Clinical trial NCT02275338
Conditions: Intestinal Obstruction
Sponsor: Ipsen
Start date: 2014-11-19; Completion date: 2017-11-09
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess the efficacy of Lanreotide Autogel 120 mg for the relief of vomiting due to inoperable malignant intestinal obstruction in patients without nasogastric tube (NGT) and to assess the efficacy of lanreotide Autogel 120 mg on removal of nasogastric tube without the recurrence of vomiting in patients with an inoperable malignant intestinal obstruction with a nasogastric tube.

Detailed description:

Arms: arm 1: 120mg administered via deep subcutaneous injection at Day 0 and Day 28.
Interventions: intervention 1: Lanreotide Autogel
Intervention descriptions: intervention 1: 120mg administered via deep subcutaneous injection at Day 0 and Day 28.

Protocol documents:
Prot_000.pdf: 
IPSEN GROUP 
 
 [:   A-48-52030-269 ] 
 
CONFIDENTIAL 
 
 
 
 
 
PROTOCOL: Final Version 1.0 18 October 2013 
 
 
 
PAGE 1 OF 57 
 
 
AN INTERNATIONAL, MULTICENTRIC, PROSPECTIVE, OPEN LABEL  STUDY 
TO ASSESS THE EFFICACY AND SAFETY OF LANREOTIDE AUTOGEL 120 MG 
ASSOCIATED TO STANDARD OF CARE IN THE TREATMENT OF CLINICAL 
SYMPTOMS ASSOCIATED WITH INOPERABLE MALIGNANT INTESTINAL 
OBSTRUCTION (IMIO) 
 
STUDY PROTOCOL 
[STUDY number:   A-48-52030-269]  
 
 [EudraCT number: 2013-002174-43] 
 
Final Version: 18 October 2013 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
Vincent De Ruyter 
Vincent De Ruyter  
Ipsen Group 
Ipsen Group  
Guldensporenpark 87 
Guldensporenpark 87 
B-9820 Merelbeke 
B-9820 Merelbeke 
Tel: 
+[32] (0)9 243 96 00 
Tel: 
 
Fax: 
 
Fax: 
 
 
 
Monitoring Office:  
Co-ordinating Investigator:  
 
Prof. Dr. K. Geboes 
Ipsen Group 
Department of Gastro-Enterology 
Guldensporenpark 87 
University Hospital of Gent 
B-9820 Merelbeke 
De Pintelaan 185 
 
Belgium 
Tel: 
 
Tel: 
 
Fax: 
 
Fax: 
 
 
Pharmacovigilance/Emergency Contact  
 
Central Department of Pharmacovigilance 
Ipsen Group 
190 Bath Road 
Slough 
Berkshire SL1 3XE 
England  
Tel:  
  
 
 – mobile telephone for emergencies  
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
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PROTOCOL SIGNATURES 
Investigator Signature: 
I have read and agree to the protocol : AN INTERNATIONAL, MULTICENTRIC, 
PROSPECTIVE, OPEN LABEL  STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF LANREOTIDE AUTOGEL 120 MG ASSOCIATED TO STANDARD OF 
CARE IN THE TREATMENT OF CLINICAL SYMPTOMS ASSOCIATED WITH 
INOPERABLE MALIGNANT INTESTINAL OBSTRUCTION 
I am aware of my responsibilities as an 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. 
 
INVESTIGATOR NAME: 
 
 
________________ 
 
TITLE: 
 
SIGNATURE : 
 
DATE : 
 
 
          
 
 
________________ 
 
________________ 
 
________________ 
 
 
 
 
 
 
 
 
 
 
 
Full investigational site contact details, including telephone numbers, will be documented in 
the Trial Master File. 
 
On behalf of the Sponsor: 
 
NAME:  DE RUYTER VINCENT 
 
 
 
TITLE:  MEDICAL ADVISOR 
 
SIGNATURE : 
 
DATE : 
 
 
 
 
________________ 
 
________________ 
 
 
 
 
                                                 
1 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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SYNOPSIS 
Study Title: 
AN INTERNATIONAL, MULTICENTRIC, PROSPECTIVE, 
OPEN LABEL  STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF LANREOTIDE AUTOGEL 120 MG 
ASSOCIATED TO STANDARD OF CARE IN THE 
TREATMENT OF CLINICAL SYMPTOMS ASSOCIATED 
WITH INOPERABLE MALIGNANT INTESTINAL 
OBSTRUCTION 
 
Study Objectives: 
Primary Objective : 
To assess the efficacy of lanreotide Autogel lanreotide Autogel 120 
mg for the relief of vomiting due to inoperable malignant intestinal 
obstruction in patients without nasogastric tube AND to assess the 
efficacy of lanreotide Autogel 120 mg to remove a nasogastric tube 
without the recurrence of vomiting in patients with an inoperable 
malignant intestinal obstruction with a nasogastric tube 
 
Secondary Objectives : 
1) To evaluate the impact on Quality of Life (Edmonton Symptom 
Assessment System) of lanreotide Autogel 120 mg assessed by both 
the patient and the caregiver  
 
2) To assess the efficacy of lanreotide Autogel 120 mg for the relief 
of other clinical symptoms due to inoperable malignant intestinal 
obstruction : 
- 
General activity (Karnofsky score) 
- 
Nausea (number of daily episodes)  
- 
Pain (Visual analogue scale)  
- 
Complete/incomplete obstruction: passage of stools 
 
3) To assess the symptom (nausea and vomiting) improvement delay 
 
4) To assess the pharmacokinetic profile of lanreotide in patients 
with inoperable malignant intestinal obstruction  
 
Safety Objectives : 
To assess the clinical and biological safety of the study treatment  
 
 
Phase of Trial: 
Phase II 
 
Study Design: 
This is an International, Multicentric, Prospective, Open-label study 
 
Phase 1 Initial Injection Lanreotide Autogel 120 mg : 
Patients meeting the selection criteria for participation will need to 
provide a written informed consent. Patient and caregiver will be 


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asked to complete the Edmonton Symptom Assessment System 
(ESAS) before any study procedure. Patients will then receive the 
following treatment :  Standard of care + 1 injection of lanreotide 
Autogel 120 mg  
Response to the treatment will be assessed based on the % of 
responders in the treatment group at Day 7, Day 14 and Day 28.  
Safety of the patients will be followed continuously during the entire 
study period. A blood sample to assess the serum levels of lanreotide 
will be taken at Day 1 , Day 7 and Day 14 and Day 28 
 
For patients who are : 
Non-responders at Day 28 OR 
Responders at day 28 but who are unwilling to receive a second 
injection with lanreotide, the participation to the study will stop here. 
Patients will then receive standard of care by the treating physician. 
 
Phase 2 Second injection Lanreotide Autogel 120 mg  : 
Patients completing the 28 days of the first phase and who  
are responders as defined by this protocol will have the possibility to 
receive a second injection with lanreotide Autogel 120 mg. Standard 
of care will be continued for all as described by the protocol. 
Response to the treatment will continued to be  assessed based on the 
% of responders at Day 35, Day 42 and Day 56   
Safety of the patients will be followed continuously during the entire 
study period. A blood sample to assess the serum levels of lanreotide 
will be taken just before the second injection at Day 28 and at Day 
35, day 42 and at day 56. 
 
Study Population:  
Patients with inoperable intestinal obstruction of malignant origin in 
centres in Belgium and Luxemburg 
 
Inclusion Criteria : 
All subjects must fulfil the following: 
1) Written informed consent before any study related 
procedure 
2) Male and female patients age 18 years or older at the 
time of enrolment 
3) Diagnosis of an intestinal obstruction of malignant 
origin 
4) In case of peritoneal carcinomatosis, confirmation by 
CT or MRI scan within the 3 months preceding the inclusion in 
the study 
5) Confirmed as inoperable after surgical advice  
6) Patient with a nasogastric tube OR presenting with 3 or 
more episodes of vomiting / 24h  in the last 48 hours 
7) Estimated life expectancy 1 month or more 


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Exclusion Criteria 
Subjects will not be included in the study if the subject : 
1) Operable obstruction or any subobstruction 
2) Bowel obstruction due to a non-malignant cause (for 
example : hypokaliaemia, drug side-effects, renal 
insufficiency, …) 
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) Previous participation in this study 
7) Is likely to require treatment during the study with 
drugs that are not permitted   
   by the study protocol (see Section 9.5). 
8) 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.  
 
 
Study Treatment: 
 
Phase 1 Initial Injection Lanreotide Autogel 120 mg  
 
Standard of care +  lanreotide Autogel 120 mg 
 
 
 
 
Phase 2 Second injection Lanreotide Autogel 120 mg  : 
Standard of care +  lanreotide Autogel 120 mg  
 
Standard of care : 
 
Compulsory for all patients : 
- 
No oral food or oral liquid intake during the first 5 days 
unless there are signs of resolution of the obstruction 
(passing stools or gas): patients can consume oral or liquids 
at the discretion of the treating physician 
- 
Intravenous corticoids : Solumedrol 40 mg/day or 
dexamethasone or methylprednisolone or equivalent at a dose 
of  1 mg/kg/day or more 
- 
Intravenous H2 antihistaminics : ranitidine 50 mg 3/d or PPI 
: omeprazole or pantoprazole or equivalent. 
 
Step up medication if not enough efficacy at Day 7: 
 
- 
butylhyoscine bromide (Buscopan): 40-120 mg SC or IV 
AND 


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- 
Haloperidol : 5 mg / 2 x day IV 
 
Authorised for all patients : 
- 
Analgesics on request 
- 
Metoclopramide 10 mg/4h or Domperidone 10 mg qid or 
Odansetron 8mg/4ml at the discretion of the investigator 
- 
Chemotherapy (if already present at study entry) 
- 
Venting Gastrostomy after Day 7 
 
Non Authorised treatments : 
- 
Somatostatin or any of its analogues other than the study 
drug 
 
Study Evaluations: 
Primary Efficacy Endpoint(s) and Evaluation(s):  
Phase 1 : Initial Injection Lanreotide Autogel 120 mg: 
Percentage of responding patients before or at D7. A responder is 
defined as a patient experiencing ≤ 2 vomiting episodes/day during 
at least 3 consecutive days at any time point between the D1 and D7 
(for patients without NGT at baseline) or as a patient in whom the 
NGT has been removed during at least 3 consecutive days at any 
time point between the D1 and D7 without vomiting recurrence. 
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting 
 
 
 
Secondary Efficacy Endpoints And Evaluations: 
Phase 1 : Initial Injection Lanreotide Autogel 120 mg: 
1) Percentage of responding patients before or at D14 (same for 
D28). A responder is defined as a patient experiencing ≤ 2 vomiting 
episodes/day during at least 3 consecutive days at any time point 
between the D1 and D14 (D28) or as a patient in whom the NGT has 
been removed during at least 3 consecutive days at any time point 
between the D1 and D14 (D28) without vomiting recurrence.  
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting 
 
2) Time between first injection and clinical response 
 
3) Changes from baseline in Quality of Life (Edmonton Symptom 
Assessment System) at Day 7, Day 14 and Day 28 assessed by both 
the patient and the caregiver.   
 
4) Changes in daily intensity and frequency at Day 7, Day 14 and 
Day 28 compared to baseline in   
- 
General activity (Karnofsky score) 


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- 
Nausea (number of daily episodes)  
- 
Pain (Visual analogue scale)  
- 
Complete/incomplete obstruction: passage of stools 
 
 
Phase 2 : Second injection Lanreotide Autogel 120 mg  : 
1) Overall Percentage of patients continuing from Phase I and 
confirmed as a responder at the end of phase I , showing a continued 
response at D35, D42 and D56. A responder is defined as a patient 
experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive 
days at any time point between the D1 and D35, D42 and D56 or as 
a patient in whom the NGT has been removed during at least 3 
consecutive days at any time point between the D1 and D35, D42 
and D56 without vomiting recurrence.  
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting 
 
2) Changes from baseline in Quality of Life (Edmonton Symptom 
Assessment System) at Day 35, Day 42 and Day 56 assessed by both 
the patient and the caregiver.   
 
 
 
Pharmacokinetic Endpoints and Evaluations: 
The PK profile of lanreotide Autogel in patients with IMIO using 
lanreotide concentration data. 
 
Safety Endpoints and Evaluations: 
Clinical and biological adverse events and serious adverse events 
throughout the study 
 
 
Statistical Methods: 
The primary endpoint is the percentage responders at D7. Sample 
size is calculated by testing 1-sided at 2.5% significance level alpha 
and a power of 80% using the z-test for binomial proportion 
assuming a proportion of responders at D7 equal to 50%. Sample 
size is 44 subjects; however taken into account 15 to 20 % drop outs, 
50 patients will be recruited for this study. It is planned to recruit 
these patients in a 2 year period. 
 


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STUDY FLOW  
 
  
IMIO patient fulfilling the 
criteria for inclusion
Standard of care 
+ Somatuline Autogel 120mg
Inclusion and treatment initiation
Efficacy evaluation
Day 7, 14, 28
Responder
Non- Responder
STOP
Day28 
Standard of care + 
Somatuline Autogel 
120mg second injection 
Continued Efficacy evaluation 
Day 35, 42, 56


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Table 1.  Phase I  
 
Visit 
V1 
V2 
V3 
V4 
Last visit 
Day 
D1 
D7 
D14 
D 28 
Informed consent 
 
 
 
 
Eligibility review 
 
 
 
 
Demography 
 
 
 
 
Medical history 
 
 
 
 
Malignancy  history## 
 
 
 
 
Clinical examination### 
 
 
 
 
Nutrition procedure 
 
 
 
 
Symptoms  and QOL 
assessment * 
 
 
 
 
Vomiting and nausea 
episodes assessment (diary 
cards)** 
 
 
 
 
Concomitant medications 
 
 
 
 
Safety biological 
####assessment (if 
applicable) 
 
 
 
 
Injection Study Treatment 
Lanreotide Autogel 120 mg 
 
 
 
 
Lanreotide 
concentrations 
(PK) 
# 
 
 
 
Adverse Events*** 
 
 
 
 
 
*:  VAS for abdominal pain, Karnofsky for daily activities, QOL by means of 
Edmonton Symptom Assessment System (caregiver and patient), and presence 
of partial/complete intestinal obstruction. Nausea and vomiting will be 
separately recorded 
 **: Diary cards will be completed every day for a total of 28 days. 
***: At Day 1 (baseline) after signature of the informed consent and after clinical 
examination and medical history  
# : Between 2 and 12h after the injection of lanreotide Autogel 120 mg 
##: Malignancy history causing Obstruction 
###: including vital signs as height, Weight, BP and HR 
####: including hematology and biochemistry (only at discretion of investigator) 


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Table 2.  Phase II  
Visit 
V5 
V6 
V7 
V8 
Last visit 
Day 
D28 
D35 
D42 
D56 
Eligibility review 
X 
 
 
 
Clinical examination## 
X 
 
 
 
Nutrition procedure 
X 
 
 
 
Symptoms  and QOL 
assessment * 
X 
 
 
 
Vomiting and nausea 
episodes assessment (diary 
cards)** 
X 
 
 
 
Concomitant medications 
X 
 
 
 
Safety biological ### 
assessment (if applicable) 
X 
 
 
 
Second lanreotide Autogel 
120 mg injection  
 
 
 
 
 
Adverse Events 
 
 
 
 
Lanreotide concentrations 
# 
 
 
 
 
 
 
 
 
*:  VAS for abdominal pain, Karnofsky for daily activities, QOL by means of 
Edmonton Symptom Assessment System (caregiver and patient), and presence 
of partial/complete intestinal obstruction. Nausea and vomiting will be 
separately recorded 
  
**: Diary cards will be completed every day for a total of 28 days. 
 
X : These data will be copied from V4 of Phase I. 
 
