Clinical trial NCT02365584
Conditions: Intestinal Obstruction
Sponsor: Ipsen
Start date: 2015-01-01; Completion date: 2018-01-16
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the impact on quality of life of Lanreotide Autogel 120 mg in combination with standard care, in comparison to the standard care alone, in subjects affected by inoperable malignant bowel obstruction.

Detailed description:

Arms: arm 1: Standard care according to site clinical practice and Lanreotide Autogel 120 mg by deep subcutaneous route, at the maximal scheduled standard dose of 120 mg/28 days, just for 1 administration. arm 2: Standard care according to site clinical practice.
Interventions: intervention 1: lanreotide (Autogel formulation)
Intervention descriptions: intervention 1: Lanreotide Autogel 120 mg by deep subcutaneous route, at the maximal scheduled standard dose of 120 mg/28 days, just for 1 administration.

Protocol documents:
Prot_001.pdf: 
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A PHASE II, MULTICENTRE, RANDOMIZED CONTROLLED STUDY EVALUATING 
THE QUALITY OF LIFE IN PATIENTS WITH INOPERABLE MALIGNANT BOWEL 
OBSTRUCTION TREATED WITH LANREOTIDE AUTOGEL 120 MG IN COMBINATION 
WITH STANDARD CARE VS. STANDARD CARE ALONE (QOL IN IMBO STUDY). 
STUDY PROTOCOL 
STUDY number: A-93-52030-279
Product Name: Ipstyl 
EudraCT number: 2013-003176-12 
 
Final Version 1.0 – 13/May/2014 
Sponsor’s Medically Responsible Person: 
Sponsor’s Co-ordinating Office: 
 
Medical Advisor  
Ipsen SpA - Italy 
 
Clinical Research Manager 
Ipsen SpA - Italy 
 
Pharmacovigilance/Emergency Contact  
 
 
Ipsen SpA
Cell: 
  
 
  
 
Full Sponsor contact details, including phone and fax 
number, will be documented in the Trial Master File and in 
the Investigator Study File. 
 
 
Co-ordinating Principal Investigator: 
Dr. Piero Morino                                                                       
Data Management & Statistic Support: 
Resp. of Palliative Care Unit of Florence ASL  
Azienda Sanitaria Firenze 
Hospice Convento delle Oblate 
Piazza di Careggi, 1 
50139 Firenze  
Tel: 
 
Fax:
 
 
Persons supplied with this information must understand that it is strictly confidential. Information contained 
herein cannot be disclosed, submitted for publication or used for any purpose other than that contemplated 
herein without the Sponsor’s prior written authorisation.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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COORDINATING INVESTIGATOR’S AGREEMENT 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol Number A-93-52030-279 and title “A PHASE II, 
MULTICENTRE, RANDOMIZED CONTROLLED STUDY EVALUATING THE QUALITY OF 
LIFE IN PATIENTS WITH INOPERABLE MALIGNANT BOWEL OBSTRUCTION TREATED 
WITH LANREOTIDE AUTOGEL 120 MG IN COMBINATION WITH STANDARD CARE VS. 
STANDARD CARE ALONE (QOL IN IMBO STUDY)”. 
I am aware of my responsibilities as a coordinating investigator under the guidelines of Good 
Clinical Practice (GCP)1, local regulations (as applicable) and the study protocol. I agree to 
conduct the study according to these guidelines and to appropriately direct and assist the staff 
under my control, who will be involved in the study. 
   
 
 
Name & Surname:________________________ Signature: _______________________ 
 
 
Title: COORDINATING  INVESTIGATOR 
 
Date: ________________ 
 
 
SITE:__________________________________ 
_________________________________________ 
_________________________________________ 
 
                                                 
1 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) 
Step 5, adopted by CPMP July 1996.  
2 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) 
Step 5, adopted by CPMP July 1996.  


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PROTOCOL SIGNATURES 
Investigator Signature: 
I have read and agree to the Protocol Number A-93-52030-279 and title “A PHASE II, 
MULTICENTRE, RANDOMIZED CONTROLLED STUDY EVALUATING THE QUALITY OF 
LIFE IN PATIENTS WITH INOPERABLE MALIGNANT BOWEL OBSTRUCTION TREATED 
WITH LANREOTIDE AUTOGEL 120 MG IN COMBINATION WITH STANDARD CARE VS. 
STANDARD CARE ALONE (QOL IN IMBO STUDY)”. 
I am aware of my responsibilities as an Investigator under the guidelines of Good Clinical 
Practice (GCP)2, local regulations (as applicable) and the study protocol. I agree to conduct 
the study according to these guidelines and to appropriately direct and assist the staff under 
my control, who will be involved in the study.
 
Name & Surname:________________________ Signature: _______________________ 
 
Title: PRINCIPAL INVESTIGATOR 
 
Date: ________________ 
 
SITE:____________________________________ 
_________________________________________  
_________________________________________ 
Full investigational site contact details, including telephone numbers, will be documented in 
the Trial Master File. 
 
On behalf of the Sponsor: 
 
Name & Surname: 
 
Signature: _______________________ 
 
Title: Medical Advisor  
 
 
 
Date: ________________ 
 
SITE: MEDICAL DIVISION  
          Ipsen SpA - Italy 
                                                 
2 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) 
Step 5, adopted by CPMP July 1996.  
PPD


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SYNOPSIS 
 
Study title 
A PHASE II, MULTICENTRE, RANDOMIZED CONTROLLED 
STUDY EVALUATING THE QUALITY OF LIFE IN PATIENTS WITH 
INOPERABLE MALIGNANT BOWEL OBSTRUCTION TREATED 
WITH LANREOTIDE AUTOGEL 120 MG IN COMBINATION WITH 
STANDARD CARE VS. STANDARD CARE ALONE (QOL IN IMBO 
STUDY)”. 
Study Objectives: 
Primary Objective:
To evaluate the impact on Quality of Life (Edmonton Symptom 
Assessment System, ESAS total score) of LAN ATG 120 mg in 
combination with standard care, in comparison to the standard care 
alone.  
Secondary Objectives: 
1) To evaluate the impact of LAN ATG 120 mg on each ESAS item 
and total score; 
2) To assess General activity (Karnofsky performance status) and 
Abdominal Pain (Visual analogue scale);  
3) To assess the efficacy of LAN ATG 120 mg for the relief of 
vomiting in patients without nasogastric tube  (NGT);  
4) To assess the efficacy of LAN ATG 120 mg on NGT secretion 
volumes or to remove NGT without recurrence of vomiting in 
patients with a nasogastric tube; 
5) Passage of stools (Yes/No); 
6) Descriptive analysis of optional ESAS item 10; 
7) To assess the efficacy in reducing concomitant medications/ 
analgesics intake. 
 
Safety objectives 
To assess the clinical and laboratory safety of the study treatment. 
Phase of Trial
Phase II 
Study Design 
This is a phase II, multicentre, prospective, randomized, parallel 
arms, open-label study.
Patients meeting the selection criteria for participation will need to 
provide a written informed consent.  
Patients will be asked to complete the Edmonton Symptom 
Assessment System (ESAS), before any study procedure.  
Patients will then be randomized in two groups:   
Group A: Standard care + 1 injection of LAN ATG 120 mg  
Group B: Standard care 
ESAS will be assessed at Day 1,2,3,4,5,6, 7, Day 14 and Day 28.  
Safety will be assessed in both arms continuously during 28 days. 
 
 


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Study Population: 
84 patients with inoperable bowel obstruction of malignant origin in 
Italy.  
 
Inclusion Criteria: 
1) Subjects must demonstrate  willingness to participate in the 
study and to be compliant with any protocol procedure. 
2) Provision of written informed consent prior to any study related 
procedure. 
3) Male or female aged  18 years at the time of enrolment. 
4) Diagnosis of an inoperable malignant bowel obstruction, 
confirmed by appropriate imaging report. 
5) In case of peritoneal carcinomatosis, diagnostic confirmation by 
CT or MRI scan; 
6) Confirmed as inoperable after medical advice; 
7) Patient with a nasogastric tube or presenting with 3 or more 
episodes of vomiting every day in the last consecutive 48 hours; 
8) Patient life expectancy must be more than 14 days. 
 
Exclusion Criteria: 
1) Operable obstruction or any subobstruction; 
2) Bowel 
obstruction 
due 
to 
a 
non-malignant 
cause; 
(hypokaliaemia, drug side-effects, renal insufficiency, etc) 
3) Signs of bowel perforation; 
4) Prior treatment with somatostatin or any analogue within the 
previous 60 days;  
5) A known hypersensitivity to any of the study treatments or 
related compounds. 
6) Is likely to require treatment during the study with somatostatin 
or any analogue other than the study treatment. 
7) Is at risk of pregnancy or lactation, or is likely to father a child 
during the study. Females of childbearing potential must 
provide a negative pregnancy test at start of study and must be 
using oral or double barrier 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. 
8) Has any mental condition rendering the subject unable to 
understand the nature, scope and possible consequences of the 
study, and/or evidence of an uncooperative attitude. 
9) Has abnormal baseline findings, any other medical condition(s) 
or laboratory findings that, in the opinion of the Investigator, 
might jeopardise the subject’s safety or decrease the chance of 
obtaining satisfactory data needed to achieve the objective(s) of 
the study.
 
 


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Study Treatment:
Investigational Medicinal Product (IMP): 
Patients will be randomized in two groups:
Group A: Standard care + 1 injection of LAN ATG 120 mg 
Group B: Standard care
 
General Definition of Standard care:
-
Oral food or oral liquid intake according to clinical 
judgement; 
-
Intravenous corticoids 
-
Intravenous H2 antihistaminics  
-
Proton Pump Inhibitors  
-
Antispasmodic 
-
Antipsychotics  
Concomitant Medications Authorised for all patients: 
-
Analgesics  
-
Antiemetic  
-
Gastroprokinetic  
-
Chemotherapy (if already present at study entry)  
-
Venting Gastrostomy  
 
Non Authorised treatments: 
Somatostatin or any of its analogues other than the study drug. 
 
LAN ATG 120 mg will be administered by deep subcutaneous 
route, at the maximal scheduled standard dose of 120 mg/28 days, 
just for 1 administration.
Study Endpoints & 
Evaluations:
Primary Efficacy Endpoint and Evaluation: 
Comparison between the mean AUC of ESAS Total Scores collected 
for the first 7 days  in patients with Standard care + 1 injection of 
LAN ATG 120 mg (Group A) and the corresponding mean AUC  in 
patients with standard care alone (Group B). 
ESAS total score is the sum of nine common symptoms affecting 
patients with cancer in their terminal phase of life. It consists of nine 
0–10 numerical scales: pain, activity, nausea, depression, anxiety, 
drowsiness, appetite, sense of well-being and shortness of breath. 
There is an optional tenth scale based on a symptom, which can be 
added by the patient. Analysis of the primary endpoint will be 
performed on the first defined 9 items total score. 
ESAS questionnaire will be assessed by the patient or filled in by the 
nurse/caregiver in case of patient’s physical inability.  
Secondary Efficacy Endpoints and Evaluations:
1) Comparison of single ESAS items symptom score and total 
score at Day 1,2,3,4,5,6 and 7, Day 14, Day 28,  between Group A 
and Group B;


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2) 
Changes 
in 
performing 
General 
activity 
(Karnofsky 
performance status) at Day 7, Day 14 and Day 28 compared to 
baseline and comparison between Group A and Group B; 
3) Changes in daily intensity of Abdominal Pain (Visual analogue 
scale) and comparison between Group A and Group B; 
4) Comparison of number of patients experiencing  2 vomiting 
episodes/day during at least 3 consecutive days at any time point 
between the D1 and D7,14,28, between Group A and Group B, in 
patients without nasogastric tube  (NGT); 
5) Comparison of number of patients in whom the NGT has been 
removed during at least 3 consecutive days at any time point, 
between the D1 and D7, 14, 28, without vomiting recurrence, 
between Group A and Group B; 
6) In patients with a NGT, changes in daily NGT secretion volume 
and comparison between Group A and Group B; 
7) Comparison of number of daily vomiting episodes and number 
of days without vomiting, between Group A and Group B; 
8) Passage of stools (Yes/No) daily assessment and comparison 
between Group A and Group B; 
9) Descriptive analysis of optional ESAS item 10; 
10) Standard care and concomitant medications will be recorded and 
analysed. In particular changes in analgesic intake. 
 
Safety Endpoints and Evaluations: 
Safety will be assessed through the collection of adverse events 
(AEs) and vital signs and fully described/presented in frequency 
tables. 
 
Statistical Methods: 
Determination of Sample Size 
Since the quality of life is a multidimensional parameter, the AUC of 
ESAS total scores measured daily and reported on the patient’s 
diary, during the first 7 days, is the primary variable which is 
calculated on, the sample size. 
ESAS total score is related to the status of the patient's illness: a low 
score indicates a good quality of life, a high score indicates a strong 
discomfort. 
In the group of patients who have added the injection LAN ATG 120 
mg to standard care (Group A), the expected outcome is a lower 
value of the mean AUC compared to the one detected in the group of 
patients who were treated with only the standard therapy. 
In order to determine the sample size, we consider, for each patient, 
the AUC corrected with the basal ESAS total score by analysis of 
covariance (ANCOVA). In fact we assume that the AUCs are related 
to basal values. In this analysis the independent variable (covariate) 


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will be the baseline values and the dependent variables will be the 
AUC of ESAS total scores collected for 7 days. 
In order to achieve a relevant clinical effect, we can assume an effect 
size of 0.60 (0.20 indicates a  small effect size; 0.50 a medium effect 
and  0.80 a large effect size). 
Chosen D = 0.05 and E = 0:20 (80% power), a total of 70 evaluable 
patients are needed: 35 patients in each treatment group. 
Finally, as literature data show that in this patient population there is 
drop-out rate of about 20%, the total number of patients to be 
recruited in the study must be at least 84. 
 
Demographic and other Baseline Characteristics  
Descriptive statistics will be used to summarize demographic 
characteristics, 
medical 
history 
and 
physical 
examination 
abnormalities of all patients included in the study. Concomitant 
medications will be reported as summary tables. 
 
Analysis of Efficacy  
As reported above, the main outcome variable (7 days AUC) will be 
analysed by the analysis of covariance (ANCOVA), where the AUC 
is the dependent, and the independent is the basal total score. This 
variable will be also analysed by the repeated measures analysis of 
variance with one group to highlight statistically significant 
differences between and within groups. 
All recorded variables will be presented in tables using standard 
procedures depending on the underlying distribution. Descriptive 
statistics on ordinal and categorical variables will be made reporting 
numbers and percentages, whereas for continuous variables mean, 
standard deviation (and standard error) together with range will be 
showed.  
To highlight statistically significant differences between and within 
groups, continuous and normally distributed variables will be 
analysed by the analysis of variance, with repeated measures (time) 
and one group (treatment). Discrete or non-normally distributed 
variables will be analysed by non-parametric tests (Mann-Whitney U 
test and Wilcoxon test). Nominal and categorical variables will be 
analysed by the Ȥ2 test with the Yates correction for 2x2 contingency 
tables. 
 
 
 
 


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Analysis of Safety  
Adverse events (AEs), including Treatment Emergent Adverse 
Events (TEAEs), and vital signs will be fully described and 
presented in frequency tables. 
 
 
Statistical Software 
Statistical tables and analyses will be conducted using SAS® 
Version 9.2 statistical software package.


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TABLE OF CONTENTS 
1
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 13
2
INTRODUCTION ......................................................................................................... 15
2.1
Disease Review ............................................................................................................... 15
2.2
Compound Review ........................................................................................................ 16
2.3
Clinical Trial Rationale ................................................................................................ 18
3
STUDY OBJECTIVES ................................................................................................. 19
3.1
Primary Study Objective .............................................................................................. 19
3.2
Secondary Study Objectives ......................................................................................... 19
4
STUDY DESIGN ........................................................................................................... 19
4.1
Overview ......................................................................................................................... 19
4.1.1
Population Characteristics .......................................................................... 19
4.1.2
Design .......................................................................................................... 20
4.1.3
Structure ...................................................................................................... 20
4.1.4
Early Study Termination ............................................................................. 20
4.2
Endpoints ....................................................................................................................... 21
4.2.1
Primary Efficacy Endpoint ......................................................................... 21
4.2.2
Secondary Efficacy Endpoints .................................................................... 21
4.2.3
Safety Endpoints .......................................................................................... 22
4.3
Justification of Design ................................................................................................... 22
4.3.1
Study Population for Analysis .................................................................... 22
4.3.2
Study Duration ............................................................................................ 22
5
COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL 
CONSIDERATIONS & INFORMED CONSENT .................................................... 22
5.1
Compliance with Good Clinical Practice and Ethical Considerations ..................... 22
5.2
Informed Consent ......................................................................................................... 23
6
STUDY POPULATION ............................................................................................... 23
6.1
Screening Log and Number of Subjects ...................................................................... 23
6.2
Inclusion criteria ........................................................................................................... 24
6.3
Exclusion Criteria ......................................................................................................... 24
6.4
Subject Withdrawal Criteria ....................................................................................... 25
6.5
Discontinuation/Withdrawal Procedures ................................................................... 25
7
METHODOLOGY ........................................................................................................ 25
7.1
Study Schedule .............................................................................................................. 25
7.2
Study Visits .................................................................................................................... 26
7.2.1
Visit 1 (Baseline) ......................................................................................... 27
7.2.2
Visits 2 (Day 7) and Visit 3 (Day 14) .......................................................... 27
7.2.3
Visit 4 - End of study/Withdrawal visit (Day 28) ........................................ 28
8
STUDY EVALUATIONS ............................................................................................. 28
8.1
Demographic data ......................................................................................................... 28
8.2
Medical History ............................................................................................................. 28


