Clinical trial NCT02075606
Conditions: NeuroEndocrine Tumours
Keywords: NET Symptomatic response Functioning NeuroEndocrine Tumours midgut region
Sponsor: Ipsen
Start date: 2014-05-01; Completion date: 2017-06-01
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Circulating tumour cells (CTCs) are detectable in the blood in around 50% of patients with functioning NeuroEndocrine Tumours (NET) arising in the midgut area (tumours which are secreting hormones and are located in the area in the middle of the digestive system) and their presence usually means that the prognosis for the patient is poor. CTCs have also been shown to be valuable as predictive markers following treatment and there is increasing interest in using CTCs as 'liquid biopsies' that can help to inform treatment decisions. CTC analysis has the benefit of being relatively non- invasive and quick compared with a conventional CT scan and is therefore an attractive method of monitoring the tumour throughout the treatment period.

The purpose of this study is to assess the clinical value that enumeration will have in predicting the clinical symptomatic response and progression free survival in patients receiving Somatuline Autogel for functioning midgut NETs over a one year period.

Detailed description:

Arms: arm 1: Somatuline Autogel® to treat Functioning Midgut NeuroEndocrine Tumours (NET)
Interventions: intervention 1: lanreotide acetate
Intervention descriptions: intervention 1: Somatuline Autogel injection 120mg for first 3 months then 120, 90 or 60 mg administered via the deep subcutaneous route every 28 days

Protocol documents:
Prot_001.pdf: 
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APPENDIX 1 
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SAP_000.pdf: 
IPSEN GROUP       
[A-97-52030-270] 
CONFIDENTIAL  
RAP Final Version 1.0 [15-SEP-2017] 
1/54
REPORTING AND ANALYSIS PLAN 
CALM-NET: A PHASE IV, MULTICENTRE, OPEN LABEL, SINGLE GROUP 
EXPLORATORY STUDY TO ASSESS THE CLINICAL VALUE OF ENUMERATION OF 
CIRCULATING TUMOUR CELLS (CTCs) TO PREDICT CLINICAL SYMPTOMATIC 
RESPONSE AND PROGRESSION FREE SURVIVAL IN PATIENTS RECEIVING DEEP 
SUBCUTANEOUS ADMINISTRATIONS OF SOMATULINE® (LANREOTIDE) 
AUTOGEL® TO TREAT THE SYMPTOMS OF FUNCTIONING MIDGUT 
NEUROENDOCRINE TUMOURS (NET). 
Protocol version and date: Final 6.0 – 27 October 2015 
RAP Version
Date
Draft – Version 0.1
23-JUL-2014
Draft – Version 0.2
12-JUL-2016
Draft – Version 0.3
30-SEP-2016
Draft – Version 0.4
12-DEC-2016
Final – Version 1.0
15-SEP-2017


IPSEN GROUP       
[A-97-52030-270] 
CONFIDENTIAL  
RAP Final Version 1.0 [15-SEP-2017] 
2/54
STUDY NUMBER:
A-97-52030-270
EUDRACT NUMBER
2013-002194-22
PROTOCOL TITLE:
CALM-NET: A Phase IV, Multicentre, Open label, 
Single Group Exploratory Study to Assess the Clinical 
Value of Enumeration of Circulating Tumour Cells 
(CTCs) to Predict Clinical Symptomatic Response and 
Progression Free Survival in Patients receiving Deep 
Subcutaneous 
Administrations 
of 
Somatuline® 
(lanreotide) Autogel® to treat the Symptoms of 
Functioning Midgut NeuroEndocrine Tumours (NET).
RAP VERSION:
Final version 1.0
RAP DATE:
15-SEP-2017
Further to your review and agreement to the Reporting and Analysis Plan version 
indicated above, please sign to indicate approval for your area of responsibility: 
RESPONSIBILITY
NAME, TITLE & OFFICE
SIGNATURE
DATE
Clinical 
Statistics 
Manager 
or 
designee
IPSEN PHARMA
65, quai Georges Gorse  
92650 Boulogne Billancourt, 
France
Clinical Study Co-
ordinator
Ipsen Ltd 
190 Bath Road, Slough 
Berkshire, SL1 3XE, 
United Kingdom
Medical Director
Ipsen Ltd 
190 Bath Road, Slough 
Berkshire, SL1 3XE, 
United Kingdom
PPD
PPD
PPD


IPSEN GROUP       
[A-97-52030-270] 
CONFIDENTIAL  
RAP Final Version 1.0 [15-SEP-2017] 
3/54
RESPONSIBILITY
NAME, TITLE & OFFICE
SIGNATURE
DATE
Statistician
Aixial
4, rue Danjou, Bâtiment B
92517 Boulogne-Billancourt 
cedex, 
France
Reviewing 
Statistician
Aixial
4, rue Danjou, Bâtiment B
92517 Boulogne-Billancourt 
cedex, 
France
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Reporting and Analysis Plan version became the Final Reporting and 
Analysis Plan
PPD
PPD
PPD
PPD
P


IPSEN GROUP       
[A-97-52030-270] 
CONFIDENTIAL  
RAP Final Version 1.0 [15-SEP-2017] 
4/54
TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 6 
1. 
INFORMATION TAKEN FROM THE PROTOCOL............................................... 8 
1.1. Study objectives............................................................................................................... 8 
1.1.1. 
Primary objective........................................................................................... 8 
1.1.2. 
Exploratory Primary objective...................................................................... 8 
1.1.3. 
Secondary objectives ..................................................................................... 8 
1.1.4. 
Exploratory Secondary objectives ................................................................ 8 
1.2. Study design..................................................................................................................... 8 
1.2.1. 
Study population ........................................................................................... 9 
1.2.2. 
Study exposure ............................................................................................ 11 
1.3. Methods and procedures.............................................................................................. 11 
1.3.1. 
Subject identification and allocation to study treatment........................... 11 
1.3.2. 
Subjects assessments................................................................................... 11 
1.3.3. 
Schedule of assessments ............................................................................. 17 
1.3.4. 
Planned sample size .................................................................................... 20 
2. 
SUBJECT POPULATIONS (ANALYSIS SETS)...................................................... 21 
2.1. Screened population ..................................................................................................... 21 
2.2. Enrolled population...................................................................................................... 21 
2.3. Efficacy .......................................................................................................................... 21 
2.3.1. 
Intention-to-treat population...................................................................... 21 
2.3.2. 
Per Protocol population.............................................................................. 21 
2.4. Safety.............................................................................................................................. 21 
2.5. Primary populations..................................................................................................... 21 
3. 
STATISTICAL METHODS ........................................................................................ 22 
3.1. Statistical analysis strategy .......................................................................................... 22 
3.1.1. 
Primary efficacy endpoint........................................................................... 22 
3.1.2. 
Exploratory primary efficacy endpoint ...................................................... 22 
3.1.3. 
Secondary efficacy endpoint(s)................................................................... 22 
3.1.4. 
Exploratory Secondary efficacy endpoint(s).............................................. 22 
3.1.5. 
Safety endpoint(s)........................................................................................ 22 
3.1.6. 
Multiplicity .................................................................................................. 22 
3.1.7. 
Significance testing and estimation............................................................ 23 
3.2. Analysis methods........................................................................................................... 23 
3.2.1. 
Efficacy........................................................................................................ 23 
3.2.2. 
Safety ........................................................................................................... 29 
3.2.3. 
Missing data and outliers............................................................................ 30 
3.2.4. 
Subject disposition....................................................................................... 31 


IPSEN GROUP       
[A-97-52030-270] 
CONFIDENTIAL  
RAP Final Version 1.0 [15-SEP-2017] 
5/54
3.2.5. 
Withdrawals................................................................................................. 32 
3.2.6. 
Demographic and baseline characteristics ................................................ 32 
3.2.7. 
Medical and surgical history ...................................................................... 32 
3.2.8. 
Prior surgical procedures for NET ............................................................ 32 
3.2.9. 
Compliance.................................................................................................. 33 
3.2.10. 
Prior and concomitant therapies................................................................ 33 
3.2.11. 
Derived data................................................................................................. 34 
3.2.12. 
Visit windows............................................................................................... 40 
3.2.13. 
Rules and data formats ............................................................................... 40 
3.2.14. 
Pooling of Centres....................................................................................... 41 
3.2.15. 
Interim analysis........................................................................................... 41 
3.2.16. 
Covariates and analysis of subgroups........................................................ 41 
4. 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS. 42 
4.1. Hardware....................................................................................................................... 42 
4.2. Software......................................................................................................................... 42 
4.3. Validation programs..................................................................................................... 42 
4.4. Restitution of the programs ......................................................................................... 42 
5. 
CHANGES FROM PROTOCOL................................................................................ 43 
6. 
REFERENCES.............................................................................................................. 44 
7. 
DATA PRESENTATION............................................................................................. 44 
7.1. Listings index................................................................................................................. 44 
7.2. Listing templates........................................................................................................... 47 
7.3. Tables index................................................................................................................... 47 
7.4. Table templates ............................................................................................................. 53 
7.5. Figure templates............................................................................................................ 54 
7.6. Statistical Appendix...................................................................................................... 54 
8. 
APPENDICES............................................................................................................... 54 


IPSEN GROUP       
[A-97-52030-270] 
CONFIDENTIAL  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE
Adverse Event 
ATC
Anatomical-Therapeutic-Chemical
BMI
Body Mass Index
CgA
Chromogranin A 
CI
Confidence Interval
CR
Complete Response
CT
Computed Tomography 
CTCs
Circulating Tumour Cells  
FITC
Fluorescein Isothiocyanate
ITT
Intention-to-treat
IVRS
Interactive Voice Response System 
MedDRA
Medical Dictionary for Regulatory activities
MRI 
Magnetic Resonance Imaging 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events
NE
Not Evaluable
NET
Neuroendocrine Tumour
OR
Odds Ratio
PD
Progression Disease
PE
Phycoerythrin
PFS
Progression free survival
PP
Per Protocol
PR
Partial Response
PT
Preferred Term
QoL
Quality of Life
RECIST
Response Evaluation Criteria Solid Tumours
ROC
Receiver Operating Characteristic
SAE
Serious adverse events
SD
Stable Disease
SOC
System Organ Class
SSA
Somatostatin Analogue
SSTR
Somatostatin Receptor 


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TEAE
Treatment Emergent Adverse Events
ULN
Upper Limit of Normal
5-HIAA
5-Hydroxyindoleacetic acid


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1.
INFORMATION TAKEN FROM THE PROTOCOL 
1.1.
Study objectives 
1.1.1.
Primary objective 
To assess the clinical value of enumeration of circulating tumour cells (CTCs) to predict the 
clinical symptomatic response in subjects receiving Somatuline Autogel. Subjects will 
provide 24 hour symptom frequency and severity on a daily basis electronically for the first 
16 weeks of the study and subsequently, on days 11 to 17 of each subsequent injection 
interval for the remainder of the study duration. After the final study drug injection at week 
49, subjects will provide 24 hour symptom frequency and severity on a daily basis on days 11 
to 28. Symptom frequency and severity will be recorded electronically after enrolment for the 
7 days preceding the first study treatment. Severity will be classed as mild, moderate and 
severe for flushing only. 
1.1.2.
Exploratory Primary objective 
To assess the clinical value of enumeration of CTCs to describe progression free survival 
(PFS) in subjects receiving Somatuline Autogel. 
1.1.3.
Secondary objectives 
To assess the effect of Somatuline Autogel on the symptoms of diarrhoea and flushing in 
subjects with a functioning Neuroendocrine Tumour (NET).  
To assess the effect of Somatuline Autogel treatment on quality of life via the EORTC QLQ-
G.I.NET 21 and the EORTC QLQ-C30. The questionnaires will be conducted at weeks 1, 13, 
25 and 53.  
Assessment of PFS at one year. Subjects will undergo a Computed Tomography (CT) or 
Magnetic Resonance Imaging (MRI) scan at screening, week 25 and week 53 within their 
local hospital Trust. Progression will be assessed using the Response Evaluation Criteria 
Solid Tumours (RECIST) criteria. 
1.1.4.
Exploratory Secondary objectives 
To assess the effect of Somatuline Autogel on plasma Chromogranin A (CgA), plasma and 
urine 5-hydroxyindoleacetic acid (5-HIAA) and neurokinin A, and whether these biomarkers 
correlate with CTC presence. 
To assess whether urinary 5-HIAA and plasma 5-HIAA levels are correlated.  
To evaluate the presence of somatostatin receptor (SSTR) subtypes 2 and 5. 
1.2.
Study design 
This is a prospective, pilot, multicentre, open label, single group phase IV study which will be 
conducted across 14 sites in the United Kingdom.  