#  :  Before the second lanreotide Autogel 120 mg injection 
##: including vital signs as height, Weight, BP and HR 
###: including hematology and biochemistry (only at discretion of investigator) 
 
 
 


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TABLE OF CONTENTS 
 
1.LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................... 16 
2.INTRODUCTION ............................................................................................................... 17 
2.1Disease Review ................................................................................................................... 17 
2.2Compound Review ............................................................................................................. 18 
2.3Clinical Trial Rationale ..................................................................................................... 20 
3 
STUDY OBJECTIVES ................................................................................................. 20 
3.1 Primary Study Objective ................................................................................................. 20 
3.2 
Secondary Study Objectives ......................................................................................... 21 
4 
STUDY DESIGN ........................................................................................................... 21 
4.1 
Overview ........................................................................................................................ 21 
4.1.1 
Population Characteristics .......................................................................... 21 
4.1.2 
Design .......................................................................................................... 21 
4.1.3 
Stopping Rules and Discontinuation Criteria ............................................ 23 
4.1.4 
Early Study Termination ............................................................................. 23 
4.2 
Endpoints ....................................................................................................................... 23 
4.2.1 
PK Endpoints ............................................................................................... 24 
4.2.2 
Safety Endpoints .......................................................................................... 24 
4.3 
Justification of Design ................................................................................................... 24 
4.3.1 
Study Population for Analysis .................................................................... 24 
4.3.2 
Study Duration ............................................................................................ 25 
5 
COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL 
CONSIDERATIONS & INFORMED CONSENT .................................................... 25 
5.1 
Compliance with Good Clinical Practice and Ethical Considerations ..................... 25 
5.2 
Informed Consent ......................................................................................................... 25 
6 
STUDY POPULATION ............................................................................................... 26 
6.1 
Screening Log and Number of Subjects ...................................................................... 26 
6.2 
Inclusion Criteria .......................................................................................................... 26 
6.3 
Exclusion Criteria ......................................................................................................... 26 
6.4 
Subject Withdrawal Criteria ....................................................................................... 27 
6.5 
Discontinuation/Withdrawal Procedures.................................................................... 27 
7 
METHODOLOGY ........................................................................................................ 27 
7.1 
Study Schedule of assessments ..................................................................................... 27 
7.2 
Study Visits .................................................................................................................... 30 
7.2.1 
Day 1 (Visit 1) .............................................................................................. 30 
7.2.2 
Day 7 and Day 14 (Visit 2-3) ....................................................................... 31 
7.2.3 
End of Part 1  Day 28 (Visit 4) or Early Withdrawal Visit Phase 1 .......... 33 
Visit 4 Phase 2 - Day 28 Post injection .......................................................................... 33 
7.2.4 
Day 35 and Day 42 (Visit 5-6 ...................................................................... 34 
7.2.5 
Day 56 (Visit 7 End of Study Phase II) or Early Withdrawal Visit  .......... 34 
8 
STUDY EVALUATIONS ............................................................................................. 35 
8.1 
Efficacy Endpoints and Evaluations ........................................................................... 35 
8.1.1 
Primary Efficacy Endpoint and Evaluations ............................................. 35 


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8.1.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 35 
8.1.3 
Pharmacokinetic Endpoints and Evaluations ............................................ 36 
8.2 
Safety Endpoints and Evaluations ............................................................................... 36 
8.2.1 
Adverse Events ............................................................................................. 36 
8.2.2 
Physical Examination ................................................................................. 36 
8.2.3 
Clinical Laboratory Tests ............................................................................ 36 
8.3 
Total Blood Volume ...................................................................................................... 36 
8.4 
Pharmacodynamic Endpoints and Evaluations ......................................................... 36 
8.5 
Pharmacokinetic Endpoints and Evaluations ............................................................ 37 
9 
STUDY TREATMENTS .............................................................................................. 37 
9.1 
Study Treatments Administered .................................................................................. 37 
9.2 
Subject Identification and Allocation to Study Treatment ....................................... 37 
9.3 
Study Treatment Supply, Packaging and Labelling .................................................. 38 
9.4 
Study Treatment Storage and Accountability ............................................................ 38 
9.5 
Mandatory and Concomitant Medication/Therapy ................................................... 38 
9.6 
Treatment of Overdose of IMP .................................................................................... 39 
10 
ADVERSE EVENT REPORTING .............................................................................. 39 
10.1 Disease Progression ....................................................................................................... 39 
10.2 Categorisation of Adverse Events ................................................................................ 40 
10.2.1 
Intensity Classification ................................................................................ 40 
10.2.2 
Causality Classification ............................................................................... 40 
10.2.3 
Assessment of expectedness ........................................................................ 40 
10.2.4 
Laboratory Test Abnormalities ................................................................... 40 
10.2.5 
Abnormal Physical Examination Findings ................................................ 40 
10.2.6 
Other Investigation Abnormal Findings .................................................... 41 
10.3 Recording and Follow-up of Adverse Events ............................................................. 41 
10.4 Serious Adverse Events ................................................................................................ 41 
10.4.1 
Definitions ................................................................................................... 41 
10.4.2 
Reporting Requirements ............................................................................. 42 
10.4.3 
Mandatory Information for Reporting an SAE ......................................... 42 
10.5 Pregnancy ...................................................................................................................... 43 
10.6 Deaths ............................................................................................................................. 43 
10.7 Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events ....... 44 
10.8 Reporting to Competent Authorities/IECs/IRBs/Other Investigators ..................... 44 
11 
STATISTICAL CONSIDERATIONS ........................................................................ 45 
11.1 Subject Classification and Definitions ......................................................................... 45 
11.2 Analyses Populations Definitions ................................................................................. 45 
11.2.1 
Populations Analysed .................................................................................. 45 
11.2.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 45 
11.3 Sample Size Determination .......................................................................................... 46 
11.3.1 
Significance Testing and Estimations ........................................................ 46 
11.4 Statistical/Analytical Methods ..................................................................................... 46 
11.5 Subgroup Analyses ........................................................................................................ 46 
11.6 Interim Analyses ........................................................................................................... 46 
12 
MONITORING PROCEDURES ................................................................................. 46 
12.1 Routine Monitoring ....................................................................................................... 47 


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13 
STUDY MANAGEMENT ............................................................................................ 47 
13.1 Inspections and Auditing Procedures ......................................................................... 47 
13.2 Data Recording of Study Data ..................................................................................... 47 
13.3 Source Data Verification .............................................................................................. 48 
13.4 Data Quality ................................................................................................................... 48 
13.5 Data Management ......................................................................................................... 49 
13.6 Record Archiving and Retention ................................................................................. 49 
14 
ADMINISTRATION PROCEDURES ........................................................................ 49 
14.1 Regulatory Approval .................................................................................................... 49 
14.2 Publication Policy .......................................................................................................... 50 
14.3 Clinical Study Report ................................................................................................... 50 
14.4 Contractual and Financial Details ............................................................................... 50 
14.5 Insurance, Indemnity and Compensation ................................................................... 51 
15 
PROTOCOL AMENDMENTS ................................................................................... 51 
16 
REFERENCES .............................................................................................................. 51 
17 
LIST OF APPENDICES .............................................................................................. 53 
 


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LIST OF TABLES 
Table 1.  Phase I ...................................................................................................................... 10 
Table 2.  Phase II .................................................................................................................... 11 
Table 1.  Part I ........................................................................................................................ 28 
Table 3.  Part II  ...................................................................................................................... 29 
 
LIST OF FIGURES 
 
Figure 1 
Insert Using Gen014 Toolbar ............................................................................. 18 
Figure 2 
Study flow ............................................................................................................. 22 
 
 
 


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1.LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Event/Experience 
CA 
Competent Authorities 
CDDS 
Clinical Development Data Sciences (relates to Sponsor) 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTSU 
Clinical Trial Supplies Unit (relates to Sponsor) 
DMC 
Data Monitoring Committee 
E 
Electronic 
EDC 
Electronic Data Capture 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product synonymous with “study drug” 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IVRS 
Interactive Voice Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTC 
National Cancer Institute – Common Toxicity Criteria 
NOS 
Not Otherwise Specified 
PI 
Package Insert 
PP 
Per Protocol 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
RAP 
Reporting and Analysis Plan 
SAE 
Serious Adverse Event/Experience 
SAS® 
Statistical Analysis Software® 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TFLs 
Tables, Figures and Listings 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial Master File 
 
 
  


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2.INTRODUCTION 
2.1Disease Review 
Intestinal obstruction is an important complication in patients with advanced 
abdominal or pelvic cancer. It occurs in 5-42 % of patients with ovarian cancer and in 
4-24% of patients with 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 (6,7,8). 
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 (8,9,10,11). 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) (9,10,11,12) 
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 (13, 14). 
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. 
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 (15, 16). 
 


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2.2Compound Review 
Figure 1 Lanreotide structural formula 
 
 
 
Lanreotide is an octapeptide analogue of somatostatin. It has marked 
release-inhibiting activity on growth hormone (GH), and a longer duration of 
actionthan the native peptide. When administered intravenously (i.v.) or 
subcutaneously 
(s.c.), lanreotide has a short half-life (T½) of approximately 1 to 2 hours, and is 
eliminated from the blood in a short time. Lanreotide was previously developed as a 
microparticle formulation (MPF). The Autogel® formulation, which was developed 
after the MPF, is a controlled release preparation of lanreotide acetate and water for 
injection which together form a supersaturated solution of the peptide. Prolonged 
release of the peptide occurs by the physical nature of the supersaturated solution. 
The formulation enables active serum levels to be maintained for 1 to 2 months. The 
usual clinical dosing regimen is one deep s.c. injection of lanreotide Autogel 60, 90 
or 120 mg into the buttocks every 28 days in adults, using a formulation that 
contains lanreotide base 0.246 mg/mg of solution. In addition, patients whose GH 
levels are controlled with lanreotide Autogel 90 or 60 mg every 4 weeks may 
benefit from transferring to treatment at 120 mg every 6 or 8 weeks, respectively. 
Lanreotide Autogel was first launched in France in 2001, and is registered in 
approximately 50 countries worldwide including countries in Africa, Asia, Central 
and Eastern Europe, the Middle East, Australasia, and North, Central and South 
America. The information provided in this protocol represents  a summary of the 
available data. This protocol focuses primarily on the lanreotide Autogel 
formulation. Data from studies in other formulations has been presented where 


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relevant. 
Pharmacology, pharmacokinetic (PK), safety pharmacology 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, 


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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 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 (Reference 1). 
 
2.3Clinical Trial Rationale 
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 (9, 10, 11, 17) 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 (18) 
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. 
 
3 STUDY OBJECTIVES 
3.1 Primary Study Objective 
To assess the efficacy of lanreotide Autogel lanreotide Autogel 120 mg for the 
relief of vomiting due to inoperable malignant intestinal obstruction in patients 
without nasogastric tube AND to assess the efficacy of lanreotide Autogel 120 mg 
to remove a nasogastric tube without the recurrence of vomiting in patients with an 
inoperable malignant intestinal obstruction with a nasogastric tube 


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3.2 
Secondary Study Objectives 
1) To evaluate the impact on Quality of Life (Edmonton Symptom Assessment 
System) of lanreotide Autogel 120 mg assessed by both the patient and the 
caregiver  
 
2) To assess the efficacy of lanreotide Autogel 120 mg for the relief of other 
clinical symptoms due to inoperable malignant intestinal obstruction : 
- 
General activity (Karnofsky score) 
- 
Nausea (number of daily episodes)  
- 
Pain (Visual analogue scale)  
- 
Complete/incomplete obstruction: passage of stools 
 
3) To assess the symptom (nausea and vomiting) improvement delay 
 
4) To assess the pharmacokinetic profile of lanreotide in patients with inoperable 
malignant intestinal obstruction  
4 
STUDY DESIGN 
4.1 
Overview  
4.1.1 
Population Characteristics 
It is planned to include 50 patients in this study. Male or female patients of 18 years 
of age or older, diagnosed with intestinal obstruction due to malignant origin, who 
are unsuitable candidates for surgery. Patients should have 3 or more episodes of 
vomiting per 24 hours in the last 48 hours or should have a nasogastric tube 
 
4.1.2 
Design 
This is a Phase II, single arm, non-randomised, prospective, open label, multicentre 
study. 


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Figure 2 Study flow 
 
 
The study will consist of 2 phases (see Figure 2) 
 
Phase 1 Initial Injection Lanreotide Autogel 120 mg : 
Patients meeting the selection criteria for participation will need to provide a 
written informed consent. Patient and caregiver will be asked to complete the 
Edmonton Symptom Assessment System (ESAS) before any study procedure. 
Patients will then receive the following treatment :  Standard of care + 1 injection 
of lanreotide Autogel 120 mg. Response to the treatment will be assessed based on 
the % of responders in the treatment group at Day 7, Day 14 and Day 28.  
Safety of the patients will be followed continuously during the entire study period. 
A blood sample to assess the serum levels of lanreotide will be taken on Day 1 and 
then on Day 7, Day 14 and Day 28. 
 