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8.3
Physical Examination ................................................................................................... 28
8.4
Vital Signs and body weight ......................................................................................... 29
8.5
Pregnancy Test .............................................................................................................. 29
8.6
Karnofsky performance status .................................................................................... 29
8.7
Edmonton Symptom Assessment System (ESAS) ...................................................... 29
8.8
Abdominal Pain assessment, vomiting episodes, NGT and Passage of stools ......... 29
8.9
Concomitant medications/therapies including standard care therapy .................... 30
8.10 Safety assessment/Adverse Events ............................................................................... 30
8.11 Clinical Laboratory Tests ............................................................................................. 30
8.12 Patient diary .................................................................................................................. 30
9
STUDY TREATMENTS .............................................................................................. 31
9.1
Study Treatments Administered .................................................................................. 31
9.2
Subject Identification and Allocation to Study Treatment ....................................... 31
9.3
Randomisation ............................................................................................................... 31
9.4
Study Treatment Supply, Packaging and Labelling .................................................. 32
9.5
Compliance .................................................................................................................... 33
9.6
Study Treatment Storage and Accountability ............................................................ 33
9.7
Reporting of Investigational Medicinal Product Quality Complaints ..................... 33
9.8
Concomitant Medication/SC therapy/Nutrition Procedures .................................... 33
9.9
Non authorized treatments ........................................................................................... 34
9.10 Treatment of Overdose of IMP .................................................................................... 34
10
ASSESSMENT OF SAFETY ....................................................................................... 35
10.1 Adverse Events .............................................................................................................. 35
10.1.1
Definition of an Adverse Event ................................................................... 35
10.2 Categorisation of Adverse Events ................................................................................ 35
10.2.1
Intensity Classification ................................................................................ 35
10.2.2
Causality Classification ............................................................................... 36
10.2.3
Assessment of expectedness ........................................................................ 36
10.2.4
Laboratory Test Abnormalities ................................................................... 36
10.2.5
Abnormal Physical Examination Findings ................................................ 36
10.2.6
Other Investigation Abnormal Findings .................................................... 36
10.3 Recording and Follow-up of Adverse Events ............................................................. 37
10.4 Serious Adverse Events ................................................................................................ 37
10.4.1
Definitions ................................................................................................... 37
10.4.2
Reporting Requirements ............................................................................. 38
10.4.3
Mandatory Information for Reporting a SAE ........................................... 38
10.5 Pregnancy ...................................................................................................................... 39
10.6 Death .............................................................................................................................. 39
10.7 Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events ....... 40
10.8 Reporting to Competent Authorities/IECs/Other Investigators .............................. 40
11
STATISTICAL CONSIDERATIONS ........................................................................ 40
11.1 Subject Classification and Definitions ......................................................................... 40
11.2 Analyses Populations Definitions ................................................................................. 41
11.2.1
Populations Analysed .................................................................................. 41


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11.2.2
Subject Allocation and Reasons for Exclusion from the Analyses ........... 41
11.3 Sample Size Determination .......................................................................................... 42
11.3.1
Significance Testing and Estimations ........................................................ 43
11.4 Statistical/Analytical Methods ..................................................................................... 43
11.4.1
Demographic and Other Baseline Characteristics .................................... 43
11.4.1.1
Homogeneity of Treatment Groups .............................................................. 44
11.4.1.2
Subject Disposition and Withdrawals .......................................................... 44
11.4.1.3
Efficacy evaluation ....................................................................................... 44
11.4.1.4
Safety Evaluation ......................................................................................... 45
11.5 Subgroup Analyses ........................................................................................................ 45
11.6 Interim Analyses ........................................................................................................... 45
12
MONITORING PROCEDURES ................................................................................. 46
12.1 Routine Monitoring ....................................................................................................... 46
13
STUDY MANAGEMENT ............................................................................................ 46
13.1 Inspections and Auditing Procedures ......................................................................... 46
13.2 Data Recording of Study Data ..................................................................................... 47
13.3 Source Data Verification .............................................................................................. 47
13.4 Data Quality ................................................................................................................... 48
13.5 Data Management ......................................................................................................... 48
13.6 Study Management Committees .................................................................................. 49
13.7 Record Archiving and Retention ................................................................................. 49
14
ADMINISTRATION PROCEDURES ........................................................................ 50
14.1 Regulatory Approval .................................................................................................... 50
14.2 Publication Policy .......................................................................................................... 50
14.3 Clinical Study Report ................................................................................................... 50
14.4 Contractual and Financial Details ............................................................................... 51
14.5 Insurance, Indemnity and Compensation ................................................................... 51
15
PROTOCOL AMENDMENTS ................................................................................... 51
16
REFERENCES .............................................................................................................. 52
17
LIST OF APPENDICES .............................................................................................. 54
Table 1 Schedule of Assessments ........................................................................................ 26
 
 
 


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1
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE
AIFA 
ATC
Adverse Event/Experience 
Agenzia Italiana del Farmaco 
Anatomical Therapeutic Chemical classification system 
AUC 
BMI 
Area Under Curve 
Body Mass Index 
CA
CRO 
Competent Authorities 
Clinical Research Organization 
CSR 
Clinical Study Report 
CT
Computerized Tomography 
DUS
Disease under study 
e-CRF 
Electronic Case Report Form 
ESAS
Edmonton Symptom Assessment System 
EU
European Union 
FDA
Food and Drug Administration 
GCP
Good Clinical Practice 
GH
Growth Hormone 
GI
Gastrointestinal 
IC
Informed Consent 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IGF-1
Insulin-like Growth Factor 
IMP 
Investigational Medicinal Product synonymous with “study drug” 
ITT
Intention to Treat 
LAN ATG 120 mg 
Lanreotide Autogel 120 mg 
MBO  
MeDRA 
Malignant Bowel Obstruction 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NET
Neuroendocrine Tumours 
NGT
Nasogastric tube 
NOS
Not Otherwise Specified 
PI
Package Insert 


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PP 
Per Protocol 
PK
Pharmacokinetics 
RAP 
Reporting and Analysis Plan 
SAE 
Serious Adverse Event/Experience 
SAS®
Statistical Analysis System® 
SC
Standard Care 
SmPC 
Summary of Product Characteristics 
SOP
Standard Operating Procedures 
SSA 
Somatostatin Analogue 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TFLs 
Tables, Figures and Listings 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial Master File 
WHO
World Health Organization 
 
 
 


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2
INTRODUCTION 
2.1
Disease Review 
Bowel obstruction is a common complication in patients with end-stage cancer, particularly in 
those with an abdominal or pelvic primary cancers. The reported frequency of bowel 
obstruction ranges from 5% to 42 % in advanced ovarian cancer and from 4% to 24% in 
advanced colorectal cancer. In bowel obstruction, the propulsion of intestinal contents is 
delayed or blocked completely, leading to symptoms of nausea, vomiting and spasmodic pain. 
Bowel distension proximal to the site of obstruction will lead to an increase in intestinal 
secretion which, acting as a feed-back, worsens the patient’s symptoms (1,2,3). 
Surgery remains the treatment of choice for malignant intestinal obstruction. However, not all 
patients are eligible for surgery. The most frequent contraindications are the presence of 
multiple partial obstructions, intra-abdominal carcinomatosis, poor nutritional status or large 
amounts of ascites. 
In inoperable patients, there is a need for a non-invasive and efficacious treatment to alleviate 
patient discomfort. Several authors have confirmed the efficacy of a pharmacological 
treatment of symptoms. Pharmacological therapy consists of analgesics (opioids or non-
opioids), anti-emetics (e.g. Metoclopramide, haloperidol), anti-inflammatory agents 
(corticosteroids) and anti-secretory drugs (e.g. scopolamine butylbromide, somatostatin 
analogues) (4,5,6,7). 
Somatostatin produced by neurones of the gastrointestinal tract acts as an inhibitor of 
numerous digestive endocrine and exocrine secretions. Somatostatin also promotes intestinal 
water absorption and influences gut transit time (8,9). 
Somatostatin's inhibitory effect on gastrointestinal secretions reduces the distension of the 
bowel. Somatostatin decreases the water and sodium secretion of the intestinal epithelium, 
thereby reducing pain and vomiting (4). 
The therapeutic use of somatostatin is, however, limited by its short half-life of only two to 
three minutes, thus necessitating continuous intravenous infusion. Therefore, synthetic 
somatostatin analogues with increased specificity and half-life duration have been developed 
for medicinal use (10,11). 
Lanreotide is a synthetic octapeptide with a biological activity similar to naturally occurring 
somatostatin. The compound is characterised by the presence of D-Tryptophan in the amino 
acid ring, increasing stability, and by the presence of D-beta Nal outside of this ring, which 
increases its selectivity. The terminal amine function reduces binding to central nervous 
system receptors. Lanreotide exhibits high affinity for the somatostatin Type 2 (SSTR2) and 
Type 5 (SSTR5) receptors found in the pituitary gland, GH-secreting pituitary tumours, 
neuroendocrine tumours, and the digestive tract. The product has a much lower affinity for 
somatostatin Type 1, 3 and 4 receptors (13). 
Lanreotide has obtained a marketing authorisation in the treatment of acromegaly and 
neuroendocrine tumours.  
Previous studies have shown that vomiting and pain due to bowel obstruction can be 
controlled by somatostatin analogues administered daily by subcutaneous injections in 
patients unresponsive to conventional therapy (4, 5, 6, 12).  
A prolonged release of somatostatin analogue would be more convenient for clinical use than 
discontinued injections. Therefore in this study, the efficacy of lanreotide 120 mg in the 


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PAGE 16/56
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and toxicology studies (including cardiovascular tolerance) have shown that Lanreotide 
Autogel is safe for chronic use in humans. 
Lanreotide is an effective treatment for acromegaly that relieves clinical symptoms in a high 
proportion of patients. It achieves its effect by inhibiting GH secretion and controlling serum 
concentrations of GH and insulin-like growth factor (IGF-1). The efficacy of Lanreotide 
Autogel in patients with acromegaly was confirmed in a placebo controlled clinical study 
where a reduction in serum GH concentration was observed after 1 month of treatment. A 
dose related reduction in serum GH and IGF-1 concentrations was observed for the 60, 90 and 
120 mg doses and serum GH concentrations were reduced to 1 ng/mL in 26.5% of patients 
following up to 52 weeks of treatment. Forty percent of patients achieved a mean serum GH 
concentration of 2.5 ng/mL The studies also confirmed that optimal doses of Lanreotide 
Autogel, administered for up to 52 weeks, reduced most symptoms of acromegaly in the 
majority of symptomatic patients. 
Lanreotide is also approved for the treatment of carcinoid neuroendocrine tumours (NET). 
The effectiveness of Lanreotide Autogel has been demonstrated in terms of treatment 
response in one open label, dose titration (60, 90 and 120 mg) study, where 71 patients 
demonstrated the effectiveness of Lanreotide Autogel in treating the clinical symptoms 
(diarrhoea or flushing) associated with carcinoid NET. The primary efficacy endpoint 
demonstrated that 38% of patients were classified as treatment responders at Month 6. The 
effectiveness of Lanreotide Autogel was supported by the secondary efficacy endpoints that 
showed improvements in the individual symptoms of carcinoid NET, including the severity of 
flushing, as well as reductions in the levels of tumour markers, Chromogranin A and 5-
hydroxyindole acetic acid (5-HIAA). 
Overall, across clinical studies, the efficacy and safety profiles did not vary with age, gender, 
body mass index (BMI), bodyweight or race, and efficacy was comparable for previously 
treated and treatment naive patients. The tendency to develop antibodies to lanreotide is low, 
does not appear to affect efficacy, and does not increase with long term treatment. 
Lanreotide Autogel was well tolerated by patients with acromegaly or carcinoid NET and 
most adverse events (AEs) observed during clinical studies were consistent with the known 
safety profile of somatostatin analogues (SSAs). The most common treatment emergent 
adverse events (TEAEs) were: gastrointestinal (GI) disorders (diarrhoea, abdominal pain, 
nausea, vomiting and constipation); hepatobiliary disorders (cholelithiasis); and nervous 
system disorders (headache). 
Data from renally impaired, hepatically impaired or elderly subjects indicate that Lanreotide 
Autogel is safe in these groups. As the dose of Lanreotide Autogel is intended to be tailored to 
individual response the starting dose in patients with renal or hepatic impairment should be 
determined based upon local prescribing information or protocol requirements in the case of 
clinical studies. For patients with acromegaly and NET, similar results are expected with 
regard to renally impaired subjects. 
Varying formulations of lanreotide (including Lanreotide Autogel) have been studied in at 
least 1270 patients in other indications including cardiac disorders, GI bleed, diabetes, 
oncology, ophthalmic Graves disease and studies in the paediatric population such as those in 
obesity and constitutional tall stature. 
The number of post marketing spontaneous safety reports was low (approximately one 
reaction per >40 patient-years of exposure), and the post marketing adverse reaction profile 


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was consistent with that for treatment related AEs in clinical studies. These findings support 
the safety of lanreotide including the Autogel formulation. 
Cardiac serious adverse reactions (SARs) were reported at the low rate of <1 per 3,800 
patient-years of exposure. Since lanreotide has similar effects on heart rate to those of 
octreotide there is potential for it to cause bradycardia in some patients in rare cases. 
Lanreotide is not associated with any increased risk of heart valve regurgitation or 
cardiovascular disease. Pregnancies that occurred during lanreotide treatment did not raise 
any safety concerns however the numbers are small so Lanreotide Autogel should be 
administered to pregnant women only if clearly needed. It is not known whether lanreotide is 
excreted in human milk. Lanreotide should not be used during breast feeding unless clearly 
necessary. Further details can be found in the Investigator’s Brochure (13). 
 
2.3
Clinical Trial Rationale 
Malignant bowel obstruction (MBO) is a challenging complication of advanced cancer and 
requires a highly individual approach, tailored to the patients.  Several pathophysiological 
mechanisms are responsible for the syndrome, including mechanical compression, motility 
disorders, accumulation of gastrointestinal secretion and inflammation (1).  Its symptoms are 
challenging to manage since nausea, vomiting, colic and abdominal pain, which are common, 
cause significant physical distress and demoralization (2).  
The medical therapy can palliate symptoms of MBO for most patients. In particular the 
combination of antisecretive, antiemetic and analgesic drugs has been proved to be effective 
in controlling gastrointestinal symptoms.  
The somatostatin analogs (SSAs) are among the antisecretory drugs recommended in 
inoperable MBO patients.  SSAs inhibit the release of various gastrointestinal secretions, 
slowing intestinal motility, decreasing splanchnic blood flow and increasing water and 
electrolyte absorption (3).  
Previous studies have shown that vomiting and pain due to bowel obstruction can be 
controlled by somatostatin analogues administered daily by subcutaneous injections in 
patients unresponsive to conventional therapy (4,5,6,12) and more recently for a slow release 
microparticles formulation delivering lanreotide for 14 days in patients suffering from 
symptoms of obstruction due to peritoneal carcinomatosis (14). 
A slow release formulation that is capable of maintaining therapeutic somatostatin analogue 
levels up to 28 days, that can be administered subcutaneously would be more convenient for 
clinical use. It would enable clinicians to treat patients ambulatory. Therefore, in this study, 
the efficacy of lanreotide autogel 120 mg in the management of symptoms secondary to 
inoperable intestinal obstruction in palliative cancer patients will be studied.  
Evidence-based evaluation of treatments for the symptomatic management of MBO continues 
to be an important area of research .The aim of this study is to add data to the body of 
evidence that establishes a key role for SSAs as a real treatment option for patients with MBO 
(15, 16).   
Palliative cancer patients experience a complex configuration of many physical and emotional 
symptoms associated with advancing disease. In order to address these complex symptoms 
experiences, Bruera and colleagues (17) developed The Edmonton Symptom Assessment 
System (ESAS), a brief and clinically useful bedside tool for self-reporting symptom intensity 


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by advanced cancer patients. The ESAS was designed to enable repeated quantitative 
measurement of symptom intensity with minimal patient burden. (18).  
ESAS is designed to assist in the assessment of nine symptoms: pain, tiredness, nausea, 
depression, anxiety, drowsiness, appetite, wellbeing and shortness of breath. There is an 
optional tenth symptom, which can be added by the patient. The severity of each symptom is 
rated from 0 to 10 on visual numeric scale.    
Since its inception in 1991, the ESAS has been adopted and widely used internationally for 
clinical and research purposes. The Italian version of ESAS has been validate in two different 
palliative care settings of patient with advanced cancer: home care patients and in-patients 
(19). 
 
 
3
STUDY OBJECTIVES 
3.1
Primary Study Objective 
To evaluate the impact on Quality of Life (Edmonton Symptom Assessment 
System, ESAS total score) of LAN ATG 120 mg in combination with standard 
care, in comparison to the standard care alone, in subjects affected by inoperable 
malignant bowel obstruction.  
 
3.2
Secondary Study Objectives 
1) To evaluate the impact of LAN ATG 120 mg on each ESAS item and total 
score; 
2) To assess General activity (Karnofsky performance status) and Abdominal Pain 
(Visual analogue scale);  
3) To assess the efficacy of LAN ATG 120 mg for the relief of vomiting in patients 
without nasogastric tube  (NGT);  
4) To assess the efficacy of LAN ATG 120 mg on NGT secretion volumes or to 
remove NGT without recurrence of vomiting in patients with a nasogastric tube; 
5) Passage of stools (Yes/No); 
6) Descriptive analysis of optional ESAS item 10; 
7) To assess the efficacy in reducing concomitant medications/ analgesics intake; 
8) To assess the safety of the study treatment. 
 
 
4
STUDY DESIGN 
4.1
Overview 
4.1.1
Population Characteristics 
It is planned to include 84 patients in this study. Male or female patients of 18 years 
of age or older, diagnosed with bowel obstruction due to malignant origin, 
confirmed by appropriate imaging report, who are unsuitable candidates for 
surgery.  


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4.1.2
Design 
This is a phase II, multicentre, prospective, randomized, parallel arms, open-label 
study to be conducted in Italian sites. 
 
4.1.3
Structure 
 
Figure 2 Study flow 
Patients meeting the selection criteria for participation will need to provide a 
written informed consent before any study related procedure.  
Patient will be asked to complete the first Edmonton Symptom Assessment System 
(ESAS) before randomization. Patients will then be randomized in two groups:  
x
Group A will receive standard care + 1 injection of LAN ATG 120 mg.  
x
Group B will receive standard care alone.  
The efficacy and safety will be evaluated until day 28. 
 
