Medical History/Current  
Medical Conditions CRF. Adverse event monitoring should be continued for at least 8 weeks 
following the last dose of study treatment. Adverse events (including lab abnormalities that 
constitute AEs) should be described using a diagnosis whenever possible, rather than 
individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each 
sign or symptom should be reported as a separate adverse event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 


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If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade 
2. Its duration 
3. Its relationship to the study treatment 
4. Action taken with respect to study or investigational treatment 
5. Whether medication or therapy was given 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is  
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for adverse events 
should be followed until they have returned to normal or an adequate explanation of the 
abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or therapy given 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. 


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8.1.3 
Adverse events of special interest 
Adverse events of special interest including the following: 
• Arrythmogenic potential 
• Bradycardia related AEs 
• Coagulation related AEs 
• Constipation related AEs 
• Diabetes insipidus related AEs 
• Diarrhoea related AEs 
• Gallbladder and biliary related AEs 
• GI bleeding related AEs 
• Growth hormone deficiency related AEs 
• Hyperglycemia-related AEs 
• Hypocalcemia related AEs 
• Hypocortisolism related AEs 
• Hypotension related AEs 
• Hypothyroidism related AEs 
• Injection site reaction related AEs 
• Liver safety related AEs 
• Low blood cell related AEs 
• Nausea related AEs 
• Pancreatitis related AEs 
• QT-prolongation-related AEs 
• Rhabdomyolysis related AEs 
8.1.3.1 
Definitions and reporting 
Adverse events of special interest consist of AEs for which there is a specific interest in 
connection with pasireotide treatment (i.e. where pasireotide may influence a common 
mechanism of action responsible for triggering them). The adverse events of special interest 
may require reporting additional information and completion of the event-specific checklists 
and/or questionnaires. 


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8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
8.2.2 
Reporting 
To ensure patient safety every SAE regardless of suspected occurring after the patient has 
provided informed consent and until at least 8 weeks after the patient has stopped study drug 
adminiatration must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 8 weeks 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 in English, 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 


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provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the current 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 
Emergency unblinding of treatment assignment 
Not applicable. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment who becomes 
pregnant during the study treatment or within 3 months after the last pasireotide LAR dose 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Newborn of a patient (or a partner of a patient) who becomes pregnant during the study 
treatment or within 3 months after the last pasireotide LAR dose should be followed for 3 
months post-delivery (from Day 0 to Month 3 of life). 


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8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee 
No Data Monitoring Committee is planned for this trial. 
8.7 
Steering Committee 
A steering committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in a SC charter. 
 
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. 


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9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate and that entry and updates are performed in a timely manner. 
9.3.1 
ECG data collection 
ECG data will be collected via 12-lead digital ECG machines. The data will be transmitted to 
an ECG vendor for centralized cardiac safety analysis, as well as further processing and data 
reconciliation. 
9.3.2 
IRT data collection 
Patient eligibility and enrollment will be tracked using an Interactive Response Technology. 
The system will be supplied by a vendor, who will also manage the database for that system. 


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9.3.3 
Central laboratory data collection 
All laboratory evaluation except urinalysis and urine pregnancy test will be conducted and its 
data will be collected by the central laboratory. 
Designated investigator staff must enter the sample information required by the protocol onto 
sample collection eCRFs, as well as central laboratory requisition forms. The requisition 
forms will be printed on 2-part, non-carbon-required paper or will available electronically. If 
paper forms will be used, one copy of the requisition form will be forwarded to the central 
laboratory along with the corresponding sample(s), and the other will be retained by the site. 
CRA will review the central laboratory requisition forms against the sample collection eCRFs 
for completeness and accuracy, and instruct site personnel to make any required corrections or 
additions. Further reconciliation of any sample collection data that were collected on both 
eCRFs and requisition forms will be performed by the designated central laboratory and 
Novartis. 
The samples will be shipped by the site to a designated central laboratory for sample 
management. 
9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator and 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). 
Patient numbers and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel (or designated CRO). 
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked. Authorization is required prior to making any database changes to locked 
data, by joint written agreement between the Global Head of Biostatistics and Data 
Management and the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 


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10 
Statistical methods and data analysis 
This is a phase IIIb exploratory study to assess the efficacy and safety of pasireotide in  
patients with acromegaly inadequately controlled with first generation somatostatin analogues. 
The data will be analyzed by Novartis and/or designed CRO. It is planned that the data from  
all centers that participate in this protocol will be used. Continuous variables will be 
summarized by number of patients, mean, standard deviation, minimum, 25th quantile, median, 
75th quantile and maximum. Categorical variables will be summarized by absolute  and  
relative frequencies. Unless otherwise stated, baseline assessment refers to the last assessment 
prior to the patient’s first study drug dose recorded after the signing of the informed consent. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication. 
10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP. The protocol deviations criteria will be defined prior to 
database lock. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (e.g. age, gender, race, GH levels, standardized IGF-1 
levels) will be summarized descriptively for the FAS. 
10.3 
Treatments (study treatment, concomitant therapies, compliance) 
Descriptive statistics will be used to summarize the dose intensity and duration of drug 
exposure. The actual and planned doses administered and reason for dose change will be 
listed. Concomitant medications and significant non-drug therapies prior to and after the start 
of the study treatment will be summarized by ATC class and preferred term. 
These analyses will be performed on the safety set. 
10.4 
Primary objective 
To evaluate the efficacy of pasireotide LAR in patients with acromegaly who are inadequately 
controlled with currently available somatostatin analogues, as measured by the proportion of 
patients with GH <1µg/L and IGF-1 <ULN at week 36. 


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10.4.1 
Variable 
The variable of interest is proportion of patients who achieved GH <1µg/L and IGF-1 <ULN 
at week 36. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The trial is exploratory in nature and no formal hypothesis testing is planned. 
The proportion of patients achieving mean GH levels < 1 µg/L and IGF-1 <ULN will be 
calculated along with its two-sided, asymptotic or exact when the criteria for asymptotic 
approximation were not fulfilled, 95% confidence interval at Week 36. 
10.4.3 
Handling of missing values/censoring/discontinuations 
If a patient has less than three samples for the assessment of the 5-point mean GH from the 2- 
hour profile, then the mean GH will be considered as missing. Patients with missing GH and 
or IGF-1 assessment at week 36 will be considered as non-responders. 
Multiple imputation method or other adequate methods will be employed to impute missing 
data and sensitivity analyses will be performed using imputed missing data to assess the 
robustness of the efficacy findings. The imputation methods as well as sensitivity analyses 
will be specified in the RAP. 
10.4.4 
Supporting Analysis of Primary Objective 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN at weeks 36 
by sub-groups of GH level at screening 
The proportion of patients who achieved GH <1µg/L and IGF-1 <ULN at week 36 among two 
sub-groups of patients, those having GH level at screening between 1µg/L and 2.5µg/L, and 
those having GH level >2.5µg/L at screening, will be reported along with their two-sided 
(exact or asymptotic, depending on assumptions being satisfied) 95% confidence interval. 
This supporting analysis is purely exploratory in nature and no statistical multiplicity 
adjustments will be performed to distinguish it from other endpoints. 
10.5 
Secondary objectives 
The secondary efficacy analysis will be performed on the FAS. The same rule of handling 
missing values for GH and IGF-1 variables as specified in the analysis of the primary efficacy 
variable will be used. 


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10.5.1 
Secondary objectives- Core phase 
To assess the changes in mean GH from study baseline to week 36 
Descriptive summaries of actual and percentage change in GH from study baseline to week 36 
values will be provided. 
To assess the changes in standardized IGF-1 from study baseline to week 36 
Descriptive summaries of actual and percentage change in standardized IGF-1 from study 
baseline to week 36 values will be provided. 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN at weeks 12 
and 24 overall and by GH level at screening 
Proportion of patients who achieved GH <1µg/L and IGF-1 <ULN at week 12 and 24 will be 
reported along with its corresponding 95% confidence interval for all patients and also among 
patients, having GH level at screening between 1 µg/L and 2.5 µg/L, and among patients 
having GH level at screening > 2.5 µg/L. 
To assess the proportion of patients achieving GH <1µg/L at weeks 12, 24 and 36, overall 
and by GH level at screening 
Proportion of patients who achieved GH <1µg/L at week 12, 24 and 36 will be reported along 
with its corresponding 95% confidence interval for all patients and also among patients, 
having GH level at screening between 1 µg/L and 2.5 µg/L, and patients having GH level at 
screening >2.5 µg/L. 
To assess the proportion of patients achieving IGF-1 levels <ULN at weeks 12, 24 and 36 
Proportion of patients who achieved IGF-1 <ULN at week 12, 24 and 36 will be reported 
along with its corresponding 95% confidence interval. 
To evaluate the effect of pasireotide LAR on HRQoL and signs and symptoms of 
acromegaly from baseline to weeks 12, 24 and 36 
Descriptive statistics, including mean, median, standard deviation, minimum and maximum, 
will be presented to describe actual standardized scores as measured by HRQoL and changes 
from baseline to weeks 12, 24 and 36. 
For each of the acromegaly symptoms (ring size, headache, fatigue, perspiration, paresthesias, 
osteoarthralgia), descriptive summaries of actual and changes from baseline to weeks 12, 24 
and 36 will be provided. Moreover, shift tables from baseline to the most extreme post- 
baseline value will also be presented for acromegaly symptoms except ring size 
To evaluate the tolerability and safety profile of pasireotide LAR 
Same analysis as in Section 10.5.3 


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10.5.2 
Secondary objectives- Extension phase 
To assess the proportion of patients achieving IGF-1 <ULN at weeks 48, 60 and 72 
Proportion of patients who achieved IGF-1 <ULN will be calculated along with its two-sided 
95% confidence interval at week 48, 60 and 72. 
To assess the proportion of patients achieving GH<1 µg/L and IGF-1<ULN at weeks 48, 
60 and 72 by treatment with pasireotide LAR alone or with concomitant medications 
used to treat acromegaly 
Proportion of patients who achieved GH<1µg/L and IGF-1<ULN by treatment with 
pasireotide LAR alone or with concomitant medications used to treat acromegaly will be 
reported separately along with its corresponding 95% confidence interval at weeks 48, 60 and 
72 
To assess the proportion of patients achieving GH <1 µg/L at weeks 48, 60 and 72 by 
treatment with pasireotide LAR alone or with concomitant medications used to treat 
acromegaly 
Proportion of patients who achieved GH<1µg/L by treatment with pasireotide LAR alone or 
with concomitant medications used to treat acromegaly will be reported separately along with 
its corresponding 95% confidence interval at weeks 48, 60 and 72 
To evaluate the long term effect of pasireotide LAR on HRQoL and signs and symptoms 
of acromegaly, from baseline and week 36 to week 72 
Change in standardized scores as measured by HRQoL and signs and symptoms of 
acromegaly from baseline and week 36 to week 72. 
Descriptive statistics, including mean, median, standard deviation, minimum and maximum, 
will be presented to describe actual standardized scores as measured by HRQoL and changes 
from baseline to week 72 and from week 36 to week 72. 
For each of the acromegaly symptoms (ring size, headache, fatigue, perspiration, paresthesias, 
osteoarthralgia), descriptive summaries of actual and changes from baseline to weeks 72, and 
from week 36 to week 72 will be provided. Moreover, shift tables from baseline to the most 
extreme post-baseline value, and from week 36 to the most extreme value up to week will also 
be presented for acromegaly symptoms except ring size. 
To evaluate the long term tolerability and safety profile of pasireotide LAR 
Same analysis as in Section 10.5.4 
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. 
For the core phase, all listings and tables will be presented overall and by maximum dose 
given. For AEs of special interest, tables will be presented by the given dose as well (AE 
starts or worsens while the patient is being treated at that dose level.) 


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For the extension phase, all listings and tables will be presented overall and by type of 
treatment (monotherapy, combination dopamine agonist, and combination with GH receptor 
antagonist). 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 56 days after last dose 
of study medication 
3. post-treatment period: starting at day 56+1 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-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment overall and by treatment group (described in 
Section 10.5.3.2 for each phase). 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group (described in Section 10.5.3.1 for each 
phase). 
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). 
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported. 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, the study’s biostatistical and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non- 
missing values not graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 


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• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) 
• 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-treatment result for overall assessments 
• listing of ECG evaluations for all patients with at least one abnormality. 
Vital signs 
Vital signs (body temperature, blood pressure, heart rate) reporting of results will include: 
• shift table baseline to worst on-treatment result 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
Gallbladder 
Gallbladder data at each visit will be summarized and listed. 
10.5.4 
Patient-reported outcomes 
AcroQoL total and subscale scores and EQ-5D-5L utility index and VAS scores will be 
generated in accordance with the respective scoring manual. The FAS will be used for 
analyzing patient-reported outcome data. 
Descriptive statistics will be used to summarize the raw and absolute change from baseline in 
AcroQoL and EQ-5D-5L scores at each scheduled assessment. Patients with an evaluable 
baseline score and at least one evaluable post baseline score during the treatment period will 
be included in the change from baseline analyses. 
Missing items data in a scale will be handled based on each instrument manual. All PRO 
analyses will include data as imputed according to the scoring manual. No imputation will be 
applied if the total or subscale scores are missing at a visit. 
Additional analyses may be performed if deemed necessary. Such analyses will be defined in 
the RAP. 


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10.6 
Interim analysis 
No formal interim analysis will be performed. Primary analysis will occur after all enrolled 
patients complete the core phase or discontinue prior to complete this phase of the trial. Final 
analysis will be conducted when all patients complete the extension phase or have 
discontinued the study prior to completing the extension phase of the trial. 
10.7 
Sample size calculation 
The sample size calculation was based on the primary endpoint (mean GH <1 µg/L and IGF-1 
<ULN at week 36). A sample size of 100 patients was chosen to enable the estimation of 
proportion of patients who achieved biochemical control at week 36 with pasireotide 40-60 
mg as 15%, with a precision of 7% for the associated asymptotic two-sided 95% confidence 
interval. 
Considering a drop-out rate of 10%, the sample size required is 112. 
Sample size calculation was performed using PASS 2008 software. 
10.8 
Power for analysis of key secondary variables 
Not applicable 
 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21) and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 


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11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e.  all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are  outlined  in 
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.5.1 Communication and Publication of Clinical Trial Results 
Novartis is committed to upholding the highest ethical standards for reporting the results of 
medical research, including the timely communication and publication of clinical trials results, 
whatever their outcome 
Novartis complies with the authorship guidelines of the International Committee of Medical 
Journal Editors (ICMJE) uniform requirements for manuscripts submitted to biomedical 
journals and other specific guidelines of the journal or congress to which the document will be 
submitted. These guidelines apply to any clinical trial publication including but not limited to 
manuscripts, abstracts, posters, and oral presentations. For more information regarding the 
ICMJE guidelines, visit ICMJE.org/index.html#author. 
Accordingly, ALL AUTHORS MUST HAVE: 


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• Contributed substantially to the study concept, design and/or conduct of the study or to the 
acquisition, analysis, and interpretation of the data AND 
• Drafted or critically revised the proposed clinical publication for important intellectual 
content AND 
• Approved the final proposed clinical publication for submission AND 
• Have intimate knowledge of trial implementation/analysis 
Substantial contribution for primary publication is defined as having active and ongoing 
participation in the study. Study steering committee members must have significant 
involvement to study concept, design, and data interpretation and patient recruitment. Each 
steering committee member must have attended the majority of the steering committee 
meetings and recruited patients into the trial from his/her own center to be included as an 
author. Study investigators must have significant contribution to patient recruitment based on 
number of eligible patients upon study entry and data quality. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries  or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported  
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs. 


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The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
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 
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Hirji K, Mehta CR, Patel NR (1987) Computing distributions for exact logistic regression. 
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Kauppinen-Makelin R, et al (2005) A nationwide survey of mortality in acromegaly. J Clin 
Endocrinol Metab; 90: 4081-6. 
Lancranjan I, Atkinson AB, Sandostatin LAR Group (1999) Results of a European 
Multicentre Study with Sandostatin LAR in Acromegalic Patients. Pituitary; 1: 105-114. 
Maurer W, et al (2011) Multiple and repeated testing of primary, coprimary, and secondary 
hypotheses. American Statistical Association; 3:336-352. 
Nathan DM, et al (2009) Medical Management of hyperglycemia in Type 2 Diabetes: a 
consensus algorithm for the initiation and adjustment of therapy. Diabetes Care; 32 (1): 193- 
203. 
Oberg K (2004) Treatment of neuroendocrine tumours of the gastrointestinal tract. Oncologia 
(Madrid); Vol. 27 (4): 57-61. 
Schmid HA (2008) Pasireotide (SOM230): development, mechanism of action and potential 
applications. Mol Cell Endocrinol; 286(1-2):69-74. 
Schmid HA, Schoeffter P (2004) Functional Activity of the Multiligand Analogue SOM230 at 
Human Recombinant Somatostatin Receptor Subtypes Supports Its Usefulness in 
Neuroendocrine Tumors. Neuroendocrinology; 80 (1): 47-50. 
Shimon I, et al (1997) Somatostatin receptor (SSTR) subtype-selective analogues 
differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas: 
novel potential therapy for functional pituitary tumors. J Clin Invest; 100: 2386-92. 
Simes RJ (1986) An improved Bonferroni procedure for multiple tests of significance. 
Biometrika; 73: 751-754. 
Taboada GF, et al (2007) Quantitative analysis of somatostatin receptor subtype (SSTR1-5) 
gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J 
Endocrinol;156(1):65-74. 
Taboada GF, et al (2008) Quantitative analysis of somatostatin receptor subtypes (1-5) gene 
expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume 
responses to treatment with octreotide LAR. Eur J Endocrinol;158(3):295-303. 
Tichomirowa, et al (2011) High prevalence of AIP gene mutations following focused 
screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol; 165: 
509-515 
Van der Hoek J, 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): E278-87. 
Wass J, Lamberts S, Melmed S (2001) Long-term treatment strategies for acromegaly. 
Handbook of Acromegaly; 7: 79-83. 


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14 
Appendices 
14.1 
Appendix 1: Acromegaly Quality of Life Questionnaire 
 
 
 
 
Today’s date 
Day 
Month 
Year 
 
 
 
 
INSTRUCTIONS FOR ANSWERING THE QUESTIONNAIRE 
In the following pages there are sentences that describe some of the problems that acromegaly 
causes to people who, like you, suffer from this illness. 
 
Each sentence is followed by some response options. Some of these refer to the frequency, 
while others refer to how much you agree or disagree with them. 
 
 
Please, read each sentence carefully. Then tick the response option which best describes 
what you think is happening to you. 
 
 
Remember that there are NO correct or incorrect answers. We are only interested in what is 
currently happening to you because of your acromegaly. 
 
It is very important to answer all the questions. 
Thank you very much for your collaboration 
 
© Badía X., Prieto Ll., Webb S. 
ACROMEGALY- QUALITY OF LIFE QUESTIONNAIRE 
(ACROQoL) 


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• Always 
• Always 
• Most of the time 
• Most of the time 
• 
• 
Sometimes 
Sometimes 
• 
• 
Rarely 
Never 
Rarely 
Never 
• 
• 
 
 
 
Because of my Acromegaly… 
 
1. My legs feel weak 
4. I look awful in photographs 
 
• Always 
•   Completely agree 
 
• Most of the time 
•   Moderately agree 
 
• Sometimes 
• Neither agree nor disagree 
 
• Rarely 
•   Moderately disagree 
 
• Never 
•   Completely disagree 
 
 
 
2. I feel ugly 
5. I avoid going out very much with 
friends because of my appearance 
 
• Completely agree 
• Always 
 
• Moderately agree 
• Most of the time 
 
• Neither agree nor disagree 
• Sometimes 
 
• Moderately disagree 
• Rarely 
 
• Completely disagree 
• Never 
 
 
 
3. I get depressed 
6. I try to avoid socialising 


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• Always 
• Always 
• Most of the time 
• Most of the time 
• 
• 
Sometimes 
Sometimes 
• 
• 
Rarely 
Never 
Rarely 
Never 
• 
• 
 
 
 
Because of my Acromegaly… 
 
7. I look different in the mirror 
10. People stare at me because of 
my appearance 
 
• Completely agree 
•   Completely agree 
 
• Moderately agree 
•   Moderately agree 
 
• Neither agree nor disagree 
• Neither agree nor disagree 
 
• Moderately disagree 
•   Moderately disagree 
 
• Completely disagree 
•   Completely disagree 
 
8. I feel rejected by people because of 
my illness 
11. Some parts of my body (nose, feet 
hands,…) are too big 
 
• Completely agree 
•   Completely agree 
 
• Moderately agree 
•   Moderately agree 
 
• Neither agree nor disagree 
• Neither agree nor disagree 
 
• Moderately disagree 
•   Moderately disagree 
 
• Completely disagree 
•   Completely disagree 
 
9. I have problems carrying out my 
usual activities (e.g. working, studying, 
doing 
household 
tasks, 
family 
or 
leisure activities) 
12. I have problems doing things 
with my hands, for example, sewing 
or handling tools 


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Because of my Acromegaly… 
 
13. The illness affects my performance 
at work or in my usual tasks 
16. I snore at night 
 
• Always 
• Always 
 
• Most of the time 
• Most of the time 
 
• Sometimes 
• Sometimes 
 
• Rarely 
• Rarely 
 
• Never 
• Never 
 
14. My joints ache 
17. It is hard for me to 
articulate words due to the size of 
my tongue 
 
• Always 
• Always 
 
• Most of the time 
• Most of the time 
 
• Sometimes 
• Sometimes 
 
• Rarely 
• Rarely 
 
• Never 
• Never 
 
15. I feel tired 
18. I have problems with 
sexual relationships 
 
• Always 
• Always 
 
• Most of the time 
• Most of the time 
 
• Sometimes 
• Sometimes 
 
• Rarely 
• Rarely 
 
• Never 
• Never 


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Because of my Acromegaly… 
 
19. I feel like a sick person 
21. I have little sexual appetite 
 
• Completely agree 
• Always 
 
• Moderately agree 
• Most of the time 
 
• Neither agree nor disagree 
• Sometimes 
 
• Moderately disagree 
• Rarely 
 
• Completely disagree 
• Never 
 
20. The physical changes produced 
by my illness govern my life 
22. I feel weak 
 
• Completely agree 
• Always 
 
• Moderately agree 
• Most of the time 
 
• Neither agree nor disagree 
• Sometimes 
 
• Moderately disagree 
• Rarely 
 
• Completely disagree 
• Never 
 
 
Finally, please check that you have answered all the questions. 
 
 
Once again thank you very much for your collaboration. 


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14.2 
Appendix 2: Patient Report Outcome Questionnaire EQ-5D5-L 
Health Questionnaire 
English version for the USA 
Under each heading, please check the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
 
SELF-CARE 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself        
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
 
USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 


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PAIN / DISCOMFORT 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
We would like to know how 
TODAY. 
good or bad your health is 
This scale is numbered from 0 to 100. 
100 
means 
the 
best 
health 
you 
can 
imagine. 
0 means the worst health you can imagine. 
Mark an X on the scale to indicate how your health is TODAY. 
Now, please write the number you marked on the scale in the box below. 
The best health 
you can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
 
60 
 
55 
 
50 
 
45 
 
40 
 
35 
 
30 
 
25 
 
20 
 
15 
 
YOUR HEALTH TODAY = 
10
 
5 
0 
The worst health 
you can imagine 


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14.3 
Appendix 3: Concomitant Medications with “known risk of TdP 
(Torsades de pointes)” 
The following list of drugs is generally recognized to have a possible association with TdP. 
This list is not considered to be all inclusive and any questions regarding concomitant 
medications with known risk of TdP should be discussed with the Novartis global team. 
//crediblemeds.org/ 


 
 
 
 
 
 
Clinical Development 
 
 
Pasireotide / SOM230 
 
 
Protocol CSOM230C2413 / NCT02354508 
 
 
A phase IIIb multicenter, open-label, single arm study to 
evaluate the efficacy and safety of pasireotide in patients 
with acromegaly inadequately controlled with first 
generation somatostatin analogues 
 
 
 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2014-002630-31 
Version number 
01 (Clean) 
Development phase 
IIIb 
Document status 
Final 
Release date 
05-Aug-2015 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of appendices ................................................................................................................ 6 
List of figures....................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Amendment 1 .................................................................................................................... 10 
Protocol summary .............................................................................................................. 13 
1 
Background ........................................................................................................................ 17 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 17 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 18 
1.2.1 
Overview of pasireotide (SOM230) ...................................................... 18 
2 
Rationale ............................................................................................................................ 20 
2.1 
Study rationale and purpose ................................................................................... 20 
2.2 
Rationale for the study design ............................................................................... 21 
2.3 
Rationale for dose and regimen selection .............................................................. 21 
2.4 
Rationale for choice of combination drugs ............................................................ 22 
2.5 
Rationale for choice of comparators drugs ............................................................ 22 
3 
Objectives and endpoints ................................................................................................... 22 
4 
Study design ...................................................................................................................... 25 
4.1 
Description of study design ................................................................................... 25 
4.2 
Timing of interim analyses and design adaptations ............................................... 28 
4.3 
Definition of end of the study ................................................................................ 28 
4.4 
Early study termination .......................................................................................... 28 
5 
Population .......................................................................................................................... 29 
5.1 
Patient population .................................................................................................. 29 
5.2 
Inclusion criteria .................................................................................................... 29 
5.3 
Exclusion criteria ................................................................................................... 29 
6 
Treatment ........................................................................................................................... 31 
6.1 
Study treatment ...................................................................................................... 31 
6.1.1 
Dosing regimen ..................................................................................... 32 
6.1.2 
Ancillary treatments .............................................................................. 33 
6.1.3 
Rescue medication ................................................................................ 33 
6.1.4 
Guidelines for continuation of treatment .............................................. 33 
6.1.5 
Treatment duration ................................................................................ 33 
6.1.6 
Dose escalation guidelines .................................................................... 34 
6.2 
Dose modifications ................................................................................................ 34 


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6.2.1 
Dose modification and dose delay ........................................................ 34 
6.2.2 
Follow-up for toxicities ......................................................................... 35 
6.2.3 
Anticipated risks and safety concerns of the study drug ....................... 42 
6.3 
Concomitant medications ...................................................................................... 42 
6.3.1 
Permitted concomitant therapy .............................................................. 42 
6.3.2 
Prohibited concomitant therapy ............................................................ 43 
6.4 
Patient numbering, treatment assignment or randomization ................................. 43 
6.4.1 
Patient numbering ................................................................................. 43 
6.4.2 
Treatment assignment or randomization ............................................... 43 
6.4.3 
Treatment blinding ................................................................................ 44 
6.5 
Study drug preparation and dispensation ............................................................... 44 
6.5.1 
Study drug packaging and labeling ....................................................... 44 
6.5.2 
Drug supply and storage ........................................................................ 44 
6.5.3 
Study drug compliance and accountability ........................................... 45 
6.5.4 
Disposal and destruction ....................................................................... 45 
7 
Visit schedule and assessments ......................................................................................... 46 
7.1 
Study flow and visit schedule ................................................................................ 46 
7.1.1 
Molecular pre-screening ........................................................................ 54 
7.1.2 
Screening ............................................................................................... 54 
7.1.3 
Run-in period......................................................................................... 54 
7.1.4 
Treatment period ................................................................................... 54 
7.1.5 
End of treatment visit including study completion and premature 
withdrawal ............................................................................................. 55 
7.1.6 
Follow-up and End of Study visit.......................................................... 57 
7.2 
Assessment types ................................................................................................... 57 
7.2.1 
Efficacy assessments ............................................................................. 57 
7.2.2 
Safety and tolerability assessments ....................................................... 59 
7.2.3 
Pharmacokinetics .................................................................................. 63 
7.2.4 
Resource utilization ............................................................................... 63 
8 
Safety monitoring and reporting ........................................................................................ 63 
8.1 
Adverse events ....................................................................................................... 63 
8.1.1 
Definitions and reporting ...................................................................... 63 
8.1.2 
Laboratory test abnormalities ................................................................ 64 
8.1.3 
Adverse events of special interest ......................................................... 64 
8.2 
Serious adverse events ........................................................................................... 65 
8.2.1 
Definitions ............................................................................................. 65 
8.2.2 
Reporting ............................................................................................... 66 
8.3 
Emergency unblinding of treatment assignment ................................................... 67 


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8.4 
Pregnancies ............................................................................................................ 67 
8.5 
Warnings and precautions ...................................................................................... 67 
8.6 
Data Monitoring Committee .................................................................................. 67 
8.7 
Steering Committee ............................................................................................... 67 
9 
Data collection and management ....................................................................................... 68 
9.1 
Data confidentiality ............................................................................................... 68 
9.2 
Site monitoring ...................................................................................................... 68 
9.3 
Data collection ....................................................................................................... 69 
9.3.1 
ECG data collection .............................................................................. 69 
9.3.2 
IRT data collection ................................................................................ 69 
9.3.3 
Central laboratory data collection ......................................................... 69 
9.4 
Database management and quality control ............................................................ 69 
10 Statistical methods and data analysis ................................................................................. 70 
10.1 
Analysis sets .......................................................................................................... 70 
10.1.1 
Full Analysis Set ................................................................................... 70 
10.1.2 
Safety Set ............................................................................................... 70 
10.1.3 
Per-Protocol Set..................................................................................... 71 
10.2 
Patient demographics/other baseline characteristics .............................................. 71 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 71 
10.4 
Primary objective ................................................................................................... 71 
10.4.1 
Variable ................................................................................................. 71 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 71 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 71 
10.4.4 
Supporting Analysis of Primary Objective ........................................... 72 
10.5 
Secondary objectives ............................................................................................. 72 
10.5.1 
Secondary objectives- Core phase ......................................................... 72 
10.5.2 
Secondary objectives- Extension phase ................................................ 73 
10.5.3 
Safety objectives ................................................................................... 74 
10.5.4 
Patient-reported outcomes ..................................................................... 75 
10.6 
Interim analysis ...................................................................................................... 76 
10.7 
Sample size calculation .......................................................................................... 76 
10.8 
Power for analysis of key secondary variables ...................................................... 76 
11 Ethical considerations and administrative procedures ....................................................... 76 
11.1 
Regulatory and ethical compliance ........................................................................ 76 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 76 
11.3 
Informed consent procedures ................................................................................. 76 
11.4 
Discontinuation of the study .................................................................................. 77 
11.5 
Publication of study protocol and results ............................................................... 77 


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11.5.1 
Communication and Publication of Clinical Trial Results .................... 77 
11.6 
Study documentation, record keeping and retention of documents ....................... 78 
11.7 
Confidentiality of study documents and patient records ....................................... 79 
11.8 
Audits and inspections ........................................................................................... 79 
11.9 
Financial disclosures .............................................................................................. 79 
12 Protocol adherence ............................................................................................................ 79 
12.1 
Amendments to the protocol .................................................................................. 79 
13 References (available upon request) .................................................................................. 80 
14 Appendices ........................................................................................................................ 82 
14.1 
Appendix 1: Acromegaly Quality of Life Questionnaire....................................... 82 
14.2 
Appendix 2: Patient Report Outcome Questionnaire EQ-5D5-L ........................... 87 
14.3 
Appendix 3: Concomitant Medications with “known risk of TdP (Torsades de 
pointes)” ................................................................................................................. 89 
14.4 
Appendix 4: Pharmacy Instructions for pasireotide LAR ..................................... 89 


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List of appendices 
Appendix 1: Acromegaly Quality of Life Questionnaire 
Appendix 2 : Patient Reported Outcome Questionnaire Eq-5D5-L 
Appendix 3: Concomitant Medications with “known risk of TdP (torsades de pointes)” 
Appendix 4: Pharmacy Instructions for pasireotide LAR 
 