For patients who are : 
IMIO patient fulfilling the 
criteria for inclusion 
Standard of care 
+ Somatuline Autogel 120mg
Inclusion and treatment initiation
Efficacy evaluation
Day 7, 14, 28
Responder 
Non- Responder
STOP
Day28
Standard of care + 
Somatuline Autogel 
120mg second injection 
Continued Efficacy evaluation 
Day 35, 42, 56


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Non-responders at Day 28 OR Responders at day 28 but who are unwilling to 
receive a second injection with lanreotide, the participation to the study will stop 
here. Patients will then receive standard of care by the treating physician. 
 
Phase 2 Second injection Lanreotide Autogel 120 mg  : 
Patients completing the 28 days of the first phase and who are responders as 
defined by this protocol will have the possibility to receive a second injection with 
lanreotide Autogel  120 mg. Standard of care will be continued for all as described 
by the protocol. 
Response to the treatment will continued to be assessed based on the % of 
responders at Day 35, Day 42 and Day 56   
Safety of the patients will be followed continuously during the entire study period. 
A blood sample to assess the serum levels of lanreotide will be taken just before the 
second injection at Day 28 and at Day 35, Day 42 and at Day 56.  
4.1.3 
Stopping Rules and Discontinuation Criteria 
Patients will be discontinued from the study if there is insufficient efficacy of the 
study treatment at 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: 
 
The incidence or severity of adverse events (AE) in this or other studies point 
to a potential health hazard for trial subjects. 
 
Insufficient subject enrolment. 
 
Any information becoming available during the study that substantially 
changes the expected benefit risk profile of the study treatments. 
 
4.2 
Endpoints 
Primary Efficacy Endpoint(s) and Evaluation(s):  
Phase 1 : Initial Injection Lanreotide Autogel 120 mg: 
Percentage of responding patients before or at D7. A responder is defined as a 
patient experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive days at 
any time point between the D1 and D7 (for patients without NGT at baseline) or as 
a patient in whom the NGT has been removed during at least 3 consecutive days at 
any time point between the D1 and D7 without vomiting recurrence. 
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting 
 
Secondary Efficacy Endpoints And Evaluations: 
Phase 1 : Initial Injection Lanreotide Autogel 120 mg: 
1) Percentage of responding patients before or at D14 (same for D28). A responder 
is defined as a patient experiencing ≤ 2 vomiting episodes/day during at least 3 
consecutive days at any time point between the D1 and D14 (D28) or as a patient in 


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whom the NGT has been removed during at least 3 consecutive days at any time 
point between the D1 and D14 (D28) without vomiting recurrence.  
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting episodes 
 
2) Time between first injection and clinical response 
 
3) Changes from baseline in Quality of Life (Edmonton Symptom Assessment 
System) at Day 7, Day 14 and Day 28 assessed by both the patient and the 
caregiver.   
 
4) Changes in daily intensity and frequency at Day 7, Day 14 and Day 28 compared 
to baseline in   
- 
General activity (Karnofsky score) 
- 
Nausea (number of daily episodes)  
- 
Pain (Visual analogue scale)  
- 
Complete/incomplete obstruction: passage of stools 
 
Phase 2 : Second injection Lanreotide Autogel 120 mg  : 
1) Overall Percentage of patients continuing from Phase I and confirmed as a 
responder at the end of phase I , showing a continued response at D35, D42 and 
D56. A responder is defined as a patient experiencing ≤ 2 vomiting episodes/day 
during at least 3 consecutive days at any time point between the D1 and D35, D42 
and D56 or as a patient in whom the NGT has been removed during at least 3 
consecutive days at any time point between the D1 and D35, D42 and D56 without 
vomiting recurrence.  
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting  
 
2) Changes from baseline in Quality of Life (Edmonton Symptom Assessment 
System) at Day 35, Day 42 and Day 56 assessed by both the patient and the 
caregiver. 
 
4.2.1 
PK Endpoints 
The PK profile of lanreotide based on lanreotide concentration-time data. 
4.2.2 
Safety Endpoints 
Clinical and biological Adverse events and serious adverse events throughout the 
study  
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/24 hours for the last 48 hours or who have a 
nasogastric tube, are the candidates to be included in this study.  


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This study aims to recruit a total of 50 patients – male or female of 18 years or older 
who fulfil the listed criteria.  
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 3 years; this includes 2 
years of recruitment: this period may be extended if needed to allow for the 
recruitment of the required number of patients. The study will be considered to have 
started when the first patient has provided signed informed consent. The study will 
be considered to have finished after the last patient has completed the last follow-up 
period in the study, this will also be considered as the “end of study “. 
For each individual subject, study participation will be 2 months. The subjects 
participation in the study is considered to have ended at the time of the last visit. 
 
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) (2) Good Clinical Practice (GCP) Guidelines.  
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a trial, the Investigator/institution should have written and dated 
approval from the IEC for the trial protocol/amendment(s), written informed 
consent form, any consent form updates, patient emergency study contact cards, 
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 
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. 


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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 
(i.e., 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 50 subjects at approximately 20 centres in 
Belgium and Luxemburg. Each centre should enrol approximately 3 subjects. 
Section 11.2 provides a discussion of sample size. 
6.2 
Inclusion Criteria 
All subjects must fulfil the following: 
1) Written informed consent before any study related procedure 
2) Male and female patients age 18 years or older at the time of enrolment 
3) Diagnosis of an intestinal obstruction of malignant origin 
4) In case of peritoneal carcinomatosis, confirmation by CT or MRI scan within the 
 
        3 months preceding the inclusion in the study 
5) Confirmed as inoperable after surgical advice  
6) Patient with a nasogastric tube OR presenting with 3 or more episodes of 
    vomiting / 24h  in the last 48 hours 
7) Estimated life expectancy 1 month or more 
 
6.3 
Exclusion Criteria 
Subjects will not be included in the study if the subject : 


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1) Operable obstruction or any sub-obstruction 
2) Bowel obstruction due to a non-malignant cause (for example : hypokaliemia, 
drug side-effects, renal insufficiency, …) 
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) Previous participation in this study 
7) Is likely to require treatment during the study with drugs that are not permitted   
   by the study protocol (see Section 9.5). 
8) 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.  
 
6.4 
Subject Withdrawal Criteria  
Patients will be discontinued from the study any time during the treatment period in 
case of any AE if serious Adverse Event (SAE) that may jeopardize the patient 
safety. Patients may also be withdrawn according to the clinical judgement of the 
investigator or at their own request. See Section 10.6 for further details. Under no 
circumstances will subjects be enrolled more than once.  
 
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 case report form (CRF). Withdrawal due to AEs should be 
distinguished from withdrawal due to insufficient response. 
In case of discontinuation due to insufficient response, the patient will be asked to 
attend the study withdrawal visit.  
In case of withdrawal due to AEs, if possible, the patient should also attend the 
study withdrawal visit and undergo the assessments of this visit or as deemed 
necessary by the Investigator. 
The withdrawal visit should be performed 4 weeks after the patient has received the 
last study drug injection. 
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 of assessments  
The schedule of observations and assessments during the study are summarised 
below. 


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Table 1.  Phase I  
 
Visit 
V1 
V2 
V3 
V4 
End of part 
1 or EOS 
Visit**** 
 
Day 
D1 
D7 
D14 
D 28 
Informed consent 
 
 
 
 
Eligibility review 
 
 
 
 
Demography 
 
 
 
 
Medical history 
 
 
 
 
Malignancy   history 
 
 
 
 
clinical examination ## 
 
 
 
 
Nutrition procedure 
 
 
 
 
Symptoms  and QOL 
assessment * 
 
 
 
 
Vomiting and nausea 
episodes assessment (diary 
cards)** 
 
 
 
 
Prior 
and 
Concomitant 
medications 
 
 
 
 
Safety biological ### 
assessment (if applicable) 
 
 
 
 
Injection Study Treatment 
Lanreotide Autogel 120 mg 
 
 
 
 
Lanreotide Concentration 
      # 
 
 
 
Adverse Events*** 
 
 
 
 
 
*:  VAS for abdominal pain, Karnofsky for daily activities, QOL by means of 
Edmonton Symptom Assessment System (caregiver and patient), and presence 
of partial/complete intestinal obstruction. Nausea and vomiting will be 
separately recorded 
 **: Diary cards will be completed every day for a total of 28 days. 
***: At Day 1 (baseline) after signature of the informed consent and after clinical 
examination and medical history  
# : Between 2 and 12 h after the injection of lanreotide Autogel 120 mg 
##: including Vital signs as Height, Weight, BP and HR 


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###: including hematology and biochemistry(upon discretion of the investigator)  
Hematology could include: RBC,Hb,Ht,MCV,MCHC,WBC,Neutro,Lymph,Monocytes,Eosino, Baso,other 
differentials, platelets.. 
Biochemistry could include 
Urea,creat,biliT,Na,K,Ca,Cl,Bicar,AlkPh,ASAT,ALAT,GGT,Alb,Prot.tot,CholT,Trigl,glucose.. 
 
               ****:  if patient is not responder then V4 is EOS – if the patient is responder he will be reinjected and                   
will continue in the study until the EOS at V7 
                ##: clinical examination will consist in vital signs: BP, HR,T°, (weight: optional) 
 
 
 
Table 3.  Phase II  
 
Visit 
V4 
V5 
V6 
V7 EOS or 
EWD Visit 
Day 
D28 
D35 
D42 
D56 
Eligibility review 
X 
 
 
 
clinical  examination## 
X 
 
 
 
Nutrition procedure 
X 
 
 
 
Symptoms  and QOL 
assessment * 
X 
 
 
 
Vomiting and nausea 
episodes assessment (diary 
cards)** 
X 
 
 
 
Concomitant medications 
X 
 
 
 
Safety biological 
assessment (if applicable) 
X 
 
 
 
Second lanreotide Autogel 
120 mg injection  
 
 
 
 
Lanreotide concentration 
# 
 
 
 
Adverse Events 
      
 
 
 
 
*:  VAS for abdominal pain, Karnofsky for daily activities, QOL by means of 
Edmonton Symptom Assessment System (caregiver and patient), and presence 
of partial/complete intestinal obstruction. Nausea and vomiting will be 
separately recorded 
  
**: Diary cards will be completed every day for a total of 28 days. 
 
X : These data will be copied from V4 of Phase 1 
##: clinical examination will consist in BP, HR,T°  
                Lanreotide Adminitration at V4 only for responders 


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                # :   Before the second lanreotide Autogel 120 mg injection 
 
Adverse Events:  At Day 1 (baseline) after signature of the informed consent and after clinical 
examination and medical history  
 Visit 4 Day 28: For subject who received an administration of Lanreotide Autogel 120 mg at 
Day 1 and who stops the study at Day 28 the EOS/EWD visit should be completed 
Lanreotide Administration at V4 only for responders 
7.2.    Study Visits 
 
Allowed time deviation for the visits : 
Phase I : 
Visit 1 (Day1) : Not applicable 
Visit 2 (Day 7): No deviations allowed 
Visit 3 (Day 14) : ± 2 days 
Visit 4 (Day 28) : ± 2 days 
 
Phase II : 
Visit 4 (Day 28) : ± 2 days  (this is Visit 4 for Phase I) 
Visit 5 (Day 35) : ± 2 days 
Visit 6 (Day 42): ± 2 days 
Visit 7 (Day 56): ± 2 days 
 
The exact date and clock-time of lanreotide Autogel 120 mg administration will be 
entered into the CRF. The exact date and clock-time of the PK blood samples will 
be entered into the CRF. 
 
 
7.2.1 Day 1 (Visit 1) 
Written informed consent should be obtained prior to enrolment when the following 
assessments will be performed: 
 
Eligibility check (inclusion/exclusion criteria) 
 
Demographics (sex, age, race,) 
 
Medical history, including ongoing medical history and physical examination 
 
Prior and concomitant medications/therapies  
 
Blood sampling for haematology and biochemistry, as deemed necessary by the 
treating physician(optional).  
 
Blood sampling for PK analysis between 2h and 12h after the lanreotide 
autogel 120 mg injection 
 
Nutrition procedure (no oral food or oral liquid intake during the first 7 days) 
 
Symptom and quality of life assessment (Edmonton Symptom Assessment 
System) by both patient and caregiver. Visual analog scale for abdominal pain 
and Karnofsky for daily activities. 
 
Vomiting and nausea episodes assessment (episodes in the last 48 hours) and 
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 
Start of compulsory medication (See Section 9.5) and injection of lanreotide 
Autogel 120 mg 
 
AEs…. 
 
7.2.2 Day 7 and Day 14 (Visit 2-3) 
The following procedures will be performed for each subject who received and 
administration with Lanreotide Autogel 120 mg at Day 1 : 
 
Physical examination 
 
Changes and initiations of concomitant medications/therapies  
 
Blood sampling for haematology and biochemistry, as deemed necessary by the 
treating physician.  
 
Blood sampling for PK analysis on Day 7  and day 14. 
 
Nutrition procedure and changes in nutrition procedure  
 
Symptom and quality of life assessment (Edmonton Symptom Assessment 
System) by both patient and caregiver. Visual analog scale for abdominal pain 
and Karnofsky for daily activities. 
 
Vomiting and nausea episodes assessment - diary cards AND/OR removal of 
nasogastric tube 
 
Start of step up medication at Day 7 in case of insufficient efficacy  
 
AEs and SA


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7.2.3a End of Phase 1  Day 28 (Visit 4) or Early 
Withdrawal Visit Phase 1 
The following procedures will be performed for each subject who received an 
administration of Lanreotide Autogel 120 mg at Day 1 and who stops the study at 
Day 28 or has an Early Withdrawal Visit Phase I : 
 
Clinical examination 
 
Changes and initiations of concomitant medications/therapies  
 
Blood sampling for haematology and biochemistry, and urinalysis as deemed 
necessary by the treating physician.  
 
Blood sampling for PK analysis on Day 28 or at early withdrawal 
 
Nutrition procedure and changes in nutrition procedure  
 
Symptom and quality of life assessment (Edmonton Symptom Assessment 
System) by both patient and caregiver. Visual analog scale for abdominal pain 
and Karnofsky for daily activities. 
 
