An Open Label, Multi-center Pasireotide Roll-over Protocol for Patients Who Have Completed a Previous Novartis-sponsored Pasireotide Study and Are Judged by the Investigator to Benefit From Continued Pasireotide Treatment
Phase: PHASE4
Conditions: Cushing's Disease, Acromegaly, Neuroendocrine Tumors, Pituitary Tumors, Ectopic ACTH Secreting (EAS) Tumors, Dumping Syndrome, Prostate Cancer, Melanoma Negative for bRAF, Melanoma Negative for nRAS
Sponsor: RECORDATI GROUP

 
 
 
 
Recordati Research and Development 
SOM230 (pasireotide)  
Clinical Trial Protocol CSOM230B2412 
An open label, multi-center pasireotide roll-over protocol for patients who have 
completed a previous Novartis-sponsored pasireotide study and are judged by 
the investigator to benefit from continued pasireotide treatment 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-000267-84 
Version number 
05 (Clean) 
Development phase 
IV 
Document status 
Final version 
Release date 
02-Nov-2021 
Sponsor 
RECORDATI AG - Lindenstrasse 8, 6340 Baar, Switzerland      
Tel: + 41 (0) 61 205 61 00 
CRO 
IQVIA 
Property of Recordati 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Recordati 
 

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Table of contents 
List of figures ...................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 11 
Amendment 5 (02-Nov-2021) ........................................................................................... 12 
Amendment 4 (06 May-2020) ........................................................................................... 13 
Amendment 3 (08-Mar-2019) ........................................................................................... 14 
Amendment 2 (29-Sep-2017) ............................................................................................ 16 
Amendment 01 .................................................................................................................. 19 
Protocol summary: ............................................................................................................. 21 
1 
Background ........................................................................................................................ 23 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 23 
1.1.1 
Overview of Cushing’s disease (CD) .................................................... 23 
1.1.2 
Overview of acromegaly ....................................................................... 24 
1.1.3 
Overview of neuroendocrine tumors (NETs) ........................................ 24 
1.1.4 
Overview of other pituitary tumors and of Ectopic ACTH secreting 
(EAS) tumors ........................................................................................ 25 
1.1.5 
Overview of patients with dumping syndrome ..................................... 26 
1.1.6 
Overview of other indications ............................................................... 26 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 26 
1.2.1 
Overview of pasireotide s.c. and LAR .................................................. 26 
2 
Rationale ............................................................................................................................ 30 
2.1 
Study rationale and purpose ................................................................................... 30 
2.2 
Rationale for the study design ............................................................................... 31 
2.3 
Rationale for dose and regimen selection .............................................................. 31 
2.4 
Rationale for choice of combination drugs ............................................................ 31 
2.5 
Rationale for choice of comparators drugs ............................................................ 32 
2.6 
Risks and benefits .................................................................................................. 32 
3 
Objectives and endpoints ................................................................................................... 35 
4 
Study design ...................................................................................................................... 35 
4.1 
Description of study design ................................................................................... 35 
4.2 
Timing of interim analyses and design adaptations ............................................... 36 
4.3 
Definition of end of the study ................................................................................ 36 
4.4 
Early study termination .......................................................................................... 36 
5 
Population .......................................................................................................................... 37 

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5.1 
Patient population .................................................................................................. 37 
5.2 
Inclusion criteria .................................................................................................... 37 
5.3 
Exclusion criteria ................................................................................................... 37 
6 
Treatment ........................................................................................................................... 38 
6.1 
Study treatment ...................................................................................................... 38 
6.1.1 
Study treatment and investigational treatment refer to pasireotide 
alone or in combination with another treatment for Cushing’s 
Disease and AcromegalyDosing regimen Pasireotide .......................... 39 
6.1.2 
Dosing regimen for patients on Pasireotide in combination with 
cabergoline treatment ............................................................................ 39 
6.1.3 
Dosing regimen for patients on Pasireotide in combination with 
another treatment for Cushing’s Disease or Acromegaly ..................... 40 
6.1.4 
Ancillary treatments .............................................................................. 40 
6.1.5 
Rescue medication ................................................................................ 40 
6.1.6 
Guidelines for continuation of treatment .............................................. 40 
6.1.7 
Treatment duration ................................................................................ 40 
6.2 
Dose modification guidelines ................................................................................ 40 
6.2.1 
Starting dose rationale ........................................................................... 40 
6.3 
Concomitant medications ...................................................................................... 41 
6.3.1 
Prohibited concomitant therapy ............................................................ 41 
6.4 
Patient numbering, treatment assignment or randomization ................................. 41 
6.4.1 
Patient numbering ................................................................................. 41 
6.4.2 
Treatment assignment or randomization ............................................... 41 
6.4.3 
Treatment blinding ................................................................................ 41 
6.5 
Study drug preparation and dispensation ............................................................... 41 
6.5.1 
Study treatment packaging and labeling ............................................... 41 
6.5.2 
Drug supply and storage ........................................................................ 42 
6.5.3 
Study drug compliance and accountability ........................................... 42 
6.5.4 
Disposal and destruction ....................................................................... 43 
7 
Visit schedule and assessments ......................................................................................... 43 
7.1 
Study flow and visit schedule ................................................................................ 43 
7.1.1 
Molecular pre-screening ........................................................................ 45 
7.1.2 
Screening ............................................................................................... 45 
7.1.3 
Treatment period ................................................................................... 45 
7.1.4 
Pregnancy and assessment of fertility ................................................... 46 
7.1.5 
Discontinuation of study treatment ....................................................... 46 
7.1.6 
Withdrawal of consent .......................................................................... 48 

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7.1.7 
Follow up for safety evaluations ........................................................... 48 
7.1.8 
Lost to follow-up ................................................................................... 49 
7.2 
Assessment types ................................................................................................... 49 
7.2.1 
Efficacy assessments ............................................................................. 49 
7.2.2 
Safety and tolerability assessments ....................................................... 49 
7.2.3 
Resource utilization ............................................................................... 49 
7.2.4 
Patient reported outcomes ..................................................................... 50 
8 
Safety monitoring and reporting ........................................................................................ 50 
8.1 
Adverse events ....................................................................................................... 50 
8.1.1 
Definitions and reporting ...................................................................... 50 
8.1.2 
Laboratory test abnormalities ................................................................ 51 
8.1.3 
Adverse events of special interest ......................................................... 52 
8.2 
Serious adverse events ........................................................................................... 52 
8.2.1 
Definitions ............................................................................................. 52 
8.2.2 
Reporting ............................................................................................... 52 
8.3 
Emergency unblinding of treatment assignment ................................................... 54 
8.4 
Pregnancies ............................................................................................................ 54 
8.5 
Warnings and precautions ...................................................................................... 54 
8.6 
Data Monitoring Committee .................................................................................. 54 
8.7 
Steering Committee ............................................................................................... 54 
9 
Data collection and management ....................................................................................... 55 
9.1 
Data confidentiality ............................................................................................... 55 
9.2 
Site monitoring ...................................................................................................... 55 
9.3 
Data collection ....................................................................................................... 56 
9.4 
Database management and quality control ............................................................ 56 
10 Statistical methods and data analysis ................................................................................ 56 
10.1 
Analysis sets .......................................................................................................... 56 
10.1.1 
Full Analysis Set ................................................................................... 56 
10.1.2 
Safety Set .............................................................................................. 56 
10.1.3 
Dose-determining analysis set............................................................... 57 
10.2 
Patient demographics/other baseline characteristics ............................................. 57 
10.3 
Treatments (study treatment, compliance) ............................................................ 57 
10.4 
Primary objective ................................................................................................... 57 
10.4.1 
Variable ................................................................................................. 57 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 57 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 57 

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10.4.4 
Supportive analyses ............................................................................... 57 
10.5 
Secondary objectives ............................................................................................. 57 
10.5.1 
Key secondary objective(s) ................................................................... 57 
10.5.2 
Other secondary efficacy objectives ..................................................... 57 
10.5.3 
Safety objectives ................................................................................... 57 
10.6 
Interim analysis ...................................................................................................... 58 
10.7 
Sample size calculation .......................................................................................... 58 
10.8 
Power for analysis of key secondary variables ...................................................... 58 
11 Ethical considerations and administrative procedures ...................................................... 58 
11.1 
Regulatory and ethical compliance ........................................................................ 58 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 59 
11.3 
Informed consent procedures ................................................................................. 59 
11.4 
Discontinuation of the study .................................................................................. 59 
11.5 
Publication of study protocol and results............................................................... 60 
11.6 
Study documentation, record keeping and retention of documents ....................... 60 
11.7 
Confidentiality of study documents and patient records ....................................... 61 
11.8 
Audits and inspections ........................................................................................... 61 
11.9 
Financial disclosures .............................................................................................. 61 
12 Protocol adherence ............................................................................................................ 61 
12.1 
Amendments to the protocol .................................................................................. 61 
13 References (available upon request) .................................................................................. 62 
14 Appendices ........................................................................................................................ 65 
14.1 
Appendix 1: Medications known to be associated with QT interval 
prolongation ........................................................................................................... 65 
14.2 
Appendix 2: Recommended hepatic safety management guidance ...................... 66 
14.3 
Appendix 3: Recommended guidance for follow up in case of QT-related 
findings during routine ECG ................................................................................. 68 
14.4 
Appendix 4: Recomended guidance for fasting blood glucose management ........ 70 
14.5 
Appendix 5: Dose modification information for acromegaly or carcinoid 
patients receiving pasireotide LAR (from protocol CSOM230C2110, 
CSOM230C2305, CSOM230C2402 and CSOM230C2413) ................................ 72 
14.6 
Appendix 6: Dose modification information for Cushing’s patients receiving 
pasireotide LAR (from protocol SOM230G2304) ................................................ 74 
14.7 
Appendix 7: Dose modification information for dumping syndrome patients 
receiving pasireotide s.c or LAR (from protocol SOM230X2203) ....................... 75 
14.8 
Appendix 8: Dose modification information for patients with metastatic 
melanoma or metastatic Merkel cell carcinoma receiving pasireotide s.c 
(from protocol SOM230X2404) ............................................................................ 78 

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14.8.1 
Guidance for diarrhea management ...................................................... 79 
14.8.2 
Dose and treatment schedule ................................................................. 81 
14.9 
Appendix 9: Dose modification information for patients with rare tumors of 
neuroendocrine origin receiving pasireotide LAR (from protocol 
SOM230D2203) .................................................................................................... 82 
14.10 Appendix 10: Dose modification information for patients with 
neuroendocrine tumors receiving pasireotide LAR (from protocol 
SOM230D2101) .................................................................................................... 83 
14.10.1 
Dose modification and dose delay ........................................................ 84 
14.10.2 
Treatment interruption and treatment discontinuation .......................... 84 
14.10.3 
Guidance for diarrhea management ...................................................... 87 
14.11 Appendix 11: Dose modification information for patients with Cushing’s 
receiving pasireotide s.c or acromegaly receiving pasireotide LAR (from 
protocols SOM230B2219 and SOM230B2305) .................................................... 90 
14.11.1 
Dose modifications for patients from protocol SOM230B2219 ........... 90 
14.11.2 
Dose modifications for patients from protocol SOM230B2305 ........... 90 
14.12 Appendix 12: Dose modification information for patients with Cushing’s 
receiving pasireotide s.c in combination with cabergoline (SOM230B2411) ....... 92 

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List of figures 
Figure 4-1 
Study design .......................................................................................... 36 
Figure 14-1 
Recommended LFT management guidance .......................................... 67 
Figure 14-2 
Recommended guidance for ECG follow up ........................................ 69 
Figure 14-3 
Recommended guidance for fasting self-monitoring blood glucose 
management .......................................................................................... 71 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 35 
Table 6-1 
Dose and treatment schedule ................................................................. 39 
Table 6-2 
Packaging and labeling ......................................................................... 42 
Table 6-3 
Supply and storage of study treatments ................................................ 42 
Table 7-1 
Visit evaluation schedule ...................................................................... 44 
Table 14-1 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 72 
Table 14-2 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2110 ..................................................................................... 72 
Table 14-3 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2305 ..................................................................................... 73 
Table 14-4 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2402 ..................................................................................... 73 
Table 14-5 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 74 
Table 14-6 
Follow up evaluation (after treatment interruption) .............................. 76 
Table 14-7 
Dose reduction steps for pasireotide LAR monthly dosing q28d ......... 76 
Table 14-8 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 77 
Table 14-9 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia for patients from protocol 
SOM230X2402 ..................................................................................... 79 
Table 14-10 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 82 
Table 14-11 
Follow-up evaluations for selected toxicties ......................................... 83 
Table 14-12 
Criteria for interruption and re-initiation of pasireotide LAR .............. 84 
Table 14-13 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 91 
Table 14-14 
Dose and treatment schedule ................................................................. 92 

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Table 14-15 
Pasireotide and cabergoline dose modification steps for pasireotide 
un-treated patients ................................................................................. 93 
Table 14-16 
Pasireotide and cabergoline dose modification steps for patients 
currently treated with maximal tolerated doses of pasireotide 
monotherapy .......................................................................................... 94 
 

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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
b.i.d. 
twice a day 
bpm 
Beats per minute 
CD 
Cushing’s disease 
CMO&PS 
Chief Medical Office & Patient Safety 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
FPFV 
First Patient First Visit 
FPG 
Fasting plasma glucose 
GDD 
Global Drug Development 
GH 
Growth Hormone  
GIP 
Glucose-dependent insulinotropic peptide 
GLP-1 
Glucagon-like peptide-1 
HBsAG 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
IB 
Investigators Brochure 
ICH 
International Conference on Harmonization 
IGF-1 
Insulin-like growth factor 1 
i.m. 
Intramuscular 
IRB 
Institutional Review Board 
IEC 
Independent Ethics Committee 
i.v. 
Intravenous(ly) 
LAR 
Long Acting Release 
MCC 
Merkel cell carcinoma 
MTD 
Maximum tolerated dose 
mUFC 
Mean urinary free cortisol 
NETs 
Neuroendocrine tumors 
OGTT 
Oral Glucose Tolerance Test 
PK 
Pharmacokinetic 
pNET 
Pancreatic neuroendocrine tumors 
q.d. 
Once per day 
QTcB 
QT corrected (Bazett) 
QTcF 
QT corrected (Fridericia) 
QTcI 
QT corrected (individualized) 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
s.c. 
Subcutaneous 
SSA 
Somatostatin analog 
sst123 
Somatostatin receptor subtypes 
sst5 
Somatostatin receptor subtypes 

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TdP 
Torsades de pointes 
ULN 
Upper limit of normal 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
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 who enrolls in the 
study 
Parent study 
The original Novartis-sponsored study where the patient was first 
enrolled and received pasireotide treatment. 
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 
Roll-over study 
A roll-over study allows patients from multiple parent studies spanning 
multiple indications to continue to be treated within one study after the 
completion of the parent study/ies 
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 

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Amendment 5 (02-Nov-2021) 
Amendment rationale 
It is anticipated that pasireotide will not be commercially available and reimbursed in all 
participating countries at study end. In order to ensure that patients deriving clinical benefit 
from pasireotide will continue receiving treatment with this drug outside the frame of the 
clinical trial, they will be allowed to obtain pasireotide through country-specific programmes 
as soon as they become available – even prior to the end of the study. This will ensure treatment 
continuity. 
The following protocol amendment is applicable to Brazil, France, Germany, India, Italy, 
Malaysia, Mexico, Peru and Thailand. 
 
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 underline for insertions. 
 
1. Section 4.3: Definition of end of the study:  the language was updated to state that even 
prior to the end of this study, patients will be allowed to receive pasireotide through 
country-specific programmes outside the frame of this clinical trial. 
2. Section 7.1.3: Treatment period: updated language to clarify that even prior to the end 
of this study, patients will be allowed to receive pasireotide through country-specific 
programmes outside the frame of this clinical trial. 
3. Section 7.1.5.1: Criteria for premature withdrawal: added language confirming that– 
even prior to the end of the study- patients will be allowed to receive pasireotide outside 
the frame of this clinical trial through country-specific programmes. 
IRBs/IECs  
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, as per local requirements. 
The changes described in this amended protocol are substantial and do require IRB/IEC 
approval prior to implementation. 

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Amendment 4 (06 May-2020) 
Amendment rationale  
Novartis has signed an agreement to transfer the worldwide rights of Signifor® and  Signifor® 
LAR to Recordati. Within the framework of such agreement, the two Companies agreed a 
sponsorship transfer of this study with pasireotide from Novartis to Recordati. 
The purpose of this substantial amendment is to reflect the change in sponsorship, and to add 
IQVIA as the CRO in charge for performing some trial-related activities on behalf of Recordati.  
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 underline for insertions. 
• All sections: were updated to substitute the name of the current sponsor Novartis with 
the name of the new sponsor Recordati or of IQVIA on behalf of Recordati, as 
applicable. 
IRBs/IECs  
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, as per local requirements. 
The changes described in this amended protocol are substantial and do require IRB/IEC 
approval prior to implementation.  
 

