Clinical trial NCT02396953
Conditions: Acromegaly
Sponsor: Ipsen
Start date: 2015-03-01; Completion date: 2017-11-28
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objectives of the protocol is to determine the maximum tolerated dose and to investigate the pharmacokinetics of a single dose of lanreotide PRF in subjects with acromegaly.

Detailed description:

Arms: arm 1: One single dose of lanreotide PRF (via subcutaneous injection) either 180mg or 270mg or 360mg.
Interventions: intervention 1: Lanreotide PRF
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 1 OF 173 
 
 
PROTOCOL TITLE: PHASE IIA, OPEN LABEL, DOSE ASCENDING STUDY TO 
DETERMINE THE MAXIMUM TOLERATED DOSE, SAFETY AND 
TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF A 
SINGLE DOSE OF LANREOTIDE PRF IN SUBJECTS WITH ACROMEGALY 
PREVIOUSLY TREATED AND CONTROLLED WITH EITHER OCTREOTIDE 
LAR OR LANREOTIDE AUTOGEL 
 
STUDY PROTOCOL 
STUDY NUMBER: 8-55-52030-309 
 
LANREOTIDE PRF SOLUTION FOR INJECTION 
EudraCT Number: 2014-002389-62 
 
Final Version (with Amendment 7): 16 December 2016 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
David Rich, MPhil 
Ipsen Pharma SAS 
Ipsen Biopharm Limited 
65 quai George Gorse 
102 Park Drive 
92100 Boulogne Billancourt (France) 
Milton Park  
Tel: +33 1 58 33 50 50 
Oxfordshire, OX14 4RY (UK) 
Fax: +33 1 58 33 50 01 
 
 
 
 
 
Monitoring Office:  
Principal Investigator: 
 
Sebastian J.C.M.M. Neggers, MD, PhD 
Ipsen Innovation 
Department of Medicine  
5 avenue du Canada 
Section Endocrinology 
91966 Les Ulis Cedex (France) 
Erasmus University MC Rotterdam 
 
PO Box 2040 
 
3000 CA Rotterdam 
 
(The Netherlands) 
 
Pharmacovigilance/Emergency Contact: 
, Global Patient Safety, Ipsen Biopharm Limited, 102 Park Drive, 
Milton Park, Oxfordshire, OX14 4RY (UK)  
Tel: 
 
 
 – mobile telephone for emergencies 
For serious adverse events (SAEs) reporting:  
 
Fax: 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PAGE 2 OF 173 
 
INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol 8-55-52030-309 entitled “phase IIA, open label, dose 
ascending study to determine the maximum tolerated dose, safety and tolerability, 
pharmacokinetics and pharmacodynamics of a single dose of lanreotide PRF in subjects with 
acromegaly previously treated and controlled with either octreotide LAR or lanreotide 
Autogel”. I am aware of my responsibilities as an investigator under the guidelines of Good 
Clinical Practice (GCP), local regulations (as applicable) and the study protocol. I agree to 
conduct the study according to these guidelines and to appropriately direct and assist the staff 
under my control, who will be involved in the study. 
NAME: 
 
 
 
TITLE: 
 
 
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
Sponsor's Representative Signature: 
NAME: 
David Rich, MPhil 
 
 
TITLE: 
Medical Development 
Director - Endocrinology 
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
 


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CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 3 OF 173 
 
COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol 8-55-52030-309 entitled “phase IIA, open label, dose 
ascending study to determine the maximum tolerated dose, safety and tolerability, 
pharmacokinetics and pharmacodynamics of a single dose of lanreotide PRF in subjects with 
acromegaly previously treated and controlled with either octreotide LAR or lanreotide 
Autogel”. I am aware of my responsibilities as a coordinating investigator under the guidelines 
of GCP, local regulations (as applicable) and the study protocol. I agree to conduct the study 
according to these guidelines and to appropriately direct and assist the staff under my control, 
who will be involved in the study. 
 
NAME: 
Sebastian J.C.M.M. Neggers, MD, PhD 
 
 
 
TITLE: 
Principal Investigator 
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
 


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PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
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SUMMARY OF CHANGES 
The initial version of the protocol dated 01 September 2014 was amended six times. The current 
version of the protocol was released on 16 December 2016 and includes Amendments 1 to 7. 
The protocol amendment forms were prepared and are provided in Appendices 3 to 8 (Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
19 November 2014 
Appendix 3 
2 
18 February 2015 
Appendix 4 
3 
12 June 2015 
Appendix 5 
4 
27 July 2015 
Appendix 6 
5 
22 March 2016 
Appendix 7 
6 
20 May 2016 
Appendix 8 
7 
16 December 2016 
Appendix 9 


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SYNOPSIS 
Name of sponsor/company: Ipsen Pharma SAS 
Name of finished product: Lanreotide prolonged release formulation (PRF), solution for injection 
Name of active ingredient(s): Lanreotide acetate 
Title of study: Phase IIa, open label, dose ascending study to determine the maximum tolerated 
dose, safety and tolerability, pharmacokinetics and pharmacodynamics of a single dose of 
lanreotide PRF in subjects with acromegaly previously treated and controlled with either octreotide 
LAR or lanreotide Autogel 
Study number: 8-55-52030-309 
Number of planned centres: up to 40 
Planned study period: 02/2015 to 06/2018 
Phase of development: Phase IIa  
Objectives:  
Primary: 
 To identify the maximum tolerated dose (MTD) and to investigate the pharmacokinetics (PK) 
of a single dose of lanreotide PRF in subjects with acromegaly 
Secondary: 
 To investigate the safety and tolerability of a single dose of lanreotide PRF 
 To investigate the pharmacodynamics (PD) of a single dose of lanreotide PRF 
 To investigate the PK of the excipient 
Exploratory: 
Biobanking of blood samples for further biomarkers analysis in subjects who consent to the 
exploratory part of the study 
Methodology:  
Subjects with acromegaly who have been well controlled for at least 3 months on a stable dose of 
octreotide long acting release (LAR) or lanreotide Autogel will be recruited to this open label study. 
Eligible subjects will enter a 4 week run in period (or up to 6 weeks under certain circumstances), 
during which they will receive the same single dose of either octreotide LAR or lanreotide Autogel 
as their previous treatment. A 12 week treatment period will then commence, during which subjects 
will receive one deep subcutaneous injection of lanreotide PRF on Day 1 (4 weeks or up to 6 weeks 
under certain circumstances after the last octreotide LAR or lanreotide Autogel administration). 
Subjects will remain at the study centre for 24 hours after the dose. A follow up period of 
12 additional weeks after the 12 week treatment period, will also be included. During the follow 
up period, subjects will not receive any treatment for acromegaly. Study visits will be performed 
on Days 1, 2, 3, and 5, and Weeks 2, 3, 4, 5, 7, 9, 11 and 13 of the treatment period, and at Weeks 
15, 17, 19, 21, 23 and 25 during follow up. All study visits can be performed at the study site. 
However, study visits on Weeks 4, 7, 11, 15, 19 and 23 can be performed at the study site and/or 
at the subjects home as per investigator’s and subject’s decision. 
It is planned to include three cohorts of subjects; Cohort 1 will receive lanreotide PRF 180 mg, 
Cohort 2 will receive 270 mg and Cohort 3 will receive 360 mg. Nine subjects will be allocated to 
each lanreotide PRF treatment cohort. Each cohort must enrol at least six subjects previously 
treated with octreotide LAR. Each cohort can enrol up to three subjects previously treated with 
lanreotide Autogel.  
Progression to each ascending dose cohort (or groups of subjects) will be dependent upon a review 
of data from the preceding cohort (or groups of subjects) during meetings of the data review 
committee (DRC). The DRC will review the safety data from each cohort after all subjects in the 
cohort completed Visit 5 (Week 2 postdose). At this time, if no unexpected safety signals have been 
observed and the overall safety is in line with the known lanreotide safety profile, the DRC will 
decide whether to proceed with the next treatment cohort (or groups of subjects). The dose 
escalation will proceed with a 3+3+3 scheme in order to enrol nine subjects within each dose cohort. 
In Cohort 2 subjects will be reviewed on a 1+2+2+2+2 scheme and in Cohort 3 on a 2+2+2+3 
scheme. 
If any serious adverse events (SAEs) occur, a relationship with the exposure to lanreotide PRF will 
be assessed. The pre-established stopping rules for the DRC decision for study discontinuation 


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and/or inclusion of the subsequent treatment cohort include the occurrence of dose limiting 
toxicities (DLTs). A DLT is defined as an adverse event (AE; excluding anorexia and fatigue) or 
an abnormal laboratory value occurring within the first week (up to Visit 5 (Week 2)) following 
lanreotide PRF administration and during the entire study duration, assessed as unrelated to 
acromegaly, intercurrent illness or concomitant medications and which meets any of the 
pre-established criteria (more often grade 3 or 4 toxicity according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) criteria). The occurrence of 
2 DLTs would trigger the organisation of an intermediate DRC meeting (ad hoc meeting) to 
evaluate the decision to test 3 more subjects (2 more subjects for Cohort 2 and Cohort 3) at the 
same dose level.  
The identification of the MTD will be left to the discretion of the DRC. 
Assessments throughout the follow up period will evaluate the safety, tolerability and PK of 
lanreotide PRF. Levels of insulin like growth factor-1 (IGF-1) and growth hormone (GH) will also 
be evaluated. The proportion of subjects with age adjusted IGF-1 levels <1.3 x upper limit of 
normal (ULN), with GH ≤2.5 ng/mL and with GH ≤1.0 ng/mL will be recorded. During the follow 
up period, if the investigator judges that the subject requires any treatment for acromegaly 
(reappearance of clinical or biochemical symptoms of acromegaly), the subject will be withdrawn 
from the study and will receive treatment according to routine clinical practice. 
The overall duration of the study will be approximately 32 months. Each subject will participate in 
the study for up to 7.5 months. 
Number of subjects planned:  
A maximum of 27 subjects will be treated with lanreotide PRF (nine subjects per cohort). 
Diagnosis and criteria for inclusion:  
Subjects with acromegaly, well controlled by a stable dose of either octreotide LAR or lanreotide 
Autogel for at least 3 months. 
All toxicities will be graded according to NCI CTCAE, Version 4.03. 
Inclusion criteria: 
All subjects must fulfil all of the following criteria to be included in the study: 
(1) 
Documented diagnosis of acromegaly. 
(2) 
Provided written informed consent prior to any study related procedures. 
(3) 
Between 18 and 75 years of age inclusive. 
(4) 
Female of nonchildbearing potential or male. Nonchildbearing potential is defined as being 
postmenopausal for at least 1 year, or women with documented infertility (natural or 
acquired).  
(5) 
Male subjects must agree that, if their partner is at risk of becoming pregnant, they will use 
a medically accepted, effective method of contraception (i.e. condom) for the duration of the 
study (up to 7.5 months). 
(6) 
Treatment with a stable dose of either octreotide LAR or lanreotide Autogel for at least 
3 months immediately prior to study entry, with confirmation of disease control during this 
treatment period (documentation of age adjusted IGF-1 <1.3 x ULN, based on local 
laboratory results, during the Screening period).  
(7) 
If the subject is receiving treatment for hypertension, the dose has been stable for at least 
1 month prior to study entry. 
(8) 
Subjects must be willing and able to comply with study restrictions and to remain at the 
clinic for the required duration during the study period and willing to return to the clinic for 
the follow up evaluation as specified in the protocol. 
Exclusion criteria: 
Subjects will not be included in the study if the subject: 
(1) 
Has undergone radiotherapy within 2 years prior to study entry. 
(2) 
Has been treated with a dopamine agonist and/or GH receptor antagonist or has undergone 
pituitary surgery within 3 months prior to study entry. 
(3) 
Is anticipated to require pituitary surgery or radiotherapy during the study.  


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(4) 
Has clinically significant hepatic abnormalities and/or alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) ≥3 x ULN and/or alkaline phosphatase (ALP) 
≥2.5 x ULN and/or total bilirubin ≥1.5 x ULN and/or gamma-glutamyl transpeptidase 
(GGT) ≥2.5 x ULN during the Screening period (central laboratory results) or a history of 
these findings when on somatostatin analogue (SSTa) treatment. 
(5) 
Has clinically significant pancreatic abnormalities and/or amylase and/or lipase ≥1.5 x ULN 
during the Screening period (central laboratory results). 
(6) 
Has any significant renal abnormalities and/or creatinine ≥1.5 x ULN during the Screening 
period (central laboratory results). 
(7) 
Has uncontrolled diabetes (glycosylated haemoglobin (HbA1c) ≥9%, centrally assessed 
during the Screening period), or has diabetes treated with insulin for less than 6 months prior 
to study entry. 
(8) 
Has any known uncontrolled cardiovascular disease or had any of the following within 
6 months of Screening: ventricular or atrial dysrhythmia ≥grade 2, bradycardia ≥grade 2, 
electrocardiogram (ECG) QT interval corrected (QTc) prolonged ≥grade 2, myocardial 
infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular 
accident or transient ischemic attack, pulmonary embolism, hypertension not adequately 
controlled by current medications. 
(9) 
Use of any hormone replacement therapy (HRT) with oestrogens.  
(10) Has symptomatic gallstones/sludge at the Screening Visit echography (local assessment) OR 
is asymptomatic but has echography showing clear evidence of impending inflammation 
such as localised mucosal thickening suggesting the subject is at high risk of developing 
acute disease. Subjects with asymptomatic gallstones/sludge and otherwise normal 
echography may be entered at the discretion of the investigator. 
(11) Has abnormal findings during the Screening period, any other medical condition(s) or 
laboratory findings that, in the opinion of the investigator, might jeopardise the subject’s 
safety. 
(12) Has been treated with any other investigational medicinal product (IMP) prior to the first 
study visit without undergoing a washout period of seven times the elimination half life of 
the investigational compound. 
(13) Has a known hypersensitivity to any of the test materials or related compounds. 
(14) Is likely to require treatment during the study with drugs that are not permitted by the study 
protocol. 
(15) Has a history of, or known current, problems with alcohol or drug abuse. 
(16) Has any mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude. 
Test product, dose, mode of administration: 
Lanreotide PRF will be supplied in a 1.2 mL prefilled syringe fitted with a 1.2/1.4 mm (inner 
diameter/outer diameter) needle packed in a laminated pouch. 
The product is intended to deliver 180, 270 or 360 mg lanreotide (potency is expressed as lanreotide 
base) for the phase 2a clinical study. The different strengths are dose proportional as syringes are 
filled with increasing quantities of the same lanreotide supersaturated bulk solution. 
All strengths will be provided in the same presentation. 
Lanreotide PRF will be administered by deep subcutaneous injection in the superior, external 
quadrant of the buttock at the doses indicated in the table below. Nine subjects will be allocated to 
each dose cohort. 
Cohort [a] 
Lanreotide PRF dose 
1 
180 mg 
2 
270 mg 
3 
360 mg 
a each subsequent dose cohort will be initiated following recommendations from the DRC. 


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Duration of treatment: 
Overall study duration: Approximately 32 months for three dose levels.  
Subject study participation: Up to 7.5 months (4 week run in period or up to 6 weeks under certain 
circumstances, a 12 week treatment period and a 12 week follow up period without treatment). 
Reference therapy, dose and mode of administration: Not applicable. 
Criteria for evaluation (treatment period): 
Safety variables: 
 
AEs, throughout the study.  
 
Vital signs (supine and standing blood pressure and heart rate, and body temperature) at 
Screening, Baseline (predose on Day 1), 6 and 24 hours postdose, and at Weeks 2, 3, 4, 5, 
7, 9, 11 and 13 of the treatment period. 
 
Physical examination at Screening, Baseline (predose on Day 1), 6 and 24 hours postdose, 
and at Weeks 2, 3, 4, 5, 7, 9, 11 and 13 of the treatment period. 
 
12-lead ECG, QTc interval will be calculated using Fridericia methodology in all subjects 
at Screening, Baseline (predose on Day 1), 6 hours postdose on Day 1, 24 hours postdose, 
and at Weeks 2, 5 and 13. 
 
Clinical laboratory assessments: haematology, coagulation, clinical biochemistry, 
urinalysis at Screening, Baseline (predose on Day 1), 6 hours postdose on Day 1, 24 hours 
postdose on Day 2, Day 3, and Weeks 2, 3, 4, 5, 9 and 13 of the treatment period. 
 
HbA1c at Screening and Week 13. 
 
Estimated glomerular filtration rate (eGFR) estimated by the Modification of Diet in Renal 
Disease (MDRD) formula [1], at Screening, Baseline (predose on Day 1), and Weeks 2, 5, 
9 and 13 of the treatment period. 
 
Gallbladder echography at Screening, Week 5 and Week 13 of the treatment period. 
 
Putative antibodies to lanreotide at Baseline (predose on Day 1) and Week 13. 
 
Evaluation of injection site reactions (appearance, local symptoms). These will be 
evaluated on a specific form in the electronic case report form (eCRF) at 1 and 6 hours 
postdose on Day 1, 24 hours postdose and at Weeks 2, 3, 4, 5, 7, 9, 11 and 13 of the 
treatment period. 
Pharmacokinetic variables: 
Lanreotide serum concentration at the following timepoints after administration of lanreotide PRF:  
 
Baseline (predose on Day 1 of lanreotide PRF administration). 
 
At 1, 2, 4, 6, 8 and 12 hours postdose on the day of dosing (Day 1). 
 
At 24 hours postdose (Day 2). 
 
On Days 3 and 5, and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration (the 
Week 13 sample will be on Day 85 and will correspond to the concentration at the end of 
the dosing interval (Ctrough)). 
 
Noncompartmental analysis will be performed and the following PK parameters will be 
computed: Ctrough, maximum serum concentration (Cmax), time to maximum serum 
concentration (Tmax), area under the serum concentration time curve from time 0 to 85 days 
(AUC0-85), area under the concentration time curve extrapolated to infinity (AUC0-), 
apparent terminal half life (t1/2), mean residence time (MRT), apparent clearance (CL/F) 
and apparent volume of distribution (V/F). 
Excipient serum concentration at the following timepoints:  
 
Baseline (predose on Day 1 of lanreotide PRF administration). 
 
At 1, 2, 4, 6, 8 and 12 hours postdose on the day of dosing (Day 1), at 24 hours postdose 
(Day 2), and on Days 3 and 5 after lanreotide PRF administration. 
 
Noncompartmental analysis of the excipient time concentration data will be performed and 
the following PK parameters will be computed: Cmax, Tmax, area under the serum 
concentration time curve from time 0 to last quantifiable timepoint (AUCt), AUC0-, t1/2, 
MRT, CL/F and V/F. 
 


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Pharmacodynamic variables: 
The following PD variables will be assessed in all subjects: 
 
IGF-1 at Screening, Baseline (predose on Day 1), at 6 hours postdose on the day of dosing 
(Day 1) and at Weeks 5, 9 and 13. 
 
GH cycle (five sampling times with a sample every 30 minutes for 2 hours in the morning) 
at Screening, Baseline (predose on Day 1) and at Weeks 5 and 13.  
 
Random GH sample at 6 hours postdose on the day of dosing (Day 1) and at Week 9. 
 
Free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH) and 
prolactin (PRL) at Screening, Baseline (predose on Day 1), and at Weeks 2, 5 and 13 of 
the treatment period. 
Biobanking: 
Blood samples will be collected at Baseline (predose on Day 1), Weeks 5 and 13 and stored for 
further biomarkers analysis after the end of the study in subjects who consent to the exploratory 
part of the study. 
Criteria for evaluation (follow up period): 
During the follow up period, study visits will be conducted every 2 weeks (±3 days).  
Assessments for all subjects will include the following safety and PK variables: 
 AEs throughout the study 
 Concomitant medications, throughout the study 
 Vital signs (supine and standing blood pressure and heart rate, and body temperature) at each 
follow up visit 
 Physical examination at each follow up visit 
 Gallbladder echography (only at Week 25 or at early withdrawal (EW)) 
 Clinical laboratory assessments at each follow up visit 
 HbA1c (only at Week 25 or at EW)  
 eGFR at Weeks 17, 21 and 25 (or at EW) 
 Evaluation of injection site reactions at each follow up visit 
 Putative antibodies to lanreotide (only at Week 25 or at EW) 
 PK blood sample for lanreotide at Weeks 17, 21 and 25 (or at EW) 
The following PD variables will also be assessed for all subjects at Weeks 17, 21 and 25 (or at 
EW): 
 IGF-1 
 Random GH sample 
 FT3, FT4, TSH, PRL (only at Week 25 or at EW) 
Statistical methods: 
Inclusion of nine subjects within a dose cohort (180, 270 or 360 mg) will be based on an adaptive 
3+3+3 decision rule (in Cohort 2 on a 1+2+2+2+2 and in Cohort 3 on a 2+2+2+3 decision rule) 
focussing a priori on the subject safety. This means that the addition of up to nine subjects would 
be based on the MTD profile and decisions made at that dose level. In addition, the sample size is 
based on prior clinical experience with this type of study and subject population and should be 
sufficient to meet the study objectives. As this is a descriptive safety, tolerability and PK/PD study, 
no formal statistical testing will be performed. 
Each subject who receives the single dose of lanreotide PRF and who has at least one postbaseline 
safety assessment will be analysed for safety (Safety population). Safety data (TEAEs, SAEs, vital 
signs, ECG and clinical laboratory tests) will be presented by dose cohort and overall. 
The analysis of PK data for lanreotide and the excipient will be performed by a contract research 
organisation (CRO) under Ipsen’s Pharmacokinetics and Drug Metabolism (PDM) Department 
supervision using a noncompartmental approach. Descriptive summary statistics (number of 
observations (n), mean, median, standard deviation (SD), range, geometric mean and geometric 
coefficient of variation for continuous variables, and n and percentage for categorical/nominal 
variables) will be presented for the serum concentration data of lanreotide and the excipient and 
PK parameters per dose cohort. 


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Additional exploratory model-based analysis (population PK analysis) might also be conducted to 
characterise lanreotide PK parameters such as clearance and volume of distribution, as well as their 
interindividual variability.  
The magnitude of the effect on PD parameters (change from Baseline) will be summarised by using 
95% confidence intervals (CIs) for the intent to treat (ITT) and per protocol (PP) populations. To 
investigate the relationship between PD variables (GH and IGF-1) and lanreotide exposure, 
exploratory PK/PD modelling may be performed if a relationship can be defined. Details regarding 
PK and PK/PD modelling will be described in a separate Data Analysis Plan and the results will be 
reported as a standalone report. 


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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 2 
COORDINATING INVESTIGATOR’S AGREEMENT..................................................... 3 
SYNOPSIS ................................................................................................................................ 5 
TABLE OF CONTENTS ....................................................................................................... 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................... 17 
1 
BACKGROUND INFORMATION ............................................................................ 20 
1.1 
Introduction ................................................................................................................... 20 
1.2 
Name and Description of Investigational Medicinal Product(s) .............................. 20 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 21 
1.4 
Known and Potential Risks and Benefits to Human Patients ................................... 22 
1.4.1 
Individual Benefits ...................................................................................... 22 
1.4.2 
Collective Benefits ....................................................................................... 22 
1.4.3 
Known and Potential Risks ......................................................................... 22 
1.5 
Selection of Investigational Medicinal Products and Doses ...................................... 23 
1.6 
Compliance Statement .................................................................................................. 24 
1.7 
Population to Be Studied .............................................................................................. 24 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 26 
2.1 
Purpose of the Study ..................................................................................................... 26 
2.2 
Study Objectives ........................................................................................................... 26 
3 
STUDY DESIGN ........................................................................................................... 27 
3.1 
General Design and Study Schema ............................................................................. 27 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 30 
3.2.1 
Safety Variables ........................................................................................... 30 
3.2.2 
Pharmacokinetic Variables ......................................................................... 30 
3.2.3 
Pharmacodynamic Variables ...................................................................... 31 
3.2.4 
Biobanking .................................................................................................. 31 
3.3 
Randomisation and Blinding ....................................................................................... 31 
3.4 
Study Treatments and Dosage ..................................................................................... 32 
3.5 
Study Duration .............................................................................................................. 32 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 33 
3.6.1 
Discontinuation ........................................................................................... 33 
3.6.2 
Stopping Rules ............................................................................................. 33 
3.6.3 
Definition of Dose Limiting Toxicity .......................................................... 33 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability ......... 34 
3.7.1 
Investigational Medicinal Product Storage and Security .......................... 34 
3.7.2 
Investigational Medicinal Product Preparation ........................................ 34 
3.7.3 
Investigational Medicinal Product Accountability .................................... 34 
3.8 
Maintenance of Randomisation and Blinding ............................................................ 35 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 35 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 36 


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4.1 
Inclusion Criteria .......................................................................................................... 36 
4.2 
Exclusion Criteria ......................................................................................................... 36 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 37 
5 
STUDY PROCEDURES .............................................................................................. 39 
5.1 
Study Schedule .............................................................................................................. 39 
5.2 
Study Visits .................................................................................................................... 43 
5.2.1 
Procedures for Screening and Enrolment (Visit 1) ................................... 43 
5.2.2 
Procedures Before Study Treatment (Baseline, Visit 2 Predose) .............. 45 
5.2.3 
Procedures During Study Treatment (Visit 2 Postdose to Visit 12) .......... 45 
5.2.4 
Procedures After Study Treatment ............................................................. 48 
5.2.4.1 
Follow Up Visits .......................................................................................... 48 
5.2.4.2 
End of Study Visit (Week 25, Visit 18) or Early Withdrawal Visit .............. 49 
6 
TREATMENT OF SUBJECTS ................................................................................... 50 
6.1 
Investigational Medicinal Product Administered ...................................................... 50 
6.1.1 
Dose Escalation Schema ............................................................................. 50 
6.1.2 
Definition of Maximum Tolerated Dose .................................................... 53 
6.1.3 
Investigational Medicinal Product ............................................................. 53 
6.2 
Concomitant Medication/Therapy .............................................................................. 53 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 53 
7 
ASSESSMENT OF EFFICACY .................................................................................. 54 
8 
ASSESSMENT OF SAFETY ....................................................................................... 55 
8.1 
Adverse Events .............................................................................................................. 55 
8.1.1 
Definition of an Adverse Event .................................................................. 55 
8.1.2 
Categorisation of Adverse Events ............................................................... 55 
8.1.2.1 
Intensity Classification ................................................................................. 55 
8.1.2.2 
Causality Classification ............................................................................... 55 
8.1.2.3 
Assessment of Expectedness ......................................................................... 55 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 55 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 55 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 55 
8.1.3 
Recording and Follow Up of Adverse Events ............................................ 56 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 56 
8.1.5 
Pregnancy .................................................................................................... 58 
8.1.6 
Deaths .......................................................................................................... 58 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 58 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 58 
8.2 
Clinical Laboratory Tests ............................................................................................ 58 
8.2.1 
Haematology ................................................................................................ 58 
8.2.2 
Coagulation ................................................................................................. 59 
8.2.3 
Blood Biochemistry ..................................................................................... 59 


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8.2.4 
Urinalysis ..................................................................................................... 59 
8.2.5 
Putative Antibody Testing ........................................................................... 59 
8.3 
Estimated Glomerular Filtration Rate ....................................................................... 59 
8.4 
Physical Examination ................................................................................................... 60 
8.5 
Vital Signs ...................................................................................................................... 60 
8.6 
Electrocardiography ..................................................................................................... 60 
8.7 
Gallbladder Echography .............................................................................................. 60 
8.8 
Evaluation of Injection Site Reactions ........................................................................ 60 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 61 
9.1 
Pharmacokinetics .......................................................................................................... 61 
9.1.1 
Sample Collection ....................................................................................... 61 
9.1.2 
Analytical Procedures ................................................................................. 61 
9.1.3 
Data Analysis ............................................................................................... 61 
9.2 
Pharmacodynamics ....................................................................................................... 62 
9.2.1 
Sample Collection ....................................................................................... 62 
9.2.2 
Analytical Procedures ................................................................................. 62 
9.2.3 
Data Analysis ............................................................................................... 62 
9.2.3.1 
IGF-1 (Age Adjusted) ................................................................................... 62 
9.2.3.2 
Growth Hormone ......................................................................................... 62 
9.2.3.3 
Other Endocrine Parameters ....................................................................... 63 
10 
STATISTICS ................................................................................................................. 64 
10.1 Analysis Populations ..................................................................................................... 64 
10.1.1 
Populations Analysed .................................................................................. 64 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 64 
10.2 Sample Size Determination .......................................................................................... 64 
10.3 Significance Testing and Estimations ......................................................................... 64 
10.4 Statistical/Analytical Methods ..................................................................................... 64 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 65 
10.4.2 
Homogeneity of Treatment Cohorts ........................................................... 65 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 65 
10.4.4 
Pharmacokinetic Data ................................................................................ 65 
10.4.5 
Efficacy Evaluation ..................................................................................... 65 
10.4.6 
Adjustment for Country/Centre Effect ....................................................... 65 
10.4.7 
Safety Evaluation ........................................................................................ 65 
10.5 Subgroup Analyses ....................................................................................................... 66 
10.6 Interim Analyses/Data Review Committee ................................................................. 66 
11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 67 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 68 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 68 
12.1.1 
Protocol Amendments ................................................................................. 68 
12.1.2 
Protocol Deviations, Violations, and Exceptions ....................................... 68 


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12.2 Information to Study Personnel .................................................................................. 68 
12.3 Study Monitoring .......................................................................................................... 68 
12.4 Audit and Inspection .................................................................................................... 69 
12.5 Data Quality Assurance ................................................................................................ 69 
13 
ETHICS ......................................................................................................................... 70 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 70 
13.2 Informed Consent ......................................................................................................... 70 
13.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 71 
13.4 Confidentiality Regarding Study Subjects ................................................................. 71 
14 
DATA HANDLING AND RECORD KEEPING ....................................................... 72 
14.1 Data Recording of Study Data ..................................................................................... 72 
14.2 Data Management ......................................................................................................... 72 
14.3 Record Archiving and Retention ................................................................................. 72 
15 
FINANCING AND INSURANCE ............................................................................... 74 
15.1 Contractual and Financial Details ............................................................................... 74 
15.2 Insurance, Indemnity and Compensation .................................................................. 74 
16 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 75 
16.1 Publication Policy ......................................................................................................... 75 
16.2 Clinical Study Report ................................................................................................... 75 
17 
REFERENCES .............................................................................................................. 76 
18 
LIST OF APPENDICES .............................................................................................. 77 
 


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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Lanreotide Doses ................................................................................................. 23 
Table 3 
Possible Subject Combinations Per Cohort ...................................................... 25 
Table 4 
Criteria for Defining Dose Limiting Toxicities ................................................. 34 
Table 5 
Study Procedures and Assessments (Screening to Week 13, Including 
Treatment Period) ............................................................................................... 40 
Table 6 
Study Procedures and Assessments (Follow Up; Weeks 15 to 25) .................. 42 
Table 7 
Blood Volume Calculation for Treatment Period ............................................ 43 
Table 8 
Blood Volume Calculation for Follow Up Period ............................................. 43 
Table 9 
Treatment Cohorts .............................................................................................. 50 
 


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LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................................ 29 
Figure 2 
Adaptive 3+3+3 Dose Escalation Scheme with the Most Likely Outcome ..... 51 
Figure 3 
Adaptive 2 per 2 Dose Escalation Scheme with the Most Likely Outcome .... 52 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
AUC0-85 
Area under the serum concentration time curve from time 0 to 85 days 
AUC0- 
Area under the concentration time curve extrapolated to infinity 
AUCt 
Area under the serum concentration time curve from time 0 to last quantifiable 
timepoint 
CA 
Competent Authorities 
CI 
Confidence interval 
CK 
Creatine kinase 
CL/F 
Apparent clearance 
Cmax 
Maximum serum concentration 
Ctrough 
Concentration at the end of the dosing interval 
CRO 
Contract research organisation 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT(s) 
Dose limiting toxicity(ies) 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EU 
European Union 
EW 
Early withdrawal 
FDA 
Food and Drug Administration 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GH 
Growth hormone 
GMP 
Good Manufacturing Practice 
HbA1c 
Glycosylated haemoglobin 
HRT 
Hormone replacement therapy 
IB 
Investigator’s brochure 


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ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IGF-1 
Insulin like growth factor-1 
IMP 
Investigational Medicinal Product 
INR 
International normalised ratio 
IRB 
Institutional review board 
ITT 
Intent to treat 
LAR 
Long acting release 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry 
LLN 
Lower limit of normal 
LSLV 
Last subject, last visit 
MDD 
Medical Development Director 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Pharmacodynamics 
PDM 
Pharmacokinetics and Drug Metabolism 
PK 
Pharmacokinetics 
PP 
Per protocol 
PR 
Prolonged release 
PRF 
Prolonged release formulation 
PRL 
Prolactin 
QTc 
QT interval corrected 
RIA 
Radioimmunoassay 
RIPA 
Radioimmunoprecipitation assay 
SAE 
Serious adverse event 
SAS® 
Statistical Analysis System® 
SD 
Standard deviation 
SOP 
Standard Operating Procedure 
SST 
Somatostatin 
SSTa 
Somatostatin analogue(s) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Apparent terminal half life 
TEAE 
Treatment emergent adverse event 


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Tmax 
Time to maximum serum concentration 
TMF 
Trial Master File 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
V/F 
Apparent volume of distribution 
WHO 
World Health Organisation 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Acromegaly is a rare (incidence approximately 3 cases per million persons per year; prevalence 
approximately 60 per million), chronic disease caused by excessive secretion of growth 
hormone (GH) from a pituitary tumour [2]. Increased plasma levels of GH cause the symptoms 
and pathology of the disease, either directly through actions on target tissues, or indirectly by 
stimulating excessive secretion of insulin like growth factor-1 (IGF-1).  
Disease control of acromegaly consists of different components: biochemical control, tumour 
volume reduction and improvement of clinical symptoms [3]. GH and IGF-1 concentrations are 
the main biochemical markers used to measure the response to treatment and represent the most 
frequent primary endpoints in clinical trials that evaluate efficacy. Both GH and 
IGF-1 responses have been associated with improved prognosis and mortality decrease. 
The treatment of choice is trans-sphenoidal surgery, sometimes in association with radiotherapy 
[4, 5]. However, despite these measures acromegaly remains active in many patients, as defined 
by increased systemic levels of GH and IGF-1, the persistence of clinical symptoms, and 
increased morbidity and mortality [4, 5]. For example, between 40% and 60% of 
macroadenomas are unlikely to be controlled with surgery alone. Primary medical therapy or 
surgical debulking followed by medical therapy and/or radiation therapy are options for 
treatment of such tumours [4]. 
Somatostatin analogues (SSTa) successfully reduce GH and IGF-1 secretion in approximately 
70% of patients [4]. They alleviate many symptoms of acromegaly, improve related comorbid 
complications, and may reduce or stabilise tumour size in a subset of patients.  
Compared to short acting SSTa, long acting formulations have been shown to provide 
equivalent or better control of acromegaly [6]. The main adverse events (AEs) associated with 
SSTa are gastrointestinal disorders, including abdominal cramps and an increased incidence of 
gallbladder sludge and/or stones [4].  
1.2 
Name and Description of Investigational Medicinal Product(s) 
Lanreotide is a well established, synthetic octapeptide analogue of the naturally occurring 
hormone somatostatin (SST). Compared to SST, the biochemical stability, and thereby the half 
life of this synthetic molecule has been increased by the incorporation of modified amino acids. 
In the same way as the native hormone, lanreotide inhibits the secretion of a variety of 
hormones, including GH, and has antiproliferative activity [7, 8, 9]. Lanreotide has a high 
affinity for human SST receptors 2 and 5, and activity at these receptors is the primary 
mechanism considered responsible for GH inhibition.  
Laboratory code: 
BIM23014 
INN: Lanreotide 
Chemical formula: 
D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2  
Empirical formula: 
C54H69N11O10S2 
Molecular weight: 
1096.34 
Lanreotide is marketed for several indications, including for the long term treatment of 
acromegaly in patients with an inadequate response to surgery and/or radiotherapy, or for whom 
pituitary surgery is not an option.  
Numerous studies have shown that various formulations of lanreotide are effective in the 
treatment of acromegaly, with no safety concerns identified [10, 11]. The recommended dosing 
intervals for current lanreotide formulations are every 7, 10 or 14 days for lanreotide prolonged 
release (PR) and every 28 days for lanreotide Autogel. However, the need for frequent repeated 