4.1.4
Early Study Termination 
The Sponsor may terminate this study at any time. Reasons for termination may 
include but are not limited to, the following: 
x
The incidence or severity of adverse events (AE) in this or other studies point 
to a potential health hazard for trial subjects.
x
Insufficient subject enrolment.
Patientsfulfillingthe
criteriaforinclusion
RANDOMIZATION
FirstESASevaluation
ContinuedEfficacy/Safetyevaluation untilday28
GroupA
Standardcare+
LANATG120mg
GroupB
Standardcare 
 


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x
Any information becoming available during the study that substantially 
changes the expected benefit risk profile of the study treatment.
4.2
Endpoints 
4.2.1
Primary Efficacy Endpoint 
Comparison between the mean AUC of ESAS Total Scores collected daily for the 
first 7 days in patients with standard care + 1 injection of LAN ATG 120 mg (Group 
A) and the corresponding mean AUC  in patients with standard care alone (Group 
B). 
ESAS total score is the sum of nine common symptoms affecting patients with 
cancer in their terminal phase of life. It consists of nine 0–10 numerical scales: pain, 
activity, nausea, depression, anxiety, drowsiness, appetite, sense of well-being and 
shortness of breath. There is an optional tenth scale based on a symptom, which can 
be added by the patient. Analysis of the primary endpoint will be performed on the 
first defined 9 items total score. 
ESAS questionnaire will be assessed by the patient or filled in by the 
nurse/caregiver in case of patient’s physical inability.  
 
4.2.2
Secondary Efficacy Endpoints 
1) Comparison of single ESAS items symptom score and total score at Day 
1,2,3,4,5,6 and 7, Day 14, Day 28,  between Group A and Group B. 
2) Changes in intensity at Day 7, Day 14 and Day 28 compared to baseline in 
General activity (Karnofsky performance status) and comparison between Group A 
and Group B. 
3) Changes in daily intensity of Abdominal Pain (Visual analogue scale) and 
comparison between Group A and Group B. 
4) Comparison of number of patients experiencing  2 vomiting episodes/day 
during at least 3 consecutive days at any time point between the D1 and D7,14,28, 
between Group A and Group B, in patients without nasogastric tube  (NGT). 
5) Comparison of number of patients in whom the NGT has been removed during 
at least 3 consecutive days at any time point, between the D1 and D7, 14, 28, 
without vomiting recurrence, between Group A and Group B. 
6) In patients with a NGT, changes in daily NGT secretion volume and comparison 
between Group A and Group B. 
7) Comparison of number of daily vomiting episodes and number of days without 
vomiting, between Group A and Group B. 
8) Passage of stools (Yes/No) daily assessment and comparison between Group A 
and Group B. 
9) Descriptive analysis of optional ESAS item 10. 
10) Standard care and concomitant medications will be recorded and analysed. In 
particular changes in analgesic score intake. 
 


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4.2.3
Safety Endpoints 
Safety will be assessed through the collection of adverse events (AEs) and vital 
signs and fully described and presented in frequency tables. 
 
4.3
Justification of Design 
4.3.1
Study Population for Analysis 
Patients with inoperable intestinal obstruction of malignant origin who have at least 
3 or more episodes of vomiting every day in the last consecutive 48 hours or who 
have a nasogastric tube and candidate to receive symptoms supportive (standard) 
care, are eligible to be included in this study.  
This study aims to recruit a total of 84 patients, 42 per group – male or female of 18 
years or older who fulfil the eligibility criteria (see Section 6.2 – 6.3).  
The primary study population for the analysis will be the ITT population.  
 
4.3.2
Study Duration 
The overall duration of the study will be approximately 2 years.  
The study will be considered to have started at first patient Informed Consent 
signature. The  study will be considered to have finished when last patient last visit 
will be performed. 
Study enrolment will last about 18 months. The subjects participation in the study is 
considered to have ended  at 28th day after randomization. 
 
 
5
COMPLIANCE 
WITH 
GOOD 
CLINICAL 
PRACTICE, 
ETHICAL 
CONSIDERATIONS & INFORMED CONSENT 
5.1
Compliance with Good Clinical Practice and Ethical Considerations 
This study must be conducted in compliance with independent ethics committees 
(IECs), informed consent regulations, the Declaration of Helsinki and International 
Conference on Harmonisation (ICH) (21) and Good Clinical Practice (GCP) 
Guidelines, Food and Drug Administration (FDA), 21 CFR Part 11, Electronic 
Records, Electronic Signatures (22) and FDA Guidance for Industry: Computerized 
Systems Used in Clinical Trials (23). In addition, this study will adhere to all local 
regulatory requirements.  
Before initiating a trial, the Investigator/institution should have written and dated 
approval/favourable opinion from the IEC for the trial protocol/amendment(s), 
written informed consent form, any consent form updates, subject recruitment 
procedures (e.g. advertisements), any written information to be provided to subjects 
and a statement from the IEC that they comply with GCP requirements. The IEC 
approval must identify the protocol version as well as the documents reviewed. 
After IEC approval, changes will require a formal amendment. Once the study has 
started, amendments should be made only in exceptional circumstances. Changes 


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that do not affect subject safety or data integrity are classified as administrative 
changes and generally do not require ethical approval. If ethically relevant aspects 
are concerned, the IEC must be informed and, if necessary, approval sought prior to 
implementation. Ethical approval on administrative changes will be obtained if 
required by local/site IEC. 
 
5.2
Informed Consent 
Prior to study entry, the Investigator, or a person designated by the Investigator, will 
explain the nature, purpose, benefits and risks of participation in the study to each 
subject, subject’s legally acceptable representative or impartial witness. Written 
informed consent must be obtained prior to the subject entering the study (before 
initiation of any study-related procedure and administration of the IMP). Sufficient 
time will be allowed to discuss any questions raised by the subject. 
The Sponsor will provide a sample informed consent form. The final version 
controlled form must be agreed to by the Sponsor, and the IEC and must contain all 
elements included in the sample form, in language readily understood by the 
subject. Each subject’s original consent form, personally signed and dated by the 
subject or by the subject’s legally acceptable representative, and by the person who 
conducted the informed consent discussion, will be retained by the Investigator. The 
Investigator will supply all enrolled subjects with a copy of their signed informed 
consent. 
The consent form may need to be revised during the trial should important new 
information become available that may be relevant to the safety of the subject or as 
a result of protocol amendments. In this instance approval should always be given 
by the IEC. It is the Investigator’s responsibility to ensure that all subjects 
subsequently entered into the study and those currently in the study sign the 
amended form. This is documented in the same way as previously described. 
Subjects who have completed the study should be informed of any new information 
that may impact on their welfare/wellbeing. 
The Investigator should, with the consent of the subject, inform the subject’s 
primary physician about their participation in the clinical trial. 
 
 
6
STUDY POPULATION 
6.1
Screening Log and Number of Subjects 
Each Investigator will maintain a record of all subjects who were considered eligible 
for entry into the study but who were not enrolled. For each subject, the primary 
reason for exclusion will be recorded. 
Each Investigator will also maintain a record of all subjects enrolled into the study 
(who signed the informed consent form). In the event that the subject was not 
receiving IMP, the primary reason will be recorded. 
It is planned to recruit approximately 84 subjects at approximately 12 sites.  


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The enrolment is competitive. Section 11.3 provides a discussion of sample size. 
6.2
Inclusion criteria 
All subjects must fulfil the following: 
a) Subjects must demonstrate willingness to participate in the study and to be 
compliant with any protocol procedure.  
b) Provision of written informed consent prior to any study related procedure.  
c) Male or female aged  18 years at the time of enrolment. 
d) Diagnosis of an inoperable malignant bowel obstruction, confirmed by 
appropriate imaging report. 
e) In case of peritoneal carcinomatosis, diagnostic confirmation by CT or MRI 
scan. 
f)
Confirmed as inoperable after medical advice. 
g) Patient with a nasogastric tube or presenting with 3 or more episodes of 
vomiting every day in the last consecutive 48 hours. 
h) Patient life expectancy must be more than 14 days. 
 
6.3
Exclusion Criteria 
Subjects will not be included in the study if the subject : 
(a) Has operable obstruction or any sub-obstruction. 
(b) Has bowel obstruction due to a non-malignant cause; (hypokaliaemia, drug 
side-effects, renal insufficiency, etc). 
(c) Has signs of bowel perforation. 
(d) Has prior treatment with somatostatin or any analogue within the previous 60 
days. 
(e) Has a known hypersensitivity to any of the study treatments or related 
compounds. 
(f)
Is likely to require treatment during the study with somatostatin or any 
analogue other than the study treatment. 
(g) Is at risk of pregnancy or lactation, or is likely to father a child during the 
study. Females of childbearing potential must provide a negative pregnancy test 
at start of study and must be using oral or double barrier 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.  
(h) Has any mental condition rendering the subject unable to understand the nature, 
scope and possible consequences of the study, and/or evidence of an 
uncooperative attitude.  


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(i)
Has abnormal baseline findings, any other medical condition(s) or laboratory 
findings that, in the opinion of the Investigator, might jeopardise the subject’s 
safety or decrease the chance of obtaining satisfactory data needed to achieve 
the objective(s) of the study.  
 
6.4
Subject Withdrawal Criteria  
Under no circumstances will subjects be enrolled more than once. As this is a single 
treatment study, subjects cannot be withdrawn from study treatment after the 
administration of IMP. However, subjects can be discontinued from study 
participation for the following reasons: 
x
Withdrawal of informed consent. 
x
Investigator’s and/or Sponsor’s decision to withdraw the subject if it is 
considered to be in the subject’s best interest. 
x
Continuous failure to comply with the provisions of the study protocol 
which is likely to have an adverse impact on the safety or wellbeing of the 
subject, or could jeopardise the scientific value of the study.  
x
Voluntary discontinuation by the patient who is at any time free to 
discontinue his/her participation in the study, without prejudice to further 
treatment. 
Every effort should be made to follow up all subjects within the framework of the 
study, especially with regard to safety assessments. See Section 10.7 for further 
details. 
 
6.5
Discontinuation/Withdrawal Procedures 
If the subject is withdrawn from the study (i.e., ceases participation in the study 
prior to completion of the assessments planned in the protocol), the primary reason 
should be recorded in the patient’s medical file and in the electronic case report 
form (eCRF).  
In case of discontinuation, the patient will be asked to attend a final visit, 
performing all assessments required by the End of Study visit.  
The Investigator will provide or arrange for appropriate follow up (if required) for 
subjects withdrawing from the study, and will document the course of the subject's 
condition. Where the subject has withdrawn due to an AE the Investigator should 
follow the procedures documented in Section 10 in order to assess the safety of the 
IMP. 
 
7
METHODOLOGY 
 
7.1
Study Schedule  
The schedule of observations and assessments during the study are summarised 
below. 


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Table 1 Schedule of Assessments 
Visit 
V1 
Baseline 
V2
V3
V4
EoS/ Early withdrawal
Day 
1
7
14 ± 2 days 
28 ± 2 days
Informed Consent 
X
 
 
Demographic data  
X
 
 
Medical history  
X
 
 
Physical examination  
X
X
X
X
Vital signs  
X
X
X
X
Body weight 
X 
 
 
 
Pregnancy test (If applicable) 
X
 
 
 
Eligibility Criteria evaluation  
X
 
 
 
Patient’s Diary (Delivery and  review) 
X
X
X
X
Concomitant medications/ SC/nutrition  
X
X
X
X
Karnofsky performance status 
X
X
X
X
ESAS questionnaire 
X (*)
X
X
X
Abdominal pain assessment (VAS) 
X (*)
X
X
X
Vomiting episodes assessment 
X
X
X
X
NGT presence secretion volume or NGT 
removal recording 
X
X
X
X
Passage of stools recording 
X
X
X
X
Safety assessment and recording (AE & SAE) 
X
X
X
X
IF ALL INCLUSION & ESCLUSION CRITERIA ARE MET: 
Randomisation 
X
 
 
Injection of LAN 120 mg (if randomized in 
Group A) 
X
 
 
7.2
Study Visits 
Allowed time deviation for the visits : 
Visit 1/Baseline (Day1) : Not applicable 
Visit 2 (Day 7): No deviations allowed 
Visit 3 (Day 14) : ± 2 days 
Visit 4/End of Study- Withdrawal visit (Day 28) : ± 2 days 
 


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Written informed consent must be obtained prior to any study procedure 
implementation, even before the Visit 1. 
(*): Prior to randomization, the Investigator must administer the first ESAS 
questionnaire and VAS to the patient. They have been arranged in a 
separated/specific form (Patient Diary pre-treatment), which must then be filed 
in the clinical records as source document.  
 
Investigators and patients should do their best to comply with study visits schedule 
to be performed at the site. If the patient is resigned from the Hospital after Visit 2 
(Day 7) and he/she is physically unable (e.g. bedridden) to reach the site for the next 
control visits, these will be replaced by a phone call: the investigator or study staff 
have to collect as many information as possible, according to the scheduled visit.  
In any case, the patient diary and ESAS questionnaires, fully completed, must be 
delivered to the investigator or study staff the day of the scheduled visit for the 
appropriate revision. 
 
7.2.1
Visit 1 (Baseline) 
x
Demographics data (sex, age, ethnic origin) 
x
Medical history, including obstruction history  
x
Physical examination  
x
Vital signs 
x
Body weight 
x
Karnofsky Performance Status  
x
Pregnancy test (if applicable) 
x
Concomitant medications/SC therapy/Nutrition procedures 
x
Vomiting episodes assessment (episodes in the last 48 hours)  
x
NGT presence and related secretion volume  
x
Eligibility criteria evaluation  
x
Quality of life assessment, using the ESAS questionnaire (*) 
x
Abdominal pain assessed using the VAS (*) 
x
Passage of stools (Yes or No)  
x
Patient’s Diary delivery and explanations  
x
AE’s and SAE’s will be collected after signature of the informed consent and 
again after clinical examination and medical history evaluation 
x
Randomisation (see section 9.3) 
x
Treatment administration (LAN ATG 120mg and/or SC therapy) 
 
7.2.2
Visits 2 (Day 7) and Visit 3 (Day 14) 
x
Vital signs 
x
Physical examination  
x
Karnofsky Performance Status  


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x
Changes in concomitant medications/ SC therapy/Nutrition procedures 
x
Quality of life assessment using the ESAS questionnaire 
x
Patient’s Diary data review: 
  
- Abdominal pain  
  
- N. of Vomiting episodes   
  
- NGT presence and secretion volume  
  
- Passage of stools (Yes or No) 
x
Collection of AEs and SAEs  
 
7.2.3
Visit 4 - End of study/Withdrawal visit (Day 28) 
The following procedures will be performed for each subject who has completed the 
study at Day 28 or is an Early Withdrawal. 
x
Vital signs 
x
Physical examination  
x
Karnofsky Performance Status  
Changes in concomitant medications/ SC therapy/Nutrition procedures 
x
Quality of life assessment using the ESAS questionnaire 
x
Patient’s Diary data review 
  
- Abdominal pain  
  
- N. of Vomiting episodes   
  
- NGT presence and secretion volume  
  
- Passage of stools (Yes or No) 
x
Collection of AEs and SAEs  
x
Reason for end of study/early withdrawal 
 
 
8
STUDY EVALUATIONS 
8.1
Demographic data 
The subject’s demographic profile will include sex, age and ethnic origin. The data 
has to be collected at the Baseline Visit and recorded on the patient’s medical file. 
8.2
Medical History  
The medical history, including on-going medical history and obstruction history, 
will be recorded on the patient’s medical file. They will be collected at the Baseline 
Visit. 
8.3
Physical Examination 
The physical examination will include inspection of the following areas: general 
appearance, head, eyes, ears, nose, throat, neck, lymph nodes, skin, lungs, heart, 
abdomen, extremities/musculoskeletal evaluation, and neurological evaluation. It 
will be carried out by a physician and has to be recorded on the patient’s medical 
file, at each patient’s visit on site. If in the opinion of the Investigator there are any 
clinically significant changes in the physical examination (abnormalities), they will 
be recorded as AEs.  


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8.4
Vital Signs and body weight 
Blood pressure and heart rate will be recorded on the patient’s medical file, at each 
patient’s visit on site.  
Body weight only at baseline visit. 
8.5
Pregnancy Test 
A pregnancy test will be performed for all female subjects of child bearing potential. 
The test will be performed on site before randomization procedure.  
8.6
Karnofsky performance status  
The Karnofsky Performance Status (24) allows patients to be classified as to their 
functional impairment. The lower the Karnofsky Performance Status, the worse the 
survival for most serious illnesses.  
The first Karnofsky Performance Status has to be assessed prior the patient 
randomization (Day 1). The Karnofsky Performance Status will be then assessed 
also at Visit 2 (Day 7), Visit 3 (Day 14) and Visit 4 (Day 28). The total score will be 
recorded on the patient’s medical file, at each patient’s visit.  
8.7
Edmonton Symptom Assessment System (ESAS)  
The ESAS (17-19) will be assessed by the patient or filled in by the nurse/caregiver 
in case of patient’s physical inability (see the Appendix n. 1). The data 
recording/symptoms evaluation should be referred to the last 24 hours (20). 
The first ESAS has to be completed sooner after the written informed consent has 
been obtained and prior the patient randomization (Day 1). For the filling of this 
questionnaire at baseline (Day 1), a separated/specific baseline form “Pre-
treatment ESAS & VAS evaluations” has been arranged and must then be filed in 
the clinical records as source document. 
The ESAS will be then performed also at day 2,3,4,5,6,7, 14 and 28 and recorded in 
a dedicated “Post-treatment ESAS Questionnaire”. 
All ESAS copies needed during the study period will be arranged in book and each 
ESAS will be in double copy: one will be kept in the patient’s medical file as source 
document at the site; the second one will be sent to the CRO, delegated for the data 
management. 
8.8
Abdominal Pain assessment, vomiting episodes, NGT and Passage of stools 
The abdominal pain, the vomiting episodes, the NGT secretion volume or NGT 
removal and passage of stools assessments have to be evaluated and recorded on 
Patient Diary daily (possibly at the same time of day) until the end of study (Day 
28), by the patient or filled in by the nurse/caregiver in case of patient’s physical 
inability. 
The first assessment of the above parameters has to occur prior the patient 
randomization (Day 1). 
In particular, the abdominal pain will be evaluated through a visual analogue scale 
(VAS) (26). For the filling of VAS at baseline (Day 1), a separated/specific 


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baseline form “Pre-treatment ESAS & VAS evaluations” has been arranged and 
must then be filed in the clinical records as source document. 
8.9
Concomitant medications/therapies including standard care therapy 
All concomitant medications, including the standard care therapy and nutrition 
procedures, have to be recorded on the patient’s medical file at the Baseline Visit 
and all changes at all patient’s visit on site. If the patient will be followed at home, 
all concomitant medications and therapies used as needed, will have to be recorded 
on the patient diary (See Section 9.6). 
8.10
Safety assessment/Adverse Events 
AEs will be monitored from the time that the subject gives informed consent to the 
end of the study (see Section 4.3.2). AEs will be elicited by direct, non-leading 
questioning or by spontaneous reports. Further details for AE reporting can be found 
in Section 10. Safety of the patients will be followed continuously during the entire 
study period. If the patient will be followed up at home, all adverse events must 
be recorded in the patient diary. 
8.11
Clinical Laboratory Tests 
All clinical laboratory tests are not mandatory; they are at the discretion of the 
investigator. 
Clinical chemistry, haematological and urinalysis tests will be repeated as clinically 
indicated as part of the routine management of the patient on the occurrence of AEs. 
8.12
Patient diary
A patient diary will be arranged and all pages will be in double copy: one will be 
kept in the patient’s medical file as source document at the site; the second one will 
be sent to the CRO, delegated for the data management. 
The patient diary will be divided in two parts: 
- Patient diary pre-treatment: it will be delivered to the patients at the baseline 
visit with the related user instructions, prior the randomization. It has to be filled in 
by the patient or by the nurse/caregiver in case of patient’s physical inability for 
recording the following data: 
o
Baseline Abdominal Pain  
o
Baseline ESAS questionnaire 
- Patient diary post-treatment: it will be delivered to the patients at the baseline 
visit with the related user instructions, after the randomization. It has to be filled in 
daily, since the second day after the drug administration, by the patient or by the 
nurse/caregiver in case of patient’s physical inability, for recording the following 
data: 
o
Abdominal Pain  
o
Vomiting episodes 
o
NGT secretion volume or NGT removal  
o
Passage of stools 
o
Concomitant Medications and Therapies used at Home, as needed 
o
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The Investigator or qualified designee has to review the patient diary at each patient 
visit on site, checking the completeness and accuracy of the reported data. 
 