Vomiting and nausea episodes assessment - diary cards AND/OR removal of 
nasogastric tube 
 
AEs and SAEs 
 
Reason for end of phase 1 / early withdrawal 
 
patient who are not responding or who do not want to be reinjected the EOS 
visit should be completed 
 
7.2.3b      Visit 4 Phase 2 - Day 28 Post injection  
The following procedures will be performed for each subject who received and 
administration with Lanreotide Autogel 120 mg at Day 1 and continues the study at 
Day 28: 
 
Eligibility Check Phase II : Proven efficacy at Day 28 : ≤ 2 vomiting 
episodes/day during at least 3 consecutive days at any time point between the 
D1 and D28 (for patients without NGT at baseline) or as a patient in whom the 
NGT has been removed during at least 3 consecutive days at any time point 
between the D1 and D28 without vomiting recurrence. 
 
Clinical examination 
 
Changes and initiations of concomitant medications/therapies  
 
Blood sampling for haematology and biochemistry as deemed necessary by the 
treating physician. 
 
Blood sampling for PK analysis on Day 28 before the second injection of 
lanreotide Autogel 120 mg. 
 
Nutrition procedure and changes in nutrition procedure  
 
Symptom and quality of life assessment (Edmonton Symptom Assessment 
System) by both patient and caregiver. Visual analog scale for abdominal pain 
and Karnofsky for daily activities. 


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 
Vomiting and nausea episodes assessment - diary cards AND/OR removal of 
nasogastric tube 
 
AEs and SAEs 
 
Second injection of Lanreotide Autogel 120 mg 
 
7.2.4 Day 35 and Day 42 (Visit 5-6) 
 
The following procedures will be performed for each subject who received a second 
administration of Lanreotide Autogel 120 mg at Day 28 : 
 
Clinical examination 
 
Changes and initiations of concomitant medications/therapies  
 
Blood sampling for haematology and biochemistry, and urinalysis as deemed 
necessary by the treating physician. 
 
Blood sampling for PK analysis on D35 and D42.  
 
Nutrition procedure and changes in nutrition procedure  
 
Symptom and quality of life assessment (Edmonton Symptom Assessment 
System) by both patient and caregiver. Visual analog scale for abdominal pain 
and Karnofsky for daily activities. 
 
Vomiting and nausea episodes assessment - diary cards AND/OR removal of 
nasogastric tube 
 
AEs and SAEs 
 
7.2.5 Day 56 (Visit 7 End of Study Phase 2) or Early 
Withdrawal Visit  
 
The following procedures will be performed for each subject who received a second 
administration with Lanreotide Autogel 120 mg at Day 28 and who ends the study at 
Day 56 or has an Early Withdrawal Visit Phase II : 
 
 
Clinical examination 
 
Changes and initiations of concomitant medications/therapies  
 
Blood sampling for haematology and biochemistry, and urinalysis as deemed 
necessary by the treating physician.  
 
Blood sampling for PK analysis on D56 or early withdrawal 
 
Nutrition procedure and changes in nutrition procedure  
 
Symptom and quality of life assessment (Edmonton Symptom Assessment 
System) by both patient and caregiver. Visual analog scale for abdominal pain 
and Karnofsky for daily activities. 
 
Vomiting and nausea episodes assessment - diary cards AND/OR removal of 
nasogastric tube 
 
AEs and SAEs 
 
Reason for end of study / early withdrawal 
 


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8 
STUDY EVALUATIONS 
For the timing of assessments during the study, refer to the study schedule in 
Section 7.1. 
 
8.1 
Efficacy Endpoints and Evaluations  
8.1.1 
Primary Efficacy Endpoint and Evaluations 
Phase 1 : Initial Injection Lanreotide Autogel 120 mg: 
Percentage of responding patients before or at D7. A responder is defined as a 
patient experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive days at 
any time point between the D1 and D7 (for patients without NGT at baseline) or as 
a patient in whom the NGT has been removed during at least 3 consecutive days at 
any time point between the D1 and D7 without vomiting recurrence. 
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting 
 
8.1.2 
Secondary 
Efficacy 
Endpoints 
and 
Evaluations 
Phase 1 : Initial Injection Lanreotide Autogel 120 mg: 
1) Percentage of responding patients before or at D14 (same for D28). A responder 
is defined as a patient experiencing ≤ 2 vomiting episodes/day during at least 3 
consecutive days at any time point between the D1 and D14 (D28) or as a patient in 
whom the NGT has been removed during at least 3 consecutive days at any time 
point between the D1 and D14 (D28) without vomiting recurrence.  
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting 
 
2) Time between first injection and clinical response 
 
3) Changes from baseline in Quality of Life (Edmonton Symptom Assessment 
System) at Day 7, Day 14 and Day 28 assessed by both the patient and the 
caregiver.   
 
4) Changes in daily intensity and frequency at Day 7, Day 14 and Day 28 compared 
to baseline in   
- 
General activity (Karnofsky score) 
- 
Nausea (number of daily episodes)  
- 
Pain (Visual analogue scale)  
- 
Complete/incomplete obstruction: passage of stools 
 
 
Phase 2 : Second injection Lanreotide Autogel 120 mg  : 
1) Overall Percentage of patients continuing from Phase I and confirmed as a 
responder at the end of phase I , showing a continued response at D35, D42 and 
D56. A responder is defined as a patient experiencing ≤ 2 vomiting episodes/day 


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during at least 3 consecutive days at any time point between the D1 and D35, D42 
and D56 or as a patient in whom the NGT has been removed during at least 3 
consecutive days at any time point between the D1 and D35, D42 and D56 without 
vomiting recurrence.  
- 
Number of daily vomiting episodes recorded on diary cards. 
- 
Number of days without vomiting 
 
2) Changes from baseline in Quality of Life (Edmonton Symptom Assessment 
System) at Day 35, Day 42 and Day 56 assessed by both the patient and the 
caregiver. 
 
 
8.1.3 
Pharmacokinetic Endpoints and Evaluations 
See 8.4 
8.2 
Safety Endpoints and Evaluations 
8.2.1 
Adverse Events 
AEs will be monitored from the time that the subject gives informed consent to the 
time when the subject‟s participation in the study is considered to have ended (as 
defined in 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 11. 
8.2.2 
Physical Examination 
A physical examination will be carried out by a physician. If in the opinion of the 
Investigator there are any clinically significant changes in the physical examination 
findings (abnormalities) they will be recorded as AEs. 
8.2.3 
Clinical Laboratory Tests 
All clinical laboratory test are at the discretion of the investigator. 
Laboratory tests, if clinically relevant will be recorded on the laboratory results 
pages of the CRF. All clinically relevant abnormal laboratory tests occurring during 
the study will be repeated at appropriate intervals until they return to baseline or to a 
level deemed acceptable by the Investigator and the Sponsor‟s clinical monitor (or 
his/her designated representative), or until the abnormality is explained by an 
appropriate diagnosis. See Section 10.2.4 for abnormal laboratory tests that should 
be recorded as AEs in the CRF. 
8.3 
Total Blood Volume 
The total blood during the whole course of the study, taken for serology, 
biochemistry, haematology, pharmacokinetics (PK) and will not exceed 15 mL per 
subject. 
8.4 
Pharmacodynamic Endpoints and Evaluations:NA 
 


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8.5 
Pharmacokinetic Endpoints and Evaluations 
Blood samples will be collected for the assay of lanreotide. The tubes should be 
centrifuged. The resulting /serum will be collected and split into two equal aliquots. 
The samples will be frozen and stored until shipment to the central laboratory. Each 
tube should be labelled with the sample identification, study number, site number, 
subject number and initials, visit number (when applicable) and the planned time of 
collection. Full details of required labelling and the shipment process for these 
samples will be documented in the Study Manual. 
On predetermined dates, samples will be shipped in different batches under frozen 
conditions to the central laboratory. For security reasons, the two aliquots of each 
sample will be shipped separately. The batch of second aliquot will not be shipped 
until the first one has arrived. 
Upon receipt at the central laboratory, samples will be checked and stored until 
serum analysis. 
 
The concentration of lanreotide will be analysed using a validated method. All 
details of samples collection, handling and shipment will be provided in the Study 
Manual. Details of the methodology and reference ranges will be provided in the 
TMF. 
 
The PK profile of lanreotide Autogel in patients with IMIO will be assessed using 
the 
population 
approach. 
The 
potential 
effect 
of 
the 
covariates 
(demographic,pathological) on the PK parameters will be explored.  
 
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 will be given a deep sub cutaneous injection of lanreotide 
Autogel 120 mg in the upper outer quadrant of the buttock on top of the mandatory 
medication (Section 9.5). Patients who respond at day 28 and who are willing to 
participate in the second phase of the study will be given an additional injection of 
lanreotide Autogel 120 mg on top of the mandatory medication (Section 9.5).  
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. 
Following confirmation of eligibility for the study, subjects will be given a unique 
patient number and receive the treatment as specified in Section 9.1. 
 


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9.3 
Study Treatment Supply, Packaging and Labelling 
The IMP will be packaged by CTSU Dreux 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 for which batch 
of IMP has been used under their study, Material Data Safety Sheet for the active 
drug, 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, national laws in force and in 
accordance with the local languages. A description of the core text of the IMP labels 
is displayed below: 
 
Sponsor name 
 
Study Number 
 
Pharmaceutical dosage form 
 
Route of administration 
 
Quantity of dose units 
 
Batch number 
 
Treatment box number  
 
‘For clinical trial use only‟  
 
„Keep out of reach of children‟ 
 
Name, address and telephone number of the Sponsor, (Reference (3)) 
 
Storage conditions 
 
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 
dispensing for each subject will be documented in the CRF.  
9.4 
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, 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. 
 
9.5 
Mandatory and Concomitant Medication/Therapy 
 
MANDATORY concomitant medication for all patients to be started the latest 
at Day 1: 
 No oral food or oral liquid intake during the first 5 days of treatment unless 
there are signs of resolution of the obstruction (passing stools or gas): 


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patients can consume oral or liquids at the discretion of the treating 
physician 
 As of Day 1 Intravenous corticoids : Solumedrol 40 mg/day or 
dexamethasone or methylprednisolone or equivalent at a dose of  1 
mg/kg/day or more 
 Intravenous H2 antihistaminics : ranitidine 50 mg 3/d or PPI : omeprazole 
or pantoprazole or equivalent. 
 
Step up medication if not enough efficacy at Day 7: 
 
 butylhyoscine bromide (Buscopan): 40-120 mg SC or IV 
 AND 
 Haloperidol : 5 mg / 2 x day IV 
 
Authorised for all patients : 
 Analgesics on request 
- 
Metoclopramide 10 mg/4h or Domperidone 10 mg qid or Odansetron 8mg/4ml at the 
discretion of the investigator  
 Chemotherapy (if already present at study entry) 
 Venting Gastrostomy after Day 7 
 
The following concomitant medications are not permitted during this study (see also 
Section 6.2): 
 
Somatostatin or any of its analogues other than the study drug 
9.6 
Treatment of Overdose of IMP 
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 CRF. 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). 
10 
ADVERSE EVENT REPORTING 
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 study treatment has been administered.  
This definition includes events occurring from the time of the subject giving 
informed consent until the end of the study (as defined in Section 4.3.2). 
10.1 
Disease Progression 
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10.2 
Categorisation of Adverse Events 
10.2.1 
Intensity Classification 
AEs will be classified as mild, moderate or severe according to the following 
criteria: 
Mild: 
symptoms do not alter the subject‟s normal functioning 
Moderate: 
symptoms produce some degree of impairment to function, but are 
not hazardous, uncomfortable or embarrassing to the subject 
Severe: 
symptoms 
definitely 
hazardous 
to 
well-being, 
significant 
impairment of function or incapacitation. 
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 expectedness of an AE/reaction shall be determined by the Sponsor according 
to the Investigator‟s Brochure for an unapproved IMP or Summary of Product 
Characteristics (SmPC) or Package Insert (PI) for an authorised medicinal product 
which is being used according to the terms and conditions of the marketing 
authorisation. If the IMP has marketing authorisations in several countries with 
different SmPCs or PIs, one will be selected as the reference document for assessing 
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:  
 
they result in a change in IMP schedule of administration (change in dosage, 
delay in administration, IMP discontinuation), 
 
they require intervention or a diagnosis evaluation to assess the risk to the 
subject, 
 
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.  


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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  
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 CRF. 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 CRF. 
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. 
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 
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(5) results in congenital anomaly/birth defect in the offspring of a subject who 
received the IMP; 
(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. 
 
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. 
 
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.  
 
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 an 
SAE 
The following information is the minimum that must be provided to the Sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
 
Trial number 
 
Centre number 


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 
Subject number 
 
AE 
 
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 and reported to the 
sponsor as an SAE.  The Sponsor will request further information from the 
Investigator as to the course and outcome of the pregnancy using the Standard 
Pregnancy Outcome Report Form.   
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 
Deaths 
All AEs resulting in death either during the study period or within 28 days after the 
last dose of IMP, 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:  
 
AE term: lead cause of death (e.g. multiple organ failure, pneumonia, 
myocardial infarction). 
 
Outcome: fatal. 
 