List of figures 
Figure 4-1 
Flow Chart for Group 1 and Group 2 Patients ....................................... 25 
Figure 4-2 
Study Design; Group 1 .......................................................................... 26 
Figure 4-3 
Study Design; Group 2 .......................................................................... 28 
Figure 6-1 
Group 1: Dose Regimen ........................................................................ 32 
Figure 6-2 
Group 2: Dose Regimen ........................................................................ 33 
Figure 6-3 
QT prolongation flowchart: 480 msec less than QTcF less than or 
equal to 500 msec .................................................................................. 36 
Figure 6-4 
QT prolongation flowchart; QTcF greater than 500msec ..................... 38 
Figure 6-5 
LFT management algorithm .................................................................. 40 
Figure 6-6 
Fasting SMBG Guidance....................................................................... 42 
 
 
List of tables 
Table 1-1 
Binding profiles for octreotide and pasireotide at  hsst1-5  (IC50, 
mol/L) .................................................................................................... 18 
Table 3-1 
Objectives and related endpoints ........................................................... 23 
Table 6-1 
Dose and treatment schedule ................................................................. 32 
Table 6-2 
Guideline for treatment of patients experiencing adverse events ......... 35 
Table 6-3 
Packaging and labeling .......................................................................... 44 
Table 6-4 
Supply and storage of study treatments ................................................. 45 
Table 7-1 
Core Phase Visit evaluation schedule – Group 1 .................................. 47 
Table 7-2 
Core Phase Visit evaluation schedule – Group 2 .................................. 50 
Table 7-3 
Extension Phase Visit evaluation schedule for both Group 1 and 
Group 2 .................................................................................................. 52 
Table 7-4 
Local or Central Clinical Laboratory Parameters Collection Plan ........ 59 
Table 7-5 
Gallbladder Ultrasound Assessment Collection Plan ............................ 61 
Table 7-6 
Central ECG Collection Plan ................................................................ 61 


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  List of abbreviations 
 
AcroQoL 
Acromegaly Quality of Life 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
Anti-HBc 
Anti-Hepatitis B core 
Anti-HCV 
Anti-Hepatitis C Virus 
Anti-HEV 
Anti-Hepatitis E Virus 
APTT 
Partial Thromboplastin Time 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC Class 
Anatomical Therapeutic Chemical Classification System 
ATG 
Autogel 
B-hCG 
β-subunit of hCG gonadotropin 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CPK 
Creatine Phosphokinase 
CPO 
(Novartis) Country Pharma Organization 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DM 
Diabetes Mellitus 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety and Epidemiology 
EBV 
Epstein Barr Virus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GH 
Growth Hormone 
GIP/GLP 
Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 
HbA1C 
Hemoglobin A1c 
Hbs-Ag 
Hepatitis B surface-Antigen 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
HRQoL 
Health Related Quality of Life 
i.m. 
Intramuscular 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF 
Insulin-like Growth Factor 
 


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IgM 
Immunoglobulin M 
IMS 
Integrated Medical Safety 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
ITT 
Intention To Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LAR 
Long Acting Release 
LDH 
Lactic Dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Testing 
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-CTCAE 
v.4.03 
National Cancer Institute-Common Toxicity Criteria Adverse Event version 4.03 
OGTT 
Oral Glucose Tolerance Test 
PCR 
Polymerase Chain Reaction 
PHI 
Protected Health Information 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PRL 
Prolactin 
PRO 
Patient Reported Outcomes 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin time 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
REB 
Research Ethics Board 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SmPc 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SSA 
Somatostatin analogues 
sst 
somatostatin receptor subtype 
TdP 
Torsades de pointes 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit Normal 
γ-GT 
Gamma-Glutamyltransferase 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This also 
includes approved drugs used outside of their indication/approved dosage, or 
that are tested in a fixed combination. Investigational treatment generally does 
not include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment 
Patient Number 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient withdrawal 
Treatment group 
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 


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Amendment 1 
Amendment rationale 
The main purpose of this amendment is to: 
• To reference the octreotide summary of product characteristics (SmPc) for guidance on 
dosing modifications and safety reporting 
• Update the safety section to reflect changes made to version 15 of the Investigator’s 
Brochure, specifically to the Referenced Safety Information Section and the reporting of 
suspected unexpected serious adverse reactions. 
• To extend the safety follow-up of patients from 8 weeks to 12 weeks (5 half-lives of 
pasireotide LAR). 
• To allow dose reductions in patients with controlled GH values, in whom treatment 
reduced IGF-1 values to below the lower limit of normal since this could lead to adverse 
events. 
• To add a recommendation for additional assessments of electrolytes. The use of 
medications with conditional risk for Torsade des Pointes and congenital long QT interval 
are permitted per protocol and several medications (e.g. diuretics) from these drug classes 
have the potential to decrease the potassium level. Therefore, additional monitoring of 
electrolytes as clinically indicated to the already frequent electrolyte monitoring as per 
protocol is recommended. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. The 
major changes to the protocol, and the sections affected, are detailed below: 
1. Protocol Summary: Corrected a typographical error in the number of weeks for the 
extension period from 76 weeks to 72 weeks. 
2. Protocol Summary: Update the safety follow-up period from the last dose of study 
medication from 8 weeks to 12 weeks (84 days) (5 half-lives of pasireotide LAR). 
3. Section 4.1 Run-in phase: Updated the language to clarify that patients will receive 
octreotide LAR 40 mg every 4 weeks. After 3 months of treatment have been completed, 
and prior to the fourth injection (at visit 5), mean GH and IGF-1 will be assessed. 
4. Section 4.1 Safety follow-up: Update the safety follow-up period from the last dose of 
study medication from 8 weeks to 12 weeks (84 days) (5 half-lives of pasireotide LAR). 
5. Section 6.1.1 Dosing regimen: Table 6-1 has been updated to include the 10mg dose of 
pasireotide LAR that will now be permitted for dose reductions. 
6. Section 6.2.1 Dose Modifications and Dose Delays: Down titrations of pasireotide LAR 
(from 60 mg to 40 mg, from 40 mg to 20 mg and from 20 mg to 10 mg) are permitted for 
patients with IGF-1 values that fall below the lower limit of normal and have controlled 
mean GH levels. The IGF-I values are required to be confirmed to be below LLN on two 
consecutive assessments; when IGF-I is found to be decreased to <LLN, a repeat 
measurement will be performed at the following visit for confirmation purposes. If 


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biochemical control is maintained, the patient can continue on the lower dose for the 
remainder of the trial. If biochemical control is lost, the dose should be increased to the 
immediate previous dose administered. 
7. Section 6.2.1 Treatment Duration: Included guidance on dosing modifications and safety 
reporting for octreotide LAR, investigators should follow the summary of product 
characteristics (SmPc). 
8. Section 6.3.1.1: Added a recommendation for more frequent monitoring of electrolytes as 
clinically indicated in patients treated with medications that may decrease potassium 
levels (e.g. diuretics). 
9. Section 6.5 Study drug preparation and dispensation: Added information on the 
preparation of the octreotide LAR dose and that the package insert should be referenced 
for further information. 
10. Section 7.1 Study Flow and Visit Schedule: Added the flexibility for a +/-2 day window 
for the screening visit. 
11. Section 7.1.2 Screening: The language has been updated to clarify that patients can be re- 
screened as long as the cause of the screen failure is normal GH and/or IGF-1 values, 
patients can be rescreened once these parameters go beyond the control level, the patient 
has continued to receive scheduled injection of the SSAs and had at least a 3-month 
treatment with maximal doses of first generation SSAs. The protocol will also limit the 
number of times a patient can be re-screened to 2 times, and Novartis must be informed of 
the intent to re-screen a patient. 
12. Section 8.1.3 Adverse Events of Special Interest: The section has been modified to 
indicate that the list of AEs considered special interest provided in the protocol is not all 
inclusive and can be modified throughout the lifetime of the trial. 
13. Section 8.2.2 Reporting: The language was updated to ensure reporting of SAEs 84 days 
after the patient has stopped study drug administration. Also any SAEs experienced after 
the 84 days should only be reported to Novartis if the investigator suspects a causal 
relationship to the study treatment. 
14. Section 8.2.2 Reporting: The language was updated to state that if an SAE is not present in 
the Reference Safety Information section of the Investigator’s Brochure (unexpected) and 
is thought to be related to the Novartis study treatment (suspected), an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Suspected Unexpected 
Serious Adverse Reactions) 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. 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. 
15. Appendix 14.4 Pharmacy instructions for pasireotide LAR: This appendix was added to 
provide instructions on how to prepare the study doses of pasireotide LAR. 


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IRB/IEC Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. 


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Protocol summary: 
Protocol number 
CSOM230C2413 
Title 
A phase IIIb multicenter, open-label, single arm study to evaluate the efficacy and 
safety of pasireotide in patients with acromegaly inadequately controlled with first 
generation somatostatin analogues 
Brief title 
Study of efficacy and safety of pasireotide LAR in patients with inadequately 
controlled acromegaly 
Sponsor and Clinical 
Phase 
Novartis, Phase lllb 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
To evaluate the efficacy and safety of pasireotide, a second generation somatostatin 
analogue with a broader affinity to sst receptors, in patients with in adequately 
controlled acromegaly after a minimum of 3 months with high doses of first generation 
somatostatin analogues. 
Primary Objective(s) 
Primary Objective 
To evaluate the efficacy of pasireotide LAR in patients with acromegaly who are 
inadequately controlled with currently available somatostatin analogues, as measured 
by the proportion of patients with GH <1µg/L and IGF-1 <ULN at week 36 overall and 
by mGH level at screening. 
Supporting Analysis for Primary 
To assess the proportion of patients achieving GH <1µg/L and IGF-1 <ULN at week 
36 by GH level at screening. 
Secondary Objectives 
Core Phase 
To assess the changes in mean GH from study baseline to week 36. 
To assess the changes in standardized IGF-1 from study baseline to week 36. 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN at weeks 
12 and 24 overall and by GH level at screening 
To assess the proportion of patients achieving GH <1µg/L at weeks 12, 24 and 36, 
overall and by GH level at screening 
To assess the proportion of patients achieving IGF-1 levels <ULN at weeks 12, 24 
and 36 
To evaluate the tolerability and safety profile of pasireotide LAR 
To evaluate the effect of pasireotide LAR on HRQoL and signs and symptoms of 
acromegaly from baseline to weeks 12, 24 and 36 
Extension Phase 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN overall 
and by GH level at screening at weeks 48, 60 and 72 during the treatment with 
pasireotide LAR monotherapy 
To evaluate the long term tolerability and safety profile of pasireotide LAR 
To evaluate the long term effect of pasireotide LAR on HRQoL and signs and 
symptoms of acromegaly, from baseline and week 36 to week 72 
Study design 
Group 1 – Patients treated with octreotide LAR 30mg from the countries where 
octreotide LAR 40mg is approved for the treatment of acromegaly at the time of 
screening – Patients participate in the run-in phase. 
Run-In phase (Screening to Baseline) 
Patients will start treatment with octreotide LAR 40 mg every 4 weeks. Patients who 
have not achieved biochemical control after 3 injections can be enrolled in the study. 
Core Phase (Baseline to week 36) 
Patients will start treatment on pasireotide LAR 40 mg every 4 weeks until week 32. A 
mean GH value and IGF-1 value will be assessed every 12 weeks until week 36. The 
dose can be adjusted after the evaluation of biochemical control. During the core 
phase any acromegaly concomitant medication is prohibited. 


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Extension Phase (week 36 to week 72) 
Patients will receive the same dose of pasireotide LAR at week 36, which is the first 
dose of study medication in the extension phase. At week 40 the dose can be 
adjusted and acromegaly concomitant medication can be added to the treatment if, 
patients remain uncontrolled. Patients will receive pasireotide LAR 40mg/60mg until 
week 68 for a total of 32 weeks in the extension phase. A mean GH value and IGF-1 
value will be assessed every 12 weeks until week 72. 
Safety follow-up 
After discontinuation or completion of study treatment, all patients will be followed for 
safety 12 weeks (84 days) weeks after the last study drug administration. 
Group 2 – Patients treated with octreotide 30 mg from countries where octreotide 
40mg has NOT been approved for the treatment of acromegaly at screening or 
patients treated with octreotide 40mg or lanreotide 120mg - Patients who do not have 
the run-in phase. 
Core Phase (Baseline to week 36) 
Same procedure to be followed as Group1 
Extension Phase (week 36 to week 72) 
Same procedure to be followed as Group1 
Safety follow-up 
Same procedure to be followed as Group1 
Population 
The eligible patient population will consist of inadequately controlled acromegalic 
patients with first generation somatostatin analogues. The study will enroll a total 
number of 112 patients. 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Male and female patients ≥18 years of age 
3. Patients with confirmed diagnosis of inadequately controlled acromegaly as 
evidenced by the following: 
● A mean GH concentration of a 5-point profile over a 2-hour period ≥1 µg/L and 
sex- and age-adjusted IGF-1 >1.3 x ULN 
4. Patients treated with high doses of octreotide LAR (30 mg or 40 mg) or lanreotide 
ATG (120 mg) given as monotherapy for at least 3 months prior to screening (Visit 1) 
● Note: Patients currently being treated with octreotide LAR 30mg from countries 
where the 40 mg dose is approved at the time of screening will start a run- in phase 
which they will receive the 3 injections of octreotide LAR 40 mg before being 
evaluated for eligibility for the core phase of the study 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. 
Concomitant treatment with other medications known to reduce GH and or IGF-1, 
other than octreotide LAR or lanreotide ATG, unless it discontinued 3 months prior to 
visit 1 (screening) 
2. Patients with compression of the optic chiasm causing any visual field defect that 
requires surgical intervention 
3. Diabetic patients with poor glycaemic control as evidenced by HbA1c >8% at visit 
1 (screening) 
4. Patients who are hypothyroid and not on adequate replacement therapy 
5. Patients with symptomatic cholelithiasis and acute or chronic pancreatitis 
6. Patients with clinically significant valvular disease 
7. Patients with risk factors for torsade de pointes, i.e. patients with a baseline 
QTcF >450 ms in males, and >460 ms in females 
8. Hypokalaemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of 
long QT syndrome or concomitant medications with known risk of TdP. Drugs with 
possible risk of TdP should be avoided whenever feasible. 
9. Patients who have congestive heart failure (NYHA Class III or IV), unstable 


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angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced 
heart block, history of acute MI less than one year prior to study entry or clinically 
significant impairment in cardiovascular function. 
10. Concomitant disease(s) that could prolong the QT interval such as autonomic 
neuropathy (caused by diabetes or Parkinson’s disease), HIV, cirrhosis, uncontrolled 
hypothyroidism or cardiac failure 
11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic 
persistent hepatitis, or patients with ALT/AST > 2.0 X ULN, serum bilirubin >2.0 X 
ULN 
12. Presence of Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody test (anti- 
HCV) 
13. Patients with serum creatinine >2.0 X ULN 
14. Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L 
15. Patients with the presence of active or suspected acute or chronic uncontrolled 
infection 
16. Patients who have undergone major surgery/surgical therapy for any cause within 
4 weeks prior to visit 1 (screening) 
17. Patients with active malignant disease within the last five years (with the exception 
of basal cell carcinoma or carcinoma in situ of the cervix) 
18. 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) 
19. History of syncope or family history of idiopathic sudden death 
20. History of immunocompromise, including a positive HIV test result (ELISA and 
Western blot). A HIV test will not be required; however, previous medical history will 
be reviewed 
21. Known hypersensitivity to somatostatin analogues or any other component of the 
pasireotide LAR 
22. Patients who have a history of alcohol or drug abuse in the 6 month period prior 
to receiving pasireotide 
23. Patients who have given a blood donation (of 400 ml or more) within 2 months 
before receiving pasireotide 
24. Patients who have participated in any clinical investigation with an investigational 
drug within 1 month prior to dosing 
25. Patients with any current or prior medical condition that, in the judgment of the 
investigator may interfere with the conduct of the study or the evaluation of the study 
results 
26. 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. 
27. Sexually active males unless they use a condom during intercourse while taking 
drug and for 3 months following last dose of pasireotide 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. 
28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test. 
29. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and 3 months following the last dose of pasireotide. Highly effective 
contraception methods include: 
● Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
● Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
● Male sterilization (at least 6 months prior to screening). For female subjects on 
the study the vasectomized male partner should be the sole partner for that subject. 
● Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or 


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other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
Investigational and 
reference therapy 
pasireotide LAR 40mg and 60mg, octreotide LAR 40mg 
Efficacy assessments 
● A 5-point GH 
● IGF1 
● Acromegaly symptoms 
● Health-related Quality of Life 
Safety assessments 
● Physical examination 
● Vital signs 
● Laboratory evaluations (hematology, clinical chemistry, liver function testing, 
coagulation, urinalysis) 
● Pregnancy 
● Gallbladder ultrasound 
● Cardiac assessments 
Other assessments 
NA 
Data analysis 
The primary variable is the proportion of patients who achieved GH < 1µg/L and IGF- 
1 < ULN at week 36. This proportion will be provided along with its asymptotic (or 
exact, depending on the sample size) 95% CI. Secondary objectives which are 
measured by proportions will be similarly reported. Descriptive summaries of actual 
and percentage change in GH, actual and percentage change in standardized IGF-1, 
from study baseline to week 36 values will be provided. Change in standardized 
scores as measured by HRQoL and signs and symptoms of acromegaly from 
baseline and week 36 to week 72 will be provided. 
Key words 
acromegaly, pasireotide LAR, octreotide LAR, 5-point GH, IGF-1 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Acromegaly is a rare growth disorder characterized by a clinical syndrome resulting primarily 
from the effects of excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on 
various organ systems. Acromegaly is caused by a GH-secreting pituitary adenoma in more 
than 90% of patients. The prevalence of acromegaly is estimated to be 40 to 70 cases per 
million, with an annual incidence of 3 to 4 new cases per million (Holdaway and Rajasoorya 
1999). However, recent studies suggest that pituitary adenomas may be more prevalent than 
previously thought, and that the prevalence of acromegaly may be well over 100 cases per 
million (Rosario 2011, Daly et al 2006). 
The clinical manifestations of acromegaly are due to the peripheral actions of the GH excess 
and elevated IGF-1 concentrations and/or local tumor mass effect. The symptoms and signs of 
acromegaly can be divided 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 (Becker et al 2000). 
The therapeutic goals in acromegaly are to reduce mortality to the expected age and sex 
adjusted rates by using treatments that remove the tumor mass and/or control its growth and 
restore GH secretion and action to normal. In the past, the biochemical goals of therapy were 
to reduce the circulating IGF-1 levels to normal for age and sex and to reduce serum GH 
concentrations to <2.5 µg/L (mean GH concentration of a 5-point profile within a 2-hour time 
period) or to less than 1 µg/L after an oral glucose load (Giustina et al 2000). Current 
guidelines recommend GH levels <1 µg/L and normalization of IGF-1 as biochemical goals of 
therapy (Melmed et al 2010). 
Treatment modalities for acromegaly include surgery, radiotherapy or treatment with drugs. 
Surgery: transphenoidal surgery is the most frequently recommended treatment however 
surgical effectiveness varies depending on expertise in pituitary surgery, on the size and 
extension of the anatomic mass, and the preoperative levels of GH. 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 throughout their lifespan 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 medications. 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 drugs in rare cases as primary treatment. It is usually reserved for patients  
who have tumor remaining after surgery, for patients who are not good candidates for surgery 


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because of other health problems; and for patients who do not respond adequately to surgery 
and medication. This treatment generally lowers GH levels over a 2-year timeframe, although 
late effects can occur in some cases. Radiation therapy causes a gradual loss of production of 
other pituitary hormones with time which can result in the undesired effect of 
panhypopituitarism. Loss of vision and brain injury, which have been reported, can be 
complications from radiation treatment. 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: the medical treatment options for acromegaly include somatostatin 
analogues, growth hormone antagonists and dopamine agonists. 
Somatostatin analogues have proven to be safe, well-tolerated and effective and are the 
medical treatment of choice for patients with acromegaly. The currently marketed 
somatostatin analogues are octreotide (Sandostatin®) and lanreotide (Somatuline®). Octreotide 
has been available for over 20 years and is considered the world-wide gold standard medical 
treatment for acromegaly. Other medical treatment options are growth hormone antagonists 
and dopamine agonists. 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of pasireotide (SOM230) 
Pasireotide (SOM230) is a cyclohexapeptide, SSA with the following chemical name: (2- 
Aminoethyl)carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4- 
benzyloxybenzyl)-14-(1H-indol-3ylmethyl)-4,7,10,13,16,19-hexaoxo-17- 
phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadeen-2-yl 
ester, 
di[(S)- 
2aminosuccinic acid] salt. Like natural somatostatin and other SSAs, pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors (sst.). Somatostatin is an 
endogenous peptide that modulates a number of exocrine and endocrine secretions. There are 
five known somatostatin receptors: sst1, 2, 3, 4 and 5 as outlined in Table 1-1. When 
compared to octreotide, pasireotide has a binding affinity which is 30-40 times greater for sst1 
and sst5, 5 times greater for sst3, and a comparable affinity for sst2 (Schmid and Brueggen 
2012). Somatostatin receptors are expressed in different tissues under normal physiological 
conditions as well as in many solid tumors, especially in neuroendocrine tumors where 
hormones are excessively secreted, e.g. acromegaly, gastroenteropancreatic neuroendocrine 
tumor (GEP/NET) and Cushing’s disease (Freda 2002, Oberg et al 2004 and Van der Hoek et 
al 2005). A detailed summary of available preclinical data is provided in the current 
[Investigator’s Brochure]. 
 
Table 1-1 
Binding profiles for octreotide and pasireotide at hsst1-5 (IC50, mol/L) 
 
Compound 
sst1 
sst2 
sst3 
sst4 
sst5 
Octreotide acetate (SMS995) 
2.8x10-7 
3.8x10-10 
7.1x10-9 
>10-6 
6.3x10-9 
Pasireotide (SOM230) 
9.3x10-9 
1.0x10-9 
1.5x10-9 
>10-6 
1.6x10-10 
Ratio of IC50:octreotide 
acetate/pasireotide 
(SMS995/SOM230) 
30 
0.4 
5 
-- 
39 


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1.2.1.1 
Non-clinical experience 
Preclinical data on binding affinity and functional activity in vitro and efficacy on hormone 
secretion in vivo have been obtained with the s.c. formulation in rats, dogs, mice and monkeys. 
Long-term in vivo studies performed using drug application by osmotic mini-pumps (Bruns 
2002, Weckbecker 2002) have shown not only that the inhibitory effect of pasireotide was 
stronger, but also that there was less response escape (Bruns 2002) and (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. 
A detailed summary of available preclinical data is provided in the current [Investigator’s 
Brochure]. 
 
1.2.1.2 
Clinical experience 
The clinical development program for pasireotide has focused on endocrine-related 
pathologies. Two formulations of pasireotide are currently in development: an immediate 
release formulation for subcutaneous (s.c.) injection and a long-acting release (LAR) 
formulation for i.m. injection. These formulations have been characterized by Phase 1 studies 
in healthy volunteers, and Phase 1 - 3 studies in patients with acromegaly, Cushing’s disease, 
and gastroenteropancreatic neuroendocrine tumors. 
The pasireotide s.c. formulation (Signifor®) is currently approved in more than 50 countries 
worldwide for the treatment of Cushing’s disease. 
The efficacy and safety of pasireotide LAR in acromegaly are primarily derived from two 
large, randomized Phase 3 studies comparing pasireotide LAR with active controls 
(superiority design): 
• Study [SOM230C2305] compared pasireotide LAR with octreotide LAR in medically 
naïve patients with active acromegaly. In this study, pasireotide LAR was shown to be 
significantly superior to octreotide LAR for the treatment of acromegaly in medically 
naïve patients in terms of biochemical control (GH < 2.5 μg/L and normalization of IGF-1 
levels) (31.3% vs. 19.2%; p-value 0.007), providing higher response rate in both de novo 
patients and in patients with prior pituitary surgery (25.7% vs. 17.3% in de novo patients; 
39.4% vs. 21.8% in post-surgical patients). Pasireotide LAR was as effective as octreotide 
LAR in reducing tumor volume, improving acromegaly symptoms and ring size, and 
quality of life [CSOM230C2305]. 
• Study [SOM230C2402] compared double-blind pasireotide LAR 40 mg and pasireotide 
LAR 60 mg with open-label octreotide LAR or lanreotide ATG– active control - in 
patients with inadequately controlled acromegaly. This study showed that both pasireotide 
LAR doses (40 mg and 60 mg) are superior to active control (octreotide LAR 30 mg or 
lanreotide ATG 120 mg). The proportion of responders at Week 24 was significantly 
higher with pasireotide LAR 40 mg (15.4%, 95% CI 7.63, 26.48) and pasireotide LAR 60 
mg (20.0%, 95% CI 11.10, 31.77) than in patients who continued their previous treatment 
(0%) (p=0.0006 and <0.0001 for pasireotide LAR 40 mg and 60 mg, respectively). Both 
pasireotide doses were superior to active control in normalizing IGF-1 levels and in 


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reducing GH to <2.5 μg/L. The proportion of patients with a reduction of GH to <2.5 μg/L 
at Week 24 was highest in the pasireotide LAR 60 mg arm (43.1%), followed by the 
pasireotide LAR 40 mg arm (35.4%), and the active control arm (13.2%) The proportion 
of patients who achieved normalization of IGF-1 at Week 24 (key secondary efficacy 
variable) was significantly higher in both pasireotide arms (24.6% and 26.2% responders) 
compared to the active control arm (zero responders) 
The safety of pasireotide has been well characterized in 491 patients with acromegaly (419 
patients using the LAR formulation, and 72 patients using the s.c. formulation). In addition, 
pasireotide s.c. and LAR formulations have been used in over 750 other subjects including 
healthy volunteer and special safety studies. The safety findings in patients with acromegaly 
are in line with expected pharmacodynamic effects of pasireotide, based on both preclinical 
and clinical experience, and are consistent with the known side effects of approved SSAs 
(with the exception of an increased incidence and magnitude of hyperglycemia) 
A detailed summary of the clinical data (including safety and PK) is provided in the current 
[Investigator’s Brochure]. 
 
2 
Rationale 
2.1 
Study rationale and purpose 
Pasireotide (SOM230) is a second generation SSA with a higher affinity to a greater number 
of somatostatin receptors compared to octreotide and lanreotide, which results in improved 
efficacy in acromegaly. Pituitary GH-secreting tumors primarily express SSTR2 and 5 (and to 
a lesser extent SSTR1 and 3). The currently available SSAs octreotide and lanreotide have 
high affinity for SSTR2, and low affinity for the remaining receptor subtypes. Although 
SSTR2 is considered the pivotal receptor subtype for regulation of GH secretion, its 
expression is variable and this may at least in part explain resistance or partial response to 
octreotide or lanreotide therapy observed in some patients. Recent data suggest that 
approximately 50% of the patients are not biochemically controlled with currently available 
SSAs (Carmichael et. all 2014). In a recently completed phase III study in medically naive 
acromegalic patients, the largest in this population, 19% of patients treated with octreotide 
LAR achieved biochemical control after one year of treatment. 
Results of clinical studies currently available with pasireotide indicate that it is a safe and 
effective treatment in patients with acromegaly. The purpose of this study is to evaluate the 
efficacy and safety of pasireotide LAR, in patients with acromegaly who are inadequately 
controlled after a minimum of 3 months with maximal approved doses of first generation 
somatostatin analogues (octreotide LAR 30 mg or 40 mg– depending on the country - or 
lanreotide ATG 120mg). The recently completed SOM230C2402 study in biochemically 
uncontrolled patients after at least 6 months of treatment with high doses of octreotide LAR or 
lanreotide ATG showed that no further benefit was achieved when this therapy was continued 
with patients achieving neither biochemical control nor normal IGF-1. Therefore, an earlier 
treatment change to pasireotide LAR might be beneficial for these patients. 
In addition, a new consensus has been reached on the definition of controlled acromegaly: 
GH<1.0 µg/L in association with normal IGF-I levels (Giustina et al 2014). Therefore, the 


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new study will enrol patients that satisfy the new criteria of uncontrolled acromegaly – 
GH≥1.0 µg/L and IGF-I>1.3xULN - and it will provide data not only in the patients with a 
GH>2.5 µg/L but also, for the first time, in the patients with a GH level between 1.0 and 2.5 
µg/L that are known to represent a large group of patients with inadequately controlled 
acromegaly. 
 
2.2 
Rationale for the study design 
The study is an open-label, single-arm; multi-centre international study to evaluate the safety 
and the efficacy of pasireotide LAR in patient with inadequately controlled acromegaly after a 
minimum of 3 months with high doses of the first generation somatostatin analogues. 
A single-arm, open-label study design was chosen since the objective of this study is to obtain 
further data of the efficacy and safety of pasireotide LAR in patients with acromegaly, but not 
as confirmation of efficacy. Efficacy of pasireotide in patients not controlled with other 
somatostatin analogues was already demonstrated in Study [CSOM230C2402], a double- 
blinded controlled study, in which patients randomized to the active control (octreotide LAR 
30mg or lanreotide ATG 120mg) did not achieve biochemical control with further treatment 
whereas patients randomly allocated to pasireotide LAR 40 mg or 60 mg were able to achieve 
biochemical control for the very first time. Additionally, the natural history of the disease is 
well understood and placebo effects on efficacy evaluations are negligible. 
The primary objective of the study was chosen based on the new published criteria for 
diagnosis and management of acromegaly (Giustina et al 2014). Elevated GH and IGF-1 
levels are predictors of mortality, and lowering GH and normalizing IGF-1 results in mortality 
rates similar to those expected in the general population. The definition of a safe GH level  
was updated, due to the new more sensitive and specific assays. This new guideline 
recommends reducing GH to levels as close to normal as possible. According to this 
consensus document optimal disease control is now defined as IGF-1 level in the sex and age- 
adjusted normal range and a GH level less than 1.0 µg/L. This data will complement the 
results obtained in study C2402, where patients achieving the previous definition of 
biochemical control (i.e. GH levels <2.5µg/L and normalization of IGF-1) were reported. 
 
2.3 
Rationale for dose and regimen selection 
The pasireotide LAR dose for acromegaly patients is based on the study CSOM230C2305. It 
was a multi-center, randomized, blinded study to assess the safety and efficacy of pasireotide 
LAR vs. octreotide LAR in patients with active acromegaly. The results of the study 
demonstrated that pasireotide LAR 40 mg every 28 days is superior to octreotide LAR 20 mg 
every 28 days in providing biochemical control in patients with medically naïve acromegaly 
i.e., suppression of GH levels to < 2.5 μg/L and normalization of IGF-1 [CSOM230C2305]. 
Patients enrolled in this study will start with pasireotide LAR 40 mg every 28days. 
Study [CSOM230C2402] demonstrated that both doses of pasireotide LAR 40mg and 60 mg 
are efficacious in patients inadequately controlled on octreotide LAR and lanreotide ATG. 
Based on these data, patients should be evaluated for clinical benefit 3 months (84 days) after 
the start of pasireotide LAR 40 mg (i.m.) therapy. A dose increase to 60 mg every 28 days 
will be mandated after 12 weeks of pasireotide LAR treatment if adequate levels of GH and 


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IGF-1 are not observed with the 40 mg dose (no reduction of mean GH level to < 1.0µg/L and 
no decrease of IGF-1 to within normal limits (age and sex related) and provided there are no 
safety concerns. 
Management of suspected adverse reactions may require temporary dose reduction of 
pasireotide LAR. Dose reduction by decrements of 20 mg every 28 days is recommended. 
Dose increase and dose reduction is to be based on investigator’s assessment of risk and 
benefit for the patient. 
In the case of octreotide LAR, in order to be enrolled in the study, patients should have been 
treated with 30 or 40 mg for at least three months and not achieved biochemical control. 
Octreotide LAR 30mg has been approved and available for over 20 years: octreotide LAR 
40mg is not approved/available in all countries. Patients enrolled in countries where the 40mg 
dose is approved, must be treated with this dose prior to enrollment or during the run-in phase 
of the study. 
 