 
9
STUDY TREATMENTS 
9.1
Study Treatments Administered 
It is forbidden to use IMP for purposes other than as defined in this protocol. 
Administration of the IMP will be supervised by the Investigator, or designee. Each 
patient who meets the eligibility criteria (inclusion/exclusion criteria) for 
participation in the study, according to a centralised randomisation list, will be given  
standard care therapy in combination with Lanreotide Autogel 120 mg (group A) or 
standard care therapy (group B). 
Lanreotide Autogel 120 mg administration, deep sub-cutaneous injection in the 
upper outer quadrant of the buttock, Administration of the Lanreotide Autogel 120 
mg will occur in conjunction with or on the same day of standard care therapy 
administration. The administrations will be supervised by the Investigator, or 
designee.     
  
9.2
Subject Identification and Allocation to Study Treatment 
All subjects enrolled must be identifiable throughout the study. The Investigator will 
maintain a list of subject numbers and names to enable records to be found at a later 
date if required.  
 
9.3
Randomisation 
Following confirmation of eligibility for the study, subjects will be given a 
randomisation/treatment allocation number and allocated to one of the treatment 
groups specified in Section 9.1. 
The Sponsor’s Randomisation Manager, a statistician independent from the study, 
will prepare and keep the master randomisation list. It will be produced in blocks by 
using an internal validated randomisation software and will be generated with a 
balance ratio [1 ‘Standard care + LAN ATG 120 mg’ versus 1 ‘Standard care 
alone’].  
Patients meeting the randomisation criteria will be allocated to a randomisation 
number through the eCRF (WEB server) in the order in which they enter the 
randomised study period.  Authorized Users at sites will open the eCRF, fill in all 
the mandatory items and then if the requirements are satisfied he can press the 
randomization button. The eCRF automatically send via Internet a request to the 
WEB server (using secure, encrypted protocols). The WEB server assigns patients 
to one of two treatment groups based on a pre-defined randomisation list. The 
Investigator can read the assigned treatment directly in the eCRF (additional details 
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Recruitment will stop once 84 evaluable patients have been randomised. Patients 
who leave the study early will not be replaced. Randomised patients who terminate 
their study participation for any reason before starting the treatment period will 
retain their randomisation number, i.e. the randomisation number will not be reused. 
The next patient will be given the next randomisation number.  
No centre will randomise more than approximately 20 patients. The subjects 
enrolled will be monitored using the remote study monitoring system. 
The Sponsor’s Randomisation Manager will keep the master list, and a copy of the 
randomisation list will be confidentially supplied to the CRO in charge of central 
randomisation allocation / eCRF. The master list and the copy supplied to the CRO 
in charge of central randomisation allocation / eCRF will be kept confidential in a 
secure location. Access to the randomisation lists must be restricted until 
authorisation is given for its release.  
 
9.4
Study Treatment Supply, Packaging and Labelling 
The IMP will be packaged by  Supply Chain CMC&E (Beaufour IPSEN Industrie, 
20 rue Ethe Virton, 28100 Dreux, France) and delivered to the investigational sites. 
A sufficient quantity of IMP will be supplied as well as an acknowledgement of 
receipt form.  
The Sponsor’s representative will receive a Certificate of Analysis and Compliance 
for which batch of IMP has been used under their study, Material Data Safety Sheet 
for  LAN ATG 120 mg, Packaging Order which reflects the product release 
statement.  
The core label texts for all packaging units will be translated or adjusted, to be in 
compliance with applicable regulatory requirements (25), national laws in force and 
in accordance with the local languages. A description of the core text of the IMP 
labels is displayed below: 
x
Name, address and telephone number of the Sponsor  
x
Name of the product with strength and potency 
x
Study Number 
x
Pharmaceutical dosage form 
x
Route of administration 
x
Quantity of dose units 
x
Batch number 
x
Treatment  number  
x
Randomisation number with specific blank space to enter the subject ID 
x
The statement ‘For clinical trial use only’   
x
The statement ‘Keep out of reach of children’ 
x
Storage conditions 
x
Expiry date 
The Investigator, or designee, will only dispense IMP to subjects included in this 
study. Each subject will only be given the IMP carrying his/her number. The 


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dispensing for each subject will be documented in the patients’ medical file and in 
the eCRF.  
 
9.5
Compliance 
If a patient after signing the IC and undergoing all entry study evaluations refuses to 
have IMP administered, this must be regarded as a major protocol violation and 
patient is automatically withdrawn. 
 
9.6
Study Treatment Storage and Accountability 
The Investigator, or an approved representative (e.g. pharmacist), will ensure that all 
IMP is stored in a secured area, under recommended temperature monitored storage 
conditions (2°C – 8°C), in accordance with applicable regulatory requirements and 
will be dispensed by qualified staff members. 
All study treatments are to be accounted for on the IMP accountability log provided 
by the Sponsor. It is essential that all used and unused supplies are retained for 
verification (by the Sponsor or Sponsor’s representative). The Investigator should 
ensure adequate records are maintained via the IMP accountability log. Any 
deviation/problems in either storage or shipping conditions must be notified to the 
Sponsor via IMP Incident Form. 
 
9.7
Reporting of Investigational Medicinal Product Quality Complaints 
Any defect or possible defect in the IMP (defined as a pharmaceutical form of an 
active substance being tested) must be reported by the Investigator or qualified 
designee to the Sponsor (study clinical monitor, designated complain officer or 
safety officer) via the Complaint Form who should report the details of the incident.
The product and packaging components in question, if available, must be stored in 
a secure area under specified storage conditions until it is determined whether the 
product is required to be returned for investigation of the defect. If the product 
complaint is associated with an SAE, the SAE must be reported separately in 
accordance with the protocol (see Section 10.4), and the SAE report should mention 
the product quality complaint.  
9.8
Concomitant Medication/SC therapy/Nutrition Procedures 
This protocol foresees a standard care defined by each hospital according to its best 
supportive standard SC and generally defined below. 
 
¾ General definition of Standard care : 
x
Oral food or oral liquid intake according to clinical judgement; 
x
Intravenous corticoids 
x
Intravenous H2 antihistaminics  
x
Proton Pump Inhibitors  
x
Antispasmodic  


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x
Antipsychotics  
¾ Concomitant Medication Authorised for all patients on request: 
x
Analgesics  
x
Antiemetic  
x
Gastroprokinetic  
x
Chemotherapy (if already present at study entry)  
x
Venting Gastrostomy  
 
9.9
Non authorized treatments 
Somatostatin or any of its analogues, other than the study treatment are not 
permitted during the study. 
 
9.10
Treatment of Overdose of IMP 
As this is a single dose administration, overdose of IMP is unexpected. In any case 
the pre-clinical data suggest an acceptable safety margin. Facilities and staff for 
resuscitation and the treatment of other medical emergencies will be provided. 
Any appropriate treatment of overdose of IMP will be determined by the 
Investigator according to the characteristics of the events and will be recorded in the 
subject’s eCRF. An event resulting from an overdose of the trial medication is not 
considered as serious unless it meets the definition of a Serious Adverse Event 
(SAE) and consequently should be reported on the SAE form (see Section 10.4). 


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10
ASSESSMENT OF SAFETY 
 
10.1
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed 
consent and throughout the study duration and will be elicited by direct, non-leading 
questioning or by spontaneous reports. 
 
10.1.1
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. 
An undesirable medical condition can be symptoms (e.g. nausea, chest pain), signs 
(e.g. tachycardia, enlarged liver) or the abnormal results of an investigation (e.g. 
laboratory findings, electrocardiogram). In clinical studies an AE can include an 
undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving written 
informed consent until the end of the study (as defined in Section 4.3.2). 
Natural progression or deterioration of the disease or related signs and 
symptoms, which are part of the efficacy evaluation, should not be recorded as 
an AE/SAE. 
Otherwise, signs and symptoms of the disease should be reported as AEs/SAEs 
(depending on the investigator’s judgement) if they are: 
•
Judged by the investigator to be unusually severe or accelerated 
disease/symptoms or 
•
if the investigator considers the deterioration of disease/symptoms signs and 
symptoms to be caused directly by the IMP. 
If there is any uncertainty about an AE being due solely to the disease/symptoms 
under study, it should be reported as an AE/SAE as appropriate. 
 
10.2
Categorisation of Adverse Events 
10.2.1
Intensity Classification 
AEs will be classified according to The Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.03 (26) or higher, as:  
Grade 1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 
Moderate: minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental ADL* 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL** 


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Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
 
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
10.2.2
Causality Classification 
The relationship of an AE to the IMP will be classified according to the following: 
Related: 
reports including good reasons and sufficient information (e.g. 
plausible time sequence, dose-response relationship, pharmacology, 
positive de-challenge and/or re-challenge) to assume a causal 
relationship with the IMP in the sense that it is plausible, 
conceivable or likely. 
Not related: 
reports including good reasons and sufficient information (e.g. 
implausible time sequence and/or attributable to concurrent disease 
or other drugs) to rule out a causal relationship with the IMP. 
 
10.2.3
Assessment of expectedness  
The reference document for assessing expectedness of AEs/reactions in this study 
will be: the current Investigator’s Brochure. 
 
10.2.4
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the 
following apply:  
x
they result in a change in IMP schedule of administration (change in dosage, 
delay in administration, IMP discontinuation), 
x
they require intervention or a diagnosis evaluation to assess the risk to the 
subject, 
x
they are considered as clinically significant by the Investigator. 
 
10.2.5
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the Investigator, in physical 
examination findings (abnormalities) will be recorded as AEs.  
 
10.2.6
Other Investigation Abnormal Findings 
Abnormal objective test findings as judged by the Investigator as clinically 
significant (e.g., electrocardiogram changes) that result in a change in IMP dosage 
or administration schedule, or in discontinuation of the IMP, or require intervention 
or diagnostic evaluation to assess the risk to the subject, should be recorded as AEs  
 


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10.3
Recording and Follow-up of Adverse Events 
At each visit the subject should be asked a non-leading question such as: “Do you 
feel different in any way since starting the new treatment/the last assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the eCRF. Events 
involving drug reactions, accidents, illnesses with onset during the treatment phase 
of the study, or exacerbation’s of pre-existing illnesses should be recorded.  
AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the Investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as a SAE requiring immediate notification to the Sponsor or its 
designated representative. For all AEs, sufficient information should be obtained by 
the Investigator to determine the causality of the AE (i.e., IMP or other illness). The 
Investigator is required to assess causality and record that assessment on the eCRF. 
Follow-up of the AE, after the date of therapy discontinuation, is required if the AE 
or its sequelae persist. Follow-up is required until the event or its sequelae resolve 
or stabilise at a level acceptable to the Investigator and the Sponsor’s clinical 
monitor or his/her designated representative. 
 
10.4
Serious Adverse Events 
10.4.1
Definitions  
All SAEs (as defined below) regardless of treatment group or suspected relationship 
to IMP must be reported immediately (within 24 hours of the Investigator’s 
knowledge of the event) to the pharmacovigilance contact specified at the beginning 
of this protocol. If the immediate report is submitted by telephone, this must be 
followed by detailed written reports using the SAE report form. 
x
A SAE is any AE occurring at any dose that: 
(1) results in death; 
(2) is life threatening, that is any event that places the subject at 
immediate risk of death from the reaction as it occurred. It does not 
include a reaction that, had it occurred in a more severe form, might 
have caused death; 
(3) results in in-patient hospitalisation or prolongation of existing 
hospitalisation, excluding admission for social or administrative 
reasons (see further); 
(4) results in a persistent or significant disability/incapacity, where 
disability is a substantial disruption of a person's ability to conduct 
normal life functions; 
(5) results in congenital anomaly/birth defect in the offspring of a 
subject who received the IMP; 


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(6) is an important medical event that may not result in death, be life-
threatening, or require hospitalisation when, based upon appropriate 
medical judgement, may jeopardise the subject and may require 
medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do 
not result in in-patient hospitalisation, or the development of drug 
dependency or drug abuse. 
Regardless of the above criteria, any additional AE that the Sponsor or an 
Investigator considers serious should be immediately reported to the Sponsor and 
included in the corporate SAEs database system. 
 
x
Hospitalisation is defined as any in-patient admission (even if less than 24 
hours). For chronic or long-term in-patients, in-patient admission also includes 
transfer within the hospital to an acute/intensive care in-patient unit. 
x
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original 
reason for the initial admission, as determined by the Investigator or 
treating physician. For protocol-specified hospitalisation in clinical trials, 
prolongation is defined as any extension beyond the length of stay described in 
the protocol. Prolongation in the absence of a precipitating, treatment-
emergent, clinical AE (i.e., not associated with the development of a new AE or 
worsening of a pre-existing condition) may meet criteria for "seriousness" but 
is not an adverse experience and thus is not subject to immediate reporting to 
the Sponsor.  
x
Pre-planned or elective treatments/surgical procedures should be noted in the 
subject’s screening documentation. Hospitalisation for a pre-planned or elective 
treatment/surgical procedure should not be reported as an SAE unless there are 
complications or sequelae which meet the criteria for seriousness described 
above. 
 
10.4.2
Reporting Requirements 
Any SAE must be reported immediately (within 24 hours), independent of the 
circumstances or suspected cause, if it occurs or comes to the attention of the 
Investigator at any time during the study period. 
Any SAE with a suspected causal relationship to the IMP occurring at any other 
time after completion of the study must be promptly reported. 
 
10.4.3
Mandatory Information for Reporting a SAE 
The following information is the minimum that must be provided to the Sponsor 
Pharmacovigilance contact within 24 hours for each SAE: 
x
Trial number 


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x
Centre number 
x
Subject number 
x
AE 
x
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the 
Sponsor or representative as soon as it is available. Upon receipt of the initial report, 
the Sponsor will ask for the Investigator's causality assessment if it was not 
provided with the initial report. 
The Investigator should report a diagnosis or a syndrome rather than individual 
signs or symptoms. The Investigator should also try to separate a primary AE 
considered as the foremost untoward medical occurrence from secondary AEs 
which occurred as complications. 
 
10.5
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP 
has interfered with a contraceptive method. If pregnancy occurs during the study, 
the outcome of the pregnancy will then need to be collected post-study and it may 
be necessary to discontinue treatment with the IMP. 
Information regarding pregnancies must be collected on the AE page of the 
CRF/eCRF and the Standard Pregnancy Outcome Report Form, including 
pregnancies with normal progress and outcome. . A Standard Pregnancy Outcome 
Report Form must be completed by the Investigator and provided to the Sponsor 
Pharmacovigilance Contact within 24 hours of the knowledge of the pregnancy in 
any study subject. 
Investigators must instruct all female subjects to inform them immediately should 
they become pregnant during the study. The Investigator should counsel the subject, 
discuss the risks of continuing with the pregnancy and the possible effects on the 
fœtus. Monitoring of the subject should continue until conclusion of the pregnancy, 
which may involve follow-up after the subject’s involvement in the study has ended. 
Pregnancies with a conception date within 90 days  after subject’s last dose of IMP 
or completion of the study must also be reported to the Investigator for onward 
reporting to the Sponsor. 
 
10.6
Death
All AEs resulting in death either during the study period or within 28 days after the  
IMP administration, must be reported as an SAE within 24 hours of the 
Investigator’s knowledge of the event.  
The convention for recording death is as follows:  
x
AE term: lead cause of death (e.g. multiple organ failure, pneumonia, 
myocardial infarction). 
x
Outcome: fatal. 


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For AEs leading to death, grade 5 is the only appropriate grade (see Section 10.2.1). 
Deaths that cannot be attributed to a specific cause have to be reported as one of 
these four AE options: 
x
Death NOS 
x
Disease progression NOS 
x
Multi-organ failure 
x
Sudden death 
 
10.7
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal due to AEs will be recorded on the eCRF page. 
The investigator must ensure the subject receives appropriate medical follow up (see 
Section 6.5). 
 
