Conditions: Acromegaly
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
The purpose of the protocol is evaluate the safety, the pharmacodynamics and the pharmacokinetic of repeated administration of BIM23B065 in subjects with acromegaly.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: BIM23B065
Intervention descriptions: intervention 1: Subcutaneous twice a day or three times a day administration of BIM23B065. Dose will be 0.4, 0.6, 0.8 or 1 mg (twice a day or three times a day).

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 1 of 78 
 
 
Protocol Title: 
A PHASE IIA, OPEN-LABEL, SINGLE-ARM, TWO STAGE, MULTI-CENTRE 
STUDY TO INVESTIGATE THE PHARMACODYNAMICS,  
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF REPEATED SUB-
CUTANEOUS ADMINISTRATION OF BIM23B065 IN SUBJECTS WITH 
ACROMEGALY 
 
Protocol D-FR-10380-002 
 
Protocol Amendment #1, Version 2.0, dated 14-SEPTEMBER-2016 
 
Sponsor:  
Ipsen Pharma SAS 
65, quai Georges Gorse 
92100 Boulogne-Billancourt, France 
 
EUDRACT Number: 2015-003868-37 
 
IND #N/A 
 
Serious adverse event reporting:  
Fax: 
 
Email: 
 
 
Pharmacovigilance contact details:  
 Global Patient Safety, Ipsen Biopharm Ltd 
EU Qualified Person for Pharmacovigilance 
102 Park Drive, Milton Park, Oxfordshire, OX14 4RY, England 
Tel: 
 
Mob: 
 
 
The person listed above is the qualified physician designated by the Sponsor as the first point 
of contact for emergency situations. 
 
Study Conduct Compliance Statement 
This study will be conducted in compliance with the protocol, in accordance with the International 
Conference on Harmonisation Good Clinical Practice (CPMP/ICH 135/35) together with such other good 
clinical practice requirements and the ethical principles that have their origin in the Declaration of 
Helsinki, as well as with all currently applicable laws and regulations of the country where the study will 
be conducted. 
This material is confidential and is the property of Aepodia S.A. and the Sponsor.  Do not disclose or use 
except as authorised. 
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 2 of 78 
 
 
Sponsor Authorised Protocol Approver 
Name, Title:  
 
Address:  
Ipsen Innovation, 5 Avenue du Canada, 91966 Les Ulis, Paris Cedex, France  
 
Sponsor’ Medical Monitor Responsible for the Study 
Name, Title:  
 Ipsen 
Address:  
102 Park Drive, Milton Park, Oxfordshire, OX14 4RY, England 
Mobil:  
 
Email:  
 
 
Coordinating Investigator 
Name, Title: 
, 
 
Address: 
 
Phone:  
 
Fax:   
 
Email:  
 
 
Project Management and Monitoring Office 
Name, Title: 
 
Address: 
Aepodia France SARL, 3 Avenue du Canada, 91940 Les Ulis, France 
Phone:  
 
Fax:   
 
Email:  
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 3 of 78 
 
Agreement on Protocol – Signature Page 
 
Protocol Title: 
A phase IIa, open-label, single-arm, Two stage, multi-centre study to 
investigate the pharmacodynamics,  pharmacokinetics, safety and tolerability of repeated sub-
cutaneous administration of BIM23B065 in Subjects with acromegaly 
Protocol Version Number: 2.0 
Protocol Version Date: 
14-SEPTEMBER-2016 
 
By signing below, I hereby confirm that I have read, discussed and understood the above 
mentioned version of the protocol D-FR-10380-002 and the background information 
concerning the study drug.  I attest that I will carry out the study according to this protocol. 
 
I also agree that the work will be performed according to Good Clinical Practice (GCP) 
guidelines, the ethical principles, and all currently applicable laws and regulations of the 
country(ies) where the study will be conducted. 
 
Investigator 
 
 
Sponsor 
 
Name 
 
 
Name: 
 
Title: 
 
 
Title: 
 
Date: 
 
 
Date: 
 
Signature: 
 
 
Signature 
 
 


 
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Page 4 of 78 
 
SYNOPSIS 
 
Title 
A phase IIa, open-label, single-arm, Two stage, multi-centre study to 
investigate the pharmacodynamics,  pharmacokinetics, safety and 
tolerability of repeated sub-cutaneous administration of BIM23B065 in 
Subjects with acromegaly 
Study Alias 
D-FR-10380-002 
EudraCT Number 
2015-003868-37 
Investigational Product 
BIM23B065 
Type of Study 
Phase IIa open-label single-arm 
Investigational Site 
The study will be performed in multiple investigational sites in multiple countries. 
Study Duration 
The overall study duration is expected to be approximately two years from first subject 
screened to last subject discharged from the study. 
Each subject will be in the study for approximately 7 weeks, including 3 weeks for 
screening activities, 2 weeks treatment and 2 weeks of post-study  follow-up. 
Objectives 
Primary: 
 
To assess the pharmacodynamics of repeated administration of BIM23B065 in 
reducing growth hormone (GH) in subjects with acromegaly 
Secondary: 
 
To assess the safety and tolerability of repeated administration of BIM23B065 
in subjects with acromegaly 
 
To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of repeated 
administration of BIM23B065 
 
To investigate the PK of BIM23B133 which is the major metabolite of 
BIM23B065  
 
To assess the correlation of BIM23B065 exposure with blood pressure and 
heart rate (HR). 
Exploratory: 
 
To correlate GH, Insulin-like Growth Factor-1 (IGF-1) and prolactin (PRL) 
responses with expression of somatostatin receptor 2 (SSTR2), somatostatin 
receptor 5 (SSTR5) and dopamine receptor sub-type 2 (D2) in pituitary 
tumour tissues, when available 
 
To assess anti-drug antibodies (ADA) 
Biobanking: 
 
To explore potential utility of biomarkers for association with drug activity, 
adverse events (AEs), to explore drug mechanism of action and/or disease 
understanding. Serum/plasma, whole blood samples will be collected for 
deoxyribonucleic acid (DNA) and whole blood samples for ribonucleic acid 
(RNA). 
Endpoint 
Primary Endpoints:  
 
The proportion of subjects with GH ≤2.5µg/l or >50% reduction from mean 
baseline GH after 6-day titration plus 8-day treatment with BIM23B065 
measured by mean serum concentration of GH over 6-hours at Day 14. 
Secondary Endpoints: 
 
To assess the safety and tolerability of BIM23B065 
 
To assess the proportion of subjects with GH <1.0μg/l after 6-day titration 
plus 8-day treatment with BIM23B065 measured by mean serum 
concentration of GH over 6-hours at Day 14. 
 