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Eligible subjects will be asked to provide written informed consent for their participation in 
this study. Subjects who have provided written informed consent will receive Somatuline 
Autogel injections for a period of one year. Subjects will initially receive Somatuline Autogel 
120 mg injections every 28 days for the first 3 injections. Subjects’s symptoms will be 
assessed after three injections, and the dose will be titrated according to clinical judgement for 
the remaining course of the study. 
During the course of the study, 15 clinic visits will be done. Study treatment will be 
administered at Visit 2 and then at each visit every 4 weeks. 
Visit
1
(Screening)
2
(Baseline)
3
4
5
6
7
8
9
10
11
12
13
14
15
(End of 
study)
Weeks following 
screening 
1
5
9
13
17
21
25
29
33
37
41
45
49
53
1.2.1.
Study population 
Approximately 50 subjects (either sex), who have received a pathological diagnosis of 
functioning midgut G1 or G2 NET and in the medical opinion of their practitioner will require 
medical treatment with a somatostatin analogue (SSA) for tumour symptom control will be 
eligible for this study. 
1.2.1.1.
Inclusion criteria 
Each subject must meet the following criteria: 
x
1- Provision of written informed consent prior to any study related procedures, 
x
2- Subjects (either sex) must be 18 years or older, 
x
3 (after amendment 2) - Subjects must be suffering from symptoms of diarrhoea and/or 
flushing at the time of study enrolment  
x
4 (after amendment 2) / 3 (before amendment 2) - Subjects must have a documented 
diagnosis of a functioning midgut NET, 
x
5 (after amendment 2) / 4 (before amendment 2) - In order to avoid subjects with 
rapidly progressing tumours, only subjects with well or moderately differentiated 
tumours and with a Ki67 proliferation index of <20% will be recruited, 
x
6 (after amendment 2) - The clinically appropriate treatment for the subject must be 
therapy with a somatostatin analogue, 
x
5 (before amendment 2) - The clinically appropriate treatment for the subject must 
primarily be monotherapy with a somatostatin analogue, 
x
7 (after amendment 2) / 6 (before amendment 2) - Subjects must have had either a 
positive somatostatin receptor scintigraphy result or a positive 68Gallium-DOTATATE 
PET imaging result, 
x
7 (before amendment) - Subjects must have a documented urinary or plasma 5-HIAA 
result within the year prior to study entry which is above the laboratory reference range. 


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1.2.1.2.
Exclusion criteria 
Subjects will not be included in the study if the subject:  
x
1 - Is at risk of pregnancy or is breast feeding, unless treatment with Somatuline 
Autogel is clearly needed (as determined by the clinician), 
x
2 - Is in the opinion of the investigator, unable to comply fully with the protocol and 
the study instructions, or present any concomitant condition which could compromise 
the objectives of the study and/or preclude the protocol-defined procedures (e.g. severe 
medical conditions, brain metastases, psychiatric disorders, active or uncontrolled 
infection, known pituitary disease), 
x
3 - Has been treated with any other unlicensed drug within the last 30 days before study 
entry or will require a concurrent treatment with any other experimental drugs or 
treatments, 
x
4A (only at V1) - Has been treated with a somatostatin analogue prior to study entry, 
unless a washout period of at least 2 weeks for subcutaneous octreotide, or at least 6 
weeks for a single dose of long acting somatostatin analogue is planned, 
x
4B (only at V2) - Has been treated with a somatostatin analogue prior to study entry, 
unless a washout period of at least 2 weeks for subcutaneous octreotide, or at least 6 
weeks for a single dose of long acting somatostatin analogue has occurred, 
x
5 (before amendment 2) - Requires medical treatment for the symptoms of the NET 
other than primarily monotherapy with a somatostatin analogue, 
x
6 (before amendment 2) / 5 (after amendment 2) - Has received interferon, 
chemotherapy, chemoembolisation or radionuclide therapy within 3 months prior to 
study entry, 
x
7 (before amendment 2) / 6 (after amendment 2) - Has a history of hypersensitivity to 
drugs with a similar chemical structure, 
x
8 (before amendment 2) / 7 (after amendment 2) - Females of childbearing potential 
must be using oral, double barrier or injectable contraception. Non childbearing 
potential is defined as post-menopause for at least 1 year, surgical sterilisation or 
hysterectomy at least three months before the start of the study, 
x
9 (before amendment 2) / 8 (after amendment 2) - Has abnormal baseline findings, any 
other medical condition(s) or laboratory findings that, in the opinion of the Investigator, 
might jeopardise the subjects’ safety or decrease the chance of obtaining satisfactory 
data needed to achieve the objective(s) of the study. 
1.2.1.3.
Washout criteria 
Any subjects who have previously received either subcutaneous octreotide or one injection of 
a long acting somatostatin analogue will also be considered for this study following a washout 
period of 2 weeks after the last subcutaneous octreotide injection or a 6 week washout period 
after a single long acting somatostatin analogue injection. 
Subjects who have already been on a regimen of long or short acting somatostatin analogue 
treatment prior to surgery with debulking or curative intent may still be included in the study. 
These subjects may have received one injection of a long acting somatostatin analogue or 
subcutaneous octreotide post surgery and must be willing to observe the relevant washout 
periods documented above. 


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1.2.2.
Study exposure 
The overall duration of the study will be approximately 33 months, which is inclusive of an 
approximate recruitment period of 21 months and a 12 month treatment period. The study will 
be considered to have started when the first subject has provided signed informed consent to 
participate in the study. The study will be considered to have finished after the last subject has 
completed the last treatment period in the study.  
1.3.
Methods and procedures 
1.3.1.
Subject identification and allocation to study treatment 
All subjects will be automatically allocated a unique subject number when an enrolment visit 
is created in the Interactive Voice Response System (IVRS). In order to maintain 
confidentiality, this number in conjunction with the subjects’ initials will be used to identify 
the subjects study data.  
As this is an open label, single arm study, no randomisation procedures apply. 
1.3.2.
Subjects assessments
Methods for derivation of calculated variables are detailed in Section 3.2.11.
1.3.2.1.
Efficacy assessments 
x
CTCs enumeration  
Subjects will have blood (10 mL) taken for CTC enumeration at weeks 1 (baseline), 5, 
17, 25, and 53. CTC enumeration will be assessed as a continuous variable. 
Subjects with at least a CTC enumeration > 0 in either or both samples will be 
considered as subjects with CTC presence. CTC presence will be assessed as a 
qualitative variable (Yes; No). 
x
Symptoms frequency (diarrhoea and flushing) and severity (flushing) 
Episodes of diarrhoea and flushing will be monitored throughout the study by the 
subject. Subjects will record their symptoms by telephoning the IVRS.  
Symptom frequency and severity will be provided after enrolment for the 7 days 
preceding the first study treatment (visit 2). For subjects who require a washout period,
these 7 days preceding the first study treatment will be during the washout period. 
Subjects who require a washout period due to previous treatment with a somatostatin 
analogue prior to study entry will require a search of their medical notes to identify 
NET symptoms upon diagnosis and during prior somatostatin analogue treatment.  
Reporting of 24 hour symptom frequency for diarrhoea and flushing will be made on a 
daily basis for the first 16 weeks of the study; during this period severity of flushing 
episodes only will be recorded. Subsequently, subjects will provide 24 hour symptom 
frequency (diarrhoea and flushing) and severity (flushing only) on days 11 to 17 of each 
subsequent injection interval until week 49. After the final study drug injection at week 
49, subjects will provide 24 hour symptom frequency and severity on a daily basis on 
days 11 to 28.  


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Symptom frequency and severity will be recorded by answering pre-determined 
questions using IVRS:  
(1)
How many times have you had diarrhoea in the last 24 hours? 
(2)
How many times have you had flushing events in the last 24 hours? 
(3)
Overall, how would you rate your flushing events in the last 24 hours? Please 
give an average rating if more than one flushing event occurred.  
Flushing symptom severity will be recorded using a 3 point scoring system: 1.Mild, 
2.Moderate and 3.Severe.  
Symptom frequency (average number of episodes) and severity (worst and mode) will 
be calculated on available data: 
x
at baseline (on the 7 days preceding the first study treatment),  
x
from visit 2 to visit 5 (on daily basis on day 1 to day before next injection),  
x
from visit 6 to visit 14 (on daily basis on days 11 to 17) 
x
at visit 14 (on daily basis on days 11 to 28) 
Average number of episodes of diarrhoea and average number of episodes of flushing 
will be assessed as quantitative variables 
Worst severity and mode severity (value that appears the most frequently) of flushing 
will be assessed as a qualitative variables (Mild; Moderate; Severe) 
x
Clinical symptomatic response 
Clinical symptomatic response will be based on 24 hour symptom frequency and 
severity.  
Subject will be considered to have a clinical symptomatic response, between baseline 
(on the 7 days preceding the first study treatment injection) and last period (on days 11 
to 17 after last injection or after theoretical injection if the subject performed the last 
visit without injection), if: 
x
the average of number of episodes of diarrhoea decreases by at least 50%, 
x
or the average of number of episodes of flushing decreases by at least 50%,  
x
or the mode severity decreases by at least one level. 
Clinical symptomatic response will be assessed as a qualitative variable (Yes; No). 
x
CT/MRI Scan  
Subjects will undergo a CT or MRI scan at screening, weeks 25 and 53 within their 
local hospitals. Scans performed within the 6 weeks prior to the screening visit will not 
need to be repeated. RECIST review from this scan would be sufficient.  
To assess PFS at the end of study, progression will be assessed by the investigator using 
the RECIST criteria version 1.1. 
The time point response at week 25 and at week 53 will be assessed as a qualitative and 
ordinal variable: Complete response (CR), Partial response (PR), Stable disease (SD), 
Progressive disease (PD) and Non evaluable (NE). 
The best overall response to study treatment is the highest time point response achieved 
by the subject and will be assessed as a qualitative variable (CR; PR; SD; PD; NE). 


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PFS and PFS time will be assessed. 
x
Quality of life (QoL) 
Subjects will have to complete QoL questionnaires using the EORTC QLQ-G.I.NET 21 
and the EORTC QLQ-C30 questionnaires to assess the effect of Somatuline Autogel 
treatment on QoL. The questionnaires will be administered at weeks 1 (baseline), 13, 25 
and 53.  
Scores and subscores of EORTC QLQ-G.I.NET 21 and EORTC QLQ-C30 will be 
calculated and assessed as continuous variables. 
x
Urine 5-HIAA and plasma 5-HIAA Samples  
Subjects will be required to provide 24 hour urine samples for 5-HIAA analyses. A 5-
HIAA test is a urine test that measures the amount of 5-HIAA (a breakdown product of 
a hormone called serotonin) that is present in the urine.  
A fasting blood sample of 7.5 mL will be drawn to complete plasma 5-HIAA analysis. 
Urine and blood samples will be collected from subjects at weeks 1 (baseline), 5, 17, 25 
and 53 weeks. Urine 5-HIAA (μmol/day) and plasma 5-HIAA (nmol/L) will be assessed 
as continuous variables. 
x
Chromogranin A (CgA) and neurokinin A  
A total blood sample of 7.5 mL will be drawn to complete CgA and neurokinin A 
analyses. Blood samples will be drawn at weeks 1 (baseline), 5, 17, 25 and 53 weeks. 
CgA (μg/L and in upper limit of normal [ULN]) and neurokinin A (pg/mL) will be 
assessed as continuous variables. 
x
SSTR 2 and SSTR 5  
Samples drawn for CTC enumeration for weeks 1, 5, 25 and 53 will also be utilised for 
SSTR subtype 2 profiling. SSTR subtype 2 will be assessed semi-quantitatively using 
an immunofluorescent marker specifically directed towards the SSTR2. A Fluorescein 
Isothiocyanate (FITC) or Phycoerythrin (PE) labelled rabbit monoclonal antibody 
validated for its specificity for these receptor subtypes will be used for this purpose.  
An additional 10 mL of blood will be drawn at weeks 1, 5, 25 and 53 for SSTR5 
profiling. SSTR subtype 5 will be assessed semi-quantitatively using an 
immunofluorescent marker specifically directed towards the SSTR5. A FITC or PE 
labelled rabbit monoclonal antibody validated for its specificity for these receptor 
subtypes will be used for this purpose.  
Samples of previous biopsies or surgical excisions of either primary tumours or liver 
metastases will be utilised for SSTR subtype 2 and 5 profiling where available using the 
above methods. Similarly, any biopsies or surgical excisions of either primary tumours 
or liver metastases conducted during the course of the study according to clinical need 
will be utilised for SSTR subtype 2 and 5 profiling using the above methods. Samples 
of previous biopsies or surgical excisions of liver metastases conducted either prior to 
the study or if clinically required during the study will also be utilised to investigate the 
genomic profile of this tissue. 