10.8
Reporting to Competent Authorities/IECs/Other Investigators 
The Sponsor will ensure that processes are in place for submission of reports of 
Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring during the 
study to the Competent Authorities (CA), IECs and other Investigators concerned by 
the IMP. Reporting will be done in accordance with the applicable regulatory 
requirements. 
 
 
11
STATISTICAL CONSIDERATIONS 
 
11.1
Subject Classification and Definitions 
x Enrolled subject: 
Subject fully informed about the study who has given 
written informed consent to participate (before any 
occurrence of trial related procedure). 
x Screened failure 
subject:
Enrolled subject who fails to fulfil one or more entry 
criteria and thus does not proceed to the treatment phase 
of the study. Although not exposed to study medication, 
they may have been exposed to some study related 
procedures. Records up to the time of premature 
termination should be completed including the reason for 
termination. 
x Treated subject/ 
Treatment 
Completed subject: 
 
Enrolled subject who received the IMP (one single dose). 
x Randomised 
subject:
Enrolled subject who is allocated to a treatment group at 
random. 


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x Study Completed 
subject:
Randomised subject who has completed all specified 
assessments of the study. 
x Drop-out: 
Randomised subject who did not complete the study.  
 
11.2
Analyses Populations Definitions 
 
x
Screened population: 
All subjects who signed the informed consent. 
x
Randomised 
population: 
All subjects randomly assigned to one of the 
treatment required by the protocol. 
x
Safety population: 
All subjects who received the dose of study 
medication.  
x
Intention-to-treat 
(ITT) population:  
All randomised subjects.
x
Per protocol (PP) 
population: 
All subjects in the ITT population for whom no 
major protocol violations/deviations occurred and 
have carefully filled in the patient diary and ESAS 
questionnaire for the first seven days of study. 
 
11.2.1
Populations Analysed 
The primary analysis based on the primary efficacy endpoint will be performed on 
the ITT subjects having the ESAS questionnaire duly filled in at baseline (before the 
randomization) and at least five out of six duly filled in ESAS questionnaires related 
to the first 6 days post baseline visit. In addition, PP analysis may be performed as 
secondary. 
The analyses of safety data will be performed based on the Safety population.  
 
11.2.2
Subject Allocation and Reasons for Exclusion from the Analyses 
The rules for the allocation of subjects to each of the analysis populations will be 
defined and documented during a “data” review meeting held prior to database lock. 
During the data review meeting, based on minor or major protocol 
violations/deviations, subjects may be excluded from the Safety/ITT/PP population. 
Subjects may be excluded from the analyses if one or more of the following 
violations/deviations occur.
x
inclusion/exclusion criteria violations 
x
did not receive any study medication 
x
prohibited medication intake 
x
deviations from time windows  
x
deviations from IMP administration 
x
no baseline evaluation of primary efficacy criterion 


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x
no valid post baseline evaluation of primary efficacy criterion 
x
other protocol violation/deviations  
 
11.3
Sample Size Determination 
Sample size estimation was based on the mean AUC of ESAS total score collected 
for 7 days after basal visit. Based on following assumptions: 
x
expected standardised difference (effect size) between mean AUC of group A 
and group B equal to 0.60. 
x
expected common standard deviation of the primary efficacy variable is equal 
to 1. 
x
type I error 0.05, two sided test, 80% power. 
the number of subjects to be randomized/treated per group is 35. By taking into 
consideration an invalidity rate of 20% for multiple centre design/premature 
withdrawals and other invalidity reasons, a total of 42 per group will be needed. 
Since the quality of life is a multidimensional parameter, the AUC of ESAS total 
scores measured daily and reported on the patient’s diary, during the first 7 days, is 
the primary variable which is calculated on, the sample size. 
ESAS total score is related to the status of the patient's illness: a low score indicates 
a good quality of life, a high score indicates a strong discomfort. 
In the group of patients who have added the injection LAN ATG 120 mg to standard 
care (Group A), the expected outcome is a lower value of the mean AUC compared 
to the one detected in the group of patients who were treated with only the standard 
therapy. 
In order to determine the sample size, we consider, for each patient, the AUC 
corrected with the basal ESAS total score by analysis of covariance (ANCOVA). In 
fact we assume that the AUCs are related to basal values. In this analysis the 
independent variable (covariate) will be the baseline values and the dependent 
variables will be the AUC of ESAS total scores collected for 7 days. 
Without preliminary data of the distribution of AUCs in the study population, we 
must assume the data have a normal distribution. Thus, in order to achieve a 
relevant clinical effect, we can assume an effect size of 0.60 (0.20 indicates a  small 
effect size; 0.50 a medium effect and  0.80 a large effect size). 
 
We state 
 
݀ൌ
หP஺െP஻ห
ɐԢ
ൌͲǤ͸Ͳ 
 
Where  
-
d is the effect size index and ı’ the standard deviation of the dependent 
corrected by the basal values (covariates); 


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-
PA is the mean AUC recorded for 7 days, adjusted for the respective baseline, in 
the group receiving standard care + Lanreotide injection; 
-
PB is the AUC recorded for 7 days adjusted mean, in the group treated with 
standard care alone; 
-
ı’ is defined as: ı’ = ı ඥሺͳ െݎଶሻ 
Where, ı is the standard deviation of the dependent variable, and r (r=0.50) is 
the correlation coefficient between basal total scores and AUC values. We set r 
=0.50 because we suppose a correlation between the basal score and AUC. 
The null hypothesis can therefore be as follow: 
H0: ~ PA - PB ~ d 0.60 
While the alternative hypothesis: 
HA: ~ PA - PB ~ > 0.60 
So chosen D = 0.05 and E = 0:20 (80% power), a total of 70 evaluable patients are 
needed: 35 patients in each treatment group. 
Finally, as literature data show in this patient population there is a drop-out rate of 
about 20%, the total number of patients to be included in the study must be at least 
84 patients, 42 per group. 
 
11.3.1
Significance Testing and Estimations 
All statistical tests will be performed two sided with a type I error rate set at 5% . 
 
11.4
Statistical/Analytical Methods 
Statistical analyses will be performed by an external Contract Research 
Organisation (CRO), managed by the Sponsor’s Clinical Development Data 
Sciences Department. 
A Reporting and Analysis plan (RAP) describing the planned statistical analysis in 
detail with tables, figures and listings (TFLs) templates will be developed as a 
separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® 
(version 9.3 or higher). 
 
11.4.1
Demographic and Other Baseline Characteristics 
In order to ensure balance of treatment groups, descriptive summary statistics (n, 
mean, standard deviation (SD), median, minimum, maximum) or frequency counts 
of demographic and baseline data (medical history, concomitant disease (pre-
treatment AEs and on-going medical history, prior medications and therapies, 
baseline symptoms etc) will be presented by treatment group and overall for the ITT 
and PP/safety population(s). 


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11.4.1.1 Homogeneity of Treatment Groups 
In order to assess the homogeneity of treatment groups at baseline, statistical 
significant testing may be carried out in selected parameters such as age, sex, body 
mass index, risk factors etc. Appropriate methods based on analysis of variance 
approach or on the Mantel –Haenszel chi-squared test will be used. Positive findings 
(p<0.05) will be discussed regarding their potential influence on the analyses of the 
primary efficacy endpoint(s). 
11.4.1.2 Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each of the ITT 
/PP and safety populations will be tabulated by centre. The reasons for subject 
exclusions from each of the populations will also be tabulated. In addition, the 
numbers of subjects who were randomized, discontinued and completed at each 
visit. Primary reasons for discontinuation of study treatment will be tabulated. 
11.4.1.3 Efficacy evaluation 
The main outcome variable (7 days AUC) will be analysed by the analysis of 
covariance (ANCOVA), where the AUC is the dependent, and the independent is 
the basal total score. This variable will be also analysed by the repeated measures 
analysis of variance with one group to highlight statistically significant differences 
between and within groups 
The secondary efficacy variables are Karnofsky performance status, abdominal pain 
(VAS) vomiting episodes (2) for 3 days, daily vomiting episodes, days without 
vomiting, removal of NGT for 3 days, NGT secretion volume, passage of stools, 
ESAS optional item 10 assessed daily and concomitant medications/analgesic 
intake. The analgesic score will be calculated given 1 to each intake of non-opioids 
analgesics and 2 to opioids analgesics. 
The basal ESAS score will be used as covariates in the primary model.  
If the parametric assumptions of the analysis are not satisfied, then a suitable 
transformation or a non-parametric procedure will be sought. 
All recorded variables will be presented in tables using standard procedures 
depending on the underlying distribution. Descriptive statistics on ordinal and 
categorical variables will be made reporting numbers and percentages, whereas for 
continuous variables mean, standard deviation (and standard error) together with 
range will be showed.  
To highlight statistically significant differences between and within groups, 
continuous and normally distributed variables will be analysed by the analysis of 
variance, with repeated measures (time) and one group (treatment). Discrete or non-
normally distributed variables will be analysed by non-parametric tests (Mann-
Whitney U test and Wilcoxon test). Nominal and categorical variables will be 
analyzed by the Ȥ2 test with the Yates correction for 2x2 contingency tables. 
 


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11.4.1.4 Safety Evaluation 
All safety data will be included in the subject data listings. Analyses and summary 
tables will be based upon the safety population. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version 16.0 and will be classified by MedDRA preferred term and 
system organ class. AE listings will be presented by subject, system organ class and 
preferred term. 
Incidence of all reported AEs/treatment emergent AEs (TEAE) and SAEs will be 
tabulated by treatment group and by overall. In addition, summary tables will be 
presented by maximum intensity, drug relationship and AEs/TEAEs associated with 
premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
it was not present prior to receiving the first dose of IMP, or  
it was present prior to receiving the first dose of IMP but the intensity increased 
during the active phase of the study, or  
it was present prior to receiving the first dose of IMP, the intensity is the same but 
the drug relationship became related during the active phase of the study.  
Treatment emergent AEs will be flagged (*) in the AEs listings.  
Concomitant medications will be coded by using Prontuario Farmeceutico Italiano 
Farmadati (available at the URL www.prontuariofarmaceutico.it/), which includes the 
same ATC codes of those in WHO Drug Dictionary, but limited to the drug on the 
Italian market. They will be summarised by treatment group and by overall with the 
number and percentage of subjects receiving concomitant medication by drug class 
and preferred drug name!. 
Summary statistics (mean, median, SD and range as appropriate) by treatment group 
and by overall will be presented for vital signs, blood pressure, heart rate, ECG 
parameters, clinical laboratory tests etc at each assessment with change from 
baseline. For laboratory data, abnormal values will be flagged in the data listings 
and a list of clinically significant abnormal values will be presented. Shift tables will 
be presented of the number and percentage of subjects with low, normal or high 
values and normal or abnormal exams. 
 
11.5
Subgroup Analyses 
It will also be detailed in the RAP if and what subgroup analyses are to be 
performed. All subgroup analyses will be performed by means of descriptive 
statistics for exploratory purposes. 
 
11.6
Interim Analyses  
No interim analysis will be performed. 
 
 


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12
MONITORING PROCEDURES 
The Investigator is responsible for the validity of all data collected at the site. The 
Sponsor is responsible for monitoring this data to verify that the rights and well-
being of subjects are protected, that trial data are accurate (complete and verifiable 
to source data) and that the trial is conducted in compliance with the protocol, GCP 
regulatory requirements and local laws. 
 
12.1
Routine Monitoring 
Sponsor-assigned monitors will conduct regular site visits. The Investigator will 
allow direct access to all relevant files (for all subjects) and clinical trial supplies 
(dispensing and storage areas) for the purpose of verifying entries made in the 
electronic Case Report Form (eCRF), and assist with the monitor’s activities, if 
requested. Adequate time and space for monitoring visits should be made available 
by the Investigator. 
The site must complete the eCRFs within 5 days after the patient’s visit and on an 
on-going basis to allow regular review by the study monitor. This time period may 
be changed at some specific stages of the study (e.g., end of study or for interim 
analysis purposes). During the study the monitor will visit the site regularly to check 
the completeness of patient’s records, the accuracy of the entries on eCRFs, the 
adherence to the protocol and to GCP, the progress of enrolment, and to ensure that 
study drug is being stored, dispensed, and accounted for according to specifications. 
Whenever a subject name is revealed on a document required by the Sponsor (e.g., 
laboratory print-outs) the name must be blacked out permanently by the site 
personnel and annotated with the subject number as identification. 
 
 
13
STUDY MANAGEMENT  
13.1
Inspections and Auditing Procedures 
Authorised personnel from external CAs and Sponsor-authorised Quality Assurance 
personnel may carry out inspections and audits. The purpose of an audit is to ensure 
that ethical, regulatory and quality requirements are fulfilled in all studies performed 
by the Sponsor. 
Auditors and inspectors must have direct access to study documents and site 
facilities as specified in section 12.1, and to any other locations used for the purpose 
of the study in question (e.g., laboratories). 
In the event of the site being notified directly of a regulatory inspection, the 
Investigator must notify the Sponsor representative as soon as possible, to assist 
with preparations for the inspection. 
 


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13.2
Data Recording of Study Data 
In compliance with GCP, the patient’s medical file/medical records/medical notes, 
etc., should be clearly marked and permit easy identification of a subject’s 
participation in the specified clinical trial. 
The Investigator must record all data relating to protocol procedures, IMP 
administration, laboratory data, safety data and efficacy ratings on the eCRFs 
provided for the study. The Investigator, by completing the signature log, may 
formally designate the qualified sub-investigators to complete eCRF. They have to 
be registered as eCRF operators into the system, though personal credentials. 
The Investigator must, as a minimum, provide an electronic signature (e-signature) 
to each “visit status” eCRF page to attest to the accuracy and completeness of all the 
data. If any changes are made to the eCRF, after a form has been locked and 
electronically signed, the Investigator will be required to perform an additional e-
signature authorising agreement with any new information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is 
always required. In the eCRF, the audit trail function will allow the changes made to 
be viewed on each item entered. 
 
The study foresees the Patient Diary (pre and post-treatment) and the ESAS 
questionnaire: they will be in paper and printed. Each page will be in double copy: 
the original will send to the CRO in charge of the statistical analysis and it will be 
responsible also for the data entry in the eCRF/database of the data collected from 
the patients and the copy will kept at the site as source document. 
 
13.3
Source Data Verification 
The FDA 21 CFR Part 11, is a regulation which provides criteria for acceptance by 
the FDA, under certain circumstances, of electronic records, e-signatures and hand-
written signatures executed to electronic records as equivalent to paper records and 
hand-written signatures on paper. 
As required by GCP, the Sponsor assigned monitor must verify, by direct reference to 
the source documents, that the data required by the protocol are accurately reported on 
the eCRF.  
The source documents must, as a minimum, contain the following; a statement that the 
subject is included in a clinical trial, the date that informed consent was obtained prior 
to participation in the study, the identity of the study, diagnosis and eligibility criteria, 
visit dates (with subject status), IMP administration, and any AEs and associated 
concomitant medication.  
Definition for source data and source documents are given below: 


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x Source Data: 
All original records and certified copies of original 
records of clinical findings, observations, or other 
activities necessary for the reconstruction and evaluation 
of the trial. Source data are contained in source 
documents (original records or certified copies). [ICH 
GCP Section 1.51] 
x Source Documents: 
Original documents, data and records (e.g. hospital 
records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified 
after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-
rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments 
involved in the clinical trial). [ICH GCP Section 1.52] 
The subject must have consented to their medical records being viewed by 
Sponsor-authorised personnel, and by local, and possibly foreign, CAs. This 
information is included in the informed consent. 
 
13.4
Data Quality 
Monitored eCRFs transferred from the investigational site to the assigned Data 
Management group will be reviewed (secondary monitoring) for completeness, 
consistency, legibility and protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require 
additional electronic manual queries to be raised to the Investigator by the monitor for 
clarification/correction. The Investigator must ensure that queries are dealt with 
promptly. All data changes and clarifications can be viewed in the audit trail function 
of the eCRF. 
 
13.5
Data Management 
eCRF will be utilized for collecting patient data. Each site is required to have a 
computer and internet connection available for site entry of clinical data. All entries in 
the eCRF will be done under the electronic signature of the person performing the 
action. This electronic signature consists of an individual and confidential username 
and password combination. It is declared to be the legally binding equivalent of the 
handwritten signature. Only Sponsor authorized users will get access to the eCRF as 
appropriate to their study responsibilities. Users must have successfully undergone 
software application training prior to entering data into the eCRF. 
Data management will be conducted by a CRO. All data management procedures will 
be completed in accordance with Ipsen and the contracted CRO SOPs. Prior to data 


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being received in-house at the assigned CRO, it will be monitored at the Investigator 
site, (see Section 12). eCRF and other data documentation removed from the 
Investigator site(s) will be tracked by the CRO and the monitor. 
The Sponsor  will ensure that an appropriate eCRF is developed to capture the data 
accurately, and suitable queries are raised to resolve any missing or inconsistent 
data. The Investigator will receive their data, from the clinical trial, in an electronic 
format (PDF files) which will be an exact copy of the eCRF, and will include the 
full audit trail, for archiving purposes and future reference. Any queries generated 
during the data management process will also be tracked by the contracted data 
management CRO/will be raised within the eCRF. It is the Sponsor’s responsibility 
to ensure that all queries are resolved by the relevant parties. The Sponsor will also 
ensure that SAE data collected in the eCRF are consistent with information provided 
to the Sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history and concomitant medication terms will be 
performed by the contracted CRO and reviewed and approved by the Sponsor. 
Concomitant medications will be coded using Prontuario Farmeceutico Italiano 
Farmadati (available at the URL www.prontuariofarmaceutico.it/) and AEs/medical 
history terms will be coded using MedDRA (version 16.1 or higher). 
 
13.6
Study Management Committees 
No Committees foreseen for study management. 
13.7
Record Archiving and Retention 
During the pre-study and initiation visits, the monitor must ensure the archiving 
facilities are adequate and archiving/retention responsibilities of the Investigator 
have been discussed.  
Trial documents must be retained according to the applicable regulatory 
requirements and national laws. The Investigator should take measures to prevent 
accidental or premature destruction of these documents. The final archiving 
arrangements will be confirmed by the monitor when closing-out the site. The Sponsor 
will inform the Investigator, in writing, as to when these documents no longer need 
to be retained. 
If the Principal Investigator relocates or retires, or otherwise withdraws his/her 
responsibility for maintenance and retention of study documents, the Sponsor must 
be notified (preferably in writing) so that adequate provision can be made for their 
future maintenance and retention. 
 