To investigate the PK profile of BIM23B065 


 
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 
To correlate the PK with changes in GH, IGF-1 and PRL 
 
To determine the efficacy of BIM23B065 in reducing IGF-1 to <Upper Limit 
of Normal (ULN) (age normalised) after 6-day titration and 8-day treatment 
period at Day 14 and Day 28. 
 
To investigate the PK profile of BIM23B133 
 
To assess the correlation of exposure of BIM23B065 with blood pressure and 
HR. 
Exploratory: 
 
To correlate GH and IGF-1 responses with expression of SSTR2, SSTR5 and 
D2 in pituitary tumour tissue 
 
To assess anti-drug antibodies 
Biobanking: 
 
To biobank whole blood samples for DNA at baseline pre-dose (Day -1), 
serum/plasma and whole blood samples for RNA at baseline pre-dose (Day -
1), at Day 14 and Day 28 (EoS/ED) 
Study Design 
This is a open-label, non randomised, multi-centres, adaptive two-stage phase II study. 
During stage 1, up to 12 subjects will be enrolled to receive BIM23B065 twice a day 
(BID) for two weeks. The primary endpoint will be the proportion of subjects with GH 
≤2.5 μg/l or >50% reduction from baseline GH on Day 14. The mean serum 
concentration of GH collected over 6 hours will be used for the baseline (Day -1) and 
endpoint (Day 14) GH determination.  
Several sequential analyses will occur during Stage 1. The Stage 1 arm (BID 
administration) may be terminated early for futility during each of these interim 
analyses if the responder rate does not exceed some pre-determined minimum efficacy 
criteria. In that case, a stage 2 arm will be initiated during which up to 12 subjects will 
be recruited to receive BIM23B065 three times a day (TID) for 14 days. The same 
sequential analysis and early termination rule for futility will apply during stage 2 as 
for stage 1. 
If the primary endpoint is met after the stage 1 BID cohort, the TID cohort 2 will not 
be started. 
Any subject who withdraws prior to the Day 14 end of treatment visit may be replaced 
except for early withdrawal due to safety and tolerability reasons. As soon as 12 
subjects (out of which at least 8 are Octreotide responders) reach Visit 8, withdrawn 
subjects will not be replaced..  
Both the BID and TID regimen parts will consist of 3 periods:  
 
A screening period of 21 days maximum during which the eligibility criteria 
will be assessed. An Octreotide test will be also performed at the latest 7 days 
prior to first Investigational Medicinal Product (IMP) administration. 
 
A treatment period that will consist of twice or three times daily 
administrations of BIM23B065. This period will last 14 days. The first 6 days 
will be a titration of BIM23B065 (0.4 mg/0.6 mg/0.8 mg BID or TID). Then a 
stable target dose (1.0 mg) of BIM23B065 will be BID or TID administered 
from Day 7 to Day 14.  
 
If a subject experiences any safety or laboratory events that meet the criteria 
in Table 1, they may have their dose reduced to the prior dose. The 
minimum dose allowed for the treatment period is 0.6mg BID or TID. 
o If the criteria for dose reduction are met when a subject is taking 
1.0mg BID or TID, they may be dose reduced to 0.8mg BID or TID. 
o 
If the criteria for dose reduction are met when a subject is taking 
0.8mg BID or TID, they may be dose reduced to 0.6mg BID or TID. 
o 
A subject may be dose reduced more than once and at anytime 
during the study. For example, from 1.0mg BID or TID to 0.8mg 
BID or TID and if safety/tolerability issues persist, they may be 
further dose reduced to 0.6mg BID or TID. 


 
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 
If the subject experiences any cardiovascular events that meet the criteria in 
Table 2 during the titration period, they must remain on their current dose and 
not be dose escalated. 
 
A follow up period that will last for 14 days during which the subjects will not 
be administered BIM23B065. 
Number of Subjects 
This study will enrol approximately 15 subjects so that 12 subjects will be evaluable 
per stage. A drop-out rate of 20% is expected requiring approximately 15 subjects to be 
treated per stage. 
Treatment: route, strength, 
regimen  
BIM23B065 will be administered twice a day (morning and evening) or three times a 
day (every 8 hours ± 1 hour). The doses administered will be : 0.4mg; 0.6mg, 0.8mg 
and 1.0 mg by subcutaneous (sc) injection.  
Reference/Control Treatment: 
route, strength, regimen 
NA 
Drug administration 
BIM23B065 will be administered by subcutaneous injection in the abdomen. There 
should be a rotation of the injection sites between left and right sides. 
Main Inclusion/Exclusion 
Criteria 
Male and female subjects between 18 and 75 years old with a confirmed diagnosis of 
acromegaly, with or without a history of pituitary surgery, will be included into this 
study. Subjects can be either treatment naïve or have received prior treatment for their 
acromegaly.  
Study Evaluation Criteria: 
Safety 
Efficacy 
Pharmacokinetic 
Pharmacodynamic 
Pharmacodynamic Assessments 
 
Mean serum concentration of GH over 6 hours at baseline, Day 7 and Day 14,  
 
IGF-1 levels at baseline, Day 14 and Day 28, 
 
PRL cycle 6 hours at baseline, Day7 and Day 14 
Pharmacokinetic Assessments: 
 
Time points will follow a sparse PK sampling approach. On Day 7 (first day 
of 1.0mg) pre-dose, 0.5h, 1h, 2h, 4h and 6h post-morning dose. On Day 14 
(last day of 1.0mg) pre-dose, 0.5h, 1h, 2h, 4h and 6h post-morning dose. 
 
One random sampling for PK analysis will also be taken at further routine 
study visits (Day 10) to co-ordinate with safety and PD assessments. 
 
BIM23B065 and its major metabolite BIM23B133 
Safety:  
 
Adverse Events.  
 
Physical examination 
 
Vital signs (supine and standing blood pressure and HR) 
 
12-lead ECG and ECG monitoring by 3-lead holter device at specific 
timepoints, corrected QT interval (QTc)  will be calculated using Fridericia 
methodology 
 
Clinical 
laboratory 
assessments: 
haematology, 
coagulation, 
clinical 
biochemistry including glucose, glucagon and insulin measurements, 
urinalysis 
 
Putative antibodies to BIM23B065 
 
Endocrine parameters: Adrenocorticotrophic Hormone (ACTH), Cortisol, 
Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Free 
Thyroxine (FT4), Thyroid Stimulating Hormone (TSH) and Testosterone (for 
males only). 
 
