Clinical trial NCT02288377
Conditions: Metastatic/Locally Advanced, Non-resectable, Duodeno-pancreatic Neuroendocrine Tumours
Keywords: Lanreotide Duodeno-pancreatic neuroendocrine tumours Maintenance treatment
Sponsor: Federation Francophone de Cancerologie Digestive
Start date: 2015-01-01; Completion date: 2020-01-01
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This European, prospective, multicentre, double-blind randomised study will evaluate the effect of lanreotide (120 mg every 28 days until disease progression) versus placebo in patients with metastatic/locally advanced, non-resectable, duodeno-pancreatic neuroendocrine tumours.

Detailed description:
This is a European, prospective, multicentre, double-blind randomised study evaluating lanreotide (120 mg every 28 days until disease progression) versus placebo in patients with metastatic/locally advanced, non-resectable, duodeno-pancreatic neuroendocrine tumours.

Depending on the phase II results, the study may be continued into phase III. The treatment and follow-up of patients will be the same in phase II and phase III.

After the first-line treatment, patients will be randomly assigned with a 1:1 ratio to receive either lanreotide or placebo. The study treatment should be initiated within 6 weeks following the confirmation date of stable disease or objective response.

Treatment period:

For each patient, the investigational products (lanreotide or placebo) will be provided according to a double-blind procedure until disease progression or toxicity, in accordance with the protocol.

The estimated average treatment duration for all patients is 12 months.

Follow-up period:

To evaluate overall survival, patients in phase II will have a minimum follow-up period of 12 months; if the study continues to phase III, these patients will have a maximum follow-up period of 10 years. Phase III patients will have a minimum follow-up period of 5 years.

Arms: arm 1: In this arm, patients will receive lanreotide 120 mg every 28 days until disease progression arm 2: In this arm, patients will receive placebo every 28 days until disease progression
Interventions: intervention 1: lanreotide intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will receive lanreotide 120 mg every 28 days until disease progression intervention 2: None

Protocol documents:
Prot_000.pdf: 
                                                               
                             
 
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PRODIGE 31 – FFCD 1301 - REMINET 
A EUROPEAN, MULTICENTRE, PHASE II/III RANDOMISED DOUBLE-BLIND, 
PLACEBO CONTROLLED STUDY EVALUATING LANREOTIDE AS MAINTENANCE 
THERAPY IN PATIENTS WITH NON-RESECTABLE DUODENO-PANCREATIC 
NEUROENDOCRINE TUMOURS AFTER FIRST-LINE TREATMENT 
 
EudraCT number 2013-004069-14 
 
 
C o o r d i n a t i n g  i n v e s t i g a t o r : 
 
 
Prof. Côme LEPAGE, representative of the FFCD 
 
Service HGE de l’Hôpital du Bocage 
 2 Bd de Lattre de Tassigny 
 
21000 DIJON - FRANCE 
 Tel.: 00 33 (0) 380 29 37 50 - Fax: 00 33 (0) 380 29 37 22 
 E-mail: come.lepage@u-bourgogne.fr 
 
C o - c o o r d i n a t i n g  i n v e s t i g a t o r s :   
 
Prof. Thomas WALTER, representative of the GTE 
 
Service HGE et oncologie médicale 
 Hôpital E. Herriot, place d’Arsonval 
 69437 LYON - FRANCE 
 Tel.: 00 33 (0) 472 11 73 98 - Fax: 00 33 (0) 472 11 91 53 
 E-mail: thomas.walter@chu-lyon.fr 
 
 
Prof. Michel DUCREUX, representative of UNICANCER 
Gustave Roussy 
Service de Gastroentérologie 
114, rue Edouard Vaillant 
 94805 VILLEJUIF Cedex - FRANCE 
Tél. : 00 33 (0) 142 114 308 - Fax: 00 33 (0) 142 115 229 
  E-mail :Michel.DUCREUX@gustaveroussy.fr 
 
 
Protocol Writing Committee: 
JL Legoux, C Lombard-Bohas, JM Phelip, K Le Malicot, E Maillard, C Lejeune, B Guiu, JY Scoazec, T 
Walter, E Mitry, S Manfredi, M Schneider, C Girault, C Lepage 
 
Translational Research Committee:  
C Lejeune, JY Scoazec, P Laurent-Puig, T Walter, E Mitry, C Lepage  
 
 
SPONSOR AND DATA CENTRE OF THE FFCD (CRGA): Fédération Francophone de Cancérologie 
Digestive (FFCD), Faculté de Médecine, 7 Boulevard Jeanne d’Arc, BP 87900, 21079 Dijon Cedex, France 
 
 
Administrative director:   
Cécile GIRAULT 
 
Tel.: 00 33 (0) 380 66 80 13 - Fax: 00 33 (0) 380 38 18 41 
 
E-mail: cecile.girault@u-bourgogne.fr 
 
 
Lead Biostatistician:  
Karine LE MALICOT 
 
Tel.: 00 33 (0) 380 39 34 71 Fax: 00 33 (0) 380 38 18 41 
 
E-mail: karine.le-malicot@u-bourgogne.fr 
 
Project Manager:  
Martina SCHNEIDER 
 
Tel.: 00 33 (0) 380 39 34 83 / 34 86 - Fax: 00 33 (0) 380 38 18 41 
 
E-mail: martina.schneider@u-bourgogne.fr


                                                                
                              
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S P O N S O R ' S  S I G N A T U R E  P A G E  A N D  
I N V E S T I G A T O R ' S  P R O T O C O L  A C C E P T A N C E  F O R M  
 
PRODIGE 31 - FFCD 1301 – REMINET 
A EUROPEAN, MULTICENTRE, PHASE II/III RANDOMISED DOUBLE-BLIND, 
PLACEBO CONTROLLED STUDY EVALUATING LANREOTIDE AS MAINTENANCE 
THERAPY IN PATIENTS WITH NON-RESECTABLE DUODENO-PANCREATIC 
NEUROENDOCRINE TUMOURS AFTER FIRST-LINE TREATMENT 
 
EUDRACT No.: 2013-004069-14 
Core Version 1.2 dated 03/11/2014 
This version has been approved by: 
The sponsor:   
Ms Cécile GIRAULT -    Date: 03/11/2014 - Signature:  
 
Coordinating investigator:  
Prof. Côme LEPAGE -          Date: 03/11/2014 -   Signature:  
 
The investigator:  
By my above signature, I hereby confirm that I agree: 
 To conduct the study described in the protocol, in compliance with the Good Clinical 
Practices (ICH-GCP), with the standard operating procedures and with all applicable 
regulations 
 To document the delegation of significant study-related duties and to notify the sponsor of 
changes in site staff involved in the study 
 To dispense, track and retain study treatments in accordance with Good Clinical Practice 
(GCP) and the protocol 
 To comply with procedures and all applicable regulations for data recording and reporting 
including Serious Adverse Events (SAEs) 
 To authorise direct access to source data for monitoring, auditing and inspection 
 To retain the study-related essential documents 15 years after the end of the study 
Furthermore, I hereby confirm that I will have and will use adequate resources in terms of staff and 
facilities for the conduct of this study. 
 
 
Name and title: 
Address and telephone number: 
Date: 
 
Signature: 
 


                                                                
                              
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SYNOPSIS 
Title  
 
A EUROPEAN, MULTICENTRE, PHASE II/III RANDOMISED 
DOUBLE-BLIND, 
PLACEBO 
CONTROLLED 
STUDY 
EVALUATING LANREOTIDE AS MAINTENANCE THERAPY IN 
PATIENTS WITH NON-RESECTABLE DUODENO-PANCREATIC 
NEUROENDOCRINE 
TUMOURS 
AFTER 
FIRST-LINE 
TREATMENT 
Study number  
PRODIGE 31 – FFCD 1301 - REMINET 
Study 
objectives  
Phase II 
Primary objective: 
 
To evaluate the rate of patients alive and progression free at 6 months, 
assessed by the investigator according to RECIST criteria (version 1.1) 
Secondary objectives: 
 
Rate of patients alive and progression free at 12 months, assessed by 
the investigator according to RECIST criteria (version 1.1) 
 
Rate of patients alive and progression free at 6 months, according to 
central review 
 
Safety 
 
Response rate at 6 months according to RECIST criteria (version 1.1) 
 
Time To Progression (TTP) 
 
Quality of life assessed with the questionnaire QLQ-C30, including 
module NET 21, and the Spitzer visual analogue scale. 
 
Phase III 
Primary objective: 
 
To assess and compare the Progression-Free Survival (PFS) of 
lanreotide versus placebo according to RECIST criteria (version 1.1) 
assessed by the investigator 
Secondary objectives: 
 
Overall Survival (OS) at 3 and 5 years 
 
PFS according to central review 
 
Safety 
 
Response rate at 6 months according to RECIST criteria (version 1.1) 
 
Chemotherapy / biotherapy-free time interval 
 
Quality of life assessed with the questionnaire QLQ-C30, including 
module NET 21, and the Spitzer visual analogue scale. 
 
Medico-economical assessment: cost-effectiveness analysis at 12 
months and cost-utility analysis at 18 months (using EQ-5D 
questionnaire) 


                                                                
                              
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Study phase 
Phase II/III 
Inclusion 
criteria for 
phases II and III 
 
 
Metastatic (synchronous or metachronous) or locally advanced, non 
resectable, 
well-differentiated 
duodeno-pancreatic 
neuroendocrine 
tumour, of grade 1 or 2 (WHO 2010 classification; Ki-67 ≤ 20%) 
 
Progressive before first-line treatment 
 
Histologically confirmed (either on primary tumour or metastases) 
 
Pathological diagnosis validated by the NET consulting pathologist 
 
Documented stable disease or objective response after first-line 
treatment, within 4 weeks (28 days) prior to randomisation 
 
The first-line treatment will consist of either a chemotherapy or 
biotherapy (everolimus or sunitinib) as referred to TNCD or ENETS 
guidelines. Treatment must have been administered for 3 to 6 months 
for chemotherapy and for 6 months for biotherapy 
 
Non-functional tumour or gastrinoma controlled by PPIs 
 
Age  18 years 
 
WHO 0, 1 or 2 
 
Effective contraception for male or female patients of childbearing age 
 
Signed informed consent prior to initiation of any study-specific 
procedures or treatment 
 
Non-inclusion 
criteria for 
phases II and III 
 
History of haematological malignancy or other cancer, except those 
treated for more than 5 years and considered as cured, carcinoma in situ 
of the cervix and treated skin cancer (excluding melanoma) 
 
Poorly differentiated neuroendocrine carcinoma or NET grade 3 ENETS 
(Ki-67> 20%) 
 
If primary resected, bone metastases exclusively 
 
Pre-treatment by somatostatin long-acting analogue 
 
Total bilirubin ≥ 60 µmol/L 
 
Uncontrolled diabetes 
 
Contraindication to the product used in the study or its components 
 
Tumour arising in the context of a genetic disease 
 
Pregnancy or lactation 
 
Patients unable to undergo medical follow-up due to geographical, 
social, psychological or legal reasons 
 
Concomitant participation in another clinical trial investigating a treatment 
during the treatment phase and within 30 days prior to the start of the 
study treatment 
 
Employment of the subject or a close relative (i.e. spouse/partner, child, 
parent or sibling) by the CRO, the study site, 
 
Patients deprived of their liberty by a judicial or administrative decision, 
patients admitted to a hospital, social institution or who are under a 
measure of legal protection, patients hospitalized without consent or who 
are in an emergency situation. 
 


                                                                
                              
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Study design 
and treatment 
plan 
 
This is a European, prospective, multicentre, double-blind randomised study 
evaluating lanreotide (120 mg every 28 days until disease progression) versus 
placebo in patients with metastatic/locally advanced, non-resectable, duodeno-
pancreatic neuroendocrine tumours. 
Depending on the phase II results, the study may be continued into phase III. 
The treatment and follow-up of patients will be the same in phase II and phase 
III. 
After the first-line treatment, patients will be randomly assigned with a 1:1 ratio to 
receive either lanreotide or placebo. The study treatment should be initiated 
within 6 weeks following the confirmation date of stable disease or objective 
response. 
Treatment period: 
For each patient, the investigational products (lanreotide or placebo) will be 
provided according to a double-blind procedure until disease progression or 
toxicity, in accordance with the protocol. 
The estimated average treatment duration for all patients is 12 months. 
Follow-up period: 
To evaluate overall survival, patients in phase II will have a minimum follow-up 
period of 12 months; if the study continues to phase III, these patients will have a 
maximum follow-up period of 10 years. Phase III patients will have a minimum 
follow-up period of 5 years. 
Statistical 
methods 
 
The analysis will be performed according to the intent-to-treat principle, i.e. data 
from all patients will be analysed according to the treatment assigned at 
randomisation.  
The population at baseline will be described using descriptive statistics as 
percentages (with 95% CI) for categorical and ordinal variables and mean (with 
standard deviation), median (with interval Inter-quartiles and Min-max) for 
continuous variables. The results will be presented by treatment and for the 
overall population. 
For the efficacy analysis, time-to-event endpoints will be calculated from the date 
of randomisation and will be estimated using the Kaplan-Meier method. The 
results will be presented by treatment group.  
All the toxicities will be described by treatment group according to the "Common 
Terminology Criteria for Adverse Events v 4.0" scale (NCI-CTCAE, Version 4.0, 
May 2009). 
A Statistical Analysis Plan (SAP) will be written before the database lock. 
Sample size 
calculation 
Phase II Study 
The following hypotheses were used for sample size calculation: 
H0: A rate of patients alive and progression free at 6 months of 45% or less is 
not sufficient to demonstrate efficacy (p≤p0 with p0=45%). A rate of patients 
alive and progression free at 6 months of 45% or less is not sufficient to 
demonstrate efficacy. The study will not be continuedH1: A rate of patients 
alive and progression free at 6 months of more than 45% is sufficient to 
demonstrate efficacy. A rate of 63% is expected (p≥p1 with p1 = 63%)A rate of 
patients alive and progression free at 6 months of more than 45% (i.e. if the 
lower bound of the exact binomial 2‐sided 95% confidence interval 
exceeds 45%) leads to the study continuation. 
With a one-sided alpha risk of 5% and a power of 85%, using a fixed-design 


                                                                
                              
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(binomial-exact method), 56 patients per arm must be randomised. 
With a rate of 5% of patients not evaluable or lost to follow-up, 59 patients per 
arm will be included (118 patients in total). 
 
The following decision rule will apply: 
If 31 patients or less are alive and progression free at 6 months, the treatment 
will be considered as not interesting. This rule will apply to the lanreotide arm 
only. The placebo arm will be kept as a reference arm for phase III. An 
independent safety committee can also recommend the discontinuation of the 
study, with respect to the occurrence of SAEs and AEs. 
 
Depending on the phase II results, the study may progress to phase III. The 
patients randomised in phase II of the study will be included in phase III. 
Because of the uncertainty regarding the phase III hypotheses at the time of the 
phase II analysis, the phase III hypotheses will be reviewed and the sample size 
will be re-estimated, if necessary. 
 
Phase III study 
The following hypotheses were used for sample size calculation: 
H0: No difference between the two treatments in term of progression-free survival 
H1: There is a difference in terms of progression-free survival between the two 
treatments; it is assumed that the median time without progression or death is of 
5 months in the placebo group and of 7.5 months in the lanreotide group. HR is 
equal to 0.67.  
With an alpha-risk (two-sided) of 5%, and a power of 80%, it is necessary to 
observe 196 events (progression or death). 
With the hypotheses of a 24-month follow-up after the last patient is included, an 
inclusion rate of 50 patients per year and a lost-to-follow-up rate of 10%, it is 
necessary to randomise 222 patients. 
Translational 
research 
1/ Research on biomarkers: 
The objective will be to test the prognostic and predictive value of the parameters 
collected during the analysis of tumour tissue slides and blood samples. 
2/ Medico-economical evaluation: 
The objectives will be: 
At 12 months: 
 
To evaluate the cost-effectiveness ratio associated with treatment with 
lanreotide versus placebo. It will be expressed in terms of cost per 
progression-free life year gained (PFLYG) 
 
To compare the average cost and average effectiveness associated with 
lanreotide versus placebo  
At 18 months:  
 
To evaluate the cost-effectiveness ratio, expressed in terms of cost per 
PFLYG 
 
To evaluate the cost-utility ratio associated with treatment with lanreotide 
versus placebo. It will be expressed in terms of cost per progression-free 
life year gained adjusted for quality of life (QAPFLYG), using the EQ-5D 
questionnaire. 
 
To compare the average cost and average utility associated with 
lanreotide versus placebo  


                                                                
                              
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 
To evaluate the share of the different items of expenditure in the total 
cost of patients’ care management at 18 months. 
Estimated 
inclusion and 
participation 
period of each 
patient 
Phase II of study: 
Start of inclusions: 2nd quarter 2014 
End of inclusions (118 randomised patients): September 2016 
End of follow-up period: September 2017 
Analysis planned: June 2017 (for the main endpoint) 
Phase III of study: 
Start of inclusions: January 2018 
End of inclusions (104 randomised patients): January 2019 
End of follow-up period: January 2024 


 
 
 
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S C H E D U L E  O F  T H E  S T U D Y  A S S E S S M E N T S  ( T A B L E  1 )
Screening / 
Randomisation
Follow-up
Assessments
D-30 to D1
Day 1 = C1
Every 28 days
Every 3 
months 
until 
progression
Every 6 
months 
Informed Consent
X
Demographic data 1
X
Relevant medical history 2
X
Eligibility criteria
X
Randomisation
X
Physical examination 3
X
X
X
WHO score
X
X
X
X
Haematology 4
X
X
Blood chemistry 5 
X
X
Thyroid blood tests 
X
Pregnancy test 6
(X)
Treatment administration
X
Tumour assessments
X 7; 8
X
Brain CT/MRI 9
X
X
Bone scan 9
X
X
CgA10
X
X
Ki-67 (according to the NET referent review)
X 
Survival status
X
Adverse Events 11 / Serious Adverse Events
X
X
X
SAEs 12
Further treatment lines
X
Tumour slide 13 
X
Informed consent for biomarker research  
X
Blood sample collection (biomarker research) 14
X
X 
QoL (QLQ C30 + NET 21)
X
X
Medico-economical evaluation (EQ-5D including the
Spitzer visual analogue scale)
X
X
X15
1: Sex, age
2: Including ongoing medical history
3: Blood pressure, heart rate, body temperature and weight 
4: CBC, platelets
6: Serum pregnancy test within 7 days prior to randomisation
9: As clinically indicated
10: CgA assessment must always be performed with the same method in the same laboratory 
11: According to NCI CTC V4.0
15: EQ-5D questionnaire will be completed until 18 months after randomisation
Treatment Phase
13: For all patients consenting to the biomarker translational research, tumour slides will be collected at the central pathological 
laboratory; biomarker translational research program will be done on these slides
12: All SAE occurring at any time after the end of the study treatment phase,  and likely to be related to the study treatment or to a study 
procedure (in investigator's opinion), must be reported according to the reporting process described in the protocol
14 : Sample to be taken while fasting, at the inclusion, at the 1st of the 3-month evaluation only, and after progression
7 : Scans showing response or stabilisation after fist line therapy should be done at least 2 weeks after the end of the first-line treatment 
and within 4 weeks before randomisation
8:  Chest, abdomen and pelvis CT scan with early arterial timing or abdominal and pelvic MRI + chest CT scan with injection of iodised 
contrast medium (CM). In case of contraindication to use of a CM, abdominal and pelvic MRI + chest CT scan without injection (see Appendix 
7, describing methods for acquisition). It is necessary to use the same evaluation method as the one used at inclusion
5: electrolytes,total protein, liver function tests (ALT, AST, ALP, GGT, total bilirubin and conjugated), albumin, LDH, HbA1c. Total cholesterol, 
HDL cholesterol and triglycerids done only at the inclusion.