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treatment for life can be inconvenient. The development of a more extended prolonged release 
formulation (PRF) of lanreotide will facilitate ease of use and treatment compliance for patients 
with acromegaly. 
A new formulation of lanreotide (lanreotide PRF) has been developed with a view to increasing 
the dosing interval compared to the currently marketed lanreotide formulations (lanreotide PR 
and lanreotide Autogel). 
The development of lanreotide PRF, with a targeted dosing interval of 12 weeks, will therefore 
aid in reducing the burden of repeat administration for patients with acromegaly. The new 
lanreotide PRF formulation is a solution for deep subcutaneous injection and includes the 
addition of glycofurol as an excipient. Lanreotide PRF is supplied in three dose strengths (180, 
270 and 360 mg) as ready to use prefilled syringes. The syringes contain the same bulk product, 
with the quantity provided in each syringe adjusted to deliver the targeted dose. A more detailed 
description of the product is given in Section 3.4. 
1.3 
Findings from Nonclinical and Clinical Studies 
Lanreotide has been extensively studied and has proved to be an effective treatment for 
acromegaly. Further details may be found in the investigator’s brochure (IB). This study 
represents the first in man study of glycofurol formulated lanreotide (lanreotide PRF).  
In the frame of the development of the new lanreotide PRF formulation, nonclinical 
pharmacokinetic (PK)/local tolerance studies performed in dogs with lanreotide PRF (270 and 
450 mg) showed a PK profile consistent with 3 month coverage, with lanreotide serum 
concentrations maintained above a target therapeutic level over 3 months. Assessment of the 
local tolerance of lanreotide PRF showed a subcutaneous granulomatous inflammation at the 
injection site at the end of 3 and 6 month periods. These histological findings have already been 
described for lanreotide Autogel in dogs. 
Glycofurol is identified as an excipient in at least two other marketed pharmaceutical products 
administered by intramuscular (Mobic® (meloxicam), a nonsteroidal anti-inflammatory drug 
supplied by Boehringer Ingelheim) or intravenous (Phenhydan® (phenytoin), an anticonvulsant 
supplied by Desitin Pharma) route. To complement the use of glycofurol in the present PRF for 
subcutaneous injection, toxicology studies were conducted in rats and dogs by daily 
subcutaneous administration of glycofurol alone at doses of 30, 90 or 180 mg/kg/day for 
4 weeks. They showed no systemic effects and glycofurol alone was rapidly absorbed (Tmax 
from 0.5 to 2 h in dogs and 0.25 to 0.5 h in rats) and eliminated (t½ from 0.37 to 1.3 h in dogs 
and 1 to 2.8 h in rats). There was no accumulation of glycofurol after daily s.c. administration 
for 4 weeks in both species. At the injection sites, a spectrum of inflammatory changes 
comprising subcutaneous necrosis, fibrosis/fibroplasia, subcutaneous subacute inflammation, 
and haemorrhage in rat and dog, as well as granulomatous panniculitis in dog were induced. 
Most of these local signs were reversible at the end of the treatment free period. In fact, in 
humans, the maximum dose of lanreotide PRF planned to be administered by single injection 
every 3 months is 360 mg, constituting approximately 2 mg/kg of glycofurol for a person of 
70 kg. Therefore, the doses of glycofurol tested in the toxicology studies (30 mg/kg to 
180 mg/kg) were not only administered with a higher frequency (daily for 4 weeks versus once 
every 3 months) but were way above the intended clinical dose (15 to 90 times, respectively). 
Consequently, the local effects that were recorded in the toxicology studies were considered 
without clinical relevance. 
Lanreotide PRF has been tested in a parallel phase I study where the participants were healthy 
volunteers with cholecystectomy (study DFR-52030-345 and EUDRACT number: 
2015-004338-85). Four healthy volunteers received a single injection of lanreotide PRF 180 mg 
in February 2016. Two of the volunteers had no side effects but two experienced abdominal 


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pain on the day of the injection and their blood biochemistry revealed elevated hepatic and 
pancreatic enzymes. These levels returned to within normal ranges by Day 5. These elevations 
met the protocol-defined criteria for DLT. As a result, no further healthy volunteers were 
entered into that study. A full safety analysis for the subjects in this study (309) was performed 
and no similar trends were seen in Cohort 1 or the first subject dosed in Cohort 2. The study 
DRC on 29th February 2016 recommended to continue study 309 as planned with some 
precautionary changes that were included in amendment 5. 
1.4 
Known and Potential Risks and Benefits to Human Patients 
1.4.1 
Individual Benefits 
Lanreotide is an effective treatment of acromegaly. It relieves clinical symptoms and reduces 
or normalises GH and IGF-1 levels. A complete overview of the efficacy of lanreotide is 
available in the IB. 
The main potential benefit of lanreotide PRF for participating subjects is a reduced number of 
SSTa injections (from 3 to 1 injection) to maintain optimal disease control.  
1.4.2 
Collective Benefits 
Eligible subjects are expected to participate for a duration of up to 7.5 months. Due to the 
shortness of this period, even with a reduced number of injections, a collective impact could 
not be expected. 
1.4.3 
Known and Potential Risks 
The most commonly expected adverse drug reactions following lanreotide treatment are 
gastrointestinal disorders (most commonly reported are diarrhoea and abdominal pain, usually 
mild or moderate and transient), cholelithiasis (often asymptomatic), and injection site reactions 
(pain, nodules and indurations). It should be emphasised that patients with acromegaly have an 
increased incidence of gallstones compared to the general population, irrespective of SSTa 
treatment. 
No specific risks are identified for the glycofurol excipient, so far. Glycofurol is nontoxic when 
administered by deep subcutaneous injection at the doses selected for clinical purposes (see 
details in the IB). 
The medical procedures during the study are considered to be safe (venous puncture and 
gallbladder echography) and do not put participating subjects at any procedure related increased 
risk. 
The half-life of lanreotide PRF in human is not yet known. However, based on dog data, 5 times 
the mean terminal half-life (t½ ~35 days) of lanreotide PRF corresponds to 175 days (i.e. 
~6 months). Therefore a 6-month follow up should be sufficient to cover more than 95% of the 
profile if the half-life in dogs is similar in human. 
The rationale for a follow up of 3 months after the potential 3 months treatment period is based 
on the need for the study subjects to resume treatment with their approved somatostatin 
analogue to control acromegaly and GH / IGF-1 levels. Given the similar class of active 
ingredient, the sponsor believes it is reasonable to let the participants go back to their regular 
treatment after three months follow up as longer periods off therapy may be associated with 
unnecessarily higher rates of symptoms. Furthermore after a single dose of lanreotide PRF, 
anticipated to provide 3 months treatment and after 3 months additional follow-up, it is 
reasonable to consider that the residual lanreotide concentrations are low enough not to trigger 
any new safety concern when standard treatment is resumed. Should any concern about this 
residual concentration arise during the study the sponsor will notify the investigators about the 


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level of residual concentration which would allow adjusting the restart of either octreotide or 
lanreotide Autogel treatment. 
The risk of reactivation of the disease with clinical symptoms within the 3 month follow up 
period is taken into consideration. IGF-1 and GH concentrations will be monitored monthly 
during this period. If the investigator judges that the subject requires any treatment for 
acromegaly (reappearance of clinical or biochemical symptoms of acromegaly) during the 
follow-up period, the subject will be withdrawn from the study and will receive treatment 
according to routine practice. 
Additional information regarding risks and benefits to human subjects may be found in the IB. 
1.5 
Selection of Investigational Medicinal Products and Doses 
The new formulation of lanreotide will present as a solution for injection in a prefilled syringe. 
Lanreotide PRF is expected to ensure a 3 month period of coverage of active serum levels of 
lanreotide compared to the currently marketed lanreotide Autogel formulation. The three levels 
of dose correspond to three times the common doses of lanreotide used for the treatment of 
acromegaly (Table 2). 
Table 2 
Lanreotide Doses 
Lanreotide dose 
Lanreotide PRF dose  
60 mg 
180 mg 
90 mg 
270 mg 
120 mg 
360 mg 
PRF=prolonged release formulation. 
Lanreotide PRF is provided in three strengths as sterile, ready to use, prefilled syringes 
containing the same lanreotide supersaturated bulk solution at 44% w/w lanreotide base.  The 
product is intended to deliver 180, 270 or 360 mg lanreotide (potency is expressed as lanreotide 
base). The different strengths are dose proportional as syringes are filled with increasing 
quantities of the same lanreotide supersaturated bulk solution. 
Lanreotide PRF will be injected via the deep subcutaneous route in the superior, external 
quadrant of the buttock according to the recommendations detailed in Section 6.1. 
The three dose levels proposed for lanreotide PRF (180 mg, 270 mg and 360 mg) are targeted 
as three times the common doses of lanreotide Autogel used for the treatment of acromegaly 
(60, 90 and 120 mg). 
A robust PK/PD model developed with lanreotide Autogel in acromegalic patients which relates 
lanreotide trough concentrations (at 1 month for Autogel) to GH and IGF-1 concentrations, has 
proven that if the lanreotide concentration remains above a target therapeutic level over the 
whole dosing interval, acromegalic patients remain controlled in terms of GH and IGF-1. 
Therefore, the trough concentrations (Ctrough) observed at 3 months with lanreotide PRF were 
compared to the target therapeutic levels reached at 1 month with lanreotide Autogel (using a 
‘translation’ from human data to dogs). In dogs, the Ctrough achieved with lanreotide PRF 240, 
270 and 450 mg were comparable to those achieved with the corresponding dose of lanreotide 
Autogel (i.e., lanreotide PRF dose divided by 3), which justifies the selected doses of lanreotide 
PRF. 
From a safety point of view, the Cmax and AUC of lanreotide PRF in dogs were carefully 
reviewed and compared to the commercial formulation lanreotide Autogel 120 mg and a 
previous development formulation of lanreotide Autogel23% 240 mg. The mean Cmax of 
58 ng/mL observed with the highest dose tested in dogs (PRF 450 mg) is increased by 60-70% 
compared to the mean Cmax of 36 ng/mL observed with lanreotide Autogel 120 mg (highest 
dose commercially available of the 1-month formulation) and in dogs the mean exposure over 


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3 months after a single injection of lanreotide PRF 450 mg (706 ng.day/mL) is similar to the 
exposure over 3 months after three injections of lanreotide Autogel 120 mg every 4 weeks 
(737 ng.day/mL). Therefore, if the PK profile of lanreotide PRF in human is consistent with 
dog data, comparable safety ratios to those observed with lanreotide Autogel 120 mg (200- to 
400-fold in rats and 16- to 23-fold in dogs) could be anticipated with lanreotide PRF. 
Moreover the mean Cmax of lanreotide PRF tested in dogs is 2-fold lower than that observed 
with a dose of 240 mg of lanreotide Autogel23% (a previous development formulation tested in 
a Phase 1 study in healthy volunteers) which was not well tolerated in healthy subjects. 
Furthermore, in the dog PK study performed with lanreotide PRF, assessment of the local 
tolerance of lanreotide PRF containing glycofurol showed a s.c. granulomatous inflammation 
at the injection site at the end of the 3-month and 6-month periods. These histological findings 
have already been described for lanreotide Autogel in dogs thus the excipient glycofurol does 
not aggravate the local tolerance of the therapeutic compound. 
In conclusion, the choice of the lanreotide PRF doses as 3 times the doses of Autogel is 
confirmed, from an efficacy perspective, by the Ctrough reached at 3 months. In terms of safety, 
the selected doses of lanreotide PRF are expected to show similar or lower exposure than with 
the highest dose of the commercially available 1-month formulation (lanreotide Autogel 
120 mg). Consequently, no change in the safety ratios is expected. Moreover, the local tolerance 
of the lanreotide PRF in dog was not different from that observed with lanreotide Autogel. 
1.6 
Compliance Statement 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. 
Any episode of noncompliance will be documented. The Electronic Data Capture (EDC) system 
will comply with the Food and Drug Administration (FDA), 21 CFR Part 11, Electronic 
Records, Electronic Signatures, and FDA, Guidance for Industry: Computerized Systems Used 
in Clinical Trials. 
In addition, the study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
1.7 
Population to Be Studied 
The study will enrol adult subjects with acromegaly who have been well controlled for at least 
3 months on a stable dose of either octreotide long acting release (LAR) or lanreotide Autogel. 
A minimum of six octreotide LAR subjects must be recruited in each cohort and up to three 
lanreotide Autogel subjects can be enrolled in each cohort. 
The choice of subjects stable on octreotide LAR as the main study population, instead of 
subjects stable on lanreotide Autogel, was guided by the need to avoid crossinterference 
between the different formulations of lanreotide in the primary PK analysis. The required PK 
analysis can be done on a minimum of six octreotide LAR subjects per cohort. The inclusion 
of up to three lanreotide Autogel subjects per cohort will provide preliminary PK data from this 
population. 
Possible subject combinations per cohort are shown in Table 3. 


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Table 3 
Possible Subject Combinations Per Cohort 
 
Octreotide LAR 
Lanreotide Autogel 
Cohort 1, 2 and 3 
6 
3 
Cohort 1, 2 and 3 
7 
2 
Cohort 1, 2 and 3 
8 
1 
Cohort 1, 2 and 3 
9 
0 


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
The role of SSTa is to provide a primary medical therapy in patients with acromegaly for whom 
a surgical cure is unlikely. These hormone analogues successfully alleviate many symptoms of 
acromegaly, improve related comorbid complications and may reduce or stabilise tumour size 
[4]. Long acting formulations have been shown to provide equivalent or better control of 
acromegaly compared to short acting SSTa [6]. As discussed in Section 1.2, the recommended 
dosing intervals for current lanreotide formulations are every 7, 10 or 14 days (lanreotide PR) 
and every 28 days (lanreotide Autogel). Lanreotide PRF has been developed with a view to 
increasing the dosing interval (up to 3 months) compared to the currently marketed lanreotide 
formulations in order to provide equivalent disease control and to decrease patient burden with 
regard to injection frequency. 
This clinical study aims to identify the maximum tolerated dose (MTD) and to investigate the 
PK, pharmacodynamics (PD), safety and tolerability of a single dose of the new lanreotide 
formulation (lanreotide PRF) in subjects with acromegaly.  
A modified lanreotide autogel formulation has been studied in a single Phase 1 study in healthy 
volunteers, however its profile was not compatible with adequate exposure for a 3 month dosing 
interval and exaggerated adverse effects were observed in the study subjects (Study 2-55-
52030-724). As mentioned in the IB, biliary toxicity (3 subjects experienced cholelithiasis 
which was symptomatic and severe in 2 of them) was described in the 16 healthy volunteers 
treated with lanreotide Autogel 240 mg (Study 2-55-52030-724).  
2.2 
Study Objectives 
The primary objective of the study is to identify the MTD and to investigate the PK of a single 
dose of lanreotide PRF in subjects with acromegaly. 
The secondary objectives of the study are as follows: 
• 
To investigate the safety and tolerability of a single dose of lanreotide PRF. 
• 
To investigate the PD of a single dose of lanreotide PRF. 
• 
To investigate the PK of the excipient. 
The exploratory objective of the study is to evaluate the impact of lanreotide PRF on gene 
expression of proteins of relevance for the mechanism of action of lanreotide and those of 
relevance for safety, tolerability and potential clinical benefit.  
Blood samples will be collected for all subjects who will sign a separate informed consent to 
participate in the optional biobanking research study. These samples will be stored in a Biobank 
for further biomarkers analysis after the end of the study. Please refer to Appendix 1 for further 
information. 


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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is an open label, dose ascending study to assess the PK, PD, safety and tolerability of a 
single dose of lanreotide PRF, a new sustained release formulation of lanreotide. Doses of 
180 mg, 270 mg and 360 mg will be investigated in adults with acromegaly previously treated 
and controlled with a stable dose of either octreotide LAR or lanreotide Autogel. The study 
consists of a 4 week (or up to 6 weeks under certain circumstances) run in period, followed by 
a 12 week treatment period, and then a 12 week follow up period. 
A maximum of 27 adult subjects, aged 18 to 75 years will be treated in the study. 
Three cohorts of subjects will be included, with nine subjects allocated to each lanreotide PRF 
treatment cohort (180 mg, 270 mg and 360 mg). Subjects in each cohort will receive one deep 
subcutaneous injection of lanreotide PRF on Day 1 (4 weeks (or up to 6 weeks if extended) 
after the last octreotide LAR or lanreotide Autogel administration). Specific details of the dose 
cohorts are given in Section 6.1. 
Each cohort of nine subjects must be made up of at least six previously controlled on octreotide 
LAR. The remaining subjects can be up to three subjects previously controlled on lanreotide 
Autogel (see Table 3). 
Progression to each ascending dose cohort (or groups of subjects) will be dependent upon a 
review of data from the preceding cohort (or groups of subjects) by a data review committee 
(DRC; see Section 10.6). The DRC will review the safety data for each dose cohort after all 
subjects in the cohort have completed Visit 5 (Week 2 postdose). If no unexpected safety 
signals have been observed and the overall safety is in line with the known lanreotide safety 
profile, the DRC will decide whether to proceed with the next dose cohort (or groups of 
subjects). The occurrence of 2 dose limiting toxicities (DLTs) would trigger the organisation of 
an intermediate DRC meeting (ad hoc meeting) to evaluate the decision to test 3 more subjects 
(2 more subjects for Cohort 2 and Cohort 3)  at the same dose level (see Section 6.1.1). 
Screening of subjects will take place 28 to 42 days before administration of study treatment 
(Day −42 to Day −28). Eligible subjects will receive the same single dose of octreotide LAR or 
lanreotide Autogel as their previous treatment and will enter a 4 week run in period. The 4 week 
run in period (28 days) can be extended to up to 6 weeks (42 days) under the following 
circumstances and only in specific cases: 
(1) 
When there is a delay in receiving blood results or having to re-collect a blood sample 
e.g. due to a clotted sample being received by the central laboratory.  
(2) 
The data review of the group of 2 prior subjects is ongoing and not completed by the end 
of a 4 week run in. In this circumstance, the run in period can be extended by a further 
2 weeks. This would make the run in a maximum of 6 weeks in total. 
(3) 
At the investigator’s discretion after discussion with the sponsor. 
Any extension to the run in period will be done in close consultation with the investigator to 
ensure that there is no safety risk to the subject. 
On Day 1, subjects will receive lanreotide PRF by deep subcutaneous injection in the superior, 
external quadrant of the buttock and a 12 week treatment period will then commence. Treatment 
will be administered at the study centre and subjects will remain at the study centre for 24 hours 
postdose. Throughout the treatment period, study assessments will be performed to evaluate 
PK, PD, safety and tolerability of lanreotide PRF. 
At the end of the 12 week treatment period, a 12 week follow up period will ensue, with further 
assessments to evaluate the PK, PD, safety and tolerability of lanreotide PRF performed 


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periodically throughout. During the follow up period, subjects will not receive any treatment 
for acromegaly. However, if the investigator judges that the subject requires treatment for 
acromegaly (reappearance of clinical or biochemical symptoms of acromegaly), the subject will 
be withdrawn from the study and receive treatment according to routine clinical practice.  
The overall study design is presented in Figure 1. 
Subjects who complete the study will have final procedures and assessments performed at the 
end of study (EOS) visit (Week 25; Visit 18). Subjects who withdraw from the study before the 
completion of the 24 week evaluation period will have Week 25 (Visit 18) procedures and 
assessments performed at their final visit (early withdrawal (EW) visit).  


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Figure 1 Study Design 
 
DRC=Data Review Committee; EOS=end of study; LAR=long acting release; PD=pharmacodynamic; PK=pharmacokinetic; PRF=prolonged release formulation. 
a 
each cohort will undergo a 4 week run in period (or, if extended, the run in can be up to a maximum of 6 weeks) and two subsequent 12 week periods for treatment and 
follow up unless the subject withdraws from the study prematurely. 
b 
each successive dose increase will proceed only on the recommendation of the DRC after review of the safety data for the preceding dose cohort after all subjects in 
the cohort have reached Visit 5 (Week 2 postdose). The DRC will meet after every 2 subjects starting from Cohort 2 onwards instead of the 3 subject blocks and prior 
to the final 3 subjects in Cohort 3.


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3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Safety Variables 
The safety and tolerability of lanreotide PRF will be assessed throughout the study by 
evaluation of the following parameters: 
• 
Adverse events, throughout the study.  
• 
Vital signs (supine and standing blood pressure, heart rate, body temperature) at 
Screening, Baseline (predose on Day 1), 6 and 24 hours postdose, and at Weeks 2, 3, 4, 
5, 7, 9, 11 and 13 of the treatment period, and at each follow up visit. 
• 
Physical examination at Screening, Baseline (predose on Day 1), 6 and 24 hours 
postdose, and at Weeks 2, 3, 4, 5, 7, 9, 11 and 13 of the treatment period, and at each 
follow up visit. 
• 
12-lead electrocardiogram (ECG), QT interval corrected (QTc) will be calculated using 
Fridericia methodology in all subjects at Screening, Baseline (predose on Day 1), 6 hours 
postdose on Day 1, 24 hours postdose, and at Weeks 2, 5 and 13. 
• 
Clinical laboratory assessments: haematology, coagulation, clinical biochemistry, 
urinalysis at Screening, Baseline (predose on Day 1), 6 hours postdose on Day 1, 
24 hours postdose (Day 2), 48 hours postdose (Day 3), at Weeks 2, 3, 4, 5, 9 and 13 of 
the treatment period, and at each follow up visit. 
• 
Glycosylated haemoglobin (HbA1c) at Screening, Week 13 and Week 25 (or EW). 
• 
Estimated glomerular filtration rate (eGFR) estimated by the Modification of Diet in 
Renal Disease (MDRD) formula [1], at Screening, Baseline (predose on Day 1), and 
Weeks 2, 5, 9 and 13 of the treatment period, and at Weeks 17, 21 and 25 (or EW) during 
follow up in all subjects. 
• 
Gallbladder echography at Screening, Week 5 and Week 13 of the treatment period and 
at Week 25 (or EW) in all subjects. 
• 
Putative antibodies to lanreotide at Baseline (predose on Day 1), Week 13 and 
Week 25 (or EW) in all subjects. 
• 
Evaluation of injection site reactions (appearance, local symptoms). These will be 
evaluated on a specific form in the electronic case report form (eCRF) at 1 and 6 hours 
postdose on Day 1, 24 hours postdose, at Weeks 2, 3, 4, 5, 7, 9, 11 and 13 of the 
treatment period, and at each follow up visit. 
3.2.2 
Pharmacokinetic Variables 
• 
Lanreotide serum concentration at the following timepoints after administration of 
lanreotide PRF:  
- 
Baseline (predose on Day 1 of lanreotide PRF administration) 
- 
At 1, 2, 4, 6, 8 and 12 hours postdose on the day of dosing (Day 1) 
- 
At 24 hours postdose (Day 2) 
- 
On Days 3 and 5, and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF 
administration (the Week 13 sample will be on Day 85 and will correspond to the 
concentration at the end of the dosing interval (Ctrough)) 
- 
At Weeks 17, 21 and 25 (or EW) during follow up 
• 
Lanreotide PK parameters: 
- 
Ctrough 
- 
maximum serum concentration (Cmax) 


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- 
Tmax 
- 
area under the serum concentration time curve from time 0 to 85 days (AUC0-85) 
- 
area under the concentration time curve extrapolated to infinity (AUC0-) 
- 
t½ 
- 
mean residence time (MRT) 
- 
apparent clearance (CL/F) 
- 
apparent volume of distribution (V/F) 
• 
Excipient serum concentration at the following timepoints after administration of 
lanreotide PRF: 
- 
Baseline (predose on Day 1 of lanreotide PRF administration) 
- 
At 1, 2, 4, 6, 8 and 12 hours postdose on the day of dosing (Day 1), at 24 hours 
postdose (Day 2), and on Days 3 and 5 after lanreotide PRF administration  
• 
Excipient PK parameters: 
- 
Cmax 
- 
Tmax 
- 
area under the serum concentration time curve from time 0 to last quantifiable 
timepoint (AUCt) 
- 
AUC0- 
- 
t½ 
- 
MRT 
- 
CL/F 
- 
V/F 
3.2.3 
Pharmacodynamic Variables 
• 
IGF-1 at Screening, Baseline (predose on Day 1), at 6 hours postdose on the day of 
dosing (Day 1), and at Weeks 5, 9 and 13 of the treatment period and Weeks 17, 21 and 
25 (or EW) during follow up. 
• 
GH cycle (five sampling times with a sample every 30 minutes for 2 hours in the 
morning) at Screening, Baseline (predose on Day 1) and at Weeks 5 and 13.  
• 
Random GH sample at 6 hours postdose on the day of dosing (Day 1), at Week 9 and 
Weeks 17, 21 and 25 (or EW) during follow up. 
• 
Free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH) 
and prolactin (PRL) at Screening, Baseline (predose on Day 1), Weeks 2, 5 and 13 of the 
treatment period, and at Week 25 (or EW). 
3.2.4 
Biobanking 
Blood samples will be collected at Baseline (predose on Day 1), Weeks 5 and 13 and stored for 
further biomarkers analysis after the end of the study in subjects who consent to the exploratory 
part of the study. 
3.3 
Randomisation and Blinding 
This is a nonrandomised, open label study. 


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3.4 
Study Treatments and Dosage 
The test product, lanreotide PRF, will be administered as a single deep subcutaneous injection 
at Visit 2 (Day 1). Depending on the dose cohort, doses of 180 mg, 270 mg or 360 mg will be 
administered. A more detailed description of administration procedures is given in Section 6.1. 
Lanreotide PRF will be packaged and released by Beaufour Ipsen Industrie (France) and 
delivered to the investigational centre or interim storage depending on the country. A sufficient 
quantity of lanreotide PRF will be supplied, as well as an acknowledgement of receipt form.  
Lanreotide PRF will be released from Beaufour Ipsen Industrie to the sponsor (Ipsen Pharma). 
A Certificate of Analysis reflecting the product release statement will be issued for each batch 
of lanreotide PRF used in this study, together with a Certificate of Compliance.  
The core label texts for all packaging units will be in compliance with Annex 13 of the European 
Union (EU) Guide to Good Manufacturing Practice (GMP) and should be translated or adjusted 
to be in compliance with applicable regulatory requirements, national laws in force and in 
accordance with the local languages. A description of the core text of the lanreotide PRF labels 
is displayed below: 
• 
Sponsor name, 
• 
Study Number, 
• 
Pharmaceutical dosage form, 
• 
Route of administration, 
• 
Quantity of dose units, 
• 
Batch number, 
• 
A treatment box number or a specific blank space to enter the subject identifier, 
• 
“Keep out of reach of children”, 
• 
“For clinical study use only” 
• 
Name, address and telephone number of the sponsor, contract research organisation 
(CRO) or investigator (the main contact for information on the product and the clinical 
study) 
• 
Storage conditions 
• 
Expiry date 
The investigator, or designee, will only administer lanreotide PRF to subjects included in this 
study. Each subject will only be given the lanreotide PRF carrying his/her number. The 
dispensing for each subject will be documented in the eCRF. 
3.5 
Study Duration 
This study will consist of a Screening visit, followed by a 4 week run in period (or up to 6 weeks 
under certain circumstances), a 12 week open label treatment period and a 12 week follow up 
period. Subjects are expected to participate in this study for up to 7.5 months.  
The subject’s participation in the study will be considered to have ended at the time of the last 
follow up visit (EOS visit) or the EW visit in the case of early withdrawals. 
The overall duration of the study will be approximately 32 months. The study will be considered 
to have started when the first subject has been screened and signed the informed consent form. 
The study will be considered to have ended after the last subject has completed the EOS or EW 
visit. 


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3.6 
Stopping Rules and Discontinuation Criteria 
3.6.1 
Discontinuation 
A subject may discontinue participation in the study at any time for any reason (e.g. lost to 
follow up, withdrawal of consent, AE). The investigator and/or sponsor can withdraw a subject 
from the study at any time for any reason (e.g. protocol violation or deviation as defined in 
Section 12.1.2, noncompliance with the protocol conditions or AE). 
Withdrawn subjects will not be replaced. 
During the follow up period, if the investigator judges that the subject requires treatment for 
acromegaly, the subject will be withdrawn from the study and will receive treatment according 
to routine clinical practice. Individual subject withdrawal criteria are specified in Section 4.3. 
An EW visit must be conducted for any subject who does not complete the study (see Section 
5.2.4.2). Subject status in the study will be recorded on the visit status page in the eCRF. 
3.6.2 
Stopping Rules 
The DRC will review the safety data from each treatment cohort to determine whether the next 
treatment cohort should ensue (Section 10.6). The pre-established stopping rules for the DRC 
decision for study discontinuation and/or inclusion of the subsequent treatment cohort include 
the occurrence of DLTs occurring within the first week (up to Week 2; Visit 5) following 
lanreotide PRF administration and during the entire study duration (see Section 3.6.3). If any 
serious adverse event (SAE) occurs (see Section 8.1.4), a relationship with the exposure to 
lanreotide PRF will be assessed.  
All toxicities will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (June, 2010; see Section 
8.1.2.1). 
The study may be terminated by the sponsor at any time. 
3.6.3 
Definition of Dose Limiting Toxicity 
Taking into account the safety profile of lanreotide (detailed in the IB), a DLT is defined as an 
AE (excluding anorexia and fatigue) or an abnormal laboratory value occurring within the first 
week (up to Week 2; Visit 5) following lanreotide PRF administration and during the entire 
study duration, assessed as unrelated to acromegaly, intercurrent illness or concomitant 
medications and which meets any of the pre-established criteria listed in Table 4. 
In the event of hepatic enzyme (aminotransferases and/or bilirubin) increases, refer to Appendix 
2 for an algorithm for safety management. 


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Table 4 
Criteria for Defining Dose Limiting Toxicities 
Toxicity 
Any of the following criteria 
Hepatic 
NCI CTCAE grade ≥3 ALT, AST  
Total bilirubin  ≥2.0 to <3.0 x ULN for >7 consecutive days 
NCI CTCAE grade  ≥2 bilirubin and NCI CTCAE grade ≥2 ALT or AST 
Renal 
NCI CTCAE grade ≥3 serum creatinine 
Serum creatinine ≥2.0 to ≤3.0 x ULN for >7 consecutive days 
Pancreatic 
NCI CTCAE grade ≥3 amylase or lipase with abdominal pain 
NCI CTCAE grade ≥3 amylase or lipase for >7 consecutive days without abdominal 
pain 
If necrotising pancreatitis is suspected, the subject should be hospitalised 
Endocrine/Metabolic 
NCI CTCAE grade ≥4 hyperglycaemia (confirmed by a repeat FPG within 24 hours) 
that does not resolve to CTCAE grade ≤2 within 14 consecutive days despite optimal 
antidiabetic treatment (14 consecutive days counts from the day of initiation of 
antidiabetic treatment) 
Cardiac 
NCI CTCAE grade ≥3 
Other AEs 
Any event CTCAE ≥3 except for ALP grade ≥4 
NCI CTCAE grade ≥3 diarrhoea despite optimal antidiarrheal treatment 
NCI CTCAE grade ≥3 vomiting despite optimal antiemetic therapy 
In the view of the investigators and Ipsen, any other unacceptable toxicity encountered 
AE=adverse event; ALT=alanine aminotransferase; ALP=alkaline phosphatase; AST=aspartate aminotransferase; 
CTCAE=Common Terminology Criteria for Adverse Events; FPG=fasting plasma glucose; NCI=National Cancer 
Institute; ULN=upper limit of normal. 
The occurrence of the following toxicities will be assessed throughout the study period and at 
the EOS or EW visit: 
• 
Grade ≥3 cholelithiasis-related gallbladder obstruction or cholecystitis, 
• 
Grade ≥3 injection site reaction,  
• 
Prolonged grade 2 toxicities or investigation abnormalities. 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability 
3.7.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all 
lanreotide PRF and any other study related material is stored in a secured area, under monitored 
conditions and at the recommended temperature (between +2°C and +8°C), in accordance with 
applicable regulatory requirements. 
3.7.2 
Investigational Medicinal Product Preparation 
Lanreotide PRF is supplied as a ready to use syringe, therefore no preparation is required. The 
investigator, or an approved representative (e.g. pharmacist), will ensure that all lanreotide PRF 
is administered by qualified staff members.  
3.7.3 
Investigational Medicinal Product Accountability 
All lanreotide PRF and any other study related material is to be accounted for on the 
accountability log provided by the sponsor. It is essential that all used and unused supplies are 
retained for verification by the sponsor or sponsor’s representative who will ensure that 
lanreotide PRF administration in the eCRF, the accountability log and the number of 
used/unused treatments are consistent. The investigator or approved representative (e.g. 
pharmacist) should ensure adequate records are maintained in the accountability log. 
Lanreotide PRF will be destroyed at the investigational site. The destruction of used and unused 
lanreotide PRF should be carried out only after any discrepancies have been investigated and 
satisfactorily explained and the reconciliation has been accepted by the sponsor or its 
representative.  


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3.8 
Maintenance of Randomisation and Blinding 
Not applicable as this is a nonrandomised, open label study.  
3.9 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP, the sponsor assigned monitor will verify, by direct reference to the source documents, 
that the data required by the protocol are accurately reported on the eCRF.  
The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the study, 
the identity of the study, diagnosis and eligibility criteria, visit dates (with subject status), 
lanreotide PRF administration, and any AEs and associated concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the investigator and the sponsor. 
The definitions of source data and source documents are given below: 
• 
Source data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents (original records or certified 
copies). 
• 
Source documents: Original documents, data and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, X rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medicotechnical departments involved in 
the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel, and by local, and possibly foreign Competent Authorities (CAs). This 
information is included in the informed consent. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
All laboratory parameters will be analysed centrally to confirm subject eligibility against the 
inclusion and exclusion criteria, with the exception of IGF-1. Age adjusted IGF-1 will be based 
on local laboratory results at Screening. Samples for analysis of IGF-1 by central laboratory 
will also be collected during Screening. Unscheduled tests may be performed during the study. 
The results will be recorded in the eCRF. All toxicities will be graded according to NCI 
CTCAE, Version 4.03. 
4.1 
Inclusion Criteria 
All subjects must fulfil all of the following criteria to be included in the study: 
(1) 
Documented diagnosis of acromegaly. 
(2) 
Provided written informed consent prior to any study related procedures.  
(3) 
Between 18 and 75 years of age inclusive. 
(4) 
Female of nonchildbearing potential or male. Nonchildbearing potential is defined as 
being postmenopausal for at least 1 year, or women with documented infertility (natural 
or acquired).  
(5) 
Male subjects must agree that, if their partner is at risk of becoming pregnant, they will 
use a medically accepted, effective method of contraception (i.e. condom) for the 
duration of the study (up to 7.5 months). 
(6) 
Treatment with a stable dose of either octreotide LAR or lanreotide Autogel for at least 
3 months immediately prior to study entry, with confirmation of disease control during 
this treatment period (documentation of age adjusted IGF-1 <1.3 x upper limit of normal 
(ULN), based on local laboratory results, during the Screening period).  
(7) 
If the subject is receiving treatment for hypertension, the dose has been stable for at least 
1 month prior to study entry. 
(8) 
Subjects must be willing and able to comply with study restrictions and to remain at the 
clinic for the required duration during the study period and willing to return to the clinic 
for the follow up evaluation as specified in the protocol. 
4.2 
Exclusion Criteria 
Subjects will not be included in the study if the subject: 
(1) 
Has undergone radiotherapy within 2 years prior to study entry. 
(2) 
Has been treated with a dopamine agonist and/or GH receptor antagonist or has 
undergone pituitary surgery within 3 months prior to study entry. 
(3) 
Is anticipated to require pituitary surgery or radiotherapy during the study. 
(4) 
Has clinically significant hepatic abnormalities and/or alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) ≥3 x ULN and/or alkaline phosphatase (ALP) 
≥2.5 x ULN and/or total bilirubin ≥1.5 x ULN and/or gamma-glutamyl transpeptidase 
(GGT) ≥2.5 x ULN during the Screening period (central laboratory results) or a history 
of these findings when on SSTa treatment. 
(5) 
Has clinically significant pancreatic abnormalities and/or amylase and/or lipase 
≥1.5 x ULN during the Screening period (central laboratory results). 
(6) 
Has any significant renal abnormalities and/or creatinine ≥1.5 x ULN during the 
Screening period (central laboratory results). 
(7) 
Has uncontrolled diabetes (HbA1c) ≥9%, centrally assessed during the Screening period) 
or has diabetes treated with insulin for <6 months prior to study entry. 