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Amendment 3 (08-Mar-2019) 
Amendment rationale  
The main purpose of this amendment is to: 
• Update the trial selection criteria to allow patients from Novartis-sponsored trials, being 
treated with pasireotide alone or in combination with another treatment for Cushing’s 
Disease and Acromegaly, to participate in this study.   Several of the participating parent 
protocols permit for pasireotide to be administered in combination with another medical 
therapy.  Revising the selection criteria would ensure those patients receiving clinical 
benefit would have continued access to the combination treatment.  Combination treatment 
through this rollover would only be available for patients with Cushing’s Disease or 
Acromegaly.  
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 underline for insertions. 
1. Protocol summary: Removed the exclusion criteria related to patients participating in 
combination treatment studies. 
2. Protocol summary: In the Investigational and reference therapy section – Combination 
therapy as per the parent protocol wording added. 
3. Section 1.2.1.2.1: Updated wording to include results from SOM230G2304 and 
SOM230C2402 trials that are now completed. 
4. Section 2.3 Rationale for dose and regimen selection: Language added to clarify that any 
medication given in combination with pasireotide must follow the dose ranges and regimen 
of the parent protocol.    
5. Section 2.4 Rationale for choice of combination drugs: language added to clarify that 
patients have been receiving combination treatment in the parent studies or an additional 
medication for acromegaly or Cushing’s disease have been added based on the 
investigator’s opinion.  Rationale language for cabergoline treatment was also added. 
6. Section 4.1: Deleted repetitive language 
7. Figure 4-1: Updated to add combination treatment language 
8. Section 5.3 Exclusion Criteria: Removed exclusion criteria number 2 related to patients 
participating in combination treatment.   
9. Section 6.1.2: Added section regarding dosing regimen for patients on combination 
treatment with cabergoline. 
10. Section 6.1.3: Added section regarding dosing guidelines for combination treatment. 
11. Section 6.1.7: Repetitive language deleted 
12. Section 6.2.1: Starting dose rationale: Language added to clarify that the starting dose of 
any medication given in combination with pasireotide must follow the last dose given in the 
parent protocol.    
13. Section 6.4.2: removed section as not applicable as this trial does not have randomization. 
14. Section 6.5.1: Updated to add language for combination treatment 

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15. Table 6-2: Dose strengths added for both pasireotide LAR and s.c. 
16. Table 6-3: Updated to add wording on combination treatment storage 
17. Section 7.1.3 Treatment Period: Corrected the timing of the visits to quarterly visits every 
12 weeks +/- 2 weeks. 
18. Section 8.1.1 Definitions and Reporting: Updated the language to define the safety reporting 
period as 30 days for s.c. formulation of pasireotide and 84 days for LAR formulation.   
19. Appendix 12 Dose modification information for patients with Cushing’s receiving 
pasireotide s.c in combination with cabergoline (SOM230B2411): The appendix added to 
provide guidance of permitted doses and dose modifications.   
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Amendment 2 (29-Sep-2017) 
Amendment rationale  
The main purpose of this amendment is to: 
• Include language on the trial end date to meet the regulatory guidelines of the Medicine and 
Health Research Authority (MHRA), in the United Kingdom (UK).   
• This trial was deemed to be a voluntary PASS (post-authorization safety study) by Novartis 
Regulatory Affairs in 2016.  An interim analysis will be performed in 2017, and every 2 
years thereafter, until the final database lock.   
• This amendment will also help to clarify the visit schedules for patients taking pasireotide 
s.c. and those taking pasireotide LAR, and further highlights the required timelines for using 
highly effective methods of contraception after last dose of study medication.   
This roll-over study has been opened since 10-Jun-2013 and has enrolled a total of 301 patients 
with 259 patients ongoing. 
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 underline for insertions. 
• Protocol Summary, Study Design Section: A trial end date was added for the UK. 
• Section 2.1 Study Rationale: Updated the language to clarify that patients will continue to 
receive study drug as long as the patient continues to receive clinical benefit as judged by 
the Investigator or one of the discontinuation criteria is met. 
• Section 4.1 Description of study design: Clarified that all patients can begin treatment with 
study drug as soon as they enter the trial and that all patients are expected to report to the 
study site for the first visit to begin study participation. 
• Section 4.1 Description of study design: Clarified the study visit schedule for patients taking 
pasireotide LAR versus those taking pasireotide s.c. and the permissible visit windows for 
those visits. 
• Section 4.1 Description of study design: Added language on the trial end date and updated 
the language that patients will continue to receive pasireotide as long as the patient continues 
to receive clinical benefit as judged by the Investigator or one of the discontinuation criteria 
is met. 
• Section 4.2 Timing of interim analysis and design adaptations: Added language that an 
interim analysis will be performed in 2017 and every 2 years thereafter until the final 
database lock. 
• Section 4.3 Definition of end of the study: Updated the language to provide a specific trial 
end date. 
• Section 5.3 Exclusion Criteria: Corrected the timing of the use of highly effective methods 
of contraception. Contraception must be used for 30 days after the final dose of pasireotide 
s.c. and 84 days after the final dose of pasireotide LAR. 
• Section 6.1.5 Treatment duration: A trial end date was added. 

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• Section 7.1.3 Treatment period: Clarified the study visit schedule for patients taking 
pasireotide LAR versus those taking pasireotide s.c. and the permissible visit windows for 
those visits.  The requirement for 5 study visits in the first year was removed as there are no 
safety concerns with the trial and there was no added value in the patients coming to clinic 
for an additional visit in the first year.         
• Section 7.1.3 Treatment duration: A trial end date was added. 
• Section 7.1.4 Pregnancy and assessment of fertility: Corrected the timing of the use of 
highly effective methods of contraception. Contraception must be used for 30 days after the 
final dose of pasireotide s.c. and 84 days after the final dose of pasireotide long-acting. 
• Section 7.1.5 Discontinuation of study treatment: Added language to provide instruction to 
investigators on patient discontinuation and corrected the reporting period for safety events 
after the patients last dose of medication is 30 days for patients on pasiroetide s.c and 84 
days for patients on pasireotide long-acting.    
• Section 7.1.5.1 Criteria for premature withdrawal: Added language confirming that when 
current treatment becomes commercially available and reimbursed in the indication, the 
patient will have to be withdrawn from the study and will have completed the treatment 
duration from the trial.  
• Section 7.1.5.1 Criteria for premature patient withdrawal: Clarified that routine examination 
is standard of care.   
• Section 7.1.7 Follow up for safety evaluations: The language was updated to state that 
patient must have safety evaluations 84 days after the last dose of study treatment for the 
pasireotide long-acting and 1 month (30 days) after s.c. dose. 
• Section 7.2.2 Safety and Tolerability Assessments: Language added to clarify that 
investigators can perform safety assessments using their local laboratories as needed per 
investigator judgement.   
• Section 8.2.2 Reporting: The section was updated to replace Drug Safety & Epidemiology 
(DS&E) with Chief Medical Office & Patient Safety (CMO&PS).  The safety reporting 
language was updated to state that patient must have safety evaluations 84 days after the 
last dose of study treatment for the LAR and 1 month (30 days) after s.c. dose. 
• Section 8.4 Pregnancies: The section was updated to replace Drug Safety & Epidemiology 
(DS&E) with Chief Medical Office & Patient Safety (CMO&PS) 
• Section 10.5.3.1 Analysis set and grouping for analyses: Clarify the duration of the safety 
follow-up period between s.c. formulation and LAR formulation. 
• Section 10.6 Interim Analysis: Added language that an interim analysis will be performed 
in 2017 and every 2 years thereafter until the final database lock.   
• Appendix 1 Medication known to be associated with QT interval prolongation: Removed 
the list of drugs with possible association with QT prolongation and added the website 
where the current list of medications can be located.   
• Appendix 2 Hepatic safety management: Updated the title to indicate this is a recommended 
guidance for hepatic management and clarified that routine examination is standard of care.   
• Appendix 3 Recommended follow-up in case of QT-related findings during routine ECG: 
Clarified this is recommended guidance.  

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• Figure 14-2: Updated title to indicate this is recommended guidance for ECG follow-up. 
• Appendix 4 Fasting blood glucose management: Clarified this is recommended guidance. 
• Figure 14-3: Updated title to indicate this is a recommended guidance for fasting self-
monitoring blood glucose management. 
• Appendix 5: Updated the title to reflect this is the dose modification information for patients 
from the parent protocol CSOM230C2110, CSOM230C2305, CSOM230C2402 and 
CSOM230C2413.   
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 

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Amendment 01 
Amendment rationale 
With this amendment, in order to clarify the main objective of this study, the previous secondary 
objective “To collect long-term data on serious adverse events and adverse events of special 
interest” has been elevated to primary objective. In addition, the protocol has been amended to 
clarify the safety monitoring guidance and to include the collection of all AEs (including non-
serious AEs) and an investigator attestation of continued clinical benefit. 
The study continues to allow continued access to pasireotide for patients treated with the 
compound in previous Novartis sponsored studies for as long as they benefit from it. This roll-
over study has been opened since 10-Jun-2013 currently with a total of 95 patients enrolled and 
80 patients ongoing. 
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 following changes have been implemented: 
The Protocol summary is also updated correspondingly 
Section 2.1: Update to the study rationale to include the primary endpoint to evaluate long term 
safety date. 
Section 2.6: The inclusion of the Risk-Benefit section 
Table 3-1: Updated with revised study objectives and endpoints. The primary objective is to 
evaluate long term safety data. The secondary objective is to evaluate clinical benefit as 
assessed by the investigator. 
Section 4.1: Updated to clarify that all adverse events and serious adverse events will be 
collected continuously throughout the study and to specify that at every visit, the investigator 
is required to confirm that the patient continues to have clinical benefit and may continue 
receiving study treatment. 
Section 6.1.5: Updated to specify that at every visit, the investigator is required to confirm that 
the patient continues to have clinical benefit and may continue receiving study treatment 
Section 6.2: Revised to refer to Appendices regarding dose modification guidelines 
Section 6.5: Clarification of drug labeling process 
Table 7-1: Updated to include collection of relevant medical history, continuous collection of 
all AEs and SAEs, investigator confirmation of clinical benefit from study treatment at every 
visit, the collection of all adverse events and clarification of the visits for LAR and S.C. 
formulation for the duration of the trial. Also to include the at home monthly pregnancy tests 
monitoring 
Section 7.1.3: Updated to specify that the investigator is required to confirm that the patient 
continues to have clinical benefit at every visit and may continue receiving study treatment. 

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Section 7.1.4: Inclusion of Pregnancy and Assessment of Fertility. Also revised language for 
highly effective contraception. 
Section 7.1.5.1: Minor updates to the criteria for premature patient withdrawal from the trial 
Section 7.2.2: Update to clarify the safety monitoring guidelines 
Section 8: Updated with new AE/SAE reporting process. 
Section 9: Clarification to personal identifiable patient information collection 
Section 10: Updated statistical analysis section based on revised study objectives. 
Section 14: Update to Appendences to reflect revised standard global language for the 
recommended safety assessments and dose modification 
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 Health Authority and IRB/IEC 
approval prior to implementation. 

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Protocol summary: 
Protocol number 
CSOM230B2412 
Title 
An open label, multi-center pasireotide roll-over protocol for patients who have 
completed a previous Novartis-sponsored pasireotide study and are judged by the 
investigator to benefit from continued pasireotide treatment 
Brief title 
Study to allow access to pasireotide for patients benefiting from pasireotide 
treatment in a Novartis-sponsored study. 
Sponsor and Clinical Phase 
Recordati IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to evaluate long term safety data and allow continued 
use of pasireotide in patients who are on pasireotide treatment in a Novartis-
sponsored study and are benefiting from the treatment as judged by the investigator. 
Primary Objective(s) 
To evaluate long term safety data, SAEs and AEs 
Secondary Objective 
To evaluate clinical benefit as assessed by the investigator 
Study design 
This is a multi-center, open label, phase IV study to provide continued supply of 
pasireotide to patients being treated in a current Novartis-sponsored study and who 
are benefiting from treatment with pasireotide. Eligible patients are to be consented 
and can then continue treatment with pasireotide in this protocol. All patients at their 
scheduled visits will have drug dispensing information and reported adverse events 
and serious adverse events collected. 
A patient will reach the end of study when pasireotide treatment is permanently 
discontinued and the end of treatment visit has been performed. All patients must be 
followed up for safety evaluations for 84 days following the last dose of pasireotide 
long acting release (LAR) treatment and for 1 month 30 days following the last dose 
of pasireotide subcutaneous (s.c.) treatment. The study is expected to remain open 
for approximately 10 years 
from First Patient First Visit (FPFV) (or until 10June2023 in the UK).  Patients will 
continue to be treated in this study until they are no longer benefiting from their 
pasireotide treatment as judged by the Investigator or until one of the protocol 
discontinuation criteria is met.   
Population 
Patients who are currently enrolled in a Novartis-sponsored study, that has fulfilled 
all required assessments and who are benefiting from treatment with pasireotide. 
Parent studies eligible to participate in the roll-over study will be decided by 
Recordati 
Inclusion criteria 
• 
Patient is currently  enrolled in a Novartis- sponsored study receiving pasireotide 
and has fulfilled all their requirements in the parent study. 
Patient is currently benefiting from the treatment with pasireotide, as determined by 
the investigator. 
• 
Patient has demonstrated compliance, as assessed by the investigator, with the 
parent study requirements. 
Exclusion criteria 
Patient has been permanently discontinued from pasireotide study treatment in 
the parent study due to unacceptable toxicity, non-compliance to study 
procedures, withdrawal of consent or any other reason. 
Investigational and 
reference therapy 
Pasireotide s.c: should follow parent study doses 
Pasireotide LAR: should follow parent study doses 
Combination therapy as per parent protocol 
Efficacy assessments 
Not applicable 
Safety assessments 
All adverse events and serious adverse events will be collected continuously 
throughout the study. Safety monitoring should follow the guidance in the locally 
approved prescribing information (for locally approved indications) or the 
requirements described in the current Investigator Brochure (for indications that are 
not yet approved locally). Additional guidance is provided in the appendices. 

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Other assessments 
Not applicable 
Data analysis 
The assessment of safety will be based mainly on the frequency and severity of AEs 
and SAEs. Proportion of patients with clinical benefit as assessed by the investigator 
will be summarized at scheduled visits. Safety information on patients from this 
protocol will link to the patient identifiers from the parent study. 
Key words 
SOM230, pasireotide, roll-over study, pasireotide LAR 

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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1 
Overview of Cushing’s disease (CD) 
Cushing’s disease (CD) is a rare but debilitating disease. Patients have excessive 
adrenocorticotropic hormone (ACTH) secretion from a benign pituitary adenoma, which 
stimulates the adrenal glands to produce excess cortisol. The incidence of Cushing’s disease 
ranges from 1-3 patients per million per year. Cushing’s disease is associated with severe 
morbidity and premature mortality and most commonly affects adults aged 20-50 years of age, 
primarily females. 
The most common pathological finding in these patients is bilateral hyperplasia of the adrenal 
cortex and cortisol hypersecretion due to excessive ACTH secretion. The primary clinical signs 
and symptoms of Cushing’s disease are due to hypercortisolism, such as change in body habitus, 
hirsutism, wasting of musculature, hypertension, weight gain, and decreased insulin sensitivity 
with disorders in glucose metabolism, Because of these alterations patients with Cushing’s 
disease have increased morbidity and mortality. 
While surgical removal of the adenoma is first line therapy for CD, the success rate of surgery 
is between 65-90% for microadenomas (tumors < 1 cm) with recurrence rates between 10 to 
20% after 10 years. The surgical cure rate for macroadenomas (>1 cm) is less than 65% and 
recurrence rates as high as 45% (Biller et al 2008). When surgery and/or irradiation fail, or for 
those patients for whom such therapies are not an option, the remaining alternatives are 
pharmacological treatment or bilateral adrenalectomy. No drugs are currently approved for the 
treatment of Cushing’s disease and the ones which physicians have available for use are fraught 
with suboptimal results and significant side effects (Miller 1993, Nieman 2002, Biller et al 
2008) and the majority are limited to inhibit steroidogenesis at the adrenals, not targeting the 
pituitary adenoma. Bilateral adrenalectomy is a definite cure of Cushing’s disease but results in 
irreversible primary adrenal insufficiency and patients need lifelong replacement therapy with 
glucocorticoids and mineralocotricoids and have a higher likelihood to develop Nelson’s 
syndrome (Sonino 1996, Assie 2004, Assie 2007). There is an unmet medical need for the 
treatment of CD as medical treatment options are limited. 
A confirmatory Phase 3 study [SOM230B2305] has been completed to support the filing of 
pasireotide s.c. for the treatment of patients with Cushing’s disease for whom medical therapy 
is appropriate. The 900 µg b.i.d group met the pre-specified criteria for the primary efficacy 
endpoint. Robust reductions in mUFC occurred relatively quickly, within the first month, and 
were sustained over the course of Months 6 and 12. Both doses were efficacious in lowering 
mUFC, with the Month 6 median percent change from baseline being -47.9% for both doses. 
The Month 12 median percent changes from baseline were -62.4% and -67.6% for 900 and 600 
µg b.i.d., respectively. Pasireotide s.c. received approval in EU in April 2012 for the treatment 
of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery 
has failed. 

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1.1.2 
Overview of acromegaly 
Acromegaly is a rare, seriously debilitating condition characterized by chronic hypersecretion 
of (GH) growth hormone, which, in over 95% of patients, is caused by a GH-secreting pituitary 
adenoma. It is estimated that about 3 out of every million people develop acromegaly each year 
and that 40 to 60 out of every million people suffer from the disease at any one time (Melmed 
et al 1998). 
The clinical manifestations of acromegaly are due to the peripheral actions of the GH excess 
and elevated insulin-like growth factor 1 (IGF-1) concentrations and/or local tumor mass effect. 
The symptoms and signs of acromegaly can be 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 or control its growth and restore GH 
secretion and action to normal. The biochemical goals of therapy are to reduce the circulating 
IGF-1 levels to normal for age and sex and to reduce serum GH concentrations to < 2.5µg/L 
(mean GH concentration of a 5-point profile within a 2-hour time period) or to less than 1µg/L 
after an oral glucose load (Giustina et al 2000). 
A multicenter, randomized, double-blinded, phase III, study [SOM230C2305] completed its 
core phase and the first year of the extension phase, and patients receiving pasireotide LAR are 
still being followed. This pivotal study compared the safety and efficacy of 40 mg of pasireotide 
LAR with 20 mg of octreotide LAR in patients with active acromegaly at 12 months of 
treatment. The primary objective was to compare the proportion of patients with a reduction of 
mean GH level to < 2.5µg/L and normalization of IGF-1 to within normal limits (age and sex 
related) between the two treatment groups at 12 months. The study met its primary endpoint, 
showing superiority of pasireotide versus octreotide. 
1.1.3 
Overview of neuroendocrine tumors (NETs) 
Neuroendocrine tumors (NETs) are a genetically diverse group of rare malignant tumors that 
arise from neuroendocrine cells throughout the body. The WHO classification of NETs has 
recently gained acceptance in the literature due to better prognostic relevance. In this anatomic 
nomenclature, neuroendocrine tumors are distinguished on the basis of primary tumor 
localization (e.g. gastrointestinal, lung, or pancreas), rather than the previous embryonic 
categories (Kloppel et al 2004). 
The incidence of NETs is approximately 2 per 100,000 per year. However, NETs has been 
reported with increasing frequency over the years from 1973 to 2004 (Yao et al 2008). 
NETs can be clinically symptomatic (functional) due to hormone or other product 
hypersecretion or clinically silent (nonfunctional). Approximately 50-60% of NETs are 
nonfunctional, i.e. do not cause clinical symptoms due to hypersecretion (Modlin et al 2008). 
Most patients with NETs present with metastatic disease at the time of diagnosis, with regional 
or distant metastasis seen in 50% of patients (Yao et al 2008). Up to 75% of patients that present 
with NETs of the mid- or hindgut region, and approximately 60% of patients with pancreatic 
NETs (pNET) have liver metastases (Falconi et al 2006). 