 
 
 
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T A B L E  O F  C O N T E N T S  
I - OBJECTIVES: ..................................................................................................................................... 22 
I.1 - PRIMARY OBJECTIVE ............................................................................................................................................... 22 
I.2 - SECONDARY OBJECTIVES ........................................................................................................................................ 22 
I.3 - OBJECTIVES OF TRANSLATIONAL STUDIES ............................................................................................................. 22 
I.3.1 - Research on biomarkers .................................................................................................................................................. 22 
I.3.2 - Medico-economical evaluation ........................................................................................................................................ 22 
II - OVERVIEW OF THE STUDY DESIGN ...................................................................................................... 23 
III - STUDY POPULATION ......................................................................................................................... 24 
III.1 - ELIGIBILITY CRITERIA ............................................................................................................................................. 24 
III.1.1 - Inclusion Criteria .............................................................................................................................................................. 24 
III.1.2 - Non-inclusion criteria ...................................................................................................................................................... 25 
III.2 - STUDY DURATION FOR EACH PATIENT ................................................................................................................... 25 
III.3 - PATIENT IDENTIFICATION ....................................................................................................................................... 25 
III.4 - PREMATURE STUDY DISCONTINUATION ................................................................................................................ 26 
III.4.1 - Definitive study treatment discontinuation ................................................................................................................... 26 
III.4.2 - Definitive study discontinuation for a patient ............................................................................................................... 26 
III.4.3 - III.4.3 - DEFINITIVE STUDY DISCONTINUATION .................................................................................................... 26 
IV - STUDY TREATMENTS ....................................................................................................................... 26 
IV.1 - STUDY TREATMENT PRESENTATION ..................................................................................................................... 26 
IV.2 - PACKAGING AND LABELLING OF STUDY TREATMENTS .......................................................................................... 27 
IV.3 - COMPLIANCE ......................................................................................................................................................... 28 
IV.4 - STUDY TREATMENT STORAGE ............................................................................................................................... 28 
IV.5 - ACCOUNTABILITY AND DESTRUCTION ................................................................................................................... 28 
IV.6 - CONCOMITANT MEDICATION / THERAPY ................................................................................................................ 28 
IV.7 - STUDY TREATMENT OVERDOSE MANAGEMENT .................................................................................................... 29 
IV.8 - STUDY TREATMENT ALLOCATION .......................................................................................................................... 29 
IV.8.1 - Randomisation ................................................................................................................................................................ 29 
IV.8.2 - Blinding and breaking the blind ..................................................................................................................................... 29 
IV.9 - TREATMENT DURATION ......................................................................................................................................... 30 
V - SCHEDULE OF ASSESSMENTS ........................................................................................................... 30 
V.1 - STUDY SCHEDULE .................................................................................................................................................. 30 
V.2 - INCLUSION/RANDOMISATION .................................................................................................................................. 30 
V.3 - TREATMENT PERIOD ............................................................................................................................................... 31 
V.4 - END-OF-TREATMENT VISIT ..................................................................................................................................... 32 
V.5 - FOLLOW-UP ............................................................................................................................................................ 32 
V.6 - ASSESSMENTS AND PROCEDURES FOR THE BIOMARKERS TRANSLATIONAL RESEARCH ...................................... 32 
V.6.1 - Tumour Tissue slides ...................................................................................................................................................... 32 
V.6.2 - Blood samples .................................................................................................................................................................. 33 


 
 
 
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VI - ENDPOINTS ...................................................................................................................................... 33 
VI.1 - PRIMARY ENDPOINT .............................................................................................................................................. 33 
VI.2 - SECONDARY ENDPOINTS ....................................................................................................................................... 33 
VII - PHARMACOVIGILANCE ............................................................................................................. 34 
VII.1 - ADVERSE EVENT .................................................................................................................................................. 34 
VII.1.1 - Definitions ....................................................................................................................................................................... 34 
Adverse Event (AE)..................................................................................................................................................................... 34 
Adverse drug reaction ................................................................................................................................................................. 34 
Unexpected adverse drug reaction ........................................................................................................................................... 35 
VII.1.2 - disease progression ...................................................................................................................................................... 35 
VII.1.3 - Laboratory test abnormalities ....................................................................................................................................... 35 
VII.1.4 - Classification of intensity of AEs .................................................................................................................................. 35 
VII.1.5 - Reporting and follow-up of adverse events ................................................................................................................ 35 
VII.2 - SERIOUS ADVERSE EVENT .................................................................................................................................. 36 
VII.2.1 - Definitions ....................................................................................................................................................................... 36 
VII.2.2 - Causality of SAE ............................................................................................................................................................ 36 
VII.2.3 - Reporting of serious adverse events ........................................................................................................................... 37 
VII.2.4 - Follow-up of serious adverse events ........................................................................................................................... 37 
VII.2.5 - Serious adverse events occurring after administration of the study medicine ...................................................... 38 
VII.2.6 - Reporting of pregnancy ................................................................................................................................................. 38 
VIII - DATA HANDLING ............................................................................................................................ 38 
VIII.1 - CASE REPORT FORM (E-CRF) ............................................................................................................................ 38 
VIII.2 - DATA MANAGEMENT ............................................................................................................................................ 39 
VIII.3 - STUDY COMMITTEES ........................................................................................................................................... 39 
VIII.3.1 - Steering committee ....................................................................................................................................................... 39 
VIII.3.2 - Data safety monitoring board ...................................................................................................................................... 39 
VIII.3.3 - Central imaging review ................................................................................................................................................. 39 
VIII.3.4 - translational research committee ................................................................................................................................ 39 
IX - STATISTICAL ANALYSES ................................................................................................................... 40 
IX.1 - SAMPLE SIZE ......................................................................................................................................................... 40 
IX.2 - STATISTICAL ANALYSIS PLAN ................................................................................................................................ 41 
IX.2.1 - Population sets ................................................................................................................................................................ 41 
IX.2.2 - Demographic and baseline characteristics .................................................................................................................. 41 
IX.2.3 - Primary endpoint analysis .............................................................................................................................................. 41 
IX.2.4 - Secondary endpoint analyses ....................................................................................................................................... 42 
IX.3 - HANDLING OF MISSING OR INVALID DATA .............................................................................................................. 42 
X - QUALITY CONTROL / MONITORING ..................................................................................................... 43 
XI - CONFIDENTIALITY ............................................................................................................................ 43 
XI.1 - RESPONSIBILITIES ................................................................................................................................................. 43 


 
 
 
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XI.1.1 - Sponsor’s responsibilities .............................................................................................................................................. 43 
XI.1.2 - Responsibilities of the investigator ............................................................................................................................... 43 
XI.2 - PERSONAL DATA PROTECTION AND CONFIDENTIALITY ......................................................................................... 44 
XI.3 - STUDY DOCUMENTATION ARCHIVING .................................................................................................................... 44 
XII - REGULATORY AND ETHICAL ASPECTS ............................................................................................. 44 
XII.1 - PATIENT INFORMATION AND CONSENT FORMS .................................................................................................... 44 
XII.2 - ACCESS TO SOURCE DATA ................................................................................................................................... 45 
XII.3 - STUDY CONDUCT .................................................................................................................................................. 45 
XII.4 - ETHICS COMMITTEES AND COMPETENT AUTHORITIES ......................................................................................... 45 
XII.5 - AMENDMENTS ....................................................................................................................................................... 45 
XII.6 - AUDIT AND INSPECTION ........................................................................................................................................ 45 
XIII - PUBLICATION OF DATA ................................................................................................................... 46 
XIV - RULES OF PUBLICATION ................................................................................................................. 46 
XV - RATIONALE OF THE STUDY .............................................................................................................. 46 
XV.1 - BACKGROUND ...................................................................................................................................................... 46 
XV.1.1 - Context ............................................................................................................................................................................ 46 
XV.1.2 - Study treatment .............................................................................................................................................................. 47 
XV.2 - RATIONALE OF THE STUDY ................................................................................................................................... 48 
XV.3 - RATIONALE FOR DOSE SELECTION ....................................................................................................................... 48 
XV.4 - REFERENCES ......................................................................................................................................................... 48 
XVI - APPENDICES .............................................................................................................................. 51 
XVI.1 - CLASSIFICATION OF NETS - WHO 2010 ........................................................................................................... 51 
XVI.2 - WHO INDEX ........................................................................................................................................................ 51 
XVI.3 - RECIST CRITERIA VERSION 1.1 ......................................................................................................................... 51 
XVI.4 - NCI-CTC AE CRITERIA VERSION 4.0 ................................................................................................................. 51 
XVI.5 - HELSINKI DECLARATION ...................................................................................................................................... 51 
XVI.6 - MANAGEMENT OF SAMPLES FOR TRANSLATIONAL BIOLOGICAL STUDIES ........................................................... 51 
XVI.7 - RADIOLOGICAL RECOMMENDATIONS .................................................................................................................. 51 
XVI.8 - RECOMMENDATIONS ON THE DRAFTING OF ANATOMIC PATHOLOGY REPORTS - MINIMUM INFORMATION THAT 
MUST APPEAR IN THE REPORT ........................................................................................................................................ 51 
APPENDIX 1: CLASSIFICATION OF DIGESTIVE NETS - WHO 2010 [RINDI 2010]. ................................................... 52 
APPENDIX 2: WHO PERFORMANCE STATUS ............................................................................................................. 53 
APPENDIX 3: RECIST CRITERIA VERSION 1.1 .......................................................................................................... 54 
APPENDIX 4: NCI-CTC AE CRITERIA VERSION 4.0 .................................................................................................. 57 
APPENDIX 5: HELSINKI DECLARATION ....................................................................................................................... 58 


 
 
 
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APPENDIX 6: BLOOD SAMPLE COLLECTION AND HANDLING FOR BIOLOGICAL TRANSLATIONAL STUDIES .............. 59 
APPENDIX 7: RADIOLOGICAL RECOMMENDATIONS ................................................................................................... 67 
APPENDIX 8: RECOMMENDATIONS FOR THE ANATOMOPATHOLOGICAL REPORTS - MINIMUM INFORMATION THAT 
MUST APPEAR IN THE REPORT ....................................................................................................................................... 68 


 
 
 
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L I S T  O F  A B B R E V I A T I O N S  
 
ALT 
ALanine-aminoTransferase 
ALP 
ALkaline Phosphatase 
AST 
ASpartate-aminoTransferase 
BRC 
Biological Research Centre 
CA 
Competent Authority 
CgA 
Chromogranin A 
CM 
Contrast Medium 
CRA 
Clinical Research Associate 
(e)CRF 
(electronic) Case Report Form 
EC 
Ethics Committee  
ENETS 
European NeuroEndocrine Tumor Society 
FFCD 
Fédération Francophone de Cancérologie Digestive (French 
Federation of Digestive Cancerology) 
GCP 
Good Clinical Practices 
GGT 
Gamma-Glutamyl Transferase 
HbA1c 
Glycated haemoglobin 
HDL 
High Density Lipoprotein 
HR 
Hazard Ratio 
ICH 
International Conference for Harmonisation 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase  
MRI 
Magnetic Resonance Imaging 
NCI- CTC 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NET 
NeuroEndocrine Tumour 
OS 
Overall Survival 
PFLYG 
Progression-Free Life-Year Gained 
PFS 
Progression-Free Survival 
PP 
Per Protocol 
PPI 
Proton Pump Inhibitor 
PR 
Prothrombin Ratio 
QAPFLYG Quality-Adjusted Progression-Free Life-Year Gained 
RECIST 
Response Evaluation Criteria In Solid Tumours  


 
 
 
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SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SP 
Safety Population 
TDM 
Tomodensitometry 
TNCD 
Thésaurus National de Cancérologie Digestive 
TSH 
Thyroid Stimulating Hormone 
WHO 
World Health Organisation 
 


 
 
 
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I -  OBJECTIVES: 
I.1 -  PRIMARY OBJECTIVE 
The primary objective of phase II is to evaluate the rate of patients alive and progression free at 6 
months, assessed by the investigator according to RECIST criteria, version 1.1 (Appendix 3). 
The primary objective of phase III is to assess and compare the Progression Free Survival (PFS) of 
lanreotide versus placebo according to RECIST criteria (version 1.1, Appendix 3), assessed by the 
investigator. 
  
I.2 -  SECONDARY OBJECTIVES 
 
Rate of patients alive and progression free at 12 months, assessed by the investigator 
according to RECIST criteria (version 1.1) 
 
Rate of patients alive and progression free at 6 months, according to central review 
 
Safety 
 
Response rate at 6 months according to RECIST criteria (version 1.1) 
 
Time To Progression (TTP) 
 
Quality of life assessed with the questionnaire QLQ-C30, including module NET 21, and the 
Spitzer visual analogue scale. 
The secondary objectives of phase III are: 
 
Overall Survival (OS) at 3 and 5 years 
 
PFS according to central review 
 
Safety 
 
Response rate at 6 months according to RECIST criteria (version 1.1) 
 
Chemotherapy / biotherapy-free time interval  
 
Quality of life assessed with the questionnaire QLQ-C30, including module NET 21, and the 
Spitzer visual analogue scale. 
 
Medico-economical evaluation: cost-effectiveness analysis at 12 months and cost-utility 
analysis at 18 months (using EQ-5D questionnaire).  
 
I.3 -  OBJECTIVES OF TRANSLATIONAL STUDIES 
I.3.1 -  RESEARCH ON BIOMARKERS 
The objective of the biological translational research project associated with this clinical study is to 
evaluate the prognostic and predictive value of the parameters collected during the analysis of 
tumour tissues and blood samples. This project will mainly allow the determination of morphological 
and molecular factors of grade G1 or G2 well-differentiated duodeno-pancreatic neuroendocrine 
tumours. Further details on the sampling time and types of samples to be collected are provided in 
chapter V.6 and Appendix 6. 
 
I.3.2 -  MEDICO-ECONOMICAL EVALUATION  
The objectives will be: 
At 12 months: 
 
To evaluate the cost-effectiveness ratio associated with treatment with lanreotide versus 
placebo. It will be expressed in terms of cost per progression-free life year gained (PFLYG) 
 
To compare the average cost and average effectiveness associated with lanreotide versus 
placebo  


 
 
 
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At 18 months:  
 
To evaluate the cost-effectiveness ratio, expressed in terms of cost per PFLYG 
 
To evaluate the cost-utility ratio associated with treatment by lanreotide versus placebo. It 
will be expressed in terms of cost per progression-free life year gained adjusted for quality of 
life (QAPFLYG), using the EQ-5D questionnaire. 
 
To compare the average cost and average utility associated with lanreotide versus placebo  
 
To evaluate the share of the different items of expenditure in the total cost of patients’ care 
management at 18 months. 
II -  OVERVIEW OF THE STUD Y DESIGN 
This is a European, prospective, multicentre, double-blind randomised study evaluating lanreotide 
(120 mg every 28 days until disease progression) versus placebo in patients with metastatic/locally 
advanced, non-resectable, duodeno-pancreatic neuroendocrine tumours, stabilised or in objective 
response after the first line of treatment. 
Depending on the phase II results, the study may be continued into phase III; the treatment and 
follow-up of patients will be the same in phase II and phase III. 
Patients in phase II will be included in phase III. 
Patients will be randomised with a 1:1 ratio, to receive either lanreotide or the placebo after the first 
line of treatment.  
Randomisation will be conducted using a minimisation technique and stratified according to the 
following parameters: 
 
Centre 
 
Grade 1 versus grade 2  
 
First-line treatment: chemotherapy  vs. biotherapy (everolimus or sunitinib) 
The randomisation will be conducted via an Interactive Web Response System (see chapter IV.8.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Figure 1: Study design 
 
 
 
 
III -  STUDY POPULATION  
III.1 -  ELIGIBILITY CRITERIA 
III.1.1 -  INCLUSION CRITERIA 
 
Metastatic (synchronous or metachronous) or locally advanced, non-resectable, well-
differentiated duodeno-pancreatic neuroendocrine tumour, of grade 1 or 2 (WHO 2010 
classification; Ki-67 ≤ 20%; Appendix 1) 
 
Progressive before first-line treatment 
 
Histologically confirmed (either on primary tumour or metastases) 
 
Pathological diagnosis validated by the NET consulting pathologist 
 
Documented stable disease or objective response after first-line treatment, within 4 weeks 
(28 days) prior to randomisation 
 
The first-line treatment will consist of either a chemotherapy or biotherapy (everolimus or 
sunitinib) as referred to TNCD or ENETS guidelines. Treatment must have been 
administered for 3 to 6 months for chemotherapy and for 6 months for biotherapy 
 
Non-functional tumour or gastrinoma controlled by PPIs 
 
Age   18 years 
 
WHO 0, 1 or 2 (Appendix 2) 
 
Effective contraception for male or female patients of childbearing age, defined as: oral 
contraceptives, intra-uterine devices, barrier contraceptive methods along with a spermicide 
gel, or surgical sterilisation. Female patients should use this contraception throughout the 
treatment period and for 6 months after the last treatment administration. Male patients 
should use contraception throughout the treatment period and for 3 months after the last 
treatment administration. 
 
Signed informed consent prior to initiation of any study-specific procedures or treatment. 
 Patients who are progressing slowly 
should not be included; disease should 
present a progression within maximum 
12 months after diagnosis. 
 


 
 
 
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III.1.2 -  NON-INCLUSION CRITERIA 
 
History of haematological malignancy or other cancer, except those treated for more than 5 
years and considered as cured, carcinoma in situ of the cervix and treated skin cancer 
(excluding melanoma) 
 
Poorly differentiated neuroendocrine carcinoma or NET grade 3 ENETS (Ki-67 > 20%) 
 
If primary resected, bone metastasis exclusively  
 
Pre-treatment by somatostatin long-acting analogue  
 
Total bilirubin ≥ 60 µmol/L 
 
Uncontrolled diabetes 
 
Contraindication to product used in the study or its components 
 
Tumour arising in the context of a genetic disease 
 
Pregnancy or lactation 
 
Patients unable to undergo medical follow-up due to geographical, social, psychological or 
legal reasons 
 
Concomitant participation in another clinical trial investigating a treatment during the 
treatment phase and within 30 days prior to the start of the study treatment 
 
Employment of the subject or a close relative (i.e. spouse/partner, child, parent or sibling) by 
the CRO, the study site 
 
Patients deprived of their liberty by a judicial or administrative decision, patients admitted to 
a hospital, social institution or who are under a measure of legal protection, patients 
hospitalized without consent or who are in an emergency situation. 
 
III.2 -  STUDY DURATION FOR EACH PATIENT 
The start of the study is defined when the first patient has provided a signed informed consent. The 
end of the study is defined as the last follow-up visit of the last patient. 
This is a phase II/III study; therefore, the total duration is described for the two parts. 
The overall study duration for phase II study will be approximately 3.5 years. The inclusion period is 
estimated at 30 months, and the last randomised patient will have a minimum follow-up period of 12 
months. 
For patients in phase II, the minimum follow-up period will be 12 months; however, if the study 
proceeds to phase III, these patients will participate in phase III and will continue the follow-up 
during phase III of the study. 
The overall duration of phase III will be approximately 6 years. The estimated inclusion period is 12 
months, and the last randomised patient will have a minimum follow-up period of 5 years. 
For each patient, the study treatment (lanreotide or placebo) will be provided by the sponsor in a 
double-blind procedure until disease progression or toxicity, according to the protocol.  
 