Gallbladder echography 
Pharmacokinetic 
Methodology 
Plasma samples will be analysed to determine concentrations of BIM23B065 and 
BIM23B133 using a validated, specific and sensitive LC MS/MS method.  
Statistical Methodology: 
 
The maximum sample size will be 24 evaluable subjects (12 per stage). Enrolled 
subjects who drop out of the study prior to Day 14 GH evaluation may be replaced. If 
12 evaluable subjects have already completed visit 8 (day 14) any subsequent 


 
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withdrawn subjects will not be replaced. 
A minimum of 8 of the 12 evaluable subjects must be responsive to a single test dose 
of octreotide pre-study defined as a >50% reduction in GH. 
Per the primary endpoint, a subject is defined as a responder if the median 
concentration of GH over 6 hours is ≤2.5µg/l or if there is at least 50% reduction from 
mean baseline in GH at Day 14 (after 6 days titration plus 8 days treatment).  
Based on the exact test for single proportion, twelve evaluable subjects per stage would 
be sufficient to have over 84% power, at a significance level of 0.05 (one sided) to 
reject the null hypothesis that there is no indication of efficacy of BIM23B065 if the 
GH responder rate is at most 33%, assuming that the GH responder rate is equal to 
75%.  


 
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RATIONALE FOR PROTOCOL AMENDMENT #1 
 
The overall changes and rationale for the changes made to this protocol are to address Ethics 
Committee request as follows:  
 To exclude patients with unsubstituted/untreated hypoadrenalism (addition of one 
exclusion criteria) 
 To add serum cortisol as safety endocrine parameter 
In addition, the following modifications have been performed: 
 To modify a mistake in calculation of the total blood volume in the Attachment 3. 
 Modifications of the Global Patient Safety contact details. 
 
All modifications are presented in the Attachment 6. 
 
 
PROTOCOL HISTORY 
Protocol version 
Rationale for amendment 
V.1.0, 27JUL2016 
NA – initial version 
V.2.0, 14SEPT2016, 
Amendment #1 
See rationale for Protocol amendment #1 (above) 


 
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TABLE OF CONTENTS 
 
SYNOPSIS ................................................................................................................................ 4 
RATIONALE FOR PROTOCOL AMENDMENT #1 ......................................................... 8 
TABLE OF CONTENTS ......................................................................................................... 9 
LIST OF DEFINITIONS AND ABBREVIATIONS........................................................... 13 
1 
STUDY DRUG BACKGROUND INFORMATION ................................................. 18 
1.1 
Investigational Medicinal Product Name ................................................................... 18 
1.2 
Findings from Nonclinical and Clinical Studies ......................................................... 18 
1.2.1 
Non Clinical Studies ................................................................................... 18 
1.2.2 
Clinical Studies ........................................................................................... 18 
1.3 
Known and Potential Risks .......................................................................................... 19 
1.4 
Selection of Investigational Medicinal Product Doses and Dose Regimen .............. 20 
1.5 
Study Population ........................................................................................................... 20 
1.6 
Potential Benefits to Participants ................................................................................ 21 
1.7 
Rationale for the Study ................................................................................................. 21 
2 
STUDY OBJECTIVES ................................................................................................. 21 
2.1 
Primary Objective(s) .................................................................................................... 21 
2.2 
Secondary Objective(s) ................................................................................................. 21 
2.3 
Exploratory Objective(s) .............................................................................................. 21 
2.4 
Biobanking ..................................................................................................................... 22 
3 
INVESTIGATIONAL PLAN ...................................................................................... 22 
3.1 
Overall Study Design and Plan .................................................................................... 22 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 25 
3.2.1 
Primary Endpoints and Evaluations .......................................................... 25 
3.2.2 
Secondary Endpoints and Evaluations ...................................................... 25 
3.2.3 
Exploratory Endpoints and Evaluations .................................................... 25 
3.2.4 
Safety Endpoints and Evaluations ............................................................. 25 
3.2.5 
Pharmacokinetics and Pharmacodynamics Endpoints and Evaluations . 25 
3.2.6 
Biobanking Endpoints and Evaluations .................................................... 26 
3.3 
Subjects Managements ................................................................................................. 26 
3.3.1 
Study Visits and Procedures ....................................................................... 26 
3.3.1.1 
Screening Period .......................................................................................... 26 
3.3.1.2 
Study Treatment Period ............................................................................... 27 
3.3.1.3 
End of Study/Early Discontinuation Visit .................................................... 28 
3.3.2 
Subjects Disposition .................................................................................... 28 
3.3.3 
Study Duration ............................................................................................ 28 
3.4 
Study Conduct ............................................................................................................... 28 
3.5 
Rationale for the Study Design .................................................................................... 29 
4 
POPULATION RECRUITMENT, ENROLMENT AND WITHDRAWAL .......... 30 
4.1 
Definitions ...................................................................................................................... 30 


 
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4.2 
Recruitment of Population ........................................................................................... 30 
4.3 
Interim Analyses during Stage 1 and Stage 2 ............................................................. 30 
4.4 
Inclusion Criteria .......................................................................................................... 34 
4.5 
Exclusion Criteria ......................................................................................................... 34 
4.6 
Randomisation .............................................................................................................. 36 
4.7 
Discontinuation of an Individual Subject ................................................................... 36 
4.7.1 
Discontinuation / Withdrawal Criteria....................................................... 36 
4.7.2 
Follow-up Procedures for Drop-out Subjects ............................................ 36 
4.7.3 
Replacement Strategy .................................................................................. 36 
4.8 
Discontinuation of Study Site(s) .................................................................................. 37 
4.9 
Discontinuation of Subject's Recruitment .................................................................. 37 
4.10 Study Termination ........................................................................................................ 37 
5 
STUDY TREATMENT ................................................................................................ 38 
5.1 
Study Drug and Treatment of Subjects ...................................................................... 38 
5.1.1 
Investigational Drug Formulation ............................................................. 38 
5.1.2 
Study Drug Administration ......................................................................... 39 
5.2 
Blinding .......................................................................................................................... 40 
5.3 
Product Complaint ....................................................................................................... 40 
6 
STUDY RESTRICTIONS ............................................................................................ 41 
6.1 
Study Drug Administration ......................................................................................... 41 
6.2 
Concomitant Therapy(ies) ........................................................................................... 41 
6.3 
Lifestyle Restrictions .................................................................................................... 42 
7 
STUDY ASSESSMENTS ............................................................................................. 43 
7.1 
Safety Assessments ........................................................................................................ 43 
7.1.1 
Adverse Events ............................................................................................ 43 
7.1.1.1 
Definition ..................................................................................................... 43 
7.1.1.2 
Adverse Event Collection ............................................................................. 44 
7.1.1.3 
Adverse Events Assessment .......................................................................... 44 
7.1.1.4 
Adverse Event Follow-up ............................................................................. 45 
7.1.1.5 
Clinical Evaluation of Safety ....................................................................... 45 
7.1.1.6 
Serious Adverse Event Assessment .............................................................. 45 
7.1.1.7 
Suspected Unexpected Serious Adverse Reactions ...................................... 46 
7.1.1.8 
Pregnancy .................................................................................................... 47 
7.1.1.9 
Death ............................................................................................................ 47 
7.1.1.10 
Reporting to Competent Authorities, IECs/IRBs and other Investigators ... 47 
7.1.2 
Physical Examination ................................................................................. 47 
7.1.3 
Vital Signs Assessments .............................................................................. 47 
7.1.4 
Electrocardiograms Assessments ............................................................... 48 
7.1.5 
Clinical Safety Laboratory Tests ................................................................ 49 
7.1.5.1 
Urinalysis ..................................................................................................... 49 
7.1.5.2 
Pregnancy Test ............................................................................................. 49 