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Subjects with a SSTR2 > 0 will be considered as subjects with SSTR2 presence. SSTR2 
presence will be assessed as a qualitative variable (Yes; No). 
Subjects with a SSTR5 > 0 will be considered as subjects with SSTR5 presence. SSTR5 
presence will be assessed as a qualitative variable (Yes; No). 
For CTC enumeration, Urine 5-HIAA and plasma 5-HIAA Samples, CgA and 
neurokinin A, all clinically relevant abnormal laboratory tests occurring during the 
study will be repeated at appropriate intervals until they return to baseline or to a level 
deemed acceptable by the Investigator and the Sponsor’s clinical monitor (or his/her 
designated representative), or until the abnormality is explained by an appropriate 
diagnosis. 
1.3.2.2.
Safety assessments 
x
AEs 
Adverse Events (AEs) will be monitored from the time that the subject gives informed 
consent to the time when the subjects’ participation in the study is considered to have 
ended. AEs will be elicited by direct, non-leading questioning or by spontaneous 
reports.  
A physical examination will be carried out by a physician. If in the opinion of the 
Investigator there are any clinically significant changes in the physical examination 
findings (abnormalities) they will be recorded as AEs.  
AEs will be coded according to the latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA) and will be classified by MedDRA preferred term 
(PT) and primary system organ class (SOC). 
x
Deaths 
A death report form will be completed including the primary reason for death (Disease 
progression; AE; Other). 
x
Vital signs 
Systolic and diastolic blood pressure (mmHg) and heart rate (bpm) (supine after resting 
for 3 minutes or standing after 1 minute), will be recorded at each study visit. Height 
(cm) and weight (kg) should be measured at weeks 1 (baseline) and 53.  
x
Concomitant medications, Concomitant medications for NET disease / symptoms, 
Concomitant non-drug therapies and Concomitant surgical procedures 
1.3.2.3.
Other assessments 
The other assessments will be the following: 
x
Demography and characteristics at screening / baseline:  
•
Age (years and in classes: ≤ 65; > 65) – calculated, 
•
Sex (Male; Female), 


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•
Race (Asian; Black/African American; Caucasian/White; Native Hawaiian/Other 
Pacific Islander, American Indian/Alaska Native, Multiple), 
•
Body mass index (BMI) at baseline (kg/m² and in classes: <18.5; ≥ 18.5 and < 
25; ≥ 25 and < 30; ≥ 30) – calculated 
x
Significant medical or surgical history (excluding the condition(s) of NET), Prior 
Surgical Procedures for NET, Prior medications, Prior non–drug therapies and Prior 
medications for NET disease / symptoms 
x
Primary Disease Diagnosis / Biopsy 
•
Time since the NET diagnosis (years and in classes: < 3; ≥ 3) – calculated 
•
Location of primary tumour (Jejunum; lleum; Appendix; Second part of the 
duodenum; Ascending colon, right colon; Transverse colon; Caecum; Unknown; 
Other) 
•
The NET is a functioning NET (Yes; No) 
•
Proliferation Index Ki67 (% - in classes: ≤2%; >2% and ≤5%; >5% and <10%; 
≥10%)
•
Result obtained is positive for somatostatin receptor scintigraphy and/or 
68Gallium-DOTATATE PET imaging (Yes; No) 
x
TNM staging  
•
T-Primary Tumour (TX; T0; T1 [T1 or T1a or T1b]; T2; T3; T4) 
•
N-Regional lymph nodes metastasis (NX; N0; N1) 
•
M-Distant metastasis (MX; M0; M1) 
•
ENETS Staging (Stage 0; Stage I [Stage I or Stage Ia or Stage Ib]; Stage IIa; 
Stage IIb; Stage IIIa; Stage IIIb; Stage IV and in 5 classes: Stage 0; Stage I; 
Stage II [Stage IIa or Stage IIb]; Stage III [Stage IIIa or Stage IIIb]; Stage IV) 
x
Urine Pregnancy Test at screening and baseline visits 
•
Urine pregnancy test performed (Yes; No; Not applicable) 
•
If Yes, Result (Positive; Negative) 
x
Diarrhoea frequency, Flushing frequency and severity at diagnosis and during 
somatostatin analogue treatment prior to the washout (only for subjects with a washout 
period) 
•
Diarrhoea (Yes; No; if Yes, number of episodes per day) 
•
Flushing (Yes; No; if Yes, number of episodes per day and intensity [mild; 
moderate; severe]) 
1.3.2.4.
Withdrawal / discontinuation from the study 
The date of early withdrawal and the primary reason for early withdrawal will be recorded 
(adverse event, protocol violation, consent withdrawn, lost-to follow-up, disease progression, 
other).  


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In accordance with the Declaration of Helsinki (in accordance with the applicable UK’s 
acceptance), each subject is free to withdraw from the study at any time. 
For subjects who have PD whilst participating in this study, the treating physician will make a 
clinical decision to continue the subject on the trial or withdraw the subject from the clinical 
trial. Justification would be recorded on the electronic-Case Report Form and subjects’ notes. 
Subjects who have PD and do continue in the clinical trial will continue with all study 
procedures, including administration of investigational medicinal product. 
1.3.2.5.
Compliance 
Compliance assessments will be the following: 
x
Injection (subcutaneous) of Somatuline Autogel performed (Yes; No) for each visit, 
x
120 mg Dose Administered (Yes; No) for visits 2 to 4, 
x
Dose administered (60 mg; 90 mg; 120 mg) for visits 5 to 14, 
x
Time between each drug intake (days and in classes: < 28; 28; > 28) – calculated. 


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1.3.3.
Schedule of assessments 
Table 1: Schedule of Assessments 
Visit
Screening 
period
Washout 
Period(=)
2
3
4
5
6
7
8
9
10
11
12
13
14
15/
early 
withdrawal
Screening Period
Washout Period(=)
2 to 6 
weeks
Weeks following screening **
1
5
9
13
17
21
25
29
33
37
41
45
49
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Informed Consent
X
Pregnancy Testing (Urine)
X
X(a)
Eligibility Criteria Check
X
Samples of previous liver biopsy 
or surgical excision of tumour for 
storage with report (b). 
X
Samples of previous primary 
tumour biopsy or surgical excision 
for storage with report (b) 
X
Samples of liver biopsy or surgical 
excision of tumour for storage with 
report during study (b).
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Samples of primary tumour biopsy 
or surgical excision for storage 
with report during study (b)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographic Data
X
Medical History
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height/Weight
X
X
WHO 2010/TNM status
X
CT/MRI scan with RECIST 
X(c)
X
X
Review subjects’ notes for NET 
symptoms at diagnosis and during 
prior somatostatin analogue 
treatment (d)
X
Subject NET symptom reporting (7 
days) (e)
X


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Visit
Screening 
period
Washout 
Period(=)
2
3
4
5
6
7
8
9
10
11
12
13
14
15/
early 
withdrawal
Screening Period
Washout Period(=)
2 to 6 
weeks
Weeks following screening **
1
5
9
13
17
21
25
29
33
37
41
45
49
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Subject NET symptom reporting
Daily subject NET symptom 
reporting IVRS
Once monthly ( days 11–17) subject  NET symptom reporting IVRS
Days 11–28 subject 
NET symptom 
reporting IVRS
Cell free DNA analyses blood 
sample
X
X
X
CTC blood sample
X
X
X
X
X
CTC genomic profiling blood 
sample (f)
X
X
X
CTC blood sample for SSTR2 
profile (f)
X
X
X
X
CTC blood sample for SSTR5 
profile (g)
X
X
X
X
5-HIAA blood sample
X
X
X
X
X
5-HIAA 24 hour  urine sample
X
X
X
X
X
Chromogranin A blood sample
X
X
X
X
X
Neurokinin A blood sample (h)
X
X
X
X
X
Liver genomic profiling (i)
X
X
X
Subject Questionnaires of Life
X
X
X
X
Clinician review of subject 
reported  NET symptoms
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Titration review
X
Dose titration decision at each visit based upon clinician review of subject reported NET symptoms
Administration of investigational 
medicinal product (120 mg) (j)
X(j)
X
X
X(k)
Administration of 60mg, 90mg or 120mg at each visit after clinician review of subject reported NET 
symptoms
Administration of investigational 
medicinal product (90mg) (j)
X(k)
Administration of investigational 
medicinal product (60mg) (j)
X(k)
Concomitant medication /Non drug 
therapies/surgical procedures 
check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Case Report Form Completion 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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 (=)  Can run alongside screening visits (only if required) 
(**)  +/- 3 days 
(a) 
Only for subjects who have had a delay due to CT/MRI scan and/or wash out period 
(b) 
Request sample for storage and report at the UCL Cancer Institute 
(c) 
To be performed only if a CT/MRI scan is not available from within the 6 weeks prior to study entry 
(d) 
Only wash out subjects
(e)    Subject symptom reporting for seven days before first dosage of Somatuline Autogel  
(f) 
Same blood sample as that taken for CTC enumeration  
(g) 
Separate blood sample to CTC enumeration sample 
(h)   Same blood sample as that taken for chromogranin A 
(i) 
Performed using liver samples available prior to study or if clinically required during study (same sample as used for SSTR profiling) 
(j)    Once all clinical procedures have been completed 
(k) 
First dosage following titration review – 60mg, 90mg or 120mg 
If a subject misses a blood sampling visit the sampling may be performed at the next visit 


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1.3.4.
Planned sample size 
A sample size of 50 subjects has been chosen for this exploratory study based on practical 
considerations with the knowledge that there was some statistical power should the 
relationship between those with measureable CTCs and those without measureable CTCs be a 
clear one. 50 subjects will give an 80% statistical power to be able to detect a difference in 
clinical response rates of around 40% (e.g. 55% in subjects with no measureable CTCs versus 
15% in subjects with measureable CTCs). 


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2.
SUBJECT POPULATIONS (ANALYSIS SETS) 
2.1.
Screened population 
The screened population is defined as all subjects fully informed about the study who have 
given written informed consent. 
2.2.
Enrolled population  
The enrolled population is defined as all screened subjects included at the end of the baseline 
visit. 
2.3.
Efficacy 
2.3.1.
Intention-to-treat population 
The Intention-to-treat (ITT) population is defined as all enrolled subjects who received at 
least one injection of study medication.  
2.3.2.
Per Protocol population  
The Per Protocol (PP) population is defined as all subjects in the ITT population for whom no 
major protocol violations/deviations occurred during the trial.  
Definition of protocol deviations will be managed in a separate document. 
The final status of deviations (minor/major) will be finalized during a blind data review 
meeting. 
Listings of subjects regarding inclusion in each population (i.e. satisfying the population 
definition) and associated data will be reviewed by the study team. Data will be excluded 
from the PP population on a subject basis and not on a visit basis. Reasons for exclusion from 
PP population will be presented in a summary table. 
2.4.
Safety 
The safety population is defined as all enrolled subjects who received at least one injection of 
study medication  
2.5.
Primary populations 
The primary analysis based on the primary efficacy endpoint will be performed on the ITT 
population. In addition a supportive analysis will be performed on the PP population. 
The exploratory primary efficacy endpoint and the secondary efficacy endpoints will be 
analysed on the ITT population and on the PP population if there is a difference of at least 
10% between both populations. 
The analyses of safety data will be performed based on the safety population. 
For all demographic data and other parameters at baseline, if there is a difference of at least 
10% between ITT population and PP population, these tables will be repeated on the PP 
population. 


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3.
STATISTICAL METHODS 
3.1.
Statistical analysis strategy 
All statistical analyses will be performed by the biostatistics unit of LINCOLN managed by 
the sponsor, using the Statistical Analysis System® (SAS®) software version 9.4 (SAS 
Institute Inc., Cary, North Carolina, USA). 
The statistical analyses will be performed in accordance with International Conference on 
Harmonisation E9 guideline. 
3.1.1.
Primary efficacy endpoint 
The primary efficacy endpoint is the assessment of the clinical value of enumerating CTCs to 
predict clinical symptomatic response in subjects receiving Somatuline Autogel. 
3.1.2.
Exploratory primary efficacy endpoint 
The exploratory primary efficacy endpoint is the assessment of the clinical value of 
enumerations of CTCs to describe PFS in subjects receiving Somatuline Autogel. 
3.1.3.
Secondary efficacy endpoint(s) 
The secondary efficacy endpoints are: 
x
Symptoms frequency of diarrhoea and flushing, severity of flushing, 
x
QoL domain scores (via the EORTC QLQ-G.I.NET 21 and EORTC QLQ-C30), 
x
PFS at end of study 
3.1.4.
Exploratory Secondary efficacy endpoint(s) 
The exploratory secondary efficacy endpoints are: 
x
Plasma CgA, urinary and plasma 5-HIAA and plasma neurokinin A levels, 
x
Correlation between urinary and plasma 5-HIAA levels, 
x
The presence of SSTR2 and SSTR5. 
3.1.5.
Safety endpoint(s) 
The safety endpoints are: 
x
AEs, 
x
Deaths, 
x
Vital signs, 
x
Concomitant medications, 
x
Concomitant medications for NET disease/symptoms, 
x
Concomitant non-drug therapies, 
x
Concomitant surgical procedures. 
3.1.6.
Multiplicity 
No adjustment for multiplicity will be performed. 


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3.1.7.
Significance testing and estimation 
As this is an exploratory study, statistical testing will only be carried out for exploratory 
purposes. Unless otherwise stated, testing will be performed two-sided with a type I error rate 
set at 5%.  
Quantitative variables will be summarised in statistical tables indicating the number of non 
missing observations (n), the number of missing data, the mean and standard deviation, the 
median, the quartiles (Q1 and Q3), the minimum and maximum. 95% confidence intervals 
(CI) of the mean and of the median will be presented. 
x
95% CI of the mean will be calculated as follows: 
Lower Limit =
 