III.3 -  PATIENT IDENTIFICATION  
Patients will be identified by their randomisation number. For more security, on important 
documents such as case report forms (CRF), SAE declaration forms and biological samples, the 
patients will be identified by this number, their initials and their date of birth. 
For phase II, recruitment will be stopped when 59 patients have been randomised in each arm, and 
for phase III, when 52 additional patients have been randomised in each arm.  


 
 
 
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III.4 -  PREMATURE STUDY DISCONTINUATION 
III.4.1 -  DEFINITIVE STUDY TREATMENT DISCONTINUATION  
Patients may stop the study treatment in the following cases: 
 
Treatment-limiting toxicity that means any toxicity of grade 3 or more, that cannot be treated 
with the usual drugs and which prevent the study treatment to be administered 
 
Disease progression  
 
Investigator's decision  
 
Patient's decision 
 
Pregnancy 
 
Administration of a cancer therapy other than the study treatment. 
 
As long as the patients have not withdrawn their consent, they will be followed according to the 
protocol. 
Patients should be treated only if the potential risks and inconveniences are medically justifiable, 
compared with the benefit for the patient. 
 
III.4.2 -  DEFINITIVE STUDY DISCONTINUATION FOR A PATIENT 
Patients may drop out of the study in case of informed consent withdrawal; in this case, no data 
relating to these patients will be used. 
No medical criteria could induce an individual patient’s premature study termination; if a patient 
stops study treatment, he will continue to be followed up according to the protocol. 
 
III.4.3 -  III.4.3 - DEFINITIVE STUDY DISCONTINUATION  
The study may be stopped prematurely by the sponsor, based on the independent data monitoring 
committee’s review, if it is considered that the benefit/risk balance is no longer in favor for the 
patients (in regard with the study data or new data available coming from other studies). 
The study could also be stopped upon Health Authorities or Ethic Committees request. 
 
IV -  S T U D Y  T R E A T M E N T S   
IV.1 -  STUDY TREATMENT PRESENTATION 
Given that lanreotide and the placebo will have different colour and aspect, and in order to maintain 
the double-blind status of the study, an independent qualified person designated by the investigator 
will prepare and carry out the injections. 
 
The provided study treatment will only be used for the purpose defined in this protocol. 
 
The Investigational Medicinal Products used in this study (lanreotide, placebo) will be provided by 
Beaufour IPSEN Industry in the following presentations: 
 
Lanreotide Autogel 120 mg: 


 
 
 
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This treatment is similar to the commercialised form available in France under the name 
SOMATULINE® LP 120 mg, apart from tertiary packaging and labelling. 
Treatment will be provided in a pre-filled syringe of 0.5 mL with a 20 mm needle of 1.2 mm external 
diameter, sealed in a laminated bag and in a cardboard box. Each pre-filled syringe has an 
automatic security system. 
Each 0.5 mL syringe contains a supersaturated acetate solution of lanreotide corresponding to 
0.246 mg of lanreotide base/mg of solution, for subcutaneous injection of a 120 mg dose of 
lanreotide. 
The lanreotide is to be stored at the recommended temperature: between +2°C and +8°C. 
The instructions regarding the product injection will be provided in a leaflet accompanying each 
batch. 
 
Placebo: 
The placebo injection will consist of a 0.9% saline solution provided as follows: 
 
A 2 mL ampoule containing 1 mL of NaCl at 0.9%  
 
An empty syringe of 0.5 ml with an automatic security system and a 20 mm needle of 
1.2 mm external diameter and 1.0 mm internal diameter sealed in a laminate bag. 
 
The placebo is to be stored at the recommended temperature: between +2°C and +8°C. 
The instructions regarding the subcutaneous product injection will be provided in a leaflet 
accompanying each batch. 
 
Both products will be provided by the logistics department of CMC&E, Beaufour IPSEN Industry, 20 
rue Ethe Virton, 28100 Dreux (France), and delivered to the study sites. 
  
The study treatment must be initiated after randomisation, within the 6 weeks following the 
confirmation date of stable disease or objective response. 
Once the randomisation has been performed, the patients will receive a single dose every 4 weeks 
(every 28 days). 
 
IV.2 -  PACKAGING AND LABELLING OF STUDY TREATMENTS  
The study treatments will be packaged by Beaufour IPSEN Industry (Dreux) and delivered to the 
study sites. 
 
Two syringes of lanreotide 120 mg and 2 syringes of the placebo will be provided after the initiation 
of the study site. 
 
Other shipments will be made according to the progress of randomisation and the inventory log 
provided by the study site. 
  
The laminated bag and the box containing the syringe will both be labelled; the labelling will be in 
compliance with national requirements and the Good Manufacturing Practices in Appendix 13. For 
both treatment arms (placebo and lanreotide), the syringe label will indicate “lanreotide 120 mg”.  
 
The study treatments will be packaged by the logistics department of CMC&E (Beaufour IPSEN 
Industry, 20 rue Ethe Virton, 28100 Dreux, France); a sufficient quantity of the study treatment will 
be delivered to the study sites. The shipment will contain an acknowledgement of receipt form. 
 


 
 
 
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The text of the labels of all packages will be translated or adapted in accordance with the applicable 
regulatory requirements, the applicable national laws, and according to the local language of the 
country.  
A description of the label text of the study treatment is presented below: 
 
Study number and EudraCT number 
 
Pharmaceutical form 
 
Route of administration 
 
Quantity of dose units 
 
Batch number 
 
Empty space for the patient number 
 
“For clinical trial use only” 
 
Name, address and telephone number of sponsor 
 
Storage instructions 
 
Expiry date 
 
The study treatment should only be administered to patients included in this study. Dispensation to 
each patient will be documented in the case report form. 
 
IV.3 -  COMPLIANCE  
The independent qualified person designated by the investigator must, without being seen, open the 
laminated bag and fill the empty syringe with the 0.9% NaCl solution (for patients assigned to the 
placebo arm) or the lanreotide solution (for patients assigned to the lanreotide arm) in order to 
administer the same volume as for the active treatment. The procedures for administering the 
placebo and lanreotide are indicated in the product leaflet accompanying each batch.  
The compliance will be assessed by recording each study treatment administration in the case 
report form and on the treatment accountability/dispensing logs. 
Any study treatment administration issues should be explained in the case report form. 
 
IV.4 -  STUDY TREATMENT STORAGE  
The investigator, or the designee (for example a pharmacist), will ensure that study treatments are 
stored in a safe place, under the controlled storage conditions, at the recommended temperature 
(between +2°C and +8°C), in compliance with the applicable regulatory requirements, and that they 
are dispensed by a qualified and independent person. 
 
IV.5 -  ACCOUNTABILITY AND DESTRUCTION 
The independent qualified person (who is not blind to the process) designated by the investigator 
will administer the study treatment to the included patients. Each patient will receive the treatment 
bearing their number only. Distribution to each patient will be documented in the case report form. 
All study treatments must be recorded on the study treatment batch accountability forms provided 
by the sponsor or its representative. It is essential that all unused batches are kept for verification 
(by the sponsor or its representative). The investigator, or designee, must ensure the input of the 
correct information on the study treatment batch accountability forms. 
All unused packs will be destroyed at the study site, and a copy of the certificate of destruction must 
be sent to the sponsor. 
 
IV.6 -  CONCOMITANT MEDICATION / THERAPY 


 
 
 
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The following concomitant medications are not allowed during this study:  
- Any tumour treatments, 
- Somatostatin analogues other than the study treatment.  
 
IV.7 -  STUDY TREATMENT OVERDOSE MANAGEMENT  
In case of an overdose of the study treatment, all required medical care will be determined by the 
investigator according to the characteristics of potential events, and recorded in the patient case 
report form.  
All overdoses should be considered as SAEs and should therefore be reported on the SAE 
declaration form. 
 
IV.8 -  STUDY TREATMENT ALLOCATION 
All patients included must be identifiable throughout the study. The investigator will keep a list of 
patient numbers and names so that any information can be retrieved if necessary. 
After confirmation of their eligibility in the study, patients will receive a randomisation / treatment 
allocation number and will be assigned to one of the treatment arms. 
 
IV.8.1 -  RANDOMISATION 
Patients will be given a randomisation / treatment arm number according to their order of entry into 
the study by an Interactive Web Response System (IWRS). The IWRS will manage the link between 
the treatment number and the randomisation number. This system offers a 24/7 service (further 
details are set out in the IWRS guide, provided to each centre). The IWRS also manages all logistic 
aspects of the treatments and the management of incidents (replacement of treatment, quarantine, 
resupply of treatment batches, expiry dates, etc.). For any questions of a medical or technical 
nature, a 24-hour hotline will be made available - see further information in the investigator's file.  
 
The randomisation will be conducted according to the technique of minimisation; treatments will be 
randomised in a 1:1 ratio, stratified according to the following criteria: 
 
Centre 
 
Grade 1 versus grade 2  
 
First-line treatment: chemotherapy  vs. biotherapy (everolimus or sunitinib)  
 
IV.8.2 -  BLINDING AND BREAKING THE BLIND 
In order to guarantee blinding of the investigator and all the staff participating in the evaluation or 
the recording of the results of the treatment, all injections carried out during the double-blind phase 
must be administered at the site by a person who is specifically trained and qualified (for example, a 
nurse), otherwise not involved in the study procedures. This person will have to ensure that this 
blindness is maintained with respect to the patients.  
Lanreotide and the placebo are not identical: lanreotide is a viscous formulation that will be supplied 
in a pre-filled syringe; the placebo is a solution that will not be provided in a pre-filled syringe. As a 
result, the person carrying out the injection will fill the syringe with the placebo solution out of the 
patient's view. In addition, both lanreotide and the placebo will be administered in the currently-
approved injection site, in the superior external quadrant of the buttock, in order to limit the patient's 
view of the injection. At each cycle, the injection site will be alternated between the left and right 
side of the body. 
 


 
 
 
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The patients, investigators, site staff, persons performing the assessments and the CRAs will 
remain blind to the process and will not have access to the identity of the treatment allocated to the 
patients (lanreotide or placebo), from the date of randomisation until the final database lock of 
phase III of the study.  
The blinding will be broken for the staff responsible for the statistical analysis at the end of phase II 
of the study, when the database will be locked for the data analysis of this phase. Individual patient 
data (with decoded treatment) will not be communicated to investigators or any other persons 
involved in the conduct of the study, in order to guarantee the absence of any bias during the long-
term survival follow-up, until the end of phase III of the study.  
To guarantee that blinding is maintained, the following methods will be applied:  
• 
 The randomisation code will be kept in the strictest confidentiality until the unblinding and 
will not be accessible to any person involved in the conduct of the study.  
• 
The identity of the treatment (lanreotide or placebo) will be hidden on the packaging and 
the label.   
  
The study randomisation code should not be broken, except in the case of a medical emergency, if 
the knowledge of the study treatment received may influence the medical care of the patient. 
 
In these medical emergency cases, the investigator may break the blind using the IWRS system.  
The date and reason for unblinding must be detailed on the IWRS and on the case report form.  
 
 
The sponsor reserves the right to break the blind for SAEs that are considered to be related to the 
study treatment and unexpected, which could therefore require expedited reporting to the regulatory 
authorities. 
 
 
IV.9 -  TREATMENT DURATION 
For each patient, the investigational products (lanreotide or placebo) will be provided according to a 
double blind procedure until disease progression or toxicity, according to the protocol.  
V -  SCHEDULE OF ASSESSME NTS  
V.1 -  STUDY SCHEDULE 
The schedule of observations and assessments conducted during the study is set out in the 
flowchart at the start of the protocol (page 8). It will be the same for phases II and III. 
 
V.2 -  INCLUSION/RANDOMISATION  
The following assessments will be performed before any administration of the study treatment: 
 
Verification of eligibility (criteria for inclusion/non-inclusion) 
 
Medical history, physical examination (blood pressure and heart rate, body temperature and 
weight) 
 
WHO performance index 
 
Serum pregnancy test (for patients of childbearing age) 
 
Chest, abdomen and pelvis CT scan with early arterial timing or abdominal and pelvic MRI + 
chest CT scan with injection of iodised contrast medium (CM). In the event of a 
contraindication to the use of a CM, abdominal and pelvic MRI + chest CT scan without 
injection (see Appendix 7, describing methods for acquisition) 
 
Haematology (haemoglobin, leukocytes, platelets) 


 
 
 
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 
Biochemistry: electrolytes, PR, liver tests (ALT, AST, ALP, GGT, total and conjugated 
bilirubin), albumin, LDH, TSH, HbA1c, total and HDL-cholesterols, triglycerides 
 
Chromogranin A; the method used to measure serum CgA in the study should always be the 
same as at inclusion 
 
Ki-67 index 
 
Evaluation of quality of life (QLQ-C30 + NET 21) 
 
Questionnaire EQ-5D including the Spitzer scale, which will be used to estimate the utility 
scores at inclusion and for the cost-utility evaluation at 18 months 
 
Randomisation  
 
Tumour tissue slides from archived samples (sample of primary tumour or metastases) for 
patient participating in the translational research  
 
If a patient participates in the translational research, a blood sample must be taken while 
fasting at the same time as the aforementioned blood tests. The plasma must be stored at 
−80°C at the site: central assessments of biomarkers (see chapter V.6 and Appendix 6). 
 
V.3 -  TREATMENT PERIOD 
During the treatment period, the following assessments must be performed until disease 
progression and according to the schedule indicated on page 8 (Table 1): 
 
Every 4 weeks, prior to injection: 
 
Physical examination  
 
WHO performance index 
 
Assessments of adverse events according to classification NCI CTC V4.0 (Appendix 4) 
 
Every 3 months:  
 
Physical examination  
 
WHO performance index  
 
Haematology (haemoglobin, leukocytes, platelets) 
 
Biochemistry: electrolytes, PR, liver function tests (ALT, AST, ALP, GGT, total and 
conjugated bilirubin), albumin, LDH, HbA1c 
 
Chromogranin A; the method used for the measurement of serum CgA under the study 
should always be the same as the one used at inclusion 
 
Chest, abdomen and pelvis CT scan with early arterial timing or abdominal and pelvic MRI + 
chest CT scan with injection of iodised contrast medium (CM). In case of contraindication to 
use of a CM, abdominal and pelvic MRI + chest CT scan without injection (see Appendix 7, 
describing methods for acquisition). It is necessary to use the same evaluation method as 
the one used at inclusion 
 
Brain or bone CT scan or MRI in case of clinical signs/symptoms of disease 
 
Evaluation of quality of life: QLQ-C30, specifically module NET 21 and the Spitzer visual 
analogue scale 
 
Questionnaire EQ-5D including the Spitzer visual analogue scale  
 
If a patient participates in the translational research, a blood sample must be taken while 
fasting at the same time as the aforementioned blood tests. The plasma must be conserved 
at −80°C at the site: central assessments of biomarkers (see chapter V.6 and Appendix 6). 
 
This quarterly follow-up will be stopped if there is a radiological progression.  
 
In case of progression, the patient may proceed to another treatment. Patient follow-up will then be 
biannually. 
 


 
 
 
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V.4 -  END-OF-TREATMENT VISIT 
The end-of-treatment visit should take place 30 days after administration of the last dose of the 
study treatment. 
The main objective is to document adverse events associated with the last administration; this visit 
will include: 
 
Physical examination  
 
WHO performance index  
 
Assessment of adverse events according to classification NCI CTC V4.0. 
 
V.5 -  FOLLOW-UP 
If treatment is stopped due to disease progression, a visit every 6 months will be scheduled to 
record the patient’s status and further treatment lines. 
If treatment is stopped for any other reason, quarterly visits will be maintained until disease 
progression (same assessments as above). Thereafter, patients will be followed-up every 6 months. 
Questionnaire EQ-5D (including the Spitzer visual analogue scale) will be filled out for each patient, 
every 3 months and until 18 months after randomisation; this will be accompanied by the WHO 
performance index. 
If a patient is unable to return to the site for a follow-up visit, the patient or primary physician will be 
contacted by telephone in order to collect these data. 
For patients in phase II, the minimum follow-up period will be 12 months; however, if the study 
proceeds to phase III, these patients will continue to be followed-up for a maximum of 10 years 
(end-of-phase-III study). Patients in phase III will have a minimum follow-up period of 5 years. 
 
 
V.6 -  ASSESSMENTS AND PROCEDURES FOR THE BIOMARKERS TRANSLATIONAL 
RESEARCH  
The objective of the biomarkers translational research associated with this clinical study will be to 
test the prognostic and predictive value of the parameters collected through the analysis of tumour 
slides and blood samples.  
This project will mainly help to determine morphological, genetic, protein and lipid characteristics of 
well-differentiated grade G1 or G2 duodeno-pancreatic neuroendocrine tumours.  
The sampling for biological translational research in each site is subject to two conditions:  
 
The approval of the establishment's ethics committee / the ethics committee (CEE/CE) 
(where applicable) and  
 
The written informed consent of the patient.  
 
V.6.1 -  TUMOUR TISSUE SLIDES 
The tumour tissue samples are only to be used for patients consenting to the translational research 
on biomarkers. Patients may refuse the storage and use of their tissue samples for translational 
research projects; however, this will not exclude them from the main study. 
Tumour tissue samples from the primary tumour or metastases will be collected at baseline and 
sent to the pathological laboratory of Prof. Jean-Yves Scoazec, at the following address: 
Professor Jean-Yves SCOAZEC  


 
 
 
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Service de Pathologie 
Département de Biopathologie 
Gustave Roussy  
114 Rue Édouard Vaillant,  
94805 Villejuif - FRANCE 
The tumour samples will be stored under his responsibility for 30 years. 
The study requires 10 to 15 tissue slices of 5 µm thick, on slides adapted to immunohistochemistry 
and hybridisation in situ in fluorescence (FISH) (no less than 5 slides for biopsy samples).  
V.6.2 -  BLOOD SAMPLES 
Blood samples will only be taken from patients consenting to biomarkers translational research. 
Patients may refuse the collection, storage and use of their blood sample for biomarker projects; 
however, this does not exclude them from the main study.  
Blood samples will be stored at the Biological Resource Centre (Centre de Ressources Biologiques) 
of Prof. Pierre Laurent-Puig, located in Paris (Laboratoire de Toxicologie moléculaire – 45, rue des 
Saints-Pères – 75006 Paris - FRANCE), for 30 years. 
On these samples, several analyses will be performed, particularly on lipids, proteins, RNA, 
microRNA, and DNA. 
If the patient consents, blood samples will be collected at baseline, at 3 months and after 
progression (before the start of the next treatment). The sample will be taken while fasting at the 
same time as the blood samples for the main study. The patient should be fasting the day before so 
that the lipid analyses can be used; if not, please note the time of the last meal on the sampling 
form. 
An EDTA tube of 10 mL of blood will be taken. These blood samples will be managed by the site 
staff; plasma will be separated from the buffy coat and red blood cells. All the three components 
obtained will be aliquoted and stored at the site, at −80°C. The shipment of the samples will be 
organised: one during the study and one at the end of the study. Further details are provided in 
Appendix 6.  
VI -  ENDPOINTS 
VI.1 -  PRIMARY ENDPOINT 
The primary endpoint for phase II is the rate of patients alive and progression free at 6 months, 
evaluated according to the results of imaging assessment done 6 months after the randomisation. 
This evaluation will be done by the investigator according to RECIST criteria (version 1.1, Appendix 
3). 
The primary endpoint for phase III is progression free survival, considering the first radiological 
progression of the patient (investigator’s opinion) or death (any reason). The time will be calculated 
between the randomisation date and the date the first event occurred. Patients who are alive and 
progression free will be censored at the time of the last news or cut-off date (the date the first of 
these occurs will be considered). 
 