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 
To evaluate the efficacy of pasireotide LAR in patients with 
acromegaly who are inadequately controlled with maximal approved 
doses of currently available somatostatin analogues, as measured by 
the proportion of patients with GH <1µg/L and IGF-1 <ULN at week 
36 
Proportion of patients who achieved GH <1µg/L and IGF-1 <ULN at 
week 36. 
Supporting Analysis for Primary 
Refer to Section 10.4.4 
To assess the proportion of patients achieving GH <1µg/L and IGF-1 
<ULN at week 36 by GH level at screening. 
Proportion of patients who achieved GH <1µg/L and IGF-1 <ULN at 
week 36 in patients having GH level at screening between 1 µg/L 
and 2.5 µg/L, and in patients having GH level at screening >2.5 µg/L 
Secondary- core phase 
Refer to Section 10.5.1 
To assess the changes in mean GH from study baseline to week 36 
Changes in mean GH from study baseline to week 36. 
To assess the changes in standardized IGF-1 from study baseline to 
week 36 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 
<ULN at weeks 12 and 24 overall and by GH level at screening 
To assess the proportion of patients achieving GH <1µg/L at weeks 
12, 24 and 36, overall and by GH level at screening 
To assess the proportion of patients achieving IGF-1 levels <ULN at 
weeks 12, 24 and 36 
Changes in standardized IGF-1 from study baseline to week 36. 
 
Proportion of patients who achieved GH <1µg/L and IGF-1 <ULN at 
week 12 and 24 overall and by GH level at screening. 
Proportion of patients who achieved GH <1µg/L at week 12, 24 and 
36 overall and by GH level at screening. 
Proportion of patients who achieved IGF-1 <ULN at week 12, 24 
and 36. 
To evaluate the tolerability and safety profile of pasireotide LAR 
Toxicity will be assessed using the National Cancer Institute- 
Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE 
v.4.03) and for laboratory assessments that include biochemistry, 
hematology, urinalysis; special safety assessments that include the 
regular monitoring and recording of blood glucose, insulin, HbA1c, 
GH and IGF-1, thyroid and liver function tests, gallbladder 
examinations and ECGs. Concomitant medications/Significant 
nondrug therapies will be assessed from study enrollment until the 
safety follow-up. 
To evaluate the effect of pasireotide LAR on HRQoL and signs and 
symptoms of acromegaly from baseline to weeks 12, 24 and 36 
Change in scores as measured by AcroQoL, EQ-5D-5L and signs 
and symptoms of acromegaly from baseline to weeks 12, 24 and 36 


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Objective 
Endpoint 
Analysis 
Secondary – extension phase 
Refer to Section 10.5.2 
To assess the proportion of patients achieving IGF-1 <ULN at weeks 
48, 60 and 72 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 
<ULN at weeks 48, 60 and 72 by treatment with pasireotide LAR 
alone or with concomitant medications used to treat acromegaly 
To assess the proportion of patients achieving GH <1 µg/L at weeks 
48, 60 and 72 by treatment with pasireotide LAR alone or with 
concomitant medications used to treat acromegaly 
To evaluate the long term tolerability and safety profile of pasireotide 
LAR 
 
 
 
 
 
 
To evaluate the long term effect of pasireotide LAR on HRQoL and 
signs and symptoms of acromegaly, from baseline and week 36 to 
week 72 
Proportion of patients who achieved IGF-1 <ULN at weeks 48, 60 
and 72 
Proportion of patients who achieved GH <1 µg/L and IGF-1 <ULN at 
weeks 48, 60 and 72 by treatment with pasireotide LAR alone or 
with concomitant medications used to treat acromegaly 
Proportion of patients who achieved GH <1 µg/L at weeks 48, 60 
and 72 by treatment with pasireotide LAR alone or with concomitant 
medications used to treat acromegaly 
Toxicity will be assessed using the National Cancer Institute- 
Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE 
v.4.03) and for laboratory assessments that include biochemistry, 
hematology, urinalysis; special safety assessments that include the 
regular monitoring and recording of blood glucose, insulin, HbA1c, 
GH and IGF-1, thyroid and liver function tests, gallbladder 
examinations and ECGs. Concomitant medications/Significant 
nondrug therapies will be assessed from study enrollment until the 
safety follow-up. 
Change in scores as measured by AcroQoL, EQ-5D-5L and signs 
and symptoms of acromegaly from baseline to week 72 and from 
week 36 to week 72. 


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4 
Study design 
4.1 
Description of study design 
This is a phase IIIb multicenter, open-label; single arm study to evaluate the efficacy and 
safety of pasireotide LAR 40 mg and 60 mg in patients with inadequately controlled 
acromegaly with maximal doses of first generation somatostatin analogues. The study will 
enroll inadequately controlled patients by high doses of first -generation somatostatin 
analogues given for at least 3 months. 
 
Figure 4-1 
Flow Chart for Group 1 and Group 2 Patients 
 
Group 1 – It consists of patients treated with octreotide LAR 30 mg from countries where 
octreotide LAR 40mg is approved for the treatment of acromegaly at the time of screening – 
These patients will start a run-in phase to receive 40mg octreotide before being considered 
eligible to enter the core treatment phase. 


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❑ Pts treated with octreotide 
30mg from the countries 
where octreotide 40mg has 
been approved at the 
screening 
 
Figure 4-2 
Study Design; Group 1 
 
Screening 
Core 
*Extension 
FU 
 
 
*Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 
 
Run-In phase (Screening to Baseline) 
Patients treated with octreotide LAR 30 mg who meet all inclusion criteria and no exclusion 
criteria will start treatment with octreotide LAR 40 mg in the run-in phase. Patients must have 
been treated with octreotide LAR 30 mg for at least three months before the screening visit. 
Patients will start treatment in the run-in phase and will receive octreotide LAR 40 mg every 4 
weeks. After 3 months of treatment have been completed, and prior to the fourth injection (at 
visit 5), a mean GH and IGF-1 will be assessed. 
Patients who are achieving biochemical control will be considered a screen failure and they 
will not qualify for the core phase of the study. They will continue treatment with octreotide 
LAR 40 mg outside the frame of this study. 
 
Core Phase (Baseline to Visit 777) 
Patients treated with octreotide LAR 40 mg in the run-in phase that meet all inclusion criteria 
and no exclusion criteria will be enrolled in the core phase of the study. The evaluation at the 
last visit of the run-in phase must be used for the eligibility assessment. Patients will start 
treatment with pasireotide LAR 40 mg every 4 weeks. At week 12, the mean GH value and 
IGF-1value will be assessed. Patients who have not achieved biochemical control by week 12 
and do not have any tolerability issues with pasireotide LAR 40 mg will have the dose 
increased to 60 mg. Patients who have achieved biochemical control by week 12 will maintain 
a dose of pasireotide LAR 40 mg. A mean GH value and IGF-1 value will be assessed every 
12 weeks until Visit 777. At weeks 16 and 28, the investigator will be able to adjust the dose 
based on the achievement of biochemical control and drug tolerability. If tolerability issues 
occur, the dose can be decreased in 20 mg. Once the tolerability issue resolves, the patients 
should return to the dose previously received. Patients will be treated for a total of 36 weeks 
during the core phase. During this period any concomitant medication for the treatment of 
acromegaly is prohibited. Patients are required to complete a core phase completion visit 4 
weeks after the last dose of pasireotide LAR is administered. Patients who discontinue from 
Safety follow up 
pasireotide 40mg or 
60mg 
pasireotide 
40mg or 
60mg 
pasireotide 
40mg 
Run-In 
octreoti 
de 40mg 
Screening 


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the core phase are also required to complete the core phase completion visit 4 weeks after 
receiving the last pasireotide LAR dose. 
 
Extension Phase (Visit 18 to Visit 778) 
Patients who have completed all visits of core phase and have completed all the assessments 
at the core phase completion visit (Visit 777) can move into the extension phase. The core 
phase completion visit performed at Visit 777, will also be the first visit (Visit 18) of the 
extension phase. At Visit 18, the patients will receive the same dose of pasireotide LAR that 
they received at week 32 (Visit 17). At week 40 (Visit 19), the investigator will decide the 
treatment regimen and the pasireotide LAR dose based on the achievement of biochemical 
control at Visit 777. Patients achieving biochemical control at the end of the core phase will 
continue pasireotide LAR monotherapy at the same dose of the core phase. Patients who are 
uncontrolled at the end of the core phase will continue pasireotide LAR 60 mg and they will 
be allowed to receive concomitant treatment with medications used to treat acromegaly based 
on the investigator’s clinical judgment. GH and IGF-1 levels will be assessed every 12 weeks 
until week 72. At weeks 52 and 64, the investigator will be able to adjust the dose of 
pasireotide LAR and the regimen of the concomitant medication used to acromegaly based on 
the patients achievement of biochemical control and drug tolerability. Patients will be treated 
for a total of 32 weeks in the extension phase and receive the last dose of study treatment at 
week 68 (Visit 26). Patients are required to complete an extension phase completion visit 
(Visit 778) 4 weeks after the last dose of pasireotide LAR is administered. Patients who 
prematurely discontinue from the extension phase are also required to complete the extension 
phase completion visit (Visit 778) 4 weeks after receiving the last dose of pasireotide LAR. 
 
Safety follow-up 
After discontinuation from the study or completion of study treatment either at the core phase 
or extension phase of the study, all patients will be followed for safety for 12 weeks (84 days) 
after the last study drug administration. This visit can be performed by phone, a study visit for 
follow-up is not mandatory. 
Group 2 – It consists of patients treated with octreotide LAR 30 mg from countries where 
octreotide 40mg is NOT yet approved at the time of screening. This group also include 
patients already treated with octreotide LAR 40 mg or lanreotide ATG 120 mg. Patients 
should have been treated with the first generation SSAs for at least 3 months prior to 
screening. Eligible patients can directly enter the core treatment phase of the study. –A run-in 
phase is not required for this patient population. 


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Figure 4-3 
Study Design; Group 2 
 
Screening 
Core 
*Extension 
FU 
 
* Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 
 
Core Phase (Baseline to Visit 777) 
Please refer to the core phase for Group 1. 
 
Extension Phase (Visit 18 to Visit 778) 
Please refer to the extension phase for Group 1. 
 
Safety follow-up 
Please refer to Safety follow-up for Group 1. 
 
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 will occur when all patients have completed their study 
completion visit and the follow up visit as per Table 7-1 and Table 7-2 (core phase) and  
Table 7-3 (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 7.1.5 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. 
❑ Pts treated with 
octreotide 30mg from 
the countries where 
octreotide 40mg has 
NOT been approved 
at the screening 
❑ Pts treated with 
octreotide 40mg 
❑ Pts treated with 
lanreotide 120mg 
pasireotide 
40mg 
Safety follow up 
pasireotide 40mg or 
60mg 
pasireotide 
40mg or 
60mg 
Screening 


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5 
Population 
5.1 
Patient population 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Male and female patients ≥ 18 years of age 
3. Patients with confirmed diagnosis of inadequately controlled acromegaly as evidenced by 
the following: 
• A mean GH concentration of a 5-point profile over a 2-hour period ≥ 1 µg/L and sex- 
and age-adjusted IGF-1 >1.3 x ULN 
4. Patients treated with high dose of octreotide LAR (30 mg or 40 mg) or lanreotide ATG 
(120 mg) given as monotherapy for at least 3 months prior to screening (Visit 1) 
• Note: Patients currently being treated with octreotide LAR 30 mg from countries 
where the octreotide LAR 40 mg dose is approved at the time of screening will start a 
run- in phase in which they will receive the 3 injections of octreotide LAR 40 mg 
before being evaluated for eligibility for the core phase of the study 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Concomitant treatment with other medications known to reduce GH and or IGF-1, other 
than octreotide LAR or lanreotide ATG, unless discontinued 3 months prior to visit 1 
(screening) 
2. Patients with compression of the optic chiasm causing any visual field defect that requires 
surgical intervention 
3. Diabetic patients with poor glycaemic control as evidenced by HbA1c >8% at Visit 1 for 
Group 2 and at both Visit 1 and Visit 5 for Group 1 
4. Patients who are hypothyroid and not on adequate replacement therapy 
5. Patients with symptomatic cholelithiasis and acute or chronic pancreatitis 
6. Patients with clinically significant valvular disease 
7. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >450 
ms in males, and >460 ms in females 
8. Hypokalaemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long 
QT syndrome or concomitant medications with known risk of Torsades de pointes (TdP). 
Drugs with posible risk of TdP should be avoided whenever feasible. 
9. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, 
history of acute MI less than one year prior to study entry or clinically significant 
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10. Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy 
(caused by diabetes or Parkinson’s disease), HIV, cirrhosis, uncontrolled hypothyroidism 
or cardiac failure 
11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent 
hepatitis, or patients with ALT/AST > 2.0 X ULN, serum bilirubin >2.0 X ULN 
12. Presence of Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody test (anti-HCV) 
13. Patients with serum creatinine >2.0 X ULN 
14. Patients with WBC <3 X 109/L; Hb 90% < LLN; PLT <100 X 109/L 
15. Patients with the presence of active or suspected acute or chronic uncontrolled infection 
16. Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks 
prior to visit 1 (screening) 
17. Patients with active malignant disease within the last five years (with the exception of 
basal cell carcinoma or carcinoma in situ of the cervix) 
18. 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) 
19. History of syncope or family history of idiopathic sudden death 
20. History of immunocompromise, including a positive HIV test result (ELISA and Western 
blot). A HIV test will not be required; however, previous medical history will be reviewed 
21. Known hypersensitivity to somatostatin analogues or any other component of the 
pasireotide LAR 
22. Patients who have a history of alcohol or drug abuse in the 6 month period prior to 
receiving pasireotide 
23. Patients who have given a blood donation (of 400 ml or more) within 2 months before 
receiving pasireotide 
24. Patients who have participated in any clinical investigation with an investigational drug 
within 1 month prior to dosing 
25. Patients with any current or prior medical condition that, in the judgment of the 
investigator may interfere with the conduct of the study or the evaluation of the study 
results 
26. 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 
27. Sexually active males unless they use a condom during intercourse while taking drug and 
for 3 months following last dose of pasireotide 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. 
28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test 
29. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and 3 months following last dose of pasireotide. Highly effective 
contraception methods include: 


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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject 
• Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential. 
 
6 
Treatment 
6.1 
Study treatment 
Pasireotide LAR 40 mg or 60 mg will be administered as intra-muscular (i.m.) injections 
every 4 weeks for the core and the extension phases of the study. Patients will begin their 
treatment with pasireotide LAR 40mg every 4 weeks. Dose down-titrations are permitted for 
patients who do not tolerate the protocol-specified dosing schedule. These dose adjustments 
are permitted in order to allow the patient to continue the study treatment. If tolerability issues 
occur, the dose is permitted to decrease by 20 mg. Please refer to Section 6.2.1 for further 
instructions of dose adjustments. Octreotide LAR 40mg will be administered as intra- 
muscular injections every 4 weeks for the run-in phase if it applies. Dose up-titration of 
pasireotide LAR to 60 mg will be allowed after 12 weeks of treatment (i.e. after 3 injections) 
in patients who do not achieve adequate biochemical control and the 40mg is well tolerated. 
Prior to dose escalation it is recommended that glucose homeostasis is adequately controlled 
and that patients with HbA1c >8% should not have the dose of the pasireotide LAR increased 
to 60 mg. 


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6.1.1 
Dosing regimen 
 
Table 6-1 
Dose and treatment schedule 
Pharmaceutical form and 
 
 
 
 
Frequency and/or 
Study treatments 
route of administration 
Dose 
Regimen 
 
 
Pasireotide LAR 
intra-muscular 
10mg, 20mg, 40mg, 60 mg 
every 4 weeks 
Octreotide LAR 
intra-muscular 
40mg 
every 4 weeks 
Group 1 – Dosing Regimen 
 
Figure 6-1 
Group 1: Dose Regimen 
 
* Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 


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Group 2 – Dosing Regimen 
 
Figure 6-2 
Group 2: Dose Regimen 
 
 
* Patients who do not achieve biochemical control at the end of the core phase (or at any time during 
the extension phase) will be allowed to use concomitant medications used to treat acromegaly based 
on the investigator’s clinical judgment. 
 
6.1.2 
Ancillary treatments 
Not applicable. 
 
6.1.3 
Rescue medication 
Not applicable. 
 
6.1.4 
Guidelines for continuation of treatment 
For guidelines for continuation of treatment, refer to Section 6.2 Dosing modification. 
6.1.5 
Treatment duration 
Run-in Phase (Group 1 only) 
Patients in this group will receive octreotide LAR 40 mg for 16 weeks in total. After the third 
month, biochemical control will be assessed for the eligibility criteria. 
 
Core phase 
Patients will continue to receive pasireotide LAR 40 mg or 60 mg until week 3 6, when all 
assessments will be done(Visit 18), receiving the last injection for the core phase at week 32 
(Visit17). 


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Extension phase 
At the end of the core phase, patients will have the option to continue study treatment with 
pasireotide LAR until week 68 (Visit 26). Patients who are not biochemically controlled 
during the extension will be allowed to receive concomitant treatment with medications used 
to treat acromegaly. 
Patients can continue with study treatment until pasireotide LAR is commercially available 
and reimbursed in their respective country or until 68 weeks whichever occurs first. If 
pasireotide LAR is not commercially available and reimbursed and the patient is still 
receiving clinical benefit at 68 weeks as assessed by the investigator, the patient will have the 
opportunity to receive pasireotide LAR via a roll over study or a local access program if 
available. 
 
6.1.6 
Dose escalation guidelines 
Not applicable. 
 
6.2 
Dose modifications 
6.2.1 
Dose modification and dose delay 
Patients will begin their treatment with pasireotide LAR 40 mg every 4 weeks. Dose up- 
titration of pasireotide LAR to 60 mg will be allowed after 12 weeks of treatment (i.e. after 3 
injections) in patients who do not achieve adequate biochemical control and the 40 mg is well 
tolerated. Prior to dose escalation it is recommended that glucose homeostasis is adequately 
controlled and that patients with HbA1c >8% should not have the dose of the pasireotide LAR 
increased to 60 mg. 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. If tolerability issues 
occur, the dose is permitted to decrease by 20 mg. Once the tolerability issue resolves, the 
dose should be returned to the one prior to the dose reduction. For guidance refer to Table 6-2. 
Down titrations of pasireotide LAR (from 60 mg to 40 mg, from 40 mg to 20 mg and from 20 
mg to 10 mg) are permitted for patients with IGF-1 values that fall below the lower limit of 
normal and have controlled mean GH levels. The IGF-I values are required to be confirmed to 
be below LLN on two consecutive assessments; when IGF-I is found to be decreased to < 
LLN, a repeat measurement will be performed at the following visit for confirmation 
purposes. If biochemical control is maintained, the patient can continue on the lower dose for 
the remainder of the trial. If biochemical control is lost, the dose should be increased to the 
immediate previous dose administered. 


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Table 6-2 
Guideline for treatment of patients experiencing adverse events 
LAR 
treatment 
Adverse event 
Action 
Pasireotide LAR i.m. 
AE CTC grade ≤ 2 
No drug adjustments 
AE CTC grade ≥ 3 and assessed 
as study drug related 
Reduce pasireotide LAR i.m. dose by 
20 mg 
If the AE improves to grade ≤ 2 before the next 
administration, increase dose back to the prior dose. 
If the dose is increased and the AE recurs at a grade 
≥ 3, the dose should be reduced again. The patient 
should stay on this lower dose if clinical benefits are 
maintained. No further dose titrations are allowed. 
If the AE does not improve to grade ≤ 2, the dose is 
to be reduced further if clinical benefits are 
maintained. If the AE does not improve to grade ≤ 2 
on the minimum study dose, the treatment should be 
stopped. The patient should be discontinued and 
followed up for safety. 
 
For the management of hyperglycemia, QT prolongation and LFT increases refer to specific instructions provided 
in Section 6.2.2.3, Section 6.2.2.1, and Section 6.2.2.2. 
 
For guidance on dosing modifications and safety reporting for octreotide LAR refer to the 
summary of product characteristics (SmPc). 
These changes must be recorded on the Dosage Administration Record CRF. 
 
6.2.2 
Follow-up for toxicities 
 
6.2.2.1 
QT-prolongation 
The results of the ECGs, cardiac examination and any recommendation provided by the 
cardiologist must be evaluated by the investigator to determine whether the patient should 
continue in the trial or not (discontinuation criteria to be followed). 
 
6.2.2.1.1 480 msec < QTcF ≤ 500 msec 
If at any visit a 480 msec < QTcF ≤ 500 msec is observed for a first time for a patient at a 
given dose level, the following steps need to be taken (refer to Figure 6-3): 
A cardiology consultation must be sought as soon as practical but within 7 days of the initial 
finding of abnormal ECG and the cardiologist must re-evaluate the ECG. The study treatment 
will be postponed until a cardiologist has re-evaluated the ECG. 
• If a QTcF > 480 msec is NOT confirmed, no further action needs to be taken. 
• If a QTcF > 480 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). 


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• If following the examination by the cardiologist, the investigator considers that there 
is no acute cardiovascular safety risk the patient could continue to receive study 
medication. 
 
Figure 6-3 
QT prolongation flowchart: 480 msec less than QTcF less than or 
equal to 500 msec 


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6.2.2.1.2 QTcF > 500msec 
If at any visit a QTcF > 500msec is observed, the following steps need to be taken (refer to 
Figure 6-4): 
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 > 500msec, the patient has to postpone study treatment until a cardiologist has re-evaluated 
the ECG. The re-evaluation needs to be done as soon as practical but within 7 days of the 
initial finding of abnormal ECG. 
• If the cardiologist confirms a mean QTcF > 500msec, the patient has to be withdrawn 
from the study. 
• Otherwise and if the cardiologist confirms that at least one ECG shows a QTcF > 480msec, 
the cardiac assessments described for a confirmed QTcF > 480msec need to be followed. 


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Figure 6-4 
QT prolongation flowchart; QTcF greater than 500msec 


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6.2.2.2 
Hepatic Safety management 
Patients who develop increased transaminase levels should be monitored with a second liver 
function evaluation to confirm the finding. If the finding is confirmed, the patient should be 
followed with frequent liver function monitoring until values return to pre-treatment levels. 
If any of the criteria below are observed at any scheduled or unscheduled visit the sponsor 
should be notified immediately upon awareness and the hepatic safety follow up should be 
performed within 72 hours of awareness of the abnormality: 
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN 
• ALT or AST > 5 x ULN and ≤ 8 x ULN 
• ALT or AST > 8 x ULN 
Hepatic Safety Follow up: 
• Perform liver-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including over-the-counter medications, inter-current 
illness, etc.) 
• Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if 
total bilirubin is > 2.0 x ULN), Albumin, PT (INR), ALP, and GGT. These tests should be 
monitored every 3-4 days until resolution or return to baseline status. 
• Perform hepatitis screen: anti-HAV, IgM (to confirm acute hepatitis A), HbsAg, Anti-HBc, 
anti-HCV (if positive, PCR viral load should be assessed), Anti-HEV, ANA antibodies, 
anti-smooth muscle anti-bodies, CMV and EBV 
• Perform abdominal ultrasound (liver and biliary tree) 
Patients should be managed according to the LFT algorithm Figure 6-5 Patients may need to 
be discontinued if the abnormal liver function criteria are met upon LFT retesting or 
immediately discontinued without LFT retesting in the case of ALT or AST > 8 times the 
upper limit of normal (see discontinuation criteria Section 7.1.5.1). Progress reports of the 
event should be maintained until resolution or return to baseline status. 
If any of these criteria are met and deemed an AE by the investigator, the event must be 
recorded on the Adverse Event CRF page; if the event is deemed serious by the investigator, 
then the SAE form should be completed. In addition, any clinically significant findings from 
the physical examination should be recorded on the Adverse Event CRF page. 


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Figure 6-5 
LFT management algorithm 
6.2.2.3 
Hyperglycemia 
Hyperglycemia is known to be associated with the treatment of somatostatin analogues (SSA). 
Clinical studies of pasireotide in healthy volunteers and in patients with Cushing’s disease, 
acromegaly or carcinoid syndrome have reported transient, asymptomatic increases in fasting 
and postprandial glucose levels. Two clinical studies have been conducted [SOM230B2216] 
and [SOM230B2124] in healthy volunteers to further understand the mechanism of 
pasireotide-induced hyperglycemia and to evaluate the potential clinical utility of anti- 
diabetes agents in the management of pasireotide-induced hyperglycemia. Data from 
[SOM230B2216] study indicate that pasireotide decreases insulin secretion, particularly in the 
postprandial period, as well as the GLP-1/GIP secretion. Results from [SOM230B2124] study 
suggest that the incretin-based therapies (GLP-1 analogues and DPP-4 inhibitors) may have 
the best potential to manage the hyperglycemia associated with pasireotide. Some patients in 
[SOM230B2305], [SOM230C2305] and the [SOM230C2402] trials required insulin to treat 
their hyperglycemia. 
Prior to dose escalation it is recommended that glucose homeostasis is adequately controlled 
and that patients with HbA1c >8% should not have the dose of the pasireotide LAR increased 
to 60 mg. 
 
6.2.2.3.1 Self-monitoring of blood glucose 
The principal investigator is to educate the patient on the signs and symptoms of 
hyperglycemia. Patients must monitor their fasting blood glucose by finger stick at home at 
least 3 times per week for the first 4-week treatment with pasireotide or when the dose of 
pasireotide is increased. If a patient does not have any fasting values above 100mg/dL, 


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monitoring can be decreased to at least 2 times per week from week 4 to week 12 and 1 time 
every week for the rest of the study. If glucose values remain normal (below 100mg/dL), 
monitoring is at the investigator’s discretion during the extension phase (where it is 
applicable). If any values are observed above 100mg/dL, the guidelines in Figure 6-6 are to be 
followed. These guidelines are based on the current recommendations from the 2012 ADA 
and EASD aiming at a glycemic treatment goal of FPG < 130mg/dL (<7.2mmol/L). 
Appropriate actions such as initiation of anti-hyperglycemic therapy (and referral to diabetes 
specialist) are to be taken by the investigator as outlined on Figure 6-6. If fasting blood 
glucose values dictate initiation of anti-hyperglycemic treatment (i.e. confirmed > 130mg/dL 
by self-monitoring), a fasting plasma glucose sample using the central laboratory is to be 
collected prior to initiation of anti-hyperglycemic treatment; however, treatment may be 
initiated using local laboratory results. 
It is recommended that the patients be encouraged to keep a diary for their blood glucose for 
appropriate management throughout the study and present the collected data to their 
physician/diabetes specialist for evaluation. These data will not be collected by the sponsor. 
In addition to self-monitoring, fasting plasma glucose and HbA1c will be collected at study 
visits per Table 7-1 to Table 7-3. Close and frequent monitoring of blood glucose is needed 
during pasireotide treatment. Intervention for hyperglycemia is to be implemented in any 
patient meeting any of the following criteria: FPG > 130mg/dL or HbA1c ≥ 6.5%. 
Patients with FPG > 160mg/dL or HbA1c > 7.5% despite adjustment of antidiabetic therapy 
should be referred to a diabetes specialist (or earlier per investigator’s judgment). 
As outlined in Table 6-2, patients with grade 3 hyperglycemia (FPG value > 250mg/dL; >13.9 
mmol/L) at any point in the study should have the dose of pasireotide decreased. Patients who 
in spite of appropriate therapeutic interventions and despite dose reduction of study drug 
develop uncontrolled diabetes mellitus and/or consistently high blood glucose values: FPG ≥ 
240mg/fdL (13.3 mmol/L) or HbA1c value ≥ 10% will require study treatment 
discontinuation. 


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Figure 6-6 
Fasting SMBG Guidance 
 
 
6.2.3 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Refer to Section 7.1.5 for details. 
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced adverse events, i.e., hyperglycemia, QT 
prolongation and LFT increases are provided in Section 6.2.2. Refer to preclinical toxicity and 
or clinical data found in the current [Investigator’s Brochure]. 
 
6.3 
Concomitant medications 
6.3.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. 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 
and Significant Non-Drug Therapies CRF. 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 three months prior to enrollment and 
must agree to continue the oral conceptive throughout the course of the study and for 12 
weeks after the last dose of study drug. 
Repeat within the 
next 24 hours 
Repeat within the 
next 24 hours 


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6.3.1.1 
Permitted concomitant therapy requiring caution and/or action 
Acromegaly concomitant therapy is allowed only during the extension period for patients who 
do not achieve biochemical control. Otherwise, investigators should discourage patients from 
taking any medication during the study, with the exception of medications that are required to 
treat an adverse event. 
In patients treated with medications that may decrease potassium levels (e.g. diuretics), more 
frequent monitoring of electrolytes is recommended as clinically indicated. 
 
6.3.2 
Prohibited concomitant therapy 
The use of concomitant medication with a known risk of TdP is prohibited. In case a patient 
needs to take medication with a known risk of TdP, it will require study drug discontinuation 
prior to starting the medication. Please see Appendix 3 for further guidance on medication 
with a known risk to TdP. 
The following washouts are to be followed prior to screening 
1. Dopamine agonists (bromocriptine, cabergoline) or pegvisomant (INN); 12 weeks 
2. Pasireotide s.c.: 12 weeks 
3. Pasireotide LAR: 12 weeks 
 
6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject Number (Subject No.) consists 
of the Center Number (Center No.) (As assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form the patient is assigned to the next 
sequential Subject No. available to the investigator. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be 
changed, even if the patient is re-screened. If the patient fails to be randomized or start 
treatment for any reason, the reason will be entered into the Screening Log. IRT must be 
notified within 2 days that the patient was not enrolled. 
 
6.4.2 
Treatment assignment or randomization 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be assigned to 
pasireotide LAR 40 mg treatment arm. The investigator or his/her delegate will call or log on 
to the IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT 
will assign a patient number to the patient, which will be used to link the patient to a treatment 
arm and will specify a unique medication number but only for the pasireotide LAR treatment. 


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6.4.3 
Treatment blinding 
Not applicable. 
 
6.5 
Study drug preparation and dispensation 
Detailed instructions on the use of pasireotide LAR for i.m. injection is provided in the 
pharmacy manual. 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
Pasireotide LAR will be provided as microparticles powder in vials containing nominally 20, 
40 and 60 mg of Pasireotide (as free base) and solvent for suspension for injection in ampules 
for the reconstitution of the LAR microparticles. 
Octreotide LAR 40 mg will be locally supplied to the site. The 40 mg dose is to be given as 2 
separate injections (depending on dose availability at each country/site: either two injections 
of 20 mg each or a 30 mg and a 10 mg injection). Refer to the octreotide LAR package insert 
for further information. 
 
6.5.1 
Study drug packaging and labeling 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms and a [specific visit or 
dose/dose level]. Responsible site personnel will identify the study treatment package(s) to 
dispense to the patient by using the IRT and obtaining the medication number(s). Site 
personnel will add the patient number on the label. Immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that patient’s unique patient 
number. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient. 
 
Table 6-3 
Packaging and labeling 
Study treatments      Packaging 
Labeling (and dosing frequency) 
Pasireotide LAR 
Microparticle powder for suspension in vial 
Solution for suspension (vehicle) in 
ampoule or pre-filled syringe 
Labeled as ‘SOM230’ LAR (once/28days) 
Labeled as ‘SOM230 Solvent’ (once/28days) 
Octreotide LAR 
Octreotide LAR sourced locally 
Octreotide LAR sourced locally 
 
 
6.5.2 
Drug supply and storage 
Study drugs must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study drugs should be stored 


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according to the instructions specified on the drug labels and in the current [Investigator’s 
Brochure]. 
 