Upper limit = 
 
with 
n = number of non-missing observations 
= mean 
z = 1.96 for two-sided 95%CI s = standard deviation 
x
95% CI of the median will be calculated using option CIPCTLDF in the PROC 
UNIVARIATE: 
PROC UNIVARIATE data=… CIPCTLDF alpha=0.05;
VAR variable; 
RUN; 
Qualitative variables will be summarised in statistical tables indicating the number of non 
missing observations (n), frequency and percentage of each modality. Where appropriate, 
95% CI of the proportion will be presented. 
x
95% CI of a proportion will be calculated using the method of Wilson’s score without 
continuity correction [(1)]:
Lower Limit = 
   Upper limit = 
with 
n = number of non-missing observations 
p = percentage 
q = 1 – p 
z = 1.96 for two-sided 95% CI 
For all parameters, the number of missing values will also be reported in the tables, 
but they will not be counted for the percentage calculation (qualitative data). 
3.2.
Analysis methods  
3.2.1.
Efficacy 
3.2.1.1.
Primary efficacy analysis 
The primary efficacy analysis of the clinical symptomatic response and its relationship with 
CTC presence at baseline will be performed on the ITT population (cf. Section 3.2.11 for 
derived CTC presence and clinical symptomatic response). 
A supportive analysis will be performed on the PP population. 
n
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Clinical symptomatic response will be described according to CTC presence at baseline and 
overall using descriptive qualitative statistics including 95% CIs. 
Clinical symptomatic response will also be described according to CTC presence at baseline 
and overall for each category of concomitant medications potentially impacting symptoms
taken (Full, Partial, No - cf Section 3.2.11 for the derivation) using descriptive qualitative 
statistics including 95% CIs. 
To assess the relationship between CTC presence at baseline and clinical symptomatic 
response, a logistic regression with clinical symptomatic response as dependent variable and 
CTC presence at baseline as explanatory variable (reference level = Yes [presence]) will be 
used. The presence of washout period (reference level = No [subjects without washout 
period]) will be taken into account as explanatory variable, if there is at least 20% of subjects 
with a washout period. Results will be presented in terms of odds ratio (OR) associated with 
95% CI and p-value for CTC presence. 
The relationship between CTC presence at baseline and clinical symptomatic response will 
also be assessed adjusted for the presence of other potentially influential subject 
characteristics using multivariate logistic regression. These subject characteristics are 
presented in the Table 2. 
The potentially influential variables will be selected initially on the basis of univariate logistic 
regressions. Only variables with a p<0.2 will be retained for the next step. 
In a second step, each pre-selected characteristic will be tested with the other retained 
characteristics at the 0.001 level to confirm that there is no strong link between them. The 
association between two categorical or binary variables will be tested using  
Chi-square or Fisher’s exact test. If independence is not met for two characteristics (p<0.001), 
the choice will be made according to clinical and statistical relevance. 
Using an appropriate stepwise procedure (entry of variable at a 20% significance level and 
retention of variable at a 5%-level), a final multivariate logistic regression model will be 
derived that includes CTC presence at baseline along with any still influential characteristics. 
From the final model the odds ratio for the effect of CTC presence at baseline on response, 
adjusted for any influential characteristics will be estimated and the associated 95% 
confidence interval calculated. 
PROC LOGISTIC data=Tab; 
Class CTCpresence FactorQuali1 
MODEL Response = CTCpresence FactorQuali1/ include=1 selection=stepwise slstay=0.05 
slentry=0.2; 
run; 


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Table 2: List of variables tested in the logistic regression model 
Factors
Coding
DEMOGRAPHICS
Age (years)
1 if ≤ 65 years (reference)
2 if > 65 years
Sex
1 if Male (reference)
2 if Female
BMI (kg/m²)
1 if < 18.5
2 if >= 18.5 - < 25 (reference)
3 if >= 25 - < 30 
4 if >= 30
PRIMARY DISEASE DIAGNOSIS / BIOPSY
Time since the NET diagnosis (months)
1 if < 3 years (reference)
2 if ≥ 3 years
Location of primary tumour
1 if Jejunum (reference)
2 if Ileum
3 if Appendix 4 if Unknown 
5 if Other (Second part of the duodenum, ascending 
colon, right colon, Transverse colon, Caecum, other)
ENETS Staging
1 if Stage 0 (reference)
2 if Stage I (Stage I or Stage Ia or Stage Ib)
3 if Stage II (Stage IIa or Stage IIb)
4 if Stage III (Stage IIIa or Stage IIIb)
5 if Stage IV
Prior medications for NET
0 if No (reference)
1 if Yes
CONCOMITANT TREATMENTS POTENTIALLY IMPACTING THE SYMPTOMS
Full concomitant medications potentially impacting the 
symptoms taken
0 if No (Partial concomitant treatment or non 
concomitant treatment potentially impacting the 
symptoms - Reference)
1 if Yes
3.2.1.2.
Exploratory primary efficacy analysis 
The exploratory primary efficacy analysis will be performed on the ITT population and on the 
PP population if there is a difference of at least 10% between both populations. 
Time point response at week 25 and at week 53 will be described by CTC presence at 
baseline and overall, using descriptive qualitative statistics including 95% CIs. 
Best Overall Response will be described by CTC presence at baseline and overall, using 
descriptive qualitative statistics including 95% CIs (cf. Section 3.2.11 for derived data). 
For PFS, event dates are assigned to:  
x
The first time when progressive disease was noted, or  
x
Date of death.  
In case of progressive disease followed by death, the first event will be considered in the 
analysis. 
The progressive disease date is assigned to the first time at which progressive disease can be 
declared. 
x
For progressive disease based on a new lesion, the progressive disease date is the date 
of the first radiological assessment when the new lesion was detected. 


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x
For progressive disease based on an increase in the sum of the target lesion 
measurements, the progressive disease date is the date of the last radiological 
assessment of target lesions that shows the predefined increase in the sum of the target 
lesion measurements. 
Censoring dates are defined in subjects with no progressive disease or death before end of 
study. In these subjects, the censoring date is defined as the last date on which progression 
status was ‘adequately’ assessed. This is taken to be the date of the last radiological 
assessment at which the target lesions were evaluated by local review:  
Table 3: Censoring Rules for PFS 
Reason for censoring
Rule
No screening evaluable* assessment 
Date of first treatment administration
One or more not evaluable (NE) assessments 
before progressive disease or death
Date of last evaluable disease assessment before the 
NE assessment
No progressive disease
Date of last evaluable disease assessment
Treatment discontinuation for toxicity or 
other reason
Date of last evaluable disease assessment
* An assessment is considered NE when no imaging/measurement is done at all at a particular time 
point, or only a subset of lesion measurements are made at the time point. The subject is considered 
NE at that time point. 
PFS time (in months) = [(Date of event – date of first injection of study drug) + 1] / 30.4375 
Completely missing tumour data: 
When tumour assessment visits are completely missing, FDA Guidance “Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics” [(3)] states that "events occurring 
after two or more missed radiological assessments will be censored in the analysis at the last 
adequate assessment’. 
The following table shows the event status for various scenarios with missing data: 
Table 4: Event status 
Scan Time
W25
W52
Event status
Scenario 1
missing
missing
Censored at screening
Scenario 2
missing
SD
Censored at W52
Scenario 3
SD
SD
Censored at W52
Scenario 4
SD
missing
Censored at W25
Scenario 5
missing
PD
Censored at W25
PFS time will be analysed by CTC presence at baseline and overall using Kaplan-Meier 
method to obtain the estimates of survival median, Q1 and Q3, the associated 95% CI, 
survival curves for each group and log-rank test p-value will be provided for group 
comparison (cf. Section 3.2.11 for derived data).  
The syntax with SAS using the LIFETEST procedure will be: 


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Proc lifetest data=… method=km outsurv=t graphics plot=(s); 
Time time*cens(1); 
Strata CTCpresence; 
Run; 
The Cox Proportional hazard model will be fitted to compute hazard ratios and the 
corresponding 95% CI with CTC presence at baseline as fixed factors. 
The syntax with SAS using the PHREG procedure will be: 
Proc phreg data=...; 
Class CTCpresence; 
Model time*cens(1) = CTCpresence / risklimits; 
Run; 
The Cox Proportional hazard model will be also fitted to compute hazard ratios and the 
corresponding 95% CI with CTC presence at baseline as fixed factors, adjusted for the 
presence of other potentially influential subject characteristics. These subject characteristics 
are presented in the Table 2.
The potentially influential variables will be selected initially on the basis of univariate 
analysis. Only variables with a Wald test p<0.2 will be retained for the next step. 
In a second step, each pre-selected characteristic will be tested with the other retained 
characteristics at the 0.001 level to confirm that there is no strong link between them. The 
association between two categorical or binary variables will be tested using  
Chi-square or Fisher’s exact test. If independence is not met for two characteristics  
(p <0.001), the choice will be made according to clinical and statistical relevance. 
Using an appropriate stepwise procedure (entry of variable at a 20% significance level and 
retention of variable at a 5%-level), a final model will be derived that includes CTC presence 
at baseline along with any still influential characteristics.  
The maximum likelihood estimates of model coefficients (with associated standard error,
Wald Chi–square statistic and p-value) will be presented for the final model along with the 
hazard ratios and 95% CIs. 
The check of the proportional hazard assumption will be performed graphically for each 
categorical or ordinal factor using the LOG of the negative LOG of survival curve. 
The syntax with SAS using the PHREG procedure is: 
Proc phreg data=…;
Class CTCpresence FactorsQuali; 
Model time*Cens(1)=CTCpresence FactorsQuali/
include=1 rl selection=stepwise 
slstay=0.05 slentry=0.2; 
Run; 
3.2.1.3.
 Secondary efficacy analyses 
The secondary efficacy analyses will be performed on the ITT population and on the PP 
population if there is a difference of at least 10% between both populations. 


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x
Description of CTC enumeration over time 
The CTC enumeration and CTC presence will be described at week 1 (baseline), 5, 17, 
25 and 53.  
For CTC enumeration, raw and change from baseline values will be described at each 
time point by sample (cf. Section 3.2.11 for calculation).  
For CTC presence, raw values will be described at each time point by sample, using 
descriptive qualitative statistics including 95% CIs. Shift table from baseline will be 
also described at each time point by sample. 
x
Effect of Somatuline Autogel on the symptoms of diarrhoea and flushing in 
subjects with a functioning NET  
Symptoms frequency of diarrhoea and flushing (average number of episodes), severity 
of flushing (worst intensity and mode) will be described at each time point.  
For symptoms frequency of diarrhoea and flushing (average number of episodes), raw 
and change from baseline values will be described at each time point by CTC presence 
at baseline and overall, for all subjects, for subjects with a washout period and for 
subjects without washout period (cf. Section 3.2.11 for calculation).  
For severity of flushing (worst intensity and mode), raw values will be described at each 
time point by CTC presence at baseline and overall, for all subjects, for subjects with a 
washout period and for subjects without washout period, using descriptive qualitative 
statistics including 95% CIs. Shift table from baseline will be also described at each 
time by CTC presence at baseline and overall, for all subjects, for subjects with a 
washout period and for subjects without washout period. 
x
Effect of Somatuline Autogel treatment on quality of life via the EORTC QLQ-
G.I.NET 21 and EORTC QLQ-C30  
The scores and subscores of EORTC QLQ-G.I.NET 21 and EORTC QLQ-C30 will be 
described at week 1 (baseline), 13, 25 and 53. Raw and change from baseline values 
will be described at each time point (cf. Section 3.2.11 for calculation). 
x
PFS at the end of study  
PFS rate at the end of study will be estimated by CTC presence and overall at baseline 
using Kaplan-Meier method (cf. Section 3.2.1.2 for definition of PFS). 
3.2.1.4.
Exploratory secondary analyses 
The exploratory secondary efficacy analyses will be performed on the ITT population. 
x
Effect of Somatuline Autogel on plasma CgA, urinary and plasma 5-HIAA and 
plasma neurokinin A, and whether these biomarkers correlate with CTC presence 
Plasma CgA, urinary and plasma 5-HIAA and plasma neurokinin A levels will be 
described at week 1 (baseline), 5, 17, 25 and 53.. Raw and change from baseline values 
will be described at each time point (cf. Section 3.2.11 for calculation). 
For each biomarker, the correlation with CTC presence will be tested at each time point 
using analysis of variance. In the event that normality is revealed to be unreasonable,
Wilcoxon test will be performed. 


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x
Correlation between urinary 5-HIAA and plasma 5-HIAA 
The correlation between urinary and plasma 5-HIAA levels will be tested at each time 
point using Pearson correlation coefficients, as well as p-values, if the normality of the 
distribution of parameters (p-value of Shapiro-Wilk test ≥ 5%) can be assumed. In case 
of strong violation of normality, Spearman coefficients of correlation will be provided. 
x
Presence of SSTR subtypes 2 and 5  
The the presence of SSTR2 and SSTR5 will be described at week 1 (baseline), 5, 25 and 
53.
For presence of SSTR2 and SSTR5 (cf. Section 3.2.11 for calculation), raw values will 
be described at each time point, using descriptive qualitative statistics including 95% 
CIs. Shift table from baseline will be also described at each time point. 
3.2.2.
Safety 
All safety data will be included in the data listings and summary tables will be based on the 
safety population. 
3.2.2.1.
Adverse events 
AEs will be coded according to the MedDRA (version 18.0) and will be classified by SOC 
and PT.
Listings will be presented and sorted by subject id, primary SOC, PT and verbatim text for all 
AEs recorded during the study. 
Listings of serious AEs (SAE), AE leading to study drug discontinuation, drug related AEs 
and listings of deaths will also be presented. 
Treatment Emergent AEs (TEAE) will be flagged (*) in the AEs listing and will be 
summarised.  
A TEAE is defined as any AE that occurs from the first study drug injection until 28 days 
after the last study drug injection if:  
x
it was not present prior to receiving the first dose of study drug, or  
x
it was present prior to receiving the first dose of study drug but the intensity increased 
during the active phase of the study, or  
x
it was present prior to receiving the first dose of study drug, the intensity is the same 
but the drug relationship became related during the active phase of the study. 
An overall summary table of all AEs will be presented. 
TEAEs will be summarised overall with the number and percentage of subjects with AEs 
classified by primary SOC, PT (ordered alphabetically). The number of occurrences of a 
TEAE will also be presented. 