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(8) 
Has any known uncontrolled cardiovascular disease or had any of the following within 
6 months of Screening: ventricular or atrial dysrhythmia ≥grade 2, bradycardia ≥grade 2, 
ECG QTc prolonged ≥grade 2, myocardial infarction, severe/unstable angina, 
symptomatic congestive heart failure, cerebrovascular accident or transient ischaemic 
attack, pulmonary embolism, hypertension not adequately controlled by current 
medications. 
(9) 
Use of any hormone replacement therapy (HRT) with oestrogens. 
(10) Has symptomatic gallstones/sludge at the Screening Visit echography (local assessment) 
OR is asymptomatic but has echography showing clear evidence of impending 
inflammation such as localised mucosal thickening suggesting the subject is at high risk 
of developing acute disease. Subjects with asymptomatic gallstones/sludge and 
otherwise normal echography may be entered at the discretion of the investigator. 
(11) Has abnormal findings during the Screening period, any other medical condition(s) or 
laboratory findings that, in the opinion of the investigator, might jeopardise the subject’s 
safety.  
(12) Has been treated with any other investigational medicinal product (IMP) prior to the first 
study visit without undergoing a washout period of seven times the elimination half life 
of the investigational compound. 
(13) Has a known hypersensitivity to any of the test materials or related compounds. 
(14) Is likely to require treatment during the study with drugs that are not permitted by the 
study protocol. 
(15) Has a history of, or known current, problems with alcohol or drug abuse. 
(16) Has any mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude.  
4.3 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, or 
other reasons concerning the health or wellbeing of the subject, or in the case of lack of 
cooperation. In addition, a subject may be withdrawn from the study as described in Sections 
3.6 and 8.1.7.  
Should a subject decide to withdraw from the study after administration of lanreotide PRF, or 
should the investigator decide to withdraw the subject, all efforts will be made to complete and 
report the observations up to the time of withdrawal as thoroughly as possible. A complete final 
evaluation at the time of the subject’s withdrawal should be made (see Section 5.2.4.2) and an 
explanation given of why the subject is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a subject 
withdraws consent, every attempt will be made to determine the reason. If the reason for 
withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, and/or until the subject is referred to the care 
of a local health care professional. The specific AE or test result(s) must be recorded on the 
eCRF. All evaluations should be performed, according to the protocol. 
Subjects participating in the optional biobanking have the right to withdraw their consent at any 
time and for any reason during the study or during the period of sample storage (i.e. the entire 
15 years during which the sample is kept).  If a subject wishes to withdraw his consent for 
biobanking and the samples are still at the investigator site or at the central laboratory at this 


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time, the investigator must first inform the study monitor in writing of the subject’s decision 
and destroy the samples, respectively after informing the monitor the investigator will need to 
contact the central laboratory to destroy the samples. If the samples are already at Fisher 
BioServices (biobanking vendor), i.e. post-study, the investigator must inform Ipsen directly 
using the following e-mail address;
, mentioning only the ID of 
the subject in this e-mail. Ipsen will ensure destruction of the samples and all corresponding 
aliquots, issue confirmation of the withdrawal, and forward corresponding destruction 
certificate to the investigator. 
 
PPD


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PAGE 39 OF 173 
 
 
5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in 
Table 5 (Screening to Week 13, including treatment period) and Table 6 (Follow up period; 
Weeks 15 to 25). 
 


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Table 5 
Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) 
Visit 
1 [a] 
2 
3 
 
4 
 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
(up to −42) 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acromegaly symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
x----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreotide or lanreotide 
Autogel administration [d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanreotide PRF 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
x--------------------------------------------------------------------------------------------x 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
Lanreotide PRF 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Excipient 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PD assessments 
IGF-1 [e] 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
GH cycle [f] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Random GH sample 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FT3, FT4, TSH, PRL 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety assessments 
AEs 
x---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 


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Table 5 
Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) (Cont.) 
Visit 
1 [a] 
2 
3 
4 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Evaluation of injection site 
reactions 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments [g] 
X 
X 
 
 
 
 
X [h] 
 
 
X [i] 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR [j] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Gallbladder echography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Putative antibodies to 
lanreotide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biobanking 
Blood sampling [k] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FT3=free triiodothyronine; 
FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; INR=international normalised ratio; LAR=long acting release; 
MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid stimulating hormone.  
a 
Screening visit. Screening of subjects will take place 28 to 42 days before administration of study treatment (Day −42 to Day −28). The 4 week run in period (28 days) can be extended 
to up to 6 weeks (42 days) under certain circumstances. 
b 
Study visits on Weeks 4, 7 and 11 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. A reduced physical examination will be 
performed at home visits and weight will not be measured. More information on how those home visits are performed are described in the study manual.  
c 
Baseline. 
d 
after Screening, subjects will enter a 4 week run in period (or up to 6 weeks under certain circumstances) and will receive a single dose of either octreotide LAR or lanreotide Autogel at 
the same dose as they received previously. 
e 
IGF-1 testing will be conducted by a central laboratory using a validated method. During the Screening period, IGF-1 will be analysed locally. 
f 
five sampling times in the morning, with a sample every 30 minutes for 2 hours.  
g 
blood and urine samples taken for clinical laboratory tests. 
h 
evaluation of the following parameters during the first day after lanreotide administration: ALT, AST, bilirubin, lipase, amylase, INR, serum creatinine, postprandial glycaemia, and 
postprandial insulinaemia. 
i 
at 24 hours postdose before hospital discharge (Day 2) only blood chemistry will be analysed. A urine sample will not be collected. 
j 
measured by MDRD formula [1]. 
k 
Biobanking: samples will only be collected for those individuals who have signed a specific consent for the biobanking samples. 
 
 


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Table 6 
Study Procedures and Assessments (Follow Up; Weeks 15 to 25) 
Visit 
13 
[a] 
14 
15 
[a] 
16 
17 
[a] 
18 (EOS or 
EW)[b] 
Week [c] 
15 
17 
19 
21 
23 
25/EW 
Acromegaly symptoms 
 
 
 
 
 
X 
Concomitant medications 
x--------------------------------------------------------------------------------------------------------------------------------------x 
PK blood samples 
Lanreotide PRF 
 
X 
 
X 
 
X 
PD assessments 
IGF-1 [d] 
 
X 
 
X 
 
X 
Random GH sample 
 
X 
 
X 
 
X 
FT3, FT4, TSH , PRL 
 
 
 
 
 
X 
Safety assessments 
AEs  
x--------------------------------------------------------------------------------------------------------------------------------------x 
Physical examination 
X 
X 
X 
X 
X 
X 
Clinical laboratory assessments 
X 
X 
X 
X 
X 
X 
HbA1c 
 
 
 
 
 
X 
eGFR [e] 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Gallbladder echography 
 
 
 
 
 
X 
Evaluation of injection site reactions 
X 
X 
X 
X 
X 
X 
Putative antibodies to lanreotide  
 
 
 
 
 
X 
AE=adverse event; eGFR=estimated glomerular filtration rate; EOS=end of study; EW=early withdrawal; FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; 
HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid 
stimulating hormone.  
a 
Study visits on Weeks 15, 19 and 23 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. A reduced physical examination will be 
performed at home visits and weight will not be measured. More information on how those home visits are performed are described in the study manual. 
b 
EOS for subjects completing the follow up period or EW visit for subjects who withdraw from the study during the follow up period. 
c 
follow up visits will be conducted every 2 weeks (±3 days). 
d 
during follow up visits, IGF-1 testing will be conducted by a central laboratory using a validated method.  
e 
measured by MDRD formula [1]. 


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The total volume of blood drawn for all evaluations throughout this study is approximately 
579 mL for each subject. The total amount of blood to be collected from all subjects is presented 
in Table 7 and Table 8. 
Table 7 
Blood Volume Calculation for Treatment Period 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments [a] 
10 
20.5 mL for 10 visits 
205 
PD 
7 IGF-1 
20 GH Cycle 
2 random GH 
2 
2 
2 
58 
PK 
15 for lanreotide;  
10 for excipient 
4 
4 
100 
HbA1c 
2 
2 
4 
FT3, FT4, TSH and PRL 
5 
3.5 
17.5 
Antibody testing 
2 
4 
8 
Biobanking [b] 
3 
10 
30 
Total 
75 
Up to 132.5 mL per 
visit (Visit 2) 
422.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; 
insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid stimulating 
hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial blood 
glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum creatinine and 
electrolytes, and urinalysis. Creatine kinase will only be measured at Baseline (predose) and 6 and 24 hours 
postdose. 
b 
the 10 mL sample blood volume collected will consist of 5 mL dry tube and 2 x 2.5 mL for RNA biobanking 
 
Table 8 
Blood Volume Calculation for Follow Up Period 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments [a] 
6 
20.5 mL  
123 
PD 
3 IGF-1 
3 random GH 
2 
2 
12 
PK 
3 for lanreotide  
4 
12 
HbA1c 
1 
2 
2 
FT3, FT4, TSH and PRL 
1 
3.5 
3.5 
Antibody testing 
1 
4 
4 
Total 
18 
Up to 38 per visit 
(Visit 18) 
156.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; 
insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid stimulating 
hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial blood 
glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum creatinine and 
electrolytes, and urinalysis. 
A volume of approximately 14 mL of urine will be collected at each of the visits that includes 
a clinical laboratory assessment. 
5.2 
Study Visits 
5.2.1 
Procedures for Screening and Enrolment (Visit 1) 
A signed and dated informed consent form will be obtained before any Screening procedures 
are started.  
After informed consent is obtained, subjects who are screened will be allocated a subject 
number which will be used in place of subject names on study records to maintain 
confidentiality. All screened subjects must be identifiable throughout the study. The 


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investigator will maintain a list of subject numbers and names to enable records to be found at 
a later date if required.  
The Screening visit (Visit 1) will take place 28 to 42 days prior to the start of treatment with 
lanreotide PRF (Day −42 to −28). 
The following assessments will be performed: 
• 
Demographic data (date of birth/age, sex will be collected according to individual 
country requirements)  
• 
Medical history, including ongoing medical history 
• 
Acromegaly symptoms 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
PD assessments (IGF-1 and GH cycle) 
• 
Physical examination 
• 
Central clinical laboratory assessments (haematology, clinical biochemistry including 
hepatic, pancreatic and renal function tests, serum electrolytes and urinalysis) 
• 
HbA1c 
• 
FT3, FT4, TSH, PRL 
• 
eGFR measured by MDRD formula [1] 
• 
Vital signs (supine and standing blood pressure and heart rate, and body temperature) 
• 
12-lead ECG 
• 
Gallbladder echography 
• 
Prior and concomitant medications/therapies, nondrug therapies and surgical procedures 
in the last month prior to study entry. Prior medication for acromegaly will be recorded 
for the last 3 months prior to study entry. 
• 
Review of AEs. Any AEs or SAEs occurring during the run in period will be reported 
but will not be included in the analysis of treatment emergent AEs (TEAEs; see Section 
10.4.7). 
Under normal circumstances subjects will not be screened more than once. There are three 
exceptions: 
(1) 
IGF-1 may be re-tested once if the screening value is just above 1.3 x ULN (analysis by 
local laboratory). The study treatment may only be administered if the re-test is <1.3 x 
ULN. 
(2) 
If the time elapsed between the original Screening visit (Visit 1) and Visit 2 is >28 days 
(±2 days) then re-screening of the subject for inclusion is permitted. 
(3) 
If deemed acceptable by the investigator, the subject may be re-screened once for 
inclusion if they previously failed screening due to the presence of asymptomatic 
gallstones/sludge. This follows the change to exclusion criterion #10 in protocol 
amendment 7. 
Following confirmation of eligibility for the study, subjects will be enrolled into the study and 
allocated to one of the dose cohorts specified in Section 6.1. At the Screening visit, enrolled 
subjects will then receive their usual dose of either octreotide LAR or lanreotide Autogel 
according to standard clinical practice.  
Each investigator will also maintain a record of all subjects screened into the study (i.e. who 
signed the informed consent form). In the event that the subject was not receiving 
lanreotide PRF, the primary reason will be recorded. 


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5.2.2 
Procedures Before Study Treatment (Baseline, Visit 2 Predose) 
On Day 1±2 days (Visit 2), subjects will be admitted to the study centre where they will undergo 
Baseline assessments prior to the administration of study treatment.  
The following procedures will be performed at Baseline on Day 1±2 days of the study, prior to 
the administration of study treatment: 
• 
Eligibility check 
• 
PK blood samples for lanreotide and excipient 
• 
Baseline PD assessments (IGF-1 and GH cycle) 
• 
Physical examination 
• 
Central clinical laboratory assessments (haematology, clinical biochemistry including 
hepatic, pancreatic and renal function tests, creatine kinase (CK), serum electrolytes and 
urinalysis) 
• 
FT3, FT4, TSH, PRL 
• 
eGFR measured by MDRD formula [1] 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature)  
• 
12-lead ECG 
• 
Putative antibodies to lanreotide 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
Biobanking samples for further biomarkers analysis will only be collected for those 
individuals who have signed a specific consent to participate in the optional biobanking 
research study  
5.2.3 
Procedures During Study Treatment (Visit 2 Postdose to Visit 12) 
Following Baseline assessments on Day 1±2 days, study treatment will be administered. 
Subjects will remain at the study centre for 24 hours postdose, during which time further 
assessments will be performed. 
The following procedures will be performed at the indicated timepoints relative to 
administration of study treatment at Visit 2 (Day 1±2 days):  
• 
PK blood samples for lanreotide and excipient at 1 (±5 min), 2 (±5 min), 4 (±10 min), 
6 (±10 min), 8 (±10 min) and 12 (±30 min) hours postdose 
• 
Evaluation of injection site reactions at 1 hour postdose 
• 
Review of AEs 
• 
Central clinical laboratory assessments (including liver function (ALT, AST, bilirubin), 
pancreatic function (lipase, amylase), serum creatinine, international normalised ratio 
(INR), postprandial glycaemia, and postprandial insulinaemia, CK) at 6 hours postdose 
• 
Evaluation of injection site reactions at 6 hours postdose 
• 
Physical examination at 6 hours postdose 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) at 
6 hours postdose 
• 
12-lead ECG (for QTc interval) at 6 hours postdose 
• 
PD assessments (IGF-1 and random GH sample) at 6 hours postdose 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 


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The following procedures will be performed 24 hours after administration of study treatment at 
Visit 2 (Day 2±2 days), before hospital discharge: 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
PK blood samples for lanreotide and excipient (24 (±2) hours) 
• 
Central clinical laboratory assessments (including liver function (ALT, AST, bilirubin), 
pancreatic function (lipase, amylase), serum creatinine, CK and GGT)  
• 
Evaluation of injection site reactions  
• 
Physical examination 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
• 
12-lead ECG 
Following the assessments on Visit 2; Day 2±2 days (24 hours postdose), subjects will be 
discharged from the study centre, returning at the following timepoints for further assessments. 
The following procedures will be performed at Visit 3 (Day 3±1 day):  
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
Central clinical laboratory assessments (haematology, clinical biochemistry including 
hepatic, pancreatic and renal function tests, serum electrolytes and urinalysis) 
• 
PK blood samples for lanreotide and excipient 
The following procedures will be performed at Visit 4 (Day 5±1 day):  
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
PK blood samples for lanreotide and excipient 
The following procedures will be performed at Visit 5 (Week 2±1 day):  
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
PK blood samples for lanreotide 
• 
Evaluation of injection site reactions 
• 
Physical examination 
• 
Central clinical laboratory assessments 
• 
FT3, FT4, TSH, PRL 
• 
eGFR measured by MDRD formula [1] 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
• 
12-lead ECG 
The 
following 
procedures 
will 
be 
performed 
at 
Visit 6 (Week 3±2 days) 
and 
Visit 7 (Week 4±2 days). Visit 7 can be performed at the study site and/or at the subject’s home 
as per investigator’s and subject’s decision. More information on how those home visits are 
performed are described in the study manual. 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
PK blood samples for lanreotide (not Week 4; Visit 7) 
• 
Evaluation of injection site reactions 


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• 
Physical examination 
• 
Central clinical laboratory assessments (haematology, clinical biochemistry including 
hepatic, pancreatic and renal function tests, serum electrolytes and urinalysis) 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
The following procedures will be performed at Visit 8 (Week 5±2 days): 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
PK blood samples for lanreotide 
• 
PD assessments (IGF-1 and GH cycle) 
• 
Evaluation of injection site reactions 
• 
Physical examination 
• 
Central clinical laboratory assessments (haematology, clinical biochemistry including 
hepatic, pancreatic and renal function tests, serum electrolytes and urinalysis) 
• 
FT3, FT4, TSH, PRL 
• 
eGFR measured by MDRD formula [1] 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
• 
12-lead ECG 
• 
Gallbladder echography 
• 
Biobanking samples for further biomarkers analysis will only be collected for those 
individuals who have signed a specific consent to participate in the optional biobanking 
research study 
The 
following 
procedures 
will 
be 
performed 
at 
Visit 9 (Week 7±2 days) 
and 
Visit 11 (Week 11±2 days). Visits 9 and 11 can be performed at the study site and/or at the 
subject’s home as per investigator’s and subject’s decision. More information on how those 
home visits are performed are described in the study manual. 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
Evaluation of injection site reactions 
• 
Physical examination 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
The following procedures will be performed at Visit 10 (Week 9±2 days): 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
PK blood samples for lanreotide  
• 
PD assessments (IGF-1 and random GH sample) 
• 
Evaluation of injection site reactions 
• 
Physical examination 
• 
Central clinical laboratory assessments (haematology, clinical biochemistry including 
hepatic, pancreatic and renal function tests, serum electrolytes and urinalysis) 
• 
eGFR measured by MDRD formula [1] 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
The following procedures will be performed at Visit 12 (Week 13±1 day): 


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• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
Acromegaly symptoms 
• 
PK blood samples for lanreotide. Importantly, this sample will be on Day 85 and will 
correspond to the concentration at the end of the dosing interval (Ctrough). Therefore, the 
visit window for this visit (±1 day) must be strictly adhered to. 
• 
PD assessments (IGF-1 and GH cycle) 
• 
Evaluation of injection site reactions 
• 
Physical examination 
• 
Central clinical laboratory assessments (haematology, clinical biochemistry including 
hepatic, pancreatic and renal function tests, serum electrolytes and urinalysis) 
• 
HbA1c 
• 
FT3, FT4, TSH, PRL 
• 
eGFR measured by MDRD formula [1] 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
• 
12-lead ECG 
• 
Gallbladder echography 
• 
Putative antibodies to lanreotide 
• 
Blood samples for further biomarkers analysis will only be collected from those 
individuals who have signed a specific consent to participate in the optional biobanking 
research study  
5.2.4 
Procedures After Study Treatment 
During the 12 week follow up period, study visits will be conducted every 2 weeks (±3 days). 
5.2.4.1 
Follow Up Visits 
The 
following 
procedures 
will 
be 
performed 
at 
Visit 13 (Week 15±3 days), 
Visit 15 (Week 19±3 days) and Visit 17 (Week 23±3 days). Visits 13 and 15 can be performed 
at the study site and/or at the subject’s home as per investigator’s and subject’s decision. More 
information on how those home visits are performed are described in the study manual. 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
Physical examination 
• 
Central clinical laboratory assessments 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
• 
Evaluation of injection site reactions 
The following procedures will be 
performed at Visit 14 (Week 17±3 days) and 
Visit 16 (Week 21±3 days): 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
PK blood samples for lanreotide 
• 
PD assessments (IGF-1 and random GH sample) 
• 
Physical examination 
• 
Central clinical laboratory assessments 


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• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
• 
Evaluation of injection site reactions 
• 
eGFR measured by MDRD formula [1] 
5.2.4.2 
End of Study Visit (Week 25, Visit 18) or Early Withdrawal Visit 
Subjects who participate in the study in compliance with the protocol until the last follow up 
visit (Visit 18) will be considered to have completed the study.  
EW should not take place before Week 13 after the injection of lanreotide PRF due to the 
expected 12 week duration of action. However, in the case of withdrawal within the 12 week 
treatment period or within the follow up period (Section 4.3), final evaluations will be 
performed as soon as possible after the decision to withdraw. Subjects with ongoing AEs or 
clinically significant laboratory test abnormalities (as determined by the investigator) will be 
monitored as described in Section 8.1.3 and Section 8.1.2.4, respectively. 
The following procedures will be performed at the EOS (Week 25±3 days; Visit 18), or EW 
visit: 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies/nondrug therapies/ surgeries 
• 
Acromegaly symptoms 
• 
PK blood samples for lanreotide 
• 
PD assessments (IGF-1 and random GH sample) 
• 
Physical examination 
• 
Central clinical laboratory assessments 
• 
HbA1c 
• 
FT3, FT4, TSH, PRL 
• 
eGFR measured by MDRD formula [1] 
• 
Vital signs (supine and standing blood pressure, heart rate and body temperature) 
• 
Gallbladder echography 
• 
Evaluation of injection site reactions 
• 
Putative antibodies to lanreotide 


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6 
TREATMENT OF SUBJECTS 
6.1 
Investigational Medicinal Product Administered 
At Screening, subjects will be allocated a subject number. Following informed consent and 
confirmation of eligibility for the study, subjects will be allocated to one of the following 
treatment cohorts: 
Table 9 
Treatment Cohorts 
Cohort [a] 
Lanreotide PRF dose 
1 
180 mg 
2 
270 mg 
3 
360 mg 
PRF=prolonged release formulation. 
a 
each subsequent dose cohort will be initiated following recommendations from the DRC. 
6.1.1 
Dose Escalation Schema  
Subjects will be assigned to a treatment cohort and will receive lanreotide PRF at a single dose 
level.  
The dose escalation will proceed with a 3+3+3 scheme. At each dose level, a total of 
nine subjects will be enrolled if ≤3 DLTs are reported. See Section 3.6.3 for the definition of 
DLT. 
Subject enrolment into the study will begin at Dose Level 1 (180 mg).  
Dose level: 180 mg. The study will start dosing three subjects. If none or one out of the three 
dosed subjects experiences a DLT, three more subjects will be dosed at the same dose. If two 
out of the three dosed subjects experiences a DLT, the DRC will decide whether three more 
subjects may be dosed. If all three subjects have experienced a DLT, dosing will be stopped 
and the dose will be declared the maximum administered dose.  
If none or one of the six dosed subjects experience a DLT, three more subjects can be dosed at 
the same dose. If two of the six dosed subjects experience a DLT, and one or both of the DLTs 
occurred in the second group of three subjects, the DRC will decide whether three more subjects 
may be dosed. If a total of three or more out of six subjects experience a DLT, dosing will be 
stopped and the dose will be declared the maximum administered dose.  
Dose escalation: If more than three out of nine subjects experience a DLT, dose escalation will 
be stopped and the dose will be declared the maximum administered dose. If ≤3 DLTs have 
been observed in the nine treated subjects, then the dose may be escalated to 270 mg. The DRC 
will determine if progression to the next dose cohort should occur after reviewing data from the 
preceding cohort. The same rules will be applied to the next dose level and the decision to 
escalate to 360 mg will be done in the same way. 
At any time the DRC can ask for an ad hoc review of the data prior to any dosing if it is judged 
necessary. 
Details of the adaptive 3+3+3 or 1+2+2+2+2 (Cohort 2) or 2+2+2+3 (Cohort 3) dose escalation 
scheme with the most likely outcome are provided in Figure 2 and Figure 3.


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Figure 2 Adaptive 3+3+3 Dose Escalation Scheme with the Most Likely Outcome 
 
DLT=dose limiting toxicity; DRC=Data Review Committee. 
 


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Figure 3 Adaptive 2 per 2 Dose Escalation Scheme with the Most Likely Outcome 
 
DLT=dose limiting toxicity; DRC=Data Review Committee. 


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6.1.2 
Definition of Maximum Tolerated Dose 
The identification of the MTD will be left to the discretion of the DRC. 
The DRC may agree to define a MTD in the absence of a DLT at Week 2 (Visit 5) if the overall 
toxicity profile of lanreotide PRF suggests that further escalation is not possible (delayed 
toxicity, i.e. symptomatic cholelithiasis, or grade ≥3 injection site reaction or prolonged grade 
≥2 toxicity). 
6.1.3 
Investigational Medicinal Product 
Lanreotide PRF formulation will be supplied in a 1.2 mL prefilled syringe fitted with a 
1.2/1.4 mm (inner diameter/outer diameter) needle packed in a laminated pouch. 
The product is intended to deliver 180, 270 or 360 mg lanreotide (potency is expressed as 
lanreotide base) for this phase 2a clinical study. The different strengths are dose proportional 
as syringes are filled with increasing quantities of the same lanreotide supersaturated bulk 
solution. 
All strengths will be evaluated (180, 270 and 360 mg) and they will be provided in the same 
presentation. 
Lanreotide PRF will be administered by deep subcutaneous injection in the superior, external 
quadrant of the buttock at the doses indicated in Table 9. Nine subjects will be allocated to each 
dose cohort.  
6.2 
Concomitant Medication/Therapy 
Any prior or concomitant therapy or medication given to a subject in the last month before 
study entry and throughout the study will be indicated on the eCRF. Prior medications for 
acromegaly for the 3 months prior to study entry will also be recorded on the eCRF. Dose and 
generic name or trade name will be indicated. 
The following concomitant medications/therapies are not permitted during this study: 
• 
Hormone replacement therapy (HRT) with oestrogens, 
• 
Dopamine agonist and GH receptor antagonist, or pituitary surgery, 
• 
Radiotherapy. 
The following concomitant medications are permitted during this study, but they must be 
monitored closely and every effort should be made to keep their dose and dose regimen constant 
throughout the course of the study.  
• 
Bradycardia inducing drugs (e.g. beta blockers), 
• 
Substrate of CYP3A4 (e.g. quinidine, erythromycin, simvastatin). 
For information regarding the effects on blood glucose and the need for monitoring and 
adjustment of anti-diabetic agents, as well as information about the possible effects on 
cyclosporine bioavailability, please refer to the IB (Summary of Data and 
Guidance for the Investigator, Section 6.4.4 Glycoregulation and Section 6.4.7 Drug 
Interactions). 
6.3 
Procedures for Monitoring Subject Compliance 
The investigator will be responsible for monitoring subject compliance. Subjects can be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol. 
Lanreotide PRF will be administered to subjects by study staff at each study site.  
Deviation from the scheduled amount of lanreotide PRF intake will be regarded as a major 
protocol violation. 


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7 
ASSESSMENT OF EFFICACY 
Efficacy is not assessed in this study. However, clinical and biochemical symptoms of 
acromegaly will be closely monitored. 


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8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study (see Section 3.5 for a definition of the study duration) and will be elicited 
by direct, non leading questioning or by spontaneous reports. Further details for AE reporting 
can be found in Section 8.1.2. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product. An undesirable medical condition can be 
symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g. laboratory findings, ECG). In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including run in or washout periods, 
even if no lanreotide PRF has been administered.  
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
All toxicities will be graded according to the NCI CTCAE Version 4.03 (June, 2010). 
8.1.2.2 
Causality Classification 
The relationship of an AE to lanreotide PRF administration will be classified according to the 
following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with lanreotide PRF administration in the 
sense that it is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with lanreotide PRF administration. 
8.1.2.3 
Assessment of Expectedness 
The reference document for assessing expectedness of AEs/events in this study will be the IB 
for lanreotide.  
8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in lanreotide PRF schedule of administration (i.e. delay in 
administration), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant (e.g. ECG 
changes) that result in a change in administration schedule, or in discontinuation of the study, 


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or require intervention or diagnostic evaluation to assess the risk to the subject, should be 
recorded as AEs.  
8.1.3 
Recording and Follow Up of Adverse Events 
During the informed consent process and on an ongoing basis subjects should be reminded to 
report any AEs as soon as possible to their study site and not to wait until their next visit if they 
experience any unexpected medical symptoms. 
At each visit, the subject should be asked a non leading question such as: “How have you felt 
since starting the new treatment/last dose/the last assessment?” All observed or volunteered 
AEs, regardless of suspected causal relationship to lanreotide PRF, will be recorded on the AE 
page(s) of the eCRF. Events involving drug reactions, accidents, illnesses with onset during the 
treatment phase of the study, or exacerbation’s of pre-existing illnesses should be recorded. 
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE (i.e. lanreotide PRF or other illness). The investigator is required to assess causality and 
record that assessment on the eCRF. Follow up of the AE is required if the AE or its sequelae 
persist. Follow up is required until the AE or its sequelae resolve or stabilise at a level 
acceptable to the investigator and the sponsor’s clinical monitor or his/her designated 
representative. 
For information on actions to be taken, monitoring and/or follow-up procedures in case of 
cardiac disorders, pancreatic and renal abnormalities, hyperglycaemia, and gallstones please 
refer to the IB (Summary of Data and Guidance for the Investigator, Section 6.4.1 Cardiac 
Safety, Section 6.4.3 Effects on Gallbladder and Pancreas, Section 6.4.4 Glycoregulation, and 
Section 6.4.6 Special Patient Populations). 
8.1.4 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of treatment cohort or suspected relationship to 
lanreotide PRF must be reported immediately (within 24 hours of the investigator’s knowledge 
of the event) to the pharmacovigilance contact specified at the beginning of this protocol either 
by faxing a detailed written report using the SAE report form or by telephone. If the report is 
first reported by telephone, this must be followed by a faxed SAE report form. The process for 
notifying the Medical Development Director (MDD) will be specified in the SAE reporting 
plan. 
An SAE is any AE that: 
(1) 
Results in death, 
(2) 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death, 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see further), 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions, 
(5) 
Results in a congenital anomaly/birth defect in the offspring of a subject who received 
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(6) 
Is an important medical event that may not result in death, be life threatening, or require 
hospitalisation when, based upon appropriate medical judgement, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalisation, or the development of drug 
dependency or drug abuse. 
In addition to the above criteria, any additional AE that the sponsor or the investigator considers 
serious should be reported immediately to the sponsor and included in the corporate SAEs 
database system. 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the investigator or treating physician. For 
protocol-specified hospitalisation in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. Prolongation in the absence 
of a precipitating, treatment emergent, clinical AE (i.e. not associated with the 
development of a new AE or worsening of a pre-existing condition) may meet the criteria 
for “seriousness” but is not an adverse experience and thus is not pertinent to immediate 
reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the subject’s 
Screening documentation. Hospitalisation for a preplanned or elective treatment/surgical 
procedure should not be reported as an SAE unless there are complications or sequelae 
that meet the criteria for seriousness described above. 
Any SAE must be reported immediately (within 24 hours), independent of the circumstances 
or suspected cause, if it occurs or comes to the attention of the investigator at any time during 
the study period. 
Any AE/SAE with a suspected causal relationship to lanreotide PRF administration occurring 
at any other time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
• 
Study number 
• 
Centre number 
• 
Subject number 
• 
AE 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. Upon receipt of the initial report, the sponsor 
will ask for the investigator's causality assessment if it was not provided with the initial report. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE, considered as the 
foremost untoward medical occurrence, from secondary AEs that occurred as complications. 


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8.1.5 
Pregnancy 
Only females of nonchildbearing potential are eligible to participate in the study (Section 4.1). 
If the investigator becomes aware of a pregnancy occurring in the partner of a male subject 
participating in the study, this should be reported to the sponsor. After the partner has given 
written consent, she should be counselled and followed up. Monitoring of the partner should 
continue until conclusion of the pregnancy. 
8.1.6 
Deaths 
All AEs resulting in death during the study, or within 12 weeks after lanreotide PRF 
administration, must be reported as an SAE within 24 hours of the investigator’s knowledge of 
the event.  
The convention for recording death is as follows:  
• 
AE term: lead cause of death (e.g. multiple organ failure, pneumonia, myocardial 
infarction), 
• 
Outcome: fatal. 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), in 
which case the AE term may be “death” or “sudden death”. 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
If a subject is discontinued due to an SAE, it must be reported immediately to the sponsor’s 
designated representative (see Section 8.1.4). In all cases, the investigator must ensure that the 
subject receives appropriate medical follow up (see Section 8.1.3). 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the CA, IECs 
and other investigators concerned with the administration of lanreotide PRF. Reporting will be 
done in accordance with the applicable regulatory requirements. 
8.2 
Clinical Laboratory Tests 
Blood and urine samples will be collected according to the study schedule in Table 5 and 
Table 6 for the evaluation of haematology, serum chemistry and urinalysis. Clinical laboratory 
tests will be conducted at a central laboratory. Details of the sample handling methodology and 
reference ranges will be provided in the study manual and archived in the Trial Master File 
(TMF). 
The investigator will review the safety laboratory test results, document the review, and record 
any clinically relevant changes occurring or observed during the study in the AE section of the 
eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded as AEs). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline or to a level deemed acceptable by the 
investigator and the sponsor’s clinical monitor (or his/her designated representative) or until the 
abnormality is explained by an appropriate diagnosis.  
Any unscheduled test (indication and results) will be recorded on the dedicated page in the 
eCRF. 
8.2.1 
Haematology 
Blood samples (3 mL) will be collected in a potassium ethylenediaminetetraacetic acid (EDTA) 
tube to assess the following parameters: red blood cell count, haemoglobin, haematocrit, mean 
corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin 


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concentration, white blood cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and others) and platelet count. 
8.2.2 
Coagulation 
Blood samples (4.5 mL) will be collected to assess the following coagulation parameters: 
activated partial thromboplastin time, prothrombin time and its derived measures of 
prothrombin ratio and INR. 
8.2.3 
Blood Biochemistry 
Blood samples (6 mL) will be collected to assess the following parameters: 
• 
urea, creatinine, CK, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, phosphate 
• 
ALP, AST, ALT, GGT 
• 
albumin, total protein, total cholesterol, triglycerides, postprandial glucose, and 
postprandial insulin  
• 
pancreatic enzymes, glucagon 
Blood samples (2 mL) will also be collected to assess HbA1c. 
8.2.4 
Urinalysis 
Fresh urine samples (approximately 14 mL) will be collected to assess the following 
parameters: chloride, bicarbonates, sodium, potassium, calcium, pH, proteins, ketones, glucose, 
blood, bilirubin and urobilinogen.  
Microscopy will be performed, if indicated, but results will not be collected in the eCRF. If in 
the opinion of the investigator there are any clinically significant abnormalities in microscopy, 
they will be recorded as AEs in the eCRF. 
8.2.5 
Putative Antibody Testing 
Blood samples (4 mL) will be collected for the assay of putative antibodies to lanreotide. The 
tubes should be left to stand for 30 minutes and then centrifuged at 1000 g to 1300 g for 
10 minutes at 4°C. The resulting serum will be stored as two 1 mL aliquots at -20°C in 
polypropylene tubes prior to shipment to the analysis laboratory 
 
 Each tube should be labelled with the sample identification, study number, 
site number, subject number and initials, visit number (when applicable) and the planned time 
of collection. 
Full details regarding the requirements for processing, labelling and shipment of these samples 
will be provided in the central laboratory manual and archived in the TMF. 
The determination of putative antibodies to lanreotide will be evaluated using a validated 
radioimmunoprecipitation assay (RIPA) method 
 
. Moreover, a few of the samples (backup samples not used for 
determination of putative antibodies by the RIPA method) will be shipped to another CRO and 
used to cross validate a new method for determination of putative antibodies 
(electrochemiluminescence assay method). The results of the cross validation will not be part 
of this study and will be reported in a separate report. 
8.3 
Estimated Glomerular Filtration Rate 
Glomerular filtration rate will be estimated from serum creatinine, age, gender and race, 
according to the MDRD formula [1]. 
Details of the sample handling methodology and reference ranges will be provided in the central 
laboratory manual and archived in the TMF. 
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Any clinically significant abnormalities will be recorded as AEs. 
8.4 
Physical Examination 
Physical examinations, including body weight, will be conducted according to the study 
schedule in Table 5 and Table 6. Height will be measured at Screening. A reduced physical 
examination will be performed at home visits and weight will not be measured. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed up by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.5 
Vital Signs 
Blood pressure and heart rate will be assessed with an automated device so that measurements 
are independent of the observer. Blood pressure and heart rate will be recorded after five 
minutes rest in a supine position and after 1 minute standing. Body temperature will also be 
recorded. 
All vital signs assessments will be conducted at the timepoints specified in the study schedule 
(Table 5 and Table 6).  
Any clinically significant abnormalities will be recorded as AEs. 
8.6 
Electrocardiography 
ECG analysis will be included as a safety evaluation/endpoint in this study. 
Computerised standard 12-lead ECGs will be used so that the different ECG parameters (sinus 
rhythm, heart rate, RR interval, PR interval, QRS interval, QT and QTc) can be measured 
automatically. QTc will be calculated using Fridericia methodology. The ECG will be recorded 
with the subject in a supine position after five minutes of rest until four regular consecutive 
complexes are available. Automated ECG interval estimates taken from the ECG recorder will 
be used in this study. 
Any clinically significant abnormalities will be recorded as AEs. A copy of the ECG trace and 
report will be retained. 
8.7 
Gallbladder Echography 
Gallbladder echography will be conducted according to study site procedures. The results will 
be recorded in the eCRF. Any clinically significant abnormalities will be recorded as AEs. In 
particular, sites should be aware of any subject who has gallstones or sludge present at baseline. 
In the case that a subject develops gallstone(s) during the study but they are asymptomatic, they 
can remain in the study and complete the protocol as planned. If a subject develops symptoms 
of either a pre-existing gallstone(s) or a newly developed gallstone, they may remain in the 
study at the discretion of the investigator. As this is a single-dose protocol, the subject will not 
be exposed to any additional IMP. 
In case of the development of (symptomatic) gallstones/sludge this will be treated according to 
the study sites’ routine practice. 
8.8 
Evaluation of Injection Site Reactions 
Injection sites will be evaluated by the investigator (or appropriately trained healthcare 
professional) for appearance and local symptoms according to NCI CTCAE criteria at the 
timepoints specified in the study schedule (Table 5 and Table 6). Results will be recorded on a 
dedicated form in the eCRF. 
Any clinically significant abnormalities will be recorded as AEs. 