VI.2 -  SECONDARY ENDPOINTS  
The secondary endpoints of phase II are the following:  
 
Rate of patients alive and progression free at 12 months (according to RECIST criteria 
version 1.1), assessed by the investigator 


 
 
 
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 
Rate of patients alive and progression free at 6 months, according to central review  
 
Safety: the toxicities will be described using the NCI-CTC AE version 4.0 (Appendix 4) 
 
Response rate according to RECIST criteria at 6 months (version 1.1), according to the 
investigator. Response rate will be defined as complete or partial response to the treatment 
 
Time to progression (median). This endpoint will be calculated from the randomisation date 
to the date of the first progression (clinical and radiological) according to the investigator 
 
Quality of life (QLQ-C30 including module NET 21, the Spitzer visual analogue scale) will be 
described at each time-point. 
The secondary endpoints of phase III will consist of the comparison between the placebo and the 
lanreotide, on: 
 
Overall survival (OS) at 3 and 5 years. This endpoint will be estimated considering all deaths 
and the time will be calculated from the randomisation date to the date of death. Patients 
alive will be censored at the date of the last news or at the cut-off date 
 
PFS according to central review, evaluated considering the first radiological progression of 
the patient (central review) or death (any reason). The time will be calculated from the 
randomisation date to the date the first event occurred. Patients alive and progression free 
will be censored at the date of the last news or at the cut-off date (the date the first of these 
occurs will be considered). 
 
Safety: the toxicities will be described using the NCI-CTC AE version 4.0 (Appendix 4) 
 
Response rate at 6 months according to RECIST criteria (version 1.1). Response rate will be 
defined as complete or partial response to the treatment 
 
Chemotherapy/biotherapy-free time interval: the time will be calculated from the last 
chemotherapy/biotherapy (first-line treatment) administration, to the date of restart of first-
line treatment or to the start of a new line (second-line treatment).  
 
Quality of life (QLQ-C30 including module NET 21, the Spitzer visual analogue scale) will be 
described at each time-point 
 
Average cost at 12 and 18 months  
 
Effectiveness average at 12 and 18 months and utility index score average at 18 months 
using EQ-5D questionnaire. 
 
Efficiency: 
- At 12 months; cost per progression free life year gained (PFLYG) 
- At 18 months: cost per PFLYG and cost per PFLYG adjusted for quality of life (QAPFLYG). 
 
VII -  PHARM ACOVIGILANCE  
VII.1 -  ADVERSE EVENT 
VII.1.1 -  DEFINITIONS 
ADVERSE EVENT (AE)  
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. In clinical studies, an AE may be an undesirable medical condition occurring at any 
time, including run-in or wash-out periods, even if no experimental treatment has been 
administered.  
ADVERSE DRUG REACTION  
An adverse drug reaction is any untoward and unintended response to an investigational medicinal 
product related to any dose administered. 


 
 
 
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UNEXPECTED ADVERSE DRUG REACTION  
Any adverse drug reaction the nature, severity or outcome of which is not described in the 
applicable product information. 
In this study, the reference document to be used to evaluate the unexpectedness of the adverse 
drug reaction will be the Investigator's Brochure (most recent version).    
 
VII.1.2 -  DISEASE PROGRESSION  
In this study, the signs and symptoms corresponding to the disease progression or worsening of the 
cancer being studied should not be reported as AEs. 
The signs and symptoms of the studied cancer will be reported as AEs if they cannot be defined as 
exclusively due to the progression or worsening of the disease.   
 
VII.1.3 -  LABORATORY TEST ABNORMALITIES 
A laboratory test abnormality should only be reported as an AE under the following cases:  
- 
when it is accompanied by clinical symptoms or is considered as medically significant 
by the investigator,  
- 
when it results in a change in the study treatment schedule of administration  (delay 
in administration, temporary or definitive discontinuation, etc.), 
- 
when it requires an intervention, a change in concomitant treatments, or a diagnostic 
evaluation in order to determine the risk for the patient. 
 
VII.1.4 -  CLASSIFICATION OF INTENSITY OF AES 
AEs will be documented and graded according to the NCI-CTCAE version 4.0.  
If, for a given AE, the NCI-CTCAE scale is not applicable, the following equivalences will be applied: 
NCI-CTCAE grade 1 corresponds to a mild intensity (does not interfere with the patient's normal 
daily activities), 
NCI-CTCAE grade 2 corresponds to a moderate intensity (interferes with the patient's normal daily 
activities), 
NCI-CTCAE grade 3 corresponds to a severe intensity (prevents the patient’s normal daily 
activities), 
NCI-CTCAE grade 4 corresponds to a life-threatening event or a disability (any event exposing the 
patient to an immediate risk of death at the time of occurrence of the adverse event) 
NCI-CTCAE grade 5 corresponds to death (related to the AE). 
 
VII.1.5 -  REPORTING AND FOLLOW-UP OF ADVERSE EVENTS 
All AEs (related and unrelated, expected and unexpected) occurring in the course of the study, from 
the signature of the informed consent form and until 30 days after the last dose of the study drug, 
will be reported by the investigator. 
All AEs reported spontaneously by the patient or observed by the investigator, regardless of 
treatment arm, will be recorded on the AE page(s) of the case report form. AEs already recorded 
and described as being "ongoing" must be reviewed at each subsequent evaluation. 


 
 
 
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For all AEs, the investigator must search and obtain the necessary information both to determine  
the outcome of the AE and to assess whether it meets one of the criteria for classification as a 
serious adverse event (SAE) requiring an immediate notification to the PV Department of ICTA 
PM. 
VII.2 -  SERIOUS ADVERSE EVENT 
VII.2.1 -  DEFINITIONS  
 
SERIOUS ADVERSE EVENT (SAE) 
Any harmful clinical manifestation that, at any dose, fulfils at least one of the following criteria: 
- 
is fatal (leads to death ; NOTE : death is an outcome, not an event), 
- 
is life-threatening (NOTE : a "life-threatening event" refers to an event in which the 
patient was at risk of death at the time of the event), 
- 
requires hospitalization or prolongation of existing hospitalization, 
- 
results in persistent or significant disability or incapacity*, 
- 
is defined as a congenital anomaly or a birth defect, 
- 
is a medically significant event.   
 
*The terms "disability" and “incapacity” mean any temporary or permanent physical or mental disability 
clinically significant which affects the physical activity and/or quality of life of the patient. 
 
Is considered medically significant any clinical event or laboratory results considered as serious by 
the investigator and not corresponding to the seriousness criteria defined above. These may pose a 
risk to the patient and may require a medical intervention to prevent an outcome corresponding to 
one of the previously mentioned seriousness criteria (for example, an overdose, a second cancer, 
pregnancy or any new event which is susceptible to compromise the safety of the patients may be 
considered as medically significant). 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) 
All adverse events, considered as related to the study drug and which are both unexpected and 
serious (SUSARs) are subject to expedited reporting to the Competent Authorities (CAs) and to the 
Ethics Committees (EC), in compliance with the local regulatory requirements.  
The sponsor will be responsible for reporting the SUSARs, on the basis of the information provided 
by the investigator. 
The local regulatory requirements for expedited reporting to the CAs and EC of each involved 
country are described in the safety management plan. 
VII.2.2 -  CAUSALITY OF SAE 
The relationship of a SAE to the study drug will be classified according to the following criteria: 
Related: an event is considered as related to the study drug when a causal relationship between the 
event and the administration of the investigational product can reasonably be suspected (plausible 
time 
sequence, 
dose-effect 
relationship, 
pharmacology, 
positive 
"dechallenge" 
and/or 
"rechallenge"). 
Unrelated: an event is considered as not related to the study drug when a causal relationship 
between the event and the administration of the investigational product cannot reasonably be 


 
 
 
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suspected (implausible time sequence and/or event attributable to an intercurrent disease or to 
other medications). 
VII.2.3 -  REPORTING OF SERIOUS ADVERSE EVENTS 
All SAEs occurring during the study, from the signature of the informed consent form and until 30 
days after the last dose of the study drug, regardless of treatment arm or causality to the study drug, 
must be reported by the investigator within 24 hours from the date of the first awareness to the 
PV Department of ICTA PM by fax/email at + 800 53 40 53 40 / pharmacovigilance@icta.fr. 
Furthermore, all SAEs susceptible to be related to the study drug or to a study procedure and 
occurring during the whole study period, including the post-treatment follow-up period, must be 
notified according to the reporting procedure described above.  
The SAE report form must be signed and dated by the principal investigator or by any other 
investigator designated by the principal investigator as authorized to notify safety issues. 
All available information concerning the SAE (laboratory results, other examinations, hospitalization 
reports, autopsy report and all other relevant documents) will be transmitted anonymously with the 
SAE report form.  
Further to the notification of a SAE, additional information relative to the SAE may be requested by 
the sponsor or its representative (by fax, telephone, mail or visit). The investigator must respond to 
these requests for additional information. 
All SAEs must be documented in the patient's medical file, and the SAE report forms (initial report 
and follow-up reports) must be kept in the investigator's file. 
The full requirements of the "ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2" will be adhered to. The study will be conducted in 
compliance with all local regulatory requirements. 
Certain events will not be considered as serious. These are: 
- 
Hospitalizations for elective surgery or treatment / procedure planned before 
inclusion in the study for a pre-existing condition / disease which has not worsened 
since the beginning of the study 
- 
Hospitalizations for comfort or social reasons 
- 
Emergency hospital consultations for an outpatient (not staying in hospital overnight) 
unless they meet one of the seriousness criteria previously described  
- 
As indicated in section VII.1.2, signs and symptoms corresponding to the disease 
progression or worsening of the cancer being studied must not be reported as 
AE/SAEs. 
 
VII.2.4 -  FOLLOW-UP OF SERIOUS ADVERSE EVENTS 
For any new information concerning an SAE that has already been notified, the investigator must 
complete a new SAE report form (follow-up report) which will be sent by fax/email within 24 hours to 
the PV Department of ICTA PM at + 800 53 40 53 40 / pharmacovigilance@icta.fr, accompanied 
by anonymised copies of the corresponding laboratory results, other examinations and/or 
hospitalisation reports. 
The reporting of the SAE follow-up information will be done in the same manner as the initial SAE 
reports. 
The SAE must be followed until its resolution or stabilisation (in case of sequelae). This may lead to 
the follow-up of the patient beyond the study period. 
 


 
 
 
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VII.2.5 -  SERIOUS ADVERSE EVENTS OCCURRING AFTER ADMINISTRATION OF THE 
STUDY MEDICINE 
All SAEs occurring at any time after the end of study treatment, susceptible to be related to the 
study drug or to a study procedure, according to the investigator, must be notified according to the 
reporting procedure described above. 
 
VII.2.6 -  REPORTING OF PREGNANCY 
If a patient becomes pregnant during the treatment period of the study or within 6 months after the 
last dose of study drug, the pregnancy must be reported; if the pregnancy occurs during the 
treatment period, the study drug should be discontinued.  
If the partner of a male patient becomes pregnant during the treatment period of the study or within 
the 3 months following the last dose of study drug, this should be reported to the investigator.  
A specific informed consent will be provided to allow the collection of data concerning the follow-up 
and outcome of the pregnancy of the patient’s partner.  
Pregnancies must be reported by the investigator, like SAEs, within 24 hours of awareness.  
The reporting of pregnancy will be done according to the procedure used for the SAEs reporting. 
The sponsor or its representative must follow each pregnancy to term. 
The pregnancy outcome must be reported by the investigator, to the sponsor or its representative. 
 
 
 
VIII -  DAT A H ANDLING  
VIII.1 -  CASE REPORT FORM (E-CRF) 
The patient data will be recorded on an electronic case report form (e-CRF) provided by the FFCD 
and developed by LINCOLN. Each user of the e-CRF will be trained and will receive a training 
certificate. 
A clinical research assistant (CRA) working on behalf of FFCD will review study documents in order 
to verify compliance with the protocol and the accuracy of the data referring to source documents. 
All information requested in the e-CRF must be completed. If any piece of information is not 
available, this must be noted. 
Any correction or modification made to the e-CRF will be followed up by the e-CRF audit trail. 
Each user will have a personal and confidential access code and user name. Each data entry will be 
attributed to a user. At the end of the study, all the e-CRFs will be signed (procedure consisting of a 
new registration of user name and password) by the investigator. This procedure will certify that all 
information entered in the e-CRF concurs with the source data and reflects the patient's state during 
the corresponding part of the study.  
Throughout the centralised process of data review, corrections or changes to the e-CRF may be 
requested. In this case, requests will be included in the corresponding e-CRF. 
 


 
 
 
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VIII.2 -  DATA MANAGEMENT  
Data management will be performed by a CRO, LINCOLN.  
 
Data will be monitored at the investigator site. Patient questionnaires collected from study sites by 
the CRA will be sent by courier to the LINCOLN data entry centre. 
The sponsor will ensure that the developed e-CRF allows data entry and submission of requests 
adapted to solve all the problems of missing or contradictory data. All requests for corrections made 
during the process of cleaning the database will be conducted electronically. It is the responsibility 
of the investigator to ensure that all requests are resolved by the relevant parties. 
 
The coding of the AE, as well as medical history and concomitant medications will be conducted by 
LINCOLN, then reviewed and approved by the sponsor. The coding of concomitant medications will be 
conducted using the dictionary WHODRUG, and that of AEs / medical history with the dictionary 
MedDRA. 
 
The investigator will receive the patient information in an electronic format (PDF) which will be an 
exact copy of the e-CRF and which will include the complete audit trail, for the purposes of archiving 
and future reference.  
 
 
VIII.3 -  STUDY COMMITTEES 
VIII.3.1 -  STEERING COMMITTEE  
A steering committee will be set up, chaired by the coordinating investigator, Professor Côme 
Lepage. This committee will include Professors Thomas Walter and Michel Ducreux, a 
representative from each participating country, the president of the FFCD, the operational 
representative and the statistician of the FFCD, as well as the president of the translational research 
committee. 
 
VIII.3.2 -  DATA SAFETY MONITORING BOARD 
An independent data safety monitoring board will be established; it will include two physicians who 
are experts in neuro-endocrinology, a statistician and a pharmacovigilance expert.  
Their functions will be described in the independent committee charter.  
 
VIII.3.3 -  CENTRAL IMAGING REVIEW  
All tumour imaging assessments performed for each patient until disease progression will be 
collected for a central review. This central review will be conducted for the final analyses, by a panel 
of radiologists, via the FFCD's imaging platform.  
 
VIII.3.4 -  TRANSLATIONAL RESEARCH COMMITTEE 
A biological translational research committee will be created to deal with questions related to tumour 
and blood samples and their biobanking. This committee, during the study, will also identify the 
pertinent prognostic and predictive biological factors, as well as the relevant polymorphisms to test. 
It will organise the analyses with the selected laboratories. This committee will include the members 
of the study steering committee; its president will be Prof. Jean-Yves Scoazec (Gustave Roussy- 
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This committee will meet regularly and will report its biological translational research projects to the 
steering committee and to the sponsor. Each country participating in the steering committee will 
have a voting member; the weighting of the votes will be proportional to the contribution of the group 
or country in terms of recruitment. 
A working group will also be specifically created for the economical analysis. This group will include, 
among others, C Lejeune, K Le Malicot, Professors C Lepage, T Walter and M Ducreux.  
 
 
IX -  STATISTICAL AN ALYSES   
IX.1 -  SAMPLE SIZE 
Phase II of the study 
The hypotheses for the calculation of the sample size as follows: 
H0: A rate of patients alive and progression free at 6 months of 45% or less is not sufficient to demonstrate 
efficacy (p≤p0 with p0=45%) The study will not be continued. 
H1: A rate of patients alive and progression free at 6 months of more than 45% is sufficient to demonstrate 
efficacy. A rate of 63% is expected (p≥p1with p1 = 63%)A rate of patients alive and progression free at 6 
months of more than 45% (i.e. if the lower bound of the exact binomial 2‐sided 95% confidence interval 
exceeds 45%) leads to the study continuation. 
With a one-sided alpha risk of 5% and power of 85% (binomial-exact method), 56 patients must be 
randomised in each arm. 
With a rate of 5% of patients being non-evaluable or lost to follow-up, 59 patients will be included in 
each arm (118 patients in total). 
 
 
The following decision rule will be applied: 
If 31 patients or less are alive and progression free at 6 months or before, the treatment will be 
considered as not interesting. 
This rule will apply only to the lanreotide arm. The placebo arm will be maintained for reference for 
phase III. A data safety monitoring board may also stop the study with regard to the occurrence of 
SAEs and AEs. 
Depending on the phase II results, the study may continue into phase III. The randomised patients 
in phase II will be included in phase III. In case of the study early termination at Phse II, the patients 
will be followed-up as planned in the protocol. 
Given the uncertainty regarding the hypotheses of phase III, at the time of the analysis of phase II, 
the hypotheses of phase III will be reviewed and if necessary, the sample size will be recalculated. 
 
Phase III of the study 
The hypotheses for the calculation of the sample size are as follows: 
H0: No difference between the two treatments in terms of progression-free survival 
H1: There is a difference between the two treatments in terms of progression-free survival; it is 
estimated that the average time without progression or until death will be 5 months in the placebo 
arm and 7.5 months in the lanreotide arm. The HR is 0.67.  


 
 
 
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With a (bilateral) alpha risk of 5% and power of 80%, 196 events must be observed (progression or 
death). 
In the hypothesis of a follow-up period of 24 months after the inclusion of the final patient, the rate of 
inclusion of 50 patients per year and a rate of 10% lost to follow-up, 222 patients must be 
randomised. 
 
IX.2 -  STATISTICAL ANALYSIS PLAN 
The data will be analysed using the SAS (Statistical Analysis System) software, version 9.3 or later 
and the statistical methods are described in a statistical analysis plan. Values of p less than or equal 
to 0,050 (rounded) will be considered as "statistically significant" in the presentation of results. Other 
modifications made before the breaking of the blinding must be documented. After breaking the 
blind, any substantial modification made to the statistical analysis plan will be documented in the 
clinical study report. 
 
IX.2.1 -  POPULATION SETS 
Three population groups will be considered for the analyses: 
The intent-to-treat population (ITT): all randomised patients in the study that meet the eligibility 
criteria. These patients will be considered in the allocated group by randomisation, even if they 
receive a different treatment. 
The safety population (SP): all patients included in the ITT population having received at least one 
treatment injection. These patients will be analysed in terms of the treatment received. 
The per-protocol population (PP): all patients in the study randomised without major deviation 
(defined before the meeting for blind review of data). These patients will be analysed in terms of the 
treatment received.  
 
IX.2.2 -  DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
The baseline characteristics will be summarised in the ITT population. The statistics will be 
calculated for each treatment arm and for all patients combined. The description of medical and 
clinical variables will be done using percentages (95% confidence interval), as well as the mean 
(standard deviation), the median (min-max) and the inter-quartile range (Q1-Q3).  
 
IX.2.3 -  PRIMARY ENDPOINT ANALYSIS 
Phase II: 
The number and percentage of patients alive and progression free at 6 months will be calculated 
and described per treatment arm. The unilateral 95% confidence intervals will also be calculated.  
For the primary endpoint,  if at 6 months the progression is not documented and no progression was 
noticed before, the patients will be reviewed in its globality to classify him as Progressive or not 
progressive at 6 months.  
Phase III:  
The primary endpoint for phase III is progression free survival, considering the first radiological 
progression of the patient (investigator’s opinion) or death (any reason). The time will be calculated 
between the randomisation date and the date the first event occurred. Patients who are alive and 
progression free will be censored at the time of the last news or cut-off date (the date the first of 
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No missing data is expected for this parameter. 
Progression-free survival will be analysed using the Kaplan Meier method. The description will be 
made using the median, and the rates will be estimated at different stages of evaluation (95% 
confidence intervals will also be provided). The comparison between the two treatment arms will be 
made using a log-rank test.  
The hazard ratio will be estimated using a Cox model. An unadjusted model (only with treatment 
effect) and a model adjusted to the stratification factors will be used. All hypotheses associated with 
the use of this model (proportionality and linearity) will be verified. 
 