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In addition, summary tables will also be presented for AEs, SAEs, non SAEs, TEAEs leading 
to study drug discontinuation, TEAE leading the study withdrawal, drug–related TEAE, 
TEAE leading to drug interruption, TEAEs per decreasing frequency and TEAEs by 
maximum intensity and causality. 
In the event of multiple AEs (corresponding to same PTs) being reported by the same subject, 
the maximum intensity (severe > missing > moderate > mild) and the most serious causality 
(related > not related) will be chosen. 
In the event of multiple adverse events (corresponding to different PTs) being reported by the 
same subject, each subject is counted for each intensity level, each causality level or each 
intensity and causality combined level. That means that the total of subjects for all levels of 
intensity / causality might be higher than the overall number of subjects with at least one AE. 
Note: For intensity*causality combined description, missing causalities are taken into account 
only in the related level / missing intensities are taken into account only in the severe level 
Moreover, the number of deaths and primary reason for death will be described. 
3.2.2.2.
Laboratory data 
All laboratory data (Section 8.3.4 of the protocol) are regarded as efficacy assessments in this 
study and therefore analyses as part of the efficacy endpoints (See Section 3.2.1).
3.2.2.3.
Vital signs 
Baseline values will be defined as the last vital signs measurement collected prior to the first 
injection of study drug i.e. at week 1 (Baseline visit).  
Vital signs (systolic and diastolic blood pressure, heart rate, height and weight) will be 
described for raw values and changes from baseline at each time point for systolic and 
diastolic blood pressure and heart rate and at weeks 1 and 53 for height and weight.  
3.2.3.
Missing data and outliers 
3.2.3.1.
Missing data 
Missing data will not be imputed and dropouts will not be replaced. 
If a value requires a retest (for laboratory values, vital signs), the closest non–missing reliable 
value to the scheduled visit is used in the summary tables. An assessment is considered 
reliable if it is performed without any technical problem and if the result is within the range of 
plausible values. 
For adverse events with missing information for the intensity and causality, the value will not 
be replaced and will be summarized as a separate category. 
Rules for missing data for PFS are addressed in Section 3.2.1.2.
Rules for missing data for the clinical symptomatic response and for the frequency and 
severity of symptoms will be addressed in Section 3.2.11.
Rules for missing data imputation for QoL scores calculation will be addressed in Section 
3.2.11.


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3.2.3.2.
Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been recorded. 
However, for calculation / sorting / assignation based on dates, the following methods will be 
used: 
x
The most conservative approach will be systematically considered (i.e. if the onset date 
concomitant medication is missing / incomplete, it is assumed to have occurred during 
the study treatment phase except if the partial onset date or other data [stop date, …] 
indicates differently). 
x
A missing/incomplete date of medical history or disease diagnosis will be assumed to 
have occurred before the study inclusion. 
x
If a partial date and the associated information do not allow to state about the 
assignation to a group / category, all the possible groups / categories will be considered 
(i.e.: a medication with partial start and stop dates could be considered as prior and 
concomitant treatment). 
x
Where this is possible, the derivations based on a partial date will be presented as 
superior inequalities (i.e. for a medication started in FEB2004 after the administration 
performed on 31JAN2004, the days since last dose will be “≥2”, similarly the duration 
of ongoing medication will be“≥xx” according to the start and last visit dates).
For partially missing dates for efficacy endpoints derived, adverse event and death, the 
following imputation rules will be used:  
x
If the day is missing, but month and year are known (UN-MMM-YYYY), it will be 
imputed by the 1st of the month (01-MMM-YYYY). If this implementation rule 
produces a date before the first injection of study treatment, then the date of start of 
study treatment is used. 
x
If the day and month is missing, but year is known (UN-UN-YYYY), it will be imputed 
by the 1st of January (01-JAN-YYYY). If this implementation rule produces a date 
before the first injection of study treatment, then the date of start of study treatment is 
used. 
3.2.3.3.
Outliers 
Any outlier identified prior to data base lock which is impossible/implausible will be 
excluded from the analysis.  
For other identified outliers, the impact should be assessed by performing the statistical 
analysis with the actual values and at least one other analysis eliminating or reducing the 
outlier effect.  
If any outliers are identified after the database lock, the statistical analysis should be 
performed with the actual values and at least one other analysis eliminating or reducing the 
outlier effect.  
A search of outliers for the CTC enumeration will be performed before the database lock and 
actions with the sponsor will be defined during data review meeting. 
3.2.4.
Subject disposition  
A listing of dates of assessments (relative day) and their study exposure will be presented by 
subject. 


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A summary table will present the number and percentages of subjects enrolled included in 
each analysis set, overall and by centre.  
The reason for subjects’ exclusion from each of the analysis set will also be tabulated.
The numbers of subjects who received the study drug, discontinued and completed the study 
will be tabulated. A subject is considered as having completed the study when “Completed 
the study” is ticked in the Case Report Form at visit 15 (Week 53). The primary reason for 
early study withdrawal will be provided (adverse event, protocol violation, consent 
withdrawn, lost-to follow-up, disease progression, other). 
A summary table (and a flow chart) will be performed for each analysis set (Safety 
population, ITT and PP population) presenting the number and proportion of subjects overall 
at each visit. 
A summary table will present the duration of study drug exposure and the extent of subject 
exposure in the study (weeks). The length of exposure is defined as the number of days 
between the date of consent and the last study visit date. 
A listing of dates of visit and calculated time interval since the baseline visit (days) will be 
presented by subject. 
3.2.5.
Withdrawals  
Discontinued subjects will be listed and a summary table of the number and percentage of 
subjects who withdrew from the study and the reasons for withdrawal will be presented 
overall. 
3.2.6.
Demographic and baseline characteristics 
All demographic and baseline characteristics will be listed by subject. 
Descriptive summary statistics will be provided by subgroup (subjects with a washout period 
versus subjects without washout period) and overall for demographic and baseline 
characteristics, for the ITT population. It includes assessments as detailed in the Section 
1.3.2.3 (Demography and characteristics at screening, , Primary Disease Diagnosis / Biopsy, 
TNM staging, Urine Pregnancy Test at screening and baseline visits, Diarrhoea frequency, 
Flushing frequency and severity at diagnosis and during somatostatin analogue treatment 
prior to the washout (only for subjects with a washout period)).  
3.2.7.
Medical and surgical history 
Significant medical or surgical history will be coded using the MedDRA version 18.0. 
Listings will present the PT and verbatim text. The listings will be sorted by subject, primary 
SOC, PT and verbatim text.  
A frequency table of the number and percentage of subjects will be provided for all medical 
and surgical history by SOC class and PT for the ITT population. 
3.2.8.
Prior surgical procedures for NET 
Prior surgical procedures will be coded using the MedDRA version 18.0. 


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Listings will present the PT and verbatim text. The listings will be sorted by subject, primary 
SOC, PT and verbatim text.  
A frequency table of the number and percentage of subjects will be provided for all prior 
surgical procedures for NET by SOC class and PT for the ITT population. 
3.2.9.
Compliance 
A listing will be presented for drug administration by subject, on the ITT population. 
Deviations from observed and scheduled times will be presented. 
The number of injections will be presented on the ITT population, as well as the number of 
subjects with a dose of 120 mg throughout the study, those who switched for a dose of 60 mg, 
those who switched for a dose of 90 mg and those with a combination of 60/90/120 mg dose. 
The cumulative dose will be also presented on the ITT population. 
The compliance (%) will be calculated as the ratio of the actual number of injections over the 
planned number of injections, then multiplied by 100 (cf. Section 3.2.11 for calculation).  
A summary table of compliance will be presented on the ITT population. Additionally, the 
number and percentage of subjects with compliance ≤ 80% will be described using descriptive 
qualitative statistics including 95% CIs. 
Descriptive summary statistics will be provided including assessments as detailed in the 
Section 1.3.2.5 ‘Compliance’ on the ITT Population. 
The number and % of subjects who took concomitant treatment potentially impacting the 
symptoms (Full, Partial, No) will be described using descriptive qualitative statistics 
including 95% CIs  (cf. Section 3.2.11 for derivation). 
3.2.10.
Prior and concomitant therapies 
Descriptive summary statistics will be provided on the ITT population for prior therapies and 
on the Safety population for concomitant therapies.  
Prior and concomitant medications / Prior medications for NET / Concomitant medications 
for NET disease/symptoms: 
Prior and concomitant medications will be coded using WHO-Drug Dictionnary Enhanced B2 
format of March 2015. The therapeutic class will correspond to the second level of Anatomic 
Therapeutic Class (ATC) code. 
A concomitant medication will be defined as a medication started prior to the baseline visit 
date and ongoing at the baseline visit date, or started the day of the baseline visit or after. A 
prior medication will be defined as a medication started prior to the baseline visit date and 
stopped prior or the day of the baseline visit date.  
Listings containing prior and concomitant medications will be presented for the therapeutic 
class, preferred name and verbatim text, and will be sorted by centre, subject, chronological 
start date, therapeutic class, preferred name and verbatim text. 
A frequency table of the number and percentage of subjects will be provided for prior and 
concomitant medications only by therapeutic class and preferred name. 
Prior and concomitant non-drug therapies and concomitant surgical procedures: 
Prior and concomitant non-drug therapies and concomitant surgical procedures will be coded 
using MedDRA version 18 and will be classified by PT and SOC. 


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A concomitant therapy will be defined as a therapy started prior to the baseline visit date and 
ongoing at the baseline visit date, or started the day of the baseline visit or after. A prior 
therapy will be defined as a therapy started prior to the baseline visit date and stopped prior or 
the day of the baseline visit date. 
Listings containing prior and concomitant non-drug therapies and concomitant surgical 
procedures will be presented for the SOC, PT and verbatim text, and will be sorted by centre, 
subject, chronological start date, SOC, PT and verbatim text. 
A frequency table of the number and percentage of subjects will be provided for prior and 
concomitant non-drug therapies and concomitant surgical procedures only by SOC and PT. 
3.2.11.
Derived data 
The derived data are variables which are calculated from the raw data and not included in the 
database. 
Date of withdrawal 
If the subject performed an early withdrawal visit, the date of withdrawal will be equal to the 
date of this visit. Else the date of withdrawal will be equal to: 
-
The date of withdrawal consent if the subject withdrew his consent, 
-
The start date of AE if the subject withdrew for AE, 
-
The date of death if the subject died, 
-
The date of withdrawal if the subject withdrew for “Other reason”. 
Age 
Age will be derived as (Date of screening – Date of birth) / 365.25. 
The result will be truncated to the largest integer that is less than or equal to the calculated 
result. 
Following classes will be defined: ≤ 65 years, > 65 years. 
BMI at baseline 
BMI (kg/m²) at baseline will be derived as [Weight (kg) at baseline / (Height (cm) at baseline/ 
100)²] 
Following classes will be defined:< 18.5 kg/m², ≥ 18.5 - < 25 kg/m², ≥ 25 - < 30 kg/m², ≥ 30 
kg/m². 
Time since the NET diagnosis 
Time since the NET diagnosis (years) will be derived as (Date of screening visit – Date of 
NET diagnosis +1)/ 365.25 
If the day is missing, it will be imputed by ’01’.
Following classes will be defined: < 3 years, ≥ 3 years. 
Time between each drug intake 
Time between each drug intake (days) will be derived as (Date of drug intake at Visitt – Date 
of drug intake at Visitt-1 +1). 


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No imputation for partial missing dates will be done. 
Following classes will be defined: <28, 28, >28. 
Compliance 
Compliance (%) will be derived as Actual number of injections / Planned number of 
injections * 100 
Following classes will be defined: ≤ 80%, > 80%. 
For medical and surgical history, prior and concomitant medication, prior and 
concomitant non-drug therapy: 
Duration of events (days) will be derived as (Date of stop – date of start or diagnosis) + 1 
Type of concomitant medications potentially impacting symptoms 
A concomitant medication potentially impacting symptoms will be considered as “Full” if :
-
The 
medication 
is 
“ANTIPROPULSIVES”, 
“SOMATOSTATIN 
AND 
ANALOGUES” or “OTHER INTESTINAL ANTIINFECTIVES”
-
And the medication was started before the start of the last period of symptoms 
collection (on days 11 to 17 after last injection) 
-
And the medication was ongoing during the last period of symptoms collection 
(i.e. ongoing at the end of study or stopped after the end of the last period of 
symptoms). 
A concomitant medication potentially impacting symptoms will be considered as “Partial” if :
-
The 
medication 
is 
“ANTIPROPULSIVES”, 
“SOMATOSTATIN 
AND 
ANALOGUES” or “OTHER INTESTINAL ANTIINFECTIVES”
-
And the medication was not started before the start of the last period of symptoms 
collection (on days 11 to 17 after last injection) or the medication was not ongoing 
during the last period of symptoms collection 
Any other concomitant medications will be considered as “No”. 
If a subject meets both the “Full” and the “Partial” definition, the subjects will be classified in 
the “Full” category. 
Changes from baseline  
Changes from baseline will be calculated as a difference from baseline (e.g. assessment at the 
visit – assessment at baseline). 
Length of subject exposure in the study 
Length of subject exposure in the study (weeks) will be calculated as [(Date of last visit 
attended – informed consent date) +1] / 7. 
Duration of study drug exposure 
Duration of study drug exposure (weeks) will be calculated as [(Date of last study drug 
administration – Date of first study drug administration) +1 ] /7. 