 
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7.1.5.3 
Investigator’s Review ................................................................................... 49 
7.1.5.4 
Sample Handling, Storage and Destruction ................................................ 50 
7.1.6 
Additional Definitions or Special Procedures............................................ 50 
7.1.6.1 
Gallbladder Echography ............................................................................. 50 
7.1.6.2 
Anti-BIM23B065 Antibodies ........................................................................ 50 
7.2 
Efficacy Assessment(s) .................................................................................................. 50 
7.3 
Pharmacokinetics Assessments .................................................................................... 51 
7.3.1 
Pharmacokinetics Sampling Schedule ....................................................... 51 
7.3.2 
Sampling Method for Pharmacokinetic Measurements ............................ 51 
7.3.3 
Bio-analytical Method ................................................................................. 51 
7.3.4 
Pharmacokinetic Parameter Estimation .................................................... 51 
7.4 
Pharmacodynamic Assessment(s) ............................................................................... 52 
7.5 
Pharmacokinetics/Pharmacodynamics Evaluation ................................................... 52 
7.6 
Optional Exploratory Assessment(s) ........................................................................... 52 
7.6.1 
Tumour Tissue Receptors Profile ............................................................... 52 
7.6.2 
Biobanking .................................................................................................. 52 
7.7 
Compliance to Study Procedures ................................................................................ 53 
7.7.1 
Compliance to Protocol ............................................................................... 53 
7.7.2 
Compliance to Timing of Procedures ......................................................... 53 
8 
STATISTICAL ANALYSES ....................................................................................... 54 
8.1 
Data Analysis Plan ........................................................................................................ 54 
8.1.1 
General Considerations .............................................................................. 54 
8.1.2 
Analyses Population .................................................................................... 54 
8.1.3 
Determination of Sample Size .................................................................... 54 
8.1.4 
Primary Analysis ......................................................................................... 54 
8.1.5 
Study Participant Disposition ..................................................................... 55 
8.1.6 
Study Participant Characteristics ............................................................... 55 
8.1.7 
Statistical Evaluation of Safety ................................................................... 55 
8.1.8 
Pharmacokinetic Analyses and Statistical Inference ................................ 55 
8.1.9 
Pharmacodynamics Analysis ...................................................................... 55 
8.2 
Preliminary and/or Interim Analysis .......................................................................... 56 
9 
DATA HANDLING AND RECORD KEEPING ....................................................... 57 
9.1 
Data Capture ................................................................................................................. 57 
9.2 
Data Handling ............................................................................................................... 57 
9.3 
Record Keeping ............................................................................................................. 57 
10 
REGULATORY AND ETHICAL CONSIDERATIONS ......................................... 58 
10.1 Subject Information Sheet and Consent ..................................................................... 58 
10.2 Ethical Review Considerations .................................................................................... 58 
10.3 Regulatory Considerations ........................................................................................... 59 
10.4 Final Report Signature ................................................................................................. 59 
11 
INSURANCE AND FINANCE .................................................................................... 60 


 
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11.1 Insurance ....................................................................................................................... 60 
11.2 Financial Agreement ..................................................................................................... 60 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 61 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 61 
12.1.1 
Protocol Amendments ................................................................................. 61 
12.1.2 
Protocol Deviations and Exceptions........................................................... 61 
12.1.3 
Information to Study Personnel ................................................................. 61 
12.2 Monitoring ..................................................................................................................... 62 
12.3 Data Review Committee ............................................................................................... 62 
12.4 Investigator’s Regulatory Obligations ........................................................................ 63 
12.4.1 
Audit and Inspection ................................................................................... 63 
12.4.2 
Data Quality Assurance .............................................................................. 63 
13 
PUBLICATION POLICY ............................................................................................ 64 
14 
REFERENCES .............................................................................................................. 65 
15 
ATTACHMENTS ......................................................................................................... 66 
15.1 Attachment 1 – Study Schedule ................................................................................... 66 
15.2 Attachment 2 –Clinical Laboratory Tests .................................................................. 70 
15.3 Attachment 3 – Blood Sampling Summary ................................................................ 71 
15.4 Attachment 4 – Liver Safety Algorithm...................................................................... 72 
15.5 Attachment 5 - Biobanking .......................................................................................... 73 
15.6 Attachment 6 – Protocol Amendment Summary ....................................................... 74 
 
LIST OF TABLES 
Table 1 Criteria for dose reduction ...................................................................................... 23 
Table 2 Criteria for not dose escalating ............................................................................... 23 
Table 3  
Criteria for Discontinuation of BIM23B065 administration and for 
definition of Dose Limiting Toxicity .................................................................. 23 
Table 4 Maximum Number of GH responders to declare futility ..................................... 56 
 
LIST OF FIGURES 
Figure 1 Study Schema .......................................................................................................... 24 
Figure 2 Treatment Period; Cohort 1 is BID dosing and a possible cohort 2 is TID 
dosing .................................................................................................................... 24 
Figure 3 BID administration part ......................................................................................... 32 
Figure 4 TID administration part ......................................................................................... 33 
 


 
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LIST OF DEFINITIONS AND ABBREVIATIONS 
 
DEFINITIONS 
 
 
 