IX.2.4 -  SECONDARY ENDPOINT ANALYSES 
Efficacy endpoints 
The quantitative variables will be described per treatment arm. The usual statistics (mean, standard 
deviation, median, inter-quartile intervals and range) will be used. The quantitative variables may 
also be categorised using the known clinical threshold. 
The qualitative variables will be classed in frequencies and percentages. The confidence intervals at 
95% may also be calculated.  
In the phase III study, the comparison of qualitative variables may be conducted using an X² test or 
a Fischer test. A Wilcoxon's or Student test may be used for quantitative variables. 
The Kaplan Meier method and the Cox method (only in phase III) will be used for the analysis of 
censored data. 
Efficiency endpoints 
For medico-economical evaluation, incremental cost-effectiveness and cost-utility ratio will be 
calculated. A sensitivity analysis will be performed on the economic parameters. It will allow the 
consideration of possible differences in costs between France and other European centres taking 
part in the study. A non-parametric bootstrap analysis of the incremental costs and effectiveness / 
utility observed between the two strategies will help to consider the uncertainty and to estimate the 
interval at 95% of the differential ratio of the base analysis.  
The costs and utility / effectiveness will not be updated in consideration of the short follow-up period 
(12 and 18 months). 
Safety endpoints 
The analyses and the summary tables will be analysed in the safety population and described per 
treatment arm. 
AEs will be coded according to the MedDRA (Medical Dictionary for Regulatory Activities) 
classification version 17.0, and classed per MedDRA term and by organ system. We will use the 
most recent version of MedDRA at the time of analysis. 
The summary tables will be presented by type of event and by grade. 
Usual statistics (mean, median, standard deviation and range) per treatment arm will be presented 
for vital signs. 
The injections and injection reports will be described. 
 
IX.3 -  HANDLING OF MISSING OR INVALID DATA 
No replacement of missing data is envisaged, for any variable.  


 
 
 
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For all the endpoints concerning time to event variable, no missing data is expected. In case the 
event is not presented (Progression or Death) then patients will be censored at the time of the last 
news (consultation, imagery...) or cut-off date (the date the first of these occurs will be considered). 
 
X -  QUALITY CONTROL / MO NITORING  
Monitoring is conducted by ICTA PM or its representative, on behalf of the sponsor; it allows the 
progression of the study to be supervised and ensures the scientific integrity of the study.  
In order to guarantee compliance with the Good Clinical Practices and the applicable regulations, 
the Clinical Research Associate (CRA) is responsible for verifying that the study is conducted in 
compliance with the protocol and all other written instructions. The main responsibilities of the CRA 
are to verify investigators’ adherence to the protocol, accurate and complete data recording and 
reporting in the CRF, and that informed consent is obtained and recorded for all patients by the 
investigator before their participation in the study.  
The CRA will contact and visit the investigator at regular intervals during the study. He/she will, 
compare the CRFs with medical records and other relevant documentation through direct access, 
during the on-site monitoring visits. He/she ensures the completeness, consistency, and accuracy of 
the data being recorded in the CRF by the investigator. 
The CRA will explain the protocol and study-related procedures to all study staff, including the 
investigator. Additional information will be made available during the study when new staff become 
involved in the study and as otherwise agreed upon with either the investigator or the CRA.  
The investigator and the study investigator collaborators commit to cooperating with the CRA to 
resolve any problems, corrections, or possible misunderstandings concerning the findings detected 
in the course of these monitoring visits. 
As part of the supervision of the study progress, other sponsor staff or ICTA PM or its representative 
may, upon request, accompany the CRA on visits to the study site.  
 
XI -  CONFIDENTI ALITY  
XI.1 -  RESPONSIBILITIES 
XI.1.1 -  SPONSOR’S RESPONSIBILITIES  
ICTA PM or its representative, on behalf of the sponsor, will submit an application to Ethics 
Committees and Competent Authorities for approval of the clinical study. A copy of the approval of 
the Ethics Committee and the Competent Authorities must be received by the sponsor before the 
study starts. 
In accordance with the provisions of the law and the GCP, the sponsor will have an insurance policy 
intended to indemnify for possible damages resulting from the research. 
The studies and/or experiments performed on behalf of the sponsor will be specifically and 
expressly guaranteed. It is advisable to underline that noncompliance with the Research Legal 
Conditions is a cause for guarantee exclusion. 
XI.1.2 -  RESPONSIBILITIES OF THE INVESTIGATOR 
The investigator will be responsible for performing the study according to this protocol, the 
procedures, the ICH GCP guidelines and the legislation in force. He/she will have to collect, record, 
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Agreement of the investigator to conduct and administer this study in accordance with the protocol 
will be documented by the signed protocol acceptance form (duplicate on page 2). 
The investigator will be responsible for giving information and training about the study to all staff 
members involved in its conduct or in the patients’ care, (e.g., when new staff become involved). 
The investigator will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). The investigator is responsible for ensuring the privacy, health, and welfare of the 
patients. 
The investigator must be familiar with the background and requirements of the study and with the 
properties of the study treatment as described in the IB. 
XI.2 -  PERSONAL DATA PROTECTION AND CONFIDENTIALITY 
The investigator must ensure that the personal data of patients, including their identity and all other 
personal medical information, will be kept confidential at all times.  
A patient number and initials will identify the patients in the CRF. On other documents or 
photographic materials (including the results of imaging) submitted to the sponsor, patients will not 
be identified by their names but by an identification code (e.g. initials and patient number). 
By signing this protocol, the investigator undertakes to ensure that the protocol and all attached 
information are and will remain confidential. The investigator agrees that after providing the protocol 
and all information necessary for the staff involved, he/she remains responsible for their complete 
confidentiality. This obligation is detailed in the confidentiality agreement signed by the investigator 
before the initiation of the study. 
The investigator agrees that, subject to local regulations and ethical considerations, a sponsor 
representative or any regulatory agency may consult directly and/or copy study documents in order 
to verify a case report, provided that the subject's identity remains anonymous. 
The investigator undertakes to treat all subject data used or disclosed in connection with the 
conduct of study in compliance with European and local applicable laws relating to data protection. 
The investigator will be responsible for keeping a list of all enrolled patients including patient 
numbers, full names and dates of birth. 
XI.3 -  STUDY DOCUMENTATION ARCHIVING 
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. The study documents, including 
patient CRFs, should be filed in the investigator's file. 
The investigator's file will contain the protocol/amendments, the correspondence with the ethics 
committee and the health authorities, a sample of informed consent form, study treatment data, staff 
curriculum vitae and authorisation forms, correspondence, etc. 
The investigator must keep the Study File until the sponsor destruction authorisation, and by default 
for at least 15 years after completion or discontinuation of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
XII -  REGULATORY AND ETHIC AL ASPECTS 
XII.1 -  PATIENT INFORMATION AND CONSENT FORMS 
The patient information sheet must be given to patients before they decide whether to participate in 
the clinical study, in compliance with local regulations and good clinical practices. 


 
 
 
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The investigator must give patients the written information sheet and the consent form, and explain 
the study verbally. The consent form must be validated and signed by the patient before beginning 
any procedure related to the study. 
There is also a specific patient information sheet for the biological translational research.  
The consent form is issued in duplicate: the original is kept by the investigator and a copy is 
provided to the patient. 
In the event new information is acquired during the study that may affect the patient's wish to 
continue their participation, this information must be given to the patient so that they can confirm 
their agreement to continue to participate.  
XII.2 -  ACCESS TO SOURCE DATA 
The investigator must authorise the CRA to have direct access to all source documents related to 
the patient, required for the verification of the data recorded in the case report form. 
In case of requests from the health authorities, it is also essential to have access to all information 
related to the study. 
XII.3 -  STUDY CONDUCT 
The study must be conducted in compliance with the ICH standards of good clinical practice, the 
Declaration of Helsinki (Appendix 5), as well as all applicable European and/or local laws and 
regulations relating to the conduct of the studies. 
XII.4 -  ETHICS COMMITTEES AND COMPETENT AUTHORITIES 
The present protocol and other documents (investigator's brochure, patient information, 
questionnaires, etc.) will be submitted by ICTA PM or its representative, on behalf of the sponsor, to 
an Ethics Committee (EC). Before beginning the study, the investigator must have received 
permission in writing for the protocol and patient information sheet from the EC. The approval of the 
EC must indicate the version of study protocol, as well as the documents reviewed. 
Throughout the study, the sponsor must inform the EC of any change to the protocol, all SUSARs, 
and any new information likely to affect the safety of the patients or the conduct of the study. 
Complying with local regulations, ICTA PM or its representative, on behalf of the sponsor, and the 
investigators must verify that all legal aspects have been complied with and that the approval of the 
competent regulatory authorities, if necessary, has been obtained prior to the beginning of the 
study. 
The competent local authorities must be informed of the conduct of the clinical study and its status 
by ICTA PM or its representative on behalf of the sponsor. 
 
XII.5 -  AMENDMENTS  
All substantial amendments are submitted for the approval / authorisation of the EC and the 
competent authorities before their implementation. 
All substantial amendments concerning safety measures are submitted for the approval / 
authorisation of the ethics committee and competent authorities, but may be immediately 
implemented in circumstances specifically defined by the sponsor. 
XII.6 -  AUDIT AND INSPECTION 
The investigator must make the source documents of this study available for staff deemed qualified 
by the sponsor or its representatives or health authority inspectors, upon prior notice. The 


 
 
 
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monitoring of data in the e-CRF must be conducted with a verification / inspection of the source 
documents. 
The investigator must be ready to respond to all questions asked by auditors / inspectors and 
prepare for the smooth performance of the audit / inspection.  
XIII -  PUBLICATION OF DAT A  
The final clinical study report must be written in compliance with the ICH E3 guidelines (Structure 
and content of clinical study reports). 
XIV -  RULES OF PUBLICATION  
All publications resulting from data generated by this Intergroup will quote PRODIGE/GTE/FFCD in 
their title.  
1) The Coordinating Investigator will be responsible for drafting any publication (abstract and/or 
manuscript). 
2) The Coordinating Investigator will chair a writing committee, comprising representatives of the 
participating countries that fulfil the Intergroup guidelines for authorship. 
3) The Steering Committee must approve the manuscript prior to submission for publication. 
4) The Coordinating Investigator will inform the Steering Committee of any publication and/or 
presentation (2 weeks’ notice). 
5) The Coordinating Investigator will be the primary (first) author of the publication of the final 
results. Co-authors are defined according to the guidelines for authorship (see below). A list of all 
the participating countries and Investigators will be published as an appendix at the end of major 
publications. Acknowledgement for any financial support or grant will be reported in each 
publication. 
6) Presentations: the Coordinating Investigator and the FFCD board (represented by its chairman) 
must agree with the contents and authorship of any presentation. 
7) Guidelines for Authorship: the following persons will be considered for authorship by the Steering 
Committee: 
- Coordinating Investigator (first author) 
- Main recruiters, biologists, …   
- Statistician taking responsibility for the analysis of the study 
- A member of the UMR866 (INSERM Unit), to which the FFCD clinical data centre is attached, as 
equally contributing last author. 
 
 
XV -  RATIONALE OF THE STU DY  
XV.1 -  BACKGROUND 
XV.1.1 -  CONTEXT 
Neuroendocrine tumours (NETs) are rare tumours with various pathological presentations. 
However, their incidence is increasing and because of a less unfavourable prognosis than most 
digestive cancers1, their prevalence is high2. Well-differentiated duodeno-pancreatic NETs represent 


 
 
 
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the second most frequent location of digestive tract NET and their 5-year survival is about 30%1, 2. 
More than half of the cases of these tumours are diagnosed at a metastatic stage, and 75% of them 
have liver metastasis. 
Patients with metastatic or locally advanced, non-resectable, well-differentiated duodeno-pancreatic 
neuroendocrine tumour, grade 1 or 2 are treated following ENETS3 and TNCD4 recommendations. 
For patients with a small tumour volume, asymptomatic, non-progressive, current recommendations 
are simply to undertake monitoring until progression3, 5. However, the majority of these patients will 
progress within one year after diagnosis: 82% of patients in a median time of 10 months after 
diagnosis (PFS median: 14 months)6. Patients with progressive and / or symptomatic metastases 
and / or with significant hepatic invasion (> 30-50%), and / or bone metastases, anti-tumour therapy 
should be started. The reference treatment is systemic combination chemotherapy adriamycin and 
streptozotocin5, 7. However, given its toxicity, some experts recommend as first-line chemotherapy 
either dacarbazine8 with or without 5FU (LV5FU2-dacarbazine)9, or its analogues, temozolomide10, 
with or without oral 5FU11 or oxaliplatin combined with 5-FU12 (FOLFOX or XELOX). These different 
strategies generally induce a response or stabilisation in 60-97% of cases after 4-6 months of 
treatment, for a period of 9-20 months13. These patients have a long life expectancy. Therefore, the 
recommendations are to stop chemotherapy once a response (partial or complete) or disease 
control is obtained, and before complications or progression under treatment occur. Unlike many 
other tumour models, it is usual to observe long periods of non-progression after a first induction 
anti-tumour treatment. Resuming treatment is advocated only in the event of progression5, which 
can be done either with the same treatment as during induction, or with a second-line therapy. For 
this second-line therapy, everolimus and sunitinib may be prescribed based on the new 
recommendations5, 14, 15. Some patients receive these medicines as first-line therapy. 
The concept of maintenance therapy has been tested in the treatment of metastatic colorectal 
cancer. It makes it possible in case of response or stabilisation, when metastases are unresectable, 
to stop chemotherapy until progression, with reassessment every 3-months. This concept has been 
validated with either the association LV5FU216, or FOLFIRI17, or FOLFOX18, 19, particularly when the 
general state of health is good (WHO 0-1), when there is one metastatic site only, and when CEA 
level is normal18, 20. This approach allows resting periods for patients, who will benefit from several 
lines of treatment and thereby improve the tolerance and quality of life of these patients. The 
OPTIMOX2 clinical trial in colorectal cancer18, 21 with a maintenance therapy and reintroduction of a 
more aggressive therapy (oxaliplatin) in case of progression reinforced this concept; it is possible to 
increase the interval of time between cycles of more aggressive treatment. The quality of life of 
patients is excellent because of a well-tolerated treatment, which at best does not require 
intravenous administration.  
Chemotherapy discontinuation with a maintenance treatment with a targeted therapy has been 
tested in colorectal cancer with cetuximab, which was continued during the chemotherapy-break 
periods (COIN study) allowing lengthening of the chemotherapy-free period22 . The same approach 
is tested in a different protocol, with bevacizumab, pursued or not after chemotherapy 
discontinuation23. 
XV.1.2 -  STUDY TREATMENT 
The somatostatin analogues are very well tolerated and could be the ideal candidates in well 
differentiated NET to play this role of maintenance therapy after an aggressive chemotherapy. The 
antiproliferative indication is, for the time being, reserved to sandostatin LAR based on PROMID24 
results in well-differentiated mid-gut tumours but this trial did not include patients with NET in the 
duodeno-pancreatic region. However, several open studies or Phase II studies have shown that it 
was possible to stabilise in 35 to 80% of cases, duodeno-pancreatic NET with both  somatostatin 
analogues (octreotide and lanreotide), and especially when the disease was slowly progressing25. 
The progression-free survival data in these studies are disparate, ranging from 5 to 25 months25. 
The CLARINET study is a large phase III trial assessing the anti-proliferative effect of lanreotide 
scheduled for a total of 24 monthly injections in neuroendocrine tumours (NETs). Compared to 
placebo, there was a highly significant advantage in progression-free survival (PFS) with the use of 


 
 
 
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lanreotide (p=0.0002 HR=0.47 [95% CI: 0.30, 0.73]). In the subgroup of patients with duodeno-
pancreatic tumours, this advantage remained interesting (p=0.0637 HR=0.58 [95% CI: 0.32, 
1.04] )4. Unlike somatostatin analogues, oral cytotoxic chemotherapy (temozolomide or 
capecitabine) and the new 'targeted therapies' (everolimus and sunitinib) do not have a very 
favourable safety profile for this potential long-term maintenance treatment role 11, 14, 15. Lanreotide is 
currently used to relieve the symptoms of NETs. Most NETs have receptors on the surface of the 
cells which respond to somatostatin. Lanreotide inhibits the signal-transmission pathways mediated 
by somatostatin receptors, causing a reduction in hormone and amine secretion, which may 
improve tumour-related symptoms and stabilise tumour growth. It is therefore a potential candidate 
for maintenance therapy in NET patients who require chemotherapy. 
 
Further details are available in the Investigators' brochure (provided in the Investigators' 
folder). 
 
XV.2 -  RATIONALE OF THE STUDY 
In consideration of the information described in chapter I.1.2, somatostatin analogues may be good 
candidates for maintenance treatment in well-differentiated NETs. 
The objective of this clinical phase II/III study is to assess if lanreotide administered at 120 mg every 
4 weeks, can maintain the objective response / stabilisation induced by a first-line treatment of 
patients with non-resectable duodeno-pancreatic neuroendocrine tumours. 
The study is currently proposed as a double-blind, placebo-controlled study in 222 patients (for 
phase II and phase III) who have received first-line chemotherapy for a duodeno-pancreatic 
neuroendocrine tumour, and who were stable or in objective response after this treatment. Patients 
may receive lanreotide in a dose of 120 mg every 4 weeks until progression of the disease.  
 
XV.3 -  RATIONALE FOR DOSE SELECTION  
Lanreotide 120 mg will be administered by deep subcutaneous injection every 28 days. It has been 
previously reported that this dose of somatostatin analogue allows anti-tumour activity26.  This anti-
proliferative effect has recently been confirmed in the CLARINET study, with a significantly high 
achievement in progression-free survival (PSF) under lanreotide compared to placebo (p=0.0002 
HR=0.47 [IC 95%: 0.30, 0.73]) for a total of 24 monthly injections of 120 mg in cases of digestive 
neuroendocrine tumours (DNET)4. Consequently, this dose of lanreotide will be used in the study. 
 
XV.4 -  REFERENCES 
1. 
Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of 
and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 
2008; 26:3063-72. 
2. 
Lepage C, Bouvier AM, Faivre J. Epidémiology of Malignant Digestive Neuroendocrine 
Tumours. Eur J Endocrinology 2013;168:R77-83. 
3. 
Pavel M, Baudin E, Couvelard A, et al., ENETS Consensus Guidelines for the 
management of patients with liver and other distant metastases from neuroendocrine neoplasms of 
foregut, midgut, hindgut, and unknown primary Neuroendocrinology Switzerland, 2012:157-76. 
4. 
Caplin M, Ruszniewski P, Pavel M, et al. A randomized, double-blind, placebo-Controlled 
study 
of 
Lanreotide 
Antiproliferative 
Response 
in 
patients 
with gastroenteropancreatic 
NeuroEndocrine Tumors (CLARINET). late breaking abstract ESMO 2013. 