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Adverse event 
Time to onset of AE (days) = AE start date – date of first study drug administration. 
Duration of AE (days) = (AE resolution date – AE start date) + 1. 
CTC presence 
CTC presence will be defined as: 
CTC presence = Yes if subject has at least CTC enumeration > 0 in either or both samples 
CTC presence = No if subject has CTC enumeration = 0 in both samples 
In case of missing value, if both (CTC for sample 1 and sample 2) are missing, the CTC will 
be considered as missing. 
In case of missing value for one CTC and the second one is equal to 0, the CTC will be 
considered as absent. 
In case of missing value for one CTC and the second one is larger than 0, the CTC will be 
considered as present. 
CTC  - Sample 1
CTC - Sample 2
CTC present
>0
>0
Yes
0
>0
Yes
0
0
No
>0
0
Yes
.
0
No
0
.
No
.
>0
Yes
>0
.
Yes
.
.
Missing
Clinical symptomatic response 
Clinical symptomatic response will be defined as: 
Clinical symptomatic response = Yes if between baseline (on the 7 days preceding the first 
study treatment) and last period (on days 11 to 17 after last injection or after theoretical 
injection if the subject performed the last visit without injection), there is  
x a reduction of at least 50% of the average number of episodes of diarrhoea = percent 
change from baseline to last period ≥ -50% 
x OR a reduction of at least 50% of the average number of episodes of flushing = percent 
change from baseline to last period ≥ -50% 
x OR a reduction of at least one level of mode severity = mode severity at last period < 
mode severity at baseline 
Clinical symptomatic response = No if between baseline (on the 7 days preceding the first 
study treatment) and last period (on days 11 to 17 after last injection), there is  
x No reduction of at least 50% of the average number of episodes of diarrhoea 
x AND no reduction of at least 50% of the average number of episodes of flushing  
x AND no reduction of at least one level of mode severity 


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If more than 50% of the 7 days are missing, no imputation will be performed for the 
concerned parameter. 
The clinical symptomatic response will be defined as soon as one parameter is available. 
Frequency and severity of symptoms 
Average number of episodes (for diarrhoea or flushing) = Sum of number of episodes / 
Number of days with available data. 
Worst severity (for flushing) = Highest severity 
Mode severity (for flushing) = Most frequent severity. In case of ties (ie 2 modes within the 
period) the highest mode (ie conservative method) will be kept. 
If more than 50% of the days are missing, the average number of episodes (for diarrhoea or 
flushing) and the mode severity (for flushing) will be missing. 
Nadir 
Nadir is defined as the smallest sum longest diameter recorded since the treatment started. 
Best overall response (RECIST version 1.1):
The best overall response to study treatment is the highest time point response achieved by 
the subject and will be classified as CR, PR, SD, PD and not evaluable (NE) 
PFS 
See in Section 3.2.1.2.
Quality of life 
x
Questionnaire EORTC QLQ-C30 score and subscores 
The scale is made of 30 items that can be divided in nine multi-item scales (including 
five functional scales (15 items), one global health status / quality of life scale (2 
items) and three general symptom scales (7 items)) and six single items. The Table 
below presents the conceptual structure of QLQ-C30. 
Possible answers to the first 28 items (all items except the two concerning global 
quality of life) go from 1 (“Not at all”) to 4 (“Very much”). No inversion is necessary 
to calculate the different corresponding scores. The answers for the two last questions 
(29, 30) go from 1 (“Very poor”) to 7 (“Excellent”).


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Table 5: Conceptual structure of QLQ-C30
Dimension
Sub-scales
Number of items
Item numbers
FUNCTION
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
5
2
4
2
2
1 to 5
6, 7
21, 22, 23, 24
20, 25
26, 27
GLOBAL HEALTH STATUS
Global quality of life
2
29, 30
GENERAL SYMPTOMS
Fatigue
Nausea and vomiting 
Pain
3
2
2
10, 12, 18
14, 15
9, 19
SPECIFIC SYMPTOMS
Dyspnoea
Insomnia
Appetite loss
Constipation
Diarrhea
Financial difficulties
1
1
1
1
1
1
8
11
13
16
17
28
Scores will be calculated in agreement with the scoring manual [(2)]. All of the scales 
and single-item measures range in score from 0 to 100. A high scale score represents a 
higher response level. Thus a high score for a functional scale represents a high / 
healthy level of functioning, a high score for the global health status / quality of life 
represents a high quality of life, but a high score for a symptom scale / item represents 
a high level of symptomatology / problems. 
For multi-item scales, the raw score will be calculated by the addition of item 
responses divided by the number of items. Then a linear transformation will be used to 
standardise the raw score, so that scores range from 0 to 100; a higher score represents 
a higher (“better”) level of functioning, or a higher (“worse”) level of symptoms.
Raw score (RS): 
RS = sum of item responses / number of items. 
Standardised score (S): 
Functional scales: S = 100 – [(RS – 1) / 3] x 100. 
Global health status: S = (RS – 1) / 6 x 100. 
Symptom scales / items: S = (RS – 1) / 3 x 100. 
Missing data 
For multi-item scales, if at least 50% of the items from the scale have been answered 
then raw score will be calculated by the addition of available responses divided by the 
number of not missing items. If less than 50% of the items from the scale have been 
answered then the raw score will be set to missing. 
x
EORTC QLQ-G.I.NET 21 score and subscores 
The scale is made of 21 items that can be divided in five multi-item scales and four 
single items. The following table presents the conceptual structure of G.I.NET 21. 


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Table 6 : Conceptual structure of G.I.NET 21 
Number of items
Item numbers
Multi-item scales
Endocrine
Gastro Intestinal
Treatment
Social function
Disease related worries
3
5
3
3
3
31, 32, 33
34, 35, 36, 37, 38
39, 40, 46
42, 44, 49
41, 43, 47
Single items
Muscle/Bone pain 
Sexual function
Information/communication 
function
Body image
1
1
1
1
48
51
50
45
Possible answers go from 1 (“Not at all”) to 4 (“Very much”). A high score is 
equivalent to worse or more problems. The subject can also answer “N.A” to items 39, 
40, 47 and 51. No inversion is necessary to calculate the different scores. 
For each scale, the raw score will be calculated by the addition of item responses 
divided by the number of items. Then a linear transformation will be used to 
standardise the raw score, so that scores range from 0 to 100. 
Raw score = sum of item responses / number of items. 
Standardised score = (raw score – 1) / 3 x 100. 
Single items will be treated individually. They will be linearly transformed to a 0-100 
scale. 
Standardised score = (raw score – 1) / 3 x 100. 
Missing data 
For multi-item scales, if at least 50% of the items from the scale have been answered 
then raw score will be calculated by the addition of available responses divided by the 
number of not missing items. 
Not applicable box 
For calculations N/A data should be managed as for missing data. 
CgA (ULN) 
CgA will be derived in ULN as CgA (μg/L) / ULN (μg/L). 
SSTR presence 
SSTR presence will be defined as: 
SSTR presence = Yes if subject has SSTR enumeration > 0 
SSTR presence = No if subject has SSTR enumeration = 0 


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3.2.12.
Visit windows 
All data will be organised and analysed according to the scheduled visits outlined in the 
protocol. However, actual observation times may differ from the scheduled visit times and 
where this occurs the results should be allocated to the most appropriate visit. Therefore, time 
intervals (e.g. visit windows) have been constructed so that every observation collected after 
the baseline visit can be allocated to a particular time point. If more than one record occurs 
within the same visit window where only one assessment is expected then the following rule 
should be applied: for pre-study assessments only one record is expected and corresponds to 
the baseline visit; for post-treatment assessments the closest non-missing result to the 
scheduled visit should be used.  
Scheduled visit
Time interval (days)
used for analysis (Consecutive 
intervals)
Treatment period
Baseline - Week 1 [V2]
Day 1
1
Week 5 [V3]
Day 29
2 to 42
Week 9 [V4]
Day 57
43 to 70
Week 13 [V5]
Day 85
71 to 98
Week 17 [V6]
Day 113
99 to 126
Week 21 [V7]
Day 141
127 to 154
Week 25 [V8]
Day 169
155 to 182
Week 29 [V9]
Day 197
183 to 210
Week 33 [V10]
Day 225
211 to 238
Week 37 [V11]
Day 253
239 to 266
Week 41 [V12]
Day 281
267 to 294
Week 45 [V13]
Day 309
295 to 322
Week 49 [V14]
Day 337
323 to 350
After study treatment
End of Study (V15) / 
Early withdrawal
Four weeks after the subject’s last 
treatment visit
Note: Any subjects who have previously received either subcutaneous octreotide or one injection of a long 
acting somatostatin analogue will also be considered for this study following a washout period of 2 weeks after 
the last subcutaneous octreotide injection or a 6 week washout period after a single long acting somatostatin 
analogue injection.
Time interval (days) = Date of visit – date of first study drug intake +1
3.2.13.
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the number of 
decimal places used does not imply undue precision). Raw data will be presented to the 
number of decimal places collected, and derived data will be presented to an appropriate 
number of decimal places.  The appropriate number of decimal places will be determined by 
general practice, mathematical rationale or scientific rationale (e.g. age should be presented in 
whole numbers).  
For summary statistics, the following will be presented: n, number of missing data, arithmetic 
mean, standard deviation, median, first quartile, third quartile, minimum and maximum. 95% 
CI of the mean and of the median will be presented. 
Mean, median, quartiles and standard deviation values will be reported to one decimal place 
greater than the raw/derived data that they summarise. Minimum and maximum values will be 
reported with the same precision as the raw data. 


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Lower and upper CI values should be presented to one decimal place more than the 
raw/derived data (i.e., to the same number of decimal places as the mean). 
Percentiles (e.g., 25%, 75%) should be presented to one decimal place more than the 
raw/derived data.  
Percentages will be reported to one decimal place and 0% will not be presented. Percentages 
will be calculated using a denominator of all subjects in a specified population with non-
missing observations. The denominator will be specified in a footnote to the tables for 
clarification if necessary. 
P-values will be reported to three decimal places (e.g.: p=0.037), after rounding.  
P-values which are less than 0.001 will be presented as ‘<0.001’.
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as such. In 
summaries of data values below limit of detection will be set to the limit of detection. Values 
above limit of detection will be set to limit of detection. 
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
not done, unknown, <4.5, …) must be decimal justified. Dates and times will be presented in 
the format as defined in the data-base, i.e.  [ddmmmyyyy] and [hh:mm] respectively. 
3.2.14.
Pooling of Centres 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
3.2.15.
Interim analysis 
No interim analysis will be performed. 
3.2.16.
Covariates and analysis of subgroups 
For the primary efficacy analysis, to assess the relationship between CTC presence at baseline 
and clinical symptomatic response, a logistic regression with clinical symptomatic response as 
dependent variable and CTC presence at baseline as explanatory variable (reference level = 
Yes [presence]) will be used. The presence of washout period (reference level = No [subjects 
without washout period]) will be taken into account as explanatory variable, if there is at least 
20% of subjects with a washout period. 
The relationship between CTC presence at baseline and clinical symptomatic response will 
also be assessed adjusted for the presence of other potentially influential subject 
characteristics using multivariate logistic regression. These subject characteristics are: Age, 
Sex and BMI, Time since diagnosis, Location of primary tumour, ENETs staging and prior 
medication for NET. 
For the exploratory primary efficacy, to assess the relationship between CTC presence at 
baseline and PFS, a Cox Proportional hazard model will be used with the same variables as 
for the primary efficacy analysis. 
Clinical symptomatic response, PFS rate and PFS will be described according to CTC 
presence (Section 3.2.1).
Symptoms frequency of diarrhoea and flushing (average number of episodes), severity of 
flushing (worst intensity and mode) will be described according to CTC presence, for all 
subjects, for subjects with a washout period and for subjects without washout period. 
Demographic and baseline characteristics will be described by subgroup (subjects with a 
washout period versus subjects without washout period).


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4.
COMPUTER 
SYSTEMS, 
SOFTWARE 
AND 
VALIDATION 
OF 
PROGRAMS 
4.1.
Hardware 
The statistical analysis will be performed using Windows 7 or XP Pro and PCs will be used to 
run the SAS programs. 
4.2.
Software 
All tables, listings and figures will be produced and statistical analysis performed using 
SAS version 9.2. All outputs will be in Microsoft Word Format. 
4.3.
Validation programs 
Validation of SAS programs will be performed by Lincoln as described in Lincoln Standard 
Operating Procedure “Analyse statistique”.
The CRO will provide a Validation Plan to Ipsen identifying the methods of validation.  
The Program Reviewer is responsible for reviewing each project program and output 
associated with the deliverable product. Program logs are reviewed for logical, syntax and 
fatal errors. The review in SAS includes, but is not limited to, all ERRORS, WARNINGS, 
BY-VALUE merge messages, NOTES, and UNINITIALIZED variables. Program logs are 
also reviewed for accurate and consistent variable and observation counts following each 
procedure and data step. 
The Reviewing/QC Statistician is responsible for checking and reviewing the work produced 
using whatever method he/she feels is appropriate (e.g., SAS code review, hand calculation, 
etc.) to reassure of the quality of the output. 
Outputs are reviewed for typographical errors, misspellings and nonsensical values or results 
and to check the consistency with the reporting and analysis plan. Outputs are cross-checked 
against each other for accuracy and consistency. For statistical tables, listings, appendix 
listings, and figures, this procedure includes comparison of subject group numbers, counts of 
subjects at each observation point, and consistency of results for variables between outputs. 
Findings of the quality control reviews are communicated to the party responsible for making 
necessary changes. The programs will be retested after modifications. 
After final review, and when no further changes are required to produce the deliverable, the 
Program Reviewer and Reviewing/QC Statistician need to complete and sign the CRO’s 
Validation Checklist/Sign-off Sheet, to indicate that they have successfully performed all of 
their responsibilities. 
Copies of the internal QC forms produced for the validation process and the Lincoln’s sign-
off forms will be provided to the sponsor to support the validation. 
4.4.
Restitution of the programs 
All programs (including Macros specifically written for this study and analysis datasets) 
producing the tables, listings and statistical output along with associated logs should be given 
to the sponsor when the tables, listings, figures and statistical analysis has been finalised. 