Audit 
A systematic and independent examination of the study-related 
activities and documents to determine whether the evaluated study-
related activities were conducted, and the data were recorded, analysed, 
and accurately reported according to the protocol, sponsor’s standard 
operating procedures (SOP), good clinical practices, and the applicable 
regulatory requirement(s). 
Complaint 
A complaint is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, purity, durability, 
reliability, safety or effectiveness, or performance of a drug or drug 
delivery system. 
Compliance 
Adherence to all the study-related requirements,  GCP requirements and 
the applicable regulatory requirements. 
End of Study 
End of study (EoS)  is the date of the last visit or last scheduled 
procedure shown in the Study Schedule for the last active subject in the 
study. 
Enrol / Randomise 
The act of assigning a subject to a treatment. Subjects who are enrolled 
in the study are those who have been assigned to a treatment. 
Enter/Consent 
The act of obtaining informed consent for participation in a clinical 
study from subjects deemed- or potentially eligible to participate in the 
clinical study. Subjects entered into a study are those who sign the 
informed consent document (ICD) directly or through their legally 
acceptable representatives. 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of 
medical professional and non-medical members whose responsibility is 
to verify that the safety, welfare, and human rights of the subjects 
participating in a clinical study are protected. 
Investigator 
A physician responsible for the conduct of a clinical study at a study 
site.  If a study is conducted by a team of individuals at a study site, the 
investigator is the responsible leader of the team and may be called the 
principal investigator. 
Preliminary 
(interim) analysis 
Any analysis intended at any time prior to the formal completion of a 
study. 
Screen 
The act of determining if an individual meets minimum requirements to 
become part of a pool of potential candidates for participation in a 
clinical study.  In this study, screening involves [invasive or diagnostic 
procedures and/or tests (for example, blood draws)].  For this type of 
screening, informed consent for these screening procedures and/or tests 
shall be obtained; this consent may be separate from obtaining consent 
for the study. 
Subject 
An individual who is or becomes a participant in clinical research, 
either as a recipient of the test article or as a control.  A subject may be 
ether a healthy human or a patient. 
 
 


 
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ABBREVIATION 
Wording Definition  
ABP 
Automated blood pressure 
ACTH 
Adrenocorticotrophic hormone 
ADA 
Anti Drug Antibodies 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the (plasma concentration vs. time) curve 
AUC0-∞ 
Area under the (plasma concentration vs. time) curve from time 0 to 
infinity 
AUC0-X 
Area under the (plasma concentration vs. time) curve from 0 to time 
X 
AUCt 
Area under the serum concentration time curve from time 0 to last 
quantifiable timepoint 
ADA 
Anti-Drug Antibodies 
BID 
Bis in die (twice a day) 
BP 
Blood pressure 
CA 
Competent Authority 
Cl 
Clearance 
Cl/F 
Apparent total clearance (from plasma) 
Cmax 
Observed maximal (peak) concentration 
CMC-SC 
Chemistry Manufacturing and Control- Supply Chain 
CRF 
Case report form:  a printed or electronic form for recording study 
subjects’ data during a clinical study, as required by the protocol. 
CRO 
Contract research organisation 
CTCAE 
Common Terminology Criteria for Adverse Event 
CVM 
Cytomegalovirus 
DA 
Dopamine agonist 
DNA 
Deoxyribonucleic acid 
D2 
Dopamine receptor sub-type 2 
DBP 
Diastolic Blood Pressure 
DLT 
Dose Limiting Toxicities 
DRC 
Data Review Committee 
EBV 
Epstein–Barr virus 
EC 
Ethics Committee 


 
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ABBREVIATION 
Wording Definition  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ED 
EoS 
Early Discontinuation 
End of Study 
FDA 
Food and Drug Administration 
FIM 
First in man 
FSH 
Follicle stimulating hormone 
FT4 
Free Thyroxine 
GCP 
Good clinical practice 
GGT  
Gamma-glutamyl transferase 
GH 
Growth Hormone 
GHRH 
Growth Hormone Releasing Hormone 
HbA1c 
Haemoglobin A1c 
HCG 
Human chorionic gonadotrophin 
HCP 
Healthcare Professional 
HCV 
Hepatitis C virus 
HR 
Heart rate 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s brochure 
ICD 
Informed consent document 
ICH 
International conference on harmonisation 
IEC 
Independent Ethic Committee 
IGF-1 
Insulin-like Growth Factor-1 
IMP 
Investigational Medicinal Product 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
ISF 
Interim Storage Facility 
ITT 
Intention to treat 
IUD 
Intra-Uterin device 
IUS 
Intra-uterin hormone-releasing system 
LAR 
Long acting release 
LC-MS 
Liquid chromatography - Mass spectrometry 
LH 
Luteinising hormone 


 
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ABBREVIATION 
Wording Definition  
MAD 
Multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intention to treat 
NA 
Not applicable 
ND 
Not done 
PD 
Pharmacodynamics 
PDM 
Pharmacokinetics and Drug Metabolism 
PP 
Per protocol 
PRL 
Prolactin 
PK 
Pharmacokinetic 
QA 
Quality assurance 
QC 
Quality control 
QD 
Quaque die (once a day) 
QTc 
Corrected QT interval 
RNA 
Ribonucleic acid 
SAD 
Single ascending dose 
SAE 
Serious Adverse Events 
SBP 
Systolic blood pressure 
sc 
subcutaneous 
SD 
Standard deviation 
SOP 
SSA 
Standard operating procedure 
Somatostatin Analogues 
SST 
Somatostatin 
SSTR2 
Somatostatin Receptor 2 
SSTR5 
Somatostatin Receptor 5 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 
tmax 
Time of observed Cmax 
TEAE 
Treatment Emergent Adverse Event 
TID 
Ter in die (Three times a day) 
TMF 
Trial master file 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
V 
Volume of distribution 


 
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ABBREVIATION 
Wording Definition  
V/F 
Apparent volume of distribution 
WHO 
World Health Organisation 
WOCBP 
Women Of Childbearing Potential 
 