Table 6-4 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
 
Pasireotide LAR 
Centrally or locally supplied by Novartis 
Refer to study treatment label 
Octreotide LAR 
Octreotide LAR sourced locally 
Refer to the label 
 
6.5.3 
Study drug compliance and accountability 
 
6.5.3.1 
Study drug compliance 
Study drug compliance will be assessed by the Dosage Administration Record. All 
information is to be noted in the Dosage Administration Record. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
 
6.5.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
 
6.5.3.3 
Handling of other study treatment 
Not applicable. 
 
6.5.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 


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7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 to Table 7-3 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. No CRF except Quality of Life Questionnaire will be used as 
a source document. 
A ± 2 day window will be permitted for the screening visit. 
For all dosing visits, there is a general ± 2 day window on assessments to take into account 
scheduling over public holidays. For all safety visits (visit without dosing), there is a general 
± 1 day window on assessments to take into account scheduling over public holidays. 
Patients who discontinue treatment early must perform an end of core/extension phase visit 28 
± 2 days from the last dose. 


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Table 7-1 
Core Phase Visit evaluation schedule – Group 1 
 
Category 
Protocol 
Section 
Screening 
Run-In 
Run-In 
Baseline 
Core phase 
completion / 
discontinuati 
on 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-20 
-16 
- 
12 
-8 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Obtain Informed Consent 
D 
7.1.2 
x 
IRT Registration 
D 
7.1.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient history 
Demography 
D 
7.1.2.3 
x 
Inclusion/exclusion 
criteria 
D 
5.2/5.3 
x 
x 
Relevant medical 
history/current medical 
conditions 
D 
7.1.2.3 
x 
Prior/concomitant 
medications 
D 
7.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
History of acromegaly 
D 
7.1.2.3 
x 
Physical examination 
S 
7.2.2.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
D 
7.2.2.3 
x 
x 
Weight 
D 
7.2.2.3 
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 
x 
x 
x 
x 
Symptoms of 
acromegaly 
D 
7.2.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Category 
Protocol 
Section 
Screening 
Run-In 
Run-In 
Baseline 
Core phase 
completion / 
discontinuati 
on 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-20 
-16 
- 
12 
-8 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1 
x 
x 
x 
x 
x 
Chemistry (except LFT) 
D 
7.2.2.4.2 
x 
x 
x 
x 
x 
LFT (ALT, AST, T-bil, 
Alb,ALP,γ-GT) 
D 
7.2.2.4.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hepatitis (Hbs-Ag, anti- 
HCV) 
D 
7.2.2.4.4 
x 
Coagulation APTT/PTT 
D 
7.2.2.4.5 
x 
x 
x 
x 
x 
Coagulation PT( INR) 
D 
7.2.2.4.5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
5-point GH and IGF-1 
D 
7.2.1.1.1/7.2.1.1.2 
x 
x 
x 
x 
x 
Fasting blood glucose 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
oGTT 
D 
7.2.2.4.6 
x 
x 
PlasmaACTH/ FreeT4, 
TSH/ Cortisol 
D 
7.2.2.4.7 
x 
x 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.8 
x 
x 
x 
x 
x 
Pregnancy test urine 
D 
7.2.2.4.9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test Serum 
D 
7.2.2.4.9 
x 
Serum 
pregnancy test 
is required 
when urine 
pregnancy test 
is positive. 
x 
x 
Serum pregnancy test is required when urine pregnancy test 
is positive. 
x 


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Category 
Protocol 
Section 
Screening 
Run-In 
Run-In 
Baseline 
Core phase 
completion / 
discontinuati 
on 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-20 
-16 
- 
12 
-8 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Imaging 
ECG 
D 
7.2.2.6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gallbladder Ultrasound 
D 
7.2.2.5 
x 
x 
x 
x 
x 
Safety 
Adverse Event 
D 
8.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient reported Outcomes 
AcroQOL/EQ-5D5-L 
D 
7.2.1.2.2 
x 
x 
x 
x 
Study Drug administration 
Octreotide LAR 40mg 
x 
x 
x 
x 
Pasireotide LAR 40mg or 
60mg 
D 
6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Phase 
Completion 
D 
7.1.4 
x 


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Table 7-2 
Core Phase Visit evaluation schedule – Group 2 
 
Category 
Protocol 
Section 
Screening 
Baseline 
Core phase 
completion 
/discontinuat 
ion 
Visit Number 
1 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Obtain Informed Consent 
D 
7.1.2 
x 
IRT Registration 
D 
7.1.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient history 
Demography 
D 
7.1.2.3 
x 
Inclusion/exclusion criteria 
D 
5.2/5.3 
x 
Relevant medical 
history/current medical 
conditions 
D 
7.1.2.3 
x 
Prior/concomitant medications 
D 
7.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
History of acromegaly 
D 
7.1.2.3 
x 
Physical examination 
S 
7.2.2.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
D 
7.2.2.3 
x 
x 
Weight 
D 
7.2.2.3 
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 
Symptoms of acromegaly 
D 
7.2.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1 
x 
x 
x 
x 
Chemistry (except LFT) 
D 
7.2.2.4.2 
x 
x 
x 
x 
LFT (ALT, AST, T-bil, 
Alb,ALP,γ-GT) 
D 
7.2.2.4.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hepatitis (Hbs-Ag, anti-HCV) 
D 
7.2.2.4.4 
x 


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Category 
Protocol 
Section 
Screening 
Baseline 
Core phase 
completion 
/discontinuat 
ion 
Visit Number 
1 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
777 
Study Week 
-4 
0 
3 
4 
7 
8 
11 
12 
16 
20 
24 
28 
32 
Coagulation APTT/PTT 
D 
7.2.2.4.5 
x 
x 
x 
x 
Coagulation PT( INR) 
D 
7.2.2.4.5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
5-point GH and IGF-1 
D 
7.2.1.1.1/7.2.1.1.2 
x 
x 
x 
x 
Fasting blood glucose 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c 
D 
7.2.2.4.6 
x 
x 
x 
x 
oGTT 
D 
7.2.2.4.6 
x 
x 
PlasmaACTH/ FreeT4, TSH/ 
Cortisol 
D 
7.2.2.4.7 
x 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.8 
x 
x 
x 
x 
Pregnancy test urine 
D 
7.2.2.4.9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test Serum 
D 
7.2.2.4.9 
x 
x 
Serum pregnancy test is required when urine pregnancy test is positive. 
x 
Imaging 
ECG 
D 
7.2.2.6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gallbladder Ultrasound 
D 
7.2.2.5 
x 
x 
x 
x 
Safety 
Adverse Event 
D 
8.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient reported Outcomes 
AcroQOL/EQ-5D5-L 
D 
7.2.1.2.2 
x 
x 
x 
x 
Study Drug administration 
Pasireotide LAR 40mg or 60mg 
D 
6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Phase Completion 
D 
7.1.4 
x 


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Table 7-3 
Extension Phase Visit evaluation schedule for both Group 1 and Group 2 
 
Category 
Protocol 
Section 
Extension 
phase 
completion / 
discontinua 
tion 
Safety 
Follow Up 
Study 
Evaluation 
Completion 
Visit Number 
18 
19 
20 
21 
22 
23 
24 
25 
26 
778 
779 
Study Week 
36 
40 
44 
48 
52 
56 
60 
64 
68 
12 weeks after 
last study 
drug 
administration 
IRT Registration 
D 
7.1.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient history 
concomitant medications 
D 
7.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
S 
7.2.2.1 
x 
x 
x 
Height 
D 
7.2.2.3 
x 
Weight 
D 
7.2.2.3 
x 
x 
x 
Vital signs 
D 
7.2.2.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Symptoms of acromegaly 
D 
7.2.1.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1 
x 
x 
x 
Clinical Chemistry (except 
LFT) 
D 
7.2.2.4.2 
x 
x 
x 
LFT (ALT, AST, T-bil, 
Alb,ALP,γ-GT) 
D 
7.2.2.4.3 
x 
x 
x 
Coagulation (APTT,PTT 
and PT(INR)) 
D 
7.2.2.4.5 
x 
x 
x 
5-point GH and IGF-1 
D 
7.2.1.1.1/7.2.1.1.2 
x 
x 
x 
Fasting blood glucose 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HbA1c 
D 
7.2.2.4.6 
x 
x 
x 
oGTT 
D 
7.2.2.4.6 
x 


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Category 
Protocol 
Section 
Extension 
phase 
completion / 
discontinua 
tion 
Safety 
Follow Up 
Study 
Evaluation 
Completion 
Visit Number 
18 
19 
20 
21 
22 
23 
24 
25 
26 
778 
779 
Study Week 
36 
40 
44 
48 
52 
56 
60 
64 
68 
12 weeks after 
last study 
drug 
administration 
PlasmaACTH/ FreeT4, 
TSH/ Serum Cortisol 
D 
7.2.2.4.7 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.8 
x 
x 
x 
Pregnancy test (urine) 
D 
7.2.2.4.9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (serum) 
D 
7.2.2.4.9 
Serum pregnancy test is required when urine pregnancy test 
is positive. 
x 
Imaging 
ECG 
D 
7.2.2.6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gallbladder Ultrasound 
D 
7.2.2.5 
x 
x 
Safety 
Adverse Event 
D 
8.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient reported Outcomes 
AcroQOL/EQ-5D5-L 
D 
7.2.1.2.2 
x 
Study Drug administration 
Pasireotide LAR 40mg or 
60mg 
D 
6.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Phase completion 
D 
7.1.4 
x 
Study Evaluation 
Completion 
x 


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7.1.1 
Molecular pre-screening 
Not applicable. 
 
7.1.2 
Screening 
The informed consent must be signed prior to ANY screening procedure being performed. 
The site should enter the IRT when a patient signs the informed consent and begins his/her 
screening. Patients that do not meet eligibility criteria are allowed to be rescreened and should 
use the same patient number. Rescreening should be documented in the source files. Should 
the cause of screening failure be normal GH and/or IGF-1, patients can be rescreened once 
these parameters go beyond the control level, the patient has continued to receive scheduled 
injection of the SSAs and had at least a 3-month treatment with maximal doses of first 
generation SSAs. Patient can only be re-screened a total of 2 times, and Novartis must be 
informed of the intent to re-screen a patient. 
 
7.1.2.1 
Eligibility screening 
Following registration in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. For Group 1 patients, patient eligibility will be checked 
again at the end of the run-in period prior to the baseline. The eligibility check will be 
embedded in the IRT system. Please refer and comply with detailed guidelines in the IRT 
Manual. 
 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign the informed consent, but fail to be started on study treatment for any 
reason will be considered a screen failure. The reason for not being started on treatment will 
be entered on the applicable Screening Failure CRF pages. If the patient fails to be enrolled, 
the IRT must be notified within 2 days of the screen fail that the patient was not enrolled. 
 
7.1.2.3 
Patient demographics and other baseline characteristics 
Standard demographic information and medical history will be collected. History of 
acromegaly, prior medications for acromegaly, AIP mutation and information on MRIs 
performed as standard of care will also be collected. Other baseline assessments will be 
collected as per Table 7-1 and Table 7-2. 
 
7.1.3 
Run-in period 
If a patient is considered as a Group 1, the run-in phase is required. Patients will be treated 
with octreotide LAR 40 mg for 16 weeks. The eligibility will be re-assessed after 3 months of 
octreotide LAR 40 mg. 
7.1.4 
Treatment period 
Core Phase 
Patients will be treated with pasireotide LAR until week 36, receiving the last core injection at 
week 32, unless they discontinue from the study treatment due to any reason. The core phase 
. 


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completion visit is required at week 36. The safety follow up assessment is also required 56 
days after the last study drug administration. 
For details of assessments refer to Table 7-1 and Table 7-2. 
 
Extension Phase 
Patients will be treated with pasireotide LAR until 68 weeks, unless they discontinue from the 
study treatment due to any reason. Starting from week 40, acromegaly concomitant therapy is 
allowed for patients who do not achieve the biomedical control. The extension phase 
completion visit is required at week 72 (Visit 778). The safety follow up assessment is also 
required 56 days after the last study drug administration. 
For details of assessments refer to Table 7-3. 
 
7.1.5 
End of treatment visit including study completion and premature 
withdrawal 
Patients who discontinue study treatment before visit 777 (week 36) in the core phase and 
visit 778 (week 72) in the extension phase, should be scheduled for a visit as soon as possible 
to have all assessments listed for the 777 or 778 visits performed (Table 7-1 to Table 7-3). A 
Study Completion CRF page should be completed, giving the date and reason for stopping the 
study treatment. At a minimum, all patients who discontinue study treatment, including those 
who refuse to return for a final visit, will be contacted for safety evaluations during the 56 
days following the last dose of study treatment. 
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Completion CRF page. Patients may be withdrawn from the 
study prematurely for one of the following reasons: 
• Adverse event(s) 
• Abnormal laboratory value(s) 
• Abnormal test procedure result(s) 
• Unsatisfactory therapeutic effect 
• Protocol violation 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Death 
The investigator must contact IRT to register the patient’s discontinuation. 
For criteria for premature withdrawal refer to Section 7.1.5.1. 


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7.1.5.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be discontinued from it at the discretion 
of the investigator at any time. Patients may be withdrawn from the study if any of the 
following occur: 
• Adverse event (s) including abnormal laboratory values (s) and abnormal test procedures 
results (s) 
• Patient withdrew consent 
• Protocol deviation 
• Physician decision 
• Administrative problems 
Patients must be withdrawn from the study in case of: 
• Pregnancy 
• Lost to follow up 
• Death 
In addition to the general withdrawal criteria, the study specific criteria below also require 
immediate study drug discontinuation. The safety follow-up management should be 
performed as outlined in Section 6.2.2. Re-challenge of study medication is prohibited once 
discontinuation criteria are met. 
 
Hepatic-related discontinuation criteria 
• Jaundice or other signs of clinically significant liver dysfunction 
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN 
• ALT or AST > 5 x ULN ≤ 8 x ULN persistent for more than 2 weeks 
• ALT or AST > 8 x ULN 
QT related discontinuation criteria 
Patients experiencing adverse events in QTc: 
• QTcF > 500 msec, if confirmed by a cardiologist. 
• QTcF > 480 msec, if the investigator determines it is no longer safe for the patient to 
continue in the study, based on ECGs, cardiac examination and recommendation from a 
cardiologist. 
• Clinically significant arrhythmias including: 
• Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms of 
hemodynamic compromise. 
• Sustained ventricular tachycardia (>30 s) irrespective of symptoms. 
• Clinically significant brady-arrhythmia or third degree AV block. 
• Need to use QT prolonging medication with known risks factors for torsade de pointes. 


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Hyperglycemia related discontinuation criteria 
• Uncontrolled diabetes mellitus (DM), consistently high capillary glucose values in excess 
of 275 mg/dL (15.5 mmol/L), FPG ≥ 240 mg/dL (13.3 mmol/L) or HbA1c value ≥ 10 % 
despite prior appropriate management and prior dose adjustment of the study drug 
The investigator must also notify the IRT of the premature withdrawal, if this occurs during 
the core period. Patients who withdraw prematurely from the core phase cannot participate in 
the extension phase. 
 
7.1.6 
Follow-up and End of Study visit 
All patients must have safety evaluations and complete the safety follow up assessments at the 
56 days after the last dose of pasireotide LAR. 
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, 
etc. Patients that meet the requirements for follow up of abnormal LFTs at the end of study 
visit should be followed up as detailed in Section.6.2.2.2. 
 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
 
7.2.1.1.1 GH (5-point mean GH level) 
A 5-point mean GH will be assessed from a 2-hour profile after one hour at rest at the hospital 
and prior to the study drug administration at week -20 (Group1 only), week -4, week 12, 24, 
36 in the core phase and at week 48, 60, 72 in the extension phase. 
The 5-point mean GH profile is to be done within a 2-hour time period prior to glucose intake 
when an oGTT is required. 
All GH 2-hour profiles should be taken at the same time in the morning. The samples for GH 
will be analyzed by the central laboratory. Please refer to the central laboratory’s [Clinical 
Trial Laboratory Manual] for processing details. 
 
7.2.1.1.2 IGF-1 
Total IGF-1 levels will be assessed at the same visits as GH with one pre-dose sample which 
is week -20 (Group1 only), week -4, week 12, 24, 36 in the core phase and at week 48, 60, 72 
in the extension phase. Blood sampling for IGF-1 will be done prior to the study drug 
administration and glucose intake for oGTT when applicable. This sample must be taken 
together with the first sample of the GH profile. The samples for IGF-1 will be analyzed by 
the central laboratory. Please refer to the laboratory’s [Clinical Trial Laboratory Manual] for 
processing details. 


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7.2.1.2 
Secondary efficacy assessments 
 
7.2.1.2.1 GH and IGF-1: 
Both values in combination or alone will be used to assess secondary efficacy parameters at 
week 12, 24 and 36 in the core phase and at week 48, 60 and 72 in the extension phase. 
 
7.2.1.2.2 Health-Related Quality of Life (HRQoL) 
 
Patient Reported Outcomes Assessment: 
HRQoL will be assessed at baseline, week 12, 24, visit 777(core phase completion) and at 
visit 778 (extension phase completion) using the AcroQoL, an acromegaly-specific quality of 
life instrument. The AcroQol instrument is comprised of 22 questions divided into two scales: 
one evaluating physical aspects (8 items) and the other that addresses psychological aspects 
(14 items). The psychological scale can also be further divided into subscale that evaluates 
physical appearance and the other subscale focused on the impact of the disease on personal 
relationships of the patient (7 items each). Each of the questions has a 5-item Likert scale. The 
instrument was developed with input from both physicians and patients to assess those 
dimensions of health-related quality of life most relevant and bothersome to patients with this 
disease. It has been found to be a valid, reliable instrument, that is sensitive to changes in the 
concepts being measured (Badia et al 2004). 
 
Health Status: 
Health status will be measured at baseline and weeks 12, 24, visit 777 and visit 778 using the 
EQ-5D-5L, a valid and reliable instrument for measuring general health status. The EQ-5D- 
5L consists of 2 pages – the descriptive system and the EQ visual analogue scale (EQ VAS) 
(Herdman M et al 2011) The descriptive system comprises 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS 
records the respondent’s self-rated health on a 20 cm vertical, visual analogue scale with 
endpoints labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’ 
Laboratory evaluations. 
 
7.2.1.2.3 Symptoms of acromegaly 
Symptom of acromegaly are to be collected at visits indicated in Table 7-1 to Table 7-3 and 
appropriate CRFs. Ring size will be measured with a gauge using 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 measurement will  
be provided on a scale of 1-15 including half sizes. The investigator will also ask the patient  
to score the following symptoms of acromegaly: headache, fatigue, perspiration, paresthesias, 
osteoarthralgia according to a five-point score scale (0=absent, 1=mild, 2=moderate, 3=severe, 
4=very severe). 


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7.2.2 
Safety and tolerability assessments 
 
7.2.2.1 
Physical examination 
A complete physical examination must be performed by the investigator at visits indicated in 
Table 7-1 to Table 7-3. The examinations will be performed according to the standards at each 
institution. 
Information about the physical examination must be present 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 Medical History/Current Medical Condition page on the patient’s CRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the patient’s CRF. 
 
7.2.2.2 
Vital signs 
Vital signs (supine blood pressure, supine pulse rate and body temperature) will be performed 
by the investigator at all visits as indicated in Table 7-1 to Table 7-3 and appropriate CRFs. 
 
7.2.2.3 
Height and weight 
Height in centimeters and weight to the nearest 0.1 kilogram (in indoor clothing, but without 
shoes) are to be collected at visits indicated in Table 7-1 to Table 7-3 and appropriate CRFs. 
 
7.2.2.4 
Laboratory evaluations 
Central laboratories will be used for the analysis of all laboratory evaluations except  
urinalysis and urine pregnancy test. Details on the collections, shipment of samples and 
reporting of results by the central laboratories will be provided to investigators in the 
[Laboratory Manual]. 
Urinalysis and urine pregnancy test will be performed by dipstick locally. The dipsticks will 
be provided to the sites by the central laboratory. 
 
Table 7-4 
Local or Central Clinical Laboratory Parameters Collection Plan 
 
Test Category 
Test Name 
Hematology (central) 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC Morphology 
with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Clinical Chemistry 
(central) 
Bicarbonate, Calcium, Chloride, Creatinine, Creatine Kinase, Total Cholesterol, LDL, 
HDL, Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, α- 
amylase, Lipase, Lactic Dehydrogenase (LDH), Magnesium, Sodium, Potassium, 
Prolactin, 
LFT (central) 
ALT, AST, Total bilirubin, (total bilirubin should be differentiated into direct and indirect 
reacting bilirubin if total bilirubin is increased > 2.0ULN), Albumin, ALP and GGT 
Hepatic Screening 
(central) 
HbsAg , AntiHCV 
Hyperglycemia 
related test (central) 
Fasting Blood Glucose, Glycosylated Hemoglobin (HbA1C), oGTT (insulin and plasma 
glucose) 
Coagulation (central) 
Prothrombin time (PT) or International normalized ratio (INR), Partial thromboplastin time 
(PTT), Activated partial thromboplastin time (APTT) 


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Test Category 
Test Name 
Thyroid and 
hormones (central) 
T4 [free], TSH, Plasma Adrenocorticotropic Hormone (ACTH), Fasting Serum Cortisol, 
Urinalysis (local) 
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
pH, Protein, Specific Gravity) 
Additional tests 
(central) 
Insulin-like growth factor 1 (IGF-1), Growth Hormone (GH) 
Pregnancy Test 
Urine (dipstick) and serum B-hCG 
 
7.2.2.4.1 Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC Morphology 
with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) are to be 
collected at visits indicated in Table 7-1 to Table 7-3. 
 
7.2.2.4.2 Clinical Chemistry 
Bicarbonate, Calcium, Chloride, Creatinine, Creatine Kinase, Total Cholesterol, LDL, HDL, 
Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, α-amylase, 
Lipase, Lactic Dehydrogenase (LDH), Magnesium, Sodium, Potassium, Prolactin are to be 
collected at visits indicated in Table 7-1 to Table 7-3. 
 
7.2.2.4.3 Liver function testing (LFT) 
ALT, AST, Total bilirubin, (total bilirubin should be differentiated into direct and indirect 
reacting bilirubin if total bilirubin is increased > 2.0ULN), Albumin, ALP and GGT are to be 
collected at visits indicated in Table 7-1 to Table 7-3. 
 
7.2.2.4.4 Hepatic Screening 
HbsAg, AntiHCV are to be collected at visit 1. 
 
7.2.2.4.5 Coagulation 
Prothrombin time (PT) or International normalized ratio (INR), Partial thromboplastin time 
(PTT), Activated partial thromboplastin time (APTT) are to be collected at visits indicated in 
Table 7-1 to Table 7-3. 
 
7.2.2.4.6 Hyperglycemia related test 
Fasting Blood Glucose, Glycosylated Hemoglobin (HbA1C), oGTT (insulin and plasma 
glucose) are to be collected at visits indicated in Table 7-1 to Table 7-3. Diabetic patients are 
not required to perform oGTT. If the patient discontinues from the study, the oGTT at visit 
777/778 can be performed based on the judgment of the investigator. 
 
7.2.2.4.7 Thyroid and hormones 
T4 (free), TSH, ACTH, Fasting Serum Cortisol are to be collected at visits indicated in    
Table 7-1 to Table 7-3. 


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7.2.2.4.8 Urinalysis 
Dipstick measurements for Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, pH, 
Protein, Specific Gravity are to be collected at visits indicated in Table 7-1 to Table 7-3. 
 
7.2.2.4.9 Pregnancy 
All pre-menopausal women who are not surgically sterile will have a serum  B-hCG 
pregnancy test at screening, baseline and end of treatment (visit 777 and visit 778) and urine 
pregnancy test at visits indicated in Table 7-1 to Table 7-3 
A positive pregnancy test by urine is required an immediate serum B-hCG pregnancy test. 
A positive pregnancy test requires immediate interruption of study treatment until the 
assessment is confirmed. If positive, the patient must discontinued from the study. 
 
7.2.2.5 
Gallbladder ultrasound 
 
Table 7-5 
Gallbladder Ultrasound Assessment Collection Plan 
 
Group 1 
 
Procedure 
Screening/Run-in/Baseline 
During Treatment/Follow-up 
Gallbladder Ultrasound 
Mandated (Week -20 and Week -4) 
Week 12, 24, Visit 777 (core phase) 
Week 60, Visit 778 (extension phase) 
 
Group 2 
 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Gallbladder Ultrasound 
Mandated (Week -4) 
Week 12, 24, Visit 777(core phase) 
Week 60, Visit 778 (extension phase) 
A gallbladder ultrasound will be performed at the sites at visits indicated in Table 7-1 to Table 
7-3. The results will be recorded in the CRFs. 
 
7.2.2.6 
Cardiac assessments 
 
7.2.2.6.1 Electrocardiogram (ECG) 
 
Table 7-6 
Central ECG Collection Plan 
 
Group 1 
 
Week 
Time 
ECG Type 
-20 (Screening Run-In) 
Pre-dose 
12 Lead 
-4 (Run-in) 
Pre-dose 
12 Lead 
0 (Baseline) 
Pre-dose 
12 Lead 
3 
At any time during the visit 
12 Lead 
4 
Pre-dose 
12 Lead 
7 
At any time during the visit 
12 Lead 
8 
Pre-dose 
12 Lead 
11 
At any time during the visit 
12 Lead 


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Week 
Time 
ECG Type 
12 
Pre-dose 
12 Lead 
Every 4 weeks until Visit 777 (core 
phase), until week Visit 778 (extension 
phase) 
Pre-dose 
12 Lead 
Unscheduled visit 
As clinically indicated 
12 Lead 
 
Group 2 
 
Week 
Time 
ECG Type 
-4 (Screening) 
Pre-dose 
12 Lead 
0 (Baseline) 
Pre-dose 
12 Lead 
3 
At any time during the visit 
12 Lead 
4 
Pre-dose 
12 Lead 
7 
At any time during the visit 
12 Lead 
8 
Pre-dose 
12 Lead 
11 
At any time during the visit 
12 Lead 
12 
Pre-dose 
12 Lead 
Every 4 weeks until Visit 777 (core 
phase), until Visit 778 (extension phase) 
Pre-dose 
12 Lead 
Unscheduled visit 
As clinically indicated 
12 Lead 
Standard 12 lead ECGs will be performed at the sites at visits indicated in Table 7-1 to    
Table 7-3. 
If at any visit QTcF >480 msec is observed, all the procedures for QT-prolongation described 
in Section 6.2.2.1 should be followed. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG CRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History CRF. Clinically significant findings must 
be discussed with Novartis prior to enrolling the patient in the study. New or worsened 
clinically significant findings occurring after informed consent must be recorded on the 
Adverse Events CRF. 
Each ECG should be taken prior to the study drug administration. At the discontinuation 
(including the core phase completion visit for patients who do not participate in the extension 
phase) or the extension phase completion visit, the ECG should be taken prior to the 
commercial drug administration. 
 
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
Not applicable. 
 
7.2.2.6.3 Cardiac enzymes 
Not applicable. 


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7.2.2.7 
Tolerability 
In addition to general safety data, information on dose changes will be collected. 
 
7.2.3 
Pharmacokinetics 
Not applicable. 
 
7.2.3.1 
Other assessments 
No additional tests will be performed on patients entered into this study. 
 
7.2.4 
Resource utilization 
Not applicable. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Except for screening failures, adverse events that begin or worsen after informed consent 
should be recorded in the Adverse Events CRF. Conditions that were already present at the 
time of informed consent should be recorded in the Relevant Medical History/Current 
Medical Conditions CRF. Adverse event monitoring should be continued for at least 12 weeks 
following the last dose of study treatment. Adverse events (including lab abnormalities that 
constitute AEs) should be described using a diagnosis whenever possible, rather than 
individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each 
sign or symptom should be reported as a separate adverse event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 


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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 
2. Its duration 
3. Its relationship to the study treatment 
4. Action taken with respect to study or investigational treatment 
5. Whether medication or therapy was given 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for adverse events 
should be followed until they have returned to normal or an adequate explanation of the 
abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or therapy given 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 
Adverse events of special interest consist of AEs for which there is a specific interest in 
connection with pasireotide treatment (i.e. where pasireotide may influence a common 
mechanism of action responsible for triggering them). The adverse events of special interest 
may require reporting additional information and completion of the event-specific checklists 
and/or questionnaires. 


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The current list of adverse events of special interest is provided below; this list is not all 
inclusive and can be modified throughout the lifetime of the trial: 
• Arrythmogenic potential 
• Bradycardia related AEs 
• Coagulation related AEs 
• Constipation related AEs 
• Diabetes insipidus related AEs 
• Diarrhoea related AEs 
• Gallbladder and biliary related AEs 
• GI bleeding related AEs 
• Growth hormone deficiency related AEs 
• Hyperglycemia-related AEs 
• Hypocalcemia related AEs 
• Hypocortisolism related AEs 
• Hypotension related AEs 
• Hypothyroidism related AEs 
• Injection site reaction related AEs 
• Liver safety related AEs 
• Low blood cell related AEs 
• Nausea related AEs 
• Pancreatitis related AEs 
• QT-prolongation-related AEs 
• Rhabdomyolysis related AEs 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
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• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
 
8.2.2 
Reporting 
To ensure patient safety every SAE regardless of suspected occurring after the patient has 
provided informed consent and until 12 weeks (84 days) after the patient has stopped study 
drug adminiatration must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after the 12 weeks (84 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 in English, 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. 
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 present in the Reference Safety Information section of the [Investigator’s 
Brochure] (unexpected) and is thought to be related to the Novartis study treatment 
(suspected), an oncology Novartis Drug Safety and Epidemiology (DS&E) department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Suspected Unexpected Serious Adverse Reactions) 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. Novartis 


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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. 
 
8.3 
Emergency unblinding of treatment assignment 
Not applicable. 
 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment who becomes 
pregnant during the study treatment or within 3 months after the last pasireotide LAR dose 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Newborn of a patient (or a partner of a patient) who becomes pregnant during the study 
treatment or within 3 months after the last pasireotide LAR dose should be followed for 3 
months post-delivery (from Day 0 to Month 3 of life). 
 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
8.6 
Data Monitoring Committee 
No Data Monitoring Committee is planned for this trial. 
 
8.7 
Steering Committee 
A steering committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team the SC will also 


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develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in a SC charter. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 


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documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate and that entry and updates are performed in a timely manner. 
 
9.3.1 
ECG data collection 
ECG data will be collected via 12-lead digital ECG machines. The data will be transmitted to 
an ECG vendor for centralized cardiac safety analysis, as well as further processing and data 
reconciliation. 
 
9.3.2 
IRT data collection 
Patient eligibility and enrollment will be tracked using an Interactive Response Technology. 
The system will be supplied by a vendor, who will also manage the database for that system. 
 
9.3.3 
Central laboratory data collection 
All laboratory evaluation except urinalysis and urine pregnancy test will be conducted and its 
data will be collected by the central laboratory. 
Designated investigator staff must enter the sample information required by the protocol onto 
sample collection eCRFs, as well as central laboratory requisition forms. The requisition 
forms will be printed on 2-part, non-carbon-required paper or will available electronically. If 
paper forms will be used, one copy of the requisition form will be forwarded to the central 
laboratory along with the corresponding sample(s), and the other will be retained by the site. 
CRA will review the central laboratory requisition forms against the sample collection eCRFs 
for completeness and accuracy, and instruct site personnel to make any required corrections or 
additions. Further reconciliation of any sample collection data that were collected on both 
eCRFs and requisition forms will be performed by the designated central laboratory and 
Novartis. 
The samples will be shipped by the site to a designated central laboratory for sample 
management. 
 