For AEs leading to death, severe 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: 
 
Death NOS 
 
Disease progression NOS 
 
Multi-organ failure 


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 
Sudden death 
10.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see Sections 6.4 
and 6.5). 
If the IMP is discontinued due to a SAE it must be reported immediately to the 
Sponsor‟s designated representative (see Section 10.4). 
In all cases the Investigator must ensure the subject receives appropriate medical 
follow-up (see Section 10.3). 
10.8 
Reporting to Competent Authorities/IECs/IRBs/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, IRBs and other Investigators 
concerned by the IMP. Reporting will be done in accordance with the applicable 
regulatory requirements. 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 
Subject Classification and Definitions 
 Enrolled subject: 
Subject fully informed about the study who has given 
written informed consent to participate (before any 
occurrence of trial related procedure)  
 Treated subject : 
Enrolled subject who is treated with at least one dose of 
study medication 
 Treatment 
Completed subject: 
Treated subject who has completed all specified phases 
of the first injection of the active treatment. 
 Study Completed 
subject: 
Treated subject who has completed all specified 
phases/assessments of the study.(day 28 or day 56) 
 Drop-out: 
Treated subject who did not complete the study and or 
discontinued treatment.  
11.2 
Analyses Populations Definitions 
 
 
Safety population: 
All subjects who received at least one dose of study 
medication  
 
 
Intention-to-treat 
(ITT) population:  
Enrolled subjects with at least one dose of study 
medication 
 
 
Per protocol (PP) 
population: 
All subjects in the ITT population for whom no 
major protocol violations/deviations occurred  
 
PK Population 
All subjects with at least one measurable lanreotide 
concentration 
11.2.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint(s) will be performed 
on the ITT population. 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.  
 
inclusion/exclusion criteria violations 
 
did not receive any study medication 
 
prohibited medication intake 
 
deviations from time windows  
 
deviations from IMP administration 


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 
no baseline evaluation of primary efficacy criterion 
 
no valid post baseline evaluation of primary efficacy criterion 
 
other protocol violation/deviations  
11.3 
Sample Size Determination 
 Sample size is calculated to test if the proportion responders at day 7 using 
Lanreotide 120 mg is larger than the reference proportion of 30% (18). The 
following assumption underlie the sample size calculation: expected proportion 
responders using lanreotide is 50%, 1-sided test, 2.5 % significance level alpha and 
power of 80 % using Z-test for binomial proportion. The required sample size is 44 
subjects. However, taken into account a certain margin for drop outs (15-20%), 50 
patients will be recruited for this study. It is planned to recruit these patients in a 2 
year period in approximately 20 centres in Belgium and Luxemburg. Each centre 
will be required to enrol between 1 and 3 subjects.  
11.3.1 
Significance Testing and Estimations 
Formal significance testing will be performed 1-sided at 2.5% significance level 
alpha using z-test for binomial proportion, for the primary efficacy endpoint (ie 
percentage of responders at day 7). This method tests if the proportion responders 
using Lanreotide 120 mg is larger than the reference proportion of 30% (18).   
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. 
The pharmacokinetic analyses will be performed independently, by IPSEN or a 
designated contract organisation 
Statistical evaluation will be performed using Statistical Analysis Software (SAS)® 
(version 8 or higher). 
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. 
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 


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to source data) and that the trial is conducted in compliance with the protocol, GCP 
and regulatory requirements. 
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 CRF, 
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 CRFs within 5 days after the patient‟s visit and on an 
ongoing 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 CRFs, 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, leaving the initials visible, 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. 
13.2 
Data Recording of Study Data 
In compliance with GCP, the 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 CRFs 
provided for the study. The Investigator must, as a minimum, sign each “visit 
status” CRF page to attest to the accuracy and completeness of all the data. 
All corrections on a CRF and on source documents must be made in a way, which 
does not obscure the original entry. The correct data must be inserted, dated and 
initialled/authorised by study site personnel. If it is not obvious why a change has 
been made, a reason must be provided. 


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13.3 
Source Data Verification 
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 CRF.  
As required by ICH GCP §6.4.9, the following items will be recorded directly on the 
CRF and will be considered as source data: 
 
Case and visit notes(hospital medical records) containing demographic and 
medical information, laboratory data,and the results of any tests or 
assessments 
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: 
 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] 
 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 CRFs 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 CRF page for any missing data and other 
protocol deviations, where space has been provided. Any data management queries 
and items not adequately explained will be returned to the Investigator by the 
monitor for clarification/correction. The Investigator must ensure that data queries 
are dealt with promptly. Copies of all data changes and clarifications must be 
retained by the Investigator and filed with the CRFs. 


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13.5 
Data Management 
Data management will be conducted either by a CRO, directed by the Sponsor‟s 
Clinical Development Data Sciences (CDDS) Group or by the Sponsor‟s CDDS 
Group. All data management procedures will be completed in accordance with Ipsen 
and the contracted CRO SOPs. Prior to data being received in-house at the assigned 
CRO, it will be monitored at the Investigator site, (for further details please see section 
12 Monitoring Procedures). CRF and other data documentation removed from the 
Investigator site(s) will be tracked by the CRO and the monitor. 
The Sponsor will ensure that appropriate data entry methods are used (e.g., double data 
entry) and suitable queries are raised to resolve any missing or inconsistent data. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO. It is the central study monitor‟s responsibility to 
ensure that all queries are resolved by the relevant parties. 
The Sponsor will also ensure that SAE data collected in the CRF 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 WHODRUG and AEs/medical 
history terms will be coded using MedDRA. 
13.6 
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 should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or planned 
marketing applications in an ICH region (that is at least 15 years) or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the 
product. However, these documents should be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the 
Sponsor. 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. 
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 in regions where an approval is required. 


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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 
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. 


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14.5 
Insurance, Indemnity and Compensation 
The Sponsor will provide Product Liability insurance for all subjects included in the 
clinical study. Where required, a hospital specific indemnity agreement will be used. 
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: 
 
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/IRBs or Competent Authorities (CA) for information purposes. 
 
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/IRBs and CA. Prior to 
implementation, documented approval must be received from the IECs/IRBs. In 
the case of the CA in the EU member states, approval or „favourable opinion‟ 
can be assumed if the CA has raised no grounds for non-acceptance during an 
allocated time period (to be confirmed with the Sponsor‟s Regulatory Affairs 
(RA) representative) following acknowledgment of receipt of a valid application 
to make a substantial amendment.  
 
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/IRBs and CA notification, 
forthwith.  
16 
REFERENCES 
(1) Investigators Brochure Lanreotide 
(2) International Conference on Harmonisation (ICH) E9 and Federal register 
Vol 63, No. 179 (September 1998). 
(3) GMP, Annex 13. 
(4) Food and Drug Administration (FDA) 21 CFR Part 11, Electronic 
Records, Electronic Signatures 
(5) FDA, Guidance for Industry: Computerized Systems Used in Clinical 
Trials 
(6) Ripamonti C.: Management of bowel obstruction in advanced cancer. 
Current Opinion in Oncology 1994; 6: 351-357. 
(7) Baines M., Oliver D.J., Carter R.L.: Medical management of intestinal 
obstruction in patients with advanced malignant disease: a clinical and 
pathological study. Lancet 1985; 2: 990-993. 


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(8) Ripamonti C., Twycross R., Baines M., and al.: Clinical-practice 
recommendations for the management of bowel obstruction in patients 
with end-stage cancer. Support Care Cancer 2001; 9 (4): 223-233. 
(9) Ripamonti C. Panzeri C., Groff L. and al.: The role of somatostatin and 
octreotide in bowel obstruction: pre-clinical and clinical results. Tumori 
2001; 87: 1-9. 
(10) Fainsinger R.L., Pisani A., Bruera E.: Use of somatostatin analogues in 
terminal cancer patients. J. Palliat. Care 1993; 9/1: 56-57. 
(11) Mercadante S., Spoldi E., Caraceni A., Maddaloni S., Simonetti M.T.: 
Octreotide in relieving gastrointestinal symptoms due to bowel 
obstruction. Palliat. Med. 1993; 7: 295-299. 
(12) Laval G. and al.: The use of steroids in the management of inoperable 
obstruction. Palliative Medicine 200; 14: 3-10. 
(13) Raptis S., Schlegel W., Lehmann E., Dollinger H.C., Zoupas C.: Effects of 
somatostatin on the exocrine pancreas and the release of duodenal 
hormones. Metabolism 1978; 27: 1321-1328. 
(14) Tulassay Z.: Somatostatin and the gastrointestinal tract. Scand. J. 
Gastroenterol 1998; 33 Suppl 228: 115-121. 
(15) Lansden F.T., Adams D.B., Anderson M.C.: Treatment of external 
pancreatic fistulas with somatostatin. Am. Surg. 1989; 55: 695-698. 
(16) Barnes S., Kontny B., and Prinz R. Somatostatin analog treatment of 
pancreatic fistulas. International Journal of Pancreatology 1993; 14 (2): 
181-188. 
(17) Mystakidou K.,Tsilika E., Kalaidopoulou O. and 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. 
(18) P. Mariani, J. Blumberg, L. Chauvenet : Efficacy of Lanreotide 30 mg as 
Symptomatic Treatment in Patients with Inoperable Bowel Obstruction 
Due to Peritoneal Carcinomatosis: A Randomized, Double-blind, Placebo-
controlled Study 


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17 
LIST OF APPENDICES 
 
No table of figures entries found. 


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Appendix 2: Visual Analogue Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3: Karnofsky performance status scale (%) 
The Karnofsky Performance Scale Index allows patients to be classified as to their functional impairment. This can be used to compare 
effectiveness of different therapies and to assess the prognosis in individual patients. The lower the Karnofsky score, the worse the 
survival for most serious illnesses.  
 
 
Able to carry on normal activity and to work; no special care needed. 
  100   Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms 
of disease.  
Unable to work; able to live at home and care for most personal needs; 
varying amount of assistance needed. 
70 
Cares for self; unable to carry on normal activity or to 
do active work. 
60 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
50 
Requires considerable assistance and frequent medical 
care.  
Unable to care for self; requires equivalent of institutional or hospital 
care; disease may be progressing rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 


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Appendix 4: Patient’s diary 
 
 
Please fill in. 
 
 
07 / 01 / 2013 
 
 
V 
 
V 
 
N 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remarks:  
 
 
_08 / 01 / 2013 
 
 
N 
 
N 
 
V 
 
N 
 
 
 
 
 
 
 
 
 
 
 
Remarks: 
 
 
___/___/20____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remarks: 
 
 
___/___/20____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remarks: 
 
 
___/___/20____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remarks: 
 
 
___/___/20____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remarks: 
 
 
___/___/20____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remarks: 
 
 
 
STUDY 
PERIOD 
SITE N° 
PATIËNT N° 
 
 DIARY 
A-48-52030-269 
DAY 1 TOT DAY 28 
0 5 6 0   
0 0 0   
                         
EXAMPLE 

SAP_001.pdf: 
 
 
 
Sponsor: IPSEN 
 
 
Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
IPSEN - IMIO - Statistical Analysis Plan - Version 1.0 - 20180615.docx                                                              - Page 1 / 29 – 
 
ITEC Services SAS - 3, Avenue Georges Clemenceau - 33150 CENON - Tél : 05.57.77.85.00 - Fax : 05.57.77.85.01 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
STUDY A-48-52030-269- IMIO 
 
AN INTERNATIONAL, MULTICENTRIC, PROSPECTIVE, OPEN LABEL  STUDY 
TO ASSESS THE EFFICACY AND SAFETY OF LANREOTIDE AUTOGEL 120 MG 
ASSOCIATED TO STANDARD OF CARE IN THE TREATMENT OF CLINICAL 
SYMPTOMS ASSOCIATED WITH INOPERABLE MALIGNANT INTESTINAL 
OBSTRUCTION (IMIO) 
 
Author: 
ITEC Services 
3, avenue Georges Clémenceau 
ZI Jean Zay – 33150 CENON 
FRAN 
CE 
 
 
Protocol version:  
 
Version 1.0 – 19/09/2013 
CRF version: 
 
Version 1.0 – 21/03/2014 
Versions: 
 
  Version 1.0 – 15/06/2018   
 
Number of pages: 29 
 
 
Edition:  
 
Friday, 15 June 2018 
 
 
 
 
 
 
 
CONFIDENTIALITY 
This statistical analysis plan is the ownership of the sponsor and cannot be given, reproduced, published or used, even partially, by any 
authorities or organism without the authorisation of the sponsor. 
 
 




 
 
 
Sponsor: IPSEN 
 
 
Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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ITEC Services SAS - 3, Avenue Georges Clemenceau - 33150 CENON - Tél : 05.57.77.85.00 - Fax : 05.57.77.85.01 
 
TABLE OF CONTENTS 
 
 
1 
ABBREVIATIONS .......................................................................................................................... 5 
2 
STUDY OBJECTIVES .................................................................................................................... 6 
2.1 
Primary objective ................................................................................................................. 6 
2.2 
Secondary objectives .......................................................................................................... 6 
2.3 
Safety objectives .................................................................................................................. 6 
3 
STUDY DESIGN ............................................................................................................................. 6 
3.1 
Type of study ........................................................................................................................ 6 
3.2 
Study Plan ............................................................................................................................. 6 
3.3 
Duration of the study ........................................................................................................... 9 
3.4 
Enrolment of patients .......................................................................................................... 9 
4 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 10 
5 
CRF VARIABLES ......................................................................................................................... 11 
6 
EFFICACY PARAMETERS .......................................................................................................... 13 
6.1 
Primary Efficacy Endpoint and Evaluations.................................................................... 13 
6.2 
Secondary Efficacy Endpoints and Evaluations............................................................. 13 
7 
DATA SETS ANALYSED ............................................................................................................. 15 
7.1 
Subject Classification and Definitions ............................................................................. 15 
7.2 
Analyses Populations Definitions .................................................................................... 16 
8 
STATISTICAL METHODOLOGY ................................................................................................. 17 
8.1 
Descriptive statistics ......................................................................................................... 17 
8.2 
Management of missing values ........................................................................................ 17 
8.2.1 
Missing data ..................................................................................................................... 17 
8.2.2 
Missing or incomplete dates ............................................................................................ 17 
8.2.3 
Outliers ............................................................................................................................. 17 
8.3 
Baseline description .......................................................................................................... 18 
8.3.1 
Subject disposition ........................................................................................................... 18 
8.3.2 
Baseline characteristics ................................................................................................... 18 
8.4 
Efficacy analysis ................................................................................................................ 20 
8.4.1 
Main analysis ................................................................................................................... 20 
8.4.2 
Secondary analyses ........................................................................................................ 21 
8.5 
Safety analysis ................................................................................................................... 23 
8.5.1 
Study drug exposure ........................................................................................................ 23 
8.5.2 
Adverse events ................................................................................................................ 23 
8.5.3 
Concomitant surgical procedures .................................................................................... 24 
8.5.4 
Concomitant medications ................................................................................................ 24 
8.5.5 
Concomitant non drug therapies...................................................................................... 24 
8.5.6 
Concomitant medications for Inoperable Malignant Intestinal Obstructions ................... 24 
8.5.7 
Nutrition procedure .......................................................................................................... 24 
8.5.8 
Vital signs ......................................................................................................................... 24 
8.5.9 
Local laboratory data ....................................................................................................... 24 


 
 
 
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8.6 
Changes from protocol ...................................................................................................... 25 
9 
SUBGROUPS ............................................................................................................................... 26 
10 
INTERIM ANALYSIS .................................................................................................................... 26 
11 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS ............................ 27 
11.1 
Hardware ............................................................................................................................. 27 
11.2 
Software .............................................................................................................................. 27 
11.3 
Validation of programs ...................................................................................................... 27 
11.4 
Restitution of the programs .............................................................................................. 27 
12 
REFERENCES ............................................................................................................................. 27 
13 
STATISTICAL APPENDICES ...................................................................................................... 28 
 