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Currently, surgical resection represents the traditional first-line therapy of NETs (Plöckinger 
and Wiedenmann 2007). The prognosis following complete surgical resection is generally 
favorable (Schurr et al 2007). However, curative surgery is often not possible because the 
majority of patients present with metastatic disease. 
In patients with inoperable NET, the treatment goal is to control tumor growth, to control 
symptoms if the tumor is functional, and to prolong survival time. Biotherapy with currently 
approved somatostatin analogs (SSAs) remains the mainstay of symptomatic therapy for NET. 
The PROMID study has shown that octreotide LAR was able to increase time to progression 
(TTP) when compared to placebo from 6.0 months to 14.3 months in patients with advanced 
(unresectable or metastatic) NET of the midgut or unknown primary tumor location (Rinke et 
al 2009). Other available treatment options for patients with NETs are: Interferon-alpha (Öberg 
2000, Arnold 2005); cytotoxic chemotherapy as single-agent or in combination (5FU, 
streptozotocine, doxorubicin, cisplatin, etc.) (Toumpanakis 2007); temozolomide (Ekeblad 
2007). For patients with PNET, two new therapies were approved by the FDA in May 2011: 
everolimus an mTOR inhibitor and sunitinib which is a multikinase inhibitor. Pasireotide s.c. 
and LAR were evaluated in patients with NETs in two phase 1 [SOM230D2201] and 
[SOM230C2110] (patients with carcinoid syndrome), one phase 2 [SOM230D2203] 
(gastrinomas, glucagonomas, insulinomas, VIPomas) and one phase 3 [SOM230C2303] 
(metastatic functioning carcinoid tumors) studies. The optimal anti-proliferative dose for 
pasireotide LAR monotherapy in NET is currently being explored in the MTD study 
[SOM230D2101]. 
1.1.4 
Overview of other pituitary tumors and of Ectopic ACTH secreting 
(EAS) tumors 
Pituitary adenomas are benign neoplasms arising from one of the five anterior pituitary cell 
types. The clinical and hormonal syndrome associated with pituitary adenomas depend on the 
cell type from which they are derived. Tumors arising from lactotrope (PRL), somatotrope 
(GH), corticotrope (ACTH), thyrotrope (TSH), or gonadotrope (LH, FSH) cells hypersecrete 
their respective hormones. About one-third of all pituitary adenomas are clinically non-
functioning (nonfunctional pituitary adenomas, NFPA) and produce no distinct clinical 
hypersecretory syndrome. Nelson’s syndrome is associated with local corticotroph (ACTH) 
pituitary tumor re-growth, extension or invasion, following a therapeutic bilateral 
adrenalectomy to control hypercortisolism, as a result of the removal of the negative feedback 
or cortisol on hypothalamic corticotropin-releasing hormone. Symptoms result from local tumor 
expansion, and from effects on other pituitary hormones and on ACTH related symptoms. 
Hypersectretion of ACTH can also occur from non-pituitary tumors and is designated as Ectopic 
ACTH secreting (EAS) tumors. The majority of these patients have non-resectable, advanced 
or metastatic tumors. Symptoms are related to hypersecretion and tumor burden or mass. 
Prognosis is usually very poor. 
Medical therapy is the main measure to alleviate the symptoms of the above diseases by 
controlling hyper-secretion of respective hormones. Somatostatin analogues are currently used 
as a medical therapy option in some of these patients. A phase 2 proof of concept study 
SOM230D2203 is ongoing evaluating the effect of pasireotide LAR in these tumors. 

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1.1.5 
Overview of patients with dumping syndrome 
“Dumping syndrome” is a debilitating complication of esophageal and gastric surgeries (such 
as bariatric and gastric cancer surgeries) estimated to occur in 5-50% of patients (Arts et al 
2009). In summary, dumping syndrome consists of (1) a too rapid gastric emptying, (2) an 
inappropriate release of GI hormones (as a reaction to the rapid delivery of carbohydrates to the 
duodenum) and (3) a hyperinsulinemic response to a too rapid absorption of glucose. (Tack et 
al 2009). The diagnosis is confirmed by an adapted 3-hour Oral Glucose Tolerance Test 
(OGTT) with 75g of glucose evaluating the presence of early changes (30 min) in hematocrit 
and pulse rate and late (120, 180 min) hypoglycemia (Tack et al 2009). 
Currently there are no approved medications to treat dumping syndrome. Dietary measures and 
addition of food additives such as guar gum and pectin are implemented to prevent late dumping 
symptoms (Arts et al 2009), (Andersen et al 1989), (Hariu and Lami 1983). Medications that 
delay carbohydrate absorption such as alpha-glucosidase inhibitors (e.g. acarbose) have been 
used in clinical practice. However, acarbose improves only the symptoms of late dumping and 
often results in bloating, flatulence or diarrhea that usually hampers treatment compliance 
(Lyons et al 1985). 
In addition, a relative large body of literature (Arts et al 2009), (Tack et al 2009) (Hopman et al 
1988), (Primrose and Johnston 1989), (Tulassay et al 1989) (Geer et al 1990), (Richards et al 
1990), (Gray et al 1991) and (Hasler et al 1996) suggests that octreotide (both s.c. and LAR 
formulations) may be effective. 
Clinical studies in healthy volunteers [CSOM230B2216] have demonstrated that pasireotide 
suppresses insulin secretion, with no changes in hepatic or peripheral insulin sensitivity. In 
addition, pasireotide significantly decreases incretin response (glugagon-like peptide-1) [GLP-
1] and (glucose-dependent insulinotropic peptide) [GIP] right after glucose ingestion during the 
OGTT until 90- 120 minutes CSOM230B2216. Since it has been shown that the somatostatin 
inhibition of GLP-1 secretion is mediated by Somatostatin-28 mainly through activation of sst5 
and with a lesser effect by sst2 (Chisholm and Greenberg 2002), this suppression is expected to 
be stronger with pasireotide than with octreotide. A phase 2 study [CSOM230X2203] is 
ongoing to evaluate the effect of pasireotide s.c. and LAR in patients with dumping syndrome. 
1.1.6 
Overview of other indications 
Pasireotide s.c. and LAR are being studied in several other indications e.g: metastatic prostate 
cancer [SOM230DE04], metastatic melanoma negative for bRAF and nRAS mutations 
[SOM230X2404], polycystic liver/renal disease and in post-operative pancreatic fistula. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of pasireotide s.c. and LAR 
Pasireotide is a cyclohexapeptide somatostatin analogue that exhibits a unique binding profile, 
binding with high affinity to four of the five known human somatostatin receptors subtypes. 
Somatostatin analogs activate these receptors with different potencies (Schmid and Schoeffter 
2004) and this activation results in a reduced cellular activity and inhibition of hormone 

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secretion. Somatostatin receptors are strongly expressed in many tumors, especially in 
neuroendocrine tumors (Oberg et al 2004), and also in pituitary tumors where hormones are 
excessively secreted, e.g. in acromegaly (Freda 2002) and Cushing’s disease (Van der Hoek et 
al 2005). Compared to Sandostatin® (octreotide acetate), pasireotide exhibits a binding affinity 
which is 30-40 times higher for human sst1 and sst5, 5 times higher for human sst3, and a 
comparable affinity (a 2.5 fold lower) for sst2 receptors. 
Pasireotide s.c. is a short acting formulation administered subcutaneously two or three times a 
day. This formulation has been tested in healthy volunteers and in patients with acromegaly, 
Cushing’s disease and metastatic carcinoid tumors. 
Pasireotide LAR is a long acting formulation administered intramuscularly every 28 days. It 
has been studied in healthy volunteers and in patients with acromegaly, Cushing’s disease, and 
metastatic carcinoid tumors. 
1.2.1.1 
Non-clinical experience 
Pre-clinical pharmacology 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. 
Extensive safety studies have been performed in mice, rats, rabbits and monkeys to support the 
administration of pasireotide. These studies include acute, subchronic and chronic toxicity 
studies, carcinogenicity studies of transgenic mice, local tolerance studies, reproduction studies, 
as well as in vitro and in vivo genotoxicity studies. Most of these studies were performed using 
the s.c. route of administration and the vast majority of the findings were considered related to 
the pharmacology of pasireotide. 
Pre-clinical long-term systemic safety profiles have been well-established for pasireotide s.c. 
The pre-clinical data from pharmacology, safety, and DMPK studies provided the basis for 
clinical development of pasireotide s.c. 
A detailed summary of available pre-clinical data is provided in the latest version of the 
pasireotide [Investigator’s Brochure]. 
1.2.1.2 
Clinical experience 
1.2.1.2.1 Clinical efficacy of pasireotide s.c. and LAR 
Pasireotide s.c. 
The pasireotide s.c. formulation has shown efficacy in a Phase III Study [CSOM230B2305] in 
162 patients with moderate to severe Cushing’s disease (CD). In addition, pasireotide s.c. was 
also evaluated in three phase II studies, two in patients with CD [CSOM230B2208], 
[CSOM230B2208E], 
two 
in 
patients 
with 
acromegaly 
[CSOM230B2201], 
[CSOM230B2201E] and one with patients metastatic carcinoid tumors [CSOM230B2202]. 
A detailed summary of available clinical efficacy data is provided in the [Investigator 
Brochure]. 

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Pasireotide LAR 
Pasireotide LAR formulation has shown efficacy in a randomized placebo-controlled Phase 3 
study [SOM230C2305] designed to compare pasireotide LAR to octreotide LAR in patients 
with acromegaly. A phase III study (CSOM230G2304) has demonstrated that Pasireotide LAR 
normalized mUFC concentration in about 40% of patients with Cushing’s disease at month 7 
and had a similar safety profile to that of twice-daily subcutaneous pasireotide.  Results of 
another clinical study have indicated that pasireotide is a safe and effective treatment in patients 
with acromegaly. Efficacy of pasireotide in patients not controlled with other somatostatin 
analogues was already demonstrated in the PAOLA study (Study CSOM230C2402).  This trial 
was 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 [at 24 weeks, 10 (15%) patients in 
the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group]. Therefore, 
it is thought that an earlier treatment change to pasireotide LAR might be beneficial for these 
patients. 
1.2.1.2.2 Clinical safety of pasireotide s.c. and LAR 
Pasireotide s.c. 
Single and multiple doses of pasireotide s.c. have generally been well tolerated by healthy 
volunteers. The most commonly reported adverse events (AEs) were GI related such as mild 
diarrhea and nausea, requiring no treatment or study discontinuation. The frequency of these 
AEs appeared to decrease overtime in multiple-dose studies. 
Hyperglycemia was the most important side effect and was observed across all indications. 
Blood glucose tended to rise with increasing dose, and appeared to be more notable in patients 
who had a history of hyperglycemia or diabetes mellitus prior to receiving pasireotide. 
However, hyperglycemia in these patients was responsive to appropriate diabetic management 
such as adjustments in oral antidiabetic treatment, or in some cases the addition of insulin. 
Pasireotide’s effect on QT prolongation was demonstrated by two thorough QT (TQT) studies 
[SOM230B2113] and [SOM230B2125]. The second TQT study SOM230B2125 was designed 
to evaluate the effect of pasireotide on cardiac intervals using an individualized correction 
method to account for the known bradycardic effect of pasireotide. It was conducted as a follow-
up to Study SOM230B2113, which showed that pasireotide at the Maximum Tolerated Dose 
(MTD) of 1950 μg b.i.d dose induced prolongation of QTcF, whereas no relevant effect on 
QTcB was observed. The second TQT study confirmed an effect of pasireotide on QTcI of 
pasireotide at both the 600 μg bid and the 1950 μg bid dose. The maximal placebo-subtracted 
change from baseline in QTcI was seen at 2 hours post dose, at which time the mean (90% CI) 
difference was 13.19 ms (11.38; 15.01) for pasireotide 600 μg bid, and 16.12 ms (14.30; 17.95) 
for pasireotide 1950 μg b.i.d. Both pasireotide doses decreased heart rate, with a maximal 
difference to placebo observed at 1 hour for pasireotide 600 μg b.i.d (-10.39 bpm), and at 0.5 
hours for pasireotide 1950 μg bid (-14.91 bpm). There were no subjects with QTcI or QTcF 
values that were increased more than 60 ms from baseline, or that exceeded 500 ms on Day 5, 
the last day of study treatment. 

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Three healthy volunteers who received pasireotide s.c. had biochemical changes that met Hy’s 
Law criteria (i.e. ALT > 3 x ULN with concurrent total bilirubin >2 x ULN, without increases 
in alkaline phosphatase and no other cause(s) identified for the abnormal findings). All 3 cases 
were asymptomatic, presented within 7 days after initial pasireotide s.c. administration, and 
were reversible after discontinuation of pasireotide. None of the cases were reported as an 
adverse event and the subjects completed the respective studies per protocol. 
One patient with Cushing’s disease fulfilled biochemical criteria for Hy’s Law nine days after 
receiving pasireotide 600 µg b.i.d. Study medication was discontinued due to the event and 
fourteen days after the discontinuation of pasireotide the patient's bilirubin decreased to 
1.6xULN) and ALT was still elevated at 5.8-fold. Liver chemistry tests were normal 45 days 
after the discontinuation of pasireotide. Follow-up information indicated that liver function tests 
were consistent with hepatitis. 
Pasireotide LAR 
Pasireotide LAR has been well tolerated by healthy volunteers and by patients. In healthy 
volunteers, pasireotide LAR has been well tolerated following single i.m. injection up to the 
highest tested dose of 60 mg LAR [CSOM230C2101]. The most common adverse events were 
gastrointestinal. Diarrhea was experienced by most of the subjects and was sometimes 
associated with flatulence and abdominal pain. The gastrointestinal events were mild or 
moderate in severity. Mild injection site pain was reported and typically resolved within a day. 
These events did not result in discontinuation from the study. 
Pasireotide LAR formulation has also been evaluated in a randomized phase 3 study in patients 
with acromegaly [SOM230C2305]. In the pasireotide group, the highest proportion of study 
drug-related AEs was reported for hyperglycemia-related AEs (58.4%), followed by gallbladder 
and biliary-related AEs (34.8%) diarrhea-related AEs (33.1%), bradycardia-related AEs 
(11.2%), pancreatitis-related AEs (11.2%) and nausea-related AEs (10. 1%). Overall the 
adverse events were similar in both arms with the exception of hyperglycemia, which was found 
to be more frequent in the pasireotide LAR arm. 
The safety and efficacy of Pasireotide LAR was confirmed in a phase 3, multicenter, 12-month 
trial in which 150 patients were randomized to receive either Pasireotide 10 mg or 30 mg 
[SOM230G2304]. The most common adverse events were hyperglycaemia (36 [49%] in the 10 
mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis 
(15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] 
and 16 [21%]). The observed safety profile of long-acting pasireotide was consistent with that 
of twice-daily pasireotide in patients with Cushing’s disease. 
Further details on pasireotide clinical safety can be found in the [Investigator Brochure]. 
1.2.1.2.3 Clinical pharmaokinetics of pasireotide 
Pasireotide s.c 
In healthy volunteers, results from the human ADME study [CSOM230B2112] with a single 
s.c. dose of 600 µg 14C-labelled pasireotide showed that pasireotide is mainly eliminated via 

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hepatic clearance, and renal clearance makes a small contribution to the elimination of 
pasireotide in man. No circulating metabolite was detected. 
In healthy volunteers, following a single s.c. injection, pasireotide pharmacokinetics 
demonstrated fast absorption, extensive distribution, low clearance, and long half-life 
[CSOM230B2101], [CSOM230B2106] and [CSOM230C2101]). The PK exposures (Cmax and 
AUCinf) were approximately dose-proportional for a wide dose range from 2.5 to 1500 µg. The 
drug was rapidly absorbed with a median Tmax of 0.25-0.5 hr post dose. 
Following q.d. dosing of s.c. injections in healthy volunteers, the steady state appeared to be 
achieved within 3 days [CSOM230B2102]. The CL/F, Tmax, and T1/2 at steady state 
CSOM230B2102 were similar to those estimated following single doses CSOM230B2101, 
CSOM230B2106, and CSOM230C2101), indicating that the PK of pasireotide s.c. is linear and 
time-independent. 
Pasireotide LAR 
Pasireotide LAR formulation has been evaluated in healthy volunteers, acromegaly patients, 
and carcinoid patients. Following a single intramuscular (i.m.) injection the LAR formulation 
demonstrated a controlled-release type of concentration versus time profile with an initial spike 
phase on day 1 (Cmax,p1), followed by a dip from Days 2 to 7, a second higher peak (Cmax,p2) 
at approximately day 21, and then a declining phase over the next 6 weeks until the last PK 
sampling point. PK exposure was dose-proportional for the tested doses 40-60 mg. The relative 
bioavailability of pasireotide LAR to pasireotide s.c. was complete. PK simulation based on 
healthy volunteer data demonstrated that steady state could be achieved after 3 monthly 
injections. 
Further details on pasireotide clinical pharmacokinetics can be found in the [Investigator 
Brochure]. 
2 
Rationale 
2.1 
Study rationale and purpose 
The purpose of this rollover study is to evaluate long term safety data and allow continued 
supply of pasireotide (s.c. and/or LAR) to patients who are currently receiving treatment in a 
Novartis-sponsored trial and have fulfilled all required assessments in the parent study, are 
benefiting from the treatment as judged by the investigator and are unable to access pasireotide 
treatment outside of a clinical study. Parent studies eligible to participate in the roll-over study 
will be decided by Recordati. Investigator initiated trials (IITs) will not be included. The patient 
must have fulfilled all required assessments in the parent study and the parent study must be in 
the process of being completed or terminated and reported. 
Patients will continue to receive pasireotide alone or in combination with another treatment for 
Cushing’s Disease and Acromegaly, as long as they continue to benefit as per Investigator 
assessment, or until one of the discontinuation criteria is met (please refer to Section 7.1.5). 