 
 
 
 


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14
ADMINISTRATION PROCEDURES 
 
14.1
Regulatory Approval 
As required by local regulations, the Sponsor’s Regulatory Affairs group will ensure 
all legal regulatory aspects are covered, and obtain approval of the appropriate 
regulatory bodies, prior to study initiation. 
 
14.2
Publication Policy 
The Sponsor encourages acknowledgement of all individuals/organisations involved 
in the funding or conduct of the study, including medical writers or statisticians 
subject to the consent of each individual and entity concerned, including 
acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings 
by the investigators involved in the study. For multicentre studies, a plan for 
scientific publication and presentation of the results may be agreed and 
implemented by the study investigators or a Steering Committee. The Sponsor 
requires that reasonable opportunity be given to review the content and conclusions 
of any abstract, presentation, or paper before the material is submitted for 
publication or communicated. This condition also applies to any amendments that 
are subsequently requested by referees or journal editors. The Sponsor will 
undertake to comment on the draft documents within the time period agreed in the 
contractual arrangements, including clinical trial agreements, governing the 
relationship between the sponsor and authors (or the author’s institution). Requested 
amendments will be incorporated by the author, provided they do not alter the 
scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until 
(i) a patent application is filed for the content of the publication in accordance with 
applicable provisions of the clinical trial agreement concerned, (ii) the Sponsor 
consents to the publication, or (iii) the time period as may be agreed in the 
contractual arrangements, including clinical trial agreements, governing the 
relationship between the sponsor and authors (or authors’ institution) after receipt of 
the proposed publication by the sponsor, whichever of (i), (ii) or (iii) occurs first. 
The author undertakes to reasonably consider the sponsor's request for delay to the 
proposed publication should the sponsor reasonably deem premature to publish the 
results obtained at the then stage of the study. 
 
14.3
Clinical Study Report 
A final clinical study report will be prepared according to the ICH guideline on 
structure and contents of clinical study reports. A final clinical study report will be 
prepared where any subject has signed informed consent, regardless of whether the 
trial is completed or prematurely terminated. Where appropriate an abbreviated report 


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may be prepared. The CSR will be in compliance with any applicable regulatory 
requirements, national laws in force and will be in English. 
 
14.4
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and 
the Sponsor will sign a clinical study agreement prior to the start of the study, outlining 
overall Sponsor and Investigator responsibilities in relation to the study. Financial 
remuneration will cover the cost per included subject, based on the calculated costs of 
performing the study assessments in accordance with the protocol, and the specified 
terms of payment will be described in the contract. The contract should describe 
whether costs for pharmacy, laboratory and other protocol-required services are being 
paid directly or indirectly. 
Financial Disclosure Statements will need to be completed, as requested by FDA 21 
CFR Part 54 and local regulation. 
 
14.5
Insurance, Indemnity and Compensation 
The Sponsor will provide Product Liability insurance for all subjects included in the 
clinical study. 
 
 
15
PROTOCOL AMENDMENTS 
In the event that an amendment to this protocol is required (see Section 5.1), is will 
be classified into one of the following three categories: 
x
Non-Substantial Amendments are those that are not considered ‘substantial’ 
(e.g. administrative changes) and as such only need to be notified to the IECs or 
Competent Authorities (CA) for information purposes. 
x
Substantial Amendments are those considered ‘substantial’ to the conduct of 
the clinical trial where they are likely to have a significant impact on: 
-
the safety or physical or mental integrity of the subjects; 
-
the scientific value of the trial; 
-
the conduct or management of the trial; or 
-
the quality or safety of the IMP used in the trial. 
Substantial amendments must be notified to the IECs and Italian central CA 
(AIFA). Prior to implementation, documented approval must be received from 
the IECs. In the case AIFA has raised no grounds for non-acceptance during an 
allocated time period, following acknowledgment of receipt of a valid 
application, the substantial amendment could be considered approved.  
x
Urgent Amendments are those that require urgent safety measures to protect 
the trial subjects from immediate hazard and as such may be implemented 
immediately by the Sponsor with subsequent IECs and CA notification, 
forthwith.  
 


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16
REFERENCES 
1) Ripamonti C. “Management of bowel obstruction in advanced 
cancer.” Current Opinion in Oncology 1994; 6: 351-357. 
2) Baines M. et al. “Medical management of intestinal obstruction in 
patients with advanced malignant disease: a clinical and pathological 
study.” Lancet 1985; 2: 990-993.  
3) Ripamonti C. et al. “Clinical-practice recommendations for the 
management of bowel obstruction in patients with end-stage cancer.” 
Support Care Cancer 2001; 9 (4): 223-233. 
4) Ripamonti C. et al. “The role of somatostatin and octreotide in bowel 
obstruction: pre-clinical and clinical results.” Tumori 2001; 87: 1-9. 
5) Fainsinger R.L. et al. “Use of somatostatin analogues in terminal 
cancer patients.” J. Palliat. Care 1993; 9/1: 56-57. 
6) Mercadante S. et al. “Octreotide in relieving gastrointestinal 
symptoms due to bowel obstruction.” Palliat. Med. 1993; 7: 295-299. 
7) Laval G. et al. “The use of steroids in the management of inoperable 
obstruction.” Palliative Medicine 2000; 14: 3-10. 
8) Raptis S. et al “Effects of somatostatin on the exocrine pancreas and 
the release of duodenal hormones.” Metabolism 1978; 27: 1321-
1328. 
9) Tulassay Z. “Somatostatin and the gastrointestinal tract.” Scand. J. 
Gastroenterol 1998; 33 Suppl 228: 115-121. 
10) Lansden F.T. et al. “Treatment of external pancreatic fistulas with 
somatostatin.” Am. Surg. 1989; 55: 695-698. 
11) Barnes S. et al. “Somatostatin analog treatment of pancreatic 
fistulas.” International Journal of Pancreatology 1993; 14 (2): 181-
188. 
12) Mystakidou K. et al. “Comparison of Octreotide administration 
versus conservative treatment in the management of inoperable 
bowel obstruction in patients with far advanced cancer: a 
randomized, double-blind, controlled clinical trial.” Anticancer 
Research 2002; 22: 1187-1192.  
13) Ipstyl Investigator’s Brochure  
14) Mariani P. et al. “Symptomatic Treatment with Lanreotide 
Microparticles in Inoperable Malignant Bowel Obstruction Resulting 
from Peritoneal Carcinomatosis: a Randomized, Double-blind, 
Placebo-controlled, Phase III Study”; JCO 2012; 30(35): 4337-4343. 
15) S. Mercadante et al. “Octreotide for Malignant Bowel Obstruction: 


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twenty years after.” Critical Reviews in Ocology/ hematology 20123; 
83: 388-392 
16)  A. Soriano and M.P. Davis. “Malignant bowel obstruction: 
individualized treatment near the end of life.” Cleveland Clinic 
Journal of Medicine 2011; vol 78, N3: 197-206 
17) Bruera E et al. “The Edmonton Symptom Assessment System 
(ESAS): a simple method for the assessment of palliatiuve care 
patients.” J. Palliat. Care, 1991; 7(2): 6-9 
18) Nekolaichuk C. et al. “The Edmonton Symptom Assessment System: 
a 15-year retrospective review of validation studies (1991-2006)”. 
Palliat Med 2008;22;111-122 
19) Moro C. et al. “Edmonton symptom assessment scale: Italian 
validation in two palliative care setting.” Support Care Cancer 2006; 
14; 30-37. 
20) Follwell M. et al. “Phase II Study of an outpatients palliative care 
intervention in patients with metastatic cancer”. J. Clin. Oncol. 2009, 
27 (2): 206-213. 
21) INTERNATIONAL CONFERENCE ON HARMONISATION (ICH) 
E9 AND FEDERAL REGISTER VOL 63, NO. 179 (SEPTEMBER 
1998) 
22) Food and Drug Administration (FDA) 21 CFR Part 11, Electronic 
Records, Electronic Signatures. 
23) FDA, Guidance for Industry: Computerized Systems Used in Clinical 
Trials. 
24) Karnofsky DA, Burchenal JH “The clinical evaluation of 
chemotherapeutic agents in cancer”. In: MacLeod CM (ed. 1949), 
Evaluation of chemotherapeutic agents. Columbia Univ Press. Page 
196. 
25) EudraLex – Vol 4 Good manufacturing practice (GMP) guidelines - 
Annex 13 – February 2010. 
26) Donald D. Price et al. “The Validation of Visual Analogue Scales as 
Ratio Scale Measures for Chronic and Experimental Pain”. Pain 17, 
1983; 45-56. 
 


IPSEN GROUP  
 
 
 
 
 
 
 
A-93-52030-279
 
CONFIDENTIAL 
 
 
PROTOCOL: Final Version 1.0  13/May/2014 
PAGE 54/56 
 
17
LIST OF APPENDICES 

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IBIS Informatica & Idee s.r.l. - Via Carlo D’Adda, 8 - 20143 Milano 
 STATISTICAL ANALYSIS PLAN (SAP) 
 
TITLE: 
 A PHASE II, MULTICENTRE, RANDOMIZED CONTROLLED STUDY EVALUATING THE 
QUALITY OF LIFE IN PATIENTS WITH INOPERABLE MALIGNANT BOWEL OBSTRUCTION 
TREATED WITH LANREOTIDE AUTOGEL 120 MG IN COMBINATION WITH STANDARD CARE 
VS. STANDARD CARE ALONE (QOL IN IMBO STUDY) 
 
PHASE: II 
 
PROTOCOL VERSION and DATE: Final Version 1.0 - 13/05/2014 
 
DISEGN: MULTICENTRE, PROSPECTIVE, RANDOMIZED, PARALLEL ARMS, OPEN-LABEL STUDY 
 
INVESTIGATIONAL MEDICINAL PRODUCT: LANREOTIDE AUTOGEL 120 MG 
 
SAP VERSION and DATE: Final Version 1.0 - 10/10/2018 
 
 
 


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Final Version 1.0 
Invii / Sent to 
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1 INDEX 
1 
INDEX .............................................................................................................................................. 3 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................11 
3 
NOTE TO THIS SAP VERSION ............................................................................................................13 
4 
INFORMATION TAKEN FROM THE PROTOCOL ..................................................................................13 
4.1 
Study objectives ......................................................................................................................13 
 
Primary study objective ................................................................................................................ 13 
 
Secondary study objectives .......................................................................................................... 13 
4.2 
Design ....................................................................................................................................14 
 
Population characteristics ............................................................................................................ 14 
 
Study duration .............................................................................................................................. 14 
4.3 
Methods and procedures ........................................................................................................15 
 
Subject identification and allocation to study treatment............................................................. 15 
 
Subjects evaluations ..................................................................................................................... 15 
4.3.2.1 
Efficacy assessments ................................................................................................................ 15 
4.3.2.2 
Safety assessments ................................................................................................................... 16 
4.3.2.3 
Other assessments ................................................................................................................... 17 
4.3.2.4 
Withdrawal/discontinuation .................................................................................................... 17 
4.3.2.5 
Schedule assessments .............................................................................................................. 18 
 
Planned sample size ...................................................................................................................... 20 
5 
SUBJECT POPULATIONS (ANALYSIS SET) ...........................................................................................22 
5.1 
Efficacy ...................................................................................................................................22 
 
Intention-To-Treat population (ITT).............................................................................................. 22 
 
Full Analysis Set (FAS) ................................................................................................................... 22 
 
Per Protocol Population (PP) ........................................................................................................ 22 
5.2 
Safety .....................................................................................................................................22 
5.3 
Pharmacokinetics ....................................................................................................................22 
 
PK Intent-To-Treat Population ...................................................................................................... 22 


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PK Per Protocol Population ........................................................................................................... 22 
5.4 
Primary population .................................................................................................................23 
6 
STATISTICAL METHODS ...................................................................................................................23 
6.1 
Statistical analysis strategy ......................................................................................................23 
 
Primary efficacy endpoint ............................................................................................................. 23 
 
Secondary efficacy endpoints ....................................................................................................... 24 
 
Safety Endpoints ........................................................................................................................... 25 
 
Multiplicity .................................................................................................................................... 25 
 
Significance testing and estimation .............................................................................................. 25 
7 
Analysis Methods ............................................................................................................................25 
7.1 
Efficacy ...................................................................................................................................25 
 
Primary efficacy analysis ............................................................................................................... 25 
 
Secondary efficacy analysis .......................................................................................................... 26 
7.2 
Safety .....................................................................................................................................27 
 
Adverse Events.............................................................................................................................. 27 
 
Death ............................................................................................................................................ 28 
 
Laboratory data ............................................................................................................................ 28 
 
Vital signs ...................................................................................................................................... 28 
7.3 
Missing values and outliers .....................................................................................................28 
 
Missing data .................................................................................................................................. 28 
 
Missing or incomplete dates ......................................................................................................... 29 
 
Outliers ......................................................................................................................................... 29 
7.4 
Subject disposition ..................................................................................................................29 
7.5 
Withdrawals ...........................................................................................................................30 
7.6 
Demographic and baseline characteristics ...............................................................................30 
7.7 
Medical and surgical history ....................................................................................................30 
7.8 
Subject compliance .................................................................................................................31 
7.9 
Prior and concomitant therapies .............................................................................................31 
7.10 
Pharmacokinetics & antibodies ...............................................................................................32 


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7.11 
Pharmacodynamics .................................................................................................................32 
7.12 
Derived data ...........................................................................................................................32 
7.13 
Visit windows .........................................................................................................................33 
7.14 
Rules and data formats ...........................................................................................................33 
7.15 
Pooling of Centres ...................................................................................................................34 
7.16 
Interim analysis.......................................................................................................................34 
7.17 
Role of independent data monitoring committee (DMC)/interim data review committee .........34 
7.18 
Covariates and analysis of subgroups .......................................................................................34 
8 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS ................................................35 
8.1 
Hardware ................................................................................................................................35 
8.2 
Software .................................................................................................................................35 
8.3 
Validation programs ................................................................................................................35 
8.4 
Restitution of the programs ....................................................................................................36 
9 
CHANGES FROM PROTOCOL ............................................................................................................36 
10 
REFERENCES ....................................................................................................................................36 
11 
DATA PRESENTATION ......................................................................................................................36 


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2 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
95% C.I. 
95% Confidence Interval 
AE 
Adverse Event/Experience 
ANCOVA 
ANalysis of COVAriance 
ANOVA 
ANalysis Of VAriance 
ATC 
Anatomical Therapeutic Chemical classification system 
AUC 
Area Under Curve 
BMI 
Body Mass Index 
CA 
Competent Authorities 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
DUS 
Disease Under Study 
E 
Electronic 
ESAS 
Edmonton Symptom Assessment System 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GH 
Growth Hormon 
GI 
Gastrointestinal 
IC 
Informed Consent 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like Growth Factor 
IMP 
Investigational Medicinal Product synonymous with “study drug” 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
LAN ATG 120 mg 
Lanreotide Autogel 120 mg 
MBO  
Malignant Bowel Obstruction 
MRI 
Magnetic Resonance Imaging 
NET 
Neuroendocrine Tumors 
NGT 
Nasogastric tube 
NOS 
Not Otherwise Specified 
PI 
Package Insert 
PP 
Per Protocol 


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PK 
Pharmacokinetics 
RAP 
Reporting and Analysis Plan 
SAE 
Serious Adverse Event/Experience 
SAS® 
Statistical Analysis System® 
SC 
Standard Care 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Porcedures 
SSA 
Somatostatin Analog 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TFLs 
Tables, Figures and Listings 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial Master File 
WHO 
World Health Organization 
 
 


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3 NOTE TO THIS SAP VERSION 
The IMBO study SAP was prepared before the decision to prematurely stop the study. Therefore to facilitate 
the review, any changes, which need to be highlighted, will be presented as notes throughout the SAP. 
4 INFORMATION TAKEN FROM THE PROTOCOL 
4.1 Study objectives 
 Primary study objective 
To evaluate the impact on Quality of Life (Edmonton Symptom Assessment System, ESAS total score) of LAN 
ATG 120 mg in combination with standard care, in comparison to the standard care alone, in subjects 
affected by inoperable malignant bowel obstruction 
 Secondary study objectives 
1) To evaluate the impact of LAN ATG 120 mg on each ESAS item and total score; 
2) To assess General activity (Karnofsky performance status) and Abdominal Pain (Visual analogue 
scale);  
3) To assess the efficacy of LAN ATG 120 mg for the relief of vomiting in patients without nasogastric 
tube (NGT);  
4) To assess the efficacy of LAN ATG 120 mg on NGT secretion volumes or to remove NGT without 
recurrence of vomiting in patients with a nasogastric tube; 
5) Passage of stools (Yes/No); 
6) Descriptive analysis of optional ESAS item 10; 
7) To assess the efficacy in reducing concomitant medications/ analgesics intake; 
8) To assess the safety of the study treatment. 


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4.2 Design 
This is a phase II, multicentre, prospective, randomized, parallel arms, open-label study. 
 