 
 
 
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5. 
Thesaurus national de cancérologie digestive (2011) Tumeurs Neuroendocrines. 
www.tncd.org. 
6. 
Panzuto F, Boninsegna L, Fazio N, et al., Metastatic and locally advanced pancreatic 
endocrine carcinomas: analysis of factors associated with disease progression J Clin Oncol United 
States, 2011:2372-7. 
7. 
Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, 
streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J 
Med 1992;326:519-23. 
8. 
Altimari AF, Badrinath K, Reisel HJ, Prinz RA. DTIC therapy in patients with malignant 
intra-abdominal neuroendocrine tumors. Surgery 1987;102:1009-17. 
9. 
Bajetta E, Ferrari L, Procopio G, et al. Efficacy of a chemotherapy combination for the 
treatment of metastatic neuroendocrine tumours. Ann Oncol 2002;13:614-21. 
10. 
Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in 
treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007;13:2986-91. 
11. 
Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and 
temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011;117:268-
75. 
12. 
Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) suitable 
treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother 
Pharmacol 2007;59:637-42. 
13. 
Walter T, Brixi-Benmansour H, Lombard-Bohas C, Cadiot G. New treatment strategies in 
advanced neuroendocrine tumours. Dig Liver Dis 2012;44:95-105. 
14. 
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic 
neuroendocrine tumors. N Engl J Med 2011;364:501-13. 
15. 
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine 
tumors. N Engl J Med 2011;364:514-23. 
16. 
Maughan TS, James RD, Kerr DJ, et al. Comparison of intermittent and continuous 
palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet 
2003;361:457-64. 
17. 
Labianca R, Floriani I, Cortesi E, et al. Alternating versus continuous "FOLFIRI" in 
advanced colorectal cancer (ACC): A randomised "GISCAD" trial (abstract). J Clin Oncol 2006;24 
3505a. 
18. 
Maindrault-Goebel F, Lledo G, Chibaudel B, et al. OPTIMOX2, a largerandomised phase II 
study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with 
metastatic colorectal cancer (MRC). A GERCOR study (abstract). J Clin Oncol 2006;24 (Suppl 
18S):3504a. 
19. 
Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTIMOX2, a large 
randomised phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after 
FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study.  . J Clin Oncol 
2007;25(Suppl 18S):4013a. 
20. 
Perez-Staub N, Chibaudel B, Figer A, et al. Who can benefit from chemotherapy holidays 
after first-line therapy for advanced colorectal cancer? A GERCOR study (abstract). J Clin Oncol 
2008;26(Suppl15S):4037a. 
21. 
Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 
or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR 
study. J Clin Oncol 2006;24:394-400. 


 
 
 
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22. 
Adams RA, Meade AM, Seymour MT, et al., Intermittent versus continuous oxaliplatin and 
fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: 
results of the randomised phase 3 MRC COIN trial Lancet Oncol England: 2011 Elsevier Ltd, 
2011:642-53. 
23. 
Aparicio T, Bennouna J, Le Malicot K, et al. Efficacy of therapeutic sequences of 
FOLFIRI+BEVACIZUMAB associated or not with a bevacizumab maintenance during Free-
Chemotherapy Intervals in metastatic colorectal cancer, a Phase III randomized trial - PRODIGE 9 – 
FFCD 0802. Digestive and Liver Disease In press. 
24. 
Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, 
prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in 
patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J 
Clin Oncol 2009;27:4656-63. 
25. 
Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the 
treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 
2010;31:169-88. 
26. 
Eriksson B, Renstrup J, Imam H, Oberg K. High-dose treatment with lanreotide of patients 
with advanced neuroendocrine gastrointestinal tumors: clinical and biological effects. Ann Oncol 
1997;8:1041-4. 


 
 
 
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XVI -  APPENDICES   
XVI.1 -  Classification of NETs - WHO 2010 
XVI.2 -  WHO Index 
XVI.3 -  RECIST criteria version 1.1 
XVI.4 -  NCI-CTC AE criteria version 4.0 
XVI.5 -  Helsinki declaration 
XVI.6 -  Management of samples for translational biological studies 
XVI.7 -  Radiological recommendations 
XVI.8 -  Recommendations on the drafting of anatomic pathology reports - Minimum information 
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APPENDIX 1: Classification of digestive NETs - WHO 2010 [RINDI 2010]. 
 
The WHO 2010 classification uses grades G1 to G3 initially proposed by the ENETS in 2006. There 
are 3 main categories: (a) neuroendocrine G1 tumours; (b) neuroendocrine G2 tumours, which are 
well-differentiated by definition and (c) neuroendocrine G3 small or large-cell carcinomas which are 
poorly differentiated by definition. It introduces mixed exocrine-endocrine carcinoma (called adeno-
neuroendocrine) and tumour-like lesions.  
• Neuroendocrine G1 tumours  
• Neuroendocrine G2 tumours  
• Neuroendocrine G3 carcinoma (as of small or large-cell)  
• Mixed adeno-neuroendocrine carcinoma  
• Tumour-like lesions. 
 
However, this classification does not take into account morphologically well-differentiated NETs with 
proliferation of > 20% and therefore grade 3, whose exact frequency is not known [Vélayoudom-
Céphise 2013].  
 
Definition of grade of tumour according to WHO 2010 
The tumour grade has been replicated from the grading defined by the ENETS in 2006 (adapted 
from [Rindi 2006] and [Rindi 2010] 
 
 
 
Grade  
 
 
Mitotic count  
(for 10 HPF)*  
 
 
Ki-67 index (%¤)**  
 
G1  
 
< 2  
 
≤ 2  
G2  
2 -20  
3 -20  
G3  
< 20  
< 20  
 
*10HPF (High Power Field) = 2 mm2, at least 40 fields (at 40x magnification) evaluated in areas of 
highest mitotic density 
** MIB1 antibody; % of 2000 tumor cells in areas of highest nuclear labelling 
 
 
 
 
 
 
 
 


 
 
 
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APPENDIX 2: WHO Performance status  
 
0 = Capable of an identical lifestyle to that prior to illness, with no restrictions. 
1 = Physical activity diminished but ambulatory and able to work 
2 = Ambulatory and capable of taking care of themselves, unable to work. Bedridden 50% of the 
time. 
3 = Capable of only some personal care. Bedridden or seated at least 50% of the time. 
4 = Unable to take care of themselves, bedridden or seated all of the time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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APPENDIX 3: RECIST criteria version 1.1 
 
“New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)” E.A. 
Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij;  
Eur J Cancer, 4 5 (2 0 0 9 ) 2 2 8 –2 4 7. 
 
1. Measurability of tumour at baseline 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
follows: 
 
Measurable:  
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II on 
imaging guidance). 
 10mm calliper measurement by clinical exam (lesions which cannot be accurately measured 
with callipers should be recorded as non-measurable). 
 20mm by chest X-ray. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
Non measurable disease 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes with 
≥ 10 to <15mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques. 
 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 
 


 
 
 
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Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
 
 
Target and non-target lesions 
 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should be 
identified as target lesions and will be recorded and measured at baseline (this means in instances 
where patients have only one or two organ sites involved a maximum of 2 and 4 lesions respectively 
will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which can 
be measured reproducibly should be selected. 
 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumour. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15mm 
by CT scan. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterise any objective tumour regression in 
the measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 
 
2. Response criteria: 
 
Evaluation of target lesions: 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 


 
 
 
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Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). 
 
Stabilisation (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Special notes on the assessment of lymph nodes: Lymph nodes identified as target lesions should 
always have the actual short axis measurement recorded (measured in the same anatomical plane 
as the baseline examination), even if the nodes regress to below 10mm on study. This means that 
when lymph nodes are included as target lesions, the ‘sum’ of the lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short axis of 
<10mm. Case report forms or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each node 
must achieve a short axis <10mm. For PR, SD and PD, the actual short axis measurement of the 
nodes is to be included in the sum of target lesions. 
 
 
Evaluation of non-target lesions 
 
Complete response: Disappearance of all non-target lesions and normalisation of tumour marker 
level. All lymph nodes must be non-pathological in size (<10mm short axis). 
 
Non-CR / Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumour 
marker level above the normal limits.  
Progressive Disease: Unequivocal increase in the size of non-target lesions or appearance of a 
new lesion (note: the appearance of one or more new lesions is also considered progression). 
 
3. Overall response: 
 
Target lesions 
Non-target lesions 
New lesions 
 
Overall response 
CR 
CR 
No 
 
CR 
CR 
Non CR/Non PD 
No 
 
PR 
CR 
PR 
Not evaluated 
Non PD or not all evaluated 
No 
No 
 
PR 
PR 
SD 
Non PD or not all evaluated 
No 
 
SD 
Not all evaluated 
PD 
Non PD 
Any 
No 
Yes or no 
 
NE 
PD 
Any 
PD 
Yes or no 
 
PD 
Any 
Any 
Yes 
 
PD 
CR: Complete Response; PR: Partial Response; PD : Progressive Disease; SD: Stable Disease; NE: Inevaluable.  
 


 
 
 
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APPENDIX 4: NCI-CTC AE criteria version 4.0 
 
Refer to the CTCAE scale of assessment of toxicity version 4.0. 
The original English version can be downloaded from the NCI website. 
 
 
http://ctep.cancer.gov/ 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
(Publication Date May 28, 2009) 
 


 
 
 
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APPENDIX 5: Helsinki declaration 
 
 


 
 
 
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APPENDIX 6: Blood sample collection and handling for biological translational studies 
 
To retrieve buffy coat and plasma from blood sample: The whole blood is collected in an EDTA tube 
(avoids blood coagulation and neutralises PCR inhibitors). 
 
 
Centrifuge the blood samples at 3000 rpm for 15 minutes at 4°C 
 
Prepare the cryotubes in the rack:  
5 to 6 for plasma 
2 for buffy coat  
2 for red blood cells 
 
Label tubes with the patient's inclusion number (followed by PL for plasma, BC for buffy coat 
and RBC for red blood cells), the name of the study and the sample date.  
 
After centrifugation, there are 3 phases:  
 
Higher phase: plasma 
 
Intermediate phase: buffy-coat (white suspension) 
 
Lower phase: red blood cells 
 
 
 
The quantity of blood drawn and aliquoted may depend on the patient. 
 
First recover the plasma (higher phase) bringing it gently to the surface until the intermediate 
phase, distribute into cryotubes 
 
Retrieve the intermediate phase bringing all of the white suspension to the surface and place it 
in the cryotubes 
 
Retrieve the end of the red blood cells 
 
Store the cryotubes at -80°C 
 
Create a table indicating the patient number, the initials, the dates of sample collection, and 
reception, and placing it into the freezing boxes. 
 
 
 


 
 
 
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APPENDIX 7: Radiological recommendations 
 
CT scan 
A tri-phasic Helical computed axial tomography scan (without injection, arterial phase, portal 
phase) of the liver must be carried out. 
It has therefore 3 helical rotation from the hepatic dome to the tip of segment VI. 
The patient must have a sufficient gauge venous line (>=18G) ideally in the elbow. Injection into a 
central venous line is perfect. 
The injection must use an iodised contrast medium with a concentration ≥ 350 mg I/mL 
The injection rate must be ≥ 4 cc/s. 
For the arterial phase, it is recommended to use a bolus detection system in the aorta and to 
release the helical rotation, 15 seconds after a detection threshold ≥ 150 UH in the aorta. 
For the portal phase, the helical rotation should start 50 seconds after the same detection 
threshold. 
 
Magnetic resonance imaging (MRI) 
MRI should include: 
 
- 
2 T2-weighted sequences:  
o a single-shot technique for liver imaging: either half-Fourier acquisition single-shot 
turbo spin echo (HASTE). 
o the other with signal saturation of the fat in fast spin echo (sequence type TSE or 
FSE) 
 
- 
A diffusion sequence with at least 2 values of b: b=100s/mm2 and b=600s/mm2. Other 
values of b are optional. 
 
- 
An echo sequence of gradient T1 without injection 
 
 
- 
All  sequences should be repeated in arterial, portal, late phase (3min and 5min). 
 
- 
The use of a standard gadolinium chelate is recommended. 
 


 
 
 
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APPENDIX 8: Recommendations for the anatomopathological reports - Minimum information 
that must appear in the report  
 
• Anatomical location  
• Specimen type  
• Macroscopic characteristics (if available)  
– number of visible tumours, size of each one  
• Diagnostic arguments  
– histological: tumour well or poorly differentiated  
– based on immunohistochemistry: chromogranin A, synaptophysine  
• Histological grade  
– mitotic index: absolute value (to be evaluated in 2 mm²)  
– Ki-67 index: absolute value (indicate the immunodetection technique and reading 
method, to evaluate in 500 to 2000 cells according to WHO recommendations)  
– Grade G1, G2, or G3  
• WHO classification of 2010  
– Neuroendocrine G1 tumour  
– Neuroendocrine G2 tumour  
– Small-cell neuroendocrine carcinoma  
– Large-cell neuroendocrine carcinoma  
– Adeno-neuroendocrine carcinoma 
• Extension of the tumour  
– Local invasion (invasion in depth in the digestive wall, peri-pancreatic adipose tissue 
invasion, invasion of adjacent organs)  
– Limits status, measurement margins  
• TNM stage  
– pT/pN: clearly indicated the classification used (minimum: TNM/UICC)  
– Number of metastatic lymph nodes/ examined  
• Other information  
– Other histoprognostic factors (vascular emboli, peri-nerve sheathing; if appendix: 
extension to the mesoappendix, depth of invasion, distance from base)  
– Lesions associated with peritumoural tissue  

SAP_001.pdf: 
FFCD 
Protocol n° PRODIGE 31 - REMINET 
Statistical Analysis Plan 
Final – 03Dec2019 
Page 1/29 
 
 
 
 
 
* 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
PRODIGE 31 – FFCD 1301 – REMINET 
 
EudraCT number 2013-004069-14 
 
A EUROPEAN, MULTICENTRE, PHASE II/III RANDOMISED DOUBLE-BLIND, 
PLACEBO CONTROLLED STUDY EVALUATING LANREOTIDE AS MAINTENANCE 
THERAPY IN PATIENTS WITH NON-RESECTABLE DUODENO-PANCREATIC 
NEUROENDOCRINE TUMOURS AFTER FIRST-LINE TREATMENT 
 
 
Final Version – 03 December 2019 
 
 
AUTHOR 
 
AIXIAL 
CRISCO – 3-5 avenue de la Cristallerie 
92310 SEVRES 
FRANCE 
 
 
COORDINATOR 
 
Prof. Côme LEPAGE, representative of the FFCD  
Service HGE de l‟Hôpital du Bocage  
2 Bd de Lattre de Tassigny  
21000 DIJON 
FRANCE 
 
 
SPONSOR 
 
Fédération Francophone de Cancérologie Digestive (FFCD) 
Faculté de Médecine 
7 Boulevard Jeanne d‟Arc 
BP 87900 
21079 DIJON CEDEX 
FRANCE 
 
 
SPONSOR’S REPRESENTATIVE 
 
Karine LE MALICOT 
 
 
 
 
CONFIDENTIAL 
 


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Protocol n° PRODIGE 31 - REMINET 
Statistical Analysis Plan 
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DOCUMENT HISTORY 
 
 
Version 
Date 
Description of change 
Performed by 
Draft 1 
19JUN2018 
Document creation 
Isabelle Josse 
Version 2.0 18 SEP2019 
Finalisation 
Karine Le Malicot 
Version 2.1 08 OCT2019 
Correction suite à Programmation des Mock Tables 
Karine Le Malicot 
Version 2.2 03 DEC 2019 
Final Version 
Karine Le Malicot 
 
 
 
 
 


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Protocol n° PRODIGE 31 - REMINET 
Statistical Analysis Plan 
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APPROVALS 
 
 
 
Name and Function 
Signature 
Date 
 
Prof. Côme LEPAGE 
Coordinator 
FFCD 
 
 
 
_____________________ 
 
 
 
___ / ___ / ___ 
 
Karine LE MALICOT 
Biostatistician 
FFCD 
 
 
 
_____________________ 
 
 
 
___ / ___ / ___ 
 
Isabelle JOSSE 
Biostatistician 
AIXIAL 
 
 
 
_____________________ 
 
 
 
___ / ___ / ___ 
 
 
 
 


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Statistical Analysis Plan 
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ABBREVIATIONS 
 
 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
CgA  
Chromogranin A  
CM  
Contrast Medium  
CR 
Complete Response 
CRO 
Clinical Research Organization 
CI 
Confidence Interval 
CT 
Computed Tomography 
ENETS  
European NeuroEndocrine Tumor Society  
FFCD  
Fédération Francophone de Cancérologie Digestive  
(French Federation of Digestive Cancerology)  
ICH  
International Conference for Harmonisation  
ITT  
Intent-To-Treat  
IWRS  
Interactive Web Response System  
NE 
mITT 
Not Evaluable 
Modified Intent-to-Treat 
MRI  
Magnetic Resonance Imaging  
NCI- CTC  
National Cancer Institute - Common Terminology Criteria 
NET  
Neuro Endocrine Tumour  
PP  
Per-Protocol  
PPI  
Proton Pump Inhibitor  
PR  
Partial Response  
PT 
Preferred Term 
RECIST  
Response Evaluation Criteria In Solid Tumours  
SAE 
Serious AEs 
SAP  
Statistical Analysis Plan  
SAS  
Statistical Analysis System  
SD 
Stable Disease 
Std 
Standard Deviation 
SOC 
System Organ Class 
TNCD  
Thésaurus National de Cancérologie Digestive  
WHO  
World Health Organisation  
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
 
1 
INTRODUCTION 
7 
2 
DESCRIPTION OF THE STUDY 
7 
2.1 STUDY OBJECTIVES 
7 
2.1.1 PRIMARY OBJECTIVE 
7 
2.1.2 SECONDARY OBJECTIVE(S) 
7 
2.2 STUDY DESIGN 
7 
2.2.1 DESCRIPTION 
7 
2.2.2 SCHEDULE OF ASSESSMENTS AND STUDY PROCEDURES 
8 
2.3 STUDY ENDPOINTS 
10 
2.3.1 PRIMARY EFFICACY ENDPOINTS 
10 
2.3.2 SECONDARY EFFICACY ENDPOINTS 
10 
2.3.3 SAFETY ENDPOINTS 
10 
2.4 STUDY TREATMENTS 
10 
2.4.1 TREATMENT GROUPS 
10 
2.4.2 TREATMENT DURATION 
10 
2.4.3 RANDOMIZATION 
11 
2.4.3.1 Randomization procedure 
11 
2.4.3.2 Blinding 
11 
2.5 SAMPLE SIZE CONSIDERATIONS 
12 
3 
ANALYSIS POPULATIONS 
13 
3.1 INTENT-TO-TREAT (ITT) POPULATION 
13 
3.2 MODIFIED INTENT-TO-TREAT (MITT) POPULATION 
13 
3.3 SAFETY POPULATION 
13 
4 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
14 
4.1 STATISTICAL HYPOTHESES 
14 
4.2 DISPLAY OF ANALYSIS RESULTS 
14 
4.3 INTERIM ANALYSES 
14 
4.4 CENTRE EFFECT MANAGEMENT 
14 
4.5 SUBGROUP ANALYSES 
14 
4.6 OTHER STRATA AND COVARIATES 
14 
4.7 MULTIPLE COMPARISONS AND MULTIPLICITY 
14 
5 
DATA HANDLING CONVENTIONS 
15 
5.1 MISSING DATA 
15 
5.2 VISIT WINDOWS 
15 
5.3 DERIVED AND TRANSFORMED DATA 
15 