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2.2 
Rationale for the study design 
This is a multi-center, open label, phase IV, roll-over study of pasireotide in patients being 
treated in a current Novartis-sponsored study and who are benefiting from treatment with 
pasireotide alone or in combination with another treatment for Cushing’s Disease and 
Acromegaly. Combination therapy will only be permitted for patients with Cushing’s Disease 
or Acromegaly. 
The study will not include a screening phase as patients will transfer directly from parent studies 
and will commence treatment with pasireotide alone or in combination with another treatment 
for Cushing’s Disease and Acromegaly, as soon as they are consented and meet the inclusion 
criteria of the roll-over protocol. Since this study is intended to provide pasireotide supply and 
no formal analysis will be performed, there is no need for randomization, nor for bias reducing 
measures. 
2.3 
Rationale for dose and regimen selection 
The selected doses and regimen will be based on the dose ranges and regimen available in the 
parent study. The starting dose of pasireotide alone or in combination with another treatment 
for Cushing’s Disease and Acromegaly, should be the same dose as that which the patient was 
receiving in the parent study at roll over. After the starting dose, changes to pasireotide dose, 
and/or any medication given in combination with pasireotide for Cushing’s Disease or 
Acromegaly, will be based on the investigator’s judgment, but must follow the dose ranges 
provided in the parent study.  Please note combination treatment in this rollover trial is only 
allowable for Cushing’s Disease and Acromegaly parent protocols. 
Pasireotide will be provided as: 
1. Pasireotide s.c. – to be administered subcutaneously two or three times a day depending 
on the parent study dosing. 
2. Pasireotide LAR to be administered as intramuscular injection every 28 days. 
2.4 
Rationale for choice of combination drugs 
Patients suffering from Cushing’s disease or Acromegaly represent a challenge because of the 
reduced control of cortisol or GH/IGF-1 levels, respectively, by some medical therapies 
especially when given as montherapy. Due to this, whilst treatment is being administered, a 
close follow up is necessary to evaluate a response to the medication while assessing the 
addition of a second medication.  
In some patients, the administration of pasireotide alone did not normalize cortisol levels. Thus, 
a second medication with another mechanism of action is added to aid the restoration of cortisol 
or GH/IGF-1 levels to the normal range, respectively. 
For subjects on combination treatment with cabergoline + pasireotide only. The treatment of 
patients with CD requires a multimodality approach. Pasireotide has a favorable benefit/risk 
profile in Cushing’s Disease. However, a main reason for treatment discontinuation is due to 
insufficient therapeutic effect. Cabergoline is often used to decrease cortisol levels but it 
presents treatment escapes in many patients. Taking into consideration that biochemical 

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remission should be rapidly achieved to reverse morbidity and mortality, drugs can be combined 
to control cortisol production within an acceptable time frame. 
Advances in combination medical therapy have opened up new perspectives for acromegaly 
patients who are poorly controlled, or nonresponsive to presently available single drug 
therapies. SSAs have a role as the primary medical therapy in patients who have a low 
likelihood of surgical remission, or who are poor surgical candidates, as adjuvant therapy in 
these patients with persistently non suppressible GH or elevated IGF-I levels (or both) after 
pituitary surgery or during the interim period after RT. In patients who do not respond 
(biochemically) to medical monotherapy, combination therapy with SSAs and cabergoline or 
pegvisomant and cabergoline can be considered, on the basis of individual clinical 
considerations including tumour size and location.  
2.5 
Rationale for choice of comparators drugs 
Not applicable. 
2.6 
Risks and benefits 
Acromegaly is a serious, chronic, debilitating disease that is associated with high morbidity, 
shortened life expectancy, and a reduced quality of life. If untreated, acromegaly is associated 
with an average 10-year reduction in life expectancy, mainly due to cardiovascular, 
cerebrovascular, metabolic, and respiratory comorbidities. While successful pituitary surgery 
leads to long-term biochemical control in more than 70% of patients with well-circumscribed 
microadenomas, the success rate for macroadenomas is around 50%, and even less for invasive 
tumors. Radiotherapy is currently mainly used in patients with recurrent or persistent tumors, 
and carries the disadvantages of a relatively long latency period; furthermore, progressive 
anterior pituitary insufficiency develops in more than 50% of patients. Medical therapy using 
SSAs is being increasingly used as first-line treatment, especially in patients with low likelihood 
of cure by surgery, in whom surgery is contraindicated, or who refuse surgery. The efficacy of 
pasireotide LAR has been demonstrated to be superior to that of first-generation SSAs both in 
terms of the probability of a patient achieving biochemical control (GH reduction and 
normalization of IGF-1 levels), and in terms of relative reduction of IGF-1 levels from baseline. 
Superiority was demonstrated, both in medically naïve patients and in patients inadequately 
controlled on prior medical therapy. 
Cushing’s disease is a very rare, debilitating, and life-threatening disease that is caused by an 
adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma most commonly affecting 
adult females. The tumors are usually microadenomas (≤ 1 cm in diameter); macroadenomas 
are rare. The elevated levels of ACTH secreted by these tumors stimulate the adrenal glands to 
produce excess cortisol, thereby leading to the subsequent development of the clinical signs and 
symptoms of hypercortisolism. The primary clinical symptoms of Cushing’s disease include 
the following: changes in body habits due to increased fat accumulation; hirsutism; skin changes 
with easy bruising, purplish striae, reddening and ulceration of the cheeks; generalized 
weakness and fatigue; wasting of musculature; menstrual disorders in females; decreased 
fertility and/or libido; hypertension; weight gain; increased insulin resistance with alterations 
in glucose metabolism; dyslipidemia; depression, mood and behavior disorders; sleep 
disturbances and osteopenia/osteoporosis. Moreover, hypercortisolism is also associated with 

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immune deficiency and an increased risk for infections. As a result, patients with Cushing's 
disease have increased morbidity and a mortality rate 4 times higher than age- and gender-
matched subjects. The initial (i.e. first line) treatment of choice for Cushing’s disease is pituitary 
adenomectomy (transphenoidal surgery). For patients with recurrent or persistent disease, 
repeat transphenoidal surgery is also recommended if possible, but it is associated with lower 
efficacy than the initial surgery. Beyond this, radiotherapy and bilateral adrenalectomy are 
alternative treatment options. All 3 treatment modalities are associated with the potential for 
serious side effects. Pasireotide is the first pituitary-targeted medical therapy to demonstrate 
efficacy directly aimed at the underlying mechanism of Cushing’s disease (i.e. increased ACTH 
secretion), with associated robust and sustained decreases in UFC and serum cortisol. 
Additionally, improvements in the clinical signs and symptoms of Cushing’s disease were 
observed and were associated with decreases in UFC even in patients that did not completely 
normalize UFC; similar findings were observed for HRQL. 
Neuroendocrine tumors (NET) are rare malignant neoplasms that arise from the diffuse 
neuroendocrine system, which is made up of peptide- and amine producing cells with different 
hormonal profiles depending on their site of origin. Secretory symptoms of NETs occur when 
hormonal secretions released by the tumors reach the systemic circulation in a sufficient 
concentration and escape hepatic degradation; this occurs most frequently with hepatic 
metastases of NETs. Many NETs of non-pancreatic origin release vasoactive peptides and 
amines, such as serotonin and tachykinins, into the systemic circulation and cause a 
characteristic set of symptoms including flushing and diarrhea, and less commonly abdominal 
pain, telangiectasia, and bronchoconstriction. Depending on the tumor location, 10-50% of 
patients will have these symptoms. These symptoms occurring collectively are classically 
referred to as “carcinoid syndrome”. Surgical resection of the primary and metastatic lesions, if 
possible, remains the mainstay of treatment, and the only way to obtain a cure. Surgery is often 
not possible, however, as NETs are detected frequently in a more advanced tumor stage, 
regardless of primary location. In addition, approximately 60% of patients will continue to 
experience symptoms after surgery. In patients with inoperable GI NET, the treatment goal is 
to control tumor growth, to control any secretory symptoms that may be present, and to prolong 
survival. Somatostatin analogs (SSA) have been approved worldwide for the control of 
secretory symptoms of patients with NET for many years, and are widely used for symptom 
control in GI NETs. Over the past years, prospective data have become available to support the 
anti-proliferative role of somatostatin analogs. Given the broader binding capacity of 
pasireotide LAR, it is anticipated that it may have a greater impact on tumor stabilization than 
other SSAs such that significant benefit can be provided to patients that have progressed on 
currently available therapies. Evidence of efficacy was obtained in study CSOM230C2303. As 
there is no current standard of care for patients with advanced progressive functional GI NET, 
offering patients improved tumor stabilization will satisfy a high unmet need. Pasireotide LAR 
may provide a next step of therapy upon progression on other SSAs and provide patients an 
alternative to more toxic regimens such as standard cytotoxic chemotherapy that has limited 
benefit in this indication. In a post-hoc analysis from study CSOM230C2303, pasireotide LAR 
was shown to improve progression-free survival (PFS) by 5 months as assessed by 
investigators, compared to octreotide LAR. 
Dumping syndrome is a debilitating complication of esophageal and gastric surgeries (such as 
bariatric and gastric cancer surgeries) estimated to occur in 5-50% of patients. These surgical 

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procedures result in a reduced gastric capacity that causes rapid influx of nutrients to the small 
intestine, inducing a cascade of pathophysiological events and leading to early and late dumping 
syndrome symptoms. Dumping syndrome consists of (1) a too rapid gastric emptying, (2) an 
inappropriate release of GI hormones (as a reaction to the rapid delivery of carbohydrates to the 
duodenum) and (3) a hyperinsulinemic response to a too rapid absorption of glucose. Early 
symptoms comprise both gastrointestinal and vasomotor symptoms. Late dumping symptoms 
include hypoglycemia, perspiration, palpitations, hunger, fatigue, confusion, aggression, tremor 
and syncope. No drugs are currently approved for the treatment of Dumping syndrome. 
Pasireotide is a potent inhibitor of incretin and insulin secretion (via sst2 and sst5), which 
prevents postprandial hypoglycaemia. Additionally, it is a more potent inhibitor of glucagon-
like-peptide-1 (GLP-1) and peptide YY secretion than octreotide. Results from a phase II study 
(CSOM230X2203) suggest that pasireotide effectively controls postprandial hypoglycaemia in 
patients with dumping syndrome and provides improvements in the hematocrit level and pulse 
rate. 
Malignant melanoma (MM) is a highly invasive form of skin cancer that arises via 
transformation of the normal melanin-producing cells of the epidermis. Clinical outcome is 
dependent on the extent of disease at diagnosis with excellent survival rates (approximately 
90% at 5 years) described for patients with stage I disease. By contrast, patients with 
unresectable metastatic melanoma (stage III-IV) have a high 5-year mortality rate. Traditional 
therapies such as conventional chemotherapy (DTIC) and immunotherapies (IFN-α, IL-2) have 
not improved OS despite responses of short duration or benefit in a small number of patients. 
Newer therapies, including ipilimumab and vemurafenib, are now considered the standard of 
care because of their demonstrated survival benefit in patients with metastatic melanoma. Many 
patients, however, still experience disease progression after treatment, especially those whose 
melanoma does not express mutations in the BRAF gene (nearly half the overall melanoma 
patient population). Therefore, the development of new strategies to improve treatment of this 
life-threatening disease is essential. Merkel cell carcinoma (MCC) is a neuroendocrine 
carcinoma of the skin and hair follicles which often follows a particularly aggressive course. 
MCC is a rare tumor, accounting for less than 1% of cutaneous malignancies. Overall, the 2-
year mortality rate is 30-50%; few studies include a longer-term follow-up. To date, there is no 
standard protocol for the management of MCC and surgical treatment of large tumors especially 
in the head and neck region can be disfiguring. There is an urgent need for new therapies to 
treat patients with MCC. Pasireotide represents a new therapeutic option for patients with 
metastatic melanoma and Merkel cell carcinoma that has low toxicity and a good safety profile. 
Preclinical evidence and extensive clinical data and experience from the use of SSAs in patients 
with other endocrine and cancer disease states support the use of pasireotide in patients with 
malignant melanoma and Merkel cell carcinoma. 
Pasireotide is currently approved for use in Cushing’s disease (s.c. formulation) in over 80 
countries, and for use in acromegaly (i.m. LAR formulation) in over 30 countries worldwide. 
The safety profile of both formulations of pasireotide has been well characterized in a 
comprehensive development program and is similar to the established profile of SSAs, except 
for the higher incidence and magnitude of hyperglycemia, which is manageable with proper 
treatment with anti-diabetic medication. The mechanism of the pasireotide-induced 
hyperglycemia has been well characterized in mechanistic studies. It is primarily a consequence 
of decreased secretion of insulin and incretins, with no change in hepatic or peripheral insulin 

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sensitivity, is less severe in responders than non-responders, and is reversible upon 
discontinuation. The risk of hyperglycemia is minimized by monitoring of patients’ FPG and 
HbA1c levels and appropriate management. Additional expected pharmacodynamic effects of 
pasireotide are well known and are primarily GI disturbances, bradycardia, mild QT 
prolongations, cholelithiasis and transient elevations in serum levels of transaminases. These 
effects can be effectively monitored and managed, as detailed in the IB and in the label. No 
unexpected new findings have emerged with long-term exposure to pasireotide. 
Overall, pasireotide has a favorable benefit/risk profile in the discussed indications. Patients 
rolled-over to this study are those who have benefited from the treatment with pasireotide and 
continue to obtain this benefit with continuation of the treatment. The current label and IB fully 
characterize both efficacy and safety aspects of pasireotide, s.c. and LAR, to enable its 
appropriate use to maximize benefit while minimizing risks to patients. The risk to patients in 
this trial may be minimized by compliance with the eligibility criteria and study procedures, 
and close clinical monitoring. There may be unforeseen risks with pasireotide which could be 
serious. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
 
To evaluate long term safety 
data i.e. SAEs and AEs 
Frequency and severity of 
AEs/SAEs 
Refer to Section 10.4  
Secondary 
 
 
To evaluate clinical benefit as 
assessed by the investigator. 
Proportion of patients with 
clinical benefit as assessed by 
the investigator at scheduled 
visits. 
Refer to Section 10.5  
Other secondary 
 
 
Not applicable 
Not applicable 
Refer to Section 10.5.2  
4 
Study design 
4.1 
Description of study design 
Those patients receiving pasireotide LAR must return to the study center monthly (+/- 7 days) 
to receive study medication.  Drug dispensing information will be collected and adverse events 
and clinical benefit will be assessed. Patients receiving pasireotide s.c. must return to the study 
center on a quarterly basis (every 12 weeks +/- 2 weeks) for resupply of study medication. Drug 
dispensing information will be collected and adverse events and clinical benefit will be 
assessed.  The patient may return to the clinic at any given time as per standard of care or 
treating physician recommendation; however, only the quarterly study visits will be recorded.   

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At every visit, the investigator is required to confirm that the patient continues to have clinical 
benefit and may continue receiving study treatment. 
All adverse events and serious adverse events will be collected continuously throughout the 
study.  Information on patient pregnancies and pregnancies of pregnant partners will be 
collected.   
The study is expected to remain open for 10 years from FPFV (or until 10-Jun-2023 in the UK). 
Patients will continue to be treated in this roll-over study until they are no longer benefiting 
from their pasireotide treatment as judged by the investigator or until one of the discontinuation 
criteria is met (please refer to Section 7.1.5). At each visit the Investigator is required to confirm 
that the patient continues to derive clinical benefit and may continue receiving study treatment.   
A patient will reach the end of study when pasireotide treatment is permanently discontinued.   
Figure 4-1 
Study design 
 
 
*Note: The starting dose of pasireotide, and any combination treatment given for Cushing’s Disease or 
Acromegaly, should be the same dose as that which the patient was receiving in the parent study at 
roll over. 
4.2 
Timing of interim analyses and design adaptations 
Interim analyses will occur every 2 years beginning in 2017 and continuing until the final trial 
database lock.   
4.3 
Definition of end of the study 
End of study is defined as either 10 years from FPFV (or until 10-Jun-2023 in the UK) or when 
all patients on this study have permanently discontinued pasireotide treatment or have been able 
to obtain commercial supply according to local regulations or have been able to receive the drug  
through country-specific programmes outside of this clinical trial (applicable to Brazil, France, 
Germany, India, Italy, Malaysia, Mexico, Peru and Thailand)  and the end of treatment visit and 
all safety follow-up procedures have been performed for each patient, whichever comes first.   
 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Recordati. Should this be necessary, 
the patient should be informed as soon as possible and should stop taking study labeled drug. 
Parent Novartis 
Novartis Sponsored study: 
Pasireotide s.c. and/or LAR 
as monotherapy or in 
combination therapy
Roll-over study:
Pasireotide* at assigned 
dose and/or in addition to 
combination treatment
End of roll-over study:
Pasireotide is permanently 
discontinued

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Assessments should be performed as described in Section 7.1.3 for a prematurely withdrawn 
patient. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial. 
5 
Population 
5.1 
Patient population 
The 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. Patient is currently participating in a Novartis-sponsored study receiving pasireotide (LAR 
and/or s.c.) on monotherapy or combination therapy (for Cushing’s Disease or 
Acromegaly),  and has fulfilled all required assessments in the parent study and patients that 
are benefiting from the study treatment have no other alternatives. 
2. Patient is currently benefiting from the treatment with pasireotide, as determined by the 
investigator 
3. Patient has demonstrated compliance, as assessed by the investigator, with the parent study 
requirements. 
4. Willingness and ability to comply with scheduled visits, treatment plans and any other study 
procedures. 
5. Written informed consent obtained prior to enrolling in roll-over study and receiving study 
medication. 
• If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patient has been permanently discontinued from pasireotide study treatment in the parent 
study due to unacceptable toxicity, non-compliance to study procedures, withdrawal of 
consent or any other reason. 
2. 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. 
3. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
the study treatment and for 30 days after the final dose of pasireotide s.c. and 84 days after 
the final dose of pasireotide LAR. Highly effective contraception is defined as either: 

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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patientt. 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 enrolling). For female patients on the study 
the vasectomized male partner should be the sole partner for that patient. 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
• 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 
(i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total 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. 
• Sexually active males unless they use a condom during intercourse while taking drug 
and for 1 months after pasireotide s.c. last dose and 3 months after pasireotide LAR last 
dose 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. 
If a study patient or partner becomes pregnant or suspects being pregnant during the study 
treatment or within 1 month after the final dose of pasireotide s.c. or 84 days after the final dose 
of pasireotide LAR, the Study Doctor needs to be informed immediately and ongoing study 
treatment with pasireotide has to be stopped immediately. For patients taking pasireotide LAR, 
the future dose injections will be cancelled. 
6 
Treatment 
6.1 
Study treatment 
Terms related to study treatment are defined below: 

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6.1.1 
Study treatment and investigational treatment refer to pasireotide alone 
or in combination with another treatment for Cushing’s Disease and 
AcromegalyDosing regimen Pasireotide 
Table 6-1 
Dose and treatment schedule 
Study 
treatments 
Pharmaceutical 
form and route of 
administration 
Dose 
Frequency and/or Regimen 
Pasireotide 
Subcutaneous 
Dose ranges should be the same as 
stated in the parent study  
b.i.d. or t.i.d depending on the 
parent study guidance 
Pasireotide 
LAR 
Intramuscular 
Dose ranges should be the same as 
stated in the parent study 
q 28 days 
Pasireotide may be provided in two different formulations LAR or s.c. (Table 6-1), depending 
on the parent study. The starting dose of pasireotide should be the same dose as that which the 
patient was receiving in the parent study at roll over. Following the starting dose patients may 
have their dose changed based on investigator’s judgment and following the dose ranges used 
in the parent study. Patients are not allowed to receive doses that are not indicated in the parent 
study. 
The investigational treatment is to be stored in a secure locked area while under the 
responsibility of the investigator. Receipt and dispensing of investigational treatment must be 
recorded by an authorized person at the investigator’s site. 
Pasireotide for the roll-over study can be provided as local commercial material or global 
clinical study supply as appropriate. As per Recordati procedures, investigational treatment will 
be shipped directly to the investigational sites. 
6.1.2 
Dosing regimen for patients on Pasireotide in combination with 
cabergoline treatment 
Cabergoline is in the form of 0.5mg tablet. Cabergoline should be taken according to guidelines 
in the parent protocol.  It is usually taken after a full meal.  As per the parent study, if 
monotherapy with pasireotide does not allow the patient to receive biochemical control, 
cabergoline can be added at a starting dose of 0.5mg once daily.  If the patient does not achieve 
biochemical control with cabergoline 0.5mg once daily treatment, in combination with 
pasireotide, then the cabergoline dose can be escalated up to 1.0mg once daily.   
Dostinex is a generic form of cabergoline and can be used in the trial. If Dostinex is not available 
in a participating country, a different type of generic form can be used. For storage conditions, 
please refer to cabergoline Package Insert and SmPC.  
For specific study treatment dose modifications regarding cabergoline in the SOM230B2411 
trial, please refer to (appendix 12). 
Cabergoline is mainly recommended for patients with borderline or moderately increased 
plasma IGF-I levels (<1.5 X the upper limit of normal), even though it is sometimes effective 
(leading to normal IGF-I levels) in patients with high baseline IGF-1 levels. More recent studies 
suggest that cabergoline, a more selective dopamine-2 receptor agonist, may be effective in a 
larger percentage of patients by further lowering GH or IGF-1 levels. Doses vary from 0.3 to 7 

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mg/wk (one to seven administrations per week). The maximum suppression of GH has been 
achieved from 0.5 mg daily to 1 mg twice weekly.  
6.1.3 
Dosing regimen for patients on Pasireotide in combination with another 
treatment for Cushing’s Disease or Acromegaly 
Please follow all dosing guidelines outlined in the parent protocol for patients on any 
combination treatments.  
6.1.4 
Ancillary treatments 
Not applicable 
6.1.5 
Rescue medication 
Not applicable 
6.1.6 
Guidelines for continuation of treatment 
Not applicable 
6.1.7 
Treatment duration 
Patients will continue to receive pasiroetide alone or in combination with another treatment for 
Cushing’s Disease and Acromegaly, as long as they continue to derive benefit as per 
Investigator assessment, the drug becomes commercially available in their country, or until one 
of the discontinuation criteria is met (please refer to Section 7.1.5). At every visit, the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment. A patient will reach the end of the roll-over study when 
pasireotide treatment is permanently discontinued. 
6.2 
Dose modification guidelines 
The starting dose of pasireotide alone or in combination with another treatment for Cushing’s 
Disease and Acromegaly, should be the same dose as that which the patient was receiving in 
the parent study at roll over. Changes to pasireotide, and any medication given in combination 
with pasireotide dose, will be based on the investigator’s judgment. 
Please refer to Appendix 2 through Appendix 12 (Section 14.2 through Section 14.12) for dose 
modification guidelines. 
6.2.1 
Starting dose rationale 
The starting dose of pasireotide alone or in combination with another treatment for Cushing’s 
Disease and Acromegaly, should be the same as that which the patient was receiving in the 
parent study at the roll over. 