9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 


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investigational site via the EDC system. Designated investigator and 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). 
Patient numbers and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel (or designated CRO). 
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked. Authorization is required prior to making any database changes to locked 
data, by joint written agreement between the Global Head of Biostatistics and Data 
Management and the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
 
10 
Statistical methods and data analysis 
This is a phase IIIb exploratory study to assess the efficacy and safety of pasireotide  in 
patients with acromegaly inadequately controlled with first generation somatostatin analogues. 
The data will be analyzed by Novartis and/or designed CRO. It is planned that the data from 
all centers that participate in this protocol will be used. Continuous variables will be 
summarized by number of patients, mean, standard deviation, minimum, 25th quantile, median, 
75th quantile and maximum. Categorical variables will be summarized by absolute  and  
relative frequencies. Unless otherwise stated, baseline assessment refers to the last assessment 
prior to the patient’s first study drug dose recorded after the signing of the informed consent. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned 
 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication. 


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10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP. The protocol deviations criteria will be defined prior to 
database lock. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (e.g. age, gender, race, GH levels, standardized IGF-1 
levels) will be summarized descriptively for the FAS. 
 
10.3 
Treatments (study treatment, concomitant therapies, compliance) 
Descriptive statistics will be used to summarize the dose intensity and duration of drug 
exposure. The actual and planned doses administered and reason for dose change will be 
listed. Concomitant medications and significant non-drug therapies prior to and after the start 
of the study treatment will be summarized by ATC class and preferred term. 
These analyses will be performed on the safety set. 
 
10.4 
Primary objective 
To evaluate the efficacy of pasireotide LAR in patients with acromegaly who are inadequately 
controlled with currently available somatostatin analogues, as measured by the proportion of 
patients with GH <1µg/L and IGF-1 <ULN at week 36. 
 
10.4.1 
Variable 
The variable of interest is proportion of patients who achieved GH <1µg/L and IGF-1 <ULN 
at week 36. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The trial is exploratory in nature and no formal hypothesis testing is planned. 
The proportion of patients achieving mean GH levels < 1 µg/L and IGF-1 <ULN will be 
calculated along with its two-sided, asymptotic or exact when the criteria for asymptotic 
approximation were not fulfilled, 95% confidence interval at Week 36. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
If a patient has less than three samples for the assessment of the 5-point mean GH from the 2- 
hour profile, then the mean GH will be considered as missing. Patients with missing GH and 
or IGF-1 assessment at week 36 will be considered as non-responders. 
Multiple imputation method or other adequate methods will be employed to impute missing 
data and sensitivity analyses will be performed using imputed missing data to assess the 
robustness of the efficacy findings. The imputation methods as well as sensitivity analyses 
will be specified in the RAP. 


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10.4.4 
Supporting Analysis of Primary Objective 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN at weeks 36 
by sub-groups of GH level at screening 
The proportion of patients who achieved GH <1µg/L and IGF-1 <ULN at week 36 among two 
sub-groups of patients, those having GH level at screening between 1µg/L and 2.5µg/L, and 
those having GH level >2.5µg/L at screening, will be reported along with their two-sided 
(exact or asymptotic, depending on assumptions being satisfied) 95% confidence interval. 
These supporting analyses is purely exploratory in nature and no statistical multiplicity 
adjustments will be performed to distinguish it from other endpoints. 
 
10.5 
Secondary objectives 
The secondary efficacy analysis will be performed on the FAS. The same rule of handling 
missing values for GH and IGF-1 variables as specified in the analysis of the primary efficacy 
variable will be used. 
 
10.5.1 
Secondary objectives- Core phase 
To assess the changes in mean GH from study baseline to week 36 
Descriptive summaries of actual and percentage change in GH from study baseline to week 36 
values will be provided. 
To assess the changes in standardized IGF-1 from study baseline to week 36 
Descriptive summaries of actual and percentage change in standardized IGF-1 from study 
baseline to week 36 values will be provided. 
To assess the proportion of patients achieving GH <1 µg/L and IGF-1 <ULN at weeks 12 
and 24 overall and by GH level at screening 
Proportion of patients who achieved GH <1µg/L and IGF-1 <ULN at week 12 and 24 will be 
reported along with its corresponding 95% confidence interval for all patients and also among 
patients, having GH level at screening between 1 µg/L and 2.5 µg/L, and among patients 
having GH level at screening > 2.5 µg/L. 
To assess the proportion of patients achieving GH <1µg/L at weeks 12, 24 and 36, overall 
and by GH level at screening 
Proportion of patients who achieved GH <1µg/L at week 12, 24 and 36 will be reported along 
with its corresponding 95% confidence interval for all patients and also among patients, 
having GH level at screening between 1 µg/L and 2.5 µg/L, and patients having GH level at 
screening >2.5 µg/L. 
To assess the proportion of patients achieving IGF-1 levels <ULN at weeks 12, 24 and 36 
Proportion of patients who achieved IGF-1 <ULN at week 12, 24 and 36 will be reported 
along with its corresponding 95% confidence interval. 
To evaluate the effect of pasireotide LAR on HRQoL and signs and symptoms of 
acromegaly from baseline to weeks 12, 24 and 36 


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Descriptive statistics, including mean, median, standard deviation, minimum and maximum, 
will be presented to describe actual standardized scores as measured by HRQoL and changes 
from baseline to weeks 12, 24 and 36. 
For each of the acromegaly symptoms (ring size, headache, fatigue, perspiration, paresthesias, 
osteoarthralgia), descriptive summaries of actual and changes from baseline to weeks 12, 24 
and 36 will be provided. Moreover, shift tables from baseline to the most extreme post- 
baseline value will also be presented for acromegaly symptoms except ring size 
To evaluate the tolerability and safety profile of pasireotide LAR 
Same analysis as in Section 10.5.3 
 
10.5.2 
Secondary objectives- Extension phase 
To assess the proportion of patients achieving IGF-1 <ULN at weeks 48, 60 and 72 
Proportion of patients who achieved IGF-1 <ULN will be calculated along with its two-sided 
95% confidence interval at week 48, 60 and 72. 
To assess the proportion of patients achieving GH<1 µg/L and IGF-1<ULN at weeks 48, 
60 and 72 by treatment with pasireotide LAR alone or with concomitant medications 
used to treat acromegaly 
Proportion of patients who achieved GH<1µg/L and IGF-1<ULN by treatment with 
pasireotide LAR alone or with concomitant medications used to treat acromegaly will be 
reported separately along with its corresponding 95% confidence interval at weeks 48, 60 and 
72 
To assess the proportion of patients achieving GH <1 µg/L at weeks 48, 60 and 72 by 
treatment with pasireotide LAR alone or with concomitant medications used to treat 
acromegaly 
Proportion of patients who achieved GH<1µg/L by treatment with pasireotide LAR alone or 
with concomitant medications used to treat acromegaly will be reported separately along with 
its corresponding 95% confidence interval at weeks 48, 60 and 72 
To evaluate the long term effect of pasireotide LAR on HRQoL and signs and symptoms 
of acromegaly, from baseline and week 36 to week 72 
Change in standardized scores as measured by HRQoL and signs and symptoms of 
acromegaly from baseline and week 36 to week 72. 
Descriptive statistics, including mean, median, standard deviation, minimum and maximum, 
will be presented to describe actual standardized scores as measured by HRQoL and changes 
from baseline to week 72 and from week 36 to week 72. 
For each of the acromegaly symptoms (ring size, headache, fatigue, perspiration, paresthesias, 
osteoarthralgia), descriptive summaries of actual and changes from baseline to weeks 72, and 
from week 36 to week 72 will be provided. Moreover, shift tables from baseline to the most 
extreme post-baseline value, and from week 36 to the most extreme value up to week 72 will 
also be presented for acromegaly symptoms except ring size. 
To evaluate the long term tolerability and safety profile of pasireotide LAR 


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Same analysis as in Section 10.5.4 
 
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. 
For the core phase, all listings and tables will be presented overall and by maximum dose 
given. For AEs of special interest, tables will be presented by the given dose as well (AE 
starts or worsens while the patient is being treated at that dose level.) 
For the extension phase, all listings and tables will be presented overall and by type of 
treatment (monotherapy, combination dopamine agonist, and combination with GH receptor 
antagonist). 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 84 days after last dose 
of study medication 
3. post-treatment period: starting at day 84+1 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-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment overall and by treatment group (described in 
Section 10.5.3.2 for each phase). 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group (described in Section 10.5.3.1 for each 
phase). 
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). 
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported. 
 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, the study’s biostatistical and reporting team will grade laboratory data 


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accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non- 
missing values not graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) 
• 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-treatment result for overall assessments 
• listing of ECG evaluations for all patients with at least one abnormality. 
Vital signs 
Vital signs (body temperature, blood pressure, heart rate) reporting of results will include: 
• shift table baseline to worst on-treatment result 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
 
Gallbladder 
Gallbladder data at each visit will be summarized and listed. 
 
10.5.4 
Patient-reported outcomes 
AcroQoL total and subscale scores and EQ-5D-5L utility index and VAS scores will be 
generated in accordance with the respective scoring manual. The FAS will be used for 
analyzing patient-reported outcome data. 
Descriptive statistics will be used to summarize the raw and absolute change from baseline in 
AcroQoL and EQ-5D-5L scores at each scheduled assessment. Patients with an evaluable 
baseline score and at least one evaluable post baseline score during the treatment period will 
be included in the change from baseline analyses. 
Missing items data in a scale will be handled based on each instrument manual. All PRO 
analyses will include data as imputed according to the scoring manual. No imputation will be 
applied if the total or subscale scores are missing at a visit. 


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Additional analyses may be performed if deemed necessary. Such analyses will be defined in 
the RAP. 
 
10.6 
Interim analysis 
No formal interim analysis will be performed. Primary analysis will occur after all enrolled 
patients complete the core phase or discontinue prior to complete this phase of the trial. Final 
analysis will be conducted when all patients complete the extension phase or have 
discontinued the study prior to completing the extension phase of the trial. 
 
10.7 
Sample size calculation 
The sample size calculation was based on the primary endpoint (mean GH <1 μg/L and IGF-1 
<ULN at week 36). A sample size of 100 patients was chosen to enable the estimation of 
proportion of patients who achieved biochemical control at week 36 with pasireotide 40-60 
mg as 15%, with a precision of 7% for the associated asymptotic two-sided 95% confidence 
interval. 
Considering a drop-out rate of 10%, the sample size required is 112. 
Sample size calculation was performed using PASS 2008 software. 
10.8 
Power for analysis of key secondary variables 
Not applicable. 
 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21) and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed where 
required by law or regulation), IRB/IEC/REB-approved informed consent 


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Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined  in  
Section 4.4. 
 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
 
11.5.1 Communication and Publication of Clinical Trial Results 
Novartis is committed to upholding the highest ethical standards for reporting the results of 
medical research, including the timely communication and publication of clinical trials results, 
whatever their outcome 
Novartis complies with the authorship guidelines of the International Committee of Medical 
Journal Editors (ICMJE) uniform requirements for manuscripts submitted to biomedical 
journals and other specific guidelines of the journal or congress to which the document will be 
submitted. These guidelines apply to any clinical trial publication including but not limited to 
manuscripts, abstracts, posters, and oral presentations. For more information regarding the 
ICMJE guidelines, visit ICMJE.org/index.html#author. 
Accordingly, ALL AUTHORS MUST HAVE: 
• Contributed substantially to the study concept, design and/or conduct of the study or to the 
acquisition, analysis, and interpretation of the data AND 
• Drafted or critically revised the proposed clinical publication for important intellectual 
content AND 
• Approved the final proposed clinical publication for submission AND 


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• Have intimate knowledge of trial implementation/analysis 
Substantial contribution for primary publication is defined as having active and ongoing 
participation in the study. Study steering committee members must have significant 
involvement to study concept, design, and data interpretation and patient recruitment. Each 
steering committee member must have attended the majority of the steering committee 
meetings and recruited patients into the trial from his/her own center to be included as an 
author. Study investigators must have significant contribution to patient recruitment based on 
number of eligible patients upon study entry and data quality. 
 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study  
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or  
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported  
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 


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permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
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) 
ADA Diagnosis and Classification of Diabetes Mellitus (2011) Diabetes Care, volume 34, 
supplement 1, January 2011. 
Badia X, et al (2004) Review: Acromegaly Quality of Life Questionnaire. Health and Quality 
of Life Outcomes; 2. 
Becker KL, et al (2000) Principles and practice of endocrinology and metabolism: Section A 
Chapter 12 - Growth hormone and its disorders: 129-145. 
Bevan J, et al (2002) Primary medical therapy for acromegaly: an open, prospective, 
multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on 
growth hormone, insulin-like growth factor-1 and tumor size. Journal of Clinical 
Endocrinology and Metabolism; 87 (10): 4554-4563. 
Bretz F, et al (2009) A graphical approach to sequentially rejective multiple test procedures. 
Statistics in Medicine; 28:586-604. 
Bretz F, et al (2011) Graphical approach for multiple comparison procedures using weight 
Bonferroni, Simes, or parametric tests. Biometrical Journal; published online. 
Bruns C, et al (2002) SOM230: a novel somatostatin peptidomimetic with broad somatotropin 
release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. European 
Journal of Endocrinology; 146: 707-716. 
Chanson P (2000) Somatostatin analogues in the treatment of acromegaly: the choice is now 
possible. European Journal of Endocrinology; 143: 573-575. 
Cozzi R, et al (2003) Four-year treatment with octreotide-long-acting repeatable in 110 
acromegalic patients: predictive value of short-term results? Journal of Clinical 
Endocrinology & Metabolism; 88 (7): 3090-3098. 
Fougner SL, et al (2008) Low levels of raf kinase inhibitory protein in growth hormone- 
secreting pituitary adenomas correlate with poor response to octreotide treatment. J Clin 
Endocrinol Metab; 93(4):1211-6. 
Freda P (2002) Somatostatin analogues in acromegaly. Journal of Clinical Endocrinology and 
Metabolism; 7: 3013-3018. 
Giustina A, et al (2000) Criteria for cure of acromegaly: a consensus statement. Journal of 
Clinical Endocrinology and Metabolism; 85: 526-529. 
Giustina A, et al (2010) A consensus on criteria for cure of acromegaly. Journal of Clinical 
Endocrinology and Metabolism; 95 (7):3141-3148. 
Hirji K, Mehta CR, Patel NR (1987) Computing distributions for exact logistic regression. 
JASA; 82: 1110-1117. 
Hochberg Y (1988) A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika; 75: 800-802. 
Holdaway IM, Rajasoorya C (1999) Epidemiology of acromegaly. Pituitary 2: 29-41. 


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Jaquet P, et al (2000) Human somatostatin receptor subtypes in acromegaly: distinct patterns 
of messenger ribonucleic acid expression and hormone suppression identify different tumoral 
phenotypes. Journal of Clinical Endocrinology and Metabolism; 85: 781-792. 
Kauppinen-Makelin R, et al (2005) A nationwide survey of mortality in acromegaly. J Clin 
Endocrinol Metab; 90: 4081-6. 
Lancranjan I, Atkinson AB, Sandostatin LAR Group (1999) Results of a European 
Multicentre Study with Sandostatin LAR in Acromegalic Patients. Pituitary; 1: 105-114. 
Maurer W, et al (2011) Multiple and repeated testing of primary, coprimary, and secondary 
hypotheses. American Statistical Association; 3:336-352. 
Nathan DM, et al (2009) Medical Management of hyperglycemia in Type 2 Diabetes: a 
consensus algorithm for the initiation and adjustment of therapy. Diabetes Care; 32 (1): 193- 
203. 
Oberg K (2004) Treatment of neuroendocrine tumours of the gastrointestinal tract. Oncologia 
(Madrid); Vol. 27 (4): 57-61. 
Schmid HA (2008) Pasireotide (SOM230): development, mechanism of action and potential 
applications. Mol Cell Endocrinol; 286(1-2):69-74. 
Schmid HA, Schoeffter P (2004) Functional Activity of the Multiligand Analogue SOM230 at 
Human Recombinant Somatostatin Receptor Subtypes Supports Its Usefulness in 
Neuroendocrine Tumors. Neuroendocrinology; 80 (1): 47-50. 
Shimon I, et al (1997) Somatostatin receptor (SSTR) subtype-selective analogues 
differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas: 
novel potential therapy for functional pituitary tumors. J Clin Invest; 100: 2386-92. 
Simes RJ (1986) An improved Bonferroni procedure for multiple tests of significance. 
Biometrika; 73: 751-754. 
Taboada GF, et al (2007) Quantitative analysis of somatostatin receptor subtype (SSTR1-5) 
gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J 
Endocrinol;156(1):65-74. 
Taboada GF, et al (2008) Quantitative analysis of somatostatin receptor subtypes (1-5) gene 
expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume 
responses to treatment with octreotide LAR. Eur J Endocrinol;158(3):295-303. 
Tichomirowa, et al (2011) High prevalence of AIP gene mutations following focused 
screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol; 165: 
509-515 
Van der Hoek J, 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): E278-87. 
Wass J, Lamberts S, Melmed S (2001) Long-term treatment strategies for acromegaly. 
Handbook of Acromegaly; 7: 79-83. 


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14 
Appendices 
14.1 
Appendix 1: Acromegaly Quality of Life Questionnaire 
 
 
 
Today’s date 
Day 
Month 
Year 
 
 
 
 
INSTRUCTIONS FOR ANSWERING THE QUESTIONNAIRE 
In the following pages there are sentences that describe some of the problems that acromegaly 
causes to people who, like you, suffer from this illness. 
 
Each sentence is followed by some response options. Some of these refer to the frequency, 
while others refer to how much you agree or disagree with them. 
 
 
 
Please, read each sentence carefully. Then tick the response option which best describes 
what you think is happening to you. 
 
 
 
Remember that there are NO correct or incorrect answers. We are only interested in what is 
currently happening to you because of your acromegaly. 
 
It is very important to answer all the questions. 
Thank you very much for your collaboration 
 
© Badía X., Prieto Ll., Webb S. 
ACROMEGALY- QUALITY OF LIFE QUESTIONNAIRE 
(ACROQoL) 


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• 
• 
Always 
Always 
• 
• 
Most of the time 
Most of the time 
• 
• 
Sometimes 
Sometimes 
• 
• 
Rarely 
Rarely 
• 
• 
Never 
Never 
 
 
 
 
Because of my Acromegaly… 
 
1. My legs feel weak 
4. I look awful in photographs 
 
• Always 
•   Completely agree 
 
• Most of the time 
•   Moderately agree 
 
• Sometimes 
• Neither agree nor disagree 
 
• Rarely 
•   Moderately disagree 
 
• Never 
•   Completely disagree 
 
 
 
2. I feel ugly 
5. I avoid going out very much with 
friends because of my appearance 
 
• Completely agree 
• Always 
 
• Moderately agree 
• Most of the time 
 
• Neither agree nor disagree 
• Sometimes 
 
• Moderately disagree 
• Rarely 
 
• Completely disagree 
• Never 
 
 
 
3. I get depressed 
6. I try to avoid socialising 


• 
• 
Always 
Always 
• 
• 
Most of the time 
Most of the time 
• 
• 
Sometimes 
Sometimes 
• 
• 
Rarely 
Rarely 
• 
• 
Never 
Never 
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Because of my Acromegaly… 
 
 
 
 
 
 
7. I look different in the mirror 
10. People stare at me because of 
my appearance 
 
• Completely agree 
•   Completely agree 
 
• Moderately agree 
•   Moderately agree 
 
• Neither agree nor disagree 
• Neither agree nor disagree 
 
• Moderately disagree 
•   Moderately disagree 
 
• Completely disagree 
•   Completely disagree 
 
8. I feel rejected by people because of 
my illness 
11. Some parts of my body (nose, feet 
hands,…) are too big 
 
• Completely agree 
•   Completely agree 
 
• Moderately agree 
•   Moderately agree 
 
• Neither agree nor disagree 
• Neither agree nor disagree 
 
• Moderately disagree 
•   Moderately disagree 
 
• Completely disagree 
•   Completely disagree 
 
9. I have problems carrying out my 
usual activities (e.g. working, studying, 
doing 
household 
tasks, 
family 
or 
leisure activities) 
12. I have problems doing things 
with my hands, for example, sewing 
or handling tools 


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Because of my Acromegaly… 
 
 
 
 
 
 
13. The illness affects my performance 
at work or in my usual tasks 
 
16. I snore at night 
 
• Always 
• Always 
 
• Most of the time 
• Most of the time 
 
• Sometimes 
• Sometimes 
 
• Rarely 
• Rarely 
 
• Never 
• Never 
 
14. My joints ache 
17. It is hard for me to 
articulate words due to the size of 
my tongue 
 
• Always 
• Always 
 
• Most of the time 
• Most of the time 
 
• Sometimes 
• Sometimes 
 
• Rarely 
• Rarely 
 
• Never 
• Never 
 
15. I feel tired 
18. I have problems with 
sexual relationships 
 
• Always 
• Always 
 
• Most of the time 
• Most of the time 
 
• Sometimes 
• Sometimes 
 
• Rarely 
• Rarely 
 
• Never 
• Never 


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Because of my Acromegaly… 
 
19. I feel like a sick person 
21. I have little sexual appetite 
 
• Completely agree 
• Always 
 
• Moderately agree 
• Most of the time 
 
• Neither agree nor disagree 
• Sometimes 
 
• Moderately disagree 
• Rarely 
 
• Completely disagree 
• Never 
 
20. The physical changes produced 
by my illness govern my life 
22. I feel weak 
 
• Completely agree 
• Always 
 
• Moderately agree 
• Most of the time 
 
• Neither agree nor disagree 
• Sometimes 
 
• Moderately disagree 
• Rarely 
 
• Completely disagree 
• Never 
 
 
Finally, please check that you have answered all the questions. 
 
 
 
Once again thank you very much for your collaboration. 


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14.2 
Appendix 2: Patient Report Outcome Questionnaire EQ-5D5-L 
Health Questionnaire 
 
English version for the USA 
Under each heading, please check the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems walking 
❑ 
I have slight problems walking 
❑ 
I have moderate problems walking 
❑ 
I have severe problems walking 
❑ 
I am unable to walk 
❑ 
 
SELF-CARE 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself       ❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
 
USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities) 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 


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The best health 
you can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
 
60 
 
55 
 
50 
 
45 
100 
means 
the 
best 
health 
you 
can 
imagine. 
40 
0 means the worst health you can imagine. 
35 
Mark an X on the scale to indicate how your health is TODAY. 
Now, please write the number you marked on the scale in the box below. 
30 
25 
20 
 
15 
 
YOUR HEALTH TODAY = 
10 
5 
 
0 
The worst health 
you can imagine 
PAIN / DISCOMFORT 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am severely anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
We would like to know how 
TODAY. 
good or bad your health is 
This scale is numbered from 0 to 100. 


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14.3 
Appendix 3: Concomitant Medications with “known risk of TdP 
(Torsades de pointes)” 
The following list of drugs is generally recognized to have a possible association with TdP. 
This list is not considered to be all inclusive and any questions regarding concomitant 
medications with known risk of TdP should be discussed with the Novartis global team. 
//crediblemeds.org/ 
 
14.4 
Appendix 4: Pharmacy Instructions for pasireotide LAR 
General Instructions 
First needle for withdrawal: 
All withdrawals need to be performed with a needle length of min. 50 mm, as otherwise the 
vial bottom is not reached, which directly affects the actual withdrawn dose. The procedures 
below describe the use of an 18 G needle for withdrawal, but nevertheless needles of 18 G to 
20 G can be used. 
Second needle for i.m. injection: 
The i.m. injection should be performed with a 20 G needle, but nevertheless needles of 18 G 
to 20 G can be used, with a length used for standard i.m. injections. 
Syringe: 
The syringe recommended should have a volume of 3 ml, but 2 ml syringes (for low doses of 
5 mg to 60 mg, only) or 5 ml syringes can be used as well. 
Vehicle: 
The vehicle for suspension is the Vehicle for microparticles, liquid in ampoules, 2 ml. (basis 
number 3705852). 
Standing time: 
For suspension in vial the standing time is 1h. As sedimentation of the suspension could lead 
to blocking of the needle, a standing time of 1h is allowed on constituted suspension in the 
vial, only. After any standing time shake the vial up and down at least 30 seconds in order to 
get a homogenous re-constituted suspension before withdrawal. 
 
Procedure for 10 mg dosage strength (20 mg per vial) 
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 


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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 an 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 (20 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 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 and by adjusting the volume in the syringe to 
0.9 ml 
• Immediately, inject the whole volume of suspension intra-muscularly to the patient 
Procedure for 20 mg dosage strength (20 mg per vial) 
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 an 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 (20 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 
• 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 
Procedure for 40 mg dosage strength (40 mg per vial) 
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. 


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• 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 an 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 
• 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 
Procedure for 60 mg dosage strength (60 mg per vial) 
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: 60 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 an 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 (60 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 
• 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 

SAP_001.pdf: 
Clinical Development
SOM230/pasireotide
CSOM230C2413 / NCT02354508
A phase IIIb multicenter, open-label, single arm study to 
evaluate the efficacy and safety of pasireotide in patients 
with acromegaly inadequately controlled with first 
generation somatostatin analogues
RAP Module 3: Detailed Statistical Methodology
Author(s):
 Trial Statistician
Document type:
RAP Module 3: Detailed Statistical Methodology 
Document status:
Amendment 1 Final 1.0
Release date:
21 Mar 2018
Number of pages
40
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
1.0
11-May-2015
First draft version
1.1
18-June-2015
Updated based on feedback received from LS, GBMD
1.2
26-June-2015
Updated based on feedback from Medical Writer and
Trial Programmer
1.3
30-June-2015
Updated after RAP I meeting
Final 1.0
30-June-2015
Final
Amendment 1
21-March-
2018

Addition of the supportive text into the AE section related to the 
tables now mandatory in CSRs in order to address all current 
Health Authority clinical trial safety data disclosure 
requirements (EudraCT and CT.gov).

To add the definition of the calculation of cumulative dose and 
dose intensity

To specify the details on the management of the Q2 serum 
creatinine issue

To specify the details on the EQ-5D-5L index scores 
calculation

To align the definition of baseline with the safety guidance 
baseline definition. 

Section 4.3: to change the Clinically notable values (above and 
below normal values) for pulse rate

Study drug start date for the extension phase was clarified.

Notable criteria for PR, QRS and VR were included.


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Table of contents
Table of contents..................................................................................................................3
List of tables ........................................................................................................................5
List of abbreviations ...................................................................................................................6
1
Introduction to RAP documentation....................................................................................8
1.1
Scope........................................................................................................................8
1.2
Changes to RAP documentation (M3).....................................................................8
2
Study objectives and design.................................................................................................9
2.1
Study reference documentation ...............................................................................9
2.2
Study objectives.......................................................................................................9
2.3
Study design and treatment....................................................................................10
3
First interpretable results (FIR)..........................................................................................11
4
Interim analyses.................................................................................................................11
5
Data included in the analysis.............................................................................................12
6
Statistical methods: Analysis sets ......................................................................................12
6.1
Run-in set...............................................................................................................12
6.2
Full analysis set......................................................................................................12
6.3
Safety set................................................................................................................12
6.4
Per-Protocol Set .....................................................................................................13
7
Protocol deviations ............................................................................................................13
8
Patient disposition, background and demographic characteristics....................................16
8.1
Patient disposition: Run-in and screen failure .......................................................16
8.2
Patient disposition: FAS ........................................................................................16
8.3
Protocol deviation summaries................................................................................17
8.4
Background and demographic characteristics .......................................................17
8.5
Medical history......................................................................................................17
8.6
Prior acromegaly therapy.......................................................................................18
8.7
Other ......................................................................................................................18
9
Extent of exposure.............................................................................................................18
9.1
Study drug..............................................................................................................18
9.2
Study medication ...................................................................................................18
9.3
Exposure ................................................................................................................18
10 Concomitant medication....................................................................................................19
11 Medications known to affect GH and IGF-1 levels...........................................................20
12 Statistical methods for run-in population ..........................................................................20
13 Statistical methods for efficacy evaluation........................................................................21


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13.1
Analyses time points..............................................................................................21
13.2
Primary efficacy evaluation...................................................................................21
13.2.1
Graphical presentation of results...........................................................21
13.2.2
Handling of missing values/censoring/discontinuations.......................21
13.2.3
Sensitivity analysis by imputing missing values...................................21
13.2.4
Supporting analysis of Primary Objective.............................................22
13.3
Secondary objectives .............................................................................................22
13.3.1
Secondary objectives – Core phase.......................................................22
13.3.2
Secondary objectives – Extension phase...............................................23
13.3.3
Graphical presentation of results...........................................................24
14 Statistical methods for safety analysis...............................................................................24
14.1
Adverse events (AE)..............................................................................................25
14.1.1
Coding of AEs.......................................................................................25
14.1.2
Grading of AEs......................................................................................25
14.1.3
General rules for AE reporting..............................................................25
14.1.4
AE summaries .......................................................................................25
14.1.5
Grouping of adverse events of special interest ......................................26
14.2
Laboratory values ..................................................................................................26
14.2.1
Graphical presentation of results...........................................................28
14.3
Vital signs and weight............................................................................................28
14.4
ECG .......................................................................................................................28
14.5
Gallbladder ultrasound...........................................................................................29
15 Sample size and power considerations ..............................................................................29
16 References..........................................................................................................................29
17 Appendix 16.1.9 Documentation of statistical methods....................................................31
17.1
Dates and time windows ........................................................................................31
17.1.1
Study drug start and end date................................................................31
17.2
Study day........................................................................................................... 31
17.3
End of treatment.....................................................................................................31
17.4
Baseline definition.................................................................................................32
17.5
Time windows........................................................................................................32
17.5.1
Evaluation time window .......................................................................33
17.6
Concomitant medications ......................................................................................33
17.7
General definitions, conventions and methods......................................................33
17.7.1
Standardized IGF-1 values ....................................................................33
17.7.2
Symptoms of acromegaly......................................................................33
17.7.3
Quality of life ........................................................................................33


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17.8
Health status...........................................................................................................34
17.9
Data handling conventions.....................................................................................35
17.10 Other rules..............................................................................................................35
17.11 Number of decimal places .....................................................................................35
17.12 SAS procedure used...............................................................................................35
List of tables
Document History – Changes compared to previous version of RAP module 3. ......................2
Table 2-1
Objectives and related end points............................................................9
Table 7-1
Protocol deviations and the corresponding actions................................13
Table 7-2
Protocol deviation severity codes and analysis sets..............................15
Table 14.2-1
Local or Central Clinical Laboratory Parameters Collection Plan........26


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List of abbreviations
AcroQOL
Acromegaly Quality of Life
ACTH
Adrenocorticotropic Hormone
AE
Adverse Event
ALP
Alkaline phosphatase
ALT
Alanine transaminase
APTT
Activated Partial Thromboplastin Time
AST
Aspartate transaminase
ATC
Anatomic Therapeutic Chemical
ATG
Autogel
CRF
Case Report/Record form
CSR
Clinical Study Report
FBG
Fasting Blood Glucose
DAR
Dose Administration Record
DBL
Database Lock
ECG
Electrocardiogram
EQ-5D-5L
European Quality of Life group-5 dimension-5 level 
GGT
Gamma-glutamyl transferase
oGTT
Oral Glucose Tolerance Test
MedDRA
Medical Dictionary for Drug Regulatory Activities
AIP
Aryl Hydrocarbon Receptor Interacting Protein
TdP
Torsades de pointes
EMA
European Medicines Agency
ADA
American Diabetes Association
GH
Growth Hormone
GPS
Global Programming and Statistical Environment
Hb
Hemoglobin
LFT
Liver Function Tests
PT(INR)
Prothrombin time (International normalized ratio)
ELISA
Enzyme-linked immunosorbent assay
HIV
Human Immunodeficiency Virus
IGF-1
Insulin-like Growth Factor 1
LAR
Long Acting Release
LPLV
Last Patient Last Visit
PLT
Platelets
PRO
Patient-reported outcome
MRI
Magnetic Resonance Imaging
PT
Preferred term
RECIST
Response evaluation criteria in solid tumors
HRQoL
Health Related Quality of Life
HbA1C
Hemoglobin A1c
PT
Prothrombin time
RAP
Report Analysis Plan
SAE
Serious Adverse Event


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SOC
System organ class
VAP
Validation Analysis Plan
VAS
Visual Analogue Scale
WBC
White blood cells
WHO
World Health Organization


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1
Introduction to RAP documentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics &
Programming input into the Clinical Study Report (CSR) for trial CSOM230C2413.
Module 3 (M3) provides the description of the statistical methodology used to analyze the
data, Module 7 (M7) details the presentation of the data, including shells of summary tables,
figures and listings, and Module 8 (M8) contains programming specifications e.g. for derived
variables and derived datasets, to support the creation of CSR outputs.
The statistical analysis of this study will be performed by Novartis personnel. A detailed
description of the statistical analysis methods will be provided in Appendix 16.1.9 of the CSR.
Analysis data sets and statistical outputs will be produced using the most recent SAS®
Version (SAS Institute Inc., Cary, NC, USA), and stored in Novartis global programming &
statistical environment (GPS).
1.2
Changes to RAP documentation (M3)
Refer to corresponding guidance and NIBR RAP Addendum template for detailed information
on the requirements of documenting changes to RAP documentation.
For the statistical methodology (M3), any major changes to the statistical methodology
should be reflected in the RAP M3 documentation via version control (M3 amendment) (new
document version to be approved by the trial team as the original module).
Such major changes could include (but are not limited to):

change in statistical methodology

substantial change in (derivation of) main endpoint

substantial change in study design (e.g. protocol amendment introducing new multiple-
dose cohorts in a so far single-dose trial)
Such changes may also require a protocol amendment to ensure consistency. In addition they
need to be mentioned (high-level) in the CSR (section for changes to planned analysis).
Minor changes to the RAP M3 documentation can be captured e.g. by a study note to file /
note in RAP Addendum or within the CSR itself.
Corrections of typographical errors or modification
of spelling (from English to American, for example) do not need to be incorporated into the
RAP M3 documentation.
Analyses and outputs related to
ad-hoc requests used for reporting are
regarded minor changes and should be documented in the RAP addendum (no RAP
amendment necessary).