 Population characteristics 
It is planned to include 84 patients in this study. Male or female patients of 18 years of age or older, 
diagnosed with bowel obstruction due to malignant origin, confirmed by appropriate imaging report, who 
are unsuitable candidates for surgery. 
Note: given the premature termination of the study, only 43 patients have been included in this study. 
 Study duration 
The overall duration of the study will be approximately 2 years.  
The study will be considered to have started at first patient Informed Consent signature. The study will be 
considered to have finished when last patient last visit will be performed. 
Study enrolment will last about 18 months. The subjects’ participation in the study is considered to have 
ended at 28th day after randomization. 
Note: the enrollment lasted for 36 months to recruit 43 patients. 
Patients fulfilling the 
Criteria for inclusion 
RANDOMIZATION
First ESAS evaluation 
Continued Efficacy/Safety evaluation until day 28
Group A 
Standard care + 
LAN ATG 120 mg 
Group B 
Standard care


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4.3 Methods and procedures 
 Subject identification and allocation to study treatment 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain a list of subject 
numbers and names to enable records to be found at a later date if required. The enrolment is competitive. 
Following confirmation of eligibility for the study, subjects will be given a randomisation/treatment 
allocation number and allocated to one of the treatment groups specified in Section 4.2. 
The Sponsor’s Randomisation Manager, a statistician independent from the study, will prepare and keep the 
master randomisation list. It will be produced in blocks by using an internal validated randomisation software 
and will be generated with a balance ratio [1 ‘Standard care + LAN ATG 120 mg’ versus 1 ‘Standard care 
alone’].  
Patients meeting the randomisation criteria will be allocated to a randomisation number through the eCRF 
(WEB server) in the order in which they enter the randomised study period.  Authorized Users at sites will 
open the eCRF, fill in all the mandatory items and then if the requirements are satisfied he can press the 
randomization button. The eCRF automatically send via Internet a request to the WEB server (using secure, 
encrypted protocols). The WEB server assigns patients to one of two treatment groups based on a pre-
defined randomisation list. The Investigator can read the assigned treatment directly in the eCRF (additional 
details may be found in the study eCRF manual provided to each site).  
Recruitment will stop once 84 evaluable patients have been randomised. Patients who leave the study early 
will not be replaced. Randomised patients who terminate their study participation for any reason before 
starting the treatment period will retain their randomisation number, i.e. the randomisation number will not 
be reused. The next patient will be given the next randomisation number.  
No centre will randomise more than approximately 20 patients. The subjects enrolled will be monitored 
using the remote study monitoring system. 
The Sponsor’s Randomisation Manager will keep the master list, and a copy of the randomisation list will be 
confidentially supplied to the CRO in charge of central randomisation allocation / eCRF. The master list and 
the copy supplied to the CRO in charge of central randomisation allocation / eCRF will be kept confidential in 
a secure location. Access to the randomisation lists must be restricted until authorisation is given for its 
release. 
Note: due to premature termination of the study, recruitment was stopped after 43 evaluable patients have 
been randomized. 
 Subjects evaluations 
4.3.2.1 
Efficacy assessments 
Primary efficacy endpoint. 


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Comparison between the mean of Area Under the Curve (AUC) of ESAS Total Scores collected daily for the 
first 7 days in patients with standard care + 1 injection of LAN ATG 120 mg (Group A) and the corresponding 
mean AUC in patients with standard care alone (Group B). 
ESAS total score is the sum of nine common symptoms affecting patients with cancer in their terminal phase 
of life. It consists of nine 0–10 numerical scales: pain, activity, nausea, depression, anxiety, drowsiness, 
appetite, sense of well-being and shortness of breath. There is an optional tenth scale based on a symptom, 
which can be added by the patient. Analysis of the primary endpoint will be performed on the first defined 9 
items total score. 
ESAS questionnaire will be assessed by the patient or filled in by the nurse/caregiver in case of patient’s 
physical inability. 
Secondary efficacy endpoints. 
1) Comparison of single ESAS items symptom score and total score at Day 1,2,3,4,5,6 and 7, Day 
14, Day 28, between Group A and Group B. 
2) Changes in intensity at Day 7, Day 14 and Day 28 compared to baseline in General activity 
(Karnofsky performance status) and comparison between Group A and Group B. 
3) Changes in daily intensity of Abdominal Pain (Visual analogue scale) and comparison between 
Group A and Group B. 
4) Comparison of number of patients experiencing ≤ 2 vomiting episodes/day during at least 3 
consecutive days at any time point between the D1 and D7,14,28, between Group A and 
Group B, in patients without nasogastric tube (NGT). 
5) Comparison of number of patients in whom the NGT has been removed during at least 3 
consecutive days at any time point, between the D1 and D7, 14, 28, without vomiting 
recurrence, between Group A and Group B. 
6) In patients with a NGT, changes in daily NGT secretion volume and comparison between 
Group A and Group B. 
7) Comparison of number of daily vomiting episodes and number of days without vomiting, 
between Group A and Group B. 
8) Passage of stools (Yes/No) daily assessment and comparison between Group A and Group B. 
9) Descriptive analysis of optional ESAS item 10. 
10) Standard care and concomitant medications will be recorded and analysed. In particular 
changes in analgesic score intake. 
4.3.2.2 
Safety assessments 
Safety will be assessed through the collection of adverse events (AEs) and vital signs and fully described and 
presented in frequency tables. 


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4.3.2.3 
Other assessments 
Demographic data 
The subject’s demographic profile will include sex, age and ethnic origin. The data have to be collected at the 
Baseline Visit and recorded on the patient’s medical file. 
Medical History  
The medical history, including on-going medical history and obstruction history, will be recorded on the 
patient’s medical file. They will be collected at the Baseline Visit. 
Physical Examination 
The physical examination will include inspection of the following areas: general appearance, head, eyes, ears, 
nose, throat, neck, lymph nodes, skin, lungs, heart, abdomen, extremities/musculoskeletal evaluation, and 
neurological evaluation. It will be carried out by a physician and has to be recorded on the patient’s medical 
file, at each patient’s visit on site. If in the opinion of the Investigator there are any clinically significant 
changes in the physical examination (abnormalities), they will be recorded as AEs.  
Vital Signs and body weight 
Blood pressure and heart rate will be recorded on the patient’s medical file, at each patient’s visit on site.  
Body weight only at baseline visit. 
Pregnancy Test 
A pregnancy test will be performed for all female subjects of child bearing potential. The test will be 
performed on site before randomization procedure. 
Concomitant medications/therapies including standard care therapy 
All concomitant medications, including the standard care therapy and nutrition procedures, have to be 
recorded on the patient’s medical file at the Baseline Visit and all changes at all patient’s visit on site. If the 
patient will be followed at home, all concomitant medications and therapies used as needed, will have to be 
recorded on the patient diary.  
Clinical Laboratory Tests   
All clinical laboratory tests are not mandatory; they are at the discretion of the investigator. 
Clinical chemistry, haematological and urinalysis tests will be repeated as clinically indicated as part of the 
routine management of the patient on the occurrence of AEs. 
4.3.2.4 
Withdrawal/discontinuation 
If the subject is withdrawn from the study (i.e., ceases participation in the study prior to completion of the 
assessments planned in the protocol), the primary reason should be recorded in the patient’s medical file 
and in the electronic case report form (eCRF).  


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In case of discontinuation, the patient will be asked to attend a final visit, performing all assessments 
required by the End of Study visit. The Investigator will provide or arrange for appropriate follow up (if 
required) for subjects withdrawing from the study and will document the course of the subject's condition. 
Where the subject has withdrawn due to an AE the Investigator should follow the procedures documented in 
Section 10 in order to assess the safety of the IMP. 
4.3.2.5 
Schedule assessments 
The schedule of observations and assessments during the study are summarised below. 
Table 1 Schedule of Assessments 
Visit 
V1 
Baseline 
V2 
V3 
V4 
EoS/ Early withdrawal 
Day 
1 
7 
14 ± 2 days 
28 ± 2 days 
Informed Consent 
X 
 
 
 
Demographic data  
X 
 
 
 
Medical history  
X 
 
 
 
Physical examination  
X 
X 
X 
X 
Vital signs  
X 
X 
X 
X 
Body weight 
X 
 
 
 
Pregnancy test (If applicable) 
X 
Eligibility Criteria evaluation  
X 
Patient’s Diary (Delivery and  review) 
X 
X 
X 
X 
Concomitant medications/ SC/nutrition  
X 
X 
X 
X 
Karnofsky performance status 
X 
X 
X 
X 
ESAS questionnaire 
X (*) 
X 
X 
X 
Abdominal pain assessment (VAS) 
X (*) 
X 
X 
X 
Vomiting episodes assessment 
X 
X 
X 
X 
NGT presence secretion volume or NGT 
removal recording 
X 
X 
X 
X 
Passage of stools recording 
X 
X 
X 
X 
Safety assessment and recording (AE & 
SAE) 
X 
X 
X 
X 
IF ALL INCLUSION & ESCLUSION CRITERIA ARE MET: 
Randomisation 
X 
 
 
 
Injection of LAN 120 mg (if randomized 
in Group A) 
X 
 
 
 
 


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Study Visits 
Allowed time deviation for the visits : 
Visit 1/Baseline (Day1) : Not applicable 
Visit 2 (Day 7): No deviations allowed 
Visit 3 (Day 14) : ± 2 days 
Visit 4/End of Study- Withdrawal visit (Day 28) : ± 2 days 
 
Written informed consent must be obtained prior to any study procedure implementation, even before 
the Visit 1. 
 
(*): Prior to randomization, the Investigator must administer the first ESAS questionnaire and VAS to 
the patient. They have been arranged in a separated/specific form (Patient Diary pre-treatment), 
which must then be filed in the clinical records as source document.  
 
Investigators and patients should do their best to comply with study visits schedule to be performed 
at the site. If the patient is resigned from the Hospital after Visit 2 (Day 7) and he/she is physically 
unable (e.g. bedridden) to reach the site for the next control visits, these will be replaced by a phone 
call: the investigator or study staff have to collect as many information as possible, according to the 
scheduled visit.  
In any case, the patient diary and ESAS questionnaires, fully completed, must be delivered to the 
investigator or study staff the day of the scheduled visit for the appropriate revision. 
 
Visit 1 (Baseline) 
x 
Demographics data (sex, age, ethnic origin) 
x 
Medical history, including obstruction history  
x 
Physical examination  
x 
Vital signs 
x 
Body weight 
x 
Karnofsky Performance Status  
x 
Pregnancy test (if applicable) 
x 
Concomitant medications/SC therapy/Nutrition procedures 
x 
Vomiting episodes assessment (episodes in the last 48 hours)  
x 
NGT presence and related secretion volume  
x 
Eligibility criteria evaluation  
x 
Quality of life assessment, using the ESAS questionnaire (*) 
x 
Abdominal pain assessed using the VAS (*) 
x 
Passage of stools (Yes or No)  
x 
Patient’s Diary delivery and explanations  
x 
AEs and SAEs will be collected after signature of the informed consent and again after clinical 
examination and medical history evaluation 
x 
Randomisation (see section 9.3) 
x 
Treatment administration (LAN ATG 120mg and/or SC therapy) 
 
Visits 2 (Day 7) and Visit 3 (Day 14) 
x 
Vital signs 
x 
Physical examination  
x 
Karnofsky Performance Status  
x 
Changes in concomitant medications/ SC therapy/Nutrition procedures 
x 
Quality of life assessment using the ESAS questionnaire 
x 
Patient’s Diary data review: 
x 
 
 
- Abdominal pain  


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x 
 
 
- N. of Vomiting episodes   
x 
 
 
- NGT presence and secretion volume  
x 
 
 
- Passage of stools (Yes or No) 
x 
Collection of AEs and SAEs 
 
Visit 4 - End of study/Withdrawal visit (Day 28) 
x 
The following procedures will be performed for each subject who has completed the study at 
Day 28 or is an Early Withdrawal. 
x 
Vital signs 
x 
Physical examination  
x 
Karnofsky Performance Status  
x 
Changes in concomitant medications/ SC therapy/Nutrition procedures 
x 
Quality of life assessment using the ESAS questionnaire 
x 
Patient’s Diary data review 
x 
 
 
- Abdominal pain  
x 
 
 
- N. of Vomiting episodes   
x 
 
 
- NGT presence and secretion volume  
x 
 
 
- Passage of stools (Yes or No) 
x 
Collection of AEs and SAEs  
x 
Reason for end of study/early withdrawal 
 Planned sample size  
Sample size estimation was based on the mean AUC of ESAS total score collected for 7 days after basal visit. 
Based on following assumptions: 
x 
expected standardised difference (effect size) between mean AUC of group A and group 
B equal to 0.60. 
x 
expected common standard deviation of the primary efficacy variable is equal to 1. 
x 
type I error 0.05, two sided test, 80% power. 
the number of subjects to be randomized/treated per group is 35. By taking into consideration an invalidity 
rate of 20% for multiple centre design/premature withdrawals and other invalidity reasons, a total of 42 per 
group will be needed. 
Since the quality of life is a multidimensional parameter, the AUC of ESAS total scores measured daily and 
reported on the patient’s diary, during the first 7 days, is the primary variable which is calculated on, the 
sample size. 
ESAS total score is related to the status of the patient's illness: a low score indicates a good quality of life, a 
high score indicates a strong discomfort. 
In the group of patients who have added the injection LAN ATG 120 mg to standard care (Group A), the 
expected outcome is a lower value of the mean AUC compared to the one detected in the group of patients 
who were treated with only the standard therapy. 
In order to determine the sample size, we consider, for each patient, the AUC corrected with the basal ESAS 
total score by analysis of covariance (ANCOVA). In fact we assume that the AUCs are related to basal values. 
In this analysis the independent variable (covariate) will be the baseline values and the dependent variables 
will be the AUC of ESAS total scores collected for 7 days. 


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Without preliminary data of the distribution of AUCs in the study population, we must assume the data have 
a normal distribution. Thus, in order to achieve a relevant clinical effect, we can assume an effect size of 0.60 
(0.20 indicates a small effect size; 0.50 a medium effect and  0.80 a large effect size). 
We state 
 ൌ
หP୅െP୆ห
ɐԢ
ൌͲǤ͸Ͳ 
Where  
d is the effect size index and σ’ the standard deviation of the dependent corrected by the basal values 
(covariates); 
PA is the mean AUC recorded for 7 days, adjusted for the respective baseline, in the group receiving standard 
care + Lanreotide injection; 
PB is the AUC recorded for 7 days adjusted mean, in the group treated with standard care alone; 
σ’ is defined as: σ’ = σ ඥሺͳ െଶሻ 
Where, σ is the standard deviation of the dependent variable, and r (r=0.50) is the correlation coefficient 
between basal total scores and AUC values. We set r =0.50 because we suppose a correlation between the 
basal score and AUC. 
The null hypothesis can therefore be as follow: 
H0: ~ PA - PB ~ d 0.60 
While the alternative hypothesis: 
HA: ~ PA - PB ~ > 0.60 
So chosen D = 0.05 and E = 0:20 (80% power), a total of 70 evaluable patients are needed: 35 patients in each 
treatment group. 
Finally, as literature data show in this patient population there is a drop-out rate of about 20%, the total 
number of patients to be included in the study must be at least 84 patients, 42 per group. 
Note: At the time of study termination, out of planned 84 patients, only 43 patients (51%) have been 
randomized, where 17 patients (40%) completed the study. 


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5 SUBJECT POPULATIONS (ANALYSIS SET) 
5.1 Efficacy 
 Intention-To-Treat population (ITT) 
The ITT population includes all randomised subjects. 
 Full Analysis Set (FAS) 
In accordance with the Intention To Treat (ITT) principle, the FAS population includes all subjects randomized 
who received the study drug and who fulfilled the ESAS questionnaire at basal visit and at least at 5 post-
treatment assessments during the first seven days of the study. 
 Per Protocol Population (PP) 
All subjects in the ITT population for whom no major protocol violations/deviations occurred and have 
carefully filled in the patient diary and ESAS questionnaire for the first seven days of study. 
IBIS DM will provide the subjects disposition with the attributed analysis population to be reviewed by the 
study team. 
5.2 Safety 
The safety population includes all randomised subjects who have received at least one dose of study therapy. 
The safety population will be analysed using subjects as treated. 
5.3 Pharmacokinetics 
 PK Intent-To-Treat Population 
Not applicable. 
 PK Per Protocol Population 
Not applicable. 


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5.4 Primary population 
The primary analysis will be based on the FAS population. 
The secondary analysis will be based on the ITT population. 
The primary efficacy analysis will be also performed on the Per Protocol Population as confirmatory analysis. 
If statistical results are different between ITT and PP Population an analysis will be performed in order to give 
reason of this finding. 
The assessment of safety and tolerability will be based on the Safety population. 
Note: due to premature termination of the study only FAS, ITT and Safety populations will be considered. 
6 STATISTICAL METHODS  
6.1 Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guideline and with the guideline on 
clinical evaluation of diagnostic agents and they will be based on data from the study sites, unless otherwise 
stated. 
The statistical analysis of efficacy, safety and tolerability will be performed by IBIS Informatica s.r.l. – Milan -
Italy 
Note: due to premature termination of the study, inferential analysis will be applied only for the analysis of 
the primary efficacy endpoint. For all other endpoints the statistical analysis will be limited to descriptive 
summaries to explore any trends or patterns between the two treatment groups. 
 Primary efficacy endpoint 
Comparison between the mean AUC of ESAS Total Scores collected daily for the first 7 days in patients with 
standard care + 1 injection of LAN ATG 120 mg (Group A) and the corresponding mean AUC in patients with 
standard care alone (Group B). 
ESAS total score is the sum of nine common symptoms affecting patients with cancer in their terminal phase 
of life. It consists of nine 0–10 numerical scales: pain, activity, nausea, depression, anxiety, drowsiness, 
appetite, sense of well-being and shortness of breath. There is an optional tenth scale based on a symptom, 
which can be added by the patient. Analysis of the primary endpoint will be performed on the first defined 9 
items total score. ESAS questionnaire will be assessed by the patient or filled in by the nurse/caregiver in 
case of patient’s physical inability. 


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The AUC is the area under the line which joins the points defined by plotting the ESAS total score on the 
vertical axis and the time values on the horizontal axis: 
The AUC is computed by the trapezoidal rule as follows: 
AUC=
ଵ
ଶ σ
ሺܶ௜ାଵെܶ௜ሻሺܧܵܣܵ௜ାଵ
଺
௜ୀଵ
൅ܧܵܣܵ௜ሻ. 
Where ܶ௜ is the ith time value and ܧܵܣܵ௜ is the ith ESAS total score value. 
Note: due to premature termination of the study, a note will be added to primary endpoint analysis to 
remind that the results are merely indicative, no conclusion can be drawn 
 Secondary efficacy endpoints 
The secondary endpoints are: 
1) Comparison of single ESAS items symptom score and total score at Day 1,2,3,4,5,6 and 7, Day 14, Day 28, 
between Group A and Group B. 
2) Changes in intensity at Day 7, Day 14 and Day 28 compared to baseline in General activity (Karnofsky 
performance status) and comparison between Group A and Group B. 
3) Changes in daily intensity of Abdominal Pain (Visual analogue scale) and comparison between Group A and 
Group B. 
4) Comparison of number of patients experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive 
days at any time point between the D1 and D7,14,28, between Group A and Group B, in patients without 
nasogastric tube (NGT). 
5) Comparison of number of patients in whom the NGT has been removed during at least 3 consecutive days 
at any time point, between the D1 and D7, 14, 28, without vomiting recurrence, between Group A and Group 
B. 
6) In patients with a NGT, changes in daily NGT secretion volume and comparison between Group A and 
Group B. 
7) Comparison of number of daily vomiting episodes and number of days without vomiting, between Group A 
and Group B. 
8) Passage of stools (Yes/No) daily assessment and comparison between Group A and Group B. 
9) Descriptive analysis of optional ESAS item 10. 
10) Standard care and concomitant medications will be recorded and analysed. In particular changes in 
analgesic score intake. 
Note: due to premature termination of the study, secondary endpoint analysis will be limited to descriptive 
summaries to explore any trends or patterns between the two treatment groups and will be done only if 
adequate data are available. 