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6.3 
Concomitant medications 
6.3.1 
Prohibited concomitant therapy 
The use of concomitant medication with known risk of Torsades de pointes (TdP) is prohibited. 
In case a patient needs to take a medication with known risk of TdP, it will require study drug 
discontinuation prior to starting the medication. Please see Appendix 1 for further guidance on 
QT prolonging medication. 
Medications with a potential risk of TdP should be avoided whenever possible. 
Refer to Appendix 1 for guidance regarding medications which pose a known risk for QT 
prolongation. 
6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is enrolled in the roll over study and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Recordati 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 through the Oracle Clinical Remote Data Capture 
interface. Additionally, an e-CRF will be completed that identifies the patient by gender and 
data of birth and previous study, site/center and subject number. 
6.4.2 
Treatment assignment or randomization 
Not applicable 
6.4.3 
Treatment blinding 
Not applicable 
6.5 
Study drug preparation and dispensation 
All dosage prescribed to the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record CRF. 
Investigator staff will identify the study treatment package(s) to dispense to the patient. 
Investigator staff will add the patient number on the label. For global supply the study 
medication packaging has a 2-part label. Immediately before dispensing the package, 
Investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique patient number. 
6.5.1 
Study treatment packaging and labeling  
Pasireotide for the roll-over study can be provided where appropriate as local commercial 
material or as global clinical study supply (Open label), packed and labeled under the 

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responsibility of the Sponsor’s Clinical Supply. Study treatment labels will be in the local 
language and comply with the legal requirements of each country. They will include storage 
conditions for the drug but no information about the patient. 
Combination treatments should be labeled and supplied in accordance with the parent protocol. 
When available, commercial treatment should be used as a first option. 
Table 6-2 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Pasireotide s.c. 
(0.3mg, 0.6mg and 
0.9mg) 
Solution for subcutaneous injection in ampoule 
Labeled as ‘SOM230’ (b.i.d. or t.i.d) 
Pasireotide LAR 
(10mg, 20mg, 
40mg and 60mg) 
Microparticle powder for suspension in vial 
Labeled as ‘SOM230 LAR’ (q28d) 
 
Solution for suspension (vehicle) in ampoule 
Labeled as ‘solvent’ (q28d) 
6.5.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, pasireotide alone or in combination with another 
treatment for Cushing’s Disease and Acromegaly, should be stored according to the instructions 
specified on the drug labels and in the [Investigator’s Brochure]. For patients receiving 
pasireotide s.c., a 3-month supply of pasireotide can be dispensed to the patient. Patients 
receiving pasireotide LAR, must return monthly to the participating site to receive their 
injections. During these visits, limited drug dispensing information will be collected and 
reported within the drug accountability log. 
Table 6-3 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
Pasireotide s.c. 
local commercial material or global clinical study 
supply (open label) supplied by Sponsor  
Refer to study treatment label 
Pasireotide LAR 
 
Combination 
treatments 
local commercial material or global clinical study 
supply (open label) supplied by Sponsor 
Should be supplied in accordance with the parent 
protocol. Where available, commercial treatment 
should be used as a first option. 
Refer to study treatment label 
 
Refer to study treatment label 
6.5.3 
Study drug compliance and accountability 
6.5.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 

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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 unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the IQVIA monitor or to the IQVIA 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 drug supply can only be destroyed once the study drug accountability check has been 
performed by the monitor. The study drug supply can be destroyed at the local Recordati 
facility, by Drug Supply group or by a third party, as appropriate. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
The table indicates which assessments produce data to be entered into the database (D) or 
remain in source documents only (S) (“Category” column). 

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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Reference 
Section 
Enrollment 
Visits during treatment phase 
End of study 
treatment 
(EoT) 
End of study 
/Safety 
Follow-up 
Visit Number 
 
 
1 
Visit 2,3,4 etc. 
777 
778 
Demographic: Patients’ previous study, site, 
subject number, study dose, formulation and 
frequency, study indication 
D 
7.1.2.3 
x 
 
 
 
Informed consent 
D 
5.2/5.3/11.3  
x 
 
 
 
Relevant medical history/current medical 
conditions 
D 
7.1.2.3  
x 
 
 
 
Inclusion/exclusion criteria 
D 
5.2/5.3  
x 
 
 
 
Pasireotide s.c. dispensing  (+combined therapy 
if applicable) 
D 
6.1  
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
Pasireotide LAR dose administration  
(+combined therapy if applicable) 
D 
6.1  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy Tests 
D 
7.1.4  
x 
Monthly (home) 
x 
x 
Investigator confirmation of continued clinical 
benefit from study treatment (at every visit) 
D 
6.1.5 
x 
Visit 2,3,4 etc. 
 
 
Serious adverse events (in safety database only) 
D 
8.2  
Continuous 
x 
AEs 
D 
8.1  
Continuous 
x 
End of treatment 
D 
7.1.5  
x 
 
x 
 
End of study 
D 
7.1.5  
 
 
 
x 

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7.1.1 
Molecular pre-screening 
Not applicable. 
7.1.2 
Screening 
There will be no screening period for this study. At the enrollment visit, the patient will need to 
complete a written informed consent. Once consented, patients will be evaluated for eligibility 
via the inclusion and exclusion criteria. 
7.1.2.1 
Eligibility screening 
Not applicable. 
7.1.2.2 
Information to be collected on screening failures 
Not applicable. 
7.1.2.3 
Patient demographics and other baseline characteristics 
For patients who are eligible to participate in this roll over study, an e-CRF will be completed 
that identifies the patients’ gender, data of birth and previous study, site /center and subject 
number. Study dose, formulation and frequency, study indication and relevant medical history 
will also be collected. 
7.1.3 
Treatment period 
The starting dose of pasireotide, and any medication given in combination with pasireotide,  
should be the same dose as that which the patient was receiving in the parent study at roll over.  
Those patients receiving pasireotide LAR must return to the study center monthly (+/- 7 days) 
to receive study medication.  Drug dispensing information will be collected and adverse events 
and clinical benefit will be assessed. Patients receiving pasireotide s.c. must return to the study 
center on a quarterly basis (every 12 weeks +/- 2 weeks) for resupply of study medication.  Drug 
dispensing information will be collected and adverse events and clinical benefit will be 
assessed.  The patient may return to the clinic at any given time as per standard of care or 
treating physician recommendation; however, only the quarterly study visits will be recorded.  
The study is expected to remain open for approximately 10 years from FPFV (or until 10-Jun-
2023 in the UK) or when all patients on this study have permanently discontinued pasireotide 
treatment or have been able to obtain commercial supply according to local regulations or have 
been able to receive the drug through country-specific programmes outside of this clinical trial 
(applicable to Brazil, France, Germany, India, Italy, Malaysia, Mexico, Peru and Thailand)  and 
the end of treatment visit and all safety follow-up procedures have been performed for each 
patient, whichever comes first.  At every visit, the investigator is required to confirm that the 
patient continues to have clinical benefit and may continue receiving study treatment. 

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7.1.4 
Pregnancy and assessment of fertility 
Since highly effective contraception is required during the study, female patients of child 
bearing potential are required to test negative for a pregnancy (either with serum testing if 
routinely/locally available or urine pregnancy test) before enrolling into the study. 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during the study and 
for 30 days after the final dose of pasireotide s.c. and 84 days after the final dose of pasireotide 
LAR. 
Highly effective contraception is defined as either: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to enrolling). For female patients on the study the 
vasectomized male partner should be the sole partner for that patient. 
• Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
If patient has tested negative at the end of study on the parent study, no pregnancy testing is 
required if enrollment into this study is carried out on the same day or within a maximum of 5 
days from each other. 
Female patients of child bearing potential are required to perform monthly home urine 
pregnancy tests and complete a simple diary with the dates and the outcome of the home urinary 
test while on study treatment and during safety follow-up (30 days after the final dose of 
pasireotide s.c. and 84 days after the final dose of pasireotide LAR). 
A pregnancy test (either with serum testing if routinely/locally available or urine pregnancy 
test) on female patients of child bearing potential is required at the final study visit. 
Any positive results will be recorded in the database and followed up as per Section 8.4. 
7.1.5 
Discontinuation of study treatment 
Patient may voluntarily discontinue from the study treatment for any reason at any time.  If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages.  
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reasons.   

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At the time the patient discontinues study treatment, a visit should be scheduled as soon as 
possible, at which time the assessments listed for the End of Treatment (EOT) visit will be 
performed. End of Treatment information will be completed in the eCRF giving the date and 
reason for stopping the study treatment (see Section 7.1.5.1). 
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 1 month following last dose of 
the s.c. dose or 3 months for patients receiving LAR, following last dose. The completion of 
the Study Evaluation Completion CRF page will be required any time a patient discontinues 
from the study and must be completed 30 days after the end of treatment. 
7.1.5.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following 
occur: 
• Death. 
• Lost to follow-up. 
• Staying in the study would be harmful. 
• Patient/guardian decision. 
• Physician decision. 
• Non-compliance to protocol requirements. 
• Protocol deviation. 
• Pregnancy. 
• Study terminated by sponsor. 
• Study treatment has become available through country-specific programmes outside of this 
clinical trial (applicable to Brazil, France, Germany, India, Italy, Malaysia, Mexico, Peru 
and Thailand). 
Study treatment has become commercially available and reimbursed (when current treatment 
becomes commercially available and reimbursed in that indication, the patient will have to be 
withdrawn from the study and will have completed the study as per protocol).   
In addition to the general withdrawal criteria, the following criteria may also require study 
treatment discontinuation: 
If any of the criteria below are met during routine examinations that are part of standard of care, 
study medication should be discontinued immediately. Re-challenge of study medication is 
prohibited once discontinuation criteria are met. 
Hepatic-related discontinuation criteria 
• Jaundice or other signs of clinically significant liver dysfunction 
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN 
• ALT or AST > 5 x ULN and ≤ 8 x ULN persistent for more than 2 weeks 
• ALT or AST > 8 x ULN 
QT related discontinuation criteria 

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• Confirmed QTcF >500 ms and discontinuation recommended 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: 
1. Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms of 
hemodynamic compromise. 
2. Sustained ventricular tachycardia (>30 s) irrespective of symptoms. 
3. Recurrent non-sustained VT (≥ 3 beats) during any 24-hour monitoring period. 
4. Clinically significant brady-arrhythmia or third degree AV block. 
5. Need to use a drug with known risk of TdP. 
Hyperglycemia related discontinuation criteria 
• Uncontrolled diabetes mellitus (DM), consistently high glucose values FPG ≥ 240 
mg/dL (13.3 mmol/L) or HbA1c value ≥ 10 % despite appropriate management of 
diabetes including diet and/or exercise with or without optimal anti-diabetic therapy 
7.1.5.2 
Replacement policy 
Not applicable. 
7.1.6 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact. 
Recordati will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations 84 days after the last dose of study treatment for the 
LAR and 1 month (30 days) after s.c. dose. 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 

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Data collected should be added to the Adverse Events eCRF. 
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Not applicable. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by collecting adverse events/serious adverse events at every visit. For 
details on AE/SAE collection and reporting, refer to Section 8. 
In addition, the following applies for safety monitoring: 
• For locally approved indications, the safety monitoring guidance in the locally approved 
prescribing information applies 
• For indications that are not yet approved locally, the safety monitoring requirements 
described in Section 7.2 of the current Investigator Brochure must be followed 
 
Patients may have safety assessments performed by the clinics local laboratory as per 
investigators judgement and standard of care at any time during the study period. 
7.2.2.1 
Hepatic related findings 
For any hepatic related findings during routine follow up, refer to Appendix 2. 
7.2.2.2 
QT-related finding 
For any QT-related finding during routine follow up, refer to Appendix 3. 
7.2.2.3 
Hyperglycemia related findings 
For any hyperglycemia related finding during routine follow up, refer to Appendix 4. 
7.2.2.4 
Additional bio-marker assessments 
Not applicable. 
7.2.3 
Resource utilization 
Not applicable. 

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7.2.4 
Patient reported outcomes 
Not applicable. 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Any ongoing adverse events from the parent study will be captured as medical history in the 
roll-over database. Any AE that begins (or worsens) after signing of the informed consent for 
the roll-over and during the 30-day (or 28-day) or 84-day (12 week) safety follow up period 
defined in the parent protocol should be reported in both clinical databases. 
Adverse event monitoring should be continued for at least 30 days for patients receiving the s.c. 
formulation and 84 days for those receiving the LAR formulation (or 5 half-lives), whichever 
is longer) 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 current version of Common Terminology 
Criteria for Adverse Events (CTCAE). 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through the EOT 
eCRF page. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (start and end dates) 
3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes) 

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4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
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. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol 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 (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days for patients on the s.c 
formulation and 84 days for patients on the LAR formulation after the patient has stopped study 
treatment must be reported to IQVIA Safety office within 24 hours of learning of its occurrence. 
IQVIA, in its turn, will promptly inform Recordati. 
 
Any SAE that begins or worsens after signing of the informed consent for the roll-over and 
during the safety follow up period defined in the parent protocol should be reported as an 
adverse event in both clinical databases; however, only one SAE report will be sent to IQVIA. 

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• Any SAE that begins or worsens during the safety follow-up period specified in the parent 
study should have an SAE report submitted to IQVIA with the parent protocol study 
number. 
• Any SAE that begins or worsens after the safety follow-up period specified in the parent 
study should have an SAE report submitted to IQVIA with the roll-over protocol study 
number. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes 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. 
The date of the informed consent signed for this roll-over study (the roll-over date) is important 
to determine how SAEs should be reported: 
• Any SAEs occurred prior to that date should be reported for the parent protocol, including 
all the follow up information relevant to such SAEs. 
• New SAEs with an onset date after the roll-over date will be reported for this protocol. 
It is important to use the right SAE form with the correct protocol number for these two 
scenarios, to avoid confusion in SAE processing. For a patient already on the roll-over protocol 
but follow up information is reported for the previous SAEs in the parent protocol, it must be 
clearly labeled that this is for the parent protocol number. 
Any SAEs experienced after the 30 day/84 day safety evaluation follow-up period (or 5 half-
lives, if half-life is established, whichever is longer) should only be reported to IQVIA if the 
investigator suspects a causal relationship to the study treatment. 
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 submit the completed form within 24 hours to IQVIA. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Reference Safety Information section of the 
Investigator’s Brochure or Package Insert (new occurrence) and is thought to be related to the 
Recordati study treatment, IQVIA (on behalf of Recordati) may urgently require further 
information from the investigator for Health Authority reporting. Recordati 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 

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committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. Recordati 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. This is an open-label study. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to IQVIA within 24 hours of learning of its occurrence. IQVIA, in its turn, will 
promptly inform Recordati. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to IQVIA. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study treatment any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
The protocol must specify how long the newborn will be followed up (just birth, or xyz months). 
Further advice on the length of post-natal follow up can be sought from Recordati and should 
be driven by the type of congenital abnormality expected. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
8.5 
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 pasireotide 
[Investigator Brochure]. For all other combination treatments, please refer to the relevant 
prescribing brochure for warnings and precautions.  Additional safety information collected 
between [Investigator Brochure] updates will be communicated in the form of INs. 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 
Not applicable. 
8.7 
Steering Committee 
Not applicable. 

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9 
Data collection and management 
9.1 
Data confidentiality 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
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 patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Recordati 
personnel (or designated CRO, IQVIA) will review the protocol and eCRFs with the 
investigators and their staff. During the study, the field monitor will visit the site regularly to 
check the completeness of patient records, the accuracy of entries on the eCRFs, the adherence 
to the protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 

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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. IQVIA monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the eCRFs are performed 
according to the study-specific monitoring plan. 
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 eCRFs is 
complete, accurate, and that entry and updates are performed in a timely manner. 
9.4 
Database management and quality control 
For studies using eCRFs, Recordati personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint written 
agreement between the Global Head of Biostatistics and Data Management and the Global Head 
of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
10.1 
Analysis sets 
The following analysis sets will be used for statistical analysis and data reporting. 
10.1.1 
Full Analysis Set 
Not applicable. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication after 
enrolling into the roll-over protocol. 