 
 
 
Sponsor: IPSEN 
 
 
Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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1 
ABBREVIATIONS 
 
ADS: 
Analysis Data Set 
 
AE: 
Adverse Event 
 
ATC: 
Anatomical Therapeutic Chemical 
 
BMI: 
Body Mass Index 
 
CI: 
Confidence Interval 
 
CRF: 
Case Report Form 
 
CRO: 
Contract Research Organisation  
 
CS 
Clinically significant 
 
CT Scan: 
Computed Tomography Scan 
 
DD: 
Derived Data  
 
DM: 
Data Management  
 
DX: 
Day X  
 
ESAS: 
Edmonton Symptoms Assessment Scale  
 
GPP: 
Good Pharmacoepidemiology Practices  
 
HADS: 
Hospital Anxiety and Depression Scale 
 
IEC: 
Independent Ethics Committee  
 
IMP 
Investigational Medicinal Product 
 
ITT: 
Intention To Treat 
 
KPS: 
Karnofsky Performance Scale   
 
MedDRA: 
Medical Dictionary for Regulatory Activities 
 
MRI Scan: 
Magnetic Resonance Imaging Scan 
 
NCS 
Not clinically significant 
 
NGT: 
Nasogastric Tube 
 
PP: 
Per Protocol  
 
PT: 
Preferred Term 
 
SAE: 
Serious Adverse Event 
 
SAP: 
Statistical Analysis Plan  
 
SAS®: 
Statistical Analysis System® 
 
SD: 
Standard Deviation 
 
SOC: 
System Organ Class 
 
SmPC: 
Summary of Product Characteristics  
 
SOP: 
Standard Operating Procedure  
 
VAS: 
Visual Analogic Scale 
 
WHO-DD: 
World Health Organization – Drug Dictionary 


 
 
 
Sponsor: IPSEN 
 
 
Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary objective  
The primary objective of this observational study is to assess the efficacy of Lanreotide Autogel 120 mg 
for the relief of vomiting due to inoperable malignant intestinal obstruction in patients without nasogastric 
tube AND to assess the efficacy of Lanreotide Autogel 120 mg to remove a nasogastric tube without the 
recurrence of vomiting in patients with an inoperable malignant intestinal obstruction with a nasogastric 
tube.  
2.2 
Secondary objectives  
The secondary objectives are as follows:  
1) To evaluate the impact on Quality of Life (Edmonton Symptom Assessment System) of Lanreotide 
Autogel 120 mg assessed by both the patient and the caregiver (healthcare professional caregiver). 
 
2) To assess the efficacy of Lanreotide Autogel 120 mg for the relief of other clinical symptoms due to 
inoperable malignant intestinal obstruction: 
- General activity (Karnofsky score) 
- Nausea (number of daily episodes)  
- Pain (Visual Analogue Scale)  
- Complete/incomplete obstruction: passage of stools 
 
3) To assess the symptom (nausea and vomiting) improvement delay 
 
4) To assess the pharmacokinetic profile of Lanreotide in patients with inoperable malignant intestinal 
obstruction  
2.3 
Safety objectives  
To assess the clinical and biological safety of the study treatment 
 
3 
STUDY DESIGN  
3.1 
Type of study  
This is a Phase II, single arm, non-randomised, prospective, open label, multicentre study.  
3.2 
Study Plan 
▪ Phase 1 Initial Injection Lanreotide Autogel 120 mg: 
Patients meeting the selection criteria for participation will need to provide a written informed consent. 
Patient and caregiver will be asked to complete the Edmonton Symptom Assessment System (ESAS) 
before any study procedure. Patients will then receive the following treatment: Standard of care + 1 
injection of lanreotide Autogel 120 mg. 
Response to the treatment will be assessed based on the % of responders in the treatment group at 
Day 7, Day 14 and Day 28. 
Safety of the patients will be followed continuously during the entire study period. A blood sample to 
assess the serum levels of lanreotide will be taken at Day 0, Day 7 and Day 14 and Day 28 
For patients who are: 
Non-responders at Day 28 OR 
Responders at day 28 but who are unwilling to receive a second injection with lanreotide, the 
participation to the study will stop here. Patients will then receive standard of care by the treating 
physician. 
 
 








 
 
 
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Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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 In case of peritoneal carcinomatosis, confirmation by CT or MRI scan within the 3 months 
preceding the inclusion in the study 
 Confirmed as inoperable after surgical advice  
 Patient with a nasogastric tube OR presenting with 3 or more episodes of vomiting / 24h  in 
the last 48 hours 
 Estimated life expectancy 1 month or more  
The non-inclusion criteria for the patients are:  
 Operable obstruction or any subobstruction 
 Bowel obstruction due to a non-malignant cause (for example: hypokalaemia, drug side-
effects, renal insufficiency, etc.) 
 Signs of bowel perforation 
 Prior treatment with somatostatin or any analogue within the previous 60 days 
 A known hypersensitivity to any of the study treatments or related compounds 
 Previous participation in this study 
 Is likely to require treatment during the study with drugs that are not permitted by the study 
protocol (see Section 9.5). 
 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. 
 
4 
DETERMINATION OF SAMPLE SIZE 
Sample size is calculated using nQuery to test if the proportion responders at day 7 using Lanreotide 
120 mg is larger than the reference proportion of 30%. The following assumption underlie the sample 
size calculation: expected proportion responders using Lanreotide is 50%, 1-sided test, 2.5 % 
significance level alpha and power of 80 % using Z-test for binomial proportion. The required sample 
size is 44 subjects. However, taken into account a certain margin for drop outs (15-20%), 50 patients 
will be recruited for this study. 
 
 
 
 


 
 
 
Sponsor: IPSEN 
 
 
Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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5 
CRF VARIABLES 
Data collection will be done through a paper based Case Report Form (CRF). 
 Day 0 (Visit 1) 
Written informed consent should be obtained prior to enrolment when the following assessments will be 
performed: 
- Eligibility check (inclusion/exclusion criteria) 
- Demographics (sex, age, race,) 
- Medical history, including ongoing medical history and physical examination 
- Prior and concomitant medications/therapies 
- Blood sampling for haematology and biochemistry, and urinalysis as deemed necessary by the treating 
physician (optional). 
- Blood sampling for PK analysis between 2h and 12h after the lanreotide autogel 120mg injection 
- Nutrition procedure (no oral food or oral liquid intake during the first 5 days) 
- Symptom and quality of life assessment (Edmonton Symptom Assessment System) by both patient 
and caregiver. Visual analog scale for abdominal pain and Karnofsky for daily activities. 
- Vomiting and nausea episodes assessment (episodes in the last 48 hours) and distribution of diary 
cards 
- Start of compulsory medication and injection of lanreotide Autogel 120 mg 
- AEs 
 
 Day 7 and Day 14 (Visit 2-3) 
The following procedures will be performed for each subject who received an administration with 
Lanreotide Autogel 120 mg at Day 0: 
- Physical examination 
- Changes and initiations of concomitant medications/therapies 
- Blood sampling for haematology and biochemistry, and urinalysis as deemed necessary by the treating 
physician. 
- Blood sampling for PK analysis on Day 7 and day 14. 
- Nutrition procedure and changes in nutrition procedure 
- Symptom and quality of life assessment (Edmonton Symptom Assessment System) by both patient 
and caregiver. Visual analog scale for abdominal pain and Karnofsky for daily activities. 
- Vomiting and nausea episodes assessment - diary cards AND/OR removal of nasogastric tube 
- Start of step up medication at Day 7 in case of insufficient efficacy 
- AEs and SAEs 
 
 End of Phase 1 Day 28 (Visit 4) or Early Withdrawal Visit Phase 1 
The following procedures will be performed for each subject who received an administration of 
Lanreotide Autogel 120 mg at Day 0 and who stops the study at Day 28 or has an Early Withdrawal Visit 
Phase I: 
- Clinical examination 
- Changes and initiations of concomitant medications/therapies 
- Blood sampling for haematology and biochemistry, and urinalysis as deemed necessary by the treating 
physician. 
- Blood sampling for PK analysis on Day 28 or at early withdrawal 
- Nutrition procedure and changes in nutrition procedure 
- Symptom and quality of life assessment (Edmonton Symptom Assessment System) by both patient 
and caregiver. Visual analog scale for abdominal pain and Karnofsky for daily activities. 
- Vomiting and nausea episodes assessment - diary cards AND/OR removal of nasogastric tube 
- AEs and SAEs 
- Reason for end of phase 1 / early withdrawal 
Patient who are not responding or who do not want to be reinjected the EOS visit should be completed 
 
 


 
 
 
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Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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 Visit 4 Phase 2 - Day 28 Post injection 
The following procedures will be performed for each subject who received and administration with 
Lanreotide Autogel 120 mg at Day 0 and continues the study at Day 28: 
Eligibility Check Phase II: Proven efficacy at Day 28: ≤ 2 vomiting episodes/day during at least 3 
consecutive days at any time point between the D0 and D28 (for patients without NGT at baseline) or 
as a patient in whom the NGT has been removed during at least 3 consecutive days at any time point 
between the D0 and D28 without vomiting recurrence. 
- Clinical examination 
- Changes and initiations of concomitant medications/therapies 
- Blood sampling for haematology and biochemistry, and urinalysis as deemed necessary by the treating 
physician. 
- Blood sampling for PK analysis on Day 28 before the second injection of lanreotide Autogel 120 mg. 
- Nutrition procedure and changes in nutrition procedure 
- Symptom and quality of life assessment (Edmonton Symptom Assessment System) by both patient 
and caregiver. Visual analog scale for abdominal pain and Karnofsky for daily activities. 
Vomiting and nausea episodes assessment - diary cards AND/OR removal of nasogastric tube 
- AEs and SAEs 
- Second injection of Lanreotide Autogel 120 mg 
 
 Day 35 and Day 42 (Visit 5-6) 
The following procedures will be performed for each subject who received a second administration of 
Lanreotide Autogel 120 mg at Day 28: 
- Clinical examination 
- Changes and initiations of concomitant medications/therapies 
- Blood sampling for haematology and biochemistry, and urinalysis as deemed necessary by the treating 
physician. 
- Blood sampling for PK analysis on D35 and D42. 
- Nutrition procedure and changes in nutrition procedure 
- Symptom and quality of life assessment (Edmonton Symptom Assessment System) by both patient 
and caregiver. Visual analog scale for abdominal pain and Karnofsky for daily activities. 
- Vomiting and nausea episodes assessment- diary cards AND/OR removal of nasogastric tube 
- AEs and SAEs 
 Day 56 (Visit 7 End of Study Phase 2) or Early Withdrawal Visit 
The following procedures will be performed for each subject who received a second administration with 
Lanreotide Autogel 120 mg at Day 28 and who ends the study at Day 56 or has an Early Withdrawal 
Visit Phase II: 
- Clinical examination 
- Changes and initiations of concomitant medications/therapies 
- Blood sampling for haematology and biochemistry, and urinalysis as deemed necessary by the treating 
physician. 
- Nutrition procedure and changes in nutrition procedure 
- Symptom and quality of life assessment (Edmonton Symptom Assessment System) by both patient 
and caregiver. Visual analog scale for abdominal pain and Karnofsky for daily activities. 
- Vomiting and nausea episodes assessment - diary cards AND/OR removal of nasogastric tube 
- AEs and SAEs 
- Reason for end of study / early withdrawal 
 


 
 
 
Sponsor: IPSEN 
 
 
Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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6 
EFFICACY PARAMETERS  
6.1 
Primary Efficacy Endpoint and Evaluations 
  Phase 1: Initial Injection Lanreotide Autogel 120 mg: 
Percentage of responding patients before or at D7. A responder is defined as a patient experiencing ≤2 
vomiting episodes/day during at least 3 consecutive days at any time point between the D0 and D7 (for 
patients without NGT at baseline)  
or  
as a patient in whom the NGT has been removed during at least 3 consecutive days at any time point 
between the D0 and D7 without vomiting recurrence. 
 
Number of daily vomiting episodes and number of days without vomiting recorded on diaries will be used 
to calculate this endpoint. 
 
6.2 
Secondary Efficacy Endpoints and Evaluations 
 Phase 1: Initial Injection Lanreotide Autogel 120 mg: 
1) Percentage of responding patients before or at D14 (same for D28). A responder is defined as a 
patient experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive days at any time point 
between the D0 and D14 (D28)  
or 
as a patient in whom the NGT has been removed during at least 3 consecutive days at any time point 
between the D0 and D14 (D28) without vomiting recurrence.  
Number of daily vomiting episodes and number of days without vomiting recorded on diaries will be used 
to calculate this endpoint. 
 
 
2) Time between first injection and clinical response 
 
3) Changes from baseline in Quality of Life (Edmonton Symptom Assessment System) at Day 7, Day 
14 and Day 28 assessed by both the patient and the caregiver.   
The Edmonton Symptom Assessment System provided is the revised system by Watanabe. This tool is 
designed to assist in the assessment of nine symptoms common in cancer patients: pain, tiredness, 
nausea, depression, anxiety, drowsiness, appetite, wellbeing and shortness of breath, (there is also a 
line labelled “Other Problem”). The severity at the time of assessment of each symptom is rated from 0 
to 10 on a numerical scale, 0 meaning that the symptom is absent and 10 that it is of the worst possible 
severity. 


 
 
 
Sponsor: IPSEN 
 
 
Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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Figure 2 – Edmonton Symptom Assessment System 
 
Each symptom rating is interpreted independently and a total symptom distress score will be calculated 
(see section 8.4.2.3). 
 
4) Changes in daily intensity and frequency at Day 7, Day 14 and Day 28 compared to baseline in: 
 
▪ General activity (Karnofsky score) 
The Karnofsky Performance Scale (KPS) Index allows patients to be classified as to their functional 
impairment. This can be used to compare effectiveness of different therapies and to assess the 
prognosis in individual patients. The lower the Karnofsky score, the worse the survival for most serious 
illnesses. 
Able to carry on normal activity and to work; no special care 
needed. 
  100   Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms 
of disease.  
Unable to work; able to live at home and care for most personal 
needs; varying amount of assistance needed. 
70 
Cares for self; unable to carry on normal activity or 
to do active work. 
60 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
50 
Requires considerable assistance and frequent 
medical care.  
40 
Disabled; requires special care and assistance. 