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2
Study objectives and design
2.1
Study reference documentation
The following documents were used to develop this RAP Module 3:

CSR template

Protocol CSOM230C2413

Protocol CSOM230C2402

Annotated Case Report Form

Guidelines for content of Statistical Appendices of the Clinical Study Report

Report & Analysis Plan for Novartis Oncology
2.2
Study objectives
Table 2-1
Objectives and related end points
Objective
End point
Primary
To evaluate the efficacy of pasireotide LAR in patients 
with acromegaly who are inadequately controlled with
maximal approved doses of currently available 
somatostatin analogues, as measured by the
proportion of patients with GH < 1μg/L and IGF-1 <ULN
at week 36
Proportion of patients who achieved GH <1μg/L and 
IGF-1 <ULN at week 36.
Supporting Analysis for Primary
To assess the proportion of patients achieving GH
< 1μg/L and IGF-1 <ULN at week 36 by GH level at
screening.
Proportion of patients who achieved GH <1μg/L and 
IGF-1 <ULN at week 36 in patients having GH level at
screening between 1 μg/L and 2.5 μg/L, and in 
patients having GH level at screening >2.5 μg/L
Secondary- core phase
To assess the changes in mean GH from study 
baseline to week 36
Changes in mean GH from study baseline to week 36.
To assess the changes in standardized IGF-1 from
study baseline to week 36
Changes in standardized IGF-1 from study baseline to 
week 36.
To assess the proportion of patients achieving GH <1 
μg/L and IGF-1 <ULN at weeks 12 and 24 overall and 
by GH level at screening
Proportion of patients who achieved GH <1μg/L and 
IGF-1 <ULN at week 12 and 24 overall and by GH
level at screening.
To assess the proportion of patients achieving GH
<1μg/L at weeks 12, 24 and 36, overall and by GH 
level at screening
Proportion of patients who achieved GH <1μg/L at 
week 12, 24 and 36 overall and by GH level at
screening.
To assess the proportion of patients achieving IGF-1 
levels <ULN at weeks 12, 24 and 36
Proportion of patients who achieved IGF-1 <ULN at
week 12, 24 and 36.
To evaluate the tolerability and safety profile of 
pasireotide LAR
Toxicity will be assessed using the National Cancer
Institute-Common Toxicology Criteria Adverse Events
version 4 (NCI-CTCAE v.4.03) and for laboratory


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assessments that include biochemistry, hematology,
urinalysis; special safety assessments that include the 
regular monitoring and recording of blood glucose, 
insulin, HbA1c, GH and IGF-1, thyroid and liver function 
tests, gallbladder examinations and ECGs.
Concomitant medications/Significant nondrug 
therapies will be assessed from study enrollment until 
the safety follow-up
To evaluate the effect of pasireotide LAR on HRQoL 
and signs and symptoms of acromegaly from baseline 
to weeks 12, 24 and 36
Change in scores as measured by AcroQoL, EQ-5D-
5L and signs and symptoms of acromegaly from
baseline to weeks 12, 24 and 36
Secondary – extension phase
To assess the proportion of patients achieving IGF-1
<ULN at weeks 48, 60 and 72
Proportion of patients who achieved IGF-1 <ULN at
weeks 48, 60 and 72
To assess the proportion of patients achieving GH <1 
μg/L and IGF-1 <ULN at weeks 48, 60 and 72 by 
treatment with pasireotide LAR alone or with 
concomitant medications used to treat acromegaly
Proportion of patients who achieved GH <1 μg/L and 
IGF-1 <ULN at weeks 48, 60 and 72 by treatment with
pasireotide LAR alone or with concomitant
medications used to treat acromegaly
To assess the proportion of patients achieving GH <1 
μg/L at weeks 48, 60 and 72 by treatment with 
pasireotide LAR alone or with concomitant 
medications used to treat acromegaly
Proportion of patients who achieved GH <1 μg/L at 
weeks 48, 60 and 72 by treatment with pasireotide 
LAR alone or with concomitant medications used to
treat acromegaly
To evaluate the long term tolerability and safety profile
of pasireotide LAR
Toxicity will be assessed using the National Cancer
Institute-Common Toxicology Criteria Adverse Events
version 4 (NCI-CTCAE v.4.03) and for laboratory 
assessments that include biochemistry, hematology, 
urinalysis; special safety assessments that include the 
regular monitoring and recording of blood glucose, 
insulin, HbA1c, GH and IGF-1, thyroid and liver 
function tests, gallbladder examinations and ECGs.
Concomitant medications/Significant nondrug 
therapies will be assessed from study enrollment until
the safety follow-up.
To evaluate the long term effect of pasireotide LAR on 
HRQoL and signs and symptoms of acromegaly, from 
baseline and week 36 to week 72
Change in scores as measured by AcroQoL, EQ-5D-
5L and signs and symptoms of acromegaly from 
baseline to week 72 and from week 36 to week 72.
2.3
Study design and treatment
This is a phase IIIb exploratory study to assess the efficacy and safety of pasireotide in
patients with acromegaly inadequately controlled with first generation somatostatin analogues.
It is planned that the data from all centers that participate in this protocol will be used.
Study drug refers to pasireotide LAR (10mg, 20 mg, 40 mg or 60 
mg). The brief description of the study design is given below:
Group 1 – Patients treated with octreotide LAR 30mg from the countries where octreotide
LAR 40mg is approved for the treatment of acromegaly at the time of screening – Patients
participate in the run-in phase.


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Run-In phase (Screening to Baseline):
Patients will start treatment with octreotide LAR 40 mg every 4 weeks. Patients who have not
achieved biochemical control after 3 injections can be enrolled in the study.
Core Phase (Baseline to week 36):
Patients will start treatment on pasireotide LAR 40 mg every 4 weeks until week 32. A mean
GH value and IGF-1 value will be assessed every 12 weeks until week 36. The dose can be
adjusted after the evaluation of biochemical control. During the core phase any acromegaly
concomitant medication is prohibited.
Extension Phase (week 36 to week 76):
Patients will receive the same dose of pasireotide LAR at week 36, which is the first dose of
study medication in the extension phase. At week 40 the dose can be adjusted and acromegaly 
concomitant medication can be added to the treatment if, patients remain uncontrolled.
Patients will receive pasireotide LAR 40mg/60mg until week 68 for a total of 32 weeks in the
extension phase. A mean GH value and IGF-1 value will be assessed every 12 weeks until
week 72.
Safety follow-up:
After discontinuation or completion of study treatment, all patients will be followed for safety
12 weeks after the last study drug administration.
Group 2 – Patients treated with octreotide 30 mg from countries where octreotide 40mg has
NOT been approved for the treatment of acromegaly at screening or patients treated with
octreotide 40mg or lanreotide 120mg - Patients who do not have the run-in phase.
Core Phase (Baseline to week 36):
Same procedure to be followed as Group 1.
Extension Phase (week 36 to week 76): 
Same procedure to be followed as Group 1.
Safety follow-up:
Same procedure to be followed as Group 1.
3
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial after the completion of the core
phase (After Visit 777) and after completion of the extension phase (After Visit 778).
Study outputs required to be created at the time of the FIRs will be highlighted in RAP
Module 7 and marked as “Key” in the M9.1 Tracking sheet output list.
4
Interim analyses
No formal interim analysis will be performed.


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5
Data included in the analysis
The analysis data cut-off for the core phase will be set as the Last Visit date for each patient
(i.e., the date when the patient completes the Week 36 visit or the early discontinuation visit).
All data reported in the database (scheduled, repeat and unscheduled visits) up to the cut-off
data will be included.
Primary analysis will occur after all enrolled patients complete the core phase or discontinue
prior to completing this phase of the trial. A CSR will be developed based on all the analyses
(efficacy and safety) and results specific to the core phase of the study.
Final analysis will be conducted when all patients complete the extension phase or have
discontinued the study prior to completing the extension phase of the trial.
The final CSR will include:

Analyses and results corresponding to both core and extension phase (wherever
applicable)

Extension phase specific results.
The final CSR will include reports based on all data that has been collected up to the final
CSR DBL (in general occurs 12 weeks after LPLV).
6
Statistical methods: Analysis sets
The definition of the analyses sets will remain same during the core and extension phase.
6.1
Run-in set
The Run-in set comprises of patients who:

Must have been treated with octreotide LAR 30 mg for at least three months before
screening visit from countries where octreotide LAR 40 mg is approved for the treatment
of acromegaly before screening visit

Signs informed consent and meet inclusion/exclusion criteria

Receives octreotide LAR 40 mg every 4 weeks for 4 months after Visit 1 (Screening) to
Visit 5.
6.2
Full analysis set
The Full Analysis Set (FAS) comprises all patients who have signed informed consent and
have been treated with at least one dose of study medication (pasireotide LAR) after
enrollment into the study. The protocol states that the FAS comprises all patients to whom 
study treatment has been assigned. The definition of the FAS in the SAP specifies that with 
study treatment it is meant Pasireotide LAR to avoid confusion with the second treatment drug 
Octreotide LAR.
6.3
Safety set
The Safety Set includes all patients who received at least one dose of study medication
(Pasireotide LAR) with a post-baseline safety assessment. The statement that a patient has no
AE constitutes a safety assessment.
The safety set will be used for all safety analyses.


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6.4
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant
with requirements of the CSP. The protocol deviations criteria will be defined prior to
database lock in VAP 3 and in section 7 of this document (an amendment to the RAP M3 will
be considered if there are new PDs occurring in the course of the study which leads to
exclusion of patients from PPS).
In section 7, detailed description of actions to be taken are described regarding data exclusion
(exclusion of patients from FAS, Safety Set or PPS) corresponding to a particular protocol
deviation.
General principles to be used: a protocol deviation should be classified as major, i.e., leading
to exclusion of patients from PPS, only:
1. If the protocol deviation is very likely to confound the scientific analysis of the primary
efficacy endpoint(s) or if it precludes any meaningful efficacy assessment,
2. If it is in direct conflict with the analysis set definition given in the title of the study (i.e.,
patient diagnosis, stage of disease or use of prior treatment does not correspond to the
intended patient population to be studied).
More specifically, the following protocol deviations are considered project standard for major
deviations:

No disease or not the type of disease or not stage of disease required by the study protocol
(e.g., incorrect diagnosis, not de novo, not refractory, not metastatic, different grade etc),

If prior surgical/radio therapy doesn’t match with protocol requirements in terms of time
of previous therapy,

If documentation of pre-baseline disease progression required and is missing,

Patient compliance as defined as patient being evaluated for primary efficacy endpoint at 
least once. Patients who discontinue prior to the first efficacy assessment due to adverse 
events, including death, will be included.
Any other deviation leading to exclusion from the PPS will be specified in study [VAP
Module 3 and section 7 of this RAP M3].
7
Protocol deviations
The following table contains the current study specific important protocol violations. The
final list of PDs might deviate from this list. The table below specifies the action to be taken if 
any of the listed deviations occur:
Table 7-1
Protocol deviations and the corresponding actions
Protocol Deviation
ID
Description used
to Report PDs to
HA/IRBs
Check
Identification
Method
Manual by FM,
Manual by
Study Lead 2 or
Direct Hit
Programming
Action


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I02
Informed consent 
not signed at all
All required
signatures are 
present.
Direct Hit 
Programming
Patient will be 
excluded from all 
analyses set
I04
GH and/or IGF-1 
missing
GH/IGF-1 Lab
report
Manual by FM 
and CTH
Patient will be 
excluded from PPS
if GH and/or IGF-1 
missing at week 36
I05
GH mean < 1ug/L or
IGF-1 < 1.3x ULN
GH/IGF-1 Lab
report
Manual by FM 
and CTH
Patient will be 
excluded from PPS
I06
Less than 3 months 
of treatment with 
high dose of 
octreotide LAR or 
lanreotide ATG
Patients should 
have confirmed
treatment with 30mg 
octreotide in
countries were the 
40mg dose is not 
approved and 40mg 
dose in countries 
where the 40mg is 
approved or 
treatment with 
120mg lanreotide 
ATG for 3 months 
prior to visit 1.
Manual by FM
Patient will be 
excluded from PPS
I07
Patient is a run-in 
failure but is
enrolled in the core 
study
Patient should not 
be biochemically 
controlled at visit 5 
or 6. (GH values 
less than or equal to 
1 and IGF-1 > 1.3x
ULN)
Manual by FM
Patient will be 
excluded from PPS
E01
GHR-antagonist or
dopamine agonists 
taken < 3 months 
prior to visit 1
Confirm the end 
date of all GHR-
antagonist or 
dopamine agonist is 
at least 3 months 
prior to visit 1.
Manual by FM
Patient will be 
excluded from PPS
G03
The time between 
the 0 minutes 
timepoint in the  GH 
5-point 
measurements and 
the 120 minutes is 
greater than 180 
minutes
Time between the 0 
minutes timepoint in 
the  GH 5-point
measurements and 
the 120 minutes 
should not be 
greater than 180 
minutes
Direct Hit 
Programming
Patient will be 
excluded from PPS 
if the time between 
the 0 minutes
timepoint in the  GH 
5-point 
measurements and 
the 120 minutes is 
greater than 180 
minutes at week 36
G13
Use of other 
investigational drug 
or therapy
Patients should not 
use any other 
investigational drug 
or therapy during 
the course of the 
study.
Manual by FM
Patient will be 
excluded from all 
analyses from the 
date of use of other 
investigational drug 
or therapy
G14
Less than 3 
GH 5-point
measurements 
or missing GH 
assessment
Patient should 
not have less 
than 3 samples 
to assess 5-point 
mean GH or
Direct Hit 
Programming
Patient should be 
excluded from PPS 
if less than 3
GH 5-point
measurements


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missing GH 
assessment
or missing GH 
assessment are 
obtained at week 36
G17
Missing IGF-1 
assessment
IGF-
1assessments 
should be done 
at all visits where
required by the 
protocol
Direct Hit 
Programming
Patient will be 
excluded from PPS 
if there is missing 
IGF-1 assessment
at week 36
G19
Missed visit
Patients should 
not miss any visit
Manual by 
CTH
Patient will be 
excluded from PPS 
if visit 36 is missed
S10
Up-/down-titrations
of pasireotide not 
done as defined in 
protocol
Dose changes of 
pasireotide should 
be done as 
described in
protocol e.g., patient 
on pasireotide LAR 
40 mg who is not 
biochemically 
controlled has to be 
uptitrated to 
pasireotide LAR 60 
mg at the next
possible visit in the 
absence of any 
safety concerns.
Manual by FM
Patient will be 
excluded from PPS
D09
Patient withdrawing 
informed consent 
but not withdrawn
Patient who 
withdraw informed 
consent have to be 
discontinued
Manual by FM
Patient should be 
excluded from all 
analyses from the 
date of withdrawal 
of informed consent
M01
Use of medication 
known to affect GH 
or IGF-1 levels
Medication known to 
affect GH or IGF-1 
levels are not 
allowed for the Core 
study(Visit 777)
Direct Hit 
Programming
Patient will be 
excluded from PPS 
from the date of use 
of this medication 
within the core 
phase
Table 7-2
Protocol deviation severity codes and analysis sets
Protocol deviation ID and description
Full analysis
set
Safety set
Per protocol
set
ID
Text
I02
Informed consent not signed at all
-
-
-
I04#
GH and/or IGF-1 missing
+
+
-
I05
GH mean < 1ug/L or IGF-1 < 1.3x ULN
+
+
-
I06
Less than 3 months of treatment with
high dose of octreotide LAR or
lanreotide ATG
+
+
-
I07
Patient is a run-in failure but is enrolled
+
+
-


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in the core study
E01
GHR-antagonist or dopamine agonists
taken < 3 months prior to visit 1
+
+
-
G03#
The time between the 0 minutes
timepoint in the GH 5-point
measurements and the 120 minutes is
greater than 180 minutes
+
+
-
G13*
Use of other investigational drug or
therapy
-
-
-
G14#
Less than 3 GH 5-point measurements
or missing GH assessment
+
+
-
G17#
Missing IGF-1 assessment
+
+
-
G19#
Missed visit
+
+
-
S10
Up-/down-titrations of pasireotide not
done as defined in protocol
+
+
-
D09**
Patient withdrawing informed consent
but not withdrawn
-
-
-
M01***
Use of medication known to affect GH
or IGF-1 levels
+
+
-
+ = include in analysis set, - = exclude from analysis set, * = Patient will be excluded from all
analyses from the date of use of other investigational drug or therapy, **= Patient should be
excluded from all analyses from the date of withdrawal of informed consent, ***= Patient should
be excluded from PPS from the date of use of this medication known to affect GH and IGF-1
within core phase (on or before Week 36), #: Patient should be excluded from PPS if the
deviation occurs in week 36
If updates to this table are needed, an amendment to RAP M3 needs to be implemented prior
to DBL.
8
Patient disposition, background and demographic
characteristics
8.1
Patient disposition: Run-in and screen failure
The following summaries will be provided:

Number (%) of patients screened

Number (%) of patients screened but did not entered run-in phase (usual screen failure) and 
reason for not continuing

Number (%) of patients who entered run-in phase

Number (%) of patients who discontinued during the run-in phase

Number (%) of patients who entered the core phase
The patients who were screened and the run-in set will be used for the above disposition.
8.2
Patient disposition: FAS
The FAS will be used for presenting patient disposition. The following summaries will be
provided:


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
Number (%) of patients who completed the core phase

Number (%) of patients who entered the extension phase

Number (%) of patients who completed the extension phase

Number (%) of patients who discontinued and reason for discontinuation at any time prior
to end of study (Week 72, Visit 778)

Number (%) of patients who discontinued and reason for discontinuation prior to week 36
(core phase, Visit 777)

Number (%) of patients who discontinued and reason for discontinuation prior to week 72
(extension phase, Visit 778) after completing the core phase
8.3
Protocol deviation summaries
The number and percentage of patients in the FAS with any CSR reportable protocol
deviation will be tabulated by major protocol deviations (excluded from PPS) and minor
protocol deviations. Listing will also be provided for all the protocol deviations based on FAS.
8.4
Background and demographic characteristics
All demographic characteristics and background data (e.g., age, gender, race, GH levels,
standardized IGF-1 levels) will be summarized and listed in the FAS.
Qualitative characteristics (e.g., gender) will be summarized by means of contingency tables.
Quantitative variables (i.e., age, weight, BMI) will be summarized by appropriate descriptive
statistics (i.e., mean, SD, median, minimum, maximum).
Information on aryl hydrocarbon receptor-interacting protein (AIP) mutation and MRIs
performed will also be summarized and listed.
Baseline diabetic status will be summarized. The status will be defined as follows:

Diabetic: Patients were taking anti-diabetic medication at baseline, or prior past
medication history of diabetes mellitus or baseline HbA1C >=6.5% or baseline fasting
glucose >=126 mg/dL or 2-H plasma glucose (during oGTT at screening visit) of greater
or equal 200 mg/dL (>=11.1 mmol/L)

Pre-diabetic: Patients with 100 mg/dL <=baseline FBG< 126 mg/dL or 5.7% <=baseline
HbA1c<6.5% or 140 mg/dL (i.e., 7.8 mmol/L) <= 2-H plasma glucose (during oGTT at
screening visit) < 200 mg/dL (i.e., < 11.1 mmol/L)

Non-diabetic: Patients not qualifying as diabetic or pre-diabetic and with baseline FBG is
not missing and < 100 mg/dL and baseline HbA1c is not missing and <5.7% and and 2-H
plasma glucose (during oGTT at screening visit) is not missing and < 140 (i.e., less than
7.8 mmol/L)

Missing − patients with no prior history of DM and no history of antidiabetic medication,
both FBG and HbA1c are missing.
8.5
Medical history
The FAS will be used for all medical history summaries and listings including medical history 
for acromegaly. Medical history and current medical conditions will be summarized


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separately by primary system organ class (SOC) and preferred term (PT) based on latest
available Medical Dictionary for Regulatory Activities (MedDRA) dictionary version at time
of database lock. The MedDRA version used for reporting the study will be specified as a
footnote in the related tables/listings. Listings will also be provided.
8.6
Prior acromegaly therapy
Prior therapy for acromegaly including surgery, radiation and medication will be summarized
and listed based on the FAS
8.7
Other
All data collected at baseline such as child bearing potential, pregnancy test results and tumor
volume (tumor evaluation using MRI) will be listed as required based on the FAS.
9
Extent of exposure
9.1
Study drug
Study drug refers to pasireotide LAR (10 mg, 20 mg, 40 mg or 60 mg).
9.2
Study medication
The safety set will be used for all summaries and listings of study medication.
Duration of exposure to study drug, number of injections taken and number of patients with
dose change and/or dose delay along with reasons for dose change/dose delay, will be
summarized by appropriate descriptive statistics. In addition, number of injections will be
summarized categorically (categories to be specified in RAP Module 7).
All doses of the study drug along with reasons for dose change/delay will be listed.
The above summaries and listings will be provided for overall study period (core + extension
phase), and separately for core phase and extension phase
9.3
Exposure
The following definitions will be used corresponding to study drug pasireotide LAR only:
Core phase:
Study drug start date is defined as the first date when a non-zero dose of study drug
(pasireotide LAR) was administered and recorded on the Drug Administration Record (DAR)
CRF page.
Study drug end date is defined as the last date when a non-zero dose of study drug
(pasireotide LAR) was administered in the core phase of the study.
Extension phase:
Study drug start date is defined as the first date when a non-zero dose of study drug 
(pasireotide LAR) was administered during the extension phase and recorded on the Drug 
Administration Record (DAR) CRF page.


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Study drug end date is defined as the last date when a non-zero dose of study drug
(pasireotide LAR) was administered in the extension phase of the study.
Duration of exposure in core phase (in weeks) will be calculated as:
{min(study drug end date in core phase + 27 days; death date) – study drug start date in core +
1 day} / 7 days.
Duration of exposure in core phase (in months) will be calculated as:
{min(study drug end date in core phase + 27 days; death date) – study drug start date in core + 
1 day} / 30.4375.
Cumulative dose (mg): total dose of study drug taken by a patient in the core phase
Dose intensity (DI) (mg/month): cumulative dose (mg) / duration of exposure (months).
Duration of exposure in extension phase (in weeks) will be calculated as:
{min(study drug end date in extension phase + 27 days; death date) – study drug start date in
core phase + 1 day} / 7 days.
Duration of exposure extension phase (in months) will be calculated as:
{min(study drug end date in extension phase + 27 days; death date) – study drug start date in
extension phase + 1 day} / 30.4375
Cumulative dose (mg): total dose of study drug taken by a patient in the extension phase
DI (mg/month): cumulative dose (mg) / duration of exposure (months).
The duration includes periods of temporary interruption for any reason.
Duration of exposure will be presented overall and for up-titrated Pasireotide LAR 60 mg 
(highest dose received during the trial.)
In addition, the number of patients on maximum dose during the core phase (20, 40 or 60 mg)
will be provided
10
Prior and concomitant medication
Prior and concomitant therapy is defined as all interventions (therapeutic treatments and
procedures) besides the study treatment that are administered to a patient preceding or
coinciding with the study assessment period.
Prior and concomitant medications and significant non-drug therapies for acromegaly and
excluding acromegaly will be listed and summarized separately in the safety set.
Summary on prior medications and significant non-drug therapies (for acromegaly and
excluding acromegaly) will be provided only for the core phase. The concomitant medications
and significant non-drug therapies (for acromegaly and excluding acromegaly) will be
provided for overall study period (core + extension phase) and separately for core phase and
extension phase.
Separate summaries on prior and concomitant anti-diabetic medication after start of study
drug (pasireotide LAR) will be provided for over study period and separately for core phase
and extension phase.
Medications will be classified as prior or concomitant based on the following rules and will be 
coded using the WHO Drug Reference List to allow for categorization by preferred term:

Prior medication are medications that started before the first dose of study drug regardless
of whether the medication ended before or after the first dose of study drug.


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
Concomitant medications are medications that started on or after the first dose of study
drug, or started before the first dose of study drug and continued after the first dose of
study drug.
In addition to categorizing medication data by preferred term, drugs will be classified
according to their ATC classification in order to present and compare how they are being
utilized. The ATC classification allows summarization of medications by a high-level
common drug class.
A separate listing will be provided for patients who take concomitant medication related to
prolonging the QT interval and therefore at the risk of ventricular arrhythmia, Torsades de


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Pointes and sudden death for the overall study period (core + extension phase). The listing
will only include the concomitant medications (with dose unit and frequency route) related to
QT prolongation taken at the time of QT prolongation along with the ECG intervals. The
patients who have > 60 ms QTcF change from baseline or QTcF > 480 ms will be flagged.
11
Medications known to affect GH and IGF-1 levels
During the core phase any acromegaly concomitant medication is prohibited. Medication
taken in core phase (other than study drug) and known to affect GH and IGF-1 levels will be
identified as protocol deviations. Patient will be excluded from Per-Protocol set for all
efficacy analysis from the date of use of this medication within the core phase (see section 7
of this RAP M3 for more details). A periodic clinical review of individual study data will be
performed in order to identify medications known to affect GH and IGF-1 levels.
Medications known to affect GH or IGF-1 levels will be allowed only during the extension
phase (starting from week 40) for patients who do not achieve biomedical control in the core
phase.
The following concomitant medications will be used to treat acromegaly (WHO dictionary
code in brackets):

Somatostatin analogs (H01CB)

Dopamine agonists (N04BC)

Growth hormone receptor antagonists (H01AX)
For patients who take concomitant medications known to affect GH or IGF-1 levels during the
core phase, a listing will be provided for those patients along with only the concomitant
medications known to affect GH or IGF-1 levels.
In the extension phase, if there are more than 10 patients who take concomitant medications
known to affect GH or IGF-1 levels, a summary table will be provided for those patients with
medication data. If not, then only a listing will be provided.
12
Statistical methods for run-in population
The run-in set will be used to find the proportion of responders (GH < 1 µg/L and IGF-1 <
ULN) among patients in Group 1 during the run-in phase.
Also listings will be provided for the patients who discontinues during the run-in phase or are
considered as screen failures (after the completion of run-in phase). The listings will include
the
following:
Demography,
relevant
medical
history/current
medical
conditions,
prior/concomitant medications for acromegaly and excluding acromegaly, prior history of
acromegaly, vital signs, symptoms of acromegaly, laboratory assessments (hematology,
chemistry, LFTs, Hepatitis screening, coagulation, hyperglycemia related tests, thyroid and
hormones, urinalysis, IGF-1, GH, pregnancy tests), ECG, gallbladder, adverse events and
study drug administration of octreotide LAR 40 mg.


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13
Statistical methods for efficacy evaluation
13.1
Analyses time points
The main analysis time point will be the 36 week time point (the time when all patients will
complete Week 36 visit or discontinued early). The primary and some secondary endpoints
(during the core phase, see section 13.3.1) will be analyzed at that time point. The other
secondary endpoints related during the core phase will be analyzed at week 12 or 24. The
secondary endpoints related during the extension phase will be analyzed at week 48, 60, or 72.
13.2
Primary efficacy evaluation
The primary objective is to obtain the proportion of patients achieving biomedical control
defined as mean GH levels < 1 µg/L and IGF-1 < ULN at 36 weeks.
The trial is exploratory in nature and no formal hypothesis testing is planned.
The primary efficacy variable is the proportion of patients with a reduction of mean GH levels 
to < 1 µg/L and IGF-1 < ULN at 36 weeks. Two-sided, exact 95% confidence interval for the
proportion will also be provided.
The analysis will be done on FAS and on PPS.
13.2.1
Graphical presentation of results
Plots for mean (+/- SE) of 5-point mean GH and standardized IGF-1 by visit will be provided
for the core phase and overall study period (core + extension phase).
13.2.2
Handling of missing values/censoring/discontinuations
If a patient has less than three samples for the assessment of the 5-point mean GH from the 2-
hour profile, then the mean GH will be considered as missing. In addition, if GH and IGF-1
measurements are taken after 35 days from the date of any injection of study drug (from the
scheduled dose date), the values will be considered as missing (the rationale has been adopted
based on study CSOM230C2402). For a patient with missing values of mean GH or IGF-1 at
36 weeks or who withdraws earlier from the study will be considered as a non-responder.
13.2.3
Sensitivity analysis by imputing missing values
A sensitivity analysis will be added for the primary efficacy variable by imputing missing 
values of mean GH and IGF-1 at week 12, week 24 and week 36 of the core phase using the
Last Observation Carried Forward (LOCF) method. Values at the screening and/or baseline
visit will not be carried forward (e.g., patient with only values at the screening and/or baseline 
visit will be considered as a non-responder). At each time point (i.e., week 12, week 24 and 
week 36) the proportion of patients with a reduction of mean GH levels to < 1 µg/L and IGF-1
< ULN with two-sided, exact 95% confidence interval for the proportion will be provided.
The analysis will be done on FAS.


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13.2.4
Supporting analysis of Primary Objective
The following supportive analyses for the primary efficacy endpoint will be performed on the
FAS.

The proportion of patients who achieved GH < 1 µg/L and IGF-1 < ULN at week 36
among two sub-groups of patients, those having GH level at screening between 1 µg/L
and 2.5 µg/L, and those having GH level > 2.5 µg/L at screening, will be reported along
with their two-sided exact 95% confidence interval.