 
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1 
STUDY DRUG BACKGROUND INFORMATION 
1.1 
Investigational Medicinal Product Name 
BIM23B065 consists of one molecule of dopamine bound to one molecule of a peptidic 
somatostatin (SST) analogue. It is a chimera of a Dopamine receptor sub-type 2 (D2) and an 
Somatostatin Receptor 2 (SSTR2) agonist. Its theoretical molecular formula is C77H101N17O10S 
corresponding to a molecular weight of 1456.8 g/mol (as free base), and the structural 
sequence 
is: 
(D-6-methyl-8β-Ergolinylmethyl)-thioethyl-cyclic [DLysyl-Arginyl-
Phenylalanyl-4-Aminophenylalanyl-DTryptophyl-Lysyl-Threonyl-Tyrosyl]. 
The single molecule is hypothesised to bridge the two receptors, bringing them physically 
together. An interaction and heterodimerisation between the two receptors has been proposed, 
resulting in stronger downstream post-receptor signalling than is observed with agonist of 
each receptor alone or in combination, suggesting a potential synergistic benefit from the 
combined targeting of these receptors. 
The original rationale for the development of BIM23B065 came from clinical literature 
indicating greater suppression of Growth Hormone (GH) in patients with acromegaly with a 
combination of SST and Dopamine agonist (DA) analogues than with either alone.  Ipsen 
began the development program with the idea of building this combined activity into a single 
molecule.  The Ipsen team subsequently found that in vitro combined SST and DA analogues 
provided no greater suppression than SST analogues alone; however, the prototype chimeric 
molecule showed increased efficacy and 100-1000 fold increased potency (1)(2).  Ipsen 
optimised the ratio of the SST and DA activities to achieve a first-generation compound with 
consistently improved efficacy/potency in suppressing GH in acromegalic tumours, as 
compared with the current clinical SST analogues (3).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
1.2 
Findings from Nonclinical and Clinical Studies 
1.2.1 
Non Clinical Studies 
Non-clinical safety findings are summarised in the BIM23B065 Investigator’s Brochure (IB) 
(4). 
1.2.2 
Clinical Studies 
A phase I study of BIM23B065 has been conducted in 71 healthy male subjects. 
No Serious Adverse Events (SAEs) were reported following single ascending dose (SAD) or 
multiple ascending dose (MAD) administrations of BIM23B065 for 14 days in this 
population. The most frequent treatment emergent adverse events (TEAEs) were injection site 
reactions, and after multiple administrations hypotension. Cases of liver transaminases 
increases were also reported. All TEAEs after multiple administrations were of mild severity. 
CCI


 
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Typical injection site reactions were described as localised erythema at the injection site (of 4 
cm to 5 cm diameter for the higher doses), of mild, not associated with pain, that spread 
outwards as it resolves. Reactions typically resolve within 2 hours post dose and can be 
managed without treatment. Hypotension, postural hypotension and HR decrease also 
occurred at 1.0 mg twice a day (BID) in this population of healthy young male subjects. To 
mitigate this risk a 6-day dose titration period prior to the starting of the maintenance dose 
was included in the MAD part of the study. Of note, decrease in HR never reached dose 
limiting toxicity (DLT) level. Subjects should be warned of the potential for the development 
of postural hypotension. Measures are outlined in this protocol which are designed to 
minimise the risk of hypotensive episodes. 
 
In the MAD part of the study, elevations of hepatic transaminases were seen in subjects who 
received BIM23B065. Increases were in the range >ULN to ≤3.0×ULN. They resolved 
spontaneously and were not accompanied by elevations of bilirubin. 
 
In addition, after multiple dosing of BIM23B065 there were no abnormalities in fasting blood 
glucose levels. 
Upper gastrointestinal symptoms, such as abdominal pain, upper abdominal pain, nausea, 
cramps or discomfort was observed in this first-in-man study. Nausea and abdominal 
discomfort were more common after the evening dose of BIM23B065 when the drug was 
administered in the fed state. These gastrointestinal TEAEs were all mild severity.  
 
Isolated cases of raised amylase and lipase (1 volunteer) and neutropenia (1 volunteer) which 
were regarded as DLTs were seen during repeated dosing with BIM23B065. All events 
resolved before the end of the study. 
Additional information regarding safety profile of BIM23B065 may be found in the IB (4). 
 
With regards to Pharmacodynamics (PD) findings, in the MAD part of the Phase I study, GH 
cycles were assessed up to 11 hours postdose. Spontaneous peak in GH levels were observed 
in subjects who received placebo, which were notably reduced in subjects receiving 
BIM23B065. 
In both single and multiple ascending dose parts of the study, dosing with BIM23B065 led to 
reductions in mean plasma prolactin (PRL) concentrations, with greater and longer lasting 
reductions in PRL concentration observed with higher individual doses. 
Finally, suppression of GH concentrations was demonstrated during the growth hormone 
releasing hormone (GHRH) stimulation test in the multiple ascending dose part of the study. 
Mean exposure to GH after GHRH stimulation was considerably lower in subjects receiving 
BIM23B065 compared to those receiving placebo. 
1.3 
Known and Potential Risks 
To date, BIM23B065 has been studied in one phase I study in healthy male subjects. Single 
doses of up to 1.5 mg and multiple doses of 1.2 mg once a day (QD) and up to 1.0 mg BID 
have been administered to healthy male subjects in a single and multiple dose escalation and 
multiple dose titration study. 
Hypotension 
Hypotension and postural hypotension occurred very commonly in healthy male subjects 
(starting half an hour after investigational medicinal product (IMP) administration with acute 


 
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effect at 2 hours after IMP administration), particularly with multiple dosing of BIM23B065. 
Subjects should be warned of the potential for the development of postural. Measures are 
outlined in this protocol which are designed to minimise the risk of hypotensive episodes. 
Heart rate decrease 
During the phase 1 study, hypotension, postural hypotension and heart rate (HR) decrease 
commonly occurred in this population of healthy young male subjects, particularly following 
multiple dosing of BIM23B065 at 1.0 mg BID. Subjects should be warned of the potential for 
the development of postural hypotension. Blood pressure and HR will be closely monitored 
during the present study. 
Increase ALT and AST 
Increases in mean alanine aminotransferase (ALT) concentration were observed during 
treatment in all dosing groups with greater increases noted with higher daily BIM23B065 
doses. All increases in ALT and aspartate aminotransferase (AST) were of mild intensity and 
resolved before the end of the study and were not accompanied by elevations in bilirubin. 
Investigators should comply with laboratory safety testing requirements and guidance on the 
management of abnormalities of liver function tests as detailed in this current study protocol. 
1.4 
Selection of Investigational Medicinal Product Doses and Dose Regimen 
The stage 1 starting dose has been selected to allow a titration period and will consist of a 
BID administration of 0.4mg at Days 1 and 2, 0.6 mg at Days 3 and 4, then 0.8 mg at Days 5 
and 6 with 1.0 mg from day 7. 
This titration schedule has been validated during the phase I study in healthy male subjects 
(with the aim of reducing the occurrence of known side-effects of dopamine agonists; 
primarily hypotension). 
Then from Day 7 to Day 14 a stable target dose of 1.0 mg will be administered BID.  
This 1.0 mg BID dose was estimated to be the maximal tolerated dose during the multiple 
ascending dose part of the Phase I study. In addition this dose level was associated with robust 
PD effects in GH and PRL. 
If during the study, a subject is unable to tolerate 1.0mg BID and meets the criteria for dose 
reduction in Table 1 (please see page 23), dose may be reduced to 0.8mg BID. If the safety or 
tolerability issue persists, the dose may be further reduced to 0.6mg BID. This decision will 
be taken in agreement with the Investigator. The dose of 0.6mg is the lowest dose permitted 
for the treatment phase and any subject unable to tolerate this dose level of 0.6mg will be 
withdrawn from the study. 
If a subject experiences changes in blood pressure or bradycardia as described in Table 2 
(please see page 23) during the titration phase, they will not have their dose increased further 
and they will remain on their current dose. 
Following an algorithm described in Figure 3 (please see page 32), a stage 2 with three times 
a day (TID) administration of the IMP with new subjects will be conducted with the same 
above described design. 
1.5 
Study Population 
Both gender subjects aged between 18 and 75 years with a confirmed diagnosis of 
acromegaly, with or without a history of pituitary surgery, will be included into this study. 
Subjects can be either treatment naïve or have received prior treatment(s) for their 
acromegaly. (See Sections 4.4 and 4.5). 