 
 
 
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Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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Unable to care for self; requires equivalent of institutional or hospital 
care; disease may be progressing rapidly. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
Figure 3 – Karnofsky Performance Scale (KPS)  
 
▪ Nausea (number of daily episodes)  
The episodes are recorded using the patient diary. 
 
▪ Pain (Visual analogue scale)  
The pain is evaluated by the patient using a 100 mm Visual Analogue Scale (VAS) from “No pain” (=0) 
to “Unbearable pain” (=100). 
 
▪ Complete/incomplete obstruction: passage of stools 
No data are collected on this point so this analysis will not be done. See section 8.6 “Changes from 
protocol” 
 
 Phase 2: Second injection Lanreotide Autogel 120 mg: 
1) Overall Percentage of patients continuing from Phase I and confirmed as a responder at the end of 
phase I, showing a continued response at D35, D42 and D56. A responder is defined as a patient 
experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive days at any time point between 
the D0 and D35, D42 and D56 
or 
as a patient in whom the NGT has been removed during at least 3 consecutive days at any time point 
between the D0 and D35, D42 and D56 without vomiting recurrence.  
 Number of daily vomiting episodes 
 Number of days without vomiting 
 
2) Changes from baseline in Quality of Life (Edmonton Symptom Assessment System) at Day 35, Day 
42 and Day 56 assessed by both the patient and the caregiver. 
 
 
7 
DATA SETS ANALYSED 
7.1 
Subject Classification and Definitions 
 Enrolled subject:  
Subject fully informed about the study who has given written informed consent to participate (before any 
occurrence of trial related procedure). 
 Treated subject: 
Enrolled subject who is treated with at least one dose of study medication. 
 Treatment Completed subject: 
Treated subject who has completed all specified assessments after the first and second IMP injections 
. 
 Study Completed subject: 
Treated subject who has completed all specific assessments of each phase of the study  
 
 Drop-out: 
Treated subject who did not complete the study and or discontinued IMP administration. 
 
 


 
 
 
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7.2 
Analyses Populations Definitions 
 Safety population:  
All subjects who received at least one dose of study medication. 
 Intention-to-treat (ITT) population:  
Enrolled subjects with at least one dose of study medication. 
 Per protocol (PP) population:  
All subjects from the ITT population for whom no major protocol violations/deviations occurred. 
 PK Population:  
All subjects with at least one measurable lanreotide concentration. 
 
The primary analysis based on the primary endpoint will be performed on the ITT population. In addition, 
per protocol (PP) analysis will be performed. All secondary efficacy endpoints will be analysed on the 
ITT population. Safety will be analysed using safety population which is identical to the ITT population. 
 
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: 
- inclusion/exclusion criteria violations 
- did not receive any study medication 
- prohibited medication intake 
- deviations from time windows 
- deviations from IMP administration 
- no baseline evaluation of primary efficacy criterion 
- no valid post baseline evaluation of primary efficacy criterion 
- other protocol violation/deviations 
 
 


 
 
 
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Study: STUDY A-48-52030-269- IMIO 
 
 
 
 
 
 
 
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8 
STATISTICAL METHODOLOGY 
The statistical analysis will be performed by ITEC Services - 3 Avenue Georges Clemenceau - 33150 
CENON – FRANCE (except pharmacokinetic analyses that will be performed by IPSEN). 
8.1 
Descriptive statistics 
Each modality of qualitative data will be presented with their number and percentage. 
For quantitative data, mean, median, minimum and maximum as well as standard deviation and 
interquartile range will be described. 
For all the variables, number of available and missing observations will be specified. If necessary, 
95 % CI will also be presented. 
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: same number of decimal as collected, 
 
Derived data: 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), 
 
Mean, median and standard deviation: reported to one decimal place greater than the 
raw/derived data that they summarize, 
 
Minimum and maximum : same precision as the raw data, 
 
Percentage: one decimal place, 
 
P-values: four decimal places (e.g.: p=0.0037), after rounding. P-values which are less than 
0.0001 will be presented as ‘<0.0001’. 
 
8.2 
Management of missing values 
8.2.1 
Missing data 
If necessary, specifications for handling missing data are provided in Appendix A. Without precision in 
this section missing data will not be replaced. 
Missing data handling for efficacy parameter is detailed in section 8.4.1. 
8.2.2 
Missing or incomplete dates 
For partial dates, if the day is missing, the convention is to use “15” (middle of the month). If the day and 
the month are missing and it’s a former date (for example date of birth), the convention is to use the 
value “1” for the day and “7” for the month (middle of the year). This convention is useful to estimate 
some time intervals and/or duration. 
8.2.3 
Outliers 
Any outlier identified prior to database lock which is impossible/implausible will be excluded from the 
analysis. A search of outliers should be performed during the data review meeting and actions with the 
sponsor should be defined. 
 
 


 
 
 
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8.3 
Baseline description 
8.3.1 
Subject disposition 
A summary table and a flow chart of subjects enrolled and included in each population will be presented 
overall and according to NGT use. The reasons for exclusion from each population will be presented in 
the same table. A listing of excluded patients from each population will also be presented. 
The number of patients by centre will be presented. 
Follow-up durationDD (days) corresponds to the time between baseline visit (Visit 1 / D0) and last visit 
recorded and will be calculated overall and a summary of the number of subjects at each assessment 
will also be provided.  
The number and percentage of subjects who withdrew from the study (overall and during each phase) 
and the primary reason for early withdrawal will be presented overall and according to NGT use. Time 
between inclusion and early withdrawalDD  (days) will also be presented overall and during each phase. 
 
8.3.2 
Baseline characteristics 
Summary statistics will be provided for data at baseline for the ITT Population. 
 
 Demographic characteristics 
The following characteristics will be presented overall and according to NGT use: 
- 
Age at inclusionDD  (years) in quantitative and in classes (<40 / [40;50[ / [50;60[ / [60;70[, >70) 
- 
Sex (Male/Female) 
- 
Race (Asian/Black-African American/Caucasian-White/Native Hawaiian-Other Pacific Islander/ 
American Indian/Alaska Native/Multiple)  
 
 Malignancy history causing obstruction 
The following characteristics will be presented overall and according to NGT use: 
- 
Time between initial diagnosis and inclusion visitDD (months) 
- 
Previous intestinal obstruction (No/Yes) 
- 
If yes, has it resolved? (No/Yes) 
- 
If Yes, Specify (Spontaneously/Medical Treatment/Surgical Treatment) 
- 
Time between current intestinal obstruction and inclusion visitDD (days) 
- 
Malignancy origin causing intestinal obstruction (Digestive/Ovarian/Other, specify) 
- 
Presence of ascites (No/Yes) 
 
 Vital signs 
The following characteristics will be presented: 
- 
Height (cm) in quantitative 
- 
Weight (kg) in quantitative 
- 
Body Mass Index (kg/m²)DD in quantitative and in classes (<18.5 / [18.5;25[ / ≥ 25) 
- 
Supin Blood pressures 
 Systolic (mmHg) in quantitative  
 Diastolic (mmHg) in quantitative  
- 
Heart rate (bpm) in quantitative  
 
 


 
 
 
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 Local laboratory data  
 
The following parameters will be presented as quantitative variables  
- 
Haematology 
 Blood sample collected (No/Yes) 
o 
If no, a listing of reasons why vital signs measurements were not done will be presented  
o 
If yes :  
 Red blood cells count (1012/L)  
 Hemoglobin (g/L)  
 
Haematocrit (RATIO) 
 
MCV (fL) 
 MCH (pg) 
 MCHC (g/dL)  
 White blood cells count (109/L)  
 Neutrophils (109/L)  
 Lymphocytes (109/L)  
 Monocytes (109/L) 
 Eosinophils (109/L)  
 Basophils (109/L)  
 Other differentials (109/L)  
 Platelets (109/L)  
- 
Biochemistry 
 Blood sample collected (No/Yes) 
o 
If no, a listing of reasons why vital signs measurements were not done will be presented  
o 
If yes :  
 Subject fasting (No/Yes) 
 Urea (mmol/L)  
 Total bilirubin (µmol/L)  
 Sodium (mmol/L)  
 Potassium (mmol/L)  
 Calcium (mmol/L)  
 Chloride (mmol/L) 
 Bicarbonate (mmol/L) 
 Alkaline phosphatase (IU/L)  
 Albumin (g/L)  
 Total protein (g/L)  
 Total cholesterol (mmol/L)  
 Triglycerides (mmol/L)  
 Glucose (mmol/L) 
 Creatinine (µmol/L)  
 ASAT (IU/L)  
 ALAT (IU/L)  
 GGT (IU/L)  
in quantitative and in classes (Normal/Abnormal NCS/Abnormal CS/Not evaluable). 
NCS=Not Clinically Significant / CS=Clinically Significant 
 
Note: Baseline laboratory parameters are discussed in Section 8.5.9 with the post baseline laboratory 
data.  
If a laboratory parameter was retested, the most recent value will be used for the description. 
 
 Significant medical and surgical history 
Significant medical and surgical history data will be coded using MedDRA dictionary version 19.0.   
Two frequency tables of the number and percentage of subjects and of events will be provided by 
primary system organ class (Primary SOC) and preferred term (PT). The first table will present medical 


 
 
 
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and surgical history ongoing at inclusionDD, and the second table will present only events ended at the 
time of inclusionDD.  
 
 Concomitant medications started prior inclusion 
Concomitant medications started prior inclusion will be coded using ATC code of the WHO-Drug 
Dictionary Version of December 2015.   
A table presenting number and percentage of subjects and concomitant medication started prior 
inclusionDD by ATC2 and Drug Name will be tabulated.  
 
 Non drug therapies started prior inclusion 
Non drug therapies started prior inclusion will be coded using MedDRA dictionary version 19.0.   
A table presenting number and percentage of subjects and concomitant non drug therapies started prior 
inclusionDD by PT will be tabulated. 
 
 Concomitant medications for Inoperable Malignant Intestinal Obstructions started 
prior inclusion 
Concomitant medications for Inoperable Malignant Intestinal Obstructions started prior inclusion will be 
coded using ATC code of the WHO-Drug Dictionary Version of December 2015.   
A table presenting number and percentage of subjects and concomitant medications for Inoperable 
Malignant Intestinal Obstructions started prior inclusionDD by ATC2 and Drug Name will be tabulated. 
 
 Nutrition procedure started prior inclusion 
Nutrition procedures started prior inclusion will be described according to route of administration (enteral 
/ intravenous / oral): 
- 
Number and percentage of patients with at least one nutrition procedure 
- 
Number and percentage of nutrition procedures 
- 
Type of food (solid / liquid)   
 
 
8.4 
Efficacy analysis 
8.4.1 
Main analysis 
▪ Primary endpoint  
The primary endpoint is the percentage of responding patients before or at D7.  
A responder is defined as a patient experiencing ≤ 2 vomiting episodes/day during at least 3 consecutive 
days at any time point between the D0 and D7 (for patients without NGT at baseline) based on diary 
cards 
or  
as a patient in whom the NGT has been removed during at least 3 consecutive days at any time point 
between the D0 and D7 without vomiting recurrence. 
 
Number of daily vomiting episodes and number of days without vomiting recorded on diaries will be used 
to calculate this endpoint. If diary cards are not available, then the assessment of vomiting reported in 
the CRF will be taken into account. 
A day with a missing number of vomiting on diary cards will be imputed by the worst case (For patients 
without NGT: >2 vomiting episodes and for patients with NGT: ≥ 1 vomiting episodes). 
Hypotheses: H0 : p = 30% versus H1 : p > 30% where p is the probability of responder and p0 = 30% is 
the reference proportion. If 𝑝̅ is the observed sample proportion of responders, E(𝑝̅) and V(𝑝̅)=p(1-p)/n; 
the Central Limit Theorem then gives the z-statistic, 


 
 
 
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𝑧=
𝑝̅ − 𝑝0
√𝑝0(1 −𝑝0)/𝑛
 
SAS code 
Proc freq data=dataset; 
  table responder/binomial(level=1 p=0.3) alpha= 0.025 
  exact binomial; * Exact p-values; 
run; 
 
The one-sided binomial test will indicate if a statistically significant difference exists between the 
observed proportion of responders and the theoretical proportion. We will conclude that the proportion 
of responders in our study is significantly superior to 30% if p-value<0.025.  
Primary analysis will be based on the ITT population. Analyses based on the PP population will be used 
as supportive. 
 
▪ Sensitivity analyses  
The following sensitivity analysis for the primary endpoint will be performed: 
- 
Same analysis with “best case” scenario, which means that all missing or unknown daily 
vomiting episodes will be imputed for patients without NGT by ≤2 vomiting episodes and for 
patients with NGT by < 1 vomiting episode 
 
8.4.2 
Secondary analyses 
Secondary analyses will be performed only on the ITT population. 
  Phase 1: Initial Injection Lanreotide Autogel 120 mg: 
 
8.4.2.1 
Responder proportions at D14 and D28 
The same rules as for the main analysis described in 8.4.1 will be used, except that no formal test will 
be done. 
 
8.4.2.2 
Time between first injection and clinical response 
Clinical response is defined (like the primary endpoint) as the occurrence of:  
- ≤ 2 vomiting episodes/day during at least 3 consecutive days at any time point (for patients without 
NGT at baseline)  
- the removal of NGT during at least 3 consecutive days at any time point between the D0 and D7 without 
vomiting recurrence (for patients with NGT at baseline) 
The time for clinical response in phase 1 will be defined as the time from inclusion (D0) to the date of 
clinical response defined above. 
Non-responder patients will be censored at their last collection data date. Withdrawal patients will be 
censored at their withdrawal date. 
Kaplan-Meier (K-M) estimates of the time to clinical response and the respective K-M curves will be 
provided by NGT status at baseline and overall. 
 
8.4.2.3 
Changes from baseline in Quality of Life (Edmonton Symptom Assessment System (ESAS)) 
For each symptom from Edmonton Symptom Assessment System (ESAS) and for total symptom 
distress scoreDD, the statistics will be provided at baseline and at D7, as well as for the absolute change 
from baselineDD.  
The significance of the difference between baseline and studied visit will be assessed using the paired 
Student t test. In case of non-normality of the data, usual transformation will be applied to normalize the 


 
 
 
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data. If the usual transformation does not end up with normal data, the Wilcoxon signed-rank test will 
be used to test the significance of the difference. 
This analysis will be done for ESAS assessed by both the patient and the investigator, at D7, D14 and 
D28, overall and according to NGT use. Associated figures (boxplots) will be presented for each 
dimensions and total at each visit, for ITT and by NGT status at baseline. 
ESAS completed by the “patient”, the “family caregiver” or “caregiver – assisted” will be considered as 
assessment by the patient. ESAS completed by “Health care professional caregiver” will be considered 
as assessment by the investigator. If 2 questionnaires are filled at the same visits by both the patient 
and the family caregiver, or both the patient and caregiver – assisted, then the patient questionnaire will 
be used in the following order of priority: 1-patient / 2-Family caregiver / 3-Caregiver-assisted. 
Only patients with data of ESAS at baseline and at Day X (DX) will be used for this analysis. 
 