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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
9.1 
Pharmacokinetics 
9.1.1 
Sample Collection 
Blood samples (4 mL each) for determination of lanreotide and excipient serum concentrations 
will be collected at the timepoints indicated in Table 5 and Table 6. Although the sample 
collection procedures for lanreotide and the excipient are the same, separate blood samples will 
be collected for each analyte.  
During the study, the nominal sample collection times may be changed, but the total number of 
samples will not increase. The exact dates and times of blood sample collection, and 
lanreotide PRF administration must be recorded in the eCRF. 
The tubes will be left to stand for 30 minutes and will then be centrifuged at 1000 g to 1300 g 
for 10 minutes at 4ºC. For each analyte, the resulting serum will be stored as two 1 mL aliquots 
at –20°C in polypropylene tubes prior to shipment to the analysis laboratory. Each tube should 
be labelled in accordance with the sponsor’s requirements. Aliquots will be shipped on dry ice. 
Details of the sample handling methodology and reference ranges will be provided in the central 
laboratory manual and archived in the TMF. 
9.1.2 
Analytical Procedures 
Serum will be analysed to determine concentrations of lanreotide using a validated, specific and 
sensitive radioimmunoassay (RIA) method 
 
 Concentrations of excipient will be analysed using a validated 
liquid chromatography tandem mass spectrometry (LC-MS/MS) method 
 under the 
supervision of Ipsen’s Pharmacokinetics and Drug Metabolism (PDM) Department. Moreover, 
a few of the PK samples (backup samples not used for determination of lanreotide 
concentrations by RIA) will be shipped to another CRO and used to cross validate a new method 
for determination of serum lanreotide concentrations (mass spectrometry method). The results 
of the cross validation will not be part of this study and will be reported in a separate report. 
9.1.3 
Data Analysis 
Individual serum concentrations for lanreotide and excipient will be listed and summarised by 
timepoint and dose level using descriptive statistics for continuous variables (number of 
available observations, mean, median, standard deviation (SD), minimum, maximum, 
geometric mean, and geometric coefficient of variation assuming log-normally distributed 
data). Linear and semilogarithmic plots of individual and mean serum concentration-time 
profiles, as well as spaghetti plots will be reported. 
The analysis of PK data will be performed by a CRO under the supervision of Ipsen’s PDM 
Department using a noncompartmental approach and Phoenix WinNonLin Version 6.3 or 
higher.  
The following parameters will be computed from lanreotide serum concentration data: Ctrough, 
Cmax, Tmax, AUC0-85, AUC0-, t½, MRT, CL/F and V/F. 
For the excipient, the following PK parameters will be computed: Cmax, Tmax, AUCt, AUC0-, 
t½, MRT, CL/F and V/F. 
Descriptive summary statistics (the number of observations (n), mean, median, SD and range 
for continuous variables, and n and percentage (%) for categorical/nominal variables) will be 
presented.  
In order to assess dose proportionality, a power model will be used for AUC0-85, AUC0- and 
Cmax. Dose independence for t1/2, V/F and CL/F will also be investigated using the same model. 
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Additional exploratory model-based analysis (population PK analysis) might also be conducted 
to characterise lanreotide PK parameters, such as clearance and volume of distribution, as well 
as their interindividual variability. 
The percentage of subjects developing putative anti-lanreotide antibodies will be calculated at 
Baseline (predose on Day 1) and at Weeks 13 and 25 (or EW).  
9.2 
Pharmacodynamics 
9.2.1 
Sample Collection 
Blood samples (2 mL) for assessment of PD parameters will be taken at the timepoints indicated 
below, as presented in Table 5 and Table 6. 
• 
IGF-1 will be assessed at Screening, Baseline (predose on Day 1), 6 hours postdose on 
Day 1 and at Weeks 5, 9, 13, 17, 21 and 25 (or EW).  
• 
A 2 hour GH cycle (5 sampling times every 30 minutes) will be performed in the 
morning at Screening, Baseline (predose on Day 1) and at Weeks 5 and 13.  
• 
Subjects will also have random GH samples taken at 6 hours postdose on Day 1 and 
Weeks 9, 17, 21 and 25 (or EW). 
Blood samples (2 mL) will also be collected to assess endocrinology parameters (FT3, FT4, TSH 
and PRL) according to the study schedule (Table 5 and Table 6). 
• 
FT3, FT4, TSH and PRL at Screening, Baseline (predose on Day 1), and at Weeks 2, 5, 
13 and 25 (or EW). 
Details of the sample handling methodology and reference ranges will be provided in the central 
laboratory manual and archived in the TMF. 
9.2.2 
Analytical Procedures 
Measurement of IGF-1 and GH concentrations will be performed by a central laboratory using 
a validated method (see the central laboratory manual for further details). 
Measurement of IGF-1 concentrations at the screening visit will be performed locally. 
9.2.3 
Data Analysis 
All summaries for the PD endpoints will be based on the intent to treat (ITT) and per protocol 
(PP) populations. To investigate the relationship between PD variables (GH and IGF-1) and 
lanreotide exposure, exploratory PK/PD modelling may be performed if a relationship can be 
defined. Details regarding PK and PK/PD modelling will be described in a separate Data 
Analysis Plan and the results will be reported as a standalone report. 
9.2.3.1 
IGF-1 (Age Adjusted) 
Summary statistics by dose cohort and overall will be tabulated for each assessment, at each 
timepoint, as well as for the changes from Baseline (predose on Day 1), with 95% confidence 
interval (CI). If needed, IGF-1 values will be log transformed. Also, at each assessment 
timepoint, the percentage of subjects with normalised IGF-1 during predose and postdose will 
be tabulated by dose cohort and overall. IGF-1 levels at each assessment for individual subjects 
will be graphically presented by dose cohort as a percentage of the ULN (i.e. % ULN). Time to 
escape (defined as time from lanreotide PRF administration to the time when the IGF-1 ≥1.3 x 
ULN) will be summarised by dose cohort. 
9.2.3.2 
Growth Hormone 
Summary statistics by dose cohort and overall will be tabulated for each assessment, at each 
timepoint, as well as for the changes from Baseline (predose on Day 1) with 95% CI. If needed, 
GH values will be log transformed. AUC0-2h will be graphically presented by dose cohort at 


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Baseline and at Day 85. The GH levels at each assessment will also be presented as % ULN. 
Also, at each assessment timepoint, the percentage of subjects with normalised GH (GH 
≤1 ng/mL or ≤2.5 ng/mL) during predose and postdose will be tabulated by dose cohort and 
overall. For those subjects who had a normalised GH value at Baseline, their time to escape 
(defined as time from lanreotide PRF administration to the time when GH >1 ng/mL or 
>2.5 ng/mL) will be summarised. 
9.2.3.3 
Other Endocrine Parameters 
For PRL, TSH, FT3 and FT4, the change from Baseline (predose on Day 1) assessment will be 
listed for each postbaseline assessment, together with the raw values, the lower limit of normal 
(LLN) and the ULN. Summary statistics by dose cohort and overall will be tabulated for each 
assessment, at each timepoint, as well as for the changes from Baseline (predose on Day 1). 
The PRL, TSH, FT3 and FT4 levels at each assessment will be graphically presented by dose 
cohort. The PRL, TSH, FT3 and FT4 levels at each assessment will also be presented as % ULN. 


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10 
STATISTICS 
10.1 
Analysis Populations 
The following populations will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent 
form). 
• 
Randomised population: Not applicable. 
• 
Safety population: All subjects who receive the single dose of lanreotide PRF and have 
at least one postbaseline safety assessment. 
• 
ITT population: All treated subjects. 
• 
PP population: All subjects in the ITT population for whom no major protocol 
violations/deviations occur. 
• 
PK valid population: All subjects who receive at least one dose and have no major 
protocol deviations affecting the PK variables and who have a sufficient number of serum 
lanreotide concentrations to estimate the main PK parameters (Cmax, Tmax, and AUC).  
10.1.1 
Populations Analysed 
The primary analysis based on the primary safety and PK will be performed on the safety and 
PK valid populations, respectively. In addition, analyses based on ITT and PP populations may 
be performed as secondary on the PD data. 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation will be described in the Protocol Deviation Document and its 
impact on inclusion in each analysis population (ITT, PP, safety and PK valid populations) for 
any subject will be specified. The final list of protocol deviations impacting the PP population 
will be reviewed during the data review meeting held prior to database lock. The list will be 
updated to include any additional major protocol deviations impacting inclusion in the PP 
population. 
10.2 
Sample Size Determination 
Inclusion of nine subjects within a dose cohort (180, 270 or 360 mg) will be based on an 
adaptive 3+3+3 decision rule focussing a priori on the subject safety. This means that the 
addition of up to nine subjects would be based on the MTD profile and decisions made at that 
dose level. In addition, the sample size is based on prior clinical experience with this type of 
study and subject population and should be sufficient to meet the study objectives. 
10.3 
Significance Testing and Estimations 
As this is a descriptive safety, tolerability and PK/PD study, no formal statistical testing will be 
carried out. 
10.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s Biometry 
Department. 
A Reporting and Analysis plan describing the planned statistical analysis in detail with tables, 
figures and listings templates will be developed as a separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS®) (Version 9 or 
higher). 


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10.4.1 
Demographic and Other Baseline Characteristics 
In order to ensure balance among dose cohorts, descriptive summary statistics (n, mean, SD, 
median, minimum, maximum) or frequency counts of demographic and Baseline data (medical 
history, concomitant  medications, etc.) will be presented by dose cohort and overall for the 
safety population(s). 
10.4.2 
Homogeneity of Treatment Cohorts 
Not applicable. 
10.4.3 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in the safety population will be 
tabulated by dose cohort. The reasons for subject exclusions from each of the populations will 
also be tabulated. In addition, the numbers of subjects who were treated, discontinued and 
completed at each dose level will be tabulated. Primary reasons for discontinuation of study 
treatment will be tabulated per dose level. 
10.4.4 
Pharmacokinetic Data 
The PK data analysis will be performed independently by a CRO under the supervision of 
Ipsen’s PDM Department as described in Section 9.1.3. 
Individual listings and summary tables of lanreotide and excipient concentrations will be 
provided. 
10.4.5 
Efficacy Evaluation 
Not applicable. For the analysis of PD data, see Section 9.2. 
10.4.6 
Adjustment for Country/Centre Effect 
Not applicable. 
10.4.7 
Safety Evaluation 
Safety analyses and summary tables will be based on the safety population. Adverse events 
reported by investigators using the NCI CTCAE classification (Version 4.03) will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA; Version 16.1 or higher).  
All safety data will be included in the subject data listings. Listings of AEs will be presented 
by subject, system organ class and preferred term.  
Based upon the definitions of DLTs provided in Section 3.6.3, subject profiles will be prepared 
for individual subjects to facilitate the review of the DRC. Summaries of DLTs by dose cohorts 
will also be provided. 
All AEs and SAEs occurring during the Screening period will be reported; however, these will 
not be considered in the analysis of TEAEs. The incidence of all reported TEAEs and SAEs 
will be tabulated by dose cohort and overall. In addition, summary tables will be presented by 
maximum intensity, drug relationship and TEAEs associated with premature withdrawal of 
study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the dose of lanreotide PRF, or  
• 
it was present prior to receiving the dose of lanreotide PRF but the intensity increased 
during the active phase of the study, or  
• 
it was present prior to receiving the dose of lanreotide PRF, the intensity is the same but 
the drug relationship became related during the active phase of the study.  
All TEAEs will be flagged in the AEs listings. 


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Summary incidence tables will be provided, classified by body system, preferred term and 
associated NCI CTCAE worst grade. In the event of multiple occurrences of the same AEs 
being reported by the same subject, the maximum intensity (grade 5 >grade 4 >grade 3 >grade 2 
>grade 1 >missing >not applicable) will be chosen.  
Haematological and biochemistry toxicities will be recorded and graded according to the NCI 
CTCAE criteria. The NCI CTCAE grade 3 and 4 haematology and biochemistry parameters by 
subject and by cycle will be listed. For white blood cells, neutrophils, platelets and 
haemoglobin, with associated grade 3 or 4 toxicities, nadir and day to nadir will be calculated. 
Concomitant medication will be coded by using the World Health Organisation (WHO) Drug 
Dictionary (Version June 2014 or higher) and will be summarised by dose cohort with the 
number and percentage of subjects receiving concomitant medication by drug class and 
preferred drug name. 
Summary statistics (mean, median, SD and range as appropriate) by treatment cohort and 
overall will be presented for vital signs (blood pressure and heart rate) and clinical laboratory 
tests at each assessment with change from Baseline. For laboratory data, abnormal values will 
be flagged in the data listings and a list of clinically significant abnormal values will be 
presented. For the ECG parameters, clinically significant findings will be listed by dose cohort 
and overall. 
10.5 
Subgroup Analyses 
If sufficient numbers of subjects are available to permit these analyses, descriptive statistics 
will be provided within each category of the following variables: Previous treatment and dose 
(octreotide LAR, lanreotide Autogel), sex, age (≤65, >65 years). 
10.6 
Interim Analyses/Data Review Committee 
Before each decision of the dose escalation, safety data will be summarised and presented to 
the DRC. This DRC will be composed of an expert in Endocrinology and an ad hoc expert in 
Hepatogastroenterology. A specific charter will be developed to define roles and 
responsibilities. 
The DRC will review safety data from each cohort after all subjects in the cohort have 
completed Visit 5 (Week 2 postdose). At this time, if no DLT or unexpected safety signals have 
been observed and the overall safety is in line with the known lanreotide safety profile, the DRC 
will decide whether to proceed with the next dose cohort.  
The DRC will also advise on any restriction on subject enrolment with regard to dose of 
pre-study octreotide or lanreotide Autogel for cohorts 2 and 3, based on considerations of safety 
and PK assessment of preceding cohort(s). 
The DRC will meet after the last subject, last visit (LSLV) has been completed to review the 
overall safety and to identify any delayed grade ≥3 adverse reactions (cholelithiasis-related 
gallbladder obstruction or cholecystitis ≥grade 3, or ≥grade 3 injection site reaction) or 
prolonged grade ≥2 toxicity. 
However, ad hoc DRC meetings would take place if 2 DLTs occur during cohort accrual. 
Details of the DRC set up, membership, management and responsibilities will be provided in 
the DRC charter and archived in the TMF. 
Details regarding stopping boundaries and early stopping rules will be described in the charter.  
Interim analyses may be performed by the Sponsor to facilitate the planning of future clinical 
studies of lanreotide PRF. 


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11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external CAs and sponsor authorised Quality Assurance personnel 
may carry out inspections and audits. The purpose of an audit is to ensure that ethical, regulatory 
and quality requirements are fulfilled in all studies performed by the sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 12.4, and to any other locations used for the purpose of the study in question 
(e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Protocol Amendments and Protocol Deviations and Violations 
12.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favourable opinion of a written amendment by the IEC/IRB, except when necessary 
to eliminate immediate safety concerns to the subjects or when the change involves only 
logistics or administration. The principal investigator and the sponsor will sign the protocol 
amendment. 
12.1.2 
Protocol Deviations, Violations, and Exceptions 
A protocol deviation is nonadherence to protocol specific study procedures or schedules that 
does not involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP 
guidelines. Deviations are considered minor and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e. nonadherence on the 
part of the subjects, the investigator, or the sponsor to protocol specific inclusion/exclusion 
criteria, primary objective evaluation criteria, and/or GCP guidelines. Protocol violations will 
be identified and recorded, by study centre personnel, on the eCRF. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria to 
allow subjects to enter a study. If under extraordinary circumstances such action is considered 
ethically, medically, and scientifically justified for a particular subject, prior approval from the 
sponsor and the responsible IRB/IEC, in accordance with the Standard Operating Procedure 
(SOP), is required before the subject will be allowed to enter the study. If investigative centre 
personnel learn that a subject who did not meet protocol eligibility criteria was entered in a 
study (a protocol violation), they must immediately inform the sponsor. Such subjects will be 
discontinued from the study, except in an exceptional instance following review and written 
approval by the sponsor and the responsible IRB/IEC, according to the applicable SOP. 
12.2 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting any study 
procedures and during the course of the study (e.g. when new staff become involved). The 
investigator must assure that all study staff members are qualified by education, experience, 
and training to perform their specific responsibilities. These study staff members must be listed 
on the study centre authorisation form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. 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 study monitor. 
12.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring these data to verify that the rights and wellbeing of 
subjects are protected, that study data are accurate (complete and verifiable to source data) and 
that the study is conducted in compliance with the protocol, GCP and regulatory requirements. 
Sponsor assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 
areas) for the purpose of verifying entries made in the eCRF, and assist with the monitor’s 


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activities, if requested. Adequate time and space for monitoring visits should be made available 
by the investigator. 
The site must complete the eCRFs according to the sponsor monitoring manual, of the subject’s 
visit and on an ongoing basis to allow regular review by the study monitor, both remotely by 
the internet and during site visits. The central study monitor at the sponsor will use functions 
of the EDC system to address any queries raised while reviewing the data entered by the study 
site personnel in a timely manner. 
Whenever a subject name is revealed on a document required by the sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel, leaving the initials 
visible, and annotated with the subject number as identification. 
12.4 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 11). 
12.5 
Data Quality Assurance 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
group will be reviewed (secondary monitoring) for completeness, consistency, legibility and 
protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol deviations. 
Any electronic queries and items not adequately explained will require additional electronic 
manual queries to be raised to the investigator by the monitor for clarification/correction. The 
investigator must ensure that queries are dealt with promptly. All data changes and clarifications 
can be viewed in the audit trail function of the eCRF. 


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13 
ETHICS 
13.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH GCP Guidelines (Section 1.6]). The EDC system will comply 
with FDA, 21 CFR Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for 
Industry: Computerized Systems Used in Clinical Trials.  
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should be made only in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
13.2 
Informed Consent 
Prior to study entry, the investigator, or a person designated by the investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study-related procedure 
and administration of lanreotide PRF). Sufficient time will be allowed to discuss any questions 
raised by the subject. 
The sponsor will provide a sample informed consent form. The final version controlled form 
must be agreed to by the sponsor, and the IEC/IRB and must contain all elements included in 
the sample form, in language readily understood by the subject. Each subject’s original consent 
form, personally signed and dated by the subject or by the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion, will be 
retained by the investigator. The investigator will supply subjects with a copy of their signed 
informed consent. 
For the storage and sampling of blood for circulating markers, including pharmacogenetic and 
pharmacogenomic biomarkers, the blood sampling procedure will be explained after the subject 
has given written informed consent for the main study. A separate consent form will then be 
requested from subjects agreeing to participate in this additional blood sampling requirement. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject or as a result of protocol 
amendments. In this instance approval should always be given by the IEC/IRB. It is the 
investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 


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13.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies, prior 
to study initiation in regions where an approval is required. 
13.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In the eCRFs and other 
documents or image material submitted to the sponsor, subjects will be identified not by their 
names, but by an identification code (e.g. initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons on 
behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal medical 
information will always be treated as confidential. 


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14 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly marked and 
permit easy identification of a subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, lanreotide PRF 
administration, laboratory data, safety data and efficacy ratings on the eCRFs provided for the 
study. The investigator, by completing the signature log, may formally designate authority to 
complete eCRFs to appropriately qualified staff having certified user access to the eCRF. 
Subject completed diaries and questionnaires will be printed or electronic. 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each case 
report book to attest to the accuracy and completeness of all the data. If any changes are made 
to the eCRF, after a form has been locked and electronically signed, the investigator will be 
required to perform an additional e-signature authorising agreement with any new information 
or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on each 
item entered. 
14.2 
Data Management 
Subject data will be collected using EDC. Each site is required to have a computer and internet 
connection available for site entry of clinical data. All entries in the eCRF will be done under the 
electronic signature of the person performing the action. This electronic signature consists of an 
individual and confidential username and password combination. It is declared to be the legally 
binding equivalent of the handwritten signature. Only sponsor authorised users will have access to 
the eCRF as appropriate to their study responsibilities. Users must have successfully undergone 
software application training prior to entering data into the eCRF. 
Data management will be conducted by a CRO (directed by the sponsor’s data management 
department). All data management procedures will be completed in accordance with the sponsor 
and the contracted CRO SOPs. Prior to data being received in-house at the assigned CRO, it will 
be monitored at the investigator site, (for further details please see Section 12.3 Study Monitoring). 
The CRF and other data documentation removed from the investigator site(s) will be tracked by 
the CRO and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, and 
suitable queries are raised to resolve any missing or inconsistent data. The investigator will receive 
their data, from the clinical study, in an electronic format (PDF files) which will be an exact copy 
of the eCRF, and will include the full audit trail, for archiving purposes and future reference. 
Any queries generated during the data management process will also be tracked by the contracted 
data management CRO/will be raised within the EDC system. It is the central study monitor’s 
responsibility to ensure that all queries are resolved by the relevant parties. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history and concomitant medication terms will be managed by 
the sponsor’s Biometry Group. Concomitant medications will be coded using WHO Drug 
Dictionary and AEs/medical history terms will be coded using MedDRA. 
14.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  


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Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 25 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the site. The sponsor will inform the investigator, in writing, as to 
when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


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15 
FINANCING AND INSURANCE 
15.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor or sponsor designee (CRO) will sign a clinical study agreement prior to the start of the 
study, outlining overall sponsor and investigator responsibilities in relation to the study. 
Financial remuneration will cover the cost per included subject, based on the calculated costs 
of performing the study assessments in accordance with the protocol, and the specified terms 
of payment will be described in the contract. The contract should describe whether costs for 
pharmacy, laboratory and other protocol required services are being paid directly or indirectly. 
Financial disclosure statements will need to be completed. 
15.2 
Insurance, Indemnity and Compensation 
The sponsor will provide Product Liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 


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16 
REPORTING AND PUBLICATIONS OF RESULTS 
16.1 
Publication Policy 
The sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the consent 
of each individual and entity concerned, including acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
investigators involved in the study. For multicentre studies, a plan for scientific publication and 
presentation of the results may be agreed and implemented by the study investigators or a 
Steering Committee. The sponsor requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper before the material is submitted 
for publication or communicated. This condition also applies to any amendments that are 
subsequently requested by referees or journal editors. The sponsor will undertake to comment 
on the draft documents within the time period agreed in the contractual arrangements, including 
clinical trial agreements, governing the relationship between the sponsor and authors (or the 
author’s institution). Requested amendments will be incorporated by the author, provided they 
do not alter the scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until (i) a patent 
application is filed for the content of the publication in accordance with applicable provisions 
of the clinical trial agreement concerned, (ii) the sponsor consents to the publication, or (iii) the 
time period as may be agreed in the contractual arrangements, including clinical trial 
agreements, governing the relationship between the sponsor and authors (or authors’ institution) 
after receipt of the proposed publication by the sponsor, whichever of (i), (ii) or (iii) occurs 
first. 
The author undertakes to reasonably consider the sponsor's request for delay to the proposed 
publication should the sponsor reasonably deem premature to publish the results obtained at the 
then stage of the study. 
16.2 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on structure 
and contents of CSRs. A final CSR will be prepared where any subject has signed informed 
consent, regardless of whether the study is completed or prematurely terminated. Where 
appropriate an abbreviated report may be prepared. The CSR will be in compliance with any 
applicable regulatory requirements, national laws in force and will be in English. 


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17 
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Melmed S. Medical progress: Acromegaly. N Engl J Med 2006;355:2558-2573. 
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Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab 2002;87:3013-
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Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management: an update. 
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Giustina A, Chanson P, Bronstein MD, et al. A consensus on criteria for cure of 
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Colao A, Auriemma RS, Lombardi G, Pivonello R. Resistance to somatostatin analogs 
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Florio T, Thellung S, Arena S, et al. Somatostatin and its analog lanreotide inhibit the 
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Florio T, Thellung S, Corsaro A, et al. Characterization of the intracellular mechanisms 
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Roelfsema F, Biermasz NR, Pereira AM, Romijn JA. Therapeutic options in the 
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11 
Mazziotti G, Giustina A. Effects of lanreotide SR and Autogel on tumor mass in patients 
with acromegaly: a systematic review. Pituitary 2010;13:60-67. 
12 
 
 
. 
13 
 
 
CCI
CCI


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18 
LIST OF APPENDICES 
Appendix 1 Biobanking ............................................................................................ 78 
Appendix 2 Liver Safety Algorithm ......................................................................... 80 
Appendix 3 Protocol Amendment 1 (19 November 2014) ....................................... 82 
Appendix 4 Protocol Amendment 2 (18 February 2015) ......................................... 95 
Appendix 5 Protocol Amendment 3 (12 June 2015) .............................................. 100 
Appendix 6 Protocol Amendment 4 (27 July 2015) ............................................... 119 
Appendix 7 Protocol Amendment 5 (22 March 2016) ........................................... 141 
Appendix 8 Protocol Amendment 6 (20 May 2016) .............................................. 163 
Appendix 9 Protocol Amendment 7 (16 December 2016) ..................................... 167 
 


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Appendix 1  Biobanking 


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Biobanking: 
One of the exploratory evaluations involves the collection of blood samples for the biobanking 
project. Blood samples will be collected only in patients who have signed a separate consent 
for the exploratory part, particularly for the biobank samples, during specific timepoints 
described in Table 5 of the protocol. One of the 3 blood samples will be centrifuged (serum 
sample); the two other samples will not be centrifuged (blood samples in RNA Paxgen tubes). 
The samples should be clearly and appropriate labelled with the following minimum 
information: study code, patient number, and visit name. The samples will be shipped to the 
central laboratory and stored at -80°C. At the end of the study one shipment will be made by 
the central laboratory with all samples to the biobanking central laboratory, FISHER, in dry ice. 
Upon receipt of each shipment of samples, an acknowledgment of receipt made out by the 
contact person will be sent to the site. The samples will then be stored at the biobanking central 
laboratory, FISHER, for future exploratory biomarker analysis, including pharmacogenetic and 
pharmacogenomic biomarker research required to further the understanding of (i) treatment 
response and the the safety profile, (ii) drug treatment mode of actions, and (iii) disease 
understanding. Samples will be stored for up to 15 years at the biobanking central laboratory, 
FISHER. After 15 years of storage any remaining samples will be destroyed. Samples may be 
destroyed earlier if subjects withdraw consent from the biobanking project. 
 
Ribonucleic Acid (RNA) Biobank 
Where not prohibited by local regulations, blood will be collected from all subjects for analysis 
of gene expression of relevance for the mechanism of lanreotide and those of relevance for 
safety, tolerability, and potential clinical benefit 
 
Serum Biobank 
Where not prohibited by local regulations, blood will be collected from all subjects for analysis 
of protein of relevance for the mechanism of Lanreotide and those of relevance for safety, 
tolerability, and potential clinical benefit 
 
All the detailed procedures will be described in a separate laboratory manual.  
 
Shipment contact and addresses  
 
FISHER (biobanking central laboratory) 
Address: Fisher BioServices, 1 Woodside, Bishops Stortford, Herts, CM23 5RG, England 
Phone: 
 
Fax: +
 
E-mail:
  
PPD
PPD
PPD


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Appendix 2 Liver Safety Algorithm 


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Increase in either ALT or AST 
ALT or AST 
≥ 2 and < 3 ULN 
ALT or AST  
≥ 3 ULN  
Repeat measurement  
• Twice during first week 
• Then weekly until return to normal  
ALT or AST 
≥ 3 ULN 
Collect blood: Freeze 
and store (5 mL serum)  
Complete Steps 1, 2 and 3 from the box 
below. If no stabilisation complete Steps 4 
& 5 
1. Perform the following tests immediately – 
 - AST, ALT, ALP (alkaline phosphatase), total and conjugated Bilirubin, Prothrombin Time/INR (as mentioned above)  
- CPK (creatine phosphokinase), serum creatinine, complete blood count 
- Anti-HIV IgM, anti-HBc IgM, anti-HCV IgM, anti-CMV IgM  
- Specific serologic markers of recent infection with EBV, Herpes viruses and toxoplasma (depending on the clinical 
context)  
- Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed)   
- Collect blood, freeze and store (5 mL serum) 
 
2. Monitor aminotransferases (AST/ALT) and/or bilirubin– 
 -Twice during the first week, then weekly until return to normal  
3. Interview the subject again –  
- Consumption of alcohol, concomitant medication, drugs and herbals before and during the study  
- Recent history of febrile illness or jaundice  
- History of blood or blood product transfusion, travel to Africa, Asia, intravenous drug addiction   
 
If values are not stabilising or reducing; 
4. Consider subject hospitalization –  
- If INR>2 (or PT<50%), or obvious bleeding or jaundice 
- And/or signs of central nervous system disturbances suggesting hepatic encephalopathy   
5. Consider consultation with hepatologist 
Liver Safety Algorithm - Increase in Aminotransferases & Bilirubin 
(Expressed as a multiple of the ULN of the Study Central Laboratory) 
Increase in total 
bilirubin 
Total bilirubin 
≥ 1.5 ULN 
Total bilirubin 
< 1.5 ULN 
As this is a single-dose study, where possible, all patients should remain in the trial during management and follow-
up of elevations in liver enzymes and/or bilirubin 


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Appendix 3  Protocol Amendment 1 
(19 November 2014) 


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STUDY NUMBER: 
8-55-52030-309 
PROTOCOL TITLE: 
Phase IIa, Open Label, Dose Ascending Study to 
Determine the Maximum Tolerated Dose, Safety and 
Tolerability, Pharmacokinetics and Pharmacodynamics 
of a Single Dose of Lanreotide PRF in Subjects with 
Acromegaly Previously Treated and Controlled with 
Octreotide LAR 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 1.0 Version 2.0: 19 November 2014 
 
 
The following amendment(s) is/are proposed: 
Version Date 
01 September 2014 
19 November 2014 
Page 
Section 
WAS 
IS 
5 
Synopsis 
If any serious adverse events 
(SAEs) occur, a relationship with 
the exposure to lanreotide PRF will 
be assessed. The pre established 
stopping rules for the DRC 
decision for study discontinuation 
and/or inclusion of the subsequent 
treatment cohort include the 
occurrence of any dose limiting 
toxicity (DLT). A DLT is defined 
as an adverse event (AE; excluding 
anorexia and fatigue) or an 
abnormal laboratory value 
occurring within the first week (up 
to Visit 5 (Week 2)) following 
lanreotide PRF administration and 
during the entire study duration, 
assessed as unrelated to 
acromegaly, intercurrent illness or 
concomitant medications and 
which meets any of the pre 
established criteria (more often 
grade 3 or 4 toxicity according to 
National Cancer Institute (NCI) 
Common Terminology Criteria for 
Adverse Events (CTCAE) criteria). 
The occurrence of ≥2 DLTs would 
trigger the organisation of an 
intermediate DRC meeting (ad hoc 
meeting) to evaluate the decision 
to test 3 more subjects at the same 
dose level.  
If any serious adverse events 
(SAEs) occur, a relationship with 
the exposure to lanreotide PRF will 
be assessed. The pre established 
stopping rules for the DRC 
decision for study discontinuation 
and/or inclusion of the subsequent 
treatment cohort include the 
occurrence of any dose limiting 
toxicity toxicities (DLTs). A DLT 
is defined as an adverse event (AE; 
excluding anorexia and fatigue) or 
an abnormal laboratory value 
occurring within the first week (up 
to Visit 5 (Week 2)) following 
lanreotide PRF administration and 
during the entire study duration, 
assessed as unrelated to 
acromegaly, intercurrent illness or 
concomitant medications and 
which meets any of the pre 
established criteria (more often 
grade 3 or 4 toxicity according to 
National Cancer Institute (NCI) 
Common Terminology Criteria for 
Adverse Events (CTCAE) criteria). 
The occurrence of ≥2 DLTs would 
trigger the organisation of an 
intermediate DRC meeting (ad hoc 
meeting) to evaluate the decision 
to test 3 more subjects at the same 
dose level.  
2 
Investigator’s 
Agreement 
NAME: Sebastian J.C.M.M. 
Neggers, MD, PhD 
TITLE: Principal Investigator 
The Principal Investigator’s name 
and title was moved from the 
Investigator’s Agreement signature 
page to the Coordinating 
Investigator’s Agreement signature 
page (page 3). 
20 
1.3 
They showed no systemic effects, 
rapid absorption (time to maximum 
They showed no systemic effects, 
rapid absorption (time to maximum 


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serum concentration (Tmax) 0.5 
hours) and elimination (apparent 
terminal half life (t½) 2.8 hours) 
phases, as well as no accumulation 
between Day 0 and Week 4. At the 
injection sites, a spectrum of 
inflammatory changes comprising 
subcutaneous necrosis, 
fibrosis/fibroplasia, subcutaneous 
subacute inflammation, and 
haemorrhage in rat and dog, as 
well as granulomatous panniculitis 
in dog were induced. Most of these 
local signs were reversible at the 
end of the treatment free period. 
Infact, in humans, the maximum 
dose of lanreotide PRF planned to 
be administered by single injection 
every 3 months is 360 mg, 
constituting approximately 
2 mg/kg of glycofurol. Therefore, 
the doses of glycofurol tested in 
the toxicology studies (30 mg/kg to 
180 mg/kg) were not only 
administered with a higher 
frequency (daily for 4 weeks 
versus once every 3 months) but 
were way above the intended 
clinical dose (15 to 90 times, 
respectively). Consequently, the 
local effects that were recorded in 
the toxicology studies were 
considered without clinical 
relevance. 
serum concentration (Tmax) 0.5 
hours) and elimination (apparent 
terminal half life (t½) 2.8 hours) 
phases, as well as no accumulation 
between Day 0 and Week 4.  and 
glycofurol alone was rapidly 
absorbed (Tmax from 0.5 to 2 h in 
dogs and 0.25 to 0.5 h in rats) 
and eliminated (t½ from 0.37 to 
1.3 h in dogs and 1 to 2.8 h in 
rats). There was no 
accumulation of glycofurol after 
daily s.c. administration for 4 
weeks in both species. At the 
injection sites, a spectrum of 
inflammatory changes comprising 
subcutaneous necrosis, 
fibrosis/fibroplasia, subcutaneous 
subacute inflammation, and 
haemorrhage in rat and dog, as 
well as granulomatous panniculitis 
in dog were induced. Most of these 
local signs were reversible at the 
end of the treatment free period. 
Infact In fact, in humans, the 
maximum dose of lanreotide PRF 
planned to be administered by 
single injection every 3 months is 
360 mg, constituting 
approximately 2 mg/kg of 
glycofurol for a person of 70 kg. 
Therefore, the doses of glycofurol 
tested in the toxicology studies (30 
mg/kg to 180 mg/kg) were not only 
administered with a higher 
frequency (daily for 4 weeks 
versus once every 3 months) but 
were way above the intended 
clinical dose (15 to 90 times, 
respectively). Consequently, the 
local effects that were recorded in 
the toxicology studies were 
considered without clinical 
relevance. 
21 
1.4.3 
The medical procedures during the 
study are considered to be safe 
(venous puncture and gallbladder 
echography) and do not put 
participating subjects at any 
procedure related increased risk. 
The risk of reactivation of the 
disease with clinical symptoms 
within the 3 month follow up 
period is taken into consideration. 
The medical procedures during the 
study are considered to be safe 
(venous puncture and gallbladder 
echography) and do not put 
participating subjects at any 
procedure related increased risk. 
The half-life of lanreotide PRF in 
human is not yet known. 
However, based on dog data, 
5 times the mean terminal 


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IGF-1 and GH concentrations will 
be monitored monthly during this 
period. If the investigator judges 
that the subject requires any 
treatment for acromegaly 
(reappearance of clinical or 
biochemical symptoms of 
acromegaly) during the follow-up 
period, the subject will be 
withdrawn from the study and will 
receive treatment according to 
routine practice. 
Additional information regarding 
risks and benefits to human 
subjects may be found in the IB. 
half-life (t½ ~35 days) of 
lanreotide PRF corresponds to 
175 days (i.e. ~6 months). 
Therefore a 6-month follow up 
should be sufficient to cover 
more than 95% of the profile if 
the half-life in dogs is similar in 
human. 
The rationale for a follow up of 
3 months after the potential 
3 months treatment period is 
based on the need for the study 
subjects to resume treatment 
with their approved somatostatin 
analogue to control acromegaly 
and GH / IGF1 levels. Given the 
similar class of active ingredient, 
the sponsor believes it is 
reasonable to let the participants 
go back to their regular 
treatment after three months 
follow up as longer periods off 
therapy may be associated with 
unnecessarily higher rates of 
symptoms. Furthermore after a 
single dose of lanreotide PRF, 
anticipated to provide 3 months 
treatment and after 3 months 
additional follow-up, it is 
reasonable to consider that the 
residual lanreotide 
concentrations are low enough 
not to trigger any new safety 
concern when standard 
treatment is resumed. Should 
any concern about this residual 
concentration arise during the 
study the sponsor will notify the 
investigators about the level of 
residual concentration which 
would allow to adjustadjusting 
the restart of octreotide 
treatment. 
The risk of reactivation of the 
disease with clinical symptoms 
within the 3 month follow up 
period is taken into consideration. 
IGF-1 and GH concentrations will 
be monitored monthly during this 
period. If the investigator judges 
that the subject requires any 
treatment for acromegaly 
(reappearance of clinical or 
biochemical symptoms of 


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acromegaly) during the follow-up 
period, the subject will be 
withdrawn from the study and will 
receive treatment according to 
routine practice. 
Additional information regarding 
risks and benefits to human 
subjects may be found in the IB. 
22 
1.5 
Lanreotide PRF will be injected 
via the deep subcutaneous route in 
the superior, external quadrant of 
the buttock according to the 
recommendations detailed in 
Section 6.1. 
Lanreotide PRF will be injected 
via the deep subcutaneous route in 
the superior, external quadrant of 
the buttock according to the 
recommendations detailed in 
Section 6.1. 
The three dose levels proposed 
for lanreotide PRF (180 mg, 
270 mg and 360 mg) are targeted 
as three times the common doses 
of lanreotide Autogel used for 
the treatment of acromegaly (60, 
90 and 120 mg). 
A robust PK/PD model 
developed with lanreotide 
Autogel in acromegalic patients 
which relates lanreotide trough 
concentrations (at 1 month for 
Autogel) to GH and IGF-1 
concentrations, has proven that 
if the lanreotide concentration 
remains above a target 
therapeutic level over the whole 
dosing interval, acromegalic 
patients remain controlled in 
terms of GH and IGF-1. 
Therefore, the trough 
concentrations (Ctrough) observed 
at 3 months with lanreotide PRF 
were compared to the target 
therapeutic levels reached at 
1 month with lanreotide Autogel 
(using a ‘translation’ from 
human data to dogs). In dogs, the 
Ctrough achieved with lanreotide 
PRF 240, 270 and 450 mg were 
comparable to those achieved 
with the corresponding dose of 
lanreotide Autogel (i.e., 
lanreotide PRF dose divided by 
3), which justifies the selected 
doses of lanreotide PRF. 
From a safety point of view, the 
Cmax and AUC of lanreotide PRF 
in dogs were carefully reviewed 
and compared to the commercial 


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formulation lanreotide Autogel 
120 mg and a previous 
development formulation of 
lanreotide Autogel23% 240 mg. 
The mean Cmax of 58 ng/mL 
observed  with the highest dose 
tested in dogs (PRF 450 mg) is 
increased by 60-70% compared 
to the mean Cmax of 36 ng/nL 
observed with lanreotide Autogel 
120 mg (highest dose 
commercially available of the 
1-month formulation) and in 
dogs the mean  exposure over 
3 months after a single injection 
of lanreotide PRF 450 mg 
(706 ng.day/mL) is similar to the 
exposure over 3 months after 
three injections of lanreotide 
Autogel 120 mg every 4 weeks 
(737 ng.day/mL). Therefore, if 
the PK profile of lanreotide PRF 
in human is consistent with dog 
data, comparable safety ratios to 
those observed with lanreotide 
Autogel 120 mg (200- to 400-fold 
in rats and 16- to 23-fold in dogs) 
could be anticipated with 
lanreotide PRF. 
Moreover the mean Cmax of 
lanreotide PRF tested in dogs is 
2-fold lower than that observed 
with a dose of 240 mg of 
lanreotide Autogel23% (a previous 
development formulation tested 
in a Phase 1 study in healthy 
volunteers) which was not well 
tolerated in healthy subjects. 
Furthermore, in the dog PK 
study performed with lanreotide 
PRF, assessment of the local 
tolerance of lanreotide PRF 
containing glycofurol showed a 
s.c. granulomatous inflammation 
at the injection site at the end of 
the 3-month and 6-month 
periods. These histological 
findings have already been 
described for lanreotide Autogel 
in dogs thus the excipient 
glycofurol does not aggravate the 
local tolerance of the therapeutic 
compound. 