The proportion of patients who achieved GH < 1 µg/L and IGF-1 < ULN at week 36
among two sub-groups of patients, those receiving 20 mg of pasireotide LAR, 40 mg of
pasireotide LAR and 60 mg of pasireotide LAR at week 36 will be reported along with
their two-sided exact 95% confidence interval.
13.3
Secondaryobjectives
The secondary efficacy analyses will be performed on the FAS. The same rule of handling
missing values for GH and IGF-1 variables as specified in the analyses of the primary efficacy
variable will be used.
13.3.1
Secondary objectives – Core phase
13.3.1.1 To assess the changes in mean GH from study baseline to week 36
Descriptive summaries of actual and percentage change in GH from study baseline to week 36
values will be provided.
13.3.1.2 To assess the changes in standardized IGF-1 from study baseline to
week 36
Descriptive summaries of actual and percentage change in standardized IGF-1 from study
baseline to week 36 values will be provided.
13.3.1.3 To assess the proportion of patients achieving GH < 1 µg/L and IGF-1
< ULN at weeks 12 and 24 overall and by GH level at screening
Proportion of patients who achieved GH < 1 µg/L and IGF-1 < ULN at week 12 and 24 will
be reported along with its corresponding 95% confidence interval for all patients and also
among patients, having GH level at screening between 1 µg/L and 2.5 µg/L, and patients
having GH level at screening > 2.5 µg/L.
13.3.1.4 To assess the proportion of patients achieving GH < 1 µg/L at weeks 
12, 24 and 36, overall and by GH level at screening
Proportion of patients who achieved GH < 1 µg/L at week 12, 24 and 36 will be reported
along with its corresponding 95% confidence interval for all patients and also among patients,
having GH level at screening between 1 µg/L and 2.5 µg/L, and patients having GH level at
screening > 2.5 µg/L.


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13.3.1.5 To assess the proportion of patients achieving IGF-1 levels < ULN at
weeks 12, 24 and 36, overall and by GH level at screening
Proportion of patients who achieved IGF-1 < ULN at week 12, 24 and 36 will be reported
along with its corresponding 95% confidence interval for all patients and also among patients,
having GH level at screening between 1 µg/L and 2.5 µg/L, and patients having GH level at
screening > 2.5 µg/L.
13.3.1.6 To evaluate the effect of pasireotide LAR on HRQoL, EQ-5D-5L and 
signs and symptoms of acromegaly from baseline to weeks 12, 24 and
36
Descriptive statistics, including mean, median, standard deviation, minimum and maximum, will 
be presented for all patient-reported outcomes (PRO) to describe actual standardized scores as 
measured by HRQoL and EQ-5D-5L index scores and EQ-VAS scores. For each acromegaly 
symptoms (ring size, headache, fatigue, perspiration, paresthesias, osteoarthralgia), descriptive 
summaries of actual and changes will be provided.
For each of the PRO variables (AcroQoL score (total score, physical sub-score and 
psychological sub-score [psychological/physical appearance and psychological/personal 
relations]), EQ-5D-5L utility index and EQ-5D-5L VAS score):

Change in PRO scores for all patients from baseline to weeks 12, 24 and week 36.
For the self-reported signs and symptoms (ring size, headache, fatigue, perspiration,
paresthesias, osteoarthralgia):

Change in symptom severity scores (for each sign and symptom) from baseline to weeks 
12, 24 and 36. 

Shift tables from baseline to most extreme post-baseline value up to week 36 will also
be presented for acromegaly symptoms except ring size.
13.3.2
Secondary objectives – Extension phase
13.3.2.1 To assess the proportion of patients achieving IGF-1 < ULN at weeks
48, 60 and 72 by treatment with pasireotide LAR alone or with
concomitant medications used to treat acromegaly
Proportion of patients who achieved IGF-1 < ULN by treatment with pasireotide LAR alone
or with concomitant medications used to treat acromegaly will be reported separately (if there
are 10 more patients with concomitant medications used to treat acromegaly in extension
phase) along with its two-sided 95% confidence interval at week 48, 60 and 72.
13.3.2.2 To assess the proportion of patients achieving GH < 1 µg/L and IGF-1
< ULN at weeks 48, 60 and 72 by treatment with pasireotide LAR alone
or with concomitant medications used to treat acromegaly
Proportion of patients who achieved GH < 1 µg/L and IGF-1 < ULN by treatment with
pasireotide LAR alone or with concomitant medications used to treat acromegaly will be
reported separately (if there are 10 more patients with concomitant medications used to treat
acromegaly in extension phase) along with its corresponding 95% confidence interval at
weeks 48, 60 and 72.
13.3.2.3 To assess the proportion of patients achieving GH < 1 µg/L at weeks 
48, 60 and 72 by treatment with pasireotide LAR alone or with
concomitant medications used to treat acromegaly
Proportion of patients who achieved GH < 1 µg/L by treatment with pasireotide LAR alone or 


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with concomitant medications used to treat acromegaly will be reported separately (if there are
10 more patients with concomitant medications used to treat acromegaly in extension phase)
along with its corresponding 95% confidence interval at weeks 48, 60 and 72.
13.3.2.4 To evaluate the long term effect of pasireotide LAR on HRQoL, EQ-5D-
5L and signs and symptoms of acromegaly, from baseline and week
36 to week 72
Descriptive statistics, including mean, median, standard deviation, minimum and maximum, will 
be presented for all patient-reported outcomes (PRO) to describe actual standardized scores as 
measured by HRQoL and EQ-5D-5L index scores and EQ-VAS scores. For each acromegaly 
symptoms (ring size, headache, fatigue, perspiration, paresthesias, osteoarthralgia), descriptive 
summaries of actual and changes will be provided.
For each of the PRO variables (AcroQoL score (total score, physical sub-score and 
psychological sub-score [psychological/physical appearance and psychological/personal 
relations]), EQ-5D-5L utility index and EQ-5D-5L VAS score):

Change in PRO scores from 
o
baseline to week 36
o
baseline to week 72
o
week 36 to week 72 
For the self-reported signs and symptoms (ring size, headache, fatigue, perspiration,
paresthesias, osteoarthralgia):

Change in symptom severity scores (for each sign and symptom) from 
o
baseline to week 36
o
baseline to week 72
o
week 36 to week 72 

Shift tables from baseline to most extreme post-baseline value up to week 72 will also
be presented for acromegaly symptoms except ring size.
13.3.3
Graphical presentation of results
Plot of mean values of AcroQoL score by visit (total score, physical sub-score and 
psychological sub-score [psychological/physical appearance and psychological/personal 
relations]), EQ-5D-5L (utility index and VAS score) by visit will be provided. A multiple
bar chart corresponding to proportion of patients to each response categories for the EQ-5D
dimension will be provided (layout will be specified in RAP Module 7). The plots will be
considered for the overall study period (core + extension phase).
14       Statistical methods for safety analysis
Safety assessments will consist of monitoring and recording all adverse events (AEs),
including serious adverse events (SAEs), the regular monitoring of hematology (including
coagulation parameters), blood chemistry (including fasting blood glucose), glycosylated
hemoglobin, fasting serum cortisol, plasma adrenocorticotropic hormone, liver and thyroid
function tests, urinalysis, injection site reactions, physical examinations including vital signs,
gallbladder ultrasound, ECGs and body weight.
All the safety analysis will be based on safety set.


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The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose
of study medication
2. on-treatment period: from day of first dose of study medication to 84 days after last dose
of study medication
3. post-treatment period: starting at day 84 days + 1 after last dose of study medication


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For the core phase, all listings and tables will be presented overall and by maximum dose
given. For AEs of special interest, tables will be presented by the given dose as well (AE
starts or worsens while the patient is being treated at that dose level).
For the extension phase, all listings and tables will be presented overall and by type of
treatment (monotherapy, combination dopamine agonist, and combination with GH receptor
antagonist).
14.1
Adverse events (AE)
14.1.1
Coding of AEs
All adverse events will be coded using the latest MedDRA coding dictionary that provides the 
system organ class and preferred term information available during the time of required
analyses.
14.1.2
Grading of AEs
Adverse events will be graded according to the Common Terminology Criteria for Adverse
Events (CTCAE) version 4.03.
14.1.3
General rules for AE reporting
Summary tables for adverse events (AEs) from the study will include AEs that started or
worsened in the period from study drug start date up to the patient’s last day on the study
(inclusive), but no later than 84 days after study drug end date. The incidence of treatment-
emergent AEs (new or worsening from baseline) will be summarized by SOC and/or PT,
severity (based on CTCAE grades), type of AE and relation to study treatment. If an AE
deteriorates or improves over time, new event will be reported accordingly with new severity.
Deaths will be listed and summarized by cause of death.
14.1.4
AE summaries
Adverse events will be summarized and listed in the following way:

AEs, regardless of study drug relationship

AEs, suspected to be study drug related

SAEs, regardless of study drug relationship

SAEs, suspected to be study drug related

AEs leading to discontinuation/dose adjustment or interruption/additional therapy

AEs of special interest

Deaths by primary system organ class and preferred term

Hyperglycemia-related AEs by diabetic status at baseline, by preferred term and
maximum CTC grade
Adverse events will be presented overall and for up-titrated Pasireotide LAR 60 mg (highest 
dose received during the trial).
The presentation of the adverse events summary based on SOC, PT, maximum grade will be
specified in appropriate layouts in RAP Module 7.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment-emergent 
adverse events which are not serious adverse events with an incidence greater than 5% and on treatment-
emergent serious adverse events and SAE suspected to be related to study treatment will be provided by 
system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, seriousness and 
severity) occurred with the same SOC and PT:


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
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.
14.1.5
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.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 (in [Cabinets/CREDI Projects/S/SOM230C/Administrative
files/CIS (Clinical Information Sciences)/Biostatistics/SOM230C_AESI_MedDRA xx x<use
the latest available version>_ddMMMyyyy.xls<use the latest available data set>]) will be
used.
The following summary will include the following:

AESI, regardless of study drug relationship, with maximum grade, suspected to be study
drug related, SAEs, leading to discontinuation and requiring dose adjustments
14.2
Laboratory values
The severity grades for laboratory values are derived using NCI/NIH Common Toxicity
Criteria (CTC). A severity grade of zero will be assigned when the value is within normal
limits. All laboratory values will be converted into SI units. However, blood glucose will also
be presented in mg/dL and assessed using the ADA criteria 2010.
The following laboratory parameters will be collected:
Table 14.2-1      Local or Central Clinical Laboratory Parameters Collection Plan
Test category
Test name
Hematology (central)
Hematocrit, Hemoglobin, Platelets, Red blood
cells, White blood cells, RBC Morphology with
differential (Basophils, Eosinophils, Lymphocytes,
Monocytes, Neutrophils)
Clinical Chemistry (central)
Bicarbonate, Calcium, Chloride, Creatinine*,
Creatine Kinase, Total Cholesterol, LDL, HDL,
Total Protein, Triglycerides, Blood Urea Nitrogen
(BUN) or Urea, Uric Acid, α-amylase, Lipase,
Lactic Dehydrogenase (LDH), Magnesium,
Sodium, Potassium, Prolactin
Liver Function Tests (Central)
ALT, AST, Total bilirubin (total bilirubin should be
differentiated into direct and indirect reacting
bilirubin if total bilirubin is increased > 2 × ULN),
Albumin, ALP and GGT
Hepatic Screening (Central)
HbsAg, AntiHCV
Hyperglycemia related test (Central)
Fasting blood glucose, Glycosylated Hemoglobin
(HbA1C), oGTT (insulin and plasma glucose)


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Coagulation (central)
Prothrombin time (PT) or International normalized
ratio (NR), Partial thromboplastin time (PTT),
Activated partial thromboplastin time (APTT)
Thyroid and hormones (central)
T4 [free], TSH, Plasma Adrenocorticotropic
Hormone (ACTH), Fasting Serum Cortisol


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Test category
Test name
Urinalysis (local)
Macroscopic Panel (Dipstick) (Bilirubin, Blood,
Glucose, Ketones, Leukocytes esterase, pH,
Protein, Specific Gravity)
Additional tests (central)
Insulin-like growth factor 1 (IGF-1), Growth
Hormone (GH)
Pregnancy test
Urine (dipstick) and serum B-hCG
(*) Q2 Serum Creatinine Issue
An equipment malfunction issue was identified with respect to one of the Beckman Coulter 
AU5400 units in the Valencia Laboratory. Serum Creatinine samples analyzed between 01-
Oct-2016 to 13-Jan-2017 were impacted. Sample results that could not be repeated for this 
study (because there was no backup sample) will be annotated in the clinical data base as 
reported but unreliable and therefore will be considered unreliable. Data will remain in the 
clinical data base, but will not be used as part of CSR statistical analyses. These unreliable 
results will appear in the listings, but they will be excluded from the biochemistry shift table 
analyses. Results obtained which were repeated and confirmed within 10% of the original 
samples will be used for statistical analyses and listed. Results obtained that were repeated 
and not within 10% of the original samples will be replaced in the clinical data base by the 
retest values and will be used for statistical analyses and listed.
Summaries for laboratory parameters will include all laboratory assessments collected in the
core and extension phase.
For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values
not graded as 1 or higher. Grade 5 will not be used. In the unlikely case when a local
laboratory normal range overlaps into the higher (i.e. non-zero) CTC grade, the laboratory
value will still be taken as within normal limits and assigned a CTC grade of zero. For
laboratory tests where grades are not defined by CTCAE, results will be graded by the
low/normal/high classifications based on laboratory normal ranges.
The following summaries will be produced for the laboratory data (by laboratory parameter)
corresponding to on-treatment period for post-baseline values:

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value,

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high classification to compare baseline to the worst on-treatment value,

Number and percentage of patients meeting individual and composite Hy’s Law criteria
(i.e. ALT > 3 × ULN with concurrent total bilirubin >2 × ULN, without increases in
alkaline phosphatase and no other cause(s) identified for the abnormal findings) for liver
injury (each patient will be counted only for the worst observed post baseline value),

Fasting blood glucose (FBG) [< 100 mg/dL, ≥100 - < 126 mg/dL and ≥ 126 mg/dL] using
the ADA (2010) classifications to compare baseline to last on-treatment value.

For the shift tables for blood glucose (HbA1C) cut-offs similar to the ADA (2010) will be
used, defined as (<5.7%, >=5.7% - <6.5%, >=6.5 - <8% and >=8%) to compare baseline
to the last on-treatment value,

Summary of responders at week 36 (primary endpoint) by baseline diabetic status 
(specified in section 8.4 of this RAP M3)

Summary of change from baseline to week 36 in HbA1C by primary response at week 36
(primary endpoint),

Summary of change from baseline to week 36 in FBG by primary response at week 36 
(primary endpoint)
The following listings will be produced for the laboratory data:

Listings of patients with laboratory values outside the laboratory reference ranges with 


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values flagged to show the corresponding CTCAE grades and the classifications relative 
to the laboratory reference ranges,

Listings of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges,


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
Listing of patients with notable laboratory abnormalities (i.e., newly occurring CTCAE
grade 3 or 4 laboratory toxicities).
14.2.1    Graphical presentation of results
Plots for mean (+/- SE) of FBG and HbA1c by visit will be provided for the core phase and
overall study period (core + extension phase).
14.3
Vital signs and weight
Vital signs (blood pressure, heart rate and body temperature) and weight will be summarized
and listed by visit and treatment group. Patients with clinically notable vital sign values will
be flagged in the listing.
The criteria for clinically notable values are defined as follows:
Clinically notable elevated values

Systolic BP: ≥180 mmHg and an increase ≥20 mmHg from baseline,

Diastolic BP: ≥ 105 mmHg and an increase ≥15 mmHg from baseline,

Body temperature: ≥ 39.1°C,

Weight: Increase from baseline of ≥10%,

Pulse rate: ≥ 100 bpm with increase from baseline of > 25%.
Clinically notable below normal values

Systolic BP: ≤90 mmHg and a decrease ≥20 mmHg from baseline,

Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline,

Body temperature: ≤35°C,

Weight: Decrease from baseline of ≥10%,

Pulse rate: ≤ 50 bpm with decrease from baseline of > 25%.
The following summaries will be produced for each vital sign parameter:

Vital signs shift table based on notable values
14.4
ECG
The following analyses will be performed for VR, PR, QT intervals and QRS duration,
ventricular rate, and QTcF (Fridericia’s formula) during the on- treatment period:

Summary statistics at baseline and all scheduled post-baseline time points,

Summary statistics of changes from baseline at each scheduled post-baseline time point,

Listing of ECG data (scheduled and unscheduled visits).
Number (%) of patients with a notable and newly occurring QT interval, based on QTcF will
be summarized. ECG shift table based on notable values from baseline to worst post-
baseline value will be summarized. Notable criteria for QT/QTcF include:

> 450 ms at any post-baseline scheduled time point and ≤450 ms at baseline,

> 480 ms at any post-baseline scheduled time point and ≤480 ms at baseline,


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
> 500 ms at any post-baseline scheduled time point and ≤500 ms at baseline,

An increase from baseline > 30 ms at any post-baseline scheduled time point,

An increase from baseline > 60 ms at any post-baseline scheduled time point.
Notable criteria for PR, QRS and VR include:

A new PR > 200 ms at any post-baseline scheduled time point,

An increase from baseline > 25% and PR > 200 ms at any post-baseline scheduled time 
point,

A new QRS > 120 ms at any post-baseline scheduled time point,

An increase from baseline > 25% and QRS  > 120 ms at any post-baseline scheduled time 
point,

An increase from baseline > 25% and VR  > 100 bpm at any post-baseline scheduled time 
point,

A decrease from baseline > 25% and VR < 50 bpm at any post-baseline scheduled time 
point,
A patient with multiple occurrences of a notable QT interval or a newly occurring ECG
abnormality is counted only once in that category.
Patients with notable QT interval values and newly occurring qualitative ECG abnormalities
will be flagged in the listings.
No imputation of missing data will be performed.
The formulae used to calculate the QT interval corrected for heart rate is:

Fridericia’s formula, QTcF = QT/
3√RR
14.5
Gallbladder ultrasound
Gallbladder data at each visit will be summarized and listed by treatment group. Shifts from
baseline to last post-baseline value will be presented for each individual item.
15
Sample size and power considerations
The sample size calculation was based on the primary endpoint (mean GH < 1 µg/L and IGF-
1 < ULN at week 36). A sample size of 100 patients was chosen to enable the estimation of
proportion of patients who achieved biochemical control at week 36 with pasireotide 40-60
mg as 15%, with a precision of 7% for the associated asymptotic two-sided 95% confidence
interval.
Considering a drop-out rate of 10%, the sample size required is 112.
Sample size calculations were performed using PASS 2008 software.
16
References
ADA Diagnosis and Classification of Diabetes Mellitus (2010) Diabetes Care, volume 33,
supplement 1, January 2010.
Badia X, et al (2004) Review: Acromegaly Quality of Life Questionnaire. Health and Quality
of Life Outcomes; (2).
Herman M, et al (2011) Development and preliminary testing of the new five-level version of
EQ-5D (EQ-5D-5L). Quality of life research; 20; 1727-1736


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Clinical Development
SOM230/pasireotide
CSOM230C2413
Appendix 16.1.9: Documentation of statistical methods
Document type:
Clinical Study Report - Appendix 16.1.9
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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17
Appendix 16.1.9 Documentation of statistical methods
This section of the RAP document presents further detail about the statistical methods not
given in section 9.7 of the Clinical Study Report (CSR).
17.1
Dates and time windows
17.1.1
Study drug start and end date
Study drug start date is defined as the first date when a non-zero dose of study drug was
administered and recorded on the Drug Administration Record (DAR) CRF page. Similarly,
study drug end date is defined as the last date when a non-zero dose of study drug was
administered and recorded on the DAR CRF page.
Note:

Study drug start date definition will remain same irrespective of whether any analyses are
done in core or extension phase.

Study drug end date definition will change, i.e.,

for any analyses in core phase where study drug end date definition is required, it will
be defined as the last date when a non-zero dose of study drug (pasireotide LAR) was
administered in the core phase of the study.

for any analyses in extension phase where study drug end date definition is required,
it will be defined as the last date when a non-zero dose of study drug (pasireotide
LAR) was administered in the extension phase of the study.
17.2
Study day
Study day will be calculated as (event date – study drug start date + 1 day) for events that
occurred on or after study drug start date (e.g. lab samples, AEs). For events prior to study
drug start date (e.g. time of diagnosis), study day will be negative and calculated as (event
date – study drug start date). Note that study drug start date is study day 1 and the day before
study drug start date is study day -1 (i.e. no study day 0).
For patients who never took study drug, the date of inform consent signed will replace study
drug start date in the above formulas (i.e. study day 1 is the date of inform consent signed).
Due to the study drug dosing schedule, one month will be considered as 28 days. However,
for ‘time since event’ data (e.g. medical history), one month will be considered as 365.25/12
days for events that occurred prior to study day 1.
17.3
End of treatment
Patients who discontinue study treatment before visit 777 (week 36) in the core phase and
visit 778 (week 72) in the extension, should be scheduled for a visit as soon as possible to
have all assessments listed for the 777 or 778 visits performed (see Table 7-1, Table 7-2,
Table 7-3 of the protocol). A Study Completion CRF page should be completed, giving the
date and reason for stopping study treatment. At a minimum, all patients who discontinue
study treatment, including those refuse to return for a final visit, will be contacted for safety
evaluations during the 84 days following the last dose of study treatment.


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If such withdrawal occurs, or if the patient fails to return for visits, the investigator must
determine the primary reason for a patient’s premature withdrawal from the study and record
this information on the Study Completion CRF page (the reasons are listed in Section 7.1.5 of
the protocol).
17.4
Baseline definition
For efficacy and safety evaluations, baseline is defined as the last available value (or
assessment) on or before the date of start of study treatment.
Moreover, for ECG, if several lab measurements are taken at pre-dose on Day 1 the last value
will be used as baseline.
If a patient has no value (or assessment) as defined above, then baseline will be considered
missing for that efficacy and/or safety evaluation.
17.5
Time windows
Summaries and analyses will be presented, when applicable, by (and/or based on data from)
the actual visit. Time windows will not be considered.
The visits 777 (End-of-Core-Study visit) and 778 (End-of-Extension-Study visit) are
scheduled when the patient decides (or is mandated by the protocol) to discontinue from the
study. If such a visit happens neither too soon nor too late after the actual last scheduled visit
then it will be mapped to the next scheduled visit that would have occurred had the patient
continued in the study. Otherwise the early discontinuation visit will not be mapped to any
scheduled visit.
The early discontinuation visit will be considered to have occurred neither too soon nor too
late after the actual last scheduled visit if number of days between the two visits is:

At least half of the way between the patients’ actual last scheduled visit and the next
planned scheduled visit, and

No more than the total of the planned gap between the patient’s actual last visit and next
scheduled visit and half of the way between the patients’ next two planned
For example, if the patients’ last actual scheduled visit is Visit 12, then the next two
planned visits (ignoring visit 7) would have been Visit 8 and Visit 9 if this patient had not
discontinued early. Thus, the study completion visit will be mapped to Visit 8 only if it occurs
between 14 days (Day 112 – Day 84)/2 and 42 days (28 + (Day 140 – Day 112)/2) after Visit
12.
If the above condition is not met, then the study completion visit will not be mapped to any
scheduled visit.


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17.5.1
Evaluation time window
There is a +/- 2 day window for the visits but the labs must be taken the same day as the visit.
MRI and gallbladder ultrasound data collected within +/- 35 days from the date of visit is
allowed. Pre-dose ECG collected within 24-hours prior to injection of study drug is allowed.
Unless otherwise noted, values outside these time windows will not be included in the
analyses.
17.6
Concomitant medications
Concomitant medications with a known risk for Torsade des Pointes are prohibited and
patients are required to discontinue the study prior to starting the respective medication with
known risk for Torsade des Pointes. Concomitant medications with a possible risk for Torsade 
des Pointes are permissible but should be avoided wherever possible. A regularly updated list
of medications with known/possible risk for Torsade des Pointes or congenital long QT is
available under https://crediblemeds.org/index.php
The description used to report PD: “Patient taking a QT prolonging medication with
known risk factors for torsade de pointes and not withdrawn” with PD code: D05 can be
used to filter out the patients who have taken concomitant medications with a known risk for
Torsade des Pointes based on the listings of the medications with known risk for Torsade des
Pointed being provided by the clinical team.
For anti-diabetic medication, any medication with ATCCODE = A10 will be considered as 
anti-diabetic medication.
17.7
General definitions, conventions and methods
17.7.1
Standardized IGF-1 values
The normal range for IGF-1 is dependent on age and sex. Therefore, unless noted otherwise,
standardized IGF-1 values will be reported. Standardized IGF-1 values are defined as:
Standardized IGF-1 = IGF-1 value / ULN
where ULN is the corresponding age- and sex-adjusted upper limit of normal.
Note that standardizing the IGF-1 values has no effect on the percentage change from baseline
calculation as this calculation is independent of the ULN.
17.7.2
Symptoms of acromegaly
Ring size will be measured at the fourth digit of the non-dominant hand. If 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: headache, fatigue, perspiration, paresthesias, osteoarthralgia
according to a five-point score scale (0=absent, 1=mild, 2=moderate, 3=severe, 4=very
severe).
17.7.3
Quality of life
The AcroQoL is a valid and reliable disease-specific patient-reported outcome (PRO) 
questionnaire designed to assess quality of life in patients aged 18 to 70 years old with 
acromegaly (Badia, et al 2004). 


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The questionnaire is uni-dimensional and contains 22 items divided in two scales: physical
aspects (eight items) and psychological aspects (14 items). The latter scale is also divided in
two sub-scales: one to evaluate physical appearance, and the other to evaluate the impact of
the disease on the personal relationships of the patient (seven items each).
Results of the AcroQoL are reported as:

A total score (22 items)

A physical sub-score (8 items)

A psychological sub-score (14 items)
The psychological sub-score is further divided into two sub-scores:

A psychological/physical appearance (7 items)

A psychological/personal relations (7 items)
Items are scored on a five point Likert-type scale assessing either the frequency of 
occurrence (always, most of the time, sometimes, rarely, or never) or the degree of 
agreement with the items (completely agree, moderately agree, neither agree nor disagree, 
moderately disagree, completely disagree). For the purpose of the clinical trial, the recall 
period of the AcroQoL has been modified to 4 weeks.
The total score and sub-scores will be calculated using the following formula established by
the tool developer (Badia, et al 2004):
((X - Y) / 4Y) × 100
X = sum of the scores for individual items (between 1 and 5 for each item)
Y = number of individual items included in above sum (i.e. 22 for the total score, 8 for the
physical sub-score, 14 for the psychological sub-score, 7 for the sub-score ‘appearance’
and ‘personal relations’)
If more than 25% of items are not completed, then the results for that patient will be
considered invalid. Specifically, results for a particular score/sub-score will not be included
for analysis if the number of missing items exceeds:

Five for the total score,

Two for the physical dimension,

Three for the psychological dimension,

One for each of the psychological sub-dimensions
17.8
Health status
Health status will be assessed using the EQ 5D-5L. The EQ- 5D-5L has two components–
the EQ-5D-5L descriptive system and the EQ-5D-5L visual analogue scale (VAS)
(Herdman M et al 2011) The descriptive system comprises 5 dimensions (mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5
levels: ‘ no problems’, ‘slight problems’, ‘moderate problems’, ‘severe problems’ and ‘unable 
to do activity or extreme problems’.
For example, the health state, 11212, represents a patient who indicates no problems on
mobility, self-care, and pain/discomfort (represented by 1s) but some problems on usual
activities and anxiety/depression (represented by 2s).
A utility index can be computed from the EQ 5D-5L descriptive system with utility scores 
ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -
0.281 representing an “unconscious” health state.  
The EQ-5D-5L index scores obtained from the directly elicited English value set based on 


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time-trade off (TTO) valuation technique will be used for summary statistics at any particular 
visit and for change from baseline calculation.
EQ-5D-5L English Value set 
An excel file contains the EQ-5D-5L English value set.  In the Excel file there are two
spreadsheets: (1) 'Calculator' allows to enter the values from the EQ-5D-5L and can
automatically calculate the index score; (2) 'English EQ-5D-5L index' provides a list of all the 
potential responses and corresponding index values. The English value set will be used to 
calculate the index scores for all patients enrolled in the study.
The excel file can be downloaded from the EuroQol Group website: https://euroqol.org/eq-5d-
instruments/eq-5d-5l-about/valuation/. The reference publication is: ”Devlin N, Shah K, Feng 
Y, Mulhern B, van Hout B.Valuing Health-Related Quality of Life: An EQ-5D-5L Value Set 
for England. OHE Research Paper January 2016. London: Office of Health Economics; 2016.”
The 
data 
will 
be 
uploaded 
in 
the 
following 
Credi 
folder: 
Cabinets/CREDI 
Projects/S/SOM230C/CREDI Studies/SOM230C2413/Administrative Files (study level)/CIS 
(Clinical 
Information 
Sciences)/Biostatistics. 
The 
excel 
file 
will 
be 
called 
“CSOM230C_CSOM230C2413_ EuroQol_EQ-5D-5L_England_Value_Set.xls ”The excel 
file will be uploaded from the website and put in final state by the CTH before being uploaded 
to GPS. Once the excel file is in final state in Credi, the Trial Programmer will be responsible 
to upload the file into GPS via WDCS. The file will be uploaded with production status in the 
following folder: \SOM230C\SOM230C2413\util\. The excel file will keep the same name as 
in Credi.
A SAS dataset will then be created by the Trial Programmer based on the excel file to allow 
further programming tasks.
This excel file will be used to derive the EQ-5D-5L index scores for their dimension 
responses.  


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The EQ-5D VAS records the subject’s self-rated health state on a 100-point vertical VAS
(0=worst imaginable health state; 100=best imaginable health state). This information can be
used as a quantitative measure of health outcome as judged by the individual respondents.
The details about the outputs and the reference EQ-5D-5L index using crosswalk value set
will be provided in RAP M7.
17.9
Data handling conventions
Date imputation for AEs and concomitant medications will be imputed according to Novartis
conventions described in [RAP Module 8].
For other date imputations and only for analysis purposes, the following imputation rules will
be used to impute partial dates: if the day and month is missing, it will be replaced by 30th
June (to be used only for events prior to study drug start date, e.g. medical history); if only the
day is missing it will be replaced by the 15th of that month. For the dates known to be within
the trial period, if this imputation makes the date later than the trial completion date, then the
trial completion date is used; if the imputed date is earlier than the study drug start date, then
the study drug start date is used.
Partial dates will remain partial in the data listings.
17.10
Other rules
Percentages in shift tables cross-tabulating baseline versus post-baseline values will be based
on all patients with a non-missing post-baseline value in the respective analysis set.
17.11
Number of decimal places
Whenever possible, minimum and maximum will be presented to the same precision as the
raw data. Mean and median will be presented to one more decimal place and standard
deviation to two more decimal places.
Unless stated otherwise, no imputation for missing data will be performed.
17.12
SAS procedure used
The 100 × (1 – alpha level)% CI for the proportion of responders (binary outcome = 1 or
“Yes”), is obtained from the following:
PROC FREQ data = dataset;
TABLES binary event / binomial (ac wilson exact ) alpha = alpha level; 
WEIGHT count;
Run;
Reference: SAS Institute Inc. 2012. Base SAS® 9.3 Procedures Guide: Statistical Procedures,
Second Edition. Cary, NC: SAS Institute Inc.