 
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1.6 
Potential Benefits to Participants 
The study participants will not have a therapeutic benefit. The study is part of a global 
development plan for BIM23B065 and the compound is at early stage of development. This 
study is designed to increase the understanding of the PD effects and safety after a short 
duration of treatment. Future studies may demonstrate a potential benefit to patients with 
acromegaly. 
1.7 
Rationale for the Study 
The development program of BIM23B065 is designed to provide evidence that the chimeric 
dual agonist peptide BIM23B065, as a single entity, is effective in treating GH-secreting 
pituitary adenomas that involve SSTR2 and D2. The purpose of this second clinical study with 
BIM23B065 is to evaluate the effect of repeated administration of BIM23B065 on the 
secretion of GH in patients with acromegaly. Results obtained in the First in man (FIM) trial 
performed in healthy subjects confirmed the pharmacological activity properties of 
BIM23B065 in reducing efficiently spontaneous GH secretion as well as GHRH induced 
secretion. The proposed study aims to confirm this pharmacological activity but in patients 
with acromegaly, as well as evaluate further the safety profile of BIM23B065 after multiple 
administrations over 14 days. The half-life (t1/2) of BIM23B065 with the current formulation 
is relatively short and therefore suggest the need of more than one injection per day. The first 
study in healthy subject assessed a twice-a-day dose regimen and provided robust data on GH 
reduction as well as optimise the safety and tolerability profile in respect to a single dose as 
well as by a dose increase titration approach. However in respect to the optimal scheme of 
administration, three injections per day could provide, potentially, an even better sustained 
reduction in GH over dosing interval. The proposed study will start with a BID dose regimen 
(stage 1) and if the results obtained after this first part are not satisfactory in terms of GH 
reduction, and provided that there are no safety and tolerability issues, the second stage will 
test a TID dose regimen. Thus at the end of this study, data will be obtained about the 
potential for BIM23B065 to effectively reduce GH secretion in patient with acromegaly as 
well as the safety and tolerability after multiple administrations of the compound. 
 
 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
• 
To assess the PD of repeated administration of BIM23B065 in reducing GH in subjects 
with acromegaly. 
2.2 
Secondary Objective(s) 
• 
To assess the safety and tolerability of repeated administration of BIM23B065 in 
subjects with acromegaly. 
• 
To assess the pharmacokinetics (PK) and PD of repeated administration of 
BIM23B065. 
• 
To investigate the PK of BIM23B133 which is the major metabolite of BIM23B065. 
• 
To assess the correlation of BIM23B065 exposure with blood pressure and HR. 
2.3 
Exploratory Objective(s) 
• 
To correlate GH, IGF-1 and PRL responses with expression of SSTR2, SSTR5 and D2 
in pituitary tumour tissues, when available. 
• 
To assess anti-drug antibodies (ADA). 
CCI


 
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2.4 
Biobanking 
• 
To explore potential utility of biomarkers for association with drug activity, adverse 
events (AEs), to explore drug mechanism of action and/or disease understanding. 
Serum/plasma, whole blood samples will be collected for deoxyribonucleic acid (DNA) 
and whole blood samples for ribonucleic acid (RNA). 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is an open-label, non randomised, multi-centres, adaptive two-stage phase II study. 
During stage 1, up to 12 subjects will be enrolled to receive BIM23B065 BID for two weeks. 
The primary endpoint will be the proportion of subjects with  GH ≤2.5 μg/l or >50% 
reduction from baseline GH on Day 14. The mean serum concentration of GH collected over 
6 hours will be used for the baseline (Day -1) and endpoint (Day 14) GH determination.  
Several sequential analyses will occur during Stage 1. The Stage 1 arm (BID administration) 
may be terminated early for futility during each of these interim analyses if the responder rate 
does not exceed the pre-determined minimum efficacy criteria (see details in section 4.3 and 
section 8.2). In that case, a stage 2 arm will be initiated during which up to 12 subjects will be 
recruited to receive BIM23B065 three times a day (TID) for 14 days. The same sequential 
analysis and early termination rule for futility will apply during stage 2 as for stage 1. 
Any subjects who withdraw prior to the Day 14 end of treatment visit may be replaced except 
for early withdrawal due to safety and tolerability reasons. As soon as 12 subjects (out of 
which at least 8 are Octreotide responders as tested during the screening period) reach Visit 8, 
withdrawn subjects will not be replaced.  
Both the BID and TID regimen parts will consist of 3 periods (See Figure 1):  
• 
A screening period of 21 days maximum during which the eligibility criteria will be 
assessed. An Octreotide test will be also performed at the latest 7 days prior to first 
IMP administration. 
• 
A treatment period that will consist of twice or three times daily administrations of 
BIM23B065. This period will last for 14 days. The first 6 days will be a titration of 
BIM23B065 (0.4 mg/0.6 mg/0.8 mg BID or TID). Then a stable target dose (1.0 mg) of  
BIM23B065 will be BID or TID administered from Day 7 to Day 14.  
• 
If during the study, a subject experiences any safety or laboratory events that meet the 
criteria in Table 1, they may have their dose reduced to the prior dose (See Figure 2). 
The minimum dose allowed for the treatment period is 0.6mg BID or TID. 
- 
For example, if the criteria for dose reduction are met when a subject is taking 
1.0mg BID or TID, they may be dose reduced to 0.8mg BID or TID. 
- 
If the criteria for dose reduction are met when a subject is taking 0.8mg BID or 
TID, they may be dose reduced to 0.6mg BID or TID. 
- 
A subject may be dose reduced more than once and at anytime during the study. 
For example, from 1.0mg BID or TID to 0.8mg BID or TID and if 
safety/tolerability issues persist, they may be further dose reduced to 0.6mg BID 
or TID. 
• 
If during the titration period, the subject experiences any cardiovascular events that 
meet the criteria in Table 2, they must remain on their current dose and not be dose 
escalated. 
• 
A follow up period that will last for 14 days during which the subjects will not be 
administered BIM23B065. 