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5.3.1 TIME TO INITIAL DIAGNOSIS FROM RANDOMISATION (MONTHS) 
15 
5.3.2 TIME TO INITIAL PROGRESSION FROM START OF 1ST LINE THERAPY (MONTHS) 
15 
5.3.3 TIME TO INITIAL PROGRESSION FROM RANDOMISATION (MONTHS) 
15 
5.3.4 DURATION OF 1ST LINE THERAPY (MONTHS) 
15 
5.3.5 NUMBER OF CYCLE PERFORMED 
16 
5.3.6 NUMBER OF CYCLE DELAYS 
16 
5.3.7 DURATION OF STUDY TREATMENT (YEARS) 
16 
5.3.8 RESPONSE 
16 
5.3.9 TIME TO PROGRESSION 
16 
5.3.10 PROGRESSION-FREE SURVIVAL 
16 
5.3.11 OVERALL SURVIVAL 
16 
5.3.12 QUALITY OF LIFE 
16 
6 
DESCRIPTION OF THE STUDY POPULATION 
18 
6.1 DISPOSITION OF PATIENTS 
18 
6.2 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
18 
6.2.1 DEMOGRAPHIC CHARACTERISTICS 
18 
6.2.2 MEDICAL OR SURGICAL HISTORY 
18 
6.2.3 PREVIOUS AND CONCOMITANT MEDICATIONS 
19 
6.2.4 OTHER BASELINE CHARACTERISTICS 
19 
6.3 TREATMENT EXPOSURE AND COMPLIANCE 
19 
7 
EFFICACY ANALYSIS 
20 
7.1 PRIMARY EFFICACY ENDPOINT 
20 
7.2 SECONDARY EFFICACY ENDPOINTS 
20 
7.2.1 RATE OF PATIENTS ALIVE AND PROGRESSION FREE AT 12 MONTHS, ASSESSED BY THE 
INVESTIGATOR 
20 
7.2.2 RESPONSE RATE AT 6 MONTHS 
20 
7.2.3 TIME TO PROGRESSION 
20 
7.2.4 PROGRESSION-FREE SURVIVAL 
20 
7.2.5 OVERALL SURVIVAL 
20 
7.2.6 QUALITY OF LIFE 
21 
8 
SAFETY ANALYSIS 
22 
8.1 ADVERSE EVENTS 
22 
8.2 VITAL SIGNS 
22 
9 
CHANGES FROM STUDY PROTOCOL 
23 
10 VALIDATION OF STATISTICAL PROGRAMMING 
23 
11 REFERENCES 
23 
APPENDIX 1. TEMPLATES FOR STATISTICAL ANALYSIS AND SUMMARY TABLES 24 
 


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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical analyses to be performed on the phase II 
of the study, contains the definition of analysis sets and protocol deviations, defines derived data, and 
specifies the methodology for analysing primary and secondary endpoints.  
This SAP is based on: 
 
Study Protocol version 3.0 dated on 16-June-2016, 
 
Case Report Form final version 3.0 dated on 28-October-2014. 
The analyses closely follow the International Conference for Harmonisation (ICH) guidelines for 
industry on topic E3 - Structure and Content of Clinical Study Reports and E9 - Statistical Principles 
for Clinical Trials.  
2 DESCRIPTION OF THE STUDY 
2.1 Study objectives 
2.1.1 Primary objective  
The primary objective of phase II is to evaluate the rate of patients alive and progression free at 6 
months, assessed by the investigator according to Response Evaluation Criteria In Solid Tumours 
(RECIST) criteria, version 1.1. 
2.1.2 Secondary objective(s)  
The secondary objectives of phase II are:  
 
Rate of patients alive and progression free at 12 months, assessed by the investigator 
according to RECIST criteria (version 1.1), 
 
Rate of patients alive and progression free at 6 months, according to central review, 
 
Safety, 
 
Response rate at 6 months according to RECIST criteria (version 1.1), 
 
Time To Progression, 
 
Quality of life assessed with the questionnaire QLQ-C30, including module NET21, and the 
Spitzer visual analogue scale. 
2.2 Study design 
2.2.1 Description 
This is a European, prospective, multicentre, double-blind randomised study evaluating lanreotide 
(120 mg every 28 days until disease progression) versus placebo in patients with metastatic/locally 
advanced, non-resectable, duodeno-pancreatic neuroendocrine tumours, stabilised or in objective 
response after the first line of treatment. 
 


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2.2.2 Schedule of assessments and study procedures 
The schedule of observations and assessments conducted during the study is set out in the following 
flowchart: 


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Flow Chart - Schedule of the study Assessments 
 
Screening / 
Randomisation 
Treatment Phase 
Follow-up 
Assessments 
D-30 à D1 
Day 1 = C1 
Every 28 days 
Every 3 
months until 
progression 
Every 6 
months  
Informed Consent 
X 
 
 
 
Demographic data 1 
X 
 
 
 
Relevant medical history 2 
X 
 
 
 
Eligibility criteria 
X 
 
 
 
Randomisation 
X 
 
 
 
Physical examination 3 
X 
X 
X 
  
World Health Organisation (WHO) score 
X 
X 
X 
X 
Haematology 4 
X 
  
X 
  
Blood chemistry 5  
X 
  
X 
  
Thyroid blood tests  
X 
  
  
  
Pregnancy test 6 
(X) 
  
  
  
Electrocardiogram 
X 
 
 
 
Treatment administration 
  
X 
  
  
Tumour assessments 
X 7; 8 
  
X 
  
Brain 
Computing 
Tomography 
(CT) 
/ 
Magnetic Resonance Imaging (MRI) 9 
X 
  
X 
  
Bone scan 9 
X 
  
X 
  
Chromogranin A (CgA) 10 
X 
  
X 
  
Ki-67 (according to the Neuro Endocrine 
Tumour [NET] referent review) 
X  
  
  
  
Survival status 
  
  
  
X 
Adverse Events (AEs) 11 / Serious AEs 
(SAEs) 
X 
X 
X 
SAEs 12 
Further treatment lines 
  
  
  
X 
Tumour slide 13  
X 
  
  
  
Informed consent for biomarker research 
X 
  
  
  
Blood 
sample 
collection 
(biomarker 
research) 14 
X 
  
X  
  
Quality of Life (QLQ-C30 + NET21) 
X 
  
X 
  
Medico-economical 
evaluation 
(EQ-5D 
including the Spitzer visual analogue scale) 
X 
  
X 
X 15 
1: Sex, age 
2: Including ongoing medical history 
3: Weight 
4: Complete blood count, platelets 
5: Electrolytes, total protein, liver function tests (alanine-aminoTransferase, aspartate-aminoTransferase, alkaline phosphatase, gamma-
glutamyl transferase, total bilirubin and conjugated), albumin, lactate dehydrogenase, glycated haemoglobin, glycaemia. Total cholesterol, 
high density lipoprotein cholesterol and triglycerids done only at the inclusion. 
6: Serum pregnancy test within 7 days prior to randomisation 
7: Scans showing response or stabilisation after fist line therapy should be done at least 2 weeks after the end of the first-line treatment 
and within 4 weeks before randomisation 
8: Chest, abdomen and pelvis CT scan with early arterial timing or abdominal and pelvic MRI + chest CT scan with injection of iodised 
contrast medium (CM). In case of contraindication to use of a CM, abdominal and pelvic MRI + chest CT scan without injection. It is 
necessary to use the same evaluation method as the one used at inclusion 
9: As clinically indicated 
10: CgA assessment must always be performed with the same method in the same laboratory 
11: According to National Cancer Institute – Common Terminology Criteria for AE V4.0 
12: All SAE occurring at any time after the end of the study treatment phase, and likely to be related to the study treatment or to a study 
procedure (in investigator's opinion), must be reported according to the reporting process described in the protocol 
13: For all patients consenting to the biomarker translational research, tumour slides will be collected at the central pathological laboratory; 
biomarker translational research program will be done on these slides 
14:  Sample to be taken while fasting, at the inclusion, at the 1st of the 3-month evaluation only, and after progression 
15:  EQ-5D questionnaire will be completed until 18 months after randomisation or until the end-of-treatment visit, in case of study drug 
discontinuation prior to 18-months post-randomization 
 


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2.3 Study endpoints 
2.3.1 Primary efficacy endpoints 
The primary endpoint for phase II is the rate of patients alive and progression free at 6 months, 
evaluated according to the results of imaging assessment done 6 months after the randomisation. 
This evaluation is done by the investigator according to RECIST criteria (version 1.1). 
2.3.2 Secondary efficacy endpoints 
The secondary efficacy endpoints of phase II are the following:  
 
Rate of patients alive and progression free at 12 months (according to RECIST criteria 
version 1.1), assessed by the investigator, 
 
Rate of patients alive and progression free at 6 months, according to central review, 
 
Response rate according to RECIST criteria at 6 months (version 1.1), according to the 
Investigator, 
 
Time to progression (median), 
 
Progression-Free Survival, 
 
Overall Survival, 
 
Quality of life (QLQ-C30 including module NET21, the Spitzer visual analogue scale). 
2.3.3 Safety endpoints 
The secondary safety endpoints of phase II are the following:  
 
Adverse Events (AEs): the toxicities will be described using the National Cancer Institute – 
Common Terminology Criteria for AE (NCI-CTC AE) version 4.0, 
 
Vital Signs (Weight) and WHO performance index. 
2.4 Study treatments 
2.4.1 Treatment groups 
The Investigational Medicinal Products used in this study (lanreotide, placebo) were provided by 
Beaufour IPSEN Industry in the following presentations: 
Lanreotide Autogel 120 mg:  
Treatment was provided in a pre-filled syringe of 0.5 mL with a 20 mm needle of 1.2 mm external 
diameter, sealed in a laminated bag and in a cardboard box. Each pre-filled syringe has an automatic 
security system. Each 0.5 mL syringe contains a supersaturated acetate solution of lanreotide 
corresponding to 0.246 mg of lanreotide base/mg of solution, for subcutaneous injection of a 120 mg 
dose of lanreotide.  
Placebo:  
The placebo injection will consist of a 0.9% saline solution provided as follows:  
 
A 2 mL ampoule containing 1 mL of NaCl at 0.9%, 
 
An empty syringe of 0.5 ml with an automatic security system and a 20 mm needle of 1.2 mm 
external diameter and 1.0 mm internal diameter sealed in a laminate bag. 
2.4.2 Treatment duration 
The study treatment should be initiated after randomisation, within the 6 weeks following the 
confirmation date of stable disease or objective response. 


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Once the randomisation has been performed, the patients received a single dose of the 
investigational products (lanreotide or placebo) every 4 weeks (every 28 days) according to a double 
blind procedure until disease progression or toxicity. 
2.4.3 Randomization 
2.4.3.1 
Randomization procedure 
After confirmation of their eligibility in the study, patients received a randomisation / treatment 
allocation number according to their order of entry into the study by an Interactive Web Response 
System (IWRS). The IWRS was manage the link between the treatment number and the 
randomisation number. 
The randomisation was conducted according to the technique of minimisation; treatments were 
randomised in a 1:1 ratio, stratified according to the following criteria: 
 
Centre, 
 
Grade 1 versus grade 2, 
 
First-line treatment: chemotherapy vs. targeted therapy (everolimus or sunitinib). 
2.4.3.2 
Blinding 
In order to guarantee blinding of the investigator and all the staff participating in the evaluation or the 
recording of the results of the treatment, all injections carried out during the double-blind phase 
should be administered at the site by a person who was specifically trained and qualified (for 
example, a nurse), otherwise not involved in the study procedures. This person had to ensure that this 
blindness was maintained with respect to the patients.  
Lanreotide and the placebo are not identical: lanreotide is a viscous formulation that was supplied in a 
pre-filled syringe; the placebo is a solution that was not provided in a pre-filled syringe. As a result, 
the person carrying out the injection filled the syringe with the placebo solution out of the patient's 
view. In addition, both lanreotide and the placebo were administered in the currently-approved 
injection site, in the superior external quadrant of the buttock, in order to limit the patient's view of the 
injection. At each cycle, the injection site was alternated between the left and right side of the body.  
The patients, investigators, site staff, persons performing the assessments and the Clinical Research 
Associate remained blind to the process and will not have access to the identity of the treatment 
allocated to the patients (lanreotide or placebo), from the date of randomisation until the final 
database lock of phase III of the study.  
The blinding will be broken for the staff responsible for the statistical analysis at the end of phase II of 
the study, when the database will be locked for the data analysis of this phase. Individual patient data 
(with decoded treatment) will not be communicated to investigators or any other persons involved in 
the conduct of the study, in order to guarantee the absence of any bias during the long-term survival 
follow-up, until the end of phase III of the study, except in case of confirmed disease progression.  
To guarantee that blinding is maintained, the following methods are applied:  
 
The randomisation code will be kept in the strictest confidentiality until the unblinding and will 
not be accessible to any person involved in the conduct of the study, 
 
The identity of the treatment (lanreotide or placebo) will be hidden on the packaging and the 
label. 
The study randomisation code should not be broken, except in the case of a medical emergency and 
in case of confirmed disease progression, if the knowledge of the study treatment received may 
influence the medical care of the patient.  
In these medical emergency cases and in case of confirmed disease progression, the investigator 
may break the blind using the IWRS system.  
The date and reason for unblinding must be detailed on the IWRS and on the case report form.  


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The sponsor reserves the right to break the blind for Serious AEs (SAEs) that are considered to be 
related to the study treatment and unexpected, which could therefore require expedited reporting to 
the regulatory authorities. 
2.5 Sample size considerations 
The hypotheses for the calculation of the sample size as follows:  
H0: A rate of patients alive and progression free at 6 months of 45% or less is not sufficient to 
demonstrate efficacy (p≤p0 with p0=45%). The study will not be continued. 
H1: A rate of patients alive and progression free at 6 months of more than 45% is sufficient to 
demonstrate efficacy. A rate of 63% is expected (p ≥ p0 with p0=45% and p=p1 = 63%). A rate of 
patients alive and progression free at 6 months of more than 45% (i.e. if the lower bound of the exact 
binomial two-sided 90% confidence interval (CI) exceeds 45%) leads to the study continuation. 
With a one-sided alpha risk of 5% and power of 85% (binomial-exact method), 56 patients should be 
randomised in each arm. 
With a rate of 5% of patients being non-evaluable or lost to follow-up, 59 patients should be included 
in each arm (118 patients in total).  
The following decision rule will be applied:  
If 31 patients or less are alive and progression free at 6 months or before, the treatment will be 
considered as not interesting. 
This rule will apply only to the lanreotide arm. The placebo arm will be maintained for reference for 
phase III. A data safety monitoring board may also stop the study with regard to the occurrence of 
SAEs and AEs.  
If the phase II results are positive, the study will continue into phase III. The randomised patients in 
phase II will be included in phase III. In case of study termination for futility at phase II, the patients 
will stop the study treatments and their care. 


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3 ANALYSIS POPULATIONS 
Three populations will be considered for the analyses: 
3.1 Intent-to-treat (ITT) population 
All randomised patients in the study. These patients will be considered in the allocated group by 
randomisation, even if they receive a different treatment. 
3.2 Modified Intent-to-treat (mITT) population 
All randomised patients in the study who did not withdrew their consent before the randomisation. 
These patients will be considered in the allocated group by randomisation, even if they receive a 
different treatment. 
mITT population will be considered as the primary population for efficacy analysis. 
3.3 Safety population 
All patients included in the mITT population having received at least one treatment injection. These 
patients will be analysed in terms of the treatment received. 
The safety population will be considered as the primary population for safety analysis. 


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4 GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Statistical analyses will be performed by the Biostatistics department of Aixial. Analyses will be 
conducted with SAS® software, version 9.4 or higher (SAS Institute, North Caroline, USA). 
All statistical tests will be two-sided and type I error (alpha) set to 10% for the primary endpoint and 
set to 5% for the other parameters.  
Continuous data will be described in summary tables presenting, for each treatment group and for the 
overall population, the number of non-missing observations (n), mean, standard deviation (StD), 
median, lower quartile (Q1), upper quartile (Q3), minimum and maximum, and 95% CI of the mean. 
Categorical data will be described in summary tables presenting, for each treatment group and for the 
overall population, the number of non-missing observations (n), count and percentage of each 
modality, and CI. 
90% CI of a proportion will be calculated using the Clopper-Pearson method for the primary endpoint 
and 95% CI of a proportion will be calculated using the score method of Wilson without continuity 
correction for the other parameters. 
Except minimum and maximum, descriptive statistics are presented with one more decimal than the 
recorded value. 
For all variables, the number of missing values will also be reported in the tables, but they will not be 
counted for the percentage calculation (categorical data). 
4.1 Statistical hypotheses 
The hypotheses as follows:  
H0: A rate of patients alive and progression free at 6 months of 45% or less is not sufficient to 
demonstrate efficacy (p≤p0 with p0=45%). The study will not be continued. 
H1: A rate of patients alive and progression free at 6 months of more than 45% is sufficient to 
demonstrate efficacy. A rate of 63% is expected (p≥p0 with p0=45% and p=p1 = 63%). A rate of 
patients alive and progression free at 6 months of more than 45% (i.e. if the lower bound of the exact 
binomial two-sided 90% CI exceeds 45%) leads to the study continuation. 
4.2 Display of analysis results 
Labels used for treatment groups will be Lanreotide and Placebo. 
4.3 Interim analyses 
No interim analysis will be performed. 
4.4 Centre effect management 
Centre effect will not be tested. 
4.5 Subgroup analyses 
No subgroup analysis is planned. 
4.6 Other strata and covariates 
No other strata or covariates will be tested. 
4.7 Multiple comparisons and multiplicity 
Not Applicable. 


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5 DATA HANDLING CONVENTIONS 
5.1 Missing data 
If a patient discontinues prematurely the study, the investigator should perform all the investigations 
planned at the final visit. 
Missing data will not be replaced. 
For the primary endpoint of the phase II, if at 6 months the progression is not documented and no 
progression was noticed before, the patients will be reviewed by the independent committee to 
classify him as progressive or not progressive at 6 months according to the medical data collected. 
5.2 Visit windows 
Not Applicable 
5.3 Derived and transformed data 
Following derived data used for analyses will be calculated. 
5.3.1 Time to initial diagnosis from randomisation (months) 
Time to initial diagnosis from randomisation (months) will be calculated as: 
(Date of randomisation – Date of initial diagnosis+1) / 30.4375. 
If the day is missing and month is present the 15 of the month will be used. Else time to initial 
diagnosis from randomisation will be missing. 
5.3.2 Time to initial progression from start of 1st line therapy (months) 
Time to initial progression from start of 1st line therapy (months) will be calculated as: 
(Star date of 1st line therapy – Date of initial progression+1) / 30.4375. 
If the day is missing and month is present the 15 of the month will be used. Else time to initial 
progression from start of 1st line therapy will be missing. 
5.3.3 Time to initial progression from randomisation (months) 
Time to initial progression from randomisation (months) will be calculated as: 
(Date of randomisation – Date of initial progression + 1) / 30.4375. 
If the day is missing and month is present the 15 of the month will be used. Else time to initial 
progression from randomisation will be missing. 
5.3.4 Duration of 1st line therapy (months) 
Duration of 1st line therapy (months) will be calculated as: 
(End date of treatment – Start date of treatment + x days ) / 30.4375. 
If the day is missing and month is present the 15 of the month will be used. Else duration of 1st line 
therapy will be missing. 
Number of days depends of the treatment taken for 1st line: 
- 
5FU/Xeloda/Oxaliplatine/Irinotecan = 14 days 
- 
Adriamycine = 28 days 
- 
Streptosocyne  = 42 days 
- 
Temozolomide (Daily Oral Treatment) 
- 
Dacarbazine= 21 jours 


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- 
Gemcitabine / Gemzar : 21 days   
- 
Carboplatin : 28 days 
- 
Doxorubicine : 28 days 
- 
Cisplatin : 21 days 
- 
Bevacizumab : 14 days 
- 
Sunitinib : 42 days 
 
5.3.5 Number of cycle performed 
A cycle will be considered as performed if administration of study treatment is performed 
5.3.6 Number of cycle delays 
A cycle will be considered as delays if: 
(Date of study treatment administration of Cycle x – Date of study treatment administration of Cycle  
x-1) > 28 
5.3.7 Duration of study treatment (years) 
Duration of study treatment (months) will be calculated as: 
(Last intake of study treatment– 1st intake of study of treatment +28) / 365.25. 
5.3.8 Response 
Response is defined as complete response (CR) or partial response (PR) to the treatment according 
to RECIST. 
5.3.9 Time to Progression  
This time to progression is calculated from the randomisation date to the date of the first progression 
(clinical or radiological) according to the investigator for progressive patients. 
5.3.10 Progression-free survival 
This time is calculated from the randomization date to the date of the first progression (clinical or 
radiological) according to the investigator. Patients alive without progression will be censored to the 
date of last news. 
 