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In conclusion, the choice of the 
lanreotide PRF doses as 3 times 
the doses of Autogel is 
confirmed, from an efficacy 
perspective, by the Ctrough 
reached at 3 months. In terms of 
safety, the selected doses of 
lanreotide PRF are expected to 
show similar or lower exposure 
than with the highest dose of the 
commercially available 1-month 
formulation (lanreotide Autogel 
120 mg). Consequently, no 
change in the safety ratios is 
expected. Moreover, the local 
tolerance of the lanreotide PRF 
in dog was not different from 
that observed with lanreotide 
Autogel. 
24 
1.7 
The choice of octreotide stable 
subjects as the study population, 
instead of lanreotide stable 
subjects, was guided by the fact 
that a 4 month washout period 
before lanreotide PRF 
administration would be avoided 
and no cross interference in 
lanreotide and octreotide 
measurements would occur. 
The choice of octreotide stable 
subjects as the study population, 
instead of lanreotide stable 
subjects, was guided by the fact 
that a 4 month washout period 
before lanreotide PRF 
administration would be avoided 
and no cross interference in 
lanreotide and octreotide 
measurements by the 
bioanalytical assay would occur. 
25 
2.1 
A first-in-man lanreotide PRF 
safety and PK/PD study in healthy 
volunteers was not planned 
because, given the previous extent 
of lanreotide use, it was not 
expected that any new information 
on lanreotide would be obtained to 
justify such a phase I study. In 
addition, it did not appear ethical 
to expose healthy volunteers to 
high doses of lanreotide. 
A first-in-man lanreotide PRF 
safety and PK/PD study in healthy 
volunteers was not planned 
because, given the previous extent 
of lanreotide use, it was not 
expected that any new information 
on lanreotide would be obtained to 
justify such a phase I study. In 
addition, it did not appear ethical 
to expose healthy volunteers to 
high doses of lanreotide. 
A modified lanreotide autogel 
formulation has been studied in 
a single Phase 1 study in healthy 
volunteers, however its profile 
was not compatible with 
adequate exposure for a 3 month  
dosing interval and exaggerated 
adverse effects were observed in 
the study subjects (Study 2-55-
52030-724). 
26 
3.1 
The occurrence of ≥2 dose limiting 
toxicities (DLTs) would trigger the 
organisation of an intermediate 
The occurrence of ≥2 dose limiting 
toxicities (DLTs) would trigger the 
organisation of an intermediate 


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DRC meeting (ad hoc meeting) to 
evaluate the decision to test 3 more 
subjects at the same dose level (see 
Section 6.1.1). 
DRC meeting (ad hoc meeting) to 
evaluate the decision to test 3 more 
subjects at the same dose level (see 
Section 6.1.1). 
31 
3.6.2 
The pre established stopping rules 
for the DRC decision for study 
discontinuation and/or inclusion of 
the subsequent treatment cohort 
include the occurrence of any DLT 
occurring within the first week (up 
to Week 2; Visit 5) following 
lanreotide PRF administration and 
during the entire study duration 
(see Section 3.6.3). 
The pre established stopping rules 
for the DRC decision for study 
discontinuation and/or inclusion of 
the subsequent treatment cohort 
include the occurrence of any 
DLTs occurring within the first 
week (up to Week 2; Visit 5) 
following lanreotide PRF 
administration and during the 
entire study duration (see Section 
3.6.3). 
43, 44, 
45 
5.2.3, 5.2.4.1, 
5.2.4.2 
• 
Clinical laboratory 
assessments 
• 
Central clinical laboratory 
assessments 
47 
6.1.1 
The dose escalation will proceed 
with a 3+3+3 scheme. At each 
dose level, a total of 9 subjects will 
be enrolled if ≤2 DLT are reported. 
See Section 3.6.3 for the definition 
of DLT. 
Subject enrolment into the study 
will begin at Dose Level 1 (180 
mg).  
Starting with the 180 mg dose 
cohort, the first 3 subjects will be 
enrolled into the study. If none or 
one (1/3; 33%) subject experiences 
a DLT, 3 more subjects will be 
enrolled at the same dose (180 
mg). However, if 2 (2/3; 67%) or 3 
(3/3; 100%) subjects experience 
DLTs, the DRC will convene 
immediately (ad hoc meeting) to 
evaluate the decision to test 3 more 
subjects at this dose level. This 
will be dependent on the DLT 
profile (i.e. identical DLTs in 
different subjects) or the frequency 
and severity of DLTs in the same 
subject. 
Based on the decision of the DRC, 
3 more subjects will be enrolled 
into the 180 mg dose cohort. Of the 
6 subjects enrolled at this dose 
level, if up to 3/6 (≤50%) 
experiences a DLT, 3 more 
subjects will be enrolled at the 
same dose (180 mg). However, if 
at least 4/6 (≤ 67%) to 6/6 (100%) 
subjects experience DLTs, the 
DRC will convene immediately (ad 
The dose escalation will proceed 
with a 3+3+3 scheme. At each 
dose level, a total of 9 subjects will 
be enrolled if ≤23 DLTs are 
reported. See Section 3.6.3 for the 
definition of DLT. 
Subject enrolment into the study 
will begin at Dose Level 1 (180 
mg).  
Starting with the 180 mg dose 
cohort, the first 3 subjects will be 
enrolled into the study. If none or 
one (1/3; 33%) subject experiences 
a DLT, 3 more subjects will be 
enrolled at the same dose (180 
mg). However, if 2 (2/3; 67%) or 3 
(3/3; 100%) subjects experience 
DLTs, the DRC will convene 
immediately (ad hoc meeting) to 
evaluate the decision to test 3 more 
subjects at this dose level. This 
will be dependent on the DLT 
profile (i.e. identical DLTs in 
different subjects) or the frequency 
and severity of DLTs in the same 
subject. 
Based on the decision of the DRC, 
3 more subjects will be enrolled 
into the 180 mg dose cohort. Of the 
6 subjects enrolled at this dose 
level, if up to 3/6 (≤50%) 
experiences a DLT, 3 more 
subjects will be enrolled at the 
same dose (180 mg). However, if 
at least 4/6 (≤ 67%) to 6/6 (100%) 
subjects experience DLTs, the 
DRC will convene immediately (ad 


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hoc meeting) to evaluate the 
decision to test 3 more subjects at 
this dose level. Again, this will be 
dependent on the DLT profile (i.e. 
identical DLTs in different 
subjects) or the frequency and 
severity of DLTs in the same 
subject. 
Based on the decision of the DRC, 
3 more subjects will be enrolled 
into the 180 mg dose cohort to give 
a total of 9 subjects. The DRC will 
evaluate the safety of lanreotide 
PRF after all 9 subjects have been 
treated at this dose level before 
authorising treatment to the next 
highest dose (270 mg). If up to 3/9 
(≤33%) subjects experience a DLT, 
dose escalation to the next highest 
dose (270 mg) will proceed. 
However, if at least 4/9, 5/9 up to 
6/9 or up to 9/9 (44%, 56%, ≤67% 
or ≤100%, respectively) subjects 
experience DLTs, the DRC will 
evaluate the decision to escalate to 
the next highest dose. Again, this 
will be dependent on the DLT 
profile (i.e. identical DLTs in 
different subjects) or the frequency 
and severity of DLTs in the same 
subject. 
These rules will apply for the 
recruitment of subjects into the 270 
mg dose cohort and for further 
escalation 
and 
recruitment 
of 
subjects into the 360 mg dose 
cohort. 
Details of the adaptive 3+3+3 dose 
escalation scheme with the most 
likely outcome are provided in 
Figure 2. 
hoc meeting) to evaluate the 
decision to test 3 more subjects at 
this dose level. Again, this will be 
dependent on the DLT profile (i.e. 
identical DLTs in different 
subjects) or the frequency and 
severity of DLTs in the same 
subject. 
Based on the decision of the DRC, 
3 more subjects will be enrolled 
into the 180 mg dose cohort to give 
a total of 9 subjects. The DRC will 
evaluate the safety of lanreotide 
PRF after all 9 subjects have been 
treated at this dose level before 
authorising treatment to the next 
highest dose (270 mg). If up to 3/9 
(≤33%) subjects experience a DLT, 
dose escalation to the next highest 
dose (270 mg) will proceed. 
However, if at least 4/9, 5/9 up to 
6/9 or up to 9/9 (44%, 56%, ≤67% 
or ≤100%, respectively) subjects 
experience DLTs, the DRC will 
evaluate the decision to escalate to 
the next highest dose. Again, this 
will be dependent on the DLT 
profile (i.e. identical DLTs in 
different subjects) or the frequency 
and severity of DLTs in the same 
subject. 
These rules will apply for the 
recruitment of subjects into the 270 
mg dose cohort and for further 
escalation and recruitment of 
subjects into the 360 mg dose 
cohort. 
Dose level: 180 mg. The study 
will start dosing 3 subjects. If 
none or 1 out of the 3 dosed 
subjects experiences a DLT, 3 
more subjects will be dosed at 
the same time. If 2 out of the 3 
dosed subjects experiences a 
DLT, the DRC will decide 
whether 3 more subjects may be 
dosed. If all 3 subjects have 
experienced a DLT, dosing will 
be stopped and the dose will be 
declared the maximum 
administered dose.  
If none or 1 of the 6 dosed 
subjects experience a DLT, 3 
more subjects can be dosed at 


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the same dose. If 2 of the 6 dosed 
subjects experience a DLT, and 
one or both of the DLTs occured 
in the second group of 3 patients, 
the DRC will decide whether 3 
more subjects may be dosed. If a 
total of 3 or more out of 6 
subjects experience a DLT, 
dosing will be stopped and the 
dose will be declared the 
maximum administered dose.  
Dose escalation: If more than 3 
out of 9 subjects experience a 
DLT, dose escalation will be 
stopped and the dose will be 
declared the maximum 
administered dose. If ≤3 DLTs 
have been observed in the 9 
treated subjects, then the dose 
may be escalated to 270 mg. The 
DRC will determine if 
progression to the next dose 
cohort should occur after 
reviewing data from the 
preceding cohort. The same rules 
will be applied to the next dose 
level and the decision to escalate 
to 360 mg will be done in the 
same way. 
Details of the adaptive 3+3+3 dose 
escalation scheme with the most 
likely outcome are provided in 
Figure 2. 
48 
6.1.1 
Figure 2 (see below) 
Figure 2 was adapted in line with 
the changes to the Dose Escalation 
Criteria outlined above. 
49 
6.2 
 Hormone replacement therapy 
(HRT) with oestrogens, 
 Dopamine agonist and GH 
receptor antagonist, or pituitary 
surgery within 3 months prior 
to study entry, 
 Radiotherapy at any time prior 
to study entry. 
 Hormone replacement therapy 
(HRT) with oestrogens, 
 Dopamine agonist and GH 
receptor antagonist, or pituitary 
surgery within 3 months prior to 
study entry, 
 Radiotherapy at any time prior to 
study entry. 
66 
10.6 
However, ad hoc DRC meetings 
would take place if ≥2 DLTs occur 
during cohort accrual. 
However, ad hoc DRC meetings 
would take place if ≥2 DLTs occur 
during cohort accrual. 


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WAS: Version Final: 01 September 2014 
Figure 2 Adaptive 3+3+3 Dose Escalation Scheme with the Most Likely Outcome 
 
DLT=dose limiting toxicity; DRC=Data Review Committee. 


IPSEN GROUP 
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IS: Amendment 1.0 Version 2.0: 19 November 2014 
Figure 2 Adaptive 3+3+3 Dose Escalation Scheme with the Most Likely Outcome 
 
DLT=dose limiting toxicity; DRC=Data Review Committee.


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Summary & outcome of changes: 
STUDY NUMBER 
8-55-52030-309 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 1.0 Version 2.0: 19 November 2014 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
To provide clarification on questions received from the authorities 
associated with safety monitoring, the pharmacokinetics of lanreotide 
PRF, the dose escalation criteria, and the dose selection rationale.  
Other Action Required? 
CRF Update  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
Local Consent Form Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Database Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Reporting & Analysis Plan 
(RAP) Update 
 
Yes 
 
  
No 
 
 
 
(tick one) 
 


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Appendix 4  Protocol Amendment 2 
(18 February 2015)


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STUDY NUMBER: 
8-55-52030-309 
PROTOCOL TITLE: 
Phase IIa, Open Label, Dose Ascending Study to 
Determine the Maximum Tolerated Dose, Safety and 
Tolerability, Pharmacokinetics and Pharmacodynamics 
of a Single Dose of Lanreotide PRF in Subjects with 
Acromegaly Previously Treated and Controlled with 
Octreotide LAR 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 2.0 Version 3.0: 18 February 2015 
 
 
The following amendment(s) is/are proposed: 
Version Date 
19 November 2014 
18 February 2015 
Page 
Section 
WAS 
IS 
1 
Title page 
Sponsor’s Medically Responsible 
Person: 
 
Ipsen Innovation 
Ipsen Research and Development 
5 avenue du Canada 
Les Ulis Cedex (France) 
  
 
Sponsor’s Medically Responsible 
Person: 
 
Ipsen Innovation 
Ipsen Research and Development 
5 avenue du Canada 
Les Ulis Cedex (France) 
  
 
 
Ipsen Biosciences, Inc. 
650 East Kendal Street 
Cambridge, MA 02142 (USA) 
 
 
1 
Title page 
Monitoring Office: 
 
Ipsen Innovation  
5 avenue du Canada 
91966 Les Ulis Cedex (France) 
 
 
Monitoring Office: 
 
 
Ipsen Innovation  
5 avenue du Canada 
91966 Les Ulis Cedex (France) 
 
 
1 
Title page 
Pharmacovigilance/ Emergency 
Contact: 
 
 
 
 
Central 
Department 
of 
Pharmacovigilance,  
Ipsen Group, 190 Bath Road, 
Slough, 
Berkshire 
SL1 
3XE, 
England 
Pharmacovigilance/ Emergency 
Contact: 
 
 
 
 
 
 
 
 
Central 
Department 
of 
Pharmacovigilance,  
Ipsen Group, 190 Bath Road, 
Slough, 
Berkshire 
SL1 
3XE, 
England 
38 
Table 4, 
footnote ‘f’ 
f 
evaluation of the following 
parameters during the first day 
after lanreotide administration: 
ALT, AST, bilirubin, lipase, 
amylase, INR, serum creatinine, 
fasting and postprandial glycaemia, 
insulinaemia. 
f 
evaluation of the following 
parameters during the first day 
after lanreotide administration: 
ALT, AST, bilirubin, lipase, 
amylase, INR, serum creatinine, 
fasting and postprandial glycaemia, 
and postprandial insulinaemia. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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40 
Table 6, 
footnote ‘a’ 
a 
clinical laboratory 
assessments include: haematology, 
coagulation, clinical biochemistry, 
fasting and postprandial blood 
glucose, fasting and postprandial 
insulin, glucagon, liver function 
parameters, pancreatic enzymes, 
serum creatinine and electrolytes, 
and urinalysis. 
a 
clinical laboratory 
assessments include: haematology, 
coagulation, clinical biochemistry, 
fasting and postprandial blood 
glucose, fasting and postprandial 
insulin, glucagon, liver function 
parameters, pancreatic enzymes, 
serum creatinine and electrolytes, 
and urinalysis. 
42 
5.2.3 
• 
Central clinical laboratory 
assessments (including liver 
function (ALT, AST, bilirubin), 
pancreatic function (lipase, 
amylase), serum creatinine, 
international normalised ratio 
(INR), fasting and postprandial 
glycaemia, insulinaemia) at 6 
hours postdose 
• 
Central clinical laboratory 
assessments (including liver 
function (ALT, AST, bilirubin), 
pancreatic function (lipase, 
amylase), serum creatinine, 
international normalised ratio 
(INR), fasting and postprandial 
glycaemia, and postprandial 
insulinaemia) at 6 hours postdose 
49 
6.2 
The following concomitant 
medications are permitted during 
this study, but they must be 
monitored closely and every effort 
should be made to keep their dose 
and dose regimen constant 
throughout the course of the study.  
•  Bradycardia inducing drugs (e.g. 
beta blockers), 
•  Substrate of CYP3A4 (e.g. 
quinidine, erythromycin, 
simvastatin). 
The following concomitant 
medications are permitted during 
this study, but they must be 
monitored closely and every effort 
should be made to keep their dose 
and dose regimen constant 
throughout the course of the study.  
•  Bradycardia inducing drugs (e.g. 
beta blockers), 
•  Substrate of CYP3A4 (e.g. 
quinidine, erythromycin, 
simvastatin). 
For information regarding the 
effects on blood glucose and the 
need for monitoring and 
adjustment of anti-diabetic 
agents, as well as information 
about the possible effects on 
cyclosporine bioavailability, 
please refer to the IB (Summary 
of Data and 
Guidance for the Investigator, 
Section 6.4.4 Glycoregulation 
and Section 6.4.7 Drug 
Interactions). 


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53 
8.1.3 
Follow up is required until the AE 
or its sequelae resolve or stabilise 
at a level acceptable to the 
investigator and the sponsor’s 
clinical monitor or his/her 
designated representative. 
Follow up is required until the AE 
or its sequelae resolve or stabilise 
at a level acceptable to the 
investigator and the sponsor’s 
clinical monitor or his/her 
designated representative. 
For information on actions to be 
taken, monitoring and/or 
follow-up procedures in case of 
cardiac disorders, pancreatic 
and renal abnormalities, 
hyperglycaemia, and gallstones 
please refer to the IB (Summary 
of Data and Guidance for the 
Investigator, Section 6.4.1 
Cardiac Safety, Section 6.4.3 
Effects on Gallbladder and 
Pancreas, Section 6.4.4 
Glycoregulation, and Section 
6.4.6 Special Patient 
Populations). 
56 
8.2.3 
• 
albumin total protein, total 
cholesterol, triglycerides, fasting 
and postprandial glucose, and 
fasting and postprandial insulin 
• 
albumin total protein, total 
cholesterol, triglycerides, fasting 
and postprandial glucose, and 
fasting and postprandial insulin 


IPSEN GROUP 
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PAGE 99 OF 173 
 
 
Summary & outcome of changes: 
STUDY NUMBER 
8-55-52030-309 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 2.0 Version 3.0: 18 February 2015 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
To update the contact details of the Sponsor’s medically responsible 
person, the monitoring office, and the pharmacovigilance/emergency 
contact. 
At the 6 hours postdose timepoint, the postprandial assessment was 
considered as the most clinically relevant. Therefore the fasting 
glucose and fasting insulin assessments were removed from Visit 2 
(postdose) to Visit 12. 
To add a reference to the IB for information regarding the effects on 
blood glucose and the need for monitoring and adjustment of 
anti-diabetic agents, as well as information about the possible effects 
on cyclosporine bioavailability. 
To add a reference to the IB for information  regarding the action to 
be taken and the patient monitoring and follow-up procedures to be 
used in cases of cardiac disorders, pancreatic and renal abnormalities, 
hyperglycaemia, and gallstones. 
Other Action Required? 
CRF Update  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
Local Consent Form Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Database Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Reporting & Analysis Plan 
(RAP) Update 
 
Yes 
 
  
No 
 
 
 
(tick one) 
 


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PAGE 100 OF 173 
 
 
Appendix 5 Protocol Amendment 3 
(12 June 2015) 


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PAGE 101 OF 173 
 
 
STUDY NUMBER: 
8-55-52030-309 
PROTOCOL TITLE: 
Phase IIa, Open Label, Dose Ascending Study to 
Determine the Maximum Tolerated Dose, Safety and 
Tolerability, Pharmacokinetics and Pharmacodynamics 
of a Single Dose of Lanreotide PRF in Subjects with 
Acromegaly Previously Treated and Controlled with 
Octreotide LAR 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 3.0 Version 4.0: 12 June 2015 
 
 
The following amendment(s) is/are proposed: 
Version Date 
18 February 2015 
12 June 2015 
Page 
Section 
WAS 
IS 
1 
Title page 
Sponsor’s Medically Responsible 
Person: 
 
Ipsen Biosciences, Inc. 
650 East Kendal Street 
Cambridge, MA 02142 (USA) 
 
 
Sponsor’s Medically Responsible 
Person: 
 
 
Ipsen Biosciences, Inc. 
650 East Kendal Street 
Cambridge, MA 02142 (USA) 
 
 
1 
Title page 
Sebastian J.C.M.M. Neggers, 
MD, PhD 
Department of Medicine  
Section Endocrinology 
Eramus University MC  
PO Box 2040 
3000 CA Rotterdam 
(The Netherlands) 
Sebastian J.C.M.M. Neggers, 
MD, PhD 
Department of Medicine  
Section Endocrinology 
Erasmus University MC  
PO Box 2040 
3000 CA Rotterdam 
(The Netherlands) 
5 
Synopsis 
Planned study period: 02/2015 to 
04/2016 
Planned study period: 02/2015 to 
04/201601/2017 
5 
Synopsis, 
Methodology 
Study visits will be performed on 
Days 1, 2, 3, and 5, and Weeks 2, 3, 
4, 5, 7, 9, 11 and 13 of the treatment 
period, and at Weeks 15, 17, 19, 21, 
23 and 25 during follow up. 
Study visits will be performed on 
Days 1, 2, 3, and 5, and Weeks 2, 3, 
4, 5, 7, 9, 11 and 13 of the treatment 
period, and at Weeks 15, 17, 19, 21, 
23 and 25 during follow up. All 
study visits can be performed at 
the study site. However, study 
visits on Weeks 4, 7, 11, 15, 19 and 
23 can be performed at the study 
site and/or at the subjects home as 
per investigator’s and subject’s 
decision. 
PPD
PPD
PPD
PPD


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PAGE 102 OF 173 
 
 
6 
Synopsis, 
Methodology 
Assessments throughout the follow 
up period will evaluate the safety, 
tolerability 
and 
PK 
of 
lanreotide PRF. Levels of insulin 
like growth factor-1 (IGF-1) and 
growth hormone (GH) will also be 
evaluated. 
The 
proportion 
of 
subjects with age adjusted IGF-1 
levels within the normal range, with 
GH ≤2.5 ng/mL and with GH ≤1.0 
ng/mL will be recorded. 
Assessments throughout the follow 
up period will evaluate the safety, 
tolerability 
and 
PK 
of 
lanreotide PRF. Levels of insulin 
like growth factor-1 (IGF-1) and 
growth hormone (GH) will also be 
evaluated. 
The 
proportion 
of 
subjects with age adjusted IGF-1 
levels within the normal range<1.3 
x upper limit of normal (ULN), 
with GH ≤2.5 ng/mL and with GH 
≤1.0 ng/mL will be recorded. 
6 
Synopsis, 
Inclusion 
criterion #6 
Treatment with a stable dose of 
octreotide LAR for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <upper limit of normal 
(ULN)).    
Treatment with a stable dose of 
octreotide LAR for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x ULN, based on 
central laboratory results, 
during the Screening 
periodupper limit of normal 
(ULN)).    
6 
Synopsis, 
Exclusion 
criterion #1 
Has undergone radiotherapy within 
3 years prior to study entry.   
Has undergone radiotherapy within 
32 years prior to study entry.   
7 
Synopsis, 
Exclusion 
criterion #6 
Has 
any 
significant 
renal 
abnormalities 
and/or 
creatinine 
≥1.5 x ULN. 
Has 
any 
significant 
renal 
abnormalities 
and/or 
creatinine 
≥1.5 x ULN during the Screening 
period 
(central 
laboratory 
results). 
28 
3.1 
Figure 1 (see below) 
Figure 
1 
was 
adapted 
for 
clarification. 
35 
4.1 
Treatment with a stable dose of 
octreotide LAR for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <upper limit of normal 
(ULN)).    
Treatment with a stable dose of 
octreotide LAR for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x upper limit of normal 
(ULN), based on central 
laboratory results, during the 
Screening period).    
35 
4.2 
Has undergone radiotherapy within 
3 years prior to study entry.   
Has undergone radiotherapy within 
32 years prior to study entry.   
35 
4.2 
Has 
any 
significant 
renal 
abnormalities 
and/or 
creatinine 
≥1.5 x ULN. 
Has 
any 
significant 
renal 
abnormalities 
and/or 
creatinine 
≥1.5 x ULN during the Screening 
period 
(central 
laboratory 
results). 


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38 
5.1 
Table 4 (see below) 
Table 4 was updated to show Visits 
7, 9 and 11 could be performed as 
home visits. 
40 
5.1 
Table 5 (see below) 
Table 5 was updated to show Visits 
13, 15 and 17 could be performed 
as home visits. 
41 
5.1 
The total volume of blood drawn 
for all evaluations throughout this 
study is approximately 410 mL for 
each subject. 
The total volume of blood drawn 
for all evaluations throughout this 
study is approximately 410571 mL 
for each subject. 
41 
5.1 
Table 6 (see below) 
Table 6 was updated with new 
blood volumes for the treatment 
period. Table 7 was created to 
show the blood volumes for the 
follow-up period. 
41 
5.1 
A volume of 10 to 12 mL of urine 
will be collected at each of the 
visits that includes a clinical 
laboratory assessment. 
A volume of approximately 10 to 
12 14 mL of urine will be collected 
at each of the visits that includes a 
clinical laboratory assessment. 
42 
5.2.1 
Under no circumstances will 
subjects be screened more than 
once. 
Under no circumstances will 
subjects be screened more than 
once, except for the IGF-1 
assessment. IGF-1 may be 
re-tested once if the screening 
value is just above the 1.3 x ULN 
limit (analysis by central 
laboratory). The study treatment 
may only be administered if the 
re-test is <1.3 x ULN. 
44 
5.2.3 
The following procedures will be 
performed at Visit 6 (Week 3±2 
days) and Visit 7 (Week 4±2 days). 
The following procedures will be 
performed at Visit 6 (Week 3±2 
days) and Visit 7 (Week 4±2 days). 
Visit 7 can be performed at the 
study site and/or at the subject’s 
home as per investigator’s and 
subject’s decision. More 
information on how those home 
visits are performed are 
described in the study manual. 
45 
5.2.3 
The following procedures will be 
performed at Visit 9 (Week 7±2 
days) and Visit 11 (Week 11±2 
days). 
The following procedures will be 
performed at Visit 9 (Week 7±2 
days) and Visit 11 (Week 11±2 
days). Visits 9 and 11 can be 
performed at the study site 
and/or at the subject’s home as 
per investigator’s and subject’s 
decision. More information on 
how those home visits are 
performed are described in the 
study manual. 


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46 
5.2.4.1 
The following procedures will be 
performed at Visit 13 (Week 15±3 
days), Visit 15 (Week 19±3 days) 
and Visit 17 (Week 23±3 days). 
The following procedures will be 
performed at Visit 13 (Week 15±3 
days), Visit 15 (Week 19±3 days) 
and Visit 17 (Week 23±3 days). 
Visits 13 and 15 can be 
performed at the study site 
and/or at the subject’s home as 
per investigator’s and subject’s 
decision. More information on 
how those home visits are 
performed are described in the 
study manual. 
58 
8.2 
All clinically relevant abnormal 
laboratory tests occurring during 
the study will be repeated at 
appropriate intervals until they 
return to Baseline or to a level 
deemed acceptable by the 
investigator and the sponsor’s 
clinical monitor (or his/her 
designated representative) or until 
the abnormality is explained by an 
appropriate diagnosis. 
All clinically relevant abnormal 
laboratory tests occurring during 
the study will be repeated at 
appropriate intervals until they 
return to Baseline or to a level 
deemed acceptable by the 
investigator and the sponsor’s 
clinical monitor (or his/her 
designated representative) or until 
the abnormality is explained by an 
appropriate diagnosis.  
Any unscheduled test (indication 
and results) will be recorded on 
the dedicated page in the eCRF. 
58 
8.2.2 
Blood samples (2 mL) will be 
collected to assess the following 
coagulation parameters: activated 
partial thromboplastin time, 
prothrombin time and its derived 
measures of prothrombin ratio and 
INR. 
Blood samples (24.5 mL) will be 
collected to assess the following 
coagulation parameters: activated 
partial thromboplastin time, 
prothrombin time and its derived 
measures of prothrombin ratio and 
INR. 
58 
8.2.3 
Blood samples (5 mL) will be 
collected to assess the following 
parameters: 
 urea, creatinine, total bilirubin, 
conjugated bilirubin 
 chloride, bicarbonate, sodium, 
potassium, calcium, phosphate 
 AP, AST, ALT, GGT 
 albumin total protein, total 
cholesterol, triglycerides, 
postprandial glucose, and 
postprandial insulin  
 pancreatic enzymes, glucagon 
Blood samples (2 mL) will also be 
collected to assess HbA1c. 
Any unscheduled test (indication 
and results) will be recorded on the 
dedicated page in the eCRF. 
Blood samples (56 mL) will be 
collected to assess the following 
parameters: 
 urea, creatinine, total bilirubin, 
conjugated bilirubin 
 chloride, bicarbonate, sodium, 
potassium, calcium, phosphate 
 AP, AST, ALT, GGT 
 albumin, total protein, total 
cholesterol, triglycerides, 
postprandial glucose, and 
postprandial insulin  
 pancreatic enzymes, glucagon 
Blood samples (2 mL) will also be 
collected to assess HbA1c. 
Any unscheduled test (indication 
and results) will be recorded on the 
dedicated page in the eCRF. 