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10.1.3 
Dose-determining analysis set 
Not applicable. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data characteristics will be summarized descriptively for the 
Safety Set. 
10.3 
Treatments (study treatment, compliance) 
Dose administration data will be summarized using the Safety Set. 
10.4 
Primary objective 
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs. 
10.4.1 
Variable 
See Section 10.5.3. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis will be tested. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Not applicable. 
10.4.4 
Supportive analyses 
No supportive analysis will be performed. 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
Not applicable. 
10.5.2 
Other secondary efficacy objectives 
The secondary objective of the study is to evaluate clinical benefit as assessed by the 
investigator. Proportion of patients with clinical benefit as assessed by the investigator will be 
summarized at scheduled visits. 
10.5.3 
Safety objectives 
The assessment of safety will be based mainly on the frequency and severity of AEs, AESI and 
SAEs. 
10.5.3.1 Analysis set and grouping for the analyses 
The overall observation period will be divided into two mutually exclusive segments: 

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1. on-treatment period: from day of first dose of study medication in the roll-over study to 3 
months (day 84) following the last dose of pasireotide LAR treatment and to 1 month (day 
30) following the last dose of pasireotide s.c. treatment.  
2. post-treatment period: starting at 3 months+1 day (day 85) following the last dose of 
pasireotide LAR treatment and at 1 month+1 day (day 31) following the last dose of 
pasireotide s.c. treatment. 
10.5.3.2 Adverse events (AEs) 
Summary tables of 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 post-treatment periods) will be listed and those collected during the 
post treatment period are to be flagged. 
The incidence of treatment emergent adverse events will be summarized by system organ class 
and/or preferred term, severity (based on CTCAE grades), type of adverse event, relation to 
study treatment. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event. 
10.5.3.3 Other safety data 
Not applicable. 
10.5.3.4 Tolerability 
Not applicable. 
10.6 
Interim analysis 
This study has also been categorized as voluntary European Post Authorization Safety Study 
(PASS). Therefore, regular interim analyses will be performed during the course of the study 
as need by the Sponsor and will occur every 2 years beginning in 2017 and continuing until the 
study end. Details will be specified in the statistical analysis plan. The final analysis will occur 
when all patients complete the study. 
10.7 
Sample size calculation 
Not applicable. 
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 

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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 IQVIA monitors, auditors, 
Recordati Clinical Quality Assurance representatives, designated agents of Recordati, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their CRFs. 
IQVIA (on behalf of Recordati) 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 Recordati before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to the IQVIA 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. 
Male participant will be asked to provide, the Female Partner of Male Participant form, to their 
partners.   
Additional consent form 
Not applicable. 
11.4 
Discontinuation of the study 
Recordati reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. 

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11.5 
Publication of study protocol and results 
Recordati assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Recordati-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, patients’ 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 patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 

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11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Recordati. 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 Recordati or designee or Health 
Authorities. 
Recordati will delegate some trial-related activities to the CRO IQVIA. IQVIA has in place its 
own Quality Management System to ensure compliance with written Standard Operating 
Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Recordati will maintain the oversight of any trial-related duties, functions and delegated 
activities that will be subcontracted to IQVIA. 
 
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 Recordati 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 Recordati  
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 Recordati, 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, Recordati 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) 
Andersen JR, Holtug K, Uhrenholt A (1989) Trial of pectin-enriched muffins in patients with 
severe dumping syndrome after gastric resection: observations on symptoms and gastric 
emptying pattern. Acta Chir. Scand; 155:39-41. 
Arnold R, Rinke A, Klose KJ, et al (2005) Octreotide versus octreotide plus interferon-alpha 
in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol; 
3(8):761-71. 
Arts J, et al (2009) Efficacy of the long-acting repeatable formulation of the somatostatin 
analog octreotide in postoperative dumping. Clin. Gastroenterol. Hepatol; 7(4):432-7. 
Assie G, Bahurel H, Coste J, et al (2007) Corticotroph tumor progression after adrenalectomy 
in Cushing’s. J Clin Endocrinol Metab; 92(1):172-79. 
Aussie G, Bahurel H, Bertherat J, Kujas M, Legmann P and Bertagna X (2004) The Nelson’s 
syndrome…revisited. Pituitary; 7(4):209-15. 
Becker KL, et al (2000) Principles and practice of endocrinology and metabolism: Growth 
hormone and its disorders; 129-45. 
Biller BMK, Grossman AB, Stewart PM, et al (2008) Treatment of Adrenocorticotropin-
Dependent Cushing’s Syndrome: A Consensus Statement. J Clin Endocrinol Metab; 
93(7):2454–62. 
Chisholm C, Greenberg G (2002) Somatostatin-28 regulates GLP-1 secretion via somatostatin 
receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab; 283(2):E311-17. 
Ekeblad S, Sundin A, Tiensuu Janson E, et al (2007) Temozolomide as Monotherapy Is 
Effective in Treatment of Advanced Malignant Neuroendocrine Tumors. Clin Cancer Res; 
13(10):2986-91. 
Falconi M, Plockinger U, Kwekkeboom DJ, et al (2006) Well-differentiated pancreatic 
nonfunctioning tumors/carcinoma. Neuroendocrinology; 84(3):196-211. 
Freda P (2002) Somatostatin Analogs in Acromegaly. Journal of Clinical Endocrinology & 
Metabolism; 87(7):3013-18. 
Geer RJ, et al (1990) Efficacy of octreotide acetate in treatment of severe postgastrectomy 
dumping syndrome. Ann. Surg; 212(6):678-87. 
Giustina A, Barkan A, Casanueva FF, et al (2000) Criteria for cure of acromegaly: a 
consensus statement. Journal of Clinical Endocrinology and Metabolism; 85(2):526-29. 
Gray JL, Debas HT, Mulvihill SJ (1991) Control of dumping symptoms by somatostatin 
analog in patients after gastric surgery. Arch. Surg; 126(10):1231-35. 
Harju E, Larmi TK (1983) Efficacy of guar gum in preventing the dumping syndrome. J 
Parenter Enteral Nutr; 7(5):470–2. 
Hasler WL, Soudah HC, Owyang C (1996) Mechanisms by which octreotide ameliorates 
symptoms in the dumping syndrome. J. Pharmacol. Exp. Ther; 277(3):1359-65. 
Hopman W, Wolberink R, Lamers C, et al (1988) Treatment of the dumping syndrome with 
the somatostatin analog SMS201-995. Ann.Surg; 207(2): 155-59. 

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Kloppel G, Perren A, Heitz PU (2004) The Gastroenteropancreatic Neuroendocrine Cell 
System and Its Tumors: The WHO Classification. Ann. N.Y. Acad. Sci; 1014:13-27. 
Lyons TJ, McLoughlin JC, Shaw C, et al (1985) Effect of acarbose on biochemical responses 
and clinical symptoms in dumping syndrome. Digestion; 31(2-3):89-96. 
Melmed S, Jackson I, Kleinberg D, et al (1998) Current Treatment Guidelines for 
Acromegaly. Journal of Clinical Endocrinology and Metabolism; 83(8):2646-52. 
Miller JW, Crapo L (1993) The medical treatment of Cushing’s syndrome. Endocr Rev; 
14(4): 443-58. 
Modlin IM, Oberg K, Chung DC, et al (2008b) Gastroenteropancreatic neuroendocrine 
tumours. Lancet Oncol; 9(1):61-72. 
Nieman LK (2002) Medical therapy of Cushing’s disease. Pituitary; 5(2):77-82. 
Oberg K, et al (2004) Consensus report on the use of somatostatin analogs for the 
management of neuroendocrine tumors of the gastroenteropancreatic system. Annals of 
Oncology; 15(6):966-73. 
Plöckinger U, Wiedenmann B (2007) Treatment of gastroenteropancreatic neuroendocrine 
tumors. Virchows Arch; 451(Suppl 1):S71-80. 
Primrose JN, Johnston D (1989) Somatostatin analog SMS 201-995 (octreotide) as a possible 
solution to the dumping syndrome after gastrectomy or vagotomy. Br. J. Surg; 76(2): 140-44. 
Richards WO, Geer R, O'Dorisio TM, et al (1990) Octreotide acetate induces fasting small 
bowel motility in patients with dumping syndrome. J. Surg. Res; 49(6):483-487. 
Rinke A, Muller H-H, Schade-Brittinger C, et al (2009) Placebo-controlled, double-blind, 
prospective, randomized study of the effect of Octreotide LAR in the control of tumor growth 
in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study 
group. J Clin Oncol; 27(28):4656-63. 
Schmid HA, Schoeffter P (2004) Functional activity of the multiligand analog SOM230 at 
human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine 
tumors. Neuroendocrinology; 80(Suppl 1): 47-50. 
Schurr PG, Strate T, Rese K, et al (2007) Aggressive Surgery Improves Long-term Survival in 
Neuroendocrine Pancreatic Tumors. Ann Surg; 245(2):273-81. 
Sonino N, Zielezny M, Fava GA, et al (1996) Risk factors and long-term outcome in pituitary-
dependent Cushing’s disease: a single centre audit. J Clin Endocrinol Metab; 81(7):2647-52. 
Tack J, Arts J, Caenepeel P, et al (2009) Pathophysiology, Diagnosis and Management of 
Postoperative Dumping Syndrome Nature Reviews Gastroenterology & Hepatology. Nat Rev 
Gastroenterol Hepatol; 6(10):583-90. 
Toumpanakis C, Meyer T, Caplin ME (2007) Cytotoxic treatment including 
embolization/chemoembolization for neuroendocrine tumours. Best Practice Research 
Clinical Endocrinology Metabolism; 21(1):131-44. 
Tulassay Z, Tulassay T, Gupta R, et al (1989) Long acting somatostatin analog in dumping 
syndrome. Br. J. Surg; 76(12):1294-1295. 

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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 coritcotroph tumor 
cells. Am J Phsyiol Endocrinol Metab; 289(2):E278-87. 
Yao JC, Phan AT, Chang DZ, et al (2008) Efficacy of RAD001 (everolimus) and octreotide 
LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II 
study. J Clin Oncol; 10(26):4311-8. 

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14 
Appendices 
14.1 
Appendix 1: Medications known to be associated with QT 
interval prolongation 
The list of drugs is generally recognized to have a possible association with QT prolongation 
can be found at //crediblemeds.org. This list is not considered to be all inclusive and any 
questions regarding the QT prolongation potential should be discussed with the Recordati 
Medical Monitor.  

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14.2 
Appendix 2: Recommended hepatic safety management 
guidance 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
If any of the criteria below are observed at any routine examinations (standard of care), 
• 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, patient should be discontinued. 
The following should be performed immediately within 72 hours of awareness of the 
abnormality (for further details refer to Figure 14-1): 
• Perform liver-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including OTC meds, inter-current illness, etc). 
• Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if 
total bilirubin is > 2.0 x ULN), Alb, PT (INR), ALP, and GGT. 
• Perform hepatitis screen: anti-HAV, IgM (to confirm acute Hepatitis A), HbsAg, Anti-
HBc, anti-HCV (if positive, PCR viral load should be assessed), Anti-HEV, ANA 
antibodies, anti-smooth muscle anti-bodies, CMV and EBV. 
• Perform abdominal ultrasound (liver and biliary tree). 
Liver chemistry tests (LFTs) should be monitored every 3-4 days until resolution or return to 
baseline status. 
Patients or subjects may need to be discontinued if the abnormal liver function criteria are met 
upon LFT retesting. Progress reports of the event should be maintained until resolution or 
stabilization (i.e. no further elevation after 2 consecutive assessments). 
For ALT or AST > 5 x ULN and ≤ 8 x ULN, the following must occur (in addition to the safety 
follow up procedures noted above). 
• Study medication should be temporarily interrupted and liver chemistry tests monitored 
every 3-4 days until resolution or return to baseline. 
• If resolution (ALT and AST ≤ 5 ULN) or return to baseline does not occur after 2 weeks, 
the patient should be discontinued. 
• If ALT or AST return to less than 5 x ULN study drug can be resumed and patient can 
continue study per protocol. 
• If ALT or AST rises above 5 x ULN any time after study drug is resumed, then study drug 
should be discontinued immediately. 
If any of these criteria are met and deemed an adverse event by the investigator, the event must 
be recorded on the Adverse Event (e) CRF page; if the event is deemed serious by the 
investigator, then proceed with completing the SAE form. In addition, any significant findings 
from the physical examination should be recorded on the Adverse Event (e) CRF page. 

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Figure 14-1 
Recommended LFT management guidance 
 

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14.3 
Appendix 3: Recommended guidance for follow up in case of QT-
related findings during routine ECG 
If at any routine ECG a QTcF> 500msec is observed, triplicate ECGs, each 2-3 minutes apart, 
need to be collected approximately 1 hour after the initial ECG. The mean QTcF from the 
triplicate ECGs will be determined and if the mean QTcF > 500msec, study treatment should 
be interrupted until a cardiologist has re-evaluated the ECG. Patient reassessment should be 
performed as early as possible but within 7 days of the initial abnormal ECG by a cardiologist 
for cardiovascular risk factors and a decision regarding study continuation. 
If mean QTcF >480msec / ≤ 500msec is observed, the repeat ECG assessment must be 
performed as soon as practical but within 7 days of the initial abnormal ECG. In addition, the 
following steps need to be taken (for more details refer to Figure 14-2 below): 
• If a QTcF >480msec / ≤ 500 msec is confirmed and QTcF change from pretreatment 
exceeds 60 msec, cardiology consultation must be sought as soon as practical (within 7 
days) for ECG re-evaluation and clinical assessment for cardiovascular risk factors and a 
decision regarding study continuation. 
• If a QTcF > 480msec / ≤ 500msec is confirmed and QTcF change from pretreatment < 60 
ms, more frequent ECG follow-up is advised. 

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Figure 14-2 
Recommended guidance for ECG follow up 
 

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14.4 
Appendix 4: Recomended guidance for fasting blood glucose 
management 
Hyperglycemia 
Two clinical studies ([SOM230B2216] and [SOM230B2124]) have been conducted 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 indicate that pasireotide decreases insulin, 
GLP-1 and GIP secretion, particularly in the postprandial period. Results from SOM230B2124 
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. In phase II and III 
studies, some patients with Cushing’s disease, acromegaly or neuroendocrine tumor required 
insulin to treat hyperglycemia. 
Glucose monitoring 
All patients need to be educated on the signs and symptoms of hyperglycemia. Patients must 
monitor their fasting blood glucose by fingerstick at home. It is recommended that a diary of 
the blood glucose values is used for appropriate management throughout the study. The 
collected data should be presented to the physician/diabetes specialist for evaluation. This data 
will not be collected by the sponsor. 
Blood glucose monitoring 
Close and frequent glucose monitoring is recommended during pasireotide treatment. 
• If any fasting values above 100 mg/dL are observed, the guidelines in Figure 14-3 are to 
be followed. These guidelines are based on the current recommendations from the 2012 
ADA and EASD aiming at a glycemic treatment goal of FPG <130 mg/dL (<7.2 mmol/L) 
(Inzucchi, SE et al. DiabetesCare June 2012 vol. 35 no. 6 1364-1379). 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 14-3. 
• If fasting blood glucose values dictate initiation of anti-hyperglycemic treatment (i.e., 
confirmed >130 mg/dL by self-monitoring), a fasting plasma glucose sample can be 
collected prior to initiation of anti-hyperglycemic treatment. 
• In case of dose increase, the glucose monitoring frequency should be increased following 
the recommendations described above at treatment initiation 
FPG and HbA1c monitoring 
• If FPG > 130 mg/dL or HbA1c ≥ 6.5 %, intervention for hyperglycemia needs to be 
implemented 
• If FPG > 160 mg/dL or HbA1c >7.5%, despite optimal anti-diabetic therapy, referral to a 
diabetologist is recommended. 
• If grade 3 hyperglycemia (FPG >250 mg/dL; >13.9 mmol/L) at any point in the study, 
despite appropriate anti-diabetic medication, pasireotide dose should be reduced 
• If consistently high glucose values [FPG ≥ 240 mg/dL (13.3 mmol/L) or HbA1c ≥ 10 %] 
despite appropriate management of diabetes including diet and/or exercise with or without 

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optimal anti-diabetic therapy and study drug dose reduction, patient must be discontinued 
from study treatment as outlined in Section 7.1.5.1. After the last study dose was received, 
patients have to monitor their fasting blood glucose for 1 month 
Figure 14-3 
Recommended guidance for fasting self-monitoring blood glucose 
management 
 

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14.5 
Appendix 5: Dose modification information for acromegaly or 
carcinoid patients receiving pasireotide LAR (from protocol 
CSOM230C2110, CSOM230C2305, CSOM230C2402 and 
CSOM230C2413) 
At any time during the roll-over, the pasireotide LAR dose may be increased up to a maximum 
dose of 60 mg per injection if biochemical control is not achieved, i.e. when their GH level ≥ 
2.5μg/L and/or IGF-1> ULN (age and sex related). Also the pasireotide LAR dose may be 
reduced if a patient is experiencing a drug related toxicity. The dose should be adjusted in 20 
mg steps, e.g. the pasireotide LAR dose can be adjusted from 60 mg to 40 mg or from 40 mg to 
20 mg. The decision to change the dose is to be made by the investigator or designee, and the 
dose change must be recorded in the Dosage Administration Record CRF. Patients should return 
to the previous dose once the tolerability issue resolves. 
Study C2413 specific: The minimum dose to be administered is 10 mg for patients with IGF-1 
levels falling below the lower limit of normal and have controlled mean GH levels. The IGF-1 
values are required to be confirmed to be below LLN on two consecutive assessments. 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. The 10 mg dose should 
be obtained from the 20 mg vial. 
Table 14-1 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study 
drug related 
Reduce pasireotide to the next lower dose level. 
• 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. 
• 
If the dose is increased and the AE recurs at a grade ≥ 3, the dose 
should be reduced again. The patient should stay on this lower dose and 
no further dose titrations are allowed. 
• 
If the AE does not improve to grade ≤ 2, the dose is to be reduced 
further. If the AE does not improve to grade ≤ 2 on the minimum study 
dose, the treatment should be stopped. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in 
, 
 and 
. 
Table 14-2 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2110 
Dose (mg) 
Volume to be injected 
20 mg 
2 x 10 mg vial + 2 mL vehicle: whole volume to be injected or 1 x 20 mg vial + 2 mL 
vehicle: whole volume to be injected 
40 mg 
1 x 40 mg vial + 2 mL vehicle: whole volume to be injected 
60mg 
2 x 10 mg vial + 1 x 40 mg vial + 2 mL vehicle; whole volume to be injected or 1 x 20 mg 
vial + 1 x 40 mg vial + 2 mL vehicle; whole volume to be injected 

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Table 14-3 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2305 
Dose (mg) 
Volume to be injected 
20 mg 
1 x 20mg vial + 2 mL vehicle, whole volume to be injected 
40 mg 
1 x 40mg vial + 2 mL vehicle, whole volume to be injected 
60 mg 
1 x 20mg + 1 x 40mg vial + 2 mL vehicle, whole volume to be injected 
Table 14-4 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2402 
Dose (mg) 
Volume to be injected 
40 mg 
1 x 20 mg vial + 1 x 20 mg vial + 2 mL vehicle, whole volume to be injected 
60 mg 
1 x 20 mg + 1 x 40 mg vial + 2 mL vehicle, whole volume to be injected 

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14.6 
Appendix 6: Dose modification information for Cushing’s 
patients receiving pasireotide LAR (from protocol 
SOM230G2304) 
Dose up-titration 
Patients will receive the same dose of pasireotide LAR as the last dose in the parent study. The 
maximum dose to be administered is 40 mg. Dose can be increased from 10 to 30 mg and from 
30 to 40 mg. During the roll-over study, the timing of the dose adjustments will be based on 
mUFC values, at the investigators discretion but must include a duration of at least 3 months 
on a current dose prior to up-titration and no tolerability issues are present. Patients receiving 
the 40 mg dose after Month 12 without tolerability issues that require a dose reduction will 
remain at this dose regardless of mUFC status (≤ 1x ULN or > 1 xULN). 
Dose down-titration 
Patients with tolerability issues can have their dose decreased as deemed necessary by the 
investigator (see Table 14-5). The dose can be increased again after the tolerability issue 
resolves. Patients unable to tolerate a minimum dose of 5 mg will be discontinued. 
These changes must be recorded on the Dosage Administration Record CRF. 
Table 14-5 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
AE CTC grade ≤ 2 
No drug adjustments 
AE CTC grade ≥ 3 and 
assessed as study drug 
related 
Reduce pasireotide LAR i.m. dose from: 
 
40mg to 30 mg 
 
30 mg to 10 mg 
 
10 mg to 5mg 
 
5mg - discontinue 
If AE improves to grade ≤ 2 before the next administration, increase dose 
to that prior to the dose reduction unless investigator opinion is to remain 
on current dose. If the dose is increased and the AE recurs at CTC grade 
≥ 3, the dose should be reduced again and the patient should stay on this 
lower dose and no further dose titrations are allowed. 
During the first 7 months of treatment, only 1 blinded dose decrease is 
allowed. If the AE persists at grade ≥ 3 after reduction, the patient is to be 
discontinued. 
After the first 7 months, If AE does not improve to grade ≤ 2 the dose is to 
be reduced further until the 5 mg dose is reached. If the AE does not 
improve to grade ≤ 2 on the minimum dose (5 mg) the patient will be 
withdrawn. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in 
, 
 and 
. 