 
 
 
 
 
 
Clinical Development 
 
 
CSOM230/Pasireotide 
 
 
CSOM230C2413 / NCT02354508 
 
 
A phase IIIb multicenter, open-label, single arm 
study to evaluate the efficacy and safety of 
pasireotide in patients with acromegaly 
inadequately controlled with first generation 
somatostatin analogues 
 
Statistical Analysis Plan (SAP) : Extension Phase 
 
 
Author: 
Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Draft 
Release date: 
06-Oct-2018 
Number of pages: 
22 
 
 
 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
SAP 
For business use only 
Page 20 
CSOM230C2413 
 
 
 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
10- 
06- 
2018 
Prior 
to 
DB 
Creation of 
final 
version 
N/A - First version 
NA 
  
lock 
 


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SAP 
For business use only 
Page 30 
CSOM230C2413 
 
 
 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
References ................................................................................................................ 6 
2 
Study objectives and design................................................................................................. 7 
2.1 
Study Objectives ...................................................................................................... 7 
2.2 
Study design and treatment ...................................................................................... 8 
3 
Data included in the analysis ............................................................................................... 9 
4 
Statistical methods : Analysis sets ....................................................................................... 9 
4.1 
Full analysis set ........................................................................................................ 9 
4.2 
Safety set ................................................................................................................ 10 
5 
Patients and treatments ...................................................................................................... 10 
5.1.1 
Patient disposition ................................................................................. 10 
5.1.2 
Protocol Deviation Summaries.............................................................. 10 
5.1.3 
Background and demographic characteristics ....................................... 10 
6 
Study Drug ......................................................................................................................... 11 
6.1 
Study medication ................................................................................................... 11 
6.2 
Exposure ................................................................................................................ 11 
7 
Prior and concomitant medication ..................................................................................... 12 
8 
Medications known to affect GH and IGF-1 levels ........................................................... 13 
9 
Analysis of efficacy endpoints .......................................................................................... 14 
9.1 
Analyses time points .............................................................................................. 14 
9.1.1 
Graphical presentation of results ........................................................... 14 
9.1.2 
Handling missing values/censoring/discontinuations ........................... 14 
9.2 
Efficacy evaluation ................................................................................................ 14 
9.2.1 
Secondary objectives – Extension phase ............................................... 14 
9.2.2 
Graphical presentation of results ........................................................... 16 
10 Statistical methods for safety analysis ............................................................................... 16 
10.1 
Adverse Events ...................................................................................................... 17 
10.1.1 
Coding of AEs .......................................................................................... 17 
10.1.2 
Grading of AEs ......................................................................................... 17 
10.1.3 
General rules for AE reporting .............................................................. 17 


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10.1.4 
AE summaries ....................................................................................... 17 
10.1.5 
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.Grouping of adverse 
events of special interest ....................................................................... 18 
10.2 
Laboratory values ................................................................................................... 18 
10.2.1 
Graphical presentation of results ........................................................... 20 
10.3 
Vital signs and weight ............................................................................................ 21 
10.4 
ECG ....................................................................................................................... 21 
10.5 
Gallbladder ultrasound ........................................................................................... 22 
11 Appendix 16.1.7 Randomization scheme and codes ......................................................... 22 
12 Appendix 16.1.9 Documentation of statistical methods .................................................... 22 
12.1 
Extension baseline definition ................................................................................. 22 


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


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1 
Introduction 
 
The RAP module describes all the planned statistical methods for all safety and efficacy analysis 
using the core and extension phase data of CSOM230C2413 study. These analyses will be 
performed for the final CSR of the study. 
Results from the primary analysis (primary endpoint and secondary endpoints for core phase) 
were described in the primary analysis CSR dated dd-Mmm-2018 with a data cut-off date of 
08-Jan-2018 at which time all enrolled patients completed the core phase (i.e. patient completed 
the Week 36 visit) or discontinued earlier duirng this core phase of the trial. 
The final CSR will focus on the analysis of long-term efficacy and safety in the subsequent 
extension phase of pasireotide LAR. 
Unless otherwise specified, same analysis as in the RAP M3 of the core phase will be used. 
Any changes made to the statistical plan and methodology after the clinical database lock will 
be documented separately. The statistical analysis of this study will be performed  by  
Novartis personnel. A detailed description of the statistical analysis methods will be provided 
in Appendix 16.1.9 of the CSR. 
Analysis data sets and statistical outputs will be produced using the most recent SAS® 
Version (SAS Institute Inc., Cary, NC, USA),  and stored in Novartis global programming  
& statistical environment (GPS). 
 
 
1.1 
References 
The following documents were used to develop the Statistical Analysis Plan. 
• CSR template 
• Protocol CSOM230C2413 
• RAP M3 : Detailed Statistical Methodology of CSOM230C2413 
• Protocol CSOM230C2402 
• RAP M3: Detailed Statistical Methodology of CSOM230C2402 
• Oncology guideline for safety analysis 
• Annotated Case Report Form 
• Report & Analysis Plan for Novartis Oncology 
• Guidelines for content of Statistical Appendices of the Clinical Study Report 


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2 
Study objectives and design 
2.1 
Study Objectives 
 
See Section 2 of RAP M3 of the core phase CSR for the objectives pertaining to the core phase. 
The primary and secondary-core phase analyses were performed at the time of the primary 
analysis (at end of core phase) and reported in the respective CSR. 
This SAP describes the planned continued efficacy and safety analyses pertaining to the 
extension phase of pasireotide LAR. Objectives and related endpoints for the extension phase 
are described below. 
 
 
Objective 
Endpoint 
Secondary-extension phase 
To assess the proportion of patients 
achieving IGF-1 <ULN at weeks 48, 60 and 
72 
Proportion of patients who achieved IGF-1 
<ULN at weeks 48, 60 and 72 
To assess the proportion of patients 
achieving GH <1 μg/L and IGF-1 <ULN at 
weeks 48, 60 and 72 by treatment with 
pasireotide LAR alone or with concomitant 
medications used to treat acromegaly 
Proportion of patients who achieved GH <1 
μg/L and IGF-1 <ULN at weeks 48, 60 and 
72 by treatment with pasireotide LAR alone 
or with concomitant medications used to treat 
acromegaly 
To assess the proportion of patients 
achieving GH <1 μg/L at weeks 48, 60 and 
72 by treatment with pasireotide LAR alone 
or with concomitant medications used to 
treat acromegaly 
Proportion of patients who achieved GH <1 
μg/L at weeks 48, 60 and 72 by treatment 
with pasireotide LAR alone or with 
concomitant medications used to 
treat acromegaly 
To evaluate the long term tolerability and 
safety profile of pasireotide LAR 
Toxicity will be assessed using the National 
Cancer 
Institute-Common 
Toxicology 
Criteria Adverse Events version 4 (NCI- 
CTCAE 
v.4.03) 
and 
for 
laboratory 
assessments 
that 
include 
biochemistry, 
hematology, 
urinalysis; 
special 
safety 
assessments 
that 
include 
the 
regular 
monitoring and recording of blood glucose, 
insulin, HbA1c, GH and IGF-1, thyroid and 


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liver function tests, gallbladder examinations 
and ECGs. 
Concomitant 
medications/Significant 
nondrug therapies will be assessed from 
study enrollment until the safety follow-up. 
To evaluate the long term effect of Change in scores as measured by AcroQoL, 
pasireotide LAR on HRQoL and signs and 
EQ-5D- 5L and signs and symptoms of 
symptoms of acromegaly, from baseline and acromegaly from baseline to week 72 and 
week 36 to week 72 
from week 36 to week 72. 
 
 
2.2 
Study design and treatment 
This is a phase IIIb exploratory study to assess the efficacy and safety of pasireotide in patients 
with acromegaly inadequately controlled with first generation somtostatin analogues.It is 
planned that the data from all centers that participate in this protocol will be used. 
Study drug refers to pasireotide LAR (10mg, 20mg,40mg or 60mg). The brief description of 
the study design is given below : 
Group 1 - Patients would be treated with octreotide LAR 30mg from the countries where 
octreotide LAR 40mg is approved for the treatment of acromegaly at the time of screening 
– Patients participate in the run-in phase. 
Run-In phase (Screening to Baseline): 
Patients would start treatment with octreotide LAR 40 mg every 4 weeks. Patients who have 
not achieved biochemical control after 3 injections can be enrolled in the study. 
Core Phase (Baseline to week 36): 
Patients would start treatment on pasireotide LAR 40 mg every 4 weeks until week 32. A 
mean GH value and IGF-1 value was assessed every 12 weeks until week 36. The dose  
could be adjusted after the evaluation of biochemical control. During the core phase any 
acromegaly concomitant medication was prohibited. 
Extension Phase (week 36 to week 76): 
Patients would receive the same dose of pasireotide LAR at week 36, which would be the 
first dose of study medication in the extension phase. At week 40 the dose could be adjusted 
and acromegaly concomitant medication could be added to the treatment if, patients remain 
uncontrolled. Patients would receive pasireotide LAR 40mg/60mg until week 68 for a total 
of 32 weeks in the extension phase. A mean GH value and IGF-1 value would be assessed 
every 12 weeks until week 72. 
Safety follow-up: 


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After discontinuation or completion of study treatment, all patients would be followed for 
safety 12 weeks after the last study drug administration. 
Group 2 – Patients who were treated with octreotide 30 mg from countries where octreotide 
40mg has NOT been approved for the treatment of acromegaly at screening or patients 
treated with octreotide 40mg or lanreotide 120mg would not have the run-in phase. 
Core Phase (Baseline to week 36): 
Same procedure to be followed as Group 1. 
Extension Phase (week 36 to week 76): 
Same procedure to be followed as Group 1. 
Safety follow-up: 
Same procedure to be followed as Group 1. 
 
3 
Data included in the analysis 
All data reported in the database (scheduled, repeat and unscheduled visits) up to the end   
of the study will be included in the final CSR. 
Final analysis will be conducted when all patients complete the extension phase or have 
discontinued the study prior to completing the extension phase of the trial. The final analysis 
will be performed on all data that has been collected up to the final CSR DBL (generally 12 
weeks after LPLV). 
The final CSR will include: 
• Analyses using data from both core and extension phase (wherever 
applicable) 
• Extension phase specific results. 
 
4 
Statistical methods : Analysis sets 
The definition of the analyses sets will remain same during the core and extension phase. 
 
4.1 
Full analysis set 
The Full Analysis Set (FAS) comprises all patients who have signed informed consent and 
have been treated with at least one dose of study medication (pasireotide LAR) after 
enrollment into the study. The protocol states that the FAS comprises all patients to whom 
study treatment has been assigned. The definition of the FAS in the SAP specifies that with 
study treatment it is meant Pasireotide LAR to avoid confusion with the second treatment drug 
Octreotide LAR. 


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Extension Full Analysis Set (Extension FAS) would include all the patients who would 
recieve at least one dose of pasireotide LAR in the extension phase. 
 
4.2 
Safety set 
The Safety Set includes all patients who received at least one dose of study medication 
(Pasireotide LAR) with a post-baseline safety assessment. The statement that a patient has no 
AE constitutes a safety assessment. 
 
5 
Patients and treatments 
5.1.1 
Patient disposition 
The number of patients who completed or discontinued the extension phase of the study will be 
summarized using the extension full analysis set by the treatment group based on the dose of 
pasireotide monotherapy and combination treatment as defined the RAP M3 for core phase. 
The following summaries will be provided: 
• Number (%) of patients who completed the core phase 
• Number (%) of patients who entered extension phase 
• Number (%) of patients who completed extension phase 
• Number (%) of patients who discontinued and reason for discontinuation prior to week 
72 (extension phase, visit 778) after completing the core phase. 
 
 
5.1.2 
Protocol Deviation Summaries 
The number and percentage of patients in the extension FAS with any CSR reportable 
protocol deviation will be tabulated  by the protocol  deviation category. Listing will also  
be provided for all the protocol deviations based on extension FAS. 
 
5.1.3 
Background and demographic characteristics 
All demographic and background data (e.g. age, gender, race) will be summarized and listed in 
the Extension FAS by treatment group. 
Qualitative characteristics (e.g., gender) will be summarized by means of contingency tables. 
Quantitative variables (i.e., age, weight, BMI) will be summarized by appropriate descriptive 
statistics (i.e., mean, SD, median, minimum, maximum). 
Baseline diabetic status, mean GH and IGF-1 at baseline will also be summarized for each 
treatment group. 
Please refer to section 8.4 of RAP M7 of the core phase for the definition of the baseline 
diabetic status. 


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6 
Study Drug 
Study drug refers to pasireotide LAR (10 mg, 20 mg, 40 mg or 60 mg). 
 
6.1 
Study medication 
The safety set and the extension safety set will be used for all summaries and listings of study 
medication. 
Duration of exposure to study drug, number of injections taken and number of patients with 
dose change and/or dose delay along with reasons for dose change/dose delay, will be 
summarized by appropriate descriptive statistics. In addition, number of injections will be 
summarized categorically (categories to be specified in RAP Module 7). 
All doses of the study drug along with reasons for dose change/delay will be listed. 
The above summaries and listings will be provided for overall study period (core + 
extension phase) using the Safety set, and separately for extension phase using the Extension 
safety set. 
 
6.2 
Exposure 
The following definitions will be used corresponding to study drug pasireotide LAR only: 
For overall study period: 
Study drug start date is defined as the first date when a non-zero dose of study drug 
(pasireotide LAR) was administered and recorded on the Drug Administration Record (DAR) 
CRF page. 
Study drug end date is defined as the  last  date  when  a  non-zero  dose  of  study 
drug (pasireotide LAR) was administered in the study (either core or extension period 
depending on when the patient discontinued study drug). 
Extension phase : 
Study drug start date is defined as the first date when a non zero dose of study drug 
(pasireotide LAR) was administered during the extension phase and recorded on the Drug 
Administration Record (DAR) CRF page. 
Study drug end date is defined as the last date when a non-zero dose of study drug 
(pasireotide LAR) was administered in the extension phase of the study. 
Duration of exposure for overall study period (in weeks) will be calculated as: 
{min(study drug end date + 27 days; death date) – study drug start date in core + 1 day} / 7 
days. 
Duration of exposure for overall study period (in months) will be calculated as: 


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{min(study drug end date + 27 days; death date) – study drug start date in core + 1 day} / 
30.4375. 
Cumulative dose (mg): total dose of study drug taken by a patient in the overall study period 
Dose intensity (DI) (mg/month): cumulative dose (mg) / duration of exposure (months). 
Note: The study drug end date for the overall study period could either be in core phase or 
extension phase depending on when the patient discontinued the study drug. 
Duration of exposure in extension phase (in weeks) will be calculated as: 
{min(study drug end date in extension phase + 27 days; death date) – study drug start date  
in extension phase + 1 day} / 7 days. 
Duration of exposure extension phase (in months) will be calculated as: 
{min(study drug end date in extension phase + 27 days; death date) – study drug start date  
in extension phase + 1 day} / 30.4375 
Cumulative dose (mg): total dose of study drug taken by a patient in the extension phase 
DI (mg/month): cumulative dose (mg) / duration of exposure (months). 
The duration includes periods of temporary interruption for any reason. 
Duration of exposure will be presented overall and for up-titrated Pasireotide LAR 60 mg 
(highest dose received during the trial.) 
 
 
 
 
7 
Prior and concomitant medication 
Prior and concomitant therapy is defined as all interventions (therapeutic treatments and 
procedures) besides the study treatment that are administered to a patient preceding or 
coinciding with the study assessment period. 
Prior and concomitant medications and significant non-drug therapies for acromegaly and 
excluding acromegaly will be listed and summarized separately in the safety set and extension 
safety set. 
The concomitant medications and significant non-drug therapies (for acromegaly and 
excluding acromegaly) will be provided for overall study period (core + extension phase) 
and separately for extension phase. 
Separate summaries on prior and concomitant anti-diabetic medication after start of study 
drug (pasireotide LAR) will be provided for over study period and separately for extension 
phase. 


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Medications will be classified as prior or concomitant based on the following rules and will 
be coded using the WHO Drug Reference List to allow for categorization by preferred term: 
• Prior medication are medications that started before the first dose of study drug 
regardless of whether the medication ended before or after the first dose of study drug. 
• Concomitant medications are the medications that started on or after the first dose of 
study drug and continued after the first dose of study drug 
 
In addition to categorizing medication data by preferred term, drugs will be classified according 
to their ATC classification in order to present and compare how they are being utilized. The 
ATC classification allows summarization of medications by a high-level common drug class. 
Same summaries will be provided as in Section 10 of RAP M7 for the core phase analysis 
will be repeated for overall study period (core+extension phase) using the safety set and 
the extension phase using the extension safety set separately. 
A separate listing will be provided for patients who take concomitant medication related to 
prolonging the QT interval and therefore at the risk of ventricular arrhythmia, Torsades de 
Pointes and sudden death for the overall study period (core + extension phase). The listing will 
only include the concomitant medications (with dose unit and frequency route) related to QT 
prolongation taken at the time of QT prolongation along with the ECG intervals. The patients 
who have > 60 ms QTcF change from baseline or QTcF > 480 ms will be flagged. 
 
 
8 
Medications known to affect GH and IGF-1 levels 
During the core phase any acromegaly  concomitant  medication  was  prohibited. 
Medication taken in core phase (other than study drug) and known to affect GH and IGF-1 
levels were identified as major protocol deviations. 
Medications known to affect GH or IGF-1 levels will be allowed during the extension phase 
(starting from week 40) for patients who do not achieve biomedical control in the core phase. 
The following concomitant medications will be used to treat acromegaly (WHO dictionary 
code in brackets): 
• Somatostatin analogs (H01CB) 
• Dopamine agonists (N04BC) 
• Growth hormone receptor antagonists (H01AX) 
In the extension phase, if there are more than 10 patients who take concomitant medications 
known to affect GH or IGF-1 levels, a summary table will be provided for those patients with 
medication data. If not, then only a listing will be provided. 


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9 
Analysis of efficacy endpoints 
9.1 
Analyses time points 
The analysis timepoint will be at week 72 of the extension phase as well as other scheduled 
visits of the extension phase 
 
9.1.1 
Graphical presentation of results 
Plots for mean (+/- SE) of 5-point mean GH and standardized IGF-1 by visit will be provided 
for the extension period. 
 
9.1.2 
Handling missing values/censoring/discontinuations 
If a patient has less than three samples for the assessment of the 5-point mean GH from the 2- 
hour profile, then the mean GH will be considered as missing.  In  addition, if GH and  IGF- 
1 measurements are taken after 35 days from the date of any injection of study drug (from 
the scheduled dose date), the values will be considered as missing (the rationale has been 
adopted based on study CSOM230C2402). For a patient with missing values of mean GH or 
IGF-1 at 72 weeks or who withdraws earlier from the study will be considered as a non- 
responder. 
 
 
9.2 
Efficacy evaluation 
The secondary efficacy analyses will be performed on the extension FAS. The same rule 
of handling missing values for GH and IGF-1 variables as specified in the analyses of the 
primary efficacy variable will be used same as in Section 13.2 of RAP M7 of the 
core phase. 
 
9.2.1 
Secondary objectives – Extension phase 
 
9.2.1.1 
To assess the proportion of patients achieving IGF-1 < ULN at weeks 
48, 60 and 72 by treatment with pasireotide LAR alone or with 
concomitant medications used to treat acromegaly 
Proportion of patients who achieved IGF-1 < ULN by treatment with pasireotide LAR alone 
or with concomitant medications used to treat acromegaly will be reported separately (if there 
are 10 more patients with concomitant medications used to treat acromegaly in extension 
phase) along with its two-sided 95% confidence interval at week 48, 60 and 72. 
 
9.2.1.2 
To assess the proportion of patients achieving GH < 1 µg/L and IGF-1 
< ULN at weeks 48, 60 and 72 by treatment with pasireotide LAR 
alone or with concomitant medications used to treat acromegaly 


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Proportion of patients who achieved GH < 1 µg/L and IGF-1 < ULN by treatment with 
pasireotide LAR alone or with concomitant medications used to treat acromegaly will be 
reported separately (if there are 10 more patients with concomitant medications used to treat 
acromegaly in extension  phase)  along  with  its  corresponding  95%  confidence  interval  
at weeks 48, 60 and 72. 
 
9.2.1.3 
To assess the proportion of patients achieving GH < 1 µg/L at weeks 
48, 60 and 72 by treatment with pasireotide LAR alone or with 
concomitant medications used to treat acromegaly 
Proportion of patients who achieved GH < 1 µg/L by treatment with pasireotide LAR alone or 
with concomitant medications used to treat acromegaly will be reported separately (if there are 
10 more patients with concomitant medications used to treat acromegaly in extension phase) 
along with its corresponding 95% confidence interval at weeks 48, 60 and 72. 
 
9.2.1.4 
To evaluate the long term effect of pasireotide LAR on HRQoL, EQ-5D- 
5L and signs and symptoms of acromegaly, from baseline and week 
36 to week 72 
Descriptive statistics, including mean, median, standard deviation, minimum and maximum, 
will be presented for all patient-reported outcomes (PRO) to describe actual standardized scores 
as measured by HRQoL and EQ-5D-5L index scores and EQ-VAS scores. For each acromegaly 
symptoms (ring size, headache, fatigue, perspiration, paresthesias, osteoarthralgia), descriptive 
summaries of actual and changes will be provided. 
For each of the PRO variables (AcroQoL score (total score, physical sub-score and 
psychological sub-score [psychological/physical appearance and psychological/personal 
relations]), EQ-5D-5L utility index and EQ-5D-5L VAS score): 
• Change in PRO scores from 
o baseline to week 72 
o week 36 to week 72 
For the self-reported signs and symptoms (ring size, headache, fatigue, perspiration, 
paresthesias, osteoarthralgia): 
• Change in symptom severity scores (for each sign and symptom) from 
o baseline to week 72 
o week 36 to week 72 
• Shift tables from baseline to most extreme post-baseline value up to week 72 will also 
be presented for acromegaly symptoms except ring size. 


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9.2.2 
Graphical presentation of results 
Plot of mean values of AcroQoL score by visit (total score, physical sub-score and 
psychological sub-score [psychological/physical appearance and psychological/personal 
relations]), EQ-5D-5L (utility index and VAS score) by visit will be provided. A multiple 
bar chart corresponding to proportion of patients to each response categories for the EQ-5D 
dimension will be provided (layout will be specified in RAP Module 7). The plots will be 
considered for the extension period only. 
 
 
10 
Statistical methods for safety analysis 
Safety assessments will consist of monitoring and recording all adverse events (AEs), 
including serious adverse events (SAEs), the regular monitoring of hematology (including 
coagulation parameters), blood chemistry (including fasting blood glucose), glycosylated 
hemoglobin, fasting serum cortisol, plasma adrenocorticotropic hormone, liver and thyroid 
function tests, urinalysis, injection site reactions, physical examinations including vital signs, 
gallbladder ultrasound, ECGs and body weight. 
All the safety analysis will be based on safety set and extension safety set (as applicable). 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
dose of study medication 
2. on-treatment period: from day of first dose of study medication to 84 days after last 
dose of study medication 
3. post-treatment period: starting at day 84 days + 1 after last dose of study medication 
 
For the overall study period and extension phase, all listings and tables will be presented 
overall, by maximum dose and by type of treatment (monotherapy, combination dopamine 
agonist, and combination with GH receptor antagonist). For AESIs tables will be presented 
by the given dose as well (AE starts or worsens while the patient is being treated at that dose 
level). 


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10.1 
Adverse Events 
10.1.1 
Coding of AEs 
All adverse events will be coded using the latest MedDRA coding dictionary that provides the 
system organ class and preferred term information available during the time of required 
analyses. 
 
10.1.2 
Grading of AEs 
Adverse events will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
 
10.1.3 
General rules for AE reporting 
Summary tables for adverse events (AEs) from the study will include AEs that started or 
worsened in the period from study drug start date up to the patient’s last day on the study 
(inclusive), but no later than 84 days after study drug end date. The incidence of treatment- 
emergent AEs (new or worsening from baseline) will be summarized by SOC and/or PT, 
severity (based on CTCAE grades), type of AE and relation to study treatment. If an AE 
deteriorates or improves over time, new event will be reported accordingly with new severity. 
Deaths will be listed and summarized by cause of death. 
 
10.1.4 
AE summaries 
Adverse events will be summarized and listed in the following way: 
• AEs, regardless of study drug relationship 
• AEs, suspected to be study drug related 
• SAEs, regardless of study drug relationship 
• SAEs, suspected to be study drug related 
• AEs leading to discontinuation/dose adjustment or interruption/additional therapy 
• AEs of special interest 
• Deaths by primary system organ class and preferred term 
• Hyperglycemia-related AEs by diabetic status at baseline, by preferred term 
and maximum CTC grade 
Adverse events will be presented overall and for up-titrated Pasireotide LAR 60 mg (highest 
dose received during the trial). 
The presentation of the adverse events summary based on SOC, PT, maximum grade will 
be specified in appropriate layouts in RAP Module 7. 


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For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment-emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and on treatment-emergent serious adverse events and SAE suspected to be 
related to study treatment will be provided by system organ class and preferred term on the 
safety set population. 
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. 
 
10.1.5 
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.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 (in [Cabinets/CREDI 
Projects/S/SOM230C/Administrative 
files/CIS 
(Clinical 
Information 
Sciences)/Biostatistics/SOM230C_AESI_MedDRA xx x<use the latest available 
version>_ddMMMyyyy.xls<use the latest available data set>]) will be used. 
The following summary will include the following: 
• AESI, regardless of study drug relationship, with maximum grade, suspected to be 
study drug related, SAEs, leading to discontinuation and requiring dose 
adjustments 
 
10.2 
Laboratory values 
The severity grades for laboratory values are  derived  using  NCI/NIH  Common 
Toxicity Criteria (CTC). A severity grade of zero will be assigned when the value is 
within normal limits. All laboratory values will be converted into SI units. However, blood 
glucose will also be presented in mg/dL and assessed using the ADA criteria 2010. 


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The following laboratory parameters will be collected: 
Test category 
Test name 
Hematology (central) 
Hematocrit, Hemoglobin, Platelets, Red blood 
cells, White blood cells, RBC Morphology with 
differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils) 
Clinical Chemistry (central) 
Bicarbonate, Calcium, Chloride, Creatinine*, 
Creatine Kinase, Total Cholesterol, LDL, HDL, 
Total Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, α-amylase, Lipase, 
Lactic Dehydrogenase (LDH), Magnesium, 
Sodium, Potassium, Prolactin 
Liver Function Tests (Central) 
ALT, AST, Total bilirubin (total bilirubin should be 
differentiated into direct and indirect reacting 
bilirubin if total bilirubin is increased > 2 × ULN), 
Albumin, ALP and GGT 
Hepatic Screening (Central) 
HbsAg, AntiHCV 
Hyperglycemia related test (Central) 
Fasting blood glucose, Glycosylated Hemoglobin 
(HbA1C), oGTT (insulin and plasma glucose) 
Coagulation (central) 
Prothrombin time (PT) or International 
normalized ratio (NR), Partial thromboplastin 
Thyroid and hormones (central) 
T4 [free], TSH, Plasma Adrenocorticotropic 
Hormone (ACTH), Fasting Serum Cortisol 
Urinalysis (local) 
Macroscopic Panel (Dipstick) (Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, pH, 
Additional tests (central) 
Insulin-like growth factor 1 (IGF-1), Growth 
Hormone (GH) 
Pregnancy test 
Urine (dipstick) and serum B-hCG 
(*) Q2 Serum Creatinine Issue 
An equipment malfunction issue was identified with respect to one of the Beckman Coulter 
AU5400 units in the Valencia Laboratory. Serum Creatinine samples analyzed between 
01-Oct-2016 to 13-Jan-2017 were impacted. Sample results that could not be repeated for 
this study (because there was no backup sample) will be annotated in the clinical data base 
as reported but unreliable and therefore will be considered unreliable. Data will remain in 
the clinical data base, but will not be used as part of CSR statistical analyses. These 
unreliable results will appear in the listings, but they will be excluded from the 
biochemistry shift table analyses. Results obtained which were repeated and confirmed 
within 10% of the original samples will be used for statistical analyses and listed. Results 
obtained that were repeated and not within 10% of the original samples will be replaced in 
the clinical data base by the retest values and will be used for statistical analyses and listed. 
Summaries for laboratory parameters will include all laboratory assessments collected in 
the core and extension phase. 


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For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing 
values not graded as 1 or higher. Grade  5  will  not  be  used.  In  the  unlikely  case  
when a local laboratory normal range overlaps into the higher  (i.e.  non-zero)  CTC 
grade, the laboratory value will still be taken as within normal limits and  assigned a  
CTC grade of zero. For laboratory tests where grades are not  defined  by  CTCAE, 
results will be graded by the low/normal/high classifications based on laboratory normal 
ranges. 
The following summaries will be produced for the laboratory data (by laboratory 
parameter) corresponding to on-treatment period for post-baseline values: 
• Shift tables using CTCAE grades to compare baseline/extension baseline to the worst 
on-treatment value, 
• For laboratory tests where CTCAE grades are not defined, shift tables using 
the low/normal/high classification to compare baseline/extension baseline to 
the worst on-treatment value, 
• Number and percentage of patients meeting individual and composite Hy’s Law 
criteria (i.e. ALT > 3 × ULN with concurrent total bilirubin >2 × ULN, without 
increases in alkaline phosphatase and no other cause(s) identified for the abnormal 
findings) for liver injury (each patient will be counted only for the worst observed 
post baseline/post extension baseline value), 
• Fasting blood glucose (FBG) [< 100 mg/dL, ≥ 100 - < 126 mg/dL and ≥ 126 mg/dL] 
using the ADA (2010) classifications to compare baseline/extension baseline to last 
on-treatment value. 
• For the shift tables for blood glucose (HbA1C) cut-offs similar to the ADA (2010) 
will be used, defined as (<5.7%, >=5.7% - <6.5%, >=6.5 - <8% and >=8%) to 
compare baseline/extension baseline to the last on-treatment value, 
The following listings will be produced for the laboratory data: 
• Listings of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTCAE grades and the classification relative 
to the laboratory reference ranges. 
• Listings of all laboratory data with values flagged to show the corresponding 
CTCAE grades and the classifications relative to the laboratory normal ranges, 
• Listing of patients with notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). 
 
 
10.2.1 Graphical presentation of results 
Plots for mean (+/- SE) of FBG and HbA1c by visit will be provided for the extension 
phase and overall study period (core + extension phase). 


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10.3 
Vital signs and weight 
Vital signs (blood pressure, heart rate and body temperature) and weight will be summarized 
and listed by visit and treatment group. Patients with clinically notable vital sign values will 
be flagged in the listing. The summaries will be provided for overall study period and for 
extension phase. 
The criteria for clinically notable values remains same as described in the core SAP. 
The following summaries will be produced for each vital sign parameter: 
• Vital signs shift table based on notable values 
10.4 
ECG 
The following analyses will be performed for VR, PR, QT intervals and QRS duration, 
ventricular rate, and QTcF (Fridericia’s formula) during the on- treatment period: 
• Summary statistics at baseline/extension baseline and all scheduled post-baseline/post 
extension baseline time points, 
• Summary statistics of changes from baseline/extension baseline at each scheduled post- 
baseline/post-extension baseline time point, 
• Listing of ECG data (scheduled and unscheduled visits). 
Number (%) of patients with a notable and newly occurring QT interval, based on QTcF will 
be summarized. ECG shift  table  based on notable values from baseline/extension baseline 
to worst post-baseline/post-extension baseline value will be summarized. The notable criteria 
for QT/QTcF, PR, VR and QRS will remain same as described in the core SAP. : 
A patient with multiple occurrences of a notable QT interval or a newly occurring   
ECG abnormality is counted only once in that category. 
Patients with notable QT interval values and newly occurring qualitative ECG 
abnormalities will be flagged in the listings. 
No imputation of missing data will be performed. 
 
The formula used to calculate the QT interval crrected for heart rate is : 
 
• Fridericia’s formula, QTcF = QT/
3√RR 


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10.5 
Gallbladder ultrasound 
Gallbladder data at each visit will be summarized and listed by treatment group. Shifts from 
baseline/extension baseline to last post-baseline/post-extension baseline value will be 
presented for each individual item. 
 
11 
Appendix 16.1.7 Randomization scheme and codes 
Not applicable for the extension phase. 
 
 
12 
Appendix 16.1.9 Documentation of statistical methods 
This section of the RAP document presents further detail about the statistical methods not given 
in Section 9.7 of the Clinical Study Report (CSR). 
 
12.1 
Extension baseline definition 
The extension baseline is defined as the last available value (or assessment) prior to the dose 
of pasireotide LAR in the extension phase (i.e., prior to Visit 18 or week 36) . The extension 
baseline definition is only applicable for patients who moved in the extension phase. 
• For Fasting glucose, HbA1c, Gallbladder, ECG, biochemistry, hematology, vital signs 
and liver, Extension baseline will be the last available value on or before the first 
injection date of the extension phase. 
• For patients having anti-diabetic intervention at extension baseline is considered, if 
patients has taken at least one antidiabetic medication (ATCCODE = ‘A10’) before 
the first injection in the extension phase.