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58 
8.2.4 
Fresh urine samples (10 to 12 mL) 
will be collected to assess the 
following parameters: chloride, 
bicarbonates, sodium, potassium, 
calcium, pH, proteins, ketones, 
glucose, blood, bilirubin and 
urobilinogen. 
Fresh urine samples (10 to 12 
approximately 14 mL) will be 
collected to assess the following 
parameters: chloride, bicarbonates, 
sodium, potassium, calcium, pH, 
proteins, ketones, glucose, blood, 
bilirubin and urobilinogen. 
59 
8.2.5 
Blood samples (3 mL) will be 
collected for the assay of putative 
antibodies to lanreotide. The tubes 
should be left to stand for 30 
minutes and then centrifuged at 
1000 g to 1300 g for 10 minutes at 
4°C. The resulting serum will be 
stored as two 500 μL aliquots at  
20°C in polypropylene tubes prior 
to shipment to the analysis 
laboratory 
 
 
Blood samples (34 mL) will be 
collected for the assay of putative 
antibodies to lanreotide. The tubes 
should be left to stand for 30 
minutes and then centrifuged at 
1000 g to 1300 g for 10 minutes at 
4°C. The resulting serum will be 
stored as two 1 mL 500 μL 
aliquots at  20°C in polypropylene 
tubes prior to shipment to the 
analysis laboratory 
 
 
 
59 
8.2.5 
Full details regarding the 
requirements for processing, 
labelling and shipment of these 
samples will be provided in the 
study  manual and archived in the 
TMF. 
Full details regarding the 
requirements for processing, 
labelling and shipment of these 
samples will be provided in the 
studycentral laboratory manual 
and archived in the TMF. 
59 
8.3 
Details of the sample handling 
methodology and reference ranges 
will be provided in the study  
manual and archived in the TMF. 
Details of the sample handling 
methodology and reference ranges 
will be provided in the 
studycentral laboratory manual 
and archived in the TMF. 
60 
8.8 
Injection sites will be evaluated by 
the investigator for appearance and 
local symptoms according to NCI 
CTCAE criteria at the timepoints 
specified in the study schedule 
(Table 4 and Table 5). 
Injection sites will be evaluated by 
the investigator (or appropriately 
trained healthcare professional) 
for appearance and local symptoms 
according to NCI CTCAE criteria 
at the timepoints specified in the 
study schedule (Table 4 and 
Table 5). 
PPD
PPD


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61 
9.1.1 
Blood samples (3 mL each) for 
determination of lanreotide and 
excipient serum concentrations 
will be collected at the timepoints 
indicated in Table 4 and Table 5. 
Although the sample collection 
procedures for lanreotide and the 
excipient are the same, separate 
blood samples will be collected for 
each analyte.  
During the study, the nominal 
sample collection times may be 
changed, but the total number of 
samples will not increase. The 
exact dates and times of blood 
sample collection, and lanreotide 
PRF administration must be 
recorded in the eCRF. 
The tubes will be left to stand for 
30 minutes and will then be 
centrifuged at 1000 g to 1300 g for 
10 minutes at 4ºC. For each 
analyte, the resulting serum will be 
stored as two 500 μL aliquots 
at -20°C in polypropylene tubes 
prior to shipment to the analysis 
laboratory. Aliquots will be 
shipped on dry ice. 
Details of the sample handling 
methodology and reference ranges 
will be provided in the study  
manual and archived in the TMF. 
Blood samples (34 mL each) for 
determination of lanreotide and 
excipient serum concentrations 
will be collected at the timepoints 
indicated in Table 4 and Table 5. 
Although the sample collection 
procedures for lanreotide and the 
excipient are the same, separate 
blood samples will be collected for 
each analyte.  
During the study, the nominal 
sample collection times may be 
changed, but the total number of 
samples will not increase. The 
exact dates and times of blood 
sample collection, and lanreotide 
PRF administration must be 
recorded in the eCRF. 
The tubes will be left to stand for 
30 minutes and will then be 
centrifuged at 1000 g to 1300 g for 
10 minutes at 4ºC. For each 
analyte, the resulting serum will be 
stored as two 1 mL500 μL aliquots 
at –20°C in polypropylene tubes 
prior to shipment to the analysis 
laboratory. Aliquots will be 
shipped on dry ice. Details of the 
sample handling methodology and 
reference ranges will be provided 
in the studycentral laboratory 
manual and archived in the TMF. 
61 
9.1.2 
Serum will be analysed to 
determine concentrations of 
lanreotide using a validated, 
specific and sensitive 
radioimmunoassay (RIA) method 
 
 
 
Concentrations of excipient will be 
analysed using a validated liquid 
chromatography tandem mass 
spectrometry (LC-MS/MS) method 
at a CRO under the supervision of 
Ipsen’s Pharmacokinetics and 
Drug Metabolism (PDM) 
Department. 
Serum will be analysed to 
determine concentrations of 
lanreotide using a validated, 
specific and sensitive 
radioimmunoassay (RIA) method 
 
 
 
Concentrations of excipient will be 
analysed using a validated liquid 
chromatography tandem mass 
spectrometry (LC-MS/MS) method 
 under the 
supervision of Ipsen’s 
Pharmacokinetics and Drug 
Metabolism (PDM) Department. 
PPD
PPD
PPD


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PAGE 107 OF 173 
 
 
62 
9.2.1 
Blood samples (3.5 mL) will also 
be collected to assess 
endocrinology parameters (FT3, 
FT4, TSH and PRL) according to 
the study schedule (Table 4 and 
Table 5). 
Blood samples (3.52 mL) will also 
be collected to assess 
endocrinology parameters (FT3, 
FT4, TSH and PRL) according to 
the study schedule (Table 4 and 
Table 5). 
62 
9.2.1 
Details of the sample handling 
methodology and reference ranges 
will be provided in the study 
manual and archived in the TMF. 
Details of the sample handling 
methodology and reference ranges 
will be provided in the study 
central laboratory manual and 
archived in the TMF. 
62 
9.2.2 
Measurement of IGF-1 and GH 
concentrations will be performed 
by a central laboratory using a 
validated method (see Laboratory 
Manual for further details). 
Measurement of IGF-1 and GH 
concentrations will be performed 
by a central laboratory using a 
validated method (see the central 
laboratory manual Laboratory 
Manual for further details). 
63 
9.2.3.1 
Time to escape (defined as time 
from lanreotide PRF 
administration to the time when the 
IGF-1 ≥ULN) will be summarised 
by dose cohort. 
Time to escape (defined as time 
from lanreotide PRF 
administration to the time when the 
IGF-1 ≥1.3 x ULN) will be 
summarised by dose cohort. 
67 
10.6 
Details regarding stopping 
boundaries and early stopping rules 
will be described in the charter. 
Details regarding stopping 
boundaries and early stopping rules 
will be described in the charter.  
Interim analyses may be 
performed by the Sponsor to 
faciliatate the planning of future 
clinical studies of lanreotide 
PRF. 


IPSEN GROUP 
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PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 108 OF 173 
 
 
WAS: Amendment 2.0 Version 3.0: 18 February 2015 
Figure 1 
Study Design 
 


IPSEN GROUP 
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IS: Amendment 3.0 Version 4.0: 12 June 2015 
Figure 1 
Study Design 
 


IPSEN GROUP 
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PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 110 OF 173 
 
 
WAS: Amendment 2.0 Version 3.0: 18 February 2015 
Table 4 Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) 
Visit 
1 [a] 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [b] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acromegaly symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
x----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreotide administration 
[c] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanreotide PRF 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
x--------------------------------------------------------------------------------------------x 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
Lanreotide 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Excipient 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PD assessments 
IGF-1 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
GH cycle [d] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Random GH sample 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FT3, FT4, TSH, PRL 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety assessments 
AEs 
x---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Evaluation of injection site 
reactions 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments [e] 
X 
X 
 
 
 
 
X [f] 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR [g] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Table 4 Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) (Cont.) 
Visit 
1 [a] 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 


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PAGE 111 OF 173 
 
 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [b] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Gallbladder echography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Putative antibodies to 
lanreotide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biobanking 
Blood sampling [h] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FT3=free triiodothyronine; 
FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; INR=international normalised ratio; LAR=long acting release; 
MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid stimulating hormone.  
a 
Screening visit.. 
b 
Baseline. 
c 
after Screening, subjects will enter a 4 week run in period and will receive a single dose of octreotide LAR at the same dose as their previous octreotide dose. 
d 
five sampling times in the morning, with a sample every 30 minutes for 2 hours.  
e 
blood and urine samples taken for clinical laboratory tests. 
f 
evaluation of the following parameters during the first day after lanreotide administration: ALT, AST, bilirubin, lipase, amylase, INR, serum creatinine, postprandial glycaemia, and 
postprandial insulinaemia. 
g 
measured by MDRD formula [1]. 
h 
Biobanking: samples will only be collected for those individuals who have signed a specific consent for the biobanking samples. 


IPSEN GROUP 
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PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 112 OF 173 
 
 
IS: Amendment 3.0 Version 4.0: 12 June 2015 
Table 4 Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) 
Visit 
1 [a] 
2 
3 
4 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [bc] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acromegaly symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
x----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreotide administration 
[cd] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanreotide PRF 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
x--------------------------------------------------------------------------------------------x 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
Lanreotide 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Excipient 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PD assessments 
IGF-1 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
GH cycle [de] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Random GH sample 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FT3, FT4, TSH, PRL 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety assessments 
AEs 
x---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Evaluation of injection site 
reactions 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments [ef] 
X 
X 
 
 
 
 
X [fg] 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR [gh] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Table 4 Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) (Cont.) 


IPSEN GROUP 
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PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 113 OF 173 
 
 
Visit 
1 [a] 
2 
3 
4 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [bc] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Gallbladder echography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Putative antibodies to 
lanreotide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biobanking 
Blood sampling [hi] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FT3=free triiodothyronine; 
FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; INR=international normalised ratio; LAR=long acting release; 
MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid stimulating hormone.  
a 
Screening visit. 
b 
Study visits on Weeks 4, 7 and 11 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. More information on how those 
home visits are performed are described in the study manual.  
bc 
Baseline. 
cd 
after Screening, subjects will enter a 4 week run in period and will receive a single dose of octreotide LAR at the same dose as their previous octreotide dose. 
de 
five sampling times in the morning, with a sample every 30 minutes for 2 hours.  
ef 
blood and urine samples taken for clinical laboratory tests. 
fg 
evaluation of the following parameters during the first day after lanreotide administration: ALT, AST, bilirubin, lipase, amylase, INR, serum creatinine, postprandial glycaemia, and 
postprandial insulinaemia. 
gh 
measured by MDRD formula [1]. 
hi 
Biobanking: samples will only be collected for those individuals who have signed a specific consent for the biobanking samples. 
 


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PAGE 114 OF 173 
 
 
WAS: Amendment 2.0 Version 3.0: 18 February 2015 
Table 5  
Study Procedures and Assessments (Follow Up; Weeks 15 to 25) 
Visit 
13 
14 
15 
16 
17 
18 (EOS or EW)[a]
Week [b] 
15 
17 
19 
21 
23 
25/EW 
Acromegaly symptoms 
 
 
 
 
 
X 
Concomitant medications 
x--------------------------------------------------------------------------------------------------------------------------------------x 
PK blood samples 
Lanreotide PRF 
 
X 
 
X 
 
X 
PD assessments 
IGF-1 
 
X 
 
X 
 
X 
Random GH sample 
 
X 
 
X 
 
X 
FT3, FT4, TSH , PRL 
 
 
 
 
 
X 
Safety assessments 
AEs  
x--------------------------------------------------------------------------------------------------------------------------------------x 
Physical examination 
X 
X 
X 
X 
X 
X 
Clinical laboratory assessments 
X 
X 
X 
X 
X 
X 
HbA1c 
 
 
 
 
 
X 
eGFR [c] 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Gallbladder echography 
 
 
 
 
 
X 
Evaluation of injection site reactions 
X 
X 
X 
X 
X 
X 
Putative antibodies to lanreotide  
 
 
 
 
 
X 
AE=adverse event; eGFR=estimated glomerular filtration rate; EOS=end of study; EW=early withdrawal; FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; 
HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid 
stimulating hormone.  
a 
EOS for subjects completing the follow up period or EW visit for subjects who withdraw from the study during the follow up period. 
b 
follow up visits will be conducted every 2 weeks (±3 days). 
c 
measured by MDRD formula [1]. 
 


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PAGE 115 OF 173 
 
 
IS: Amendment 3.0 Version 4.0: 12 June 2015 
Table 5  
Study Procedures and Assessments (Follow Up; Weeks 15 to 25) 
Visit 
13 
[a] 
14 
15 
[a] 
16 
17 
[a] 
18 (EOS or 
EW)[ab] 
Week [bc] 
15 
17 
19 
21 
23 
25/EW 
Acromegaly symptoms 
 
 
 
 
 
X 
Concomitant medications 
x--------------------------------------------------------------------------------------------------------------------------------------x 
PK blood samples 
Lanreotide PRF 
 
X 
 
X 
 
X 
PD assessments 
IGF-1 
 
X 
 
X 
 
X 
Random GH sample 
 
X 
 
X 
 
X 
FT3, FT4, TSH , PRL 
 
 
 
 
 
X 
Safety assessments 
AEs  
x--------------------------------------------------------------------------------------------------------------------------------------x 
Physical examination 
X 
X 
X 
X 
X 
X 
Clinical laboratory assessments 
X 
X 
X 
X 
X 
X 
HbA1c 
 
 
 
 
 
X 
eGFR [cd] 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Gallbladder echography 
 
 
 
 
 
X 
Evaluation of injection site reactions 
X 
X 
X 
X 
X 
X 
Putative antibodies to lanreotide  
 
 
 
 
 
X 
AE=adverse event; eGFR=estimated glomerular filtration rate; EOS=end of study; EW=early withdrawal; FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; 
HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid 
stimulating hormone.  
a 
Study visits on Weeks 15, 19 and 23 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. More information on how 
those home visits are performed are described in the study manual. 
ab 
EOS for subjects completing the follow up period or EW visit for subjects who withdraw from the study during the follow up period. 
bc 
follow up visits will be conducted every 2 weeks (±3 days). 
cd 
measured by MDRD formula [1]. 
 


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PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 116 OF 173 
 
 
WAS: Amendment 2.0 Version 3.0: 18 February 2015 
Table 6  
Blood Volume Calculation 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments [a] 
16 
12 
192 
PD 
9 IGF-1 
20 GH Cycle 
5 random GH 
2 
68 
PK 
18 for lanreotide;  
10 for excipient 
3 
84 
HbA1c 
3 
2 
6 
FT3, FT4, TSH and PRL 
6 
3.5 
21 
Antibody testing 
3 
3 
9 
Biobanking [b] 
3 
10 
30 
Total 
93 
35.5 
410 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; insulin 
like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid stimulating hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial blood 
glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum creatinine and 
electrolytes, and urinalysis. 
b 
the 10 mL sample blood volume collected will consist of 5 mL dry tube and 2 x 2.5 mL for RNA biobanking 
 
 


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PAGE 117 OF 173 
 
 
IS: Amendment 3.0 Version 4.0: 12 June 2015 
Table 6 Blood Volume Calculation for Treatment Period 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments [a] 
1610 
1220.5 mL for 
9 visits and 14.5 mL 
for 1 visit (Vist 2 
postdose) 
192199 
PD 
96 IGF-1 
20 GH Cycle 
52 random GH 
2 
2 
2 
6856 
PK 
1815 for lanreotide;  
10 for excipient 
34 
4 
112100 
HbA1c 
32 
2 
64 
FT3, FT4, TSH and PRL 
65 
3.5 
2117.5 
Antibody testing 
32 
34 
98 
Biobanking [b] 
3 
10 
30 
Total 
9375 
35.5Up to 132.5 mL 
per visit (Visit 2) 
410414.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; 
insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid stimulating 
hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial blood 
glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum creatinine and 
electrolytes, and urinalysis. 
b 
the 10 mL sample blood volume collected will consist of 5 mL dry tube and 2 x 2.5 mL for RNA biobanking 
 
Table 7 Blood Volume Calculation for Follow Up Period 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments 
[a] 
6 
20.5 mL  
123 
PD 
3 IGF-1 
3 random GH 
2 
2 
12 
PK 
3 for lanreotide  
4 
12 
HbA1c 
1 
2 
2 
FT3, FT4, TSH and PRL 
1 
3.5 
3.5 
Antibody testing 
1 
4 
4 
Total 
18 
Up to 38 per visit 
(Visit 18) 
156.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; 
IGF-1; insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; 
TSH=thyroid stimulating hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial 
blood glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum 
creatinine and electrolytes, and urinalysis. 
 


IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 118 OF 173 
 
 
Summary & outcome of changes: 
STUDY NUMBER 
8-55-52030-309 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 3.0 Version 4.0: 12 June 2015 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
To update the Sponsor’s medically responsible person and contact 
details. 
To extend the planned study period to January 2017. 
To include the option for home visits on Weeks 4, 7, 11, 15, 19 and 
23. 
To increase the IGF-1 limit from within the normal range to <1.3 x 
ULN and clarify that the assessment during the Screening period 
must be analyzed by the central laboratory. 
To reduce the period in which the patient has had radiotherapy from 
3 years to 2 years prior to study entry. 
To clarify that any significant renal abnormalities and/or creatinine 
values ≥1.5 x ULN should be measured during the Screening period 
must be analyzed by the central laboratory. 
To update Figure 1 for clarification of the DRC decisions. 
To update the Schedule of Assessments to include the option of 
home visits. 
To update the blood and urine volumes to be collected according to 
the central laboratory manual. 
To include an opportunity to re-test the screening IGF-1 value once if 
it is just above the 1.3 x ULN limit. 
To ensure the central laboratory manual is referred to consistently 
throughout the protocol. 
To include an option for the Sponsor to conduct an interim analysis 
in relation to the clinical development of lanreotide PRF. 
Other Action Required? 
CRF Update  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
Local Consent Form Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Database Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Reporting & Analysis Plan 
(RAP) Update 
 
Yes 
 
  
No 
 
 
 
(tick one) 
 


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PAGE 119 OF 173 
 
 
Appendix 6 Protocol Amendment 4 
(27 July 2015) 


IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 120 OF 173 
 
 
STUDY NUMBER: 
8-55-52030-309 
PROTOCOL TITLE: 
Phase IIa, Open Label, Dose Ascending Study to 
Determine the Maximum Tolerated Dose, Safety and 
Tolerability, Pharmacokinetics and Pharmacodynamics 
of a Single Dose of Lanreotide PRF in Subjects with 
Acromegaly Previously Treated and Controlled with 
Either Octreotide LAR or Lanreotide Autogel 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 4.0 Version 5.0: 27 July 2015 
 
 
The following amendment(s) is/are proposed: 
Version Date 
12 June 2015 
27 July 2015 
Page 
Section 
WAS 
IS 
1 
Title page 
PROTOCOL TITLE: PHASE IIA, 
OPEN LABEL, DOSE 
ASCENDING STUDY TO 
DETERMINE THE MAXIMUM 
TOLERATED DOSE, SAFETY 
AND TOLERABILITY, 
PHARMACOKINETICS AND 
PHARMACODYNAMICS OF A 
SINGLE DOSE OF 
LANREOTIDE PRF IN 
SUBJECTS WITH 
ACROMEGALY PREVIOUSLY 
TREATED AND CONTROLLED 
WITH OCTREOTIDE LAR 
PROTOCOL TITLE: PHASE IIA, 
OPEN LABEL, DOSE 
ASCENDING STUDY TO 
DETERMINE THE MAXIMUM 
TOLERATED DOSE, SAFETY 
AND TOLERABILITY, 
PHARMACOKINETICS AND 
PHARMACODYNAMICS OF A 
SINGLE DOSE OF 
LANREOTIDE PRF IN 
SUBJECTS WITH 
ACROMEGALY PREVIOUSLY 
TREATED AND CONTROLLED 
WITH EITHER OCTREOTIDE 
LAR OR LANREOTIDE 
AUTOGEL 
5 
Synopsis 
Title of study: Phase IIa, open 
label, dose ascending study to 
determine the maximum tolerated 
dose, safety and tolerability, 
pharmacokinetics and 
pharmacodynamics of a single 
dose of lanreotide PRF in subjects 
with acromegaly previously treated 
and controlled with octreotide 
LAR 
Title of study: Phase IIa, open 
label, dose ascending study to 
determine the maximum tolerated 
dose, safety and tolerability, 
pharmacokinetics and 
pharmacodynamics of a single 
dose of lanreotide PRF in subjects 
with acromegaly previously treated 
and controlled with either 
octreotide LAR or lanreotide 
Autogel 
5 
Synopsis 
Number of planned centres: 20 to 
25 
Number of planned centres: 20 to 
25 up to 30 


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PAGE 121 OF 173 
 
 
5 
Synopsis, 
Methodology 
Subjects with acromegaly who have 
been well controlled for at least 3 
months on a stable dose of 
octreotide 
long 
acting 
release 
(LAR) will be recruited to this open 
label study. Eligible subjects will 
enter a 4 week run in period, during 
which they will receive the same 
single dose of octreotide LAR as 
their previous treatment (Day −28). 
A 12 week treatment period will 
then commence, during which 
subjects will receive one deep 
subcutaneous 
injection 
of 
lanreotide PRF on Day 1 (4 weeks 
after the last octreotide LAR 
administration). 
Subjects with acromegaly who have 
been well controlled for at least 3 
months on a stable dose of 
octreotide 
long 
acting 
release 
(LAR) or lanreotide Autogel will 
be recruited to this open label study. 
Eligible subjects will enter a 4 week 
run in period, during which they 
will receive the same single dose of 
either 
octreotide 
LAR 
or 
lanreotide 
Autogel 
as 
their 
previous treatment (Day −28). A 
12 week treatment period will then 
commence, during which subjects 
will receive one deep subcutaneous 
injection of lanreotide PRF on 
Day 1 (4 weeks 
after 
the 
last 
octreotide LAR  or lanreotide 
Autogel administration). 
5 
Synopsis, 
Methodology 
It is planned to include three cohorts 
of subjects; Cohort 1 will receive 
lanreotide PRF 180 mg, Cohort 2 
will receive 270 mg and Cohort 3 
will receive 360 mg. Nine subjects 
will be allocated to each lanreotide 
PRF treatment cohort. 
It is planned to include three cohorts 
of subjects; Cohort 1 will receive 
lanreotide PRF 180 mg, Cohort 2 
will receive 270 mg and Cohort 3 
will receive 360 mg. Nine subjects 
will be allocated to each lanreotide 
PRF treatment cohort. Each cohort 
must enrol at least six subjects 
previously treated with octreotide 
LAR. Each cohort can enrol up to 
three subjects previously treated 
with lanreotide Autogel. 
5, 6, 9, 
63 
Synopsis, 
Methodology, 
Number of 
Subjects 
Planned, 10.2 
9 subjects 
9nine subjects 
6 
Synopsis, 
Diagnosis and 
criteria for 
inclusion 
Subjects with acromegaly, well 
controlled by a stable dose of 
octreotide LAR for at least 3 
months. 
Subjects with acromegaly, well 
controlled by a stable dose of 
either octreotide LAR or 
lanreotide Autogel for at least 3 
months. 


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6 
Synopsis, 
Inclusion 
criterion #6 
Treatment with a stable dose of 
octreotide LAR for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x ULN, based on 
central laboratory results, during 
the Screening period). 
Treatment with a stable dose of 
either octreotide LAR or 
lanreotide Autogel for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x ULN, based on 
central local laboratory results, 
during the Screening period. 
Samples for analysis by central 
laboratory will also be collected 
during Screening). 
23 
1.4.3 
Should any concern about this 
residual concentration arise during 
the study the sponsor will notify 
the investigators about the level of 
residual concentration which 
would allow to adjustadjusting the 
restart of octreotide treatment. 
Should any concern about this 
residual concentration arise during 
the study the sponsor will notify 
the investigators about the level of 
residual concentration which 
would allow to adjustadjusting the 
restart of either octreotide or 
lanreotide Autogel treatment. 


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PAGE 123 OF 173 
 
 
25 
1.7 
The study will enrol adult subjects 
with acromegaly who have been 
well controlled for at least 3 months 
on a stable dose of octreotide long 
acting release (LAR). 
The choice of octreotide stable 
subjects as the study population, 
instead of lanreotide stable subjects, 
was guided by the fact that a 
4 month washout period before 
lanreotide 
PRF 
administration 
would be avoided and no cross 
interference 
in 
lanreotide 
and 
octreotide measurements by the 
bioanalytical assay would occur. 
The study will enrol adult subjects 
with acromegaly who have been 
well controlled for at least 3 months 
on a stable dose of either octreotide 
long acting release (LAR) or 
lanreotide Autogel. A minimum 
of six octreotide LAR subjects 
must be recruited in each cohort 
and up to three lanreotide 
Autogel subjects can be enrolled 
in each cohort. 
The choice of octreotide stable 
subjects stable on octreotide LAR 
as the main study population, 
instead of lanreotide stable subjects 
stable on lanreotide Autogel, was 
guided by the fact that a 4 month 
washout period before lanreotide 
PRF 
administration 
would 
be 
avoided and no cross interference in 
lanreotide 
and 
octreotide 
measurements by the bioanalytical 
assay would occur need to avoid 
crossinterference between the 
different 
formulations 
of 
lanreotide in the primary PK 
analysis. 
The 
required 
PK 
analysis can be done with a 
minimum of six octreotide LAR 
subjects per cohort. 
The inclusion of up to three 
lanreotide Autogel subjects per 
cohort will provide preliminary 
PK data from this population.  
Possible subject combinations per 
cohort are shown in Table 3. (new 
Table 3 added; see below) 
Added new table: 
Table 3 Possible Subject Combinations Per Cohort 
 
Octreotide LAR 
Lanreotide Autogel 
Cohort 1, 2 and 3 
6 
3 
Cohort 1, 2 and 3 
7 
2 
Cohort 1, 2 and 3 
8 
1 
Cohort 1, 2 and 3 
9 
0 
 
 
26 
2.1 
3 subjects 
3 three subjects 


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PAGE 124 OF 173 
 
 
27 
3.1 
This is an open label, dose 
ascending study to assess the PK, 
PD, safety and tolerability of a 
single dose of lanreotide PRF, a 
new sustained release formulation 
of lanreotide. Doses of 180 mg, 270 
mg and 360 mg will be investigated 
in 
adults 
with 
acromegaly 
previously treated and controlled 
with a stable dose of octreotide 
LAR. 
A maximum of 27 adult subjects, 
aged 18 to 75 years will be treated 
in the study. 
Three cohorts of subjects will be 
included, with 9 subjects allocated 
to each lanreotide PRF treatment 
cohort (180 mg, 270 mg and 360 
mg). Subjects in each cohort will 
receive one deep subcutaneous 
injection of lanreotide PRF on Day 
1 (4 weeks after the last octreotide 
LAR 
administration). 
Specific 
details of the dose cohorts are given 
in Section 6.1. 
This is an open label, dose 
ascending study to assess the PK, 
PD, safety and tolerability of a 
single dose of lanreotide PRF, a 
new sustained release formulation 
of lanreotide. Doses of 180 mg, 270 
mg and 360 mg will be investigated 
in 
adults 
with 
acromegaly 
previously treated and controlled 
with a stable dose of either 
octreotide LAR or lanreotide 
Autogel. 
A maximum of 27 adult subjects, 
aged 18 to 75 years will be treated 
in the study. 
Three cohorts of subjects will be 
included, 
with 
9nine 
subjects 
allocated to each lanreotide PRF 
treatment cohort (180 mg, 270 mg 
and 360 mg). Subjects in each 
cohort will receive one deep 
subcutaneous 
injection 
of 
lanreotide PRF on Day 1 (4 weeks 
after the last octreotide LAR or 
lanreotide 
Autogel 
administration). Specific details of 
the dose cohorts are given in 
Section 6.1. 
Each cohort of nine subjects must 
be made up of at least six 
previously 
controlled 
on 
octreotide LAR. The remaining 
subjects can be up to three 
subjects previously controlled on 
lanreotide Autogel (see Table 3). 
27 
3.1 
Screening of subjects will take 
place 28 days before administration 
of study treatment (Day −28). 
Eligible subjects will receive the 
same single dose of octreotide LAR 
as their previous treatment and will 
enter a 4 week run in period. 
Screening of subjects will take 
place 28 days before administration 
of study treatment (Day −28). 
Eligible subjects will receive the 
same single dose of octreotide LAR 
or lanreotide Autogel as their 
previous treatment and will enter a 
4 week run in period. 
29 
3.1 
Figure 1 (see below) 
Figure 
1 
was 
adapted 
for 
clarification. 


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30 
3.2.2 
- 
At 1, 2, 4, 6, 8 and 12 hours 
postdose on thAll laboratory 
parameters will be analysed 
centrally to confirm subject 
eligibility 
against 
the 
inclusion 
and 
exclusion 
criteria. e day of dosing 
(Day 1), 
at 
24 hours 
postdose (Day 2), and on 
Days 3 and 5 after 
lanreotide PRF 
administration  
 
- 
At 1, 2, 4, 6, 8 and 12 hours 
postdose on the day of 
dosing (Day 1), at 24 hours 
postdose (Day 2), and on 
Days 3 and 5 after 
lanreotide PRF 
administration  
Note: If the elimination half-life 
of glycofurol in all cohort 1 
subjects is short (e.g. <5 hours), 
then there is no need for the 
subjects in cohorts 2 and 3 to 
perform Visit 4 at Day 5 since 
only PK data are collected. In 
addition at Visit 3 (Day 3) 
excipient PK may be removed. 
25 
4 
All laboratory parameters will be 
analysed centrally to confirm 
subject eligibility against the 
inclusion and exclusion criteria. 
All laboratory parameters will be 
analysed 
centrally 
to 
confirm 
subject 
eligibility 
against 
the 
inclusion and exclusion criteria, 
with the exception of IGF-1. Age 
adjusted IGF-1 will be based on 
local 
laboratory 
results 
at 
Screening. Samples for analysis 
of IGF-1 by central laboratory 
will also be collected during 
Screening. 
36 
4.1 
Treatment with a stable dose of 
octreotide LAR for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF 1 <1.3 x upper limit of normal 
(ULN), based on central laboratory 
results, during the Screening 
period). 
Treatment with a stable dose of 
either octreotide LAR or 
lanreotide Autogel for at least 3 
months immediately prior to study 
entry, with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF 1 <1.3 x upper limit of normal 
(ULN), based on central local 
laboratory results, during the 
Screening period Samples for 
analysis by central laboratory 
will also be collected during 
Screening). 
39 
5.1 
Table 4 (see below) 
Table 5 (previously Table 4) was 
updated to add lanreotide Autogel 
as a previous treatment option and 
to include a footnote regarding 
DRC review of PK data from the 
excipient. 


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41 
5.1 
Table 5 (see below) 
Table 6 (previously Table 5) 
Added footnote [d] to the IGF-1 PD 
assessment. 
d 
during follow up visits, 
IGF-1 testing will be conducted 
by a central laboratory using a 
validated method. 
42 
5.1 
Table 6 (see below) 
Table 7 (previously Table 6) was 
updated with the number of IGF-1 
blood samples and the total blood 
volumes. 
43 
5.2.1 
Under no circumstances will 
subjects be screened more than 
once, except for the IGF-1 
assessment. IGF-1 may be re-
tested once if the screening value is 
just above the 1.3 x ULN limit 
(analysis by central laboratory). 
The study treatment may only be 
administered if the re-test is <1.3 x 
ULN. 
Following confirmation of 
eligibility for the study, subjects 
will be enrolled into the study and 
allocated to one of the dose cohorts 
specified in Section 6.1. At the 
Screening visit, enrolled subjects 
will then receive their usual dose 
of octreotide LAR according to 
standard clinical practice. 
Under normal circumstances will 
subjects will not be screened more 
than once., There are two 
exceptions except for the IGF-1 
assessment. 1). IGF-1 may be re-
tested once if the screening value is 
just above the 1.3 x ULN limit 
(analysis by central local 
laboratory). The study treatment 
may only be administered if the re-
test is <1.3 x ULN. 2). If the time 
elapsed between the original 
Screening visit (Visit 1) and Visit 
2 is >28 days (±2 days) then re-
screening of the subject for 
inclusion is permitted. 
Following confirmation of 
eligibility for the study, subjects 
will be enrolled into the study and 
allocated to one of the dose cohorts 
specified in Section 6.1. At the 
Screening visit, enrolled subjects 
will then receive their usual dose 
of either octreotide LAR or 
lanreotide Autogel according to 
standard clinical practice. 
43 
5.2.2 
On Day 1 (Visit 2), subjects will be 
admitted to the study centre where 
they will undergo Baseline 
assessments prior to the 
administration of study treatment.  
The following procedures will be 
performed at Baseline on Day 1 of 
the study, prior to the 
administration of study treatment: 
On Day 1±2 days (Visit 2), 
subjects will be admitted to the 
study centre where they will 
undergo Baseline assessments 
prior to the administration of study 
treatment.  
The following procedures will be 
performed at Baseline on 
Day 1±2 days of the study, prior to 
the administration of study 
treatment 


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44 
5.2.3 
Following Baseline assessments on 
Day 1, study treatment will be 
administered. Subjects will remain 
at the study centre for 24 hours 
postdose, during which time 
further assessments will be 
performed. 
The following procedures will be 
performed at the indicated 
timepoints relative to 
administration of study treatment 
at Visit 2 (Day 1): 
 
The following procedures will be 
performed 24 hours after 
administration of study treatment 
at Visit 2 (Day 2): 
 
Following the assessments on 
Visit 2; Day 2 
Following Baseline assessments on 
Day 1±2 days, study treatment will 
be administered. Subjects will 
remain at the study centre for 24 
hours postdose, during which time 
further assessments will be 
performed. 
The following procedures will be 
performed at the indicated 
timepoints relative to 
administration of study treatment 
at Visit 2 (Day 1±2 days): 
 
The following procedures will be 
performed 24 hours after 
administration of study treatment 
at Visit 2 (Day 2±2 days): 
 
Following the assessments on 
Visit 2; Day 2±2 days  
45 
5.2.3 
The following procedures will be 
performed at Visit 3 (Day 3±1 
day):  
… 
• 
PK 
blood 
samples 
for 
lanreotide and excipient  
The following procedures will be 
performed at Visit 4 (Day 5±1 
day):  
… 
• 
PK 
blood 
samples 
for 
lanreotide and excipient  
The following procedures will be 
performed at Visit 3 (Day 3±1 
day):  
… 
• 
PK 
blood 
samples 
for 
lanreotide and excipient (if 
the elimination half-life of 
glycofurol in all cohort 1 
subjects is short (e.g. <5 
hours), then excipient PK 
may be removed for Visit 
3). 
The following procedures will be 
performed at Visit 4 (Day 5±1 
day):  
… 
• 
PK 
blood 
samples 
for 
lanreotide and excipient (if 
the elimination half-life of 
glycofurol in all cohort 1 
subjects is short (e.g. <5 
hours), then there is no 
need for the subjects in 
cohorts 2 and 3 to perform 
Visit 4 at Day 5 since only 
PK data are collected.) 


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50 
6.1.1 
Dose level: 180 mg. The study will 
start dosing 3 subjects. If none or 
one out of the 3 dosed subjects 
experiences a DLT, 3 more 
subjects will be dosed at the same 
time. If 2 out of the 3 dosed 
subjects experiences a DLT, the 
DRC will decide whether three 
more subjects may be dosed. If all 
3 subjects have experienced a 
DLT, dosing will be stopped and 
the dose will be declared the 
maximum administered dose.  
If none or 1 of the 6 dosed subjects 
experience a DLT, three more 
subjects can be dosed at the same 
dose. If 2 of the 6 dosed subjects 
experience a DLT, , and one or 
both of the DLTs occured in the 
second group of three patients, the 
DRC will decide whether three 
more subjects may be dosed. If a 
total of three or more out of six 
subjects experience a DLT, dosing 
will be stopped and the dose will 
be declared the maximum 
administered dose.  
Dose escalation: If more than 3 out 
of 9 subjects experience a DLT, 
dose escalation will be stopped and 
the dose will be declared the 
maximum administered dose. If ≤3 
DLTs have been observed in the 9 
treated subjects, then the dose may 
be escalated to 270 mg. The DRC 
will determine if progression to the 
next dose cohort should occur after 
reviewing data from the preceding 
cohort. The same rules will be 
applied to the next dose level and 
the decision to escalate to 360 mg 
will be done in the same way. 
Dose level: 180 mg. The study will 
start dosing 3three subjects. If 
none or one out of the three dosed 
subjects experiences a DLT, 
3three more subjects will be dosed 
at the same timedose. If 2two out 
of the 3three dosed subjects 
experiences a DLT, the DRC will 
decide whether 3three more 
subjects may be dosed. If all 
3three subjects have experienced a 
DLT, dosing will be stopped and 
the dose will be declared the 
maximum administered dose.  
If none or 1one of the 6six dosed 
subjects experience a DLT, 3three 
more subjects can be dosed at the 
same dose. If 2two of the 6six 
dosed subjects experience a DLT, , 
and 1one or both of the DLTs 
occured in the second group of 
3three patientssubjects, the DRC 
will decide whether 3three more 
subjects may be dosed. If a total of 
3three or more out of 6six subjects 
experience a DLT, dosing will be 
stopped and the dose will be 
declared the maximum 
administered dose.  
Dose escalation: If more than 
3three out of 9nine subjects 
experience a DLT, dose escalation 
will be stopped and the dose will 
be declared the maximum 
administered dose. If ≤3 DLTs 
have been observed in the 9nine 
treated subjects, then the dose may 
be escalated to 270 mg. The DRC 
will determine if progression to the 
next dose cohort should occur after 
reviewing data from the preceding 
cohort. The same rules will be 
applied to the next dose level and 
the decision to escalate to 360 mg 
will be done in the same way. 


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62 
9.2.2 
Measurement of IGF-1 and GH 
concentrations will be performed 
by a central laboratory using a 
validated method (see the central 
laboratory manual for further 
details). 
Measurement of IGF-1 and GH 
concentrations will be performed 
by a central laboratory using a 
validated method (see the central 
laboratory manual for further 
details).  
Measurement of IGF-1 
concentrations at the screening 
visit will be performed locally 
and centrally. 
66 
10.5 
If sufficient numbers of subjects 
are available to permit these 
analyses, descriptive statistics will 
be provided within each category 
of the following variables: 
previous dose of octreotide, sex, 
age (≤65, >65 years). 
If sufficient numbers of subjects 
are available to permit these 
analyses, descriptive statistics will 
be provided within each category 
of the following variables: 
Previous treatment amd dose 
(octreotide, lanreotide Autogel), 
previous dose of octreotide, sex, 
age (≤65, >65 years). 
66 
10.6 
The DRC will review safety data 
from each cohort after all subjects 
in the cohort have completed Visit 
5 (Week 2 postdose). At this time, 
if no DLT or unexpected safety 
signals have been observed and the 
overall safety is in line with the 
known lanreotide safety profile, 
the DRC will decide whether to 
proceed with the next dose cohort.  
The DRC will review safety data 
from each cohort after all subjects 
in the cohort have completed Visit 
5 (Week 2 postdose). At this time, 
if no DLT or unexpected safety 
signals have been observed and the 
overall safety is in line with the 
known lanreotide safety profile, 
the DRC will decide whether to 
proceed with the next dose cohort.  
The DRC will also review the PK 
data from the excipient when 
available and if the elimination 
half-life of glycofurol in all 
cohort 1 subjects is short (e.g. 
<5 hours), then there is no need 
for the subject to perform Visit 4 
at Day 5 since only PK data are 
collected. In addition at Visit 3 
(Day 3) excipient PK will be 
removed. 
The DRC will also advise on 
any restriction on subject 
enrolment with regard to dose 
of pre-study octreotide or 
lanreotide Autogel for cohorts 
2 and 3, based on 
considerations of safety and 
PK assessment of preceding 
cohort(s). 