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14.7 
Appendix 7: Dose modification information for dumping 
syndrome patients receiving pasireotide s.c or LAR (from 
protocol SOM230X2203) 
During the roll-over, dose increase will be allowed up to 60 mg (30, 40 and 60 mg) in the event 
that control is lost (glucose levels < 60 mg/dL at 90,120, 150 or 180 min during the OGTT or 
presence of symptoms). The up- titration must be in increments of 10 mg with the exception of 
patients receiving 40 mg when an increment of 20 mg (from 40 mg to 60 mg) is allowed. 
In case a dose reduction is needed due to toxicity (Table 14-8), the dose can be reduced to the 
immediate lower dose level (Table 14-7) and can be kept at this level if necessary. The lowest 
dose level allowed is 10 mg. In case a dose reduction is needed due to toxicity at 10mg, the 
patient can have a dose interruption up to 28 days from the intended day of the scheduled dose 
or can be discontinued and followed up for toxicity as defined in Table 14-6. If a patient requires 
a dose interruption of more than 28 days due to toxicity, then the patient must be discontinued 
from the study and followed up for toxicity Table 14-6. When treatment is interrupted or 
permanently discontinued due to an AE or abnormal laboratory value the patient must be 
followed at least once a week for 4 weeks, and subsequently in 4-week intervals, until resolution 
or stabilization of the event, whichever occurs first. 
Patients will be followed for adverse events and serious adverse events for 56 days following 
the last dose of pasireotide LAR treatment and for 28 days in case of discontinuation during 
pasireotide s.c. treatment. 
Table 14-6 outlines the follow-up required for toxicities of specific types and CTCAE grades- 

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Table 14-6 
Follow up evaluation (after treatment interruption) 
Toxicity 
Follow-up evaluation (after treatment interruption) 
Hematology 
If ≥ CTCAE grade 3 neutropenia or ≥ CTCAE grade 3 thrombocytopenia has been 
demonstrated, these parameters must be assessed at least twice a week until 
resolution to ≤ CTCAE grade 1 and then at least weekly until stabilization. 
Renal 
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be 
assessed at least twice a week until resolution to ≤ CTCAE grade 1 or baseline to and 
then at least weekly until stabilization. 
Hepatic 
For details on hepatic safety management, please refer to Appendix 2: Hepatic Safety 
Management 
Pancreatic 
If amylase and/or lipase ≥ CTCAE grade 3 has been demonstrated, these parameters 
must be assessed once at 2-4 days and once again at 7 days (± 1 day) and be 
repeated twice a week until resolution to ≤ CTCAE grade 2 and then at least weekly 
until stabilization. 
A CT scan or other imaging study to assess the pancreas, liver and gallbladder must 
be performed within 1 week of the first occurrence of any ≥ CTCAE grade 3 of 
amylase and/or lipase. 
In patients with serum triglycerides ≥ 500 mg/dL, urine amylase needs to be tested. 
Endocrine/ 
metabolic 
For details on hyperglycemia management, please refer to Appendix 4: ‘Fasting blood 
glucose management’. 
Cardiac 
For details on the follow-up and treatment of QT prolongation, please refer to 
Appendix 3 ‘Recommended follow up in case of QT-related findings during routine 
ECG’ 
Non-
laboratory 
Patients who experience non-laboratory AEs must be evaluated at least once a week 
following demonstration of the toxicity until resolution of the toxicity until stabilization 
of the toxicity, or until study completion. 
Table 14-7 
Dose reduction steps for pasireotide LAR monthly dosing q28d 
Dose reduction* 
 
Dose level - 0 
Dose level - 1 
Study Phase 
Pasireotide LAR 
60 mg q28d 
40 mg q28d 
Extension phase 
Pasireotide LAR 
40 mg q28d 
30 mg q28d 
Extension phase 
Pasireotide LAR 
30 mg q28d 
20 mg q28d 
Extension phase 
Pasireotide LAR 
20 mg q28d 
10 mg q28d *** 
LAR or Extension phases 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
*** The lowest dose allowed 10 mg. 

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Table 14-8 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study 
drug related 
Reduce pasireotide to the next lower dose level. 
• 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. 
• 
If the dose is increased and the AE recurs at a grade ≥ 3, the dose 
should be reduced again. The patient should stay on this lower dose and 
no further dose titrations are allowed. 
• 
If the AE does not improve to grade ≤ 2, the dose is to be reduced 
further. If the AE does not improve to grade ≤ 2 on the minimum study 
dose, the treatment should be stopped. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. 

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14.8 
Appendix 8: Dose modification information for patients with 
metastatic melanoma or metastatic Merkel cell carcinoma 
receiving pasireotide s.c (from protocol SOM230X2404) 
Patients will continue receiving the dose of pasiroetide LAR q28 d at the same dose received 
during the follow-up period (20, 40, 60 or 80 mg). 
In case a dose reduction is needed due to toxicity, the dose can be reduced to the immediate 
lower dose level (from 80 mg q 28 d to 60 mg q 28 d, from 60 mg q 28 d to 40 mg q 28 d, and 
from 40 mg q 28 d to 20 mg q 28 d) and can be kept at this level if necessary for the duration 
of the study or until disease progression or death. However, the dose will not be re-escalated 
once reduced. In case patients receiving 20 mg q 28 d need to reduce the dose further, they 
should be discontinued from the study. If a patient requires a dose interruption of > 7 
consecutive days from the intended day of the scheduled dose, then the patient must be 
discontinued from the study and only follow up for toxicity defined in (reference table below). 
When treatment is interrupted or permanently discontinued due to an AE or abnormal laboratory 
value the patient must be followed at least once a week for 4 weeks, and subsequently in 4-
week intervals, until resolution or stabilization of the event, whichever occurs first. 
Patients who experience non-laboratory AEs should be evaluated at least once a week following 
demonstration of the toxicity until a resolution of the toxicity or study treatment completion 
occurs. 
Treatment interruption and treatment discontinuation 
Patients experiencing unacceptable toxicity (AE grade 3 or higher) that the investigator 
considers directly attributable to pasireotide should have their dose reduced or should be 
withdrawn from the study. (reference table below) should be regarded as a guideline for the 
treatment of patients experiencing Adverse Events which are judged to be drug related. Any 
deviation from these guidelines should be discussed and approved by the sponsor. 
Adverse events are described as mild (Grade 1), moderate (Grade 2), severe (Grade 3) or life-
threatening (Grade 4). Guidelines for treatment of patients experiencing adverse events are 
indicated below (reference table below). 

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Table 14-9 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia for patients from protocol SOM230X2402 
Patients 
Adverse event 
Action 
All 
AE grade ≤ 2 (mild to 
moderate) 
No drug adjustments 
 
AE grade ≥ 3 (severe to life-
threatening) and judged as 
drug related*# 
Reduce dose by 20 mg q 28 d to the next dose level as 
described above in this appendix (Appendix 8). 
Once the dose is reduced, the patient will stay on the 
lowered dose for the entire duration of the roll-over 
If AE recurs at grade ≥ 3, reduce dose by 20 mg q 28 d 
again and remain at lower dose. If AE does not improve 
to grade ≤ 2 the dose is to be reduced further (following 
the guidance as described above in this appendix 
(Appendix 8). If the AE does not improve to grade ≤ 2 on 
the minimum dose (20 mg q 28 d), patient is to 
discontinue treatment and followed for safety. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. For management of diarrhea, please 
refer to (reference below section) 
14.8.1 
Guidance for diarrhea management 
General recommendations: 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (Metamucil, Procter & Gamble), and stool softeners (docusate 
sodium; Colace, Roberts) 
• Drink 8 to 10 large glasses of clear liquids per day (water, Pedialyte (Ross),Gatorade 
(Quaker), broth) 
• Eat frequent small meals (bananas, rice, applesauce, Ensure, toast) 
• Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with fiber) 
It is recommended that patients be provided loperamide tablets. It is mandatory that patients are 
instructed on the use of loperamide at cycle 1 in order to manage signs or symptoms of diarrhea 
at home. Patients should be instructed to start oral loperamide (initial administration of 4mg, 
then 2mg every 4 hours (maximum of 16 mg/day) at the first sign of loose stool or symptoms 
of abdominal pain. These instructions should be provided at each cycle and the site should 
ensure that the patient understood the instruction. At the beginning of each cycle, each patient 
should be specifically questioned regarding any experience of diarrhea or diarrhea related 
symptoms. If symptoms were experienced, then the site should question the patient regarding 
the actions taken for these symptoms. 
Treatment of diarrhea grade 1 or 2 
Diarrhea grade 1 or 2 will be treated with standard loperamide (initial at first administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool). 

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12-24 hours later: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12-hours diarrhea-free interval 
Diarrhea unresolved 
Persisting diarrhea grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of patients condition to rule out 
dehydration, sepsis, ileus) medical check and selected workup if patient does not need 
hospitalization (see section Diarrhea workup and additional test in the particular trial protocol). 
Observe patient for response to antidiarrheal treatment. 
Persisting diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide 
(initial 4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (perform 
appropriate additional testing). Observe patient for response. 
After 12-24 hours: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide and/or other treatment after 12-hours diarrhea-free interval 
Diarrhea unresolved 
• If diarrhea still persisting (NCI CTC grades 1 and 2), after 2x 24 hours with high dose 
loperamide and opiates then admit to hospital and employ measures as for grade 3 and 4 
until diarrhea resolved 
• If diarrhea still persisting and progressed to NCI grades 3 and 4, employ measures 
described below. 
Treatment of diarrhea grade 3 or 4 
Severe diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide (initial 
4 mg, then 2 mg every 2 hours and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (see section 
Diarrhea workup and additional test in the particular trial protocol). Observe patient for 
response. 
After 12-24 hours: 
• If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 µg tid) 

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• Continue IV fluids and antibiotics as needed 
• If diarrhea grade 3 or 4 still persists patients should receive opium tincture or 
dihydrocodeine tartrate injections s.c. or i.m. 
• If diarrhea grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 µg tid) 
should be administered. 
• To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 2 
weeks. Treatment should be continued only when diarrhea resolved. 
Diarrhea workup 
Perform appropriate tests (Fine and Schiller 1999). 
Spot stool analysis 
• Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or 
• Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immonunosuppressed 
patients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., 
possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in 
undertaking these invasive procedures. 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis 
14.8.2 
Dose and treatment schedule 
Study treatments 
in the follow-up 
phase 
Pharmaceutical 
form and route of 
administration 
Total 
Monthly 
Dose 
Frequency 
and/or 
Regimen 
Vials Used 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
20mg 
20 mg q 28 d 
1 vial of 20 mg powder, 
(+1 vial of 2 ml vehicle) 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
40 mg 
40 mg q 28 d 
1 vial of 40 mg powder, 
(+1 vial of 2 ml vehicle) 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
60 mg 
60 mg q 28 d 
1 vial of 20 mg + 1 vial of 40 
mg or 1 vial of 60 mg 
powder, 
(+ 1 vial of 2 ml vehicle) 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
80 mg 
80 mg q 28 d 
2 vials of 40 mg powder, 
(+ 1 vial of 2 ml vehicle) 

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14.9 
Appendix 9: Dose modification information for patients with rare 
tumors of neuroendocrine origin receiving pasireotide LAR (from 
protocol SOM230D2203) 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study drug. 
Study drug for this study will be pasireotide LAR at 60 mg every 28 days. If tolerability issues 
occur, the treatment dose may be reduced to pasireotide LAR at 40 mg with next scheduled 
injection. A patient receiving 40 mg showing further tolerability issues may reduce the dose 
level to 20 mg at the next injection. The investigator may, at his or her discretion, increase the 
patient’s dose of study medication after resolution of tolerability issue. However, patients not 
able to tolerate the minimum pasireotide LAR dose of 20 mg will be discontinued from study. 
Patients who have not achieved symptom control or in whom adequate control is not maintained 
are permitted to use rescue dose of pasireotide s.c. up to 600 µg b.i.d to control their symptoms 
at anytime during the study duration. If tolerability issues arise upon use of s.c. injections for 
rescue purposes, these injections should be stopped. Once the tolerability issue has resolved, 
the s.c. injections may be resumed if needed. The rescue s.c. dose may not exceed 600 µg b.i.d. 
All dose changes must be recorded on the Dosage Administration Record CRF. 
Table 14-10 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study 
drug related 
Reduce pasireotide to the next lower dose level. 
• 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. 
• 
If the dose is increased and the AE recurs at a grade ≥ 3, the dose 
should be reduced again. The patient should stay on this lower dose and 
no further dose titrations are allowed. 
• 
If the AE does not improve to grade ≤ 2, the dose is to be reduced 
further. If the AE does not improve to grade ≤ 2 on the minimum study 
dose, the treatment should be stopped. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. 

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14.10 
Appendix 10: Dose modification information for patients with 
neuroendocrine tumors receiving pasireotide LAR (from protocol 
SOM230D2101) 
Patients continuing into the roll-over study will receive the same dose of pasireotide LAR every 
28 days as the last dose administered during the parent study. 
When treatment is interrupted or permanently discontinued due to an AE or abnormal laboratory 
value the patient must be followed at least once a week for 8 weeks, and subsequently in 4-
week intervals, until resolution or stabilization of the event, whichever comes first. If a patient 
requires a dose delay of > 21 days from the intended day of the scheduled dose, then the patient 
must be discontinued from the study. However, the patient will be followed up for toxicity as 
previously described. All patients will be followed for adverse events and serious adverse events 
for at least 56 days following the last dose of pasireotide LAR treatment. 
Table 14-11 outlines the follow-up required for toxicities of specific types and CTCAE grades. 
Table 14-11 
Follow-up evaluations for selected toxicties 
Toxicity 
Follow-up evaluation 
Hematology 
If ≥ CTCAE grade 3 neutropenia or ≥ CTCAE grade 3 thrombocytopenia have been 
demonstrated, these parameters must be repeated at least twice a week until 
resolution to ≤ CTCAE grade 1 to allow for initiation of re-treatment, and then at 
least weekly until either initiation of retreatment or until stabilization. 
Renal 
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be 
repeated at least twice a week until resolution to ≤ CTCAE grade 1 or baseline to 
allow for initiation of re-treatment, and then at least weekly until either initiation of 
re-treatment or until stabilization. 
Hepatic 
For details on hepatic safety management, please refer to Appendix 2: Hepatic 
Safety Management 
Pancreatic 
If amylase and/or lipase ≥ CTCAE grade 3 has been demonstrated, these 
parameters must be assessed once at 2-4 days and once again at 7 days (± 1 day) 
and be repeated twice a week until resolution to ≤ CTCAE grade 2 to allow for 
initiation of re-treatment, and then at least weekly until either resolution to ≤ CTCAE 
grade 1 or until stabilization. 
A CT scan or other imaging study to assess the pancreas, liver and gallbladder 
must be performed within 1 week of the first occurrence of any ≥ CTCAE grade 3 of 
amylase and/or lipase. 
In patients with serum triglycerides ≥ 500 mg/dL, urine amylase needs to be tested. 
Endocrine/ 
metabolic 
For details on hyperglycemia management, please refer to Appendix 4: ‘Fasting 
blood glucose management’. 
Cardiac 
For details on the follow-up and treatment of QT prolongation, please refer to 
Appendix 3 ‘Recommended follow up in case of QT-related findings during routine 
ECG’ 
Non-laboratory 
Patients who experience non-laboratory DLTs must be evaluated at least once a 
week following demonstration of the toxicity until resolution of the toxicity to allow for 
re-treatment, until stabilization of the toxicity, or until study completion. 