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 Safety Endpoints 
Due to the premature termination of the study, adverse events, deaths, laboratory values and vital signs will 
be carefully analysed, interpreted and reported 
 Multiplicity 
No multiple testing will be performed in this study. 
 Significance testing and estimation 
All the statistical tests will be two-sided at the 5% level of significance. Significance testing will be done only 
for the primary endpoint. 
7 Analysis Methods  
7.1 Efficacy 
 Primary efficacy analysis 
The main outcome variable (7 days AUC) will be analysed by the analysis of covariance (ANCOVA), where the 
AUC is the dependent, and the independent is the basal total score. The comparison between standard 
therapy and standard therapy + Lanreotide will be performed using the adjusted means if the covariate is 
statistically significant. The assumptions required for the analysis of covariance will be tested as follows: 
x 
The equality of variances will be verified using the Levene’s test. If it is significant AUC 
values will be properly transformed. 
x 
The linear relationship of AUC with the basal total score within treatment group will be 
tested by a regression analysis. 
x 
The parallelism of the regression lines between groups and the slope non zero value with 
the appropriate F tests. 
If the assumptions of linear relationship of AUC with the basal total score or of parallelism of the regression 
lines between groups are not met then some AUC values transformations (e.g. AUC square root, rank 
transformation) or non-parametric procedures will be applied (e.g. Mann-Whitnay U-test). The ESAS total 
score of the first 7 days will be also analyzed by the repeated measures analysis of variance with one group 
to highlight statistically significant differences between and within groups. Multiple comparisons between 
and within groups will be adjusted according to Bonferroni’s correction. Results will be reported as p-values 
and 95% Confidence Interval (95% C.I.). 
Descriptive statistics will be reported as frequency, mean, standard deviation, median, first and third 
quartile, minimum and maximum. 


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Subjects with available basal value and at least 5 post-treatment assessments of ESAS total score will belong 
to the FAS. 
Note: due to premature termination of the study, the results of this analysis should be interpreted cautiously 
and no conclusions should be made. 
 Secondary efficacy analysis 
The secondary endpoints will be analysed as follows: 
1) Comparison of single ESAS items symptom score and total score at Day 1,2,3,4,5,6 and 7, Day 14, Day 28, 
between Group A and Group B will be performed by an ANOVA with repeated measures. Multiple 
comparisons between and within treatment group will be calculated at each assessment time as difference 
from baseline. The Bonferroni’s correction will be applied. If the parametric assumptions of the analysis are 
not satisfied, then a suitable transformation or/and a non-parametric procedure will be applied.   
2) Changes in intensity at Day 7, Day 14 and Day 28 compared to baseline in General activity (Karnofsky 
performance status) and comparison between Group A and Group B. McNemar non-parametric test will be 
used to test changes between baseline assessment and post-treatment assessments (Day 7, Day 14 and Day 
28) within study groups. The distribution of changes from the baseline between treatment groups will be 
analysed at each time assessment (Day 7, Day 14 and Day 28) by Chi square test.  
3) Changes in daily intensity of Abdominal Pain (Visual analogue scale) and comparison between Group A and 
Group B will be analysed as planned for the ESAS score at point 1. 
4) Comparison of number of patients experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive 
days at any time point between the D1 and D7,14,28, between Group A and Group B, in patients without 
nasogastric tube (NGT). The statistical analysis will be performed as reported at point 2 for Karnofsky 
performance status.  
5) Comparison of number of patients in whom the NGT has been removed during at least 3 consecutive days 
at any time point, between the D1 and D7, 14, 28, without vomiting recurrence, between Group A and Group 
B. Same analysis as stated at point 2 for Karnofsky performance status. 
6) In patients with a NGT, changes in daily NGT secretion volume and comparison between Group A and 
Group B. This parameter will be analysed as planned for ESAS score. If the distribution is too unbalanced 
between treatment groups the analysis will be descriptive only. 
7) Comparison of number of daily vomiting episodes and number of days without vomiting, between Group A 
and Group B. 
The daily vomiting episodes will be classified as 0 (absent), 1, 2 and more than 2 and they will be reported in 
a contingency table with treatment arm in columns. The statistical analysis will be performed as reported at 
point 2 for Karnofsky performance status. 
The number of days without vomiting will be analysed performing a Student t test for unpaired data 
considering the first seven days of treatment and the whole study period (28 days). If the parametric 
assumptions of the analysis are not satisfied, then a suitable transformation or/and a non-parametric 
procedure will be applied (Mann-Whitney rank-sum test). 


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8) Passage of stools (Yes/No) daily assessment and comparison between Group A and Group B. The 
comparison will be evaluated either between or within study groups and it will be tested as reported at point 
2 for Karnofsky performance status. 
9) Descriptive analysis of optional ESAS item 10. 
10) Standard care and concomitant medications will be recorded and analysed. In particular changes in 
analgesic score intake will be compared between and within treatment groups using an ANOVA model with 
repeated measures as reported at point 1 for ESAS score. 
Note: secondary endpoint analyses will be limited to descriptive summaries to explore any trends or patterns 
between the two group. 
7.2 Safety 
All safety data will be included in the data listings and summary tables will be based on the safety population. 
Note: due to premature termination of the study, any safety signal will be carefully analyzed, interpreted and 
reported. 
 Adverse Events 
Adverse events will be coded using the latest version available at the time of the start of the study of Medical 
Dictionary for Regulatory Activities (MedDRA). 
Incidence of all reported Adverse Events (AEs)/Treatment Emergent AEs (TEAE) and Serious AEs SAEs) will be 
tabulated by treatment group and by overall. In addition, summary tables will be presented with the number 
and percentage of subjects with AEs classified by primary system organ class, preferred term (ordered 
alphabetically) and by maximum intensity and drug relationship. 
 
A TEAE is defined as any AE that occurs during the active phase of the study (starting after randomization, 
Visit 1 day 1, until the end of the study, Visit 4 day 28) if:  
it was not present prior to receiving the first dose of IMP, or: 
it was present prior to receiving the first dose of IMP but the intensity increased during the active phase of 
the study, or  
it was present prior to receiving the first dose of IMP, the intensity is the same but the drug relationship 
became related during the active phase of the study.  
The contingency tables will be analysed by the χ2 test with the Yates correction for 2x2 contingency tables.  
Listings will be presented and sorted by treatment group, subject id, start time of AEs, primary system organ 
class, preferred term for all adverse events recorded during the study.  


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Listings of serious adverse events (SAE), adverse events leading to withdrawal and listings of deaths will also 
be presented. 
Treatment Emergent Adverse Events (TEAE) will be flagged (*) in the adverse events listing and will be 
summarised. 
In the event of multiple adverse events being reported by the same subject, the maximum intensity (severe > 
missing > moderate > mild) and the most serious causality (related > not related) will be chosen. 
 Death 
Listings will be presented and sorted by treatment group, subject id, death time reporting narrative of death. 
 Laboratory data 
Not applicable, the study protocol states that all clinical laboratory tests are at the discretion of the 
investigator and they are not reported in the e-CRF. 
 Vital signs 
Vital signs will be listed at each assessment by treatment group and subject. 
Summary statistics by treatment group will be presented at each scheduled assessment for actual values and 
changes from baseline. 
Comparison of vital signs at Baseline, Day 7, Day 14 and Day 28 between Group A and Group B will be 
performed by an ANOVA with repeated measures. Multiple comparisons between and within treatment 
group will be calculated at each assessment time as difference from baseline. The Bonferroni’s correction will 
be applied. If the parametric assumptions of the analysis are not satisfied, then a suitable transformation 
or/and a non-parametric procedure will be applied. 
Body weight at baseline visit will be tested for homogeneity between treatment groups using Student t test 
for unpaired data or Mann-Whitney U test in case of unmet parametric assumptions. 
Note: due to premature termination of the study, vital signs will be summarized reporting descriptive 
statistics by treatment groups for each scheduled assessment both actual values and changes from baseline. 
7.3 Missing values and outliers 
 Missing data 
Related to the main outcome variable (7 days AUC) subjects will not belong the full analysis set if basal 
assessment or more than one post treatment assessments result missing. If the analysis population results 
significant lower than ITT population any eventually sensitivity analysis will be performed replacing post-
treatment missing data with the closest non-missing value. The handling of baseline missing data will be 


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replace applying the most suitable technique (e.g. worst value, group mean, ecc..) after consultation with the 
sponsor.   
For the secondary endpoints parameters if there is a significant number of missing values for a subject (or if 
there is confirmed data appearing spurious), a decision will be made following consultation with the sponsor 
regarding the handling of these data in summaries, prior to proceed with the statistical analysis. 
Any repeat or additional assessments performed will be included in the individual subject data listings. 
Note: given the premature termination of the study, the amount of missing data will be assessed and a 
decision will be made to only report summary statistics based on any available data. Regarding the primary 
analysis any missing value of ESAS score will not be replace and no one sensitivity analysis will be performed. 
 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: 
¾ The most conservative approach will be systematically considered (i.e. if the onset date of 
an AE/concomitant medication is missing / incomplete, it will be assumed to have occurred 
during the study treatment phase (i.e. a TEAE for AEs) except if the partial onset date or 
other data [stop date, …] indicates differently). 
¾ A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment. 
¾ 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. 
¾ Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the administration performed on 
31JAN2004, the days since last dose will be “≥2”, similarly the duration of ongoing AEs or 
medication will be“≥xx” according to the start and last visit dates). 
 Outliers 
A search of outliers by the IBIS DM should be done before performing the statistical analysis and any outlier 
should be solved through a query issuance.  The handling of outliers which cannot be solved contacting the 
study site will be defined after consultation of the sponsor. 
7.4 Subject disposition 
A listing of dates of assessments (relative day) and their study exposure will be presented by subject for each 
treatment group. 
A summary table and a flow chart will be presented for each subject population presenting the number of 
subjects in each treatment group at each assessment and identifying the number of subjects who withdrew 
over time. 


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A summary table will present the extent of subject exposure in the study for each treatment group. The 
definition of the length of exposure is from date of baseline visit (day 1) to the date of the last contact with 
the study subject. 
7.5 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 by treatment group. 
Fisher’s exact test will be used to compare the proportion of subjects discontinuing within the first 7 days 
(from Visit 1 to Visit 2) of the study, both overall and for specific reasons, between treatment groups. 
A survival analysis according to Kaplan-Meier method will be performed to study discontinuation along the 
whole study period (from day 1  to day 28) comparing the two treatment groups by means of log-rank test.  
Note: due to premature termination of the study no one inferential test will be performed. The 95% 
Confidence Intervals (95% C.I.) will be reported, overall and for each treatment group, for the percentage of 
withdrawal patients within the first 7 days of study and for the median time to withdrawal along the whole 
study period. 
7.6 Demographic and baseline characteristics 
All demographic and baseline characteristics will be listed by treatment group and subject. 
Summary statistics will be provided for demographic and baseline characteristics (age, sex, race, age, weight 
and vital signs), by treatment group, for the ITT and/or Safety population. 
No statistical comparison of the treatment groups will be performed and only 95% Confidence Intervals will 
be reported. 
7.7 Medical and surgical history 
Medical and surgical history will be coded using MedDRA dictionary according to the latest version available 
at the time of the start of the study. 
Listings will present the preferred term. The listings will be sorted by treatment group, subject, primary 
system organ class, preferred term.  


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A frequency table of the number and percentage of subjects will be provided for active medical and surgical 
history by primary system organ class and preferred term for each treatment group. 
7.8 Subject compliance 
A listing will be presented for drug administration (dose, quantity, date) by subject for Lanreotide group only. 
Deviations from observed and scheduled time and dose will be presented. 
Descriptive statistics (frequency table for each Standard Care category) will be reported for the Standard 
Care, generally defined as: 
x 
Oral food or oral liquid intake according to clinical judgement; 
x 
Intravenous corticoids 
x 
Intravenous H2 antihistaminics  
x 
Proton Pump Inhibitors  
x 
Antispasmodic  
x 
Antipsychotics. 
for each treatment group. 
A listing will be presented for prohibited concomitant medication for any subject who has received this 
prohibited medication. Subjects excluded from the Per Protocol population due to receiving prohibited 
concomitant medication (Somatostatin or any of its analogues) will be flagged (+). 
All the protocol deviations identified before of the statistical analysis will be also listed by subject for each 
treatment group/sequence.  
The impact of major protocol deviation on the primary efficacy analysis will be investigated by comparing the 
results of the ITT and PP population analyses. 
Note: given the premature termination of the study, the impact of major protocol deviation on the primary 
efficacy analysis will not be performed because the analysis will be performed on the ITT population. 
7.9 Prior and concomitant therapies 
Concomitant therapies will be coded using the WHO-Drug Dictionary according to the latest version available 
at the time of the start of the study. The therapeutic class will correspond to the second level of ATC code, 
that is, corresponding to the first 3 figures. 
Listings will be presented for the therapeutic class, preferred term and verbatim text. The listings will be 
sorted by treatment group, subject, chronological start date, therapeutic class, preferred name and verbatim 
name.  


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A frequency table of the number and percentage of subjects will be provided for concomitant therapies by 
therapeutic class and preferred name for each treatment group. 
Prohibited concomitant medication (Somatostatin or any of its analogues) will be flagged (+). 
7.10 Pharmacokinetics & antibodies 
Not applicable. 
7.11 Pharmacodynamics 
Not applicable. 
7.12 Derived data 
The derived data are variables which are calculated from the raw data in the CRF/eCRF and not included in 
the database (e.g.: AUC, total score, duration, summary value from repeated observations, study exposure, 
study drug exposure, study drug cumulative dose, …). 
The following derived data will be calculated and included in the listings: 
Age: Subject age (years) will be derived as (screening date – birth date)/365.25 and truncated to the largest 
integer that is less than or equal to the calculated result. 
ESAS AUC over the first seven days (Visit 1 to Visit 2): AUC of the total score of the first nine items of the ESAS 
questionnaire will be calculated via the trapezoidal rule. 
Changes from baseline: Changes from baseline will be calculated as a difference from baseline (e.g. 
assessment at the visit – assessment at baseline). 
Number of Vomiting episodes: For each diary page filled in (fill in with date and other items), the number of 
vomiting episodes will be set to 0 if none box related to the vomiting episodes has been filled in. 


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7.13 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 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 the last non-missing result prior to study drug administration 
should be used; for post-treatment assessments the closest non-missing result to the scheduled visit should 
be used. 
Study phase 
Scheduled visit 
Time interval (days) 
 
 
 
Active phase 
Baseline 
1 (prior to first dose) 
Week 1 
7 
Week 2 
12 to 16 
Week 8 
26 to 30 
 
 
 
7.14 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 values, arithmetic mean, 
standard deviation, median and the range (minimum, maximum). 
Mean, median, standard deviation and standard errors of the mean (SE) 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. 
Percentages will be reported to one/two decimal place(s) and 0% will not be presented.  Percentages will be 
calculated using a denominator of all subjects in a specified population. The denominator will be specified in 
a footnote to the tables for clarification if necessary.  
Lower and upper confidence interval 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.  


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P-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-values which are less than 
0.0001 will be presented as ‘<0.0001’. 
However, the ways these values will be taken into account for any analyses should be described. 
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 will be presented in the format [ddmmmyyyy] and times 
in the format [hh:mm]. The format for presentation of other data types should be specified. 
7.15 Pooling of Centres 
The method for handling centres with small sample sizes will be described and determined prior to proceed 
with the statistical analysis (e.g.: combining centres with small sample sizes, geographical location, centre 
type etc).. 
7.16 Interim analysis 
No interim analysis will be performed. 
7.17 Role of independent data monitoring committee 
(DMC)/interim data review committee 
Neither a data monitoring committee nor an interim data review committee will be set up for the study 
conduction. 
7.18 Covariates and analysis of subgroups 
The ESAS total score will be used as covariate for the primary efficacy analysis as described in the statistical 
methods. 


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8 COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF 
PROGRAMS 
8.1 Hardware 
The statistical analysis will be performed using SONY VAIO personal computer with Windows 7 professional 
as operating system. 
8.2 Software 
All tables, listings and figures will be produced and statistical analysis performed using SAS version 9.3.  All 
output will be in Microsoft Word Format. 
8.3 Validation programs 
IBIS 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. 


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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 CRO’s sign-off forms will be 
provided to the sponsor to support the validation. 
8.4 Restitution of the programs 
All programs (including Macros 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. 
9 CHANGES FROM PROTOCOL 
Due to the low accrual rate despite the extension of the planned enrollment period (from 18 to 36 months) 
the study has come to a premature termination. 
43 patients have been recruited from the planned 84 patients. 
The statistical analysis will be performed only on ITT and Safety population.  The inferential tests will be 
performed only for the primary endpoint on the FAS population. A note will be added to primary endpoint 
analysis to remind that the results are merely indicative, no conclusion can be drawn 
For all other endpoints, the statistical analysis will be mainly descriptive in nature with the aim to explore any 
trend or patterns between the two treatment groups 
10 REFERENCES 
11 DATA PRESENTATION 
Data listings are presented for all screened subjects. 
Footnotes should be used to clarify ambiguities (e.g.: the denominator used to calculate a percentage or for 
notes for the programmer). If the number of footnotes is high, they could be presented only in the last page, 


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with on each page the following footnote “See last page for listing notes”.  The order of the footnotes for key 
symbols (*, ~) will be in the order that they appear in the listing.