5.3.11 Overall Survival 
 
This time is calculated from the randomization date to the date of death (whatever the cause is). 
Patients alive will be censored to the date of last news. 
 
5.3.12 Quality of life 
EORTC QLQ-C30 score and subscores 
The scale is made of 30 items that can be divided in nine multi-item scales (including five functional 
scales (15 items), one global health status / quality of life scale (2 items) and three general symptom 
scales (7 items)) and six single items. The Table below presents the conceptual structure of  
QLQ-C30. 
Possible answers to the first 28 items (all items except the two concerning global quality of life) go 
from 1 (“Not at all”) to 4 (“Very much”). No inversion is necessary to calculate the different 


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corresponding scores. The answers for the two last questions (29, 30) go from 1 (“Very poor”) to 7 
(“Excellent”). 
 
Dimension 
Sub-scales 
Number of items 
Item numbers 
FUNCTION 
Physical functioning 
Role functioning 
Emotional functioning 
Cognitive functioning 
Social functioning 
5 
2 
4 
2 
2 
1 to 5 
6, 7 
21, 22, 23, 24 
20, 25 
26, 27 
GLOBAL HEALTH STATUS 
Global quality of life 
2 
29, 30 
GENERAL SYMPTOMS 
Fatigue 
Nausea and vomiting 
Pain 
3 
2 
2 
10, 12, 18 
14, 15 
9, 19 
SPECIFIC SYMPTOMS 
Dyspnoea 
Insomnia 
Appetite loss 
Constipation 
Diarrhea 
Financial difficulties 
1 
1 
1 
1 
1 
1 
8 
11 
13 
16 
17 
28 
 
Scores will be calculated in agreement with the scoring manual [5]. All of the scales and single-item 
measures range in score from 0 to 100. A high scale score represents a higher response level. Thus 
a high score for a functional scale represents a high / healthy level of functioning, a high score for the 
global health status / quality of life represents a high quality of life, but a high score for a symptom 
scale / item represents a high level of symptomatology / problems. 
For multi-item scales, the raw score will be calculated by the addition of item responses divided by the 
number of items. Then a linear transformation will be used to standardise the raw score, so that 
scores range from 0 to 100; a higher score represents a higher (“better”) level of functioning, or a 
higher (“worse”) level of symptoms. 
Raw score (RS): 
RS = sum of item responses / number of items. 
Standardised score (S): 
Functional scales: S = 100 – [(RS – 1) / 3] x 100. 
Global health status: S = (RS – 1) / 6 x 100. 
Symptom scales / items: S = (RS – 1) / 3 x 100. 
Missing data: For multi-item scales, if at least 50% of the items from the scale have been answered 
then raw score will be calculated by the addition of available responses divided by the number of not 
missing items. If less than 50% of the items from the scale have been answered then the raw score 
will be set to missing. 
 
EORTC QLQ-G.I.NET 21 score and subscores 
The scale is made of 21 items that can be divided in five multi-item scales and four single items. The 
following table presents the conceptual structure of G.I.NET 21. 
 
 
 
Number of items 
Item numbers 
Multi-item scales 
Endocrine 
Gastro Intestinal 
Treatment 
Social function 
Disease related worries 
3 
5 
3 
3 
3 
31, 32, 33 
34, 35, 36, 37, 38 
39, 40, 46 
42, 44, 49 
41, 43, 47 
Single items 
Muscle/Bone pain  
Sexual function 
Information/communication 
function 
Body image 
1 
1 
1 
 
1 
48 
51 
50 
 
45 
 


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Possible answers go from 1 (“Not at all”) to 4 (“Very much”). A high score is equivalent to worse or 
more problems. The patient can also answer “N.A” to items 39, 40, 47 and 51. No inversion is 
necessary to calculate the different scores. 
For each scale, the raw score will be calculated by the addition of item responses divided by the 
number of items. Then a linear transformation will be used to standardise the raw score, so that 
scores range from 0 to 100. 
Raw score = sum of item responses / number of items. 
Standardised score = (raw score – 1) / 3 x 100. 
Single items will be treated individually. They will be linearly transformed to a 0-100 scale. 
Standardised score = (raw score – 1) / 3 x 100. 
Missing data: For multi-item scales, if at least 50% of the items from the scale have been answered 
then raw score will be calculated by the addition of available responses divided by the number of not 
missing items. 
Not applicable box: for calculations N/A data should be managed as for missing data. 
 
 
6 DESCRIPTION OF THE STUDY POPULATION 
6.1 Disposition of patients 
Patients’ disposition will be described for each treatment group and for the overall population. 
The number and percentage of screened and randomised patients will be presented, as well as the 
number of patients in all analysis populations. 
Following data will be described on mITT population: 
 
The number of patients per visit/cycle, 
 
The number of patients per centre, 
 
The number of patients who stopped the treatment and the reason of treatment withdrawal, 
 
The number of patients who stopped the follow-up visit and the last status reported. 
The number of patients with at least one major protocol deviation will be described for each treatment 
group and for the mITT population. Major deviations will be also presented in an individual data listing. 
6.2 Demographics and baseline characteristics 
The demographics and baseline characteristics of the patients will be described by treatment group 
and overall on mITT population. 
6.2.1 Demographic characteristics 
The following characteristics will be summarised by treatment group and overall: 
 
Age (years), 
 
Gender. 
6.2.2 Medical or surgical history 
Medical or surgical history will be coded using the Medicinal Dictionary for Regulatory Activities 
(MedDRA) version 22.0. 
Number (%) of patients will be presented by System Organ Class (SOC) and Preferred Term (PT) by 
treatment group and overall. 


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6.2.3 Previous and concomitant medications 
Previous and concomitant medications will be coded using the World Health Organisation-Drug 
Dictionary (WHO-Drug) version Q1-2018. 
Treatments will be summarized according to the Anatomical Therapeutic Chemical (ATC) class (level 
2 and level 4) of the WHO-Drug by treatment group and overall.  
A previous treatment will be defined as a treatment stopped prior to (or the same day as) the first 
intake of the study treatment.  
A concomitant treatment will be defined as a treatment i) started after (or the same day as) the first 
intake of the study treatment, ii) started prior to and continued after the first intake of the study 
treatment. If the classification is not possible due to partial start/end date(s) of treatment, the 
treatment will be considered as concomitant. 
6.2.4 Other baseline characteristics 
Cancer history will be summarised by treatment group and overall: 
 
Time to initial diagnosis from randomisation (months), 
 
Resectable cancer (Yes/No), 
 
Type de cancer and details: 
o 
Type of cancer (Locally advanced / Metastatic), 
o 
If metastatic, localisation (Hepatic / Pulmonary / Bone / Other; Note: A same patient 
can have several localisations), 
 
Histological grade (Grade 1 / Grade 2 / Grade 3), 
 
Ki67 (%), 
 
Ki67 assessed by the referent NET pathologist (Yes/No). 
First line of therapy will be summarised by treatment group and overall: 
 
Time to initial progression from start of 1st line therapy (months), 
 
Time to initial progression from randomisation (months), 
 
Treatment: 
o 
Type of treatment (Conventional / Targeted), 
o 
If conventional therapy, details of treatment (5FU / Oxaliplatine / Irinotecan / 
Adriamycine / Streptosotocyne / Xeloda / Temozolomide / Dacarbazine / Other). In 
case where a patient received several treatments, should we count the patient in only 
for the combination 
o 
 If targeted therapy, details of treatment (Sunitinib / Evorolimus / Other), 
o 
Duration of therapy (months). 
 
Response of first line treatment (CR / PR / Stable Disease [SD] / Progression [PD] / Not 
Evaluable [NE]). 
 
Values before first study treatment intake of the efficacy and safety endpoints will be provided in 
statistical tables with assessments post-baseline (see Section 6). 
6.3 Treatment exposure and compliance 
The following data on the use of study treatment will be summarized by treatment group and overall 
on the Safety population. 
 
Number of cycles performed, 
 
Number of cycles delays, 
 
Duration of study treatments (years). 
 


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7 EFFICACY ANALYSIS 
Primary efficacy endpoint will be primarily analysed on the mITT population. Secondary efficacy 
endpoints will be analysed on the mITT population. 
7.1 Primary efficacy endpoint 
The primary endpoint for phase II is the rate of patients alive and progression free at 6 months, 
evaluated according to the results of imaging assessment done 6 months after the randomisation. 
This evaluation is done by the investigator according to RECIST criteria (version 1.1). 
The number and percentage of patients alive and progression free at 6 months will be calculated and 
described by treatment group and overall on the mITT population. The two-sided 90% CIs will also be 
calculated. 
7.2 Secondary efficacy endpoints 
7.2.1 Rate of patients alive and progression free at 12 months, assessed 
by the investigator 
The number and percentage of patients alive and progression free at 12 months will be calculated 
and described by treatment group and overall on the mITT population based on Kaplan-Meier method 
with the estimation of this number at 12 months. Rate of patients alive and progression free at 6 
months, according to central review 
The number and percentage of patients alive and progression free at 6 months will be calculated and 
described by treatment group and overall on the mITT population. Data taken into account will be 
overall response at Cycle 4 and Cycle 7 + death if before injection of cycle 7. Patients alive and 
progression free before or at cycle 7 will be reviewed separately. 
7.2.2 Response rate at 6 months 
Overall Response (CR, PR, SD, PD, NE) and Clinical Progression (Yes/No) will be presented every 3 
months (at Cycles 4, 7, 10, 13, 16, …). 
Response rate according to RECIST criteria at 6 months (version 1.1), according to the investigator 
will be calculated and described.  
Patients alive and progression free before or at cycle 7 will be reviewed separately. 
7.2.3 Time to progression 
Among the patient with a progression during the phase II, the time to progression will be calculated 
and described by treatment group and overall. 
7.2.4 Progression-Free Survival 
 
 Progression-free survival will be analysed using the Kaplan Meier method. The description will be 
made using the median, and the rates will be estimated at different stages of evaluation (95% 
confidence intervals will also be provided). The comparison between the two treatment arms will be 
made using a log-rank test.  
The hazard ratio will be estimated using a Cox model. An unadjusted model (only with treatment 
effect) and a model adjusted to the stratification factors will be used. All hypotheses associated with 
the use of this model (proportionality and linearity) will be verified. 
7.2.5  Overall Survival 
 
Overall survival will be analysed using the Kaplan Meier method. The description will be made using 
the median, and the rates will be estimated at different stages of evaluation (95% confidence intervals 


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will also be provided). The comparison between the two treatment arms will be made using a log-rank 
test.  
The hazard ratio will be estimated using a Cox model. An unadjusted model (only with treatment 
effect) and a model adjusted to the stratification factors will be used. All hypotheses associated with 
the use of this model (proportionality and linearity) will be verified. 
7.2.6 Quality of life 
The scores and subscores of EORTC QLQ-G.I.NET 21 and EORTC QLQ-C30 as well as the Spitzer 
visual analogue scale will be described every 3 months (at Cycles 4, 7, 10, 13, 16, …). 


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8 SAFETY ANALYSIS 
Safety endpoints will be analysed on the Safety population. 
8.1 Adverse events 
Adverse events will be coded using MedDRA version 22.0. Pre-defined AEs and other AEs should be 
analysed together. 
An overall summary table presenting the number and the percentage of patients with at least one AE 
and one with at least SAE will be presented by treatment group and overall. 
Following descriptions will be performed by treatment group and overall: 
 
Number of patients with AEs by SOC and PT, 
 
Number of patients with AEs by SOC, PT and maximal grade, 
In addition, the same description will be performed for SAEs. 
A patient with more than one AE within a particular SOC and PT are counted only once for that SOC 
and PT. Percentages are based on the number of patients actually receiving a given treatment (based 
on the safety population) within each treatment group. 
A listing of all AEs will be provided. 
No formal statistical tests will be performed. 
8.2 Vital signs 
Vital Signs (Weight) and WHO performance index will be described by treatment group and overall, at 
each cycle and at end of treatment visit. For Weight, change from baseline will be also described by 
treatment group and overall. 
 


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9 CHANGES FROM STUDY PROTOCOL 
Not Applicable. 
10 VALIDATION OF STATISTICAL PROGRAMMING 
Validation of statistical programming will be performed in agreement with Aixial’s Standard Operating 
Procedure on Statistical Analysis. 
Logs of all programs used for analysis and data preparation will be checked for errors and 
unexpected warnings. 
A third party will review all statistical outputs (tables, figures) and results from statistical tests/models, 
as well as SAS code of all statistical programs. This includes programs used to derive data and 
macros developed for the study. 
Any undocumented updating of study data in statistical programs instead of change in clinical 
database (or source data) is not allowed. Specifically, this refers to the cases where patients or the 
data are added/changed using a statistical program rather than updating the database. This kind of 
hard coding is usually proposed to correct deficiencies (missing values, wrong values, and wrong 
measurement units) in the database when these errors are detected after database lock.  
No hard coding is done in any programs used for the creation of analysis data sets, tables, listings, or 
analyses that are intended for external reporting after database lock (i.e. clinical study reports, 
publications, abstracts, etc.).   
This policy ensures integrity of clinical data, since no changes are made to the study data without 
appropriate documentation from the investigator sites and appropriate audit trails within the clinical 
trial database. 
11 REFERENCES 
[1] ICH guidelines - E9: Statistical Principles for Clinical Trials, Adopted in EU by CPMP, March 
1998, issued as CPMP/ICH/363/96 
[2] ICH guidelines - E3: Structure and Content of Clinical Study Reports, Adopted in EU by CPMP, 
December 95, issued as CPMP/ICH/137/95  
[3] SAS 9.4; © 2008 by SAS Institute Inc., Cary, NC, USA; OnLine Doc. 
[4] NewCombe R.G. (1998) Two sided confidence intervals for the single proportion: comparison of 
seven methods in Medicine; 17,857-872. 
[5] Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published 
by: European Organisation for Research and Treatment of Cancer, Brussels 2001. 
 


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APPENDIX 1. TEMPLATES FOR STATISTICAL ANALYSIS AND 
SUMMARY TABLES 
 
 


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Study: XXXXX 
Page X / N 
Population: XXXXX 
 
Table X – Summary of patients disposition 
 
 
Lanreotide 
Placebo 
Total 
Screened patients 
 
 
xx 
Randomised patients 
xx 
xx 
xx (xx.x%) 
Safety population 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
ITT population 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
mITT population 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Per-Protocol population 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Name of SAS program: P:\XXXXX\XXXX\Analysis\Pgm\program_name.sas 
Date and time program was run: JJMMMYYYY HH:MM 
 


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Study: XXXXX 
Page X / N 
Population: XXXXX 
 
Table X – Summary of visits/cycles 
 
 
Lanreotide 
(N=XX 
Placebo 
(N=xx) 
Total 
(N=xx) 
Screening/Randomisation 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Cycle 1 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Cycle 2 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
…. 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Follow-up 1  
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Follow-up 2 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
… 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Name of SAS program: P:\XXXXX\XXXX\Analysis\Pgm\program_name.sas 
Date and time program was run: JJMMMYYYY HH:MM 


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Study: XXXXX 
Page X / N 
Population: XXXXX 
 
Table X – Summary / Analysis of qualitative and quantitative variables 
 
 
Lanreotide 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
Quantitative variable 
 
 
 
   n 
xx 
xx 
xx 
   Mean (SD) 
xx.x (xx.x) xx.x (xx.x) xx.x (xx.x) 
   95%CI mean 
[xx.x ; xx.x] [xx.x ; xx.x] [xx.x ; xx.x] 
   Median 
xx.x 
xx.x 
xx.x 
   Q1 ; Q3 
xx.x ; xx.x xx.x ; xx.x xx.x ; xx.x 
   Min. ; Max. 
xx ; xx 
xx ; xx 
xx ; xx 
   Missing data 
xx 
xx 
xx 
 
 
 
 
Qualitative variable 
 
 
 
   n 
xx 
xx 
xx 
   Modality 1 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
   95%CI (Modality 1)* 
[xx.x ; xx.x] [xx.x ; xx.x] [xx.x ; xx.x] 
   Modality 2 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
   95%CI (Modality 2)* 
[xx.x ; xx.x] [xx.x ; xx.x] [xx.x ; xx.x] 
   … 
… 
… 
… 
   Modality n 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
   95%CI (Modality n)* 
[xx.x ; xx.x] [xx.x ; xx.x] [xx.x ; xx.x] 
   Missing data 
xx 
xx 
xx 
 
 
 
 
* Will be replaced by 90%CI for primary endpoint 
 
Name of SAS program: P:\XXXXX\XXXX\Analysis\Pgm\program_name.sas 
Date and time program was run: JJMMMYYYY HH:MM 


FFCD 
Protocol n° PRODIGE 31 - REMINET 
Statistical Analysis Plan 
Final – 18SEP2019 
Page 28/29 
 
 
 
 
 
 
 
 
Study: XXXXX 
Page X / N 
Population: XXXXX 
 
Table X – Summary of events per System Organ Class and Preferred term 
 
 
Lanreotide 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
 
Nb (%) of 
patients 
Nb (%) of 
patients 
Nb (%) of 
patients 
At least one AE 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
Body system 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       … 
 
 
 
Preferred term n 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Body system 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       … 
 
 
 
Preferred term n 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
…. 
 
 
 
Body system n 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       … 
 
 
 
Preferred term n 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Nb (%) of patients : Number (%) of patients with at least one AE 
Each patient is counted once per Preferred Term then per System Organ Class 
 
Name of SAS program: P:\XXXXX\XXXX\Analysis\Pgm\program_name.sas 
Date and time program was run: JJMMMYYYY HH:MM 


FFCD 
Protocol n° PRODIGE 31 - REMINET 
Statistical Analysis Plan 
Final – 18SEP2019 
Page 29/29 
 
 
 
 
 
 
 
Study: XXXXX 
Page X / N 
Population: XXXXX 
 
Table X – Summary of events per SOC, PT and grade 
 
 
Lanreotide 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
 
Nb (%) of 
patients 
Nb (%) of 
patients 
Nb (%) of 
patients 
At least one AE 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
Body system 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
…. 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
…. 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Preferred term 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
…. 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
Preferred term n 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
…. 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
…. 
 
 
 
 
 
 
 
Nb (%) of patients : Number (%) of patients with at least one AE 
Each patient is counted once per Grade, Preferred Term then per System Organ 
Class 
 
Name of SAS program: P:\XXXXX\XXXX\Analysis\Pgm\program_name.sas 
Date and time program was run: JJMMMYYYY HH:MM