 
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Table 1 Criteria for dose reduction 
Body System 
Criteria 
Cardiovascular 
Any symptomatic hypotensive event that does not meet the criteria for drug withdrawal 
(please see Table 3) but in the opinion of the Investigator requires dose reduction. For 
example, severe dizziness requiring the subject to sit or lie down post-dose on 2 or more 
occasions 
 
Table 2 Criteria for not dose escalating 
Body System 
Criteria for not dose escalating: If at any time point with a given dose the subject 
has: 
Cardiovascular 
Systolic hypotension <100 mmHg for supine SBP 
Postural hypotension (drop in either SBP or more than 25 mmHg or DBP of more than 10 
mmHg) 
Bradycardia <50 beats/min and decrease from baseline exceeding 20 beats/min (assuming 
supine position) 
Criteria should be confirmed by a repeat assessment (3 measurements over 1 hour) after 10-15 
minutes rest in supine position. 
SBP=systolic blood pressure, DBP=diastolic blood pressure,  
Table 3  Criteria for Discontinuation of BIM23B065 administration and for definition of Dose Limiting 
Toxicity 
Body System 
Criteria 
Cardiovascular 
Systolic hypotension <80 mmHg for supine SBP or symptomatic 
Postural hypotension (drop in either SBP or more than 30 mmHg or DBP of more than 
15 mmHg), symptomatic and/or requiring treatment 
Bradycardia <40 beats/min and decrease from baseline exceeding 20 beats/min 
(assuming supine position) and associated with symptoms 
QTcF interval >500 ms or QTcF over 460 ms and increase exceeding 60 ms as 
compared to baseline value 
Hepatic 
AST/ALT ≥ 5xULN 
Bilirubin ≥2xULN 
AST/ALT > 3xULN and Bilirubin > 2x ULN and ALP > 2xULN 
Renal 
Serum creatinine ≥1.5xULN 
Other AEs 
In the view of the Investigator, any other unacceptable toxicity or clinically significant 
abnormality in laboratory tests, vital signs or ECG 
Cardiovascular criteria should be confirmed by a repeat assessment after 10-15 minutes rest in 
supine position 
SBP=systolic 
blood 
pressure, 
DBP=diastolic 
blood 
pressure, 
AST=aspartate 
aminotransferase, ALT=alanine aminotransferase, ULN=upper limit of normal range, 
QTcF=QT interval corrected for HR according to Fredericia, ECG=electrocardiogram 


 
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Figure 1 Study Schema 
 
 
Figure 2 Treatment Period; Cohort 1 is BID dosing and a possible cohort 2 is TID dosing 
 
Day 
-21 
Day 
-7 
Day 
1 
Day 
7 
Day 
14 
Day 
28 
Octreotide 
Test 
14 days 
Follow Up 
14 days 
Treatment 
bid/tid 
21 days 
Screening 
Titration 
Stable 
dose 


 
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3.2 
Primary and Secondary Endpoints and Evaluations 
Pharmacokinetic and Pharmacodynamic endpoints are primary and secondary endpoints in 
this study and are further described below. 
3.2.1 
Primary Endpoints and Evaluations 
• 
The proportion of subjects with GH ≤2.5µg/l or >50% reduction from mean baseline 
GH after 6-day titration plus 8-day treatment with BIM23B065 measured by mean 
serum concentration of GH over 6-hours at Day 14. 
3.2.2 
Secondary Endpoints and Evaluations 
• 
To assess safety and tolerability. 
• 
To assess the proportion of subjects with GH <1.0μg/l after 6-day titration plus 8-day 
treatment with BIM23B065 measured by mean serum concentration of GH over 6-
hours at Day 14. 
• 
To investigate the PK profile of BIM23B065. 
• 
To correlate the PK with changes in GH, IGF-1 and PRL. 
• 
To determine the efficacy of BIM23B065 in reducing IGF-1 to <ULN (age normalised) 
after 6 day-titration and 8-day treatment period at Day 14 and Day 28. 
• 
To investigate the PK profile of BIM23B133. 
• 
To assess the correlation of exposure of BIM23B065 with blood pressure and HR. 
3.2.3 
Exploratory Endpoints and Evaluations 
• 
To assess anti-drug antibodies. 
• 
To explore the relationship between drug concentrations and potential changes in PD 
markers (PK/PD relationship). 
• 
To explore the relationship between response to BIM23B065 and the expression of 
SSTR2, SSTR5 and D2 in those subjects with available tumour tissue. 
3.2.4 
Safety Endpoints and Evaluations 
• 
Adverse Events.  
• 
Vital signs (supine and standing blood pressure and HR). 
• 
12-lead ECG and ECG monitoring by 3-lead Holter device at specific timepoints, QTc 
interval will be calculated using Fridericia methodology. 
• 
Clinical laboratory assessments: haematology, coagulation, clinical biochemistry 
including glucose, glucagon and insulin measurements, urinalysis. 
• 
Putative antibodies to BIM23B065. 
• 
Endocrine parameters: Adrenocorticotrophic Hormone (ACTH), Cortisol, Luteinizing 
Hormone (LH), Follicle Stimulating Hormone (FSH), Free Thyroxine (FT4), Thyroid 
Stimulating Hormone (TSH) and Testosterone (for males only). 
• 
Gallbladder echography. 
3.2.5 
Pharmacokinetics and Pharmacodynamics Endpoints and Evaluations 
• 
PD Assessments 
- 
Mean serum concentration of GH over 6 hours at baseline, Day 7 and Day 14. 
- 
IGF-1 levels at baseline, Day 14 and Day 28.  
- 
PRL levels over 6 hours at baseline, Day 7 and Day 14. 
• 
PK Assessments: 


 
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- 
Time points will follow a sparse PK sampling approach. On day 7 (first day of 
1.0mg) pre-dose, 0.5h, 1h, 2h, 4h and 6h post-morning dose. On day 14 (last day 
of 1.0mg) pre-dose, 0.5h, 1h 2h, 4h and 6h post-morning dose. 
- 
One random sampling for PK analysis will also be taken at further routine study 
visits (Day 10) to co-