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PAGE 130 OF 173 
 
 
73 
14.2 
The coding of an AE, medical 
history and concomitant 
medication terms will be 
performed by the contracted 
CRO/a CRO, directed by the 
sponsor’s Biometry Group, and 
reviewed and approved by the 
sponsor. 
The coding of an AE, medical 
history and concomitant 
medication terms will be 
managed by the sponsor’s 
Biometry Group. 


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PAGE 131 OF 173 
 
 
WAS: Amendment 3.0 Version 4.0: 12 June 2015 
Figure 1 
Study Design 
 
 


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IS: Amendment 4.0 Version 5.0: 27 July 2015 
Figure 1 
Study Design 
 


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WAS: Amendment 3.0 Version 4.0: 12 June 2015 
Table 4 Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) 
Visit 
1 [a] 
2 
3 
4 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acromegaly symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
x----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreotide administration 
[d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanreotide PRF 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
x--------------------------------------------------------------------------------------------x 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
Lanreotide 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Excipient 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PD assessments 
IGF-1 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
GH cycle [e] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Random GH sample 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FT3, FT4, TSH, PRL 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety assessments 
AEs 
x---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Evaluation of injection site 
reactions 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments [f] 
X 
X 
 
 
 
 
X [g] 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR [h] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


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PAGE 134 OF 173 
 
 
Table 4 
Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) (Cont.) 
Visit 
1 [a] 
2 
3 
4 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Gallbladder echography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Putative antibodies to 
lanreotide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biobanking 
Blood sampling [i] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FT3=free triiodothyronine; 
FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; INR=international normalised ratio; LAR=long acting release; 
MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid stimulating hormone.  
a 
Screening visit. 
b 
Study visits on Weeks 4, 7 and 11 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. More information on how those home 
visits are performed are described in the study manual.  
c 
Baseline. 
d 
after Screening, subjects will enter a 4 week run in period and will receive a single dose of octreotide LAR at the same dose as their previous octreotide dose. 
e 
five sampling times in the morning, with a sample every 30 minutes for 2 hours.  
f 
blood and urine samples taken for clinical laboratory tests. 
g 
evaluation of the following parameters during the first day after lanreotide administration: ALT, AST, bilirubin, lipase, amylase, INR, serum creatinine, postprandial glycaemia, and 
postprandial insulinaemia. 
h 
measured by MDRD formula [1]. 
i 
Biobanking: samples will only be collected for those individuals who have signed a specific consent for the biobanking samples. 
 


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IS: Amendment 4.0 Version 5.0: 27 July 2015 
Table 5 
Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) 
Visit 
1 [a] 
2 
3 
[e] 
4 
[e] 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acromegaly symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
x----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreotide or lanreotide 
Autogel administration [d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanreotide PRF 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
x--------------------------------------------------------------------------------------------x 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
Lanreotide PRF 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Excipient 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
[e] 
X 
[e] 
X 
[e] 
 
 
 
 
 
 
 
 
PD assessments 
IGF-1 [f] 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
GH cycle [eg] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Random GH sample 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FT3, FT4, TSH, PRL 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety assessments 
AEs 
x---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
 
Table 5 
Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) (Cont.) 
Visit 
1 [a] 
2 
3 
[e] 
4 
[e] 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 


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Evaluation of injection site 
reactions 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments [fh] 
X 
X 
 
 
 
 
X [gi] 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR [hj] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Gallbladder echography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Putative antibodies to 
lanreotide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biobanking 
Blood sampling [ik] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FT3=free triiodothyronine; 
FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; INR=international normalised ratio; LAR=long acting release; 
MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid stimulating hormone.  
a 
Screening visit. 
b 
Study visits on Weeks 4, 7 and 11 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. More information on how those home 
visits are performed are described in the study manual.  
c 
Baseline. 
d 
after Screening, subjects will enter a 4 week run in period and will receive a single dose of octreotide LAR at the same dose as their previous octreotide dose.  
 
after Screening, subjects will enter a 4 week run in period and will receive a single dose of either octreotide LAR or lanreotide Autogel at the same dose as their previous octreotide 
dose they received previously. 
e 
if the elimination half-life of glycofurol in all cohort 1 subjects is short (e.g. <5 hours), then there is no need for the subject to perform Visit 4 at Day 5 since only PK data are 
collected. In addition at Visit 3 (Day 3) excipient PK may be removed. 
f 
IGF-1 testing will be conducted by a central laboratory using a validated method. During the Screening period, IGF-1 will be analysed locally and centrally. 
g 
five sampling times in the morning, with a sample every 30 minutes for 2 hours.  
h 
blood and urine samples taken for clinical laboratory tests. 
i 
evaluation of the following parameters during the first day after lanreotide administration: ALT, AST, bilirubin, lipase, amylase, INR, serum creatinine, postprandial glycaemia, and 
postprandial insulinaemia. 
j 
measured by MDRD formula [1]. 
k 
Biobanking: samples will only be collected for those individuals who have signed a specific consent for the biobanking samples. 
 


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WAS: Amendment 3.0 Version 4.0: 12 June 2015 
 
Table 6 
Blood Volume Calculation for Treatment Period 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments [a] 
10 
20.5 mL for 9 visits 
and 14.5 mL for 1 
visit (Vist 2 
postdose) 
199 
PD 
6 IGF-1 
20 GH Cycle 
2 random GH 
2 
2 
2 
56 
PK 
15 for lanreotide;  
10 for excipient 
4 
4 
100 
HbA1c 
2 
2 
4 
FT3, FT4, TSH and PRL 
5 
3.5 
17.5 
Antibody testing 
2 
4 
8 
Biobanking [b] 
3 
10 
30 
Total 
75 
Up to 132.5 mL per 
visit (Visit 2) 
414.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; 
insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid stimulating 
hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial blood 
glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum creatinine and 
electrolytes, and urinalysis. 
b 
the 10 mL sample blood volume collected will consist of 5 mL dry tube and 2 x 2.5 mL for RNA biobanking 
 
 


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IS: Amendment 4.0 Version 5.0: 27 July 2015 
 
Table 7 Blood Volume Calculation for Treatment Period 
Description 
Number of samples 
Volume (mL) 
Total volume 
(mL) 
Clinical laboratory assessments 
[a] 
10 
20.5 mL for 9 visits 
and 14.5 mL for 1 
visit (Vist 2 
postdose) 
199 
PD 
67 IGF-1 
20 GH Cycle 
2 random GH 
2 
2 
2 
5658 
PK 
15 for lanreotide;  
10 for excipient 
4 
4 
100 
HbA1c 
2 
2 
4 
FT3, FT4, TSH and PRL 
5 
3.5 
17.5 
Antibody testing 
2 
4 
8 
Biobanking [b] 
3 
10 
30 
Total 
75 
Up to 132.5 mL per 
visit (Visit 2) 
414.5416.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; 
insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid 
stimulating hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial 
blood glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum 
creatinine and electrolytes, and urinalysis. 
b 
the 10 mL sample blood volume collected will consist of 5 mL dry tube and 2 x 2.5 mL for RNA 
biobanking 
 
 


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Summary & outcome of changes: 
STUDY NUMBER 
8-55-52030-309 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 4.0 Version 5.0: 27 July 2015 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
To allow up to three subjects previously controlled on lanreotide 
Autogel to be enrolled per cohort of nine. The choice of subjects 
stable on octreotide LAR as the main study population, instead of 
subjects stable on lanreotide Autogel, was guided by the need to 
avoid crossinterference between the different formulations of 
lanreotide in the primary PK analysis. The required PK analysis can 
be done on a minimum of six octreotide LAR subjects per cohort. 
The inclusion of up to three lanreotide Autogel subjects per cohort 
will provide preliminary PK data from the intended indication of 
switch from lanreotide Autogel to lanreotide PRF. 
To amend the title of the protocol to reflect this change to the 
subjects enrolled from just octreotide LAR to either octreotide LAR 
or lanreotide Autogel. 
To allow the screening for subject enrolment regarding IGF-1 levels 
to be assessed on an IGF-1 level analysed at a local laboratory 
instead of only at the central laboratory. This is because of the known 
variability in the different IGF-1 assays used at local and central 
laboratories. We want to avoid an eligible subject (whom the 
investigator knows is stable) being excluded from the study due to a 
higher reading from the central lab when the IGF-1 levels have been 
well controlled as analysed by local laboratories. The subject must 
comply with all inclusion criteria and be well controlled according to 
the experienced investigator. All subsequent IGF-1 analysis in the 
study will be performed at the central laboratory. This change is just 
for entry criteria only. 
To update the number of IGF-1 samples and total blood volumes to 
account for the additional sample collected during screening for 
assessment by local laboratory. 
To add an additional subgroup analysis due to the change in subjects 
eligible for the study - from only octreotide LAR to either octreotide 
LAR or lanreotide Autogel. The additional subgroup analysis will be 
performed to assess the PK and safety of these two groups of 
subjects depending on their prior treatment. 
To add the possibility not to perform Visit 4 Day 5 according to PK 
excipient data further to DRC review. Indeed if the half life of the 
excipient is short there is no need to follow it any longer and adding 
blood sampling and visits to the subject if it is not needed. Also the 
excipient PK may also be removed at Visit 3 Day 3. 
To add a ±2 day window for Visit 2 Day 1 and 2. 
Other Action Required? 
CRF Update  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
Local Consent Form Update  
Yes 
 
  
No 
 
 
 
(tick one) 


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Database Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Reporting & Analysis Plan 
(RAP) Update 
 
Yes 
 
  
No 
 
 
 
(tick one) 


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Appendix 7 Protocol Amendment 5 
(22 March 2016)


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STUDY NUMBER: 
8-55-52030-309 
PROTOCOL TITLE: 
Phase IIa, Open Label, Dose Ascending Study to 
Determine the Maximum Tolerated Dose, Safety and 
Tolerability, Pharmacokinetics and Pharmacodynamics 
of a Single Dose of Lanreotide PRF in Subjects with 
Acromegaly Previously Treated and Controlled with 
Either Octreotide LAR or Lanreotide Autogel 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 5.0 Version 6.0: 22 March 2016 
The following amendment(s) is/are proposed: 
Version Date 
27 July 2015 
22 March 2016 
Page 
Section 
WAS 
IS 
1 
Title page 
Sponsor’s Medically Responsible 
Person: 
 
Ipsen Biosciences, Inc. 
650 East Kendal Street 
Cambridge, MA 02142 (USA) 
 
 
Sponsor’s Medically Responsible 
Person: 
David Rich, MPhil 
Ipsen Biopharm Limited 
190 Bath Road 
Slough, SL1 3XE (UK) 
 
 
 
Ipsen Biosciences, Inc. 
650 East Kendal Street 
Cambridge, MA 02142 (USA) 
 
 
5 
Synopsis 
Number of planned centres: up 
to 30 
Number of planned centres: up 
to 40 30 
5 
Synopsis 
Planned study period: 02/2015 to 
01/2017 
Planned study period: 02/2015 to 
01/2017 06/2018 
5 
Synopsis, 
Methodology 
Subjects with acromegaly who have 
been well controlled for at least 3 
months on a stable dose of 
octreotide 
long 
acting 
release 
(LAR) or lanreotide Autogel will be 
recruited to this open label study. 
Eligible subjects will enter a 4 week 
run in period, during which they 
will receive the same single dose of 
either octreotide LAR or lanreotide 
Autogel as their previous treatment 
(Day −28). A 12 week treatment 
period will then commence, during 
which subjects will receive one 
deep subcutaneous injection of 
lanreotide PRF on Day 1 (4 weeks 
after the last octreotide LAR or 
lanreotide Autogel administration). 
Subjects with acromegaly who have 
been well controlled for at least 3 
months on a stable dose of 
octreotide 
long 
acting 
release 
(LAR) or lanreotide Autogel will be 
recruited to this open label study. 
Eligible subjects will enter a 4 week 
run in period (or up to 6 weeks 
under certain circumstances), 
during which they will receive the 
same 
single 
dose 
of 
either 
octreotide 
LAR 
or 
lanreotide 
Autogel as their previous treatment 
(Day −28). A 12 week treatment 
period will then commence, during 
which subjects will receive one 
deep subcutaneous injection of 
lanreotide PRF on Day 1 (4 weeks 
or up to 6 weeks under certain 
circumstances 
after 
the 
last 
octreotide 
LAR 
or 
lanreotide 
Autogel administration). 
PPD
PPD
PPD
PPD
PPD


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5 
Synopsis, 
Methodology 
Progression to each ascending dose 
cohort will be dependent upon a 
review of data from the preceding 
cohort during meetings of the data 
review committee (DRC). The 
DRC will review the safety data 
from each cohort after all subjects 
in 
the 
cohort 
completed 
Visit 5 (Week 2 postdose). At this 
time, if no unexpected safety 
signals have been observed and the 
overall safety is in line with the 
known lanreotide safety profile, the 
DRC will decide whether to 
proceed with the next treatment 
cohort. The dose escalation will 
proceed with a 3+3+3 scheme in 
order to enrol nine subjects within 
each dose cohort. 
Progression to each ascending dose 
cohort (or groups of subjects) will 
be dependent upon a review of data 
from the preceding cohort (or 
groups of subjects) during 
meetings of the data review 
committee (DRC). The DRC will 
review the safety data from each 
cohort after all subjects in the 
cohort completed Visit 5 (Week 2 
postdose). At this time, if no 
unexpected safety signals have 
been observed and the overall 
safety is in line with the known 
lanreotide safety profile, the DRC 
will decide whether to proceed 
with the next treatment cohort (or 
groups of subjects). The dose 
escalation will proceed with a 
3+3+3 scheme in order to enrol 
nine subjects within each dose 
cohort. In Cohort 2 subjects will 
be reviewed on a 1+2+2+2+2 
scheme and in Cohort 3 on a 
2+2+2+2+1 scheme. 
6 
Synopsis, 
Methodology 
The occurrence of 2 DLTs would 
trigger the organisation of an 
intermediate DRC meeting (ad hoc 
meeting) to evaluate the decision 
to test 3 more subjects at the same 
dose level. 
The occurrence of 2 DLTs would 
trigger the organisation of an 
intermediate DRC meeting (ad hoc 
meeting) to evaluate the decision 
to test 3 more subjects (2 more 
subjects for Cohort 2 and Cohort 
3) at the same dose level. 
6 
Synopsis, 
Methodology 
The overall duration of the study 
will be approximately 13 to 14 
months. Each subject will 
participate in the study for 
approximately 7 months. 
The overall duration of the study 
will be approximately 13 to 14 
32 months. Each subject will 
participate in the study for up to 
7.5 approximately 7 months. 


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6 
Synopsis, 
Inclusion 
criteria 
(5) Male subjects must agree that, 
if their partner is at risk of 
becoming pregnant, they will use a 
medically accepted, effective 
method of contraception (i.e. 
condom) for the duration of the 
study (maximum of 7 months). 
 
(6) Treatment with a stable dose of 
either octreotide LAR or lanreotide 
Autogel for at least 3 months 
immediately prior to study entry, 
with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x ULN, based on local 
laboratory results, during the 
Screening period. Samples for 
analysis by central laboratory will 
also be collected during 
Screening). 
(5) Male subjects must agree that, 
if their partner is at risk of 
becoming pregnant, they will use a 
medically accepted, effective 
method of contraception (i.e. 
condom) for the duration of the 
study (maximum of 7 up to 
7.5 months).  
(6) Treatment with a stable dose of 
either octreotide LAR or lanreotide 
Autogel for at least 3 months 
immediately prior to study entry, 
with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x ULN, based on local 
laboratory results, during the 
Screening period. Samples for 
analysis by central laboratory will 
also be collected during 
Screening). 
8 
Synopsis, 
Duration of 
treatment 
Overall study duration: 
Approximately 13 to 14 months for 
three dose levels.  
Subject study participation: 
Approximately 7 months (4 week 
run in period, 12 week treatment 
period and 12 week follow up 
period without treatment). 
Overall study duration: 
Approximately 13 to 1432 months 
for three dose levels.  
Subject study participation: Up to 
7.5 Approximately 7 months 
(4 week run in period or up to 6 
weeks under certain 
circumstances, a 12 week 
treatment period and a 12 week 
follow up period without 
treatment). 
8 
Synopsis, 
Safety 
variables 
• Clinical laboratory assessments: 
haematology, coagulation, clinical 
biochemistry, urinalysis at 
Screening, Baseline (predose on 
Day 1), 6 hours postdose on Day 1, 
Day 3, and Weeks 2, 3, 4, 5, 9 and 
13 of the treatment period. 
• Clinical laboratory assessments: 
haematology, coagulation, clinical 
biochemistry, urinalysis at 
Screening, Baseline (predose on 
Day 1), 6 hours postdose on Day 1, 
24 hours postdose on Day 2, 
Day 3, and Weeks 2, 3, 4, 5, 9 and 
13 of the treatment period. 
9 
Synopsis, 
Statistical 
methods 
Inclusion of nine subjects within a 
dose cohort (180, 270 or 360 mg) 
will be based on an adaptive 3+3+3 
decision rule focussing a priori on 
the subject safety. 
Inclusion of nine subjects within a 
dose cohort (180, 270 or 360 mg) 
will be based on an adaptive 3+3+3 
decision rule (in Cohort 2 on a 
1+2+2+2+2 and in Cohort 3 on a 
2+2+2+2+1 decision rule) 
focussing a priori on the subject 
safety. 


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21 
1.3 
Consequently, the local effects that 
were recorded in the toxicology 
studies were considered without 
clinical relevance. 
Consequently, the local effects that 
were recorded in the toxicology 
studies were considered without 
clinical relevance. 
Lanreotide PRF has been tested 
in a parallel phase I study where 
the participants were healthy 
volunteers with cholecystectomy 
(study DFR-52030-345 and 
EUDRACT number: 2015-
004338-85). Four healthy 
volunteers received a single 
injection of lanreotide PRF 180 
mg in February 2016. Two of the 
volunteers had no side effects but 
two experienced abdominal pain 
on the day of the injection and 
their blood biochemistry 
revealed elevated hepatic and 
pancreatic enzymes. These levels 
returned to within normal 
ranges by Day 5. These 
elevations met the protocol-
defined criteria for DLT. As a 
result, no further healthy 
volunteers were entered into that 
study. A full safety analysis for 
the subjects in this study (309) 
was performed and no similar 
trends were seen in Cohort 1 or 
the first subject dosed in Cohort 
2. The study DRC on 29th 
February 2016 recommended to 
continue study 309 as planned 
with some precautionary 
changes that were included in 
amendment 5. 
22 
1.4.2 
Eligible subjects are expected to 
participate for a duration of up to 
7 months. 
Eligible subjects are expected to 
participate for a duration of up to 
7.5 months. 
27 
3.1 
The study consists of a 4 week run 
in period, followed by a 12 week 
treatment period, and then a 12 
week follow up period. 
 
The study consists of a 4 week (or 
up to 6 weeks under certain 
circumstances) run in period, 
followed by a 12 week treatment 
period, and then a 12 week follow 
up period. 
27 
3.1 
Subjects in each cohort will 
receive one deep subcutaneous 
injection of lanreotide PRF on 
Day 1 (4 weeks after the last 
octreotide LAR or lanreotide 
Autogel administration). 
Subjects in each cohort will 
receive one deep subcutaneous 
injection of lanreotide PRF on 
Day 1 (4 weeks (or up to 6 weeks 
if extended) after the last 
octreotide LAR or lanreotide 
Autogel administration). 


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27 
3.1 
Progression to each ascending dose 
cohort will be dependent upon a 
review of data from the preceding 
cohort by a data review committee 
(DRC; see Section 10.6). The DRC 
will review the safety data for each 
dose cohort after all subjects in the 
cohort have completed Visit 5 
(Week 2 postdose). If no 
unexpected safety signals have 
been observed and the overall 
safety is in line with the known 
lanreotide safety profile, the DRC 
will decide whether to proceed 
with the next dose cohort. The 
occurrence of 2 dose limiting 
toxicities (DLTs) would trigger the 
organisation of an intermediate 
DRC meeting (ad hoc meeting) to 
evaluate the decision to test 3 more 
subjects at the same dose level (see 
Section 6.1.1). 
Progression to each ascending dose 
cohort (or groups of subjects) will 
be dependent upon a review of data 
from the preceding cohort (or 
groups of subjects) by a data 
review committee (DRC; see 
Section 10.6). The DRC will 
review the safety data for each 
dose cohort after all subjects in the 
cohort have completed Visit 5 
(Week 2 postdose). If no 
unexpected safety signals have 
been observed and the overall 
safety is in line with the known 
lanreotide safety profile, the DRC 
will decide whether to proceed 
with the next dose cohort (or 
groups of subjects). The 
occurrence of 2 dose limiting 
toxicities (DLTs) would trigger the 
organisation of an intermediate 
DRC meeting (ad hoc meeting) to 
evaluate the decision to test 3 more 
subjects (2 more subjects for 
Cohort 2 and Cohort 3)  at the 
same dose level (see Section 
6.1.1). 


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27 
3.1 
Screening of subjects will take 
place 28 days before 
administration of study treatment 
(Day −28). Eligible subjects will 
receive the same single dose of 
octreotide LAR or lanreotide 
Autogel as their previous treatment 
and will enter a 4 week run in 
period. 
 
Screening of subjects will take 
place 28 to 42 days before 
administration of study treatment 
(Day −42 to Day −28). Eligible 
subjects will receive the same 
single dose of octreotide LAR or 
lanreotide Autogel as their 
previous treatment and will enter a 
4 week run in period. The 4 week 
run in period (28 days) can be 
extended to up to 6 weeks (42 
days) under the following 
circumstances and only in 
specific cases: 
(1) When there is a delay in 
receiving blood results or having 
to re-collect a blood sample e.g. 
due to a clotted sample being 
received by the central 
laboratory.  
(2) The data review of the group 
of 2 prior subjects is ongoing and 
not completed by the end of a 4 
week run in. In this 
circumstance, the run in period 
can be extended by a further 2 
weeks. This would make the run 
in a maximum of 6 weeks in 
total. 
(3) At the investigator’s 
discretion after discussion with 
the sponsor. 
Any extension to the run in 
period will be done in close 
consultation with the 
investigator to ensure that there 
is no safety risk to the subject. 
29 
3.1 
Figure 1 (see below) 
Figure 1 was adapted for 
clarification. 
30 
3.2.1 
• Clinical laboratory assessments: 
haematology, coagulation, clinical 
biochemistry, urinalysis at 
Screening, Baseline (predose on 
Day 1), 6 hours postdose on Days 
1, 3, at Weeks 2, 3, 4, 5, 9 and 13 
of the treatment period, and at each 
follow up visit. 
• Clinical laboratory assessments: 
haematology, coagulation, clinical 
biochemistry, urinalysis at 
Screening, Baseline (predose on 
Day 1), 6 hours postdose on Days 
1, 24 hours postdose (Day 2), and 
48 hours postdose (Day 3), at 
Weeks 2, 3, 4, 5, 9 and 13 of the 
treatment period, and at each 
follow up visit. 


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31 
3.2.2 
• Excipient serum concentration at 
the following timepoints after 
administration of lanreotide PRF: 
- Baseline (predose on Day 1 of 
lanreotide PRF administration) 
- At 1, 2, 4, 6, 8 and 12 hours 
postdose on the day of dosing 
(Day 1), at 24 hours postdose 
(Day 2), and on Days 3 and 5 after 
lanreotide PRF administration  
Note: If the elimination half-life of 
glycofurol in all cohort 1 subjects 
is short (e.g. <5 hours), then there 
is no need for the subjects in 
cohorts 2 and 3 to perform Visit 4 
at Day 5 since only PK data are 
collected. In addition at Visit 3 
(Day 3) excipient PK may be 
removed. 
• Excipient serum concentration at 
the following timepoints after 
administration of lanreotide PRF: 
- Baseline (predose on Day 1 of 
lanreotide PRF administration) 
- At 1, 2, 4, 6, 8 and 12 hours 
postdose on the day of dosing 
(Day 1), at 24 hours postdose 
(Day 2), and on Days 3 and 5 after 
lanreotide PRF administration  
Note: If the elimination half-life of 
glycofurol in all cohort 1 subjects 
is short (e.g. <5 hours), then there 
is no need for the subjects in 
cohorts 2 and 3 to perform Visit 4 
at Day 5 since only PK data are 
collected. In addition at Visit 3 
(Day 3) excipient PK may be 
removed. 
32 
3.5 
This study will consist of a 
Screening visit, followed by a 4 
week run in period, a 12 week 
open label treatment period and a 
12 week follow up period. Subjects 
are expected to participate in this 
study for approximately 7 months. 
The overall duration of the study 
will be approximately 13 to 14 
months. 
This study will consist of a 
Screening visit, followed by a 4 
week run in period (or up to 6 
weeks under certain 
circumstances), a 12 week open 
label treatment period and a 12 
week follow up period. Subjects 
are expected to participate in this 
study for approximately up to 
7.5 months. 
The overall duration of the study 
will be approximately 13 to 14 
32 months. 
36 
 
4.1 
(5) Male subjects must agree that, 
if their partner is at risk of 
becoming pregnant, they will use a 
medically accepted, effective 
method of contraception (i.e. 
condom) for the duration of the 
study (maximum of 7 months). 
 
(6) Treatment with a stable dose of 
either octreotide LAR or lanreotide 
Autogel for at least 3 months 
immediately prior to study entry, 
with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x ULN, based on local 
laboratory results, during the 
Screening period. Samples for 
analysis by central laboratory will 
also be collected during 
Screening). 
(5) Male subjects must agree that, 
if their partner is at risk of 
becoming pregnant, they will use a 
medically accepted, effective 
method of contraception (i.e. 
condom) for the duration of the 
study (maximum of 7 up to 
7.5 months).  
(6) Treatment with a stable dose of 
either octreotide LAR or lanreotide 
Autogel for at least 3 months 
immediately prior to study entry, 
with confirmation of disease 
control during this treatment period 
(documentation of age adjusted 
IGF-1 <1.3 x ULN, based on local 
laboratory results, during the 
Screening period. Samples for 
analysis by central laboratory will 
also be collected during 
Screening). 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 149 OF 173 
 
 
39 
5.1 
Table 5 (see below) 
Table 5 was updated to include the 
option to extend the run in period; 
to add an additional blood sample 
at 24 hours postdose (before 
hospital discharge); to state that a 
reduced physical examination 
would be performed at home visits 
and weight would not be 
measured; IGF-1 will not be 
measured centrally during the 
screening period. 
42 
5.1 
Table 6 (see below) 
Table 6 was updated to state that a 
reduced physical examination 
would be performed at home visits 
and weight would not be measured. 
43 
5.1 
The total volume of blood drawn 
for all evaluations throughout this 
study is approximately 571 mL for 
each subject. 
The total volume of blood drawn 
for all evaluations throughout this 
study is approximately 579 mL for 
each subject. 
43 
5.1 
Table 7 (see below) 
Table 7 was updated with the 
additional blood volume taken at 
24 hours postdose. 
44 
5.2.1 
The Screening visit (Visit 1) will 
take place 28 days prior to the start 
of treatment with lanreotide PRF. 
The Screening visit (Visit 1) will 
take place 28 to 42 days prior to 
the start of treatment with 
lanreotide PRF (Day −42 to −28). 
45 
5.2.2 
• Central clinical laboratory 
assessments (haematology, clinical 
biochemistry including hepatic, 
pancreatic and renal function tests, 
serum electrolytes and urinalysis) 
• Central clinical laboratory 
assessments (haematology, clinical 
biochemistry including hepatic, 
pancreatic and renal function tests, 
creatine kinase (CK), serum 
electrolytes and urinalysis) 
45 
5.2.3 
• Central clinical laboratory 
assessments (including liver 
function (ALT, AST, bilirubin), 
pancreatic function (lipase, 
amylase), serum creatinine, 
international normalised ratio 
(INR), postprandial glycaemia, and 
postprandial insulinaemia) at 
6 hours postdose 
• Central clinical laboratory 
assessments (including liver 
function (ALT, AST, bilirubin), 
pancreatic function (lipase, 
amylase), serum creatinine, 
international normalised ratio 
(INR), postprandial glycaemia, and 
postprandial insulinaemia, CK) at 
6 hours postdose 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 150 OF 173 
 
 
45 
5.2.3 
The following procedures will be 
performed 24 hours after 
administration of study treatment 
at Visit 2 (Day 2±2 days):  
• Review of AEs 
• New or changed concomitant 
medications/therapies/nondrug 
therapies/ surgeries 
• PK blood samples for lanreotide 
and excipient (24 (±2) hours) 
The following procedures will be 
performed 24 hours after 
administration of study treatment 
at Visit 2 (Day 2±2 days), before 
hospital discharge:  
• Review of AEs 
• New or changed concomitant 
medications/therapies/nondrug 
therapies/ surgeries 
• PK blood samples for lanreotide 
and excipient (24 (±2) hours) 
• Central clinical laboratory 
assessments (including liver 
function (ALT, AST, bilirubin), 
pancreatic function (lipase, 
amylase), serum creatinine, CK 
and GGT) 
46 
5.2.3 
The following procedures will be 
performed at Visit 3 (Day 3±1 
day):  
• Review of AEs 
• New or changed concomitant 
medications/therapies/nondrug 
therapies/ surgeries 
• Central clinical laboratory 
assessments (haematology, clinical 
biochemistry including hepatic, 
pancreatic and renal function tests, 
serum electrolytes and urinalysis) 
• PK blood samples for lanreotide 
and excipient (if the elimination 
half-life of glycofurol in all cohort 
1 subjects is short (e.g. <5 hours), 
then excipient PK may be removed 
for Visit 3).  
The following procedures will be 
performed at Visit 4 (Day 5±1 
day):  
• Review of AEs 
• New or changed concomitant 
medications/therapies/nondrug 
therapies/ surgeries 
• PK blood samples for lanreotide 
and excipient (if the elimination 
half-life of glycofurol in all cohort 
1 subjects is short (e.g. <5 hours), 
then there is no need for the 
subjects in cohorts 2 and 3 to 
perform Visit 4 at Day 5 since only 
PK data are collected.) 
The following procedures will be 
performed at Visit 3 (Day 3±1 
day):  
• Review of AEs 
• New or changed concomitant 
medications/therapies/nondrug 
therapies/ surgeries 
• Central clinical laboratory 
assessments (haematology, clinical 
biochemistry including hepatic, 
pancreatic and renal function tests, 
serum electrolytes and urinalysis) 
• PK blood samples for lanreotide 
and excipient (if the elimination 
half-life of glycofurol in all cohort 
1 subjects is short (e.g. <5 hours), 
then excipient PK may be removed 
for Visit 3).  
The following procedures will be 
performed at Visit 4 (Day 5±1 
day):  
• Review of AEs 
• New or changed concomitant 
medications/therapies/nondrug 
therapies/ surgeries 
• PK blood samples for lanreotide 
and excipient (if the elimination 
half-life of glycofurol in all cohort 
1 subjects is short (e.g. <5 hours), 
then there is no need for the 
subjects in cohorts 2 and 3 to 
perform Visit 4 at Day 5 since only 
PK data are collected.) 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 151 OF 173 
 
 
50 
6.1.1 
Details of the adaptive 3+3+3 dose 
escalation scheme with the most 
likely outcome are provided in 
Figure 2. 
At anytime the DRC can ask for 
an ad hoc review of the data 
prior to any dosing if it is judged 
necessary. 
Details of the adaptive 3+3+3 or 
2+2+2+2+1 dose escalation 
scheme with the most likely 
outcome are provided in Figure 2 
and Figure 3. 
52 
Figure 3 
N/A 
Addition of Figure 3 to show the 
adaptive 2 per 2 dose escalation 
scheme 
60 
8.2.3 
Blood samples (6 mL) will be 
collected to assess the following 
parameters: 
• urea, creatinine, total bilirubin, 
conjugated bilirubin 
Blood samples (6 mL) will be 
collected to assess the following 
parameters: 
• urea, creatinine, CK, total 
bilirubin, conjugated bilirubin 
61 
8.4 
Physical examinations, including 
body weight, will be conducted 
according to the study schedule in 
Table 5 and Table 6. Height will be 
measured at Screening. 
Physical examinations, including 
body weight, will be conducted 
according to the study schedule in 
Table 5 and Table 6. Height will be 
measured at Screening. A reduced 
physical examination will be 
performed at home visits and 
weight will not be measured. 
63 
9.2.2 
Measurement of IGF-1 
concentrations at the screening 
visit will be performed locally and 
centrally. 
Measurement of IGF-1 
concentrations at the screening 
visit will be performed locally and 
centrally. 
67 
10.6 
The DRC will review safety data 
from each cohort after all subjects 
in the cohort have completed Visit 
5 (Week 2 postdose). At this time, 
if no DLT or unexpected safety 
signals have been observed and the 
overall safety is in line with the 
known lanreotide safety profile, 
the DRC will decide whether to 
proceed with the next dose cohort.  
The DRC will also review the PK 
data from the excipient when 
available and if the elimination 
half-life of glycofurol in all cohort 
1 subjects is short (e.g. <5 hours), 
then there is no need for the 
subject to perform Visit 4 at Day 5 
since only PK data are collected. In 
addition at Visit 3 (Day 3) 
excipient PK will be removed. 
The DRC will review safety data 
from each cohort after all subjects 
in the cohort have completed Visit 
5 (Week 2 postdose). At this time, 
if no DLT or unexpected safety 
signals have been observed and the 
overall safety is in line with the 
known lanreotide safety profile, 
the DRC will decide whether to 
proceed with the next dose cohort.  
The DRC will also review the PK 
data from the excipient when 
available and if the elimination 
half-life of glycofurol in all cohort 
1 subjects is short (e.g. <5 hours), 
then there is no need for the 
subject to perform Visit 4 at Day 5 
since only PK data are collected. In 
addition at Visit 3 (Day 3) 
excipient PK will be removed. 


IPSEN GROUP 
 
8-55-52030-309 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 152 OF 173 
 
 
WAS: Amendment 4.0 Version 5.0: 27 July 2015 
Figure 1 
Study Design 
  
DRC=Data Review Committee; EOS=end of study; LAR=long acting release; PD=pharmacodynamic; PK=pharmacokinetic; PRF=prolonged release formulation. 
a 
each cohort will undergo a 4 week run in period and two subsequent 12 week periods for treatment and follow up unless the subject withdraws from the study 
prematurely. 
b 
each successive dose increase will proceed only on the recommendation of the DRC after review of the safety data for the preceding dose cohort after all subjects in 
the cohort have reached Visit 5 (Week 2 postdose).  


IPSEN GROUP 
 
8-55-52030-309 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 153 OF 173 
 
 
IS: Amendment 5.0 Version 6.0: 22 March 2016 
Figure 1 
Study Design 
 
DRC=Data Review Committee; EOS=end of study; LAR=long acting release; PD=pharmacodynamic; PK=pharmacokinetic; PRF=prolonged release formulation. 
a 
each cohort will undergo a 4 week run in period (or, if extended, the run in can be up to a maximum of 6 weeks) and two subsequent 12 week periods for treatment 
and follow up unless the subject withdraws from the study prematurely. 
b 
each successive dose increase will proceed only on the recommendation of the DRC after review of the safety data for the preceding dose cohort after all subjects in 
the cohort have reached Visit 5 (Week 2 postdose). The DRC will meet after every 2 subjects starting from Cohort 2 onwards instead of the 3 subject blocks.


IPSEN GROUP 
 
8-55-52030-309 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 154 OF 173 
 
 
WAS: Amendment 4.0 Version 5.0: 27 July 2015 
Table 5 Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) 
Visit 
1 [a] 
2 
3 
[e] 
4 
[e] 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acromegaly symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
x----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreotide or lanreotide 
Autogel administration [d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanreotide PRF 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
x--------------------------------------------------------------------------------------------x 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
Lanreotide PRF 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Excipient 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
[e] 
X 
[e] 
X  
[e] 
 
 
 
 
 
 
 
 
PD assessments 
IGF-1 [f] 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
GH cycle [g] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Random GH sample 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FT3, FT4, TSH, PRL 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety assessments 
AEs 
x---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 


IPSEN GROUP 
 
8-55-52030-309 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 155 OF 173 
 
 
Table 5 
Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) (Cont.) 
Visit 
1 [a] 
2 
3 
[e] 
4 
[e] 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Evaluation of injection site 
reactions 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments [h] 
X 
X 
 
 
 
 
X [i] 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR [j] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Gallbladder echography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Putative antibodies to 
lanreotide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biobanking 
Blood sampling [k] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FT3=free triiodothyronine; 
FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; INR=international normalised ratio; LAR=long acting release; 
MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid stimulating hormone.  
a 
Screening visit. 
b 
Study visits on Weeks 4, 7 and 11 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. More information on how those home 
visits are performed are described in the study manual.  
c 
Baseline. 
d 
after Screening, subjects will enter a 4 week run in period and will receive a single dose of either octreotide LAR or lanreotide Autogel at the same dose as they received previously. 
e 
if the elimination half-life of glycofurol in all cohort 1 subjects is short (e.g. <5 hours), then there is no need for the subject to perform Visit 4 at Day 5 since only PK data are collected. 
In addition at Visit 3 (Day 3) excipient PK may be removed. 
f 
IGF-1 testing will be conducted by a central laboratory using a validated method. During the Screening period, IGF-1 will be analysed locally and centrally. 
g 
five sampling times in the morning, with a sample every 30 minutes for 2 hours.  
h 
blood and urine samples taken for clinical laboratory tests. 
i 
evaluation of the following parameters during the first day after lanreotide administration: ALT, AST, bilirubin, lipase, amylase, INR, serum creatinine, postprandial glycaemia, and 
postprandial insulinaemia. 
j 
measured by MDRD formula [1]. 
k 
Biobanking: samples will only be collected for those individuals who have signed a specific consent for the biobanking samples. 
 