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5.
CHANGES FROM PROTOCOL 
Genomic profile of CTCs, genomic profile of liver metastases and density of SSTR2 and 
SSTR5 were not collected. Therefore, the following exploratory secondary objectives on 
these criteria will be not investigated: 
x
To investigate the genomic profile of CTCs at baseline and at the time of any observed 
progression (RECIST review). 
x
To investigate the genomic profile of liver metastases at the time of any observed 
progression (RECIST review) in appropriate subjects. 
x
To evaluate the density of SSTR2 and SSTR5, and compare the density with subjects’ 
clinical symptomatic response and PFS during Somatuline Autogel treatment. 
x
To compare the density of SSTR2 and SSTR5 with the density on primary tumour and 
liver metastasis in patients where the primary tumour or liver metastasis samples are 
available. 
More precisely, density analyses planned in the protocol will not be performed and are 
therefore not detailed in this RAP. The density/intensity of staining was not validated at the 
time of the genomic analyses by UCL. In order to validate density of staining, UCL would 
have required several cell lines with various expression levels and these were not available.   
The correlation of biomarkers (CgA, plasma and urine 5-HIAA and neurokinin A) will be 
explored with CTC presence instead of CTC number and no plot will be performed. 
Before 24APR2015, SSTR2 and SSTR5 were not analysed. Therefore only one sample was 
taken for CTC dosage. 
After 24APR2015, SSTR2 and SSTR5 were analysed. Therefore two samples were taken and 
CTC dosage were performed for both samples, except for Visit 6 (as per protocol, only CTC 
dosage were planned). 
The definition of the safety population has been modified and defined as all enrolled subjects 
who received at least one injection of study medication instead of all enrolled subjects who 
received at least one dose of study medication and have at least one post-baseline safety 
assessment (AE, vital signs). 
For subjects with a washout period, symptom frequency and severity are provided during the 
washout period for the 7 days preceding the first study treatment. Therefore, as the baseline 
data could be different between subjects: 
x
Demographic and baseline characteristics will be described by subgroup (subgroup 
(subjects with a washout period versus subjects without washout period). 
x
For the primary endpoint, the washout period presence (Yes / No) will be taken into 
account in the model if there is at least 20% of patients with a washout. 
x
The effect of Somatuline Autogel on the symptoms of diarrhoea and flushing in 
subjects with a functioning NET will be analysed by subgroup (subjects with a washout 
period versus subjects without washout period) and overall. 
Medications potentially impacting symptoms (eg loperamide, nifuroxazide, octreotide 
infusion) were not forbidden for ethical reasons. Subjects having taken these treatments were 
identified (Full, Partial, No - cf. Section 3.2.11 for derivation) and the following analyses
were added: 
x
Clinical symptomatic response will be described according to CTC presence at baseline 
and overall for each category of concomitant medications potentially impacting 
symptoms taken (Full, Partial, No),




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16.2.3 SUBJECTS EXCLUDED FROM THE PP ANALYSIS 
Listing 16.2.3: Subjects Excluded from the ITT, Safety or PP Populations – Screened 
Population 
16.2.4 DEMOGRAPHIC DATA 
Listing 16.2.4.1: Demographics – Screened Population 
Listing 16.2.4.2: Urine Pregnancy Test – Screened Population 
Listing 16.2.4.3: Tumour Characteristics – Screened Population 
Listing 16.2.4.4/1: Significant Medical or Surgical History – Verbatim Terms and Associated 
MedDRA Terms 
Listing 16.2.4.4/2: Significant Medical or Surgical History – Screened Population 
Listing 16.2.4.5/1: Prior Surgical Procedures for Neuroendocrine Tumour – Verbatim Term 
and Associated MedDRA Terms 
Listing 16.2.4.5/2: Prior Surgical Procedures for Neuroendocrine Tumour – Screened 
Population 
Listing 16.2.4.6/1: Prior Medications for Neuroendocrine Tumour – Drug Name and 
Associated WHO-DD Terms 
Listing 16.2.4.6/2: Prior Medications for Neuroendocrine Tumour – Screened Population 
Listing 16.2.4.7/1: Prior and Concomitant Medications – Drug Name and Associated WHO-
DD Names 
Listing 16.2.4.7/2: Prior and Concomitant Medications – Screened Population 
Listing 16.2.4.8/1: Prior and Concomitant Non-Drug Therapies – Verbatim Term and 
Associated MedDRA Terms 
Listing 16.2.4.8/2: Prior and Concomitant Non-Drug Therapies – Screened Population 
Listing 16.2.4.8/3: Prior and Concomitant Non-Drug Therapies – Screened Population 
Listing 16.2.4.9/1: Concomitant Medications for Neuroendocrine Tumour Disease / 
Symptoms – Drug Name and Associated WHO-DD Names 
Listing 16.2.4.9/2: Concomitant Medications for Neuroendocrine Tumour Disease / 
Symptoms – Screened Population 
Listing 16.2.4.9/3: Concomitant Medications for Neuroendocrine Tumour Disease / 
Symptoms – Screened Population 
Listing 16.2.4.10/1: Concomitant Surgical Procedures – Verbatim Term and Associated 
MedDRA Terms 
Listing 16.2.4.10/2: Concomitant Surgical Procedures – Screened Population 
Listing 16.2.4.11/1: Baseline Symptoms: Diarrhoea and Flushing at Diagnosis – Only for 
Subjects with a Washout Period - Screened Population 
Listing 16.2.4.11/2: Baseline Symptoms: Diarrhoea and Flushing during Somatostatin 
Analogue Treatment Prior to the Washout Period – Only for Subjects with a Washout Period - 
Screened Population 
Listing 16.2.4.12/1: Adverse Events Starting Prior to First Study Drug Administration –
Verbatim Terms and Associated MedDRA Terms 
Listing 16.2.4.12/2: Adverse Events Starting Prior to First Study Drug Administration –
Screened Population 


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Listing 16.2.4.12/3: Adverse Events Starting Prior to First Study Drug Administration –
Screened Population 
16.2.5 COMPLIANCE AND/OR DRUG CONCENTRATION DATA 
Listing 16.2.5.1: Study Drug Administration – Screened Population 
Listing 16.2.5.2: Overall Study Drug Exposure – Screened Population 
16.2.6 INDIVIDUAL EFFICACY RESPONSE DATA 
Listing 16.2.6.1: Clinical Symptomatic Response – Screened Population 
Listing 16.2.6.2.1/1: Assessment of Target Lesions – Screened Population 
Listing 16.2.6.2.1/2: Assessment of Target Lesions – Screened Population 
Listing 16.2.6.2.2: Target Lesions Response Assessment – Screened Population 
Listing 16.2.6.2.3/1: Assessment of Non-Target Lesions – Screened Population 
Listing 16.2.6.2.3/2: Assessment of Non-Target Lesions – Screened Population 
Listing 16.2.6.2.4: Assessment of New Lesions – Screened Population 
Listing 16.2.6.2.5: Overall Response Assessment – Screened Population 
Listing 16.2.6.2.6: Progression Free Survival – Screened Population 
Listing 16.2.6.3.1: CTC Evaluation – Screened Population 
Listing 16.2.6.3.2: CTC Enumeration – Screened Population 
Listing 16.2.6.4.1: Diarrhoea Frequency – Screened Population 
Listing 16.2.6.4.2: Flushing Frequency and Severity – Screened Population 
Listing 16.2.6.5.1: EORTC-QLQ-C30 Quality of Life Questions 
Listing 16.2.6.5.2/1: EORTC-QLQ-C30 Quality of Life Responses – Screened Population 
Listing 16.2.6.5.2/2: EORTC-QLQ-C30 Quality of Life Responses – Screened Population 
Listing 16.2.6.5.3/1: EORTC-QLQ-C30 Quality of Life Scale Scores – Screened Population 
Listing 16.2.6.5.3/2: EORTC-QLQ-C30 Quality of Life Scale Scores – Screened Population 
Listing 16.2.6.5.3/3: EORTC-QLQ-C30 Quality of Life Scale Scores – Screened Population 
Listing 16.2.6.5.4: EORTC QLQ-G.I.NET21 Quality of Life Questions 
Listing 16.2.6.5.5: EORTC QLQ-G.I.NET21 Quality of Life Responses – Screened 
Population 
Listing 16.2.6.5.6/1: EORTC QLQ-G.I.NET21 Quality of Life Scale Scores – Screened 
Population 
Listing 16.2.6.5.6/2: EORTC QLQ-G.I.NET21 Quality of Life Scale Scores – Screened 
Population 
Listing 16.2.6.6.1: Urine 5-HIAA Samples Evaluation – Screened Population 
Listing 16.2.6.6.2: Plasma 5-HIAA Samples Evaluation – Screened Population 
Listing 16.2.6.6.3: Neurokin A and Chromogranin A (CgA) Evaluation – Screened Population 
Listing 16.2.6.6.4: Tumour Markers, with Change from Baseline – Screened Population 
Listing 16.2.6.6.5: SSTR2 and SSTR5 – Screened Population 
Listing 16.2.6.6.6: Death Reporting Status During the Course of the Study – Screened 
Population 


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16.2.7 ADVERSE EVENT LISTINGS (EACH SUBJECT) 
Listing 16.2.7.1: All Adverse Events – Screened Population 
Listing 16.2.7.2: Serious Adverse Events – Screened Population 
Listing 16.2.7.3: Adverse Events Leading to Study Drug Discontinuation – Screened 
Population 
Listing 16.2.7.4: Drug Related Adverse Events – Screened Population 
Listing 16.2.7.5: Deaths – Screened Population 
16.2.8 LISTING OF INDIVIDUAL LABORATORY MEASUREMENTS BY SUBJECT 
Listing 16.2.8.1/1: Vital Signs – Screened Population 
Listing 16.2.8.1/2: Vital Signs – Screened Population 
Listing 16.2.8.2: Physical Examination – Screened Population 
7.2.
Listing templates 
Listing templates are provided in Appendix 8.1. The listings will be presented in landscape, in 
a fixed font (courier or SAS monospace) with a minimum size as 8 and according to the 
standard margins defined in SOP GEN014. 
The page number of each listing shell (n of N) represent n=page number of the listing and 
N=total number of pages for that specific listing. 
7.3.
Tables index 
14. TABLES, FIGURES AND GRAPHS 
14.1 DEMOGRAPHIC DATA 
Table 14.1.1.1: Study Periods and Sample Sizes – Screened Population 
 
Table 14.1.1.2: Subject Disposition – Screened Population  
Table 14.1.2: Subject Populations – Screened Population  
Table 14.1.3: End of Study Record (Reason for Withdrawals) – Enrolled Population 
 
Table 14.1.4: Primary Reasons for Study Withdrawals by Visit – Screened Population  
Table 14.1.5: Reasons for Exclusion from the Analysis – Screened Population 
 
Table 14.1.6.1: Subject Disposition – ITT Population 
 
Table 14.1.6.2: Subject Disposition – PP Population 
 
Table 14.1.7: Study Administration and Study Exposure – ITT Population 
 
Table 14.1.8.1: Demographics and Baseline Characteristics – ITT Population 
 
Table 14.1.8.2: Demographics and Baseline Characteristics – PP Population 
 
Table 14.1.9.1: Tumour Characteristics – ITT Population  
Table 14.1.9.2: Tumour Characteristics – PP Population 
 
Table 14.1.10.1 Tumour Symptoms – Only for Subjects with a Washout Period – ITT 
Population 
 
Table 14.1.10.2: Tumour Symptoms – Only for Subjects with a Washout Period – PP
Population 
 


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Table 14.1.11.1: Significant Medical or Surgical History – ITT Population 
 
Table 14.1.11.2: Significant Medical or Surgical History – PP Population  
Table 14.1.12.1: Prior Surgical Procedures for Neuroendocrine Tumour – ITT Population 
Table 14.1.12.2: Prior Surgical Procedures for Neuroendocrine Tumour – PP Population 
Table 14.1.13.1: Prior Medications for Neuroendocrine Tumour – ITT Population 
 
Table 14.1.13.2: Prior Medications for Neuroendocrine Tumour – PP Population  
Table 14.1.14.1: Prior Medications – ITT Population 
 
Table 14.1.14.2: Prior Medications – PP Population 
 
Table 14.1.15.1: Prior Non-Drug Therapies – ITT Population 
 
Table 14.1.15.2: Prior Non-Drug Therapies – PP Population 
 
Table 14.1.16: Concomitant Medications for Neuroendocrine Tumour – Safety Population 
Table 14.1.17: Concomitant Medications – Safety Population 
 
Table 14.1.18: Concomitant Non-Drug Therapies – Safety Population 
 
Table 14.1.19: Concomitant Surgical Procedures – Safety Population 
 
14.2 EFFICACY DATA 
Table 14.2.1.1: Primary Efficacy Endpoint – Clinical Symptomatic Response According to 
CTC Presence at Baseline – ITT Population  
Table 14.2.1.2: Primary Efficacy Endpoint – Relationship between CTC Presence at Baseline 
and Clinical Symptomatic Response Adjusted on Influential Characteristics – Univariate 
Logistic Regression – ITT Population 
 
Table 14.2.1.3: Primary Efficacy Endpoint – Relationship between CTC Presence at Baseline 
and Clinical Symptomatic Response Adjusted on Influential Characteristics – Association 
between the Significant Variables at 20% Level in the Univariate Logistic Regression – ITT 
Population 
 
Table 14.2.1.4: Primary Efficacy Endpoint – Relationship between CTC Presence at Baseline 
and Clinical Symptomatic Response Adjusted on Influential Characteristics – Multiple 
Logistic Regression with Stepwise Selection – ITT Population 
 