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14.10.1 Dose modification and dose delay 
The patient should be followed as described in Table 14-12 until the toxicity in question has 
resolved to CTCAE grade 1 or to the patients’ baseline value, or until the toxicity is deemed 
irreversible. 
Patients who cannot be treated with pasireotide LAR within 21 days of the intended dosing day 
due to drug-related toxicity should have weekly follow-ups that include a physical examination, 
vital signs including weight, performance status, ECGs, and assessment of adverse events and 
concomitant medication. Following toxicity, ECG, hematology, renal and liver function tests 
should be performed as appropriate. 
If a patient requires a dose delay of > 21 days from the intended day of the next scheduled dose 
of pasireotide LAR, then the patient must be discontinued from the study. Patients who 
discontinue from the study for a study drug-related adverse event or an abnormal laboratory 
value, must be followed as described in Table 14-11. 
For each patient, only one dose reduction will be allowed after which the patient should be 
discontinued from the study. For each patient, once a dose level reduction has occurred, the 
dose level may not be re-escalated during subsequent treatment cycles with pasireotide LAR. 
Dose reduction for pasireotide LAR means treatment at a lower pasireotide LAR dose level. 
Dose modification for patients treated at the starting dose of 80 mg will be 60 mg. 
All interruptions or changes to study drug administration must be recorded on the Dosage and 
Administration Record eCRF. 
14.10.2 Treatment interruption and treatment discontinuation 
All dose modifications should be based on the worst preceding toxicity. 
Each patient is only allowed one dose reduction. In addition, a patient must discontinue 
treatment with pasireotide LAR if, after treatment is resumed at a lower dose, the toxicity recurs 
with the same or worse severity 
Table 14-12 
Criteria for interruption and re-initiation of pasireotide LAR 
Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
No toxicity 
Maintain dose level 
Hematologic 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 
1500/mm3) 
Maintain dose level 
Grade 2 (ANC < 1500 - 
1000/mm3) 
Maintain dose level 
Grade 3 (ANC < 1000 - 
500/mm3) 
Omit dose until resolved to ≤ Grade 2, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 

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Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
Grade 4 (ANC < 500/mm3) 
Omit dose until resolved to ≤ Grade 2, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN - 
75,000/mm3) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 
50,000/mm3) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 
25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 4 (PLT < 25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Febrile neutropenia (ANC < 1.0 
x 109/L, fever ≥ 38.5°C) 
Omit dose until resolved, then  1 dose level 
Renal 
Serum creatinine 
 
< 2 x ULN 
Maintain dose level 
2-3 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 6.0 x ULN) 
Omit dose and discontinue patient from study treatment 
Grade 4 (> 6.0 x ULN) 
Omit dose and discontinue patient from study treatment 
Hepatic 
Bilirubin 
 
< 2 x ULN 
Maintain dose level 
2-3 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 4 (> 10.0 x ULN) 
Omit dose and discontinue patient from study treatment 
NOTE: If grade 3 or 4 hyperbilirubinemia is due to the indirect 
(unconjugated) component only, and hemolysis as the etiology has 
been ruled out as per institutional guidelines (e.g. review of 
peripheral blood smear and haptoglobin determination), then  1 
dose level and continue treatment at the discretion of the 
investigator 
AST or ALT 
Grade 1 (> ULN - 2.5 x ULN) 
Maintain dose level 
Grade 2 (> 2.5 - 5.0 x ULN) 
Maintain dose level 

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Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
( >5.0 and ≤ 8 x ULN) 
If ALT or AST return to less than 5 x ULN study drug can be 
resumed and patient can continue study per protocol. 
If persistent for more than 14 days, discontinue patient from study 
treatment. 
In the event of a re-occurrence, discontinue patient from study 
treatment. 
(> 8 x ULN) 
Omit dose and discontinue patient from study treatment 
Pancreatic 
Pancreatitis 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Maintain dose level 
Maintain dose level 
Omit dose and discontinue patient from study treatment 
Omit dose and discontinue patient from study treatment 
Amylase and/or lipase 
Grade 1 (> ULN - 1.5 x ULN) 
Grade 2 (> 1.5 - 2.0 x ULN) 
Grade 3 (> 2.0 - 5.0 x ULN) 
 
 
 
 
 
Grade 4 (> 5.0 x ULN) 
 
Maintain dose level 
Maintain dose level 
For asymptomatic: 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
For symptomatic: 
Omit dose and discontinue patient from study treatment 
Omit dose and discontinue patient from study treatment 
A CT scan or other imaging study to assess the pancreas, liver and 
gallbladder must be performed within 1 week of the first occurrence 
of any ≥ CTCAE grade 3 of amylase and/or lipase. 
Endocrine/metabolic 
Fasting plasma glucose (FPS) 
or 2-hour postprandial capillary 
glucose (PPG) 
FPG <126 mg/dL or PPG < 140 
mg/dL 
Grade 1 (> ULN – 160 mg/dL) 
Grade 2 (> 160 – 250 mg/dL) 
Grade 3 (> 250 – 500 mg/dL) 
Grade 5 (> 500 mg/dL) 
 
 
 
Maintain dose level 
Please refer to Appendix 14.2 ‘Guideline for study drug-induced 
hyperglycemia’ 
Cardiac 
Cardiac - prolonged QTc 
interval 
- QTcF > 480 ms and ≤ 500 ms 
 
 
If at any time a QTcF > 480 ms and ≤ 500 ms is observed a 
cardiology consultation must be sought to re-evaluate the abnormal 
ECG finding. 

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Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
- QTcF > 500 msec 
1. Triplicate ECGs (2-3 minutes apart) need to be taken 
approximately 1 hour after the initial ECG. 
2. If the mean QTcF is > 500 ms, the patient must postpone study 
treatment until a cardiologist has re-evaluated the ECG. 
3. The re-evaluation of ECG needs to be done as soon as 
practical but within 7 days of the initial abnormal ECG. 
4. If the cardiologist confirms a mean QTcF > 500 ms, the patient 
must be discontinued. 
Cardiac general 
Grade 1 or 2 
Grade 3 
Grade 4 
 
Maintain dose level 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Omit dose and discontinue patient from study treatment 
Other adverse events 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Omit dose and discontinue patient from study treatment 
14.10.3 Guidance for diarrhea management 
General recommendations: 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (Metamucil, Procter & Gamble), and stool softeners (docusate 
sodium; Colace, Roberts) 
• Drink 8 to 10 large glasses of clear liquids per day (water, Pedialyte (Ross),Gatorade 
(Quaker), broth) 
• Eat frequent small meals (bananas, rice, applesauce, Ensure, toast) 
• Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with fiber) 
It is recommended that patients be provided loperamide tablets. It is mandatory that patients are 
instructed on the use of loperamide at cycle 1 in order to manage signs or symptoms of diarrhea 
at home. Patients should be instructed to start oral loperamide (initial administration of 4mg, 
then 2mg every 4 hours (maximum of 16 mg/day) at the first sign of loose stool or symptoms 
of abdominal pain. These instructions should be provided at each cycle and the site should 
ensure that the patient understood the instruction. At the beginning of each cycle, each patient 
should be specifically questioned regarding any experience of diarrhea or diarrhea related 
symptoms. If symptoms were experienced, then the site should question the patient regarding 
the actions taken for these symptoms. 
Treatment of diarrhea grade 1 or 2 
Diarrhea grade 1 or 2 will be treated with standard loperamide (initial at first administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool). 

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12-24 hours later: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12-hours diarrhea-free interval 
Diarrhea unresolved 
Persisting diarrhea grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of patients condition to rule out 
dehydration, sepsis, ileus) medical check and selected workup if patient does not need 
hospitalization (see section Diarrhea workup and additional test in the particular trial protocol). 
Observe patient for response to antidiarrheal treatment. 
Persisting diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide 
(initial 4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (perform 
appropriate additional testing). Observe patient for response. 
After 12-24 hours: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide and/or other treatment after 12-hours diarrhea-free interval 
Diarrhea unresolved 
• If diarrhea still persisting (NCI CTC grades 1 and 2), after 2x 24 hours with high dose 
loperamide and opiates then admit to hospital and employ measures as for grade 3 and 4 
until diarrhea resolved 
• If diarrhea still persisting and progressed to NCI grades 3 and 4, employ measures 
described below. 
Treatment of diarrhea grade 3 or 4 
Severe diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide (initial 
4 mg, then 2 mg every 2 hours and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (see section 
Diarrhea workup and additional test in the particular trial protocol). Observe patient for 
response. 
After 12-24 hours: 
• If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 µg tid) 

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• Continue IV fluids and antibiotics as needed 
• If diarrhea grade 3 or 4 still persists patients should receive opium tincture or 
dihydrocodeine tartrate injections s.c. or i.m. 
• If diarrhea grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 µg tid) 
should be administered. 
• To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 2 
weeks. Treatment should be continued only when diarrhea resolved. 
Diarrhea workup 
Perform appropriate tests (Fine and Schiller 1999). 
Spot stool analysis 
• Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or 
• Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immonunosuppressed 
patients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., 
possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in 
undertaking these invasive procedures. 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis 

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14.11 
Appendix 11: Dose modification information for patients with 
Cushing’s receiving pasireotide s.c or acromegaly receiving 
pasireotide LAR (from protocols SOM230B2219 and 
SOM230B2305) 
Cushing’s disease: Pasireotide (SOM230) s.c. injection: 300, 600 or 900 µg b.i.d.; Acromegaly: 
Pasireotide (SOM230) i.m. LAR: 20, 40 or 60 mg every 28 days 
14.11.1 Dose modifications for patients from protocol SOM230B2219 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following guidelines 
need to be applied: 
Cushing’s disease: At any time during the study the pasireotide dose may be reduced by 300 µg 
b.i.d for safety or tolerability reasons. Dose may be increased to 600 or 900 µg b.i.d if 
tolerability issues have resolved per investigator’s discretion. 
Acromegaly: Dose up-titration of pasireotide LAR to 60 mg i.m. once/28 days will be allowed 
in patients without adequate levels of GH and IGF-1 (no reduction of mean GH level to <2.5 
µg/L and no normalization of IGF-1 to within normal limits (age and sex related)) as determined 
locally. A dose reduction by 20 mg will be permitted in case of tolerability issues, but the patient 
may return to previous dose once tolerability issues are resolved. 
Dose should also be modified for adverse events as described in Table 14-13. 
Any dose change must be recorded on the respective Dosage Administration Record CRF. 
14.11.2 Dose modifications for patients from protocol SOM230B2305 
For patients who are unable to tolerate the protocol-specified dose level, dose adjustments are 
permitted in order to keep the patient on study drug. (Refer to Table 14-13). At any time during 
the study, patients with an early morning (between 8 and 10am) serum cortisol < 3 µg/dl and a 
UFC measurement < LLN or symptoms suggestive of hypoadrenalism (e.g. postural 
hypotension, nausea, and abdominal pain) and a UFC measurement <LLN should have their 
dose reduced. 
During the roll-over, the investigator may reduce the dose in 300 µg s.c. b.i.d. steps at any time 
if the patient does not tolerate the given pasireotide dose. The minimum dose to be administered 
will be 300 µg s.c. b.i.d.. If the patient does not tolerate the 300 µg s.c. b.i.d. dose, he/she will 
be withdrawn from the study. 
These changes must be recorded on the Dosage Administration Record. 

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Table 14-13 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study drug 
related 
Reduce pasireotide to the next dose level. 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. If the dose is increased and the AE recurs at a 
grade ≥ 3, the dose should be reduced again. The patient should stay on 
this lower dose and no further dose titrations are allowed. 
If the AE does not improve to grade ≤ 2, the dose is to be reduced further. 
If the AE does not improve to grade ≤ 2 on the minimum study dose, the 
treatment should be stopped. The patient should be discontinued and 
followed up for safety. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. 

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14.12 
Appendix 12: Dose modification information for patients with 
Cushing’s receiving pasireotide s.c in combination with 
cabergoline (SOM230B2411) 
Table 14-14 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
Pasireotide 
Subcutaneous 
0.3mg, 0.6mg, and 0.9mg 
Twice a day 
Cabergoline 
Oral 
0.5mg or 1.0mg 
Once a day 
Pasireotide untreated patients: will begin their treatment with pasireotide 0.6mg twice a day 
monotherapy for 8 weeks. If biochemical control is not achieved by the end of the 8-week 
period, and the 0.6mg dose is well tolerated, the dose of pasireotide will be increased to 0.9mg 
twice a day for another 8 weeks. If biochemical control is still not achieved at 0.9mg twice a 
day and the dose is well tolerated, the combination treatment of pasireotide 0.9mg twice a day 
plus cabergoline 0.5mg once a day will be given for another 8 weeks. If biochemical control is 
not yet achieved either during or at the end of the 8-week period, cabergoline dose will be 
increased to 1.0mg once a day. 
If a patient shows high sensitivity to pasireotide 0.6mg bid resulting in cortisol values <LLN 
and/or signs/symptoms consistent with the diagnosis of hypocortisolism, the dose of pasireotide 
can be decreased to 0.3mg bid. Despite the dose reduction, some patients may still present with 
cortisol values <LLN and/or signs/symptoms consistent with hypocortisolism; in this case the 
dose of pasireotide can be further reduced to 0.3 mg qd in order to achieve and maintain normal 
cortisol levels. 
If the 0.9mg twice a day dose is not tolerated and biochemical control is not achieved, patient 
will begin combination treatment of pasireotide at 0.6mg twice a day plus cabergoline at 0.5mg 
once a day for 8 weeks. If during or at the end of the 8-week period, the biochemical control is 
not achieved, the combination dose will be increased to pasireotide at 0.6mg twice a day plus 
cabergoline at 1.0mg once a day for 8 weeks. The patient will continue with the highest 
combination dose of 0.6mg pasireotide twice a day plus 1.0mg cabergoline once a day, or  
0.9mg pasireotide twice a day plus 1.0mg of cabergoline once a day for 8 weeks. (see Table 14-
15) 
If patient does not tolerate 0.6mg twice a day, the dose of pasireotide should be decreased to 
0.3mg twice a day. If pasireotide 0.3mg twice a day does not lead to biochemical control after 
at least 8 weeks of treatment, combination with cabergoline as described above can be initiated 
(see Table 14-15). 
If patient cannot increase from 0.6mg twice a day to 0.9mg twice a day due to safety, and is not 
yet biochemically controlled, combination with cabergoline 0.5mg qd can be initiated right 
away with pasireotide at 0.6mg twice a day (see Table 14-15).   
If patient is being escalated to 0.9mg twice a day, but cannot tolerate the dose, dose should be 
reduced to 0.6mg twice a day. If the latter dose does not lead to biochemical control, 
combination with cabergoline as described above can be initiated (see Table 14-15). 

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If combination pasireotide and cabergoline 0.5mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 0.5mg every other day. If 0.5mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-15). 
If combination pasireotide and cabergoline 1.0mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 1.0mg every other day. If 1.0mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-15). 
The minimum treatment of any regimen is 8 weeks. Patients losing biochemical control at any 
time point after the 8 week period will have the dose of the study mediation increased 
immediately to the next level provided that the dose is well tolerated. 
Table 14-15 
Pasireotide and cabergoline dose modification steps for pasireotide 
un-treated patients 
Pasireotide: pasi 
Cabergoline: 
cabe 
Starting dose 
level 
Dose 
modification 
level – 1 
Dose 
modification 
level – 2 
Dose 
modification 
level - 3 
Dose 
medication 
level - 4 
Modification # 1 
0.6mg bid pasia 
0.3mg bid pasib 
0.3mg bid pasi 
+ 0.5mg cabe 
qdb 
0.3mg bid pasi 
+ 1.0mg cabe 
qd 
 
Modification # 2 
0.6mg bid pasib 
0.9mg bid pasib 
0.9mg bid pasi 
+ 0.5mg qd 
cabeb 
0.9mg bid pasi 
+ 1.0mg qd 
cabe 
 
Modification # 3 
0.6mg bid pasib  
0.9mg bid pasia 
0.6mg bid pasib 
0.6mg bid pasi 
+ 0.5mg cabe 
qdb 
0.6mg bid 
pasi + 
1.0mg cabe 
qd 
Modification # 4 
0.6mg bid pasic 
0.6mg bid pasi 
+ 0.5mg qd 
cabeb  
0.6mg bid pasi 
+ 1.0mg cabe 
qd 
 
 
Modification # 5 
0.9mg bid pasiab  0.6mg bid pasi 
+ 0.5mg qd 
cabeb 
0.6mg bid pasi 
+ 1.0mg qd 
cabe 
 
 
Modification # 6 
0.3, 0.6 or 
0.9mg bid pasi 
+ 0.5mg qd 
cabea 
0.3, 0.6 or 
0.9mg bid pasi 
+ 0.5mg every 
other day 
cabeab 
Discontinuation 
if no clinical 
benefit 
 
 
Modification # 7  
0.3, 0.6 or 
0.9mg bid pasi 
+ 1.0mg qd 
cabea 
0.3, 0.6 or 0.9 
mg bid pasi + 
1.0mg every 
other day 
cabeab 
Discontinuation 
if no clinical 
benefit 
 
 
aDose modification is initiated if the current dose is not tolerated 
bDose modification is initiated if biochemical control is not achieved 
cDose cannot be increased to the next level due to toxicity but biochemical control is not achieved 
Patients currently treated with maximal tolerated doses of pasireotide monotherapy: 
0.3mg bid, 0.6mg bid or 0.9mg bid, for at least 8 weeks but did not achieve biochemical control 
will begin their combination treatment of pasireotide at 0.3mg, 0.6mg  or 0.9mg bid plus 0.5mg 
of cabergoline once a day at study entry. They will continue the treatment for 8 weeks. If 

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biochemical control is not achieved at the end of the 8-week period, the dose of cabergoline 
will be increased to 1.0mg once a day and continue with the combination treatment for the 
remainder of study treatment.  
If combination pasireotide and cabergoline 0.5mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 0.5mg every other day. If 0.5mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-16). 
If combination pasireotide and cabergoline 1.0mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 1.0mg every other day. If 1.0mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-16). 
The minimum treatment of any regimen is 8 weeks. Patients losing biochemical control at any 
time point after the 8-week treatment period at the starting combination dose will have the dose 
of the study mediation increased immediately to the next level provided that the dose is well 
tolerated (see Table 14-16). 
Table 14-16 
Pasireotide and cabergoline dose modification steps for patients 
currently treated with maximal tolerated doses of pasireotide 
monotherapy 
Pasireotide: pasi 
Cabergoline: cabe 
Starting dose level 
Dose modification 
level – 1 
Dose modification 
level – 2 
Modification # 1 
0.3, 0.6 or 0.9mg bid 
pasi + 0.5mg qd cabea 
0.3, 0.6 or 0.9mg bid pasi + 
0.5mg every other day cabea 
Discontinuation if no 
clinical benefit 
Modification # 2 
0.3, 0.6 or 0.9mg bid 
pasi + 0.5mg qd cabeb 
0.3, 0.6 or 0.9mg bid pasi + 
1.0mg qd cabea  
 
Modification # 3 
0.3, 0.6 or 0.9mg bid 
pasi + 1.0mg qd cabea 
0.3, 0.6 or 0.9 mg bid pasi + 
1.0mg every other day cabea 
0.3, 0.6 or 0.9mg bid pasi 
+ 0.5mg qd cabe 
aDose modification is initiated if the current dose is not tolerated 
bDose modification is initiated if biochemical control is not achieved