 


IPSEN GROUP 
 
8-55-52030-309 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 156 OF 173 
 
 
IS: Amendment 5.0 Version 6.0: 22 March 2016 
Table 5 Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) 
Visit 
1 [a] 
2 
3 
[e] 
4 
[e] 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
(up to −42) 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acromegaly symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
x----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreotide or lanreotide 
Autogel administration [d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanreotide PRF 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalisation 
 
x--------------------------------------------------------------------------------------------x 
 
 
 
 
 
 
 
 
 
 
PK blood samples 
Lanreotide PRF 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Excipient 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
[e] 
X 
[e] 
X  
[e] 
 
 
 
 
 
 
 
 
PD assessments 
IGF-1 [fe] 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
GH cycle [gf] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Random GH sample 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
FT3, FT4, TSH, PRL 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Safety assessments 
AEs 
x---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------x 


IPSEN GROUP 
 
8-55-52030-309 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 157 OF 173 
 
 
Table 5 
Study Procedures and Assessments (Screening to Week 13, Including Treatment Period) (Cont.) 
Visit 
1 [a] 
2 
3 
[e] 
4 
[e] 
5 
6 
7 
[b] 
8 
9 
[b] 
10 
11 
[b] 
12 
Week 
 
1 
2 
3 
4 
5 
7 
9 
11 
13 
Day 
−28 
1 
2 
3 
5 
8 
15 
22 
29 
43 
57 
71 
85 
Hour 
 
Predose [c] 
0 
1 
2 
4 
6 
8 
12 
24 
 
 
 
 
 
 
 
 
 
 
Evaluation of injection site 
reactions 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
assessments [hg] 
X 
X 
 
 
 
 
X [ih] 
 
 
X [i] 
X 
 
X 
X 
X 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR [j] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Gallbladder echography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Putative antibodies to 
lanreotide 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biobanking 
Blood sampling [k] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FT3=free triiodothyronine; 
FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; INR=international normalised ratio; LAR=long acting release; 
MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid stimulating hormone.  
a 
Screening visit. Screening of subjects will take place 28 to 42 days before administration of study treatment (Day −42 to Day −28). The 4 week run in period (28 days) can be 
extended to up to 6 weeks (42 days) under certain circumstances. 
b 
Study visits on Weeks 4, 7 and 11 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. A reduced physical examination will be 
performed at home visits and weight will not be measured. More information on how those home visits are performed are described in the study manual.  
c 
Baseline. 
d 
after Screening, subjects will enter a 4 week run in period (or up to 6 weeks under certain circumstances) and will receive a single dose of either octreotide LAR or lanreotide 
Autogel at the same dose as they received previously. 
e 
if the elimination half-life of glycofurol in all cohort 1 subjects is short (e.g. <5 hours), then there is no need for the subject to perform Visit 4 at Day 5 since only PK data are collected. 
In addition at Visit 3 (Day 3) excipient PK may be removed. 
fe 
IGF-1 testing will be conducted by a central laboratory using a validated method. During the Screening period, IGF-1 will be analysed locally and centrally. 
gf 
five sampling times in the morning, with a sample every 30 minutes for 2 hours.  
hg 
blood and urine samples taken for clinical laboratory tests. 
ih 
evaluation of the following parameters during the first day after lanreotide administration: ALT, AST, bilirubin, lipase, amylase, INR, serum creatinine, postprandial glycaemia, and 
postprandial insulinaemia. 
i 
at 24 hours postdose before hospital discharge (Day 2) only blood chemistry will be analysed. A urine sample will not be collected. 
j 
measured by MDRD formula [1]. 
k 
Biobanking: samples will only be collected for those individuals who have signed a specific consent for the biobanking samples. 
 
 


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8-55-52030-309 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 158 OF 173 
 
 
WAS: Amendment 4.0 Version 5.0: 27 July 2015 
Table 6 Study Procedures and Assessments (Follow Up; Weeks 15 to 25) 
Visit 
13 
[a] 
14 
15 
[a] 
16 
17 
[a] 
18 (EOS or 
EW)[b] 
Week [c] 
15 
17 
19 
21 
23 
25/EW 
Acromegaly symptoms 
 
 
 
 
 
X 
Concomitant medications 
x--------------------------------------------------------------------------------------------------------------------------------------x 
PK blood samples 
Lanreotide PRF 
 
X 
 
X 
 
X 
PD assessments 
IGF-1 [d] 
 
X 
 
X 
 
X 
Random GH sample 
 
X 
 
X 
 
X 
FT3, FT4, TSH , PRL 
 
 
 
 
 
X 
Safety assessments 
AEs  
x--------------------------------------------------------------------------------------------------------------------------------------x 
Physical examination 
X 
X 
X 
X 
X 
X 
Clinical laboratory assessments 
X 
X 
X 
X 
X 
X 
HbA1c 
 
 
 
 
 
X 
eGFR [e] 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Gallbladder echography 
 
 
 
 
 
X 
Evaluation of injection site reactions 
X 
X 
X 
X 
X 
X 
Putative antibodies to lanreotide  
 
 
 
 
 
X 
AE=adverse event; eGFR=estimated glomerular filtration rate; EOS=end of study; EW=early withdrawal; FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; 
HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid 
stimulating hormone.  
a 
Study visits on Weeks 15, 19 and 23 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. More information on how those home 
visits are performed are described in the study manual. 
b 
EOS for subjects completing the follow up period or EW visit for subjects who withdraw from the study during the follow up period. 
c 
follow up visits will be conducted every 2 weeks (±3 days). 
d 
during follow up visits, IGF-1 testing will be conducted by a central laboratory using a validated method.  
e 
measured by MDRD formula [1]. 


IPSEN GROUP 
 
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CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 159 OF 173 
 
 
IS: Amendment 5.0 Version 6.0: 22 March 2016 
Table 6 Study Procedures and Assessments (Follow Up; Weeks 15 to 25) 
Visit 
13 
[a] 
14 
15 
[a] 
16 
17 
[a] 
18 (EOS or 
EW)[b] 
Week [c] 
15 
17 
19 
21 
23 
25/EW 
Acromegaly symptoms 
 
 
 
 
 
X 
Concomitant medications 
x--------------------------------------------------------------------------------------------------------------------------------------x 
PK blood samples 
Lanreotide PRF 
 
X 
 
X 
 
X 
PD assessments 
IGF-1 [d] 
 
X 
 
X 
 
X 
Random GH sample 
 
X 
 
X 
 
X 
FT3, FT4, TSH , PRL 
 
 
 
 
 
X 
Safety assessments 
AEs  
x--------------------------------------------------------------------------------------------------------------------------------------x 
Physical examination 
X 
X 
X 
X 
X 
X 
Clinical laboratory assessments 
X 
X 
X 
X 
X 
X 
HbA1c 
 
 
 
 
 
X 
eGFR [e] 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Gallbladder echography 
 
 
 
 
 
X 
Evaluation of injection site reactions 
X 
X 
X 
X 
X 
X 
Putative antibodies to lanreotide  
 
 
 
 
 
X 
AE=adverse event; eGFR=estimated glomerular filtration rate; EOS=end of study; EW=early withdrawal; FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; 
HbA1c=glycosylated haemoglobin; IGF-1=insulin like growth factor-1; MDRD=modification of diet in renal disease; PRF=prolonged release formulation; PRL=prolactin; TSH=thyroid 
stimulating hormone.  
a 
Study visits on Weeks 15, 19 and 23 can be performed at the study site and/or at the subject’s home as per investigator’s and subject’s decision. A reduced physical examination will 
be performed at home visits and weight will not be measured. More information on how those home visits are performed are described in the study manual. 
b 
EOS for subjects completing the follow up period or EW visit for subjects who withdraw from the study during the follow up period. 
c 
follow up visits will be conducted every 2 weeks (±3 days). 
d 
during follow up visits, IGF-1 testing will be conducted by a central laboratory using a validated method.  
e 
measured by MDRD formula [1]. 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 160 OF 173 
 
 
WAS: Amendment 4.0 Version 5.0: 27 July 2015 
Table 7 Blood Volume Calculation for Treatment Period 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments [a] 
10 
20.5 mL for 9 visits 
and 14.5 mL for 1 
visit (Vist 2 
postdose) 
199 
PD 
7 IGF-1 
20 GH Cycle 
2 random GH 
2 
2 
2 
58 
PK 
15 for lanreotide;  
10 for excipient 
4 
4 
100 
HbA1c 
2 
2 
4 
FT3, FT4, TSH and PRL 
5 
3.5 
17.5 
Antibody testing 
2 
4 
8 
Biobanking [b] 
3 
10 
30 
Total 
75 
Up to 132.5 mL per 
visit (Visit 2) 
416.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; 
insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid stimulating 
hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial blood 
glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum creatinine and 
electrolytes, and urinalysis. 
b 
the 10 mL sample blood volume collected will consist of 5 mL dry tube and 2 x 2.5 mL for RNA biobanking 
 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 161 OF 173 
 
 
IS: Amendment 5.0 Version 6.0: 22 March 2016 
Table 7 Blood Volume Calculation for Treatment Period 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Clinical laboratory assessments [a] 
10 
20.5 mL for 
109 visits and 
14.5 mL for 1 visit 
(Vist 2 postdose) 
199205 
PD 
7 IGF-1 
20 GH Cycle 
2 random GH 
2 
2 
2 
58 
PK 
15 for lanreotide;  
10 for excipient 
4 
4 
100 
HbA1c 
2 
2 
4 
FT3, FT4, TSH and PRL 
5 
3.5 
17.5 
Antibody testing 
2 
4 
8 
Biobanking [b] 
3 
10 
30 
Total 
75 
Up to 132.5 mL per 
visit (Visit 2) 
416.5422.5 
FT3=free triiodothyronine; FT4=free thyroxine; GH=growth hormone; HbA1c=glycosylated haemoglobin; IGF-1; 
insulin like growth factor-1; PD=pharmacodynamic; PK=pharmacokinetic; PRL=prolactin; TSH=thyroid stimulating 
hormone. 
a 
clinical laboratory assessments include: haematology, coagulation, clinical biochemistry, postprandial blood 
glucose, postprandial insulin, glucagon, liver function parameters, pancreatic enzymes, serum creatinine and 
electrolytes, and urinalysis. Creatine kinase will only be measured at Baseline (predose) and 6 and 24 hours 
postdose. 
b 
the 10 mL sample blood volume collected will consist of 5 mL dry tube and 2 x 2.5 mL for RNA biobanking 
 
 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 162 OF 173 
 
 
Summary & outcome of changes: 
STUDY NUMBER 
8-55-52030-309 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 5.0 Version 6.0: 22 March 2016 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
To allow the addition of safety information gathered from the phase I 
study D-FR-52030-345 conducted with Lanreotide PRF for 
transparency reasons. 
An additional blood sample at 24 hours postdose and the analysis of 
creatine kinase at Baseline (predose), 6 and 24 hours postdose have 
been implemented as precautions. 
To increase the frequency of DRC meetings to ensure closer subject 
safety monitoring. Respective figures and paragraphs in the study 
protocol have been updated to show the adaptive 2 per 2 dose 
escalation scheme. 
To update the Sponsor’s medically responsible person and contact 
details. 
To extend the study timelines and increase the number of 
participating sites. 
To allow more flexibility for the run in period by extending the run 
in period up to 6 weeks under specified circumstances. 
To remove the central laboratory analysis of IGF-1 during Screening 
as this is assessed by the local laboratory. 
To clarify that a reduced physical examination would be performed 
at home visits and weight would not be measured. 
Other Action Required? 
CRF Update  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
Local Consent Form Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Database Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Reporting & Analysis Plan 
(RAP) Update 
 
Yes 
 
  
No 
 
 
 
(tick one) 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 163 OF 173 
 
 
Appendix 8 Protocol Amendment 6 
(20 May 2016)


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 164 OF 173 
 
 
STUDY NUMBER: 
8-55-52030-309 
PROTOCOL TITLE: 
Phase IIa, Open Label, Dose Ascending Study to 
Determine the Maximum Tolerated Dose, Safety and 
Tolerability, Pharmacokinetics and Pharmacodynamics 
of a Single Dose of Lanreotide PRF in Subjects with 
Acromegaly Previously Treated and Controlled with 
Either Octreotide LAR or Lanreotide Autogel 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 6.0 Version 7.0: 20 May 2016 
The following amendment(s) is/are proposed: 
Version Date 
22 March 2016 
20 May 2016 
Page 
Section 
WAS 
IS 
33 
3.6.3 
Taking into account the safety 
profile of lanreotide (detailed in 
the IB), a DLT is defined as an AE 
(excluding anorexia and fatigue) or 
an abnormal laboratory value 
occurring within the first week (up 
to Week 2; Visit 5) following 
lanreotide PRF administration and 
during the entire study duration, 
assessed as unrelated to 
acromegaly, intercurrent illness or 
concomitant medications and 
which meets any of the pre-
established criteria listed in Table 
4. 
Taking into account the safety 
profile of lanreotide (detailed in 
the IB), a DLT is defined as an AE 
(excluding anorexia and fatigue) or 
an abnormal laboratory value 
occurring within the first week (up 
to Week 2; Visit 5) following 
lanreotide PRF administration and 
during the entire study duration, 
assessed as unrelated to 
acromegaly, intercurrent illness or 
concomitant medications and 
which meets any of the pre-
established criteria listed in Table 
4. 
In the event of hepatic enzyme 
(aminotransferases and/or 
bilirubin) increases, refer to 
Appendix 2 for an algorithm for 
safety management. 
34 
3.6.3 
Table 4 (see below) 
The criteria for defining a 
pancreatic dose limiting toxicity 
was clarified in Table 4.  
82 
Appendix 2 
N/A 
Addition of liver safety algorithm 
to show the management of 
subjects with elevations in hepatic 
enzymes and/or bilirubin. 
 


IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 165 OF 173 
 
 
WAS: Amendment 5.0 Version 6.0: 22 March 2016 
 
Table 4 Criteria for Defining Dose Limiting Toxicities 
Toxicity 
Any of the following criteria 
Hepatic 
NCI CTCAE grade ≥3 ALT, AST  
Total bilirubin  ≥2.0 to <3.0 x ULN for >7 consecutive days 
NCI CTCAE grade  ≥2 bilirubin and NCI CTCAE grade ≥2 ALT or AST 
Renal 
NCI CTCAE grade ≥3 serum creatinine 
Serum creatinine ≥2.0 to ≤3.0 x ULN for >7 consecutive days 
Pancreatic 
NCI CTCAE grade ≥3 amylase or lipase with symptoms 
NCI CTCAE grade ≥3 amylase or lipase for >7 consecutive days without symptoms 
Endocrine/Metabolic 
NCI CTCAE grade ≥4 hyperglycaemia (confirmed by a repeat FPG within 24 hours) 
that does not resolve to CTCAE grade ≤2 within 14 consecutive days despite optimal 
antidiabetic treatment (14 consecutive days counts from the day of initiation of 
antidiabetic treatment) 
Cardiac 
NCI CTCAE grade ≥3 
Other AEs 
Any event CTCAE ≥3 except for AP grade ≥4 
NCI CTCAE grade ≥3 diarrhoea despite optimal antidiarrheal treatment 
NCI CTCAE grade ≥3 vomiting despite optimal antiemetic therapy 
In the view of the investigators and Ipsen, any other unacceptable toxicity encountered 
AE=adverse event; ALT=alanine aminotransferase; AP=alkaline phosphatase; AST=aspartate aminotransferase; 
CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; ULN=upper limit of normal. 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 166 OF 173 
 
 
IS: Amendment 6.0 Version 7.0: 20 May 2016 
 
Table 4 Criteria for Defining Dose Limiting Toxicities 
Toxicity 
Any of the following criteria 
Hepatic 
NCI CTCAE grade ≥3 ALT, AST  
Total bilirubin  ≥2.0 to <3.0 x ULN for >7 consecutive days 
NCI CTCAE grade  ≥2 bilirubin and NCI CTCAE grade ≥2 ALT or AST 
Renal 
NCI CTCAE grade ≥3 serum creatinine 
Serum creatinine ≥2.0 to ≤3.0 x ULN for >7 consecutive days 
Pancreatic 
NCI CTCAE grade ≥3 amylase or lipase with symptoms abdominal pain 
NCI CTCAE grade ≥3 amylase or lipase for >7 consecutive days without symptoms 
abdominal pain 
If necrotising pancreatitis is suspected, the subject should be hospitalised 
Endocrine/Metabolic 
NCI CTCAE grade ≥4 hyperglycaemia (confirmed by a repeat FPG within 24 hours) 
that does not resolve to CTCAE grade ≤2 within 14 consecutive days despite optimal 
antidiabetic treatment (14 consecutive days counts from the day of initiation of 
antidiabetic treatment) 
Cardiac 
NCI CTCAE grade ≥3 
Other AEs 
Any event CTCAE ≥3 except for ALP grade ≥4 
NCI CTCAE grade ≥3 diarrhoea despite optimal antidiarrheal treatment 
NCI CTCAE grade ≥3 vomiting despite optimal antiemetic therapy 
In the view of the investigators and Ipsen, any other unacceptable toxicity encountered 
AE=adverse event; ALT=alanine aminotransferase; ALP=alkaline phosphatase; AST=aspartate aminotransferase; 
CTCAE=Common Terminology Criteria for Adverse Events; FPG=fasting plasma glucose; NCI=National Cancer 
Institute; ULN=upper limit of normal. 
 
Summary & outcome of changes: 
STUDY NUMBER 
8-55-52030-309 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 6.0 Version 7.0: 20 May 2016 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
To add a liver safety algorithm for the management of subjects with 
elevations in hepatic enzymes and/or bilirubin following a 
recommendation by the Competent Authority in France. 
To clarify the criteria for pancreatic dose limiting toxicities by 
specifying that ‘abdominal pain’ rather than ‘symptoms’ should 
accompany raised pancreatic enzymes (amylase and lipase). 
Clarification was also added that a subject should be hospitalised if 
necrotising pancreatitis is suspected. 
Other Action Required? 
CRF Update  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
Local Consent Form Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Database Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Reporting & Analysis Plan 
(RAP) Update 
 
Yes 
 
  
No 
 
 
 
(tick one) 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 167 OF 173 
 
 
Appendix 9 Protocol Amendment 7 
(16 December 2016)


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 168 OF 173 
 
 
STUDY NUMBER: 
8-55-52030-309 
PROTOCOL TITLE: 
Phase IIa, Open Label, Dose Ascending Study to 
Determine the Maximum Tolerated Dose, Safety and 
Tolerability, Pharmacokinetics and Pharmacodynamics 
of a Single Dose of Lanreotide PRF in Subjects with 
Acromegaly Previously Treated and Controlled with 
Either Octreotide LAR or Lanreotide Autogel 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Amendment 7.0 Version 8.0: 16 December 2016 
The following amendment(s) is/are proposed: 
Version Date 
20 May 2016 
16 December 2016 
Page 
Section 
WAS 
IS 
1 
Title Page 
David Rich, MPhil 
Ipsen Biopharm Limited 
190 Bath Road 
Slough, SL1 3XE (UK) 
 
 
David Rich, MPhil 
Ipsen Biopharm Limited 
102 Park Drive 
Milton Park 
Oxfordshire, OX14 4RY (UK) 
Tel: +44 (0)7736 615866 
190 Bath Road 
Slough, SL1 3XE (UK) 
 
 
1 
Title Page 
, 
Central Department of 
Pharmacovigilance, Ipsen Group,  
190 Bath Road, Slough, Berkshire 
SL1 3XE, England  
 
,  
Global Patient Safety, Central 
Department of Pharmacovigilance, 
Ipsen Biopharm Ltd Group,  
190 Bath Road, Slough, Berkshire 
SL1 3XE, England  
 
102 Park Drive, Milton Park, 
Oxfordshire, OX14 4RY (UK) 
 
5 
Synopsis 
In Cohort 2 subjects will be 
reviewed on a 1+2+2+2+2 scheme 
and in Cohort 3 on a 2+2+2+2+1 
scheme. 
In Cohort 2 subjects will be 
reviewed on a 1+2+2+2+2 scheme 
and in Cohort 3 on a 2+2+2+32+1 
scheme. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 169 OF 173 
 
 
7 and 
37 
Synopsis and 
Section 4.2 
(10) Has a history of gallstones or 
any gallstones/sludge observed at 
Screening gallbladder echography 
(local assessment). 
(10) Has a history of gallstones or 
any gallstones/sludge observed at 
Screening gallbladder echography 
(local assessment). Has 
symptomatic gallstones/sludge at 
the Screening Visit echography 
(local assessment) OR is 
asymptomatic but has 
echography showing clear 
evidence of impending 
inflammation such as localised 
mucosal thickening suggesting 
the subject is at high risk of 
developing acute disease. 
Subjects with asymptomatic 
gallstones/sludge and otherwise 
normal echography may be 
entered at the discretion of the 
investigator. 
9 
Synopsis 
Inclusion of nine subjects within a 
dose cohort (180, 270 or 360 mg) 
will be based on an adaptive 3+3+3 
decision rule (in Cohort 2 on a 
1+2+2+2+2 and in Cohort 3 on a 
2+2+2+2+1 decision rule) 
Inclusion of nine subjects within a 
dose cohort (180, 270 or 360 mg) 
will be based on an adaptive 3+3+3 
decision rule (in Cohort 2 on a 
1+2+2+2+2 and in Cohort 3 on a 
2+2+2+32+1 decision rule) 
29 
Figure 1, 
footnote b 
each successive dose increase will 
proceed only on the 
recommendation of the DRC after 
review of the safety data for the 
preceding dose cohort after all 
subjects in the cohort have reached 
Visit 5 (Week 2 postdose). The 
DRC will meet after every 2 
subjects starting from Cohort 2 
onwards instead of the 3 subject 
blocks. 
each successive dose increase will 
proceed only on the 
recommendation of the DRC after 
review of the safety data for the 
preceding dose cohort after all 
subjects in the cohort have reached 
Visit 5 (Week 2 postdose). The 
DRC will meet after every 2 
subjects starting from Cohort 2 
onwards instead of the 3 subject 
blocks and prior to the final 3 
subjects in Cohort 3. 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 170 OF 173 
 
 
37 
Section 4.3 
The specific AE or test result(s) 
must be recorded on the eCRF. All 
evaluations should be performed, 
according to the protocol. 
The specific AE or test result(s) 
must be recorded on the eCRF. All 
evaluations should be performed, 
according to the protocol. 
Subjects participating in the 
optional biobanking have the 
right to withdraw their consent 
at any time and for any reason 
during the study or during the 
period of sample storage (i.e. the 
entire 15 years during which the 
sample is kept).  If a subject 
wishes to withdraw his consent 
for biobanking and the samples 
are still at the investigator site or 
at the central laboratory at this 
time, the investigator must first 
inform the study monitor in 
writing of the subject’s decision 
and destroy the samples, 
respectively after informing the 
monitor the investigator will 
need to contact the central 
laboratory to destroy the 
samples. If the samples are 
already at Fisher BioServices 
(biobanking vendor), i.e. post-
study, the investigator must 
inform Ipsen directly using the 
following e-mail address; 
, 
mentioning only the ID of the 
subject in this e-mail. Ipsen will 
ensure destruction of the samples 
and all corresponding aliquots, 
issue confirmation of the 
withdrawal, and forward 
corresponding destruction 
certificate to the investigator. 
PPD


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 171 OF 173 
 
 
44 
Section 5.2.1 
Under normal circumstances 
subjects will not be screened more 
than once. There are two 
exceptions; 
(1) IGF-1 may be re-tested once if 
the screening value is just above 
1.3 x ULN (analysis by local 
laboratory). The study treatment 
may only be administered if the re-
test is <1.3 x ULN. 
(2) If the time elapsed between the 
original Screening visit (Visit 1) 
and Visit 2 is >28 days (±2 days) 
then re-screening of the subject for 
inclusion is permitted. 
Under normal circumstances 
subjects will not be screened more 
than once. There are threetwo 
exceptions: 
(1) IGF-1 may be re-tested once if 
the screening value is just above 
1.3 x ULN (analysis by local 
laboratory). The study treatment 
may only be administered if the re-
test is <1.3 x ULN. 
(2) If the time elapsed between the 
original Screening visit (Visit 1) 
and Visit 2 is >28 days (±2 days) 
then re-screening of the subject for 
inclusion is permitted. 
(3) If deemed acceptable by the 
investigator, the subject may be 
re-screened once for inclusion if 
they previously failed screening 
due to the presence of 
asymptomatic gallstones/sludge. 
This follows the change to 
exclusion criterion #10 in 
protocol amendment 7. 
50 
Section 6.1.1 
Details of the adaptive 3+3+3 or 
2+2+2+2+1 dose escalation 
scheme with the most likely 
outcome are provided in Figure 2 
and Figure 3. 
Details of the adaptive 3+3+3 or 
1+2+2+2+2+1 (Cohort 2) or 
2+2+2+3 (Cohort 3) dose 
escalation scheme with the most 
likely outcome are provided in 
Figure 2 and Figure 3. 
56 
Section 8.1.3 
At each visit, the subject should be 
asked a non leading question such 
as: “How have you felt since 
starting the new treatment/last 
dose/the last assessment?” 
During the informed consent 
process and on an ongoing basis 
subjects should be reminded to 
report any AEs as soon as 
possible to their study site and 
not to wait until their next visit if 
they experience any unexpected 
medical symptoms. 
At each visit, the subject should be 
asked a non leading question such 
as: “How have you felt since 
starting the new treatment/last 
dose/the last assessment?” 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 172 OF 173 
 
 
60 
Section 8.7 
Gallbladder echography will be 
conducted according to study site 
procedures. The results will be 
recorded in the eCRF. Any 
clinically significant abnormalities 
will be recorded as AEs. 
Gallbladder echography will be 
conducted according to study site 
procedures. The results will be 
recorded in the eCRF. Any 
clinically significant abnormalities 
will be recorded as AEs. In 
particular, sites should be aware 
of any subject who has gallstones 
or sludge present at baseline. 
In the case that a subject 
develops gallstone(s) during the 
study but they are 
asymptomatic, they can remain 
in the study and complete the 
protocol as planned. If a subject 
develops symptoms of either a 
pre-existing gallstone(s) or a 
newly developed gallstone, they 
may remain in the study at the 
discretion of the investigator. As 
this is a single-dose protocol, the 
subject will not be exposed to 
any additional IMP. 
In case of the development of 
(symptomatic) gallstones/sludge 
this will be treated according to 
the study sites’ routine practice. 
79 
Appendix 1 
The samples will be stored 
at -80°C at the site. The samples 
will then be shipped regularly to 
the biobanking central laboratory, 
FISHER, in dry ice. 
The samples will be shipped to 
the central laboratory and stored 
at -80°C at the site. At the end of 
the study one shipment will be 
made by the central laboratory 
with all samplesThe samples will 
then be shipped regularly to the 
biobanking central laboratory, 
FISHER, in dry ice. 
 


IPSEN GROUP 
8-55-52030-309 
 
CONFIDENTIAL 
PROTOCOL FINAL (WITH AMENDMENT 7): 16 DECEMBER 2016 
PAGE 173 OF 173 
 
 
Summary & outcome of changes: 
STUDY NUMBER 
8-55-52030-309 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Amendment 7.0 Version 8.0: 16 December 2016 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
To allow inclusion of patients with asymptomatic gallstones or 
sludge, and the re-screening of patients who previously failed this 
exclusion criteria. This extension of the study population follows 
requests from investigators participating in the 8-55-52030-309 
study, who asked to include these patients for two main reasons: 
(1) A significant proportion of acromegaly patients in clinical 
practice have gallstones, mostly being asymptomatic even when 
treated with somatostatin analogue for several years, (2) in the 
investigator’s opinion, there is no reason to exclude these patients 
from a clinical study, as long as they are monitored regularly and as 
long as the gallstone(s) is(are) asymptomatic. These patients are 
prescribed somatostatin analogues in real world clinical practice in 
the same way as patients without gallstones. This decision follows a 
thorough review of all available safety data coming from both 
clinical investigations and the market use, which led to the 
conclusion that the benefit risk balance of lanreotide PRF for the 
above referenced patients is unchanged compared to the current 
study population. In addition to the monitoring measures already 
included in the study protocol (4 gallbladder echography and 18 
face-to-face visits over 25 weeks) which provide a sufficient safety 
coverage to prevent the safety issues related to the gallstones, namely 
acute cholecystitis, the patients will be reminded to immediately 
report any AEs to their study team and not to wait until the next visit. 
Other changes include: 
To update the contact details for the Sponsor’s Medically 
Responsible Person and Pharmacovigilance/Emergency contact. 
To change the DRC frequency for Cohort 3 from 2+2+2+2+1 to 
2+2+2+3. 
To better clarify the follow-up and reporting of AEs. 
To include details of withdrawal of consent for biobanking in the 
protocol for clarity and amend the procedure in Appendix 1 for the 
shipment of biobanking samples. 
Other Action Required? 
CRF Update  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
Local Consent Form Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Database Update  
Yes 
 
  
No 
 
 
 
(tick one) 
 
Reporting & Analysis Plan 
(RAP) Update 
 
Yes 
 
  
No 
 
 
 
(tick one) 
 

SAP_001.pdf: 
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1.1.1 
Primary objective ........................................................................................... 9 
1.1.2 
Secondary objectives ..................................................................................... 9 
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1.2.1 
Study population ......................................................................................... 12 
1.2.2 
Study exposure ............................................................................................ 12 
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1.3.1 
Subject identification and allocation to study treatment ........................... 12 
1.3.1.1 
Subject identification ................................................................................... 12 
1.3.1.2 
Treatment of subjects ................................................................................... 12 
1.3.1.3 
Dose Escalation Schema .............................................................................. 13 
1.3.1.4 
Definition of a Dose Limiting Toxicity ......................................................... 16 
1.3.1.5 
Definition of the Maximum Tolerated Dose ................................................. 16 
1.3.2 
Subjects assessments ................................................................................... 16 
1.3.2.1 
Efficacy assessments .................................................................................... 16 
1.3.2.2 
Safety assessments ....................................................................................... 17 
1.3.2.3 
Other assessments ........................................................................................ 19 
1.3.2.4 
Withdrawal/discontinuation ......................................................................... 19 
1.3.2.5 
Stopping Rules ............................................................................................. 20 
1.3.3 
Schedule of assessments ............................................................................. 20 
1.3.4 
Planned sample size .................................................................................... 24 
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2.2.1 
Screened population .................................................................................... 24 
2.2.2 
Safety population ......................................................................................... 24 
2.2.3 
Intention-To-Treat population (ITT) ......................................................... 24 
2.2.4 
Per Protocol population (PP) ..................................................................... 24 
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2.3.1 
PK valid population ..................................................................................... 24 
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3.1.1 
Efficacy endpoint(s) .................................................................................... 25 
3.1.2 
Primary safety endpoint .............................................................................. 25 
3.1.3 
Secondary safety endpoints ......................................................................... 25 


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Multiplicity .................................................................................................. 25 
3.1.5 
Significance testing and estimation ............................................................ 26 
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3.2.1 
Efficacy ........................................................................................................ 26 
3.2.2 
Safety ........................................................................................................... 26 
3.2.2.1 
MTD determination ...................................................................................... 26 
3.2.2.2 
Adverse events .............................................................................................. 26 
3.2.2.3 
Laboratory data ........................................................................................... 27 
3.2.2.4 
Vital signs ..................................................................................................... 28 
3.2.2.5 
Physical Examination .................................................................................. 28 
3.2.2.6 
ECG .............................................................................................................. 28 
3.2.2.7 
Glycosylated haemoglobin (HbA1c) ............................................................ 29 
3.2.2.8 
Estimated glomerular filtration rate (eGFR) ............................................... 29 
3.2.2.9 
Gallbladder echography .............................................................................. 29 
3.2.2.10 
Putative antibodies to lanreotide ................................................................. 29 
3.2.2.11 
Evaluation of injection site reactions .......................................................... 29 
3.2.2.12 
Acromegaly symptoms ................................................................................. 30 
3.2.3 
Missing data and outliers ............................................................................ 30 
3.2.3.1 
Missing data ................................................................................................. 30 
3.2.3.2 
Missing or incomplete dates ........................................................................ 30 
3.2.3.3 
Outliers ........................................................................................................ 30 
3.2.4 
Subject disposition ....................................................................................... 30 
3.2.5 
Withdrawals ................................................................................................. 31 
3.2.6 
Demographic and baseline characteristics ................................................ 31 
3.2.7 
Medical and surgical history ...................................................................... 31 
3.2.8 
Subject compliance ..................................................................................... 31 
3.2.9 
Prior and concomitant therapies ................................................................ 32 
3.2.9.1 
Prior and Concomitant medications ............................................................ 32 
3.2.9.2 
Prior and Concomitant medications for acromegaly .................................. 32 
3.2.9.3 
Prior and concomitant non-drug therapies ................................................. 32 
3.2.9.4 
Concomitant surgical procedures ................................................................ 33 
3.2.10 
Pharmacokinetics and Pharmacodynamics ............................................... 33 
3.2.11 
Derived data ................................................................................................. 34 
3.2.12 
Visit windows ............................................................................................... 34 
3.2.13 
Rules and data formats ............................................................................... 35 
3.2.14 
Pooling of Centres ....................................................................................... 36 
3.2.15 
Interim analysis ........................................................................................... 36 
3.2.16 
Role of the Data Review Committee (DRC) ............................................... 36 
3.2.17 
Covariates and analysis of subgroups ........................................................ 37 
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1.3.1
Subject identification and allocation to study treatment  
1.3.1.1
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Treatment of subjects 
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1.3.1.3
Dose Escalation Schema 
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1.3.1.4
Definition of a Dose Limiting Toxicity 
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3.1.1
Efficacy endpoint(s) 
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3.1.2
Primary safety endpoint 
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3.1.3
Secondary safety endpoints 
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3.1.4
Multiplicity 
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3.1.5
Significance testing and estimation 
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3.2.1
Efficacy 
1RWDSSOLFDEOH
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3.2.2
Safety 
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3.2.2.1
MTD determination 
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3.2.2.2
Adverse events 
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3.2.2.3
Laboratory data 
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3.2.2.4
Vital signs 
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3.2.2.5
Physical Examination 
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3.2.2.6
ECG 
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3.2.2.7
Glycosylated haemoglobin (HbA1c)  
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3.2.2.8
Estimated glomerular filtration rate (eGFR) 
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3.2.2.9
Gallbladder echography 
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3.2.2.10 Putative antibodies to lanreotide 
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3.2.2.11 Evaluation of injection site reactions 
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3.2.2.12 Acromegaly symptoms 
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3.2.3
Missing data and outliers 
3.2.3.1
Missing data 
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3.2.3.2
Missing or incomplete dates 
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3.2.3.3
Outliers 
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3.2.4
Subject disposition 
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3.2.5
Withdrawals 
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3.2.6
Demographic and baseline characteristics 
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3.2.7
Medical and surgical history 
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3.2.8
Subject compliance 
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3.2.9
Prior and concomitant therapies 
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3.2.9.1
Prior and Concomitant medications 
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3.2.9.2
Prior and Concomitant medications for acromegaly 
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3.2.9.3
Prior and concomitant non-drug therapies 
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3.2.9.4
Concomitant surgical procedures 
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3.2.10
Pharmacokinetics and Pharmacodynamics  
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3.2.11
Derived data 
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3.2.12
Visit windows   
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3.2.13
Rules and data formats 
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3.2.14
Pooling of Centres 
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3.2.15
Interim analysis 
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3.2.16
Role of the Data Review Committee (DRC)
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3.2.17
Covariates and analysis of subgroups 
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