8.4.2.4 
Changes in daily intensity and frequency at D7, D14 and D28 compared to baseline 
 
▪ General activity (Karnofsky score) 
Karnofsky Performance Status (KPS) score will be presented as a continuous variable (/100) and in 
classes ([0;40] / [50;70] / [80;100]). The statistics will be provided at baseline and at D7 (respectively 
D14 and D28), as well as for the absolute change from baselineDD.Associated figures (boxplots) will be 
presented at each visit. 
The significance of the difference between baseline and studied visit will be assessed using paired 
Student t test. In case of non-normality of the data, usual transformation will be applied to normalize the 
data. If the usual transformation does not end up with normal data, the Wilcoxon signed-rank test will 
be used to test the significance of the difference. 
Only patients with data of KPS at baseline and at DX will be used for this analysis. 
 
▪ Nausea (number of daily episodes)  
The number of daily episodes at DX will be calculated as the sum of episodes of nausea reported the 
last 3 days before DX divided by 3. 
The statistics will be provided at baseline and at D7 (respectively D14 and D28), as well as for the 
absolute change from baselineDD. 
The significance of the difference between baseline and studied visit will be assessed using the paired 
Student t test. In case of non-normality of the data, usual transformation will be applied to normalize the 
data. If the usual transformation do not end up with normal data, the Wilcoxon signed-rank test will be 
used to test the significance of the difference. 
Only patients with data of episodes of nausea at baseline and at DX will be used for this analysis. 
 
▪ Pain (Visual Analogue Scale)  
The score of the Visual Analogue Scale (VAS) will be presented at baseline and at D7 (respectively D14 
and D28), as well as for the absolute change from baselineDD.Associated figures (boxplots) will be 
presented at each visit. 
The significance of the difference between baseline and studied visit will be assessed using the paired 
Student t test. In case of non-normality of the data, usual transformation will be applied to normalize the 
data. If the usual transformation do not end up with normal data, the Wilcoxon signed-rank test will be 
used to test the significance of the difference. 
Only patients with data of VAS at baseline and at DX will be used for this analysis. 
 
▪ Complete/Incomplete obstruction: passage of stools 
No data are collected on this point so this analysis will not be done. See section 8.6 “Changes from 
protocol” 
 


 
 
 
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  Phase 2: Second injection Lanreotide Autogel 120 mg: 
 
8.4.2.5 
Responder proportions at D35, D42 and D56 
The same rules as for the main analysis described in 8.4.1 will be used, except that no formal test will 
be done. 
 
8.4.2.6 
Changes from baseline in Quality of Life (Edmonton Symptom Assessment System) 
The same analysis as described in 8.4.2.3 will be done for D35, D42 and D56. 
 
8.5 
Safety analysis 
8.5.1 
Study drug exposure 
For 1st injection (SC) of Lanreotide Autogel 120 mg at D0 and 2nd injection at D28, a table will present if 
the administration was performed (No/Yes) and if planned dose was administered (No/Yes).  
A listing of difficulties during drug administration will also be presented. 
8.5.2 
Adverse events 
The number and percentage of patients with at least one:  
 Adverse event (AE)  
 Serious Adverse Event (SAE) 
 SAE with outcome=fatal  
 Non serious AE 
 AE of mild intensity 
 AE of moderate intensity 
 AE of severe intensity 
 AE leading to drug withdrawn 
 SAE leading to drug withdrawn 
 AE related to study treatment 
 SAE related to study treatment 
 AE leading to patient withdrawal 
 SAE leading to patient withdrawal 
will be presented. For each category listed, the number of AEs will be presented in another table. 
Adverse events (AE) will be coded using MedDRA dictionary version 19.0.  Detailed description of all 
Adverse Events in terms of Preferred Term (PT) and Primary System Organ Class (SOC) per patient 
and by episode of Adverse Event will be done. In the description per patient, a given patient presenting 
several Adverse Events in the same SOC is counted only once in this System Organ Class. Moreover, 
a patient presenting several episodes of the same Adverse Event is counted only once in the 
corresponding PT. All the percentages correspond to the number of patients presenting one type of 
Adverse Event for each treatment group. This analysis will be conducted on the following types of AEs: 
 All the AEs  
 SAE 
 SAE with outcome=fatal  
 Non serious AE 
 AE leading to drug withdrawal 
 SAE leading to drug withdrawal 
 AE related to study treatment 
 SAE related to study treatment 
 
The total number of deaths will be given and a listing of dead patients will be provided. 
 


 
 
 
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8.5.3 Concomitant surgical procedures 
Concomitant surgical procedures data will be coded using MedDRA dictionary version 19.0.   
A table presenting number and percentage of subjects and concomitant surgical procedures by PT will 
be tabulated. 
 
8.5.4 Concomitant medications 
Concomitant medications data will be coded using ATC code of the WHO-Drug Dictionary Version of 
December 2015.   
A table presenting number and percentage of subjects and concomitant medication by ATC2 and Drug 
Name will be tabulated. 
 
8.5.5 Concomitant non drug therapies 
Concomitant non drug therapies data will be coded using MedDRA dictionary version 19.0.   
A table presenting number and percentage of subjects and concomitant non drug therapies on by PT 
will be tabulated. 
 
8.5.6 Concomitant medications for Inoperable Malignant Intestinal Obstructions 
Concomitant medications for Inoperable Malignant Intestinal Obstructions data will be coded using ATC 
code of the WHO-Drug Dictionary Version of December 2015.   
A table presenting number and percentage of subjects and concomitant medications for Inoperable 
Malignant Intestinal Obstructions by ATC2 and Drug Name will be tabulated. 
 
8.5.7 Nutrition procedure 
Nutrition procedures will be described according to route of administration (enteral / intravenous / oral): 
- 
Number and percentage of patients with at least one nutrition procedure 
- 
Number and percentage of nutrition procedures 
- 
Type of food (solid / liquid)   
 
8.5.8 Vital signs 
The vital signs (weight, Systolic blood pressure, Diastolic blood pressure and Heart rate) will be 
described quantitatively at each visit. Percentage change from baseline will be also calculated in 
quantitative and in classes (<20% vs ≥20%). 
 
8.5.9 Local laboratory data  
▪ Haematology 
The haematology parameters will be described quantitatively at each visit and percentage change from 
baseline will be also calculated. 
The clinical evaluation in classes (Normal/Abnormal NCS/Abnormal CS/Not evaluable) between 
baseline and each visit will be described with shift tables. 
The following haematology parameters will be described: 
 Red blood cells count (1012/L)  


 
 
 
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 Haemoglobin (g/L)  
 
Haematocrit (RATIO) 
 
MCV (fL) 
 MCH (pg) 
 MCHC (g/dL)  
 White blood cells count (109/L)  
 Neutrophils (109/L)  
 Lymphocytes (109/L)  
 Monocytes (109/L) 
 Eosinophils (109/L)  
 Basophils (109/L)  
 Other differentials (109/L)  
 Platelets (109/L)  
 
▪ Biochemistry 
The biochemistry parameters will be described at each visit in quantitative and percentage change from 
baseline will be also calculated. 
The clinical evaluation in classes (Normal/Abnormal NCS/Abnormal CS/Not evaluable) between 
baseline and each visit will be described with shift tables. 
The following biochemistry parameters will be described: 
 Urea (mmol/L)  
 Total bilirubin (µmol/L)  
 Sodium (mmol/L)  
 Potassium (mmol/L)  
 Calcium (mmol/L)  
 Chloride (mmol/L) 
 Bicarbonate (mmol/L) 
 Alkaline phosphatase (IU/L)  
 Albumin (g/L)  
 Total protein (g/L)  
 Total cholesterol (mmol/L)  
 Triglycerides (mmol/L)  
 Glucose (mmol/L) 
 Creatinine (mmol/L)  
 ASAT (UI/L)  
 ALAT (UI/L)  
 GGT (UI/L)  
 
If a laboratory parameter was retested, the most recent value will be used for the description. 
 
8.6 
Changes from protocol 
- The secondary efficacy endpoint concerning complete/incomplete obstruction (passage of stools) 
cannot be analysed as no data are collected on this point. 
- The definitions of “Treatment Completed subject”, “Study Completed subject” and “Drop-out” (see 
section 7.1) have been readjusted. 
- In the protocol, the mentioning of “caregiver” in the first secondary objective as well as the QOL 
analysis, is represented by the health care professional caregiver. Therefore, a clarification is made in 
this SAP to indicate this fact. 
- If the patient evaluation is missing due to his/her inability to complete the QOL questionnaire, then we 
will replace this missing data by using family caregiver/caregiver assisted evaluation, whichever is 
available. 
 
 


 
 
 
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9 
SUBGROUPS 
Some subgroup analyses will be done on primary endpoint using the following baseline characteristics:  
▪ Age (≤65 / >65) 
▪ Gender (Male / Female) 
▪ Time between initial diagnosis and inclusion visit (≤ median / > median) 
▪ Previous intestinal obstruction (No / Yes) 
▪ Time between current intestinal obstruction and inclusion visit (≤ median / > median) 
▪ Malignancy origin causing intestinal obstruction (Digestive / Ovarian / Other) 
▪ Presence of ascites (No / Yes) 
▪ Body Mass Index (kg/m²) in classes (< 25 / ≥ 25) 
 
 
10 INTERIM ANALYSIS 
No interim analysis will be performed for this study. 
 
 


 
 
 
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11 COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
11.1 Hardware 
The statistical analysis will be performed using Windows 7 professional and a 64-bit operating system. 
11.2 Software 
All tables, listings and figures will be produced and statistical analysis performed using SAS® version 
9.3 or above. All outputs will be edited in Microsoft Word Format. 
11.3 Validation of programs 
Validations will be done according to the procedure of the CRO ITEC Services. 
The program reviewer is responsible for reviewing each project program and output provided to the 
sponsor. 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 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 statistical and analysis plan. Outputs are cross-checked against each 
other for accuracy and consistency. For statistical tables, listings, appendix listings, and figures, this 
procedure includes comparison of subject group numbers, counts of subjects at each observation point, 
and consistency of results for variables between outputs. 
Findings of the quality control reviews are communicated to the party responsible for making necessary 
changes. The programs will be retested after modifications. 
After final review, and when no further changes are required to produce the deliverable, the program 
reviewer and the statistician in charge of the study need to complete and sign a validation checklist, to 
indicate that they have successfully performed all of their responsibilities. 
Copies of the internal quality control forms produced for the validation process and the sign-off forms 
will be provided to the sponsor to support the validation if asked. 
11.4 Restitution of the programs 
All programs (including Macros and SAS® analysis datasets) producing the tables, listings and statistical 
output along with associated logs will be given to the sponsor when the tables, listings, figures and 
statistical analysis has been finalised and the clinical study report is approved. 
 
 
 
12 REFERENCES 
 
 


 
 
 
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13 STATISTICAL APPENDICES  
APPENDIX A: Derived data (DD) 
The derived data are variables which are calculated from the raw data in the eCRF and not included in 
the database (e.g.: age, total score, duration, summary value from repeated observations, follow-up 
duration, study drug exposure, study drug cumulative dose, etc.). 
 
The following derived data will be calculated and included in the TFLs: 
(1) Follow-up duration (days) 
(Last visit date recorded - date of visit 1+ 1) 
(2) Time between inclusion and early withdrawal (days) 
(Date of withdrawal - date of visit 1+ 1) only for patients who prematurely withdrew 
(3) Age at inclusion (years) 
Year of inclusion visit - Year of birth 
(4) Time between initial diagnosis and inclusion visit (months) 
(Date of inclusion visit - Date of initial diagnosis + 1)/ 30.4375 
(5)  Time between current intestinal obstruction and inclusion visit (days) 
(Date of inclusion visit – Start date of current intestinal obstruction + 1) 
(6)  Body Mass Index (kg/m²) 
(Weight in kg) / (Height in m)² 
(7) Medical and surgical history ongoing at inclusion 
Any medical or surgical event still continuing at inclusion and without resolution date or a resolution date 
≥ date of inclusion visit 
(8) Medical and surgical history ended at time of  inclusion 
Any medical or surgical event not continuing at inclusion and/or with a reported resolution date < date 
of inclusion visit 
(9) Concomitant medication / concomitant non drug therapies / Concomitant medications for 
Inoperable Malignant Intestinal Obstructions / Nutrition procedure/ started prior inclusion 
Any medication or procedure with (start date < date of inclusion visit or started prior to study early is 
ticked) and (end date ≥ date of inclusion visit or continuing at the end of the study is ticked)  
(10) Edmonton Symptom Assessment System (ESAS) total symptom distress score 
Represents the sum of all ESAS symptoms ( from 0 to 100)  
Total symptom distress score will be calculated only when all of the 9th dimensions (except the optional 
one) will be reported. If one of the dimension is missing then the total distress score will be considered 
as missing. 
(11) Absolute change from baseline  
Absolute change from baseline will be calculated as: post baseline assessment at Dx – baseline 
assessment at D0. 
(12) Percentage change from baseline (%) 
Percentage change from baseline will be calculated as: [post baseline assessment at Dx – baseline 
assessment at D0] * 100 %/ baseline assessment at D0 * 100). 
 
 


 
 
 
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APPENDIX B: Algorithm to categorize patient in subgroup of nasogastric tube at baseline  
NGT group 
Algorithm 
Patient with NGT at baseline 
If NGT was inserted before or at baseline and is ongoing at baseline:  
Date tube inserted ≤ date of baseline visit < date tube removed 
Patient without NGT at 
baseline 
If “Was a Nasogastric tube inserted” is ticked “No” 
 
If NGT was inserted and removed before or at baseline: 
 
date tube inserted ≤ date tube removed ≤ Date of baseline 
 
If NGT was inserted after baseline:  
Date of baseline < date tube inserted