Table 14.2.1.5: Primary Efficacy Endpoint – Clinical Symptomatic Response According to 
CTC Presence at Baseline – PP Population  
Table 14.2.1.6: Primary Efficacy Endpoint – Relationship between CTC Presence at Baseline 
and Clinical Symptomatic Response Adjusted on Influential Characteristics – Univariate 
Logistic Regression – PP Population 
Table 14.2.1.7: Primary Efficacy Endpoint – Relationship between CTC Presence at Baseline 
and Clinical Symptomatic Response Adjusted on Influential Characteristics – Association 
between the Significant Variables at 20% Level in the Univariate Logistic Regression – PP 
Population 
 
Table 14.2.1.8: Primary Efficacy Endpoint – Relationship between CTC Presence at Baseline 
and Clinical Symptomatic Response Adjusted on Influential Characteristics – Multiple 
Logistic Regression with Stepwise Selection– PP Population 
 
Table 14.2.2.1: Exploratory Primary Efficacy Endpoint – Time Point Response at Week 25 
and Week 53 – ITT Population 
 
Table 14.2.2.2: Exploratory Primary Efficacy Endpoint – Best Overall Response – ITT 
Population 
 
Table 14.2.2.3: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – ITT Population  


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Figure 14.2.2.1: Exploratory Primary Efficacy Endpoint – Kaplan-Meier plot for Progression 
Free Survival at the End of the Study – Survival Curve by Group – ITT Population 
 
Figure 14.2.2.2: Exploratory Primary Efficacy Endpoint – Kaplan-Meier plot for Progression 
Free Survival at the End of the Study – Survival Curve – ITT Population  
Table 14.2.2.4: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – Cox Proportional Hazard Model Adjusted on Influential Characteristics –
Univariate Analyses – ITT Population 
 
Table 14.2.2.5: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – Associations between the Significant Variable at a 20% Level in the 
Univariate Analyses (Cox Proportional Hazard Model) – ITT Population  
Table 14.2.2.6: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – Cox Proportional Hazard Regression Models – Multivariate Analysis with 
Stepwise Selection – ITT Population 
Table 14.2.2.7: Exploratory Primary Efficacy Endpoint – Time Point Response at Week 25 
and Week 53 – PP Population 
 
Table 14.2.2.8: Exploratory Primary Efficacy Endpoint – Best Overall Response – PP 
Population 
 
Table 14.2.2.9: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – PP Population 
 
Figure 14.2.2.3: Exploratory Primary Efficacy Endpoint – Kaplan-Meier plot for Progression 
Free Survival at the End of the Study – Survival Curve by Group – PP Population 
 
Figure 14.2.2.4: Exploratory Primary Efficacy Endpoint – Kaplan-Meier plot for Progression 
Free Survival at the End of the Study – Survival Curve – PP Population  
Table 14.2.2.10: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – Cox Proportional Hazard Model Adjusted on Influential Characteristics –
Univariate Analyses – PP Population 
 
Table 14.2.2.11: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – Associations between the Significant Variable at a 20% Level in the 
Univariate Analyses (Cox Proportional Hazard Model) – PP Population  
Table 14.2.2.12: Exploratory Primary Efficacy Endpoint – Progression Free Survival at the 
End of the Study – Cox Proportional Hazard Regression Models – Multivariate Analysis with 
Stepwise Selection– PP Population  
Table 14.2.3.1.1: Secondary Efficacy Endpoint – CTC Enumeration Over Time – Summary 
Statistics on Raw Data with Change from Baseline – ITT Population 
 
Table 14.2.3.1.2: Secondary Efficacy Endpoint – CTC Presence Over Time – Summary 
Statistics on Raw Data – ITT Population 
 
Table 14.2.3.1.3: Secondary Efficacy Endpoint – CTC Presence Over Time – Shift Table –
ITT Population 
 
Table 14.2.3.1.4: Secondary Efficacy Endpoint – CTC Enumeration Over Time – Summary 
Statistics on Raw Data with Change from Baseline – PP Population 
 
Table 14.2.3.1.5: Secondary Efficacy Endpoint – CTC Presence Over Time – Summary 
Statistics on Raw Data – PP Population 
 
Table 14.2.3.1.6: Secondary Efficacy Endpoint – CTC Presence Over Time – Shift Table – PP
Population 
 


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Table 14.2.3.2.1.1/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline – ITT Population 
Table 14.2.3.2.1.1/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline – ITT Population 
Table 14.2.3.2.1.2/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects with 
a Washout Period – ITT Population  
Table 14.2.3.2.1.2/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects with 
a Washout Period – ITT Population  
Table 14.2.3.2.1.3/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects 
without Washout Period – ITT Population  
Table 14.2.3.2.1.3/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects 
without Washout Period – ITT Population  
Table 14.2.3.2.2.1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Summary Statistics on Raw Data – ITT Population  
Table 14.2.3.2.2.2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Summary Statistics on Raw Data for Subjects with a Washout Period – ITT Population  
Table 14.2.3.2.2.3: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Summary Statistics on Raw Data for Subjects without Washout Period – ITT Population 
Table 14.2.3.2.3.1/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table – ITT Population  
Table 14.2.3.2.3.1/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table – ITT Population  
Table 14.2.3.2.3.2/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects with a Washout Period – ITT Population  
Table 14.2.3.2.3.2/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects with a Washout Period – ITT Population  
Table 14.2.3.2.3.3/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects without Washout Period – ITT Population 
 


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Table 14.2.3.2.3.3/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects without Washout Period – ITT Population 
 
Table 14.2.3.2.4.1/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline – PP Population 
Table 14.2.3.2.4.1/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline – PP Population 
Table 14.2.3.2.4.2/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects with 
a Washout Period – PP Population  
Table 14.2.3.2.4.2/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects with 
a Washout Period – PP Population  
Table 14.2.3.2.4.3/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects 
without Washout Period – PP Population 
 
Table 14.2.3.2.4.3/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Diarrhoea or Flushing in Subjects with a Functioning NET – Average Number 
of Episodes – Summary Statistics on Raw Data with Change from Baseline for Subjects 
without Washout Period – PP Population 
 
Table 14.2.3.2.5.1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Summary Statistics on Raw Data – PP Population  
Table 14.2.3.2.5.2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Summary Statistics on Raw Data for Subjects with a Washout Period – PP Population  
Table 14.2.3.2.5.3: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Summary Statistics on Raw Data for Subjects without Washout Period – ITT Population 
Table 14.2.3.2.6.1/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table – PP Population  
Table 14.2.3.2.6.1/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table – PP Population  
Table 14.2.3.2.6.2/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects with a Washout Period – PP Population  
Table 14.2.3.2.6.2/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects with a Washout Period – PP Population  


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Table 14.2.3.2.6.3/1: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects without Washout Period – PP Population  
Table 14.2.3.2.6.3/2: Secondary Efficacy Endpoint – Effect of Somatuline Autogel on the 
Symptoms of Flushing in Subjects with a Functioning NET – Worst and Mode Severity –
Shift Table for Subjects without Washout Period – PP Population  
Table 14.2.3.3.1: Secondary Efficacy Endpoint – Quality of Life – EORTC QLQ-C30 –
Summary Statistics on Raw Data with Change from Baseline – ITT Population  
Table 14.2.3.3.2: Secondary Efficacy Endpoint – Quality of Life – EORTC QLQ-G.I.NET21 
– Summary Statistics on Raw Data with Change from Baseline – ITT Population  
Table 14.2.3.3.3: Secondary Efficacy Endpoint – Quality of Life – EORTC QLQ-C30 –
Summary Statistics on Raw Data with Change from Baseline – PP Population 
 
Table 14.2.3.3.4: Secondary Efficacy Endpoint – Quality of Life – EORTC QLQ-G.I.NET21 
– Summary Statistics on Raw Data with Change from Baseline – PP Population  
Table 14.2.3.4.1: Secondary Efficacy Endpoint – Progression-Free Survival Rate at the End of 
Study – Kaplan Meier Analysis – ITT Population  
Table 14.2.3.4.2: Secondary Efficacy Endpoint – Progression-Free Survival Rate at the End of 
Study – Kaplan Meier Analysis – PP Population 
 
Table 14.2.4.1.1: Exploratory Secondary Endpoint – Urine 5-HIAA, Plasma 5-HIAA, 
Chromogranin A (CgA) and Neurokinin A Samples – Summary Statistics on Raw Data with 
Change from Baseline – ITT Population 
 
Table 14.2.4.1.2: Exploratory Secondary Endpoint – Correlation between Biomarker and CTC 
presence at baseline – ITT Population 
 
Table 14.2.4.1.3: Exploratory Secondary Endpoint – Urine 5-HIAA, Plasma 5-HIAA, 
Chromogranin A (CgA) and Neurokinin A Samples – Summary Statistics on Raw Data with 
Change from Baseline – PP Population 
 
Table 14.2.4.1.4: Exploratory Secondary Endpoint – Correlation between Biomarker and 
CTCs Value – PP Population  
Table 14.2.4.2.1: Exploratory Secondary Endpoint – Correlation between Urinary 5-HIAA 
and Plasma 5-HIAA – ITT Population 
 
Table 14.2.4.2.2: Exploratory Secondary Endpoint – Correlation between Urinary 5-HIAA 
and Plasma 5-HIAA – PP Population 
 
Table 14.2.4.3.1: Exploratory Secondary Endpoint – Enumeration of SSTR 2 and SSTR 5–
Summary Statistics on Raw Data with Change from Baseline – ITT Population  
Table 14.2.4.3.2: Exploratory Secondary Endpoint – Presence of SSTR 2 and SSTR 5–
Summary Statistics on Raw Data – ITT Population  
Table 14.2.4.3.3: Exploratory Secondary Endpoint – Presence of SSTR 2 and SSTR 5– Shift 
Table – ITT Population 
 
Table 14.2.4.3.4: Exploratory Secondary Endpoint – Enumeration of SSTR 2 and SSTR 5–
Summary Statistics on Raw Data with Change from Baseline – PP Population 
 
Table 14.2.4.3.5: Exploratory Secondary Endpoint – Presence of SSTR 2 and SSTR 5–
Summary Statistics on Raw Data – PP Population  
Table 14.2.4.3.6: Exploratory Secondary Endpoint – Presence of SSTR 2 and SSTR 5– Shift 
Table – PP Population 
 


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14.3 SAFETY DATA 
14.3.1 Display of Adverse Events 
Table 14.3.1.1: Overall Summary of Adverse Events – Safety Population  
Table 14.3.1.2: Number (%) of Subjects Reporting Treatment Emergent Adverse Events by 
Primary System Organ Class and Preferred Term – Safety Population 
 
Table 14.3.1.3: Number (%) of Subjects Reporting Adverse Events by Primary System Organ 
Class and Preferred Term – Safety Population 
 
Table 14.3.1.4: Number (%) of Subjects Reporting Serious Adverse Events by Primary 
System Organ Class and Preferred Term – Safety Population 
 
Table 14.3.1.5: Number (%) of Subjects Reporting Non Serious Adverse Events by Primary 
System Organ Class and Preferred Term – Safety Population 
 
Table 14.3.1.6: Number (%) of Subjects Reporting TEAEs Leading to Study Drug 
Discontinuation by Primary System Organ Class and Preferred Term – Safety Population 
Table 14.3.1.7: Number (%) of Subjects Reporting TEAEs Leading to the Study Withdrawal 
by Primary System Organ Class and Preferred Term – Safety Population  
Table 14.3.1.8: Number (%) of Subjects Reporting Drug-Related TEAE by Primary System 
Organ Class and Preferred Term – Safety Population 
 
Table 14.3.1.9: Number (%) of Subjects Reporting TEAE Leading to Drug Interrupted by 
Primary System Organ Class and Preferred Term – Safety Population 
 
Table 14.3.1.10: Number (%) of Subjects Reporting TEAEs Per Decreasing Frequency of 
Primary System Organ Class and Preferred Term – Safety Population 
 
Table 14.3.1.11: Number (%) of Subjects Reporting TEAEs by Maximal Intensity and 
Causality – Safety Population 
 
14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2.1: Listing of Deaths – Safety Population 
 
Table 14.3.2.2: Listing of Serious Adverse Events – Safety Population 
 
Table 14.3.2.3: Listing of Adverse Events Leading to Study Drug Discontinuation – Safety 
Population 
 
Table 14.3.2.4: Listing of Drug-Related Adverse Events – Safety Population 
 
14.3.3 Vital Signs 
Table 14.3.3.1: Vital Signs – Systolic and Diastolic Blood Pressure and Heart Rate – Safety 
Population 
 
Table 14.3.3.2: Vital Signs – Height and Weight – Safety Population 
 
7.4.
Table templates 
Table templates are provided for each unique table in Appendix 8.2. The tables will be 
presented in landscape, in a fixed font (courier or SAS monospace) with a minimum size as 8 
and according to the standard margins defined in SOP GEN014. 


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7.5.
Figure templates 
Figure templates are provided for each unique figure in Appendix 8.3. The figures will be 
presented in landscape, in a fixed font (courier or SAS monospace) with a minimum size as 8 
and according to the standard margins defined in SOP GEN014. 
7.6.
Statistical Appendix  
A Statistical Appendix for inclusion in the study report will be provided. All the methods used 
in checking the assumptions of the analyses and conclusions should be included and 
explained. Transformation of the data or other methods used for the statistical analysis other 
than the ones detailed in the RAP will be described and the change will be justified. All the 
SAS output will be included without reworking the data (raw output).  
This output should contain the study number, the date, the number of pages printed by SAS 
and the table number to which it refers. Any other relevant information (e.g. statistical 
references…) will be added in the Statistical Appendix.
8.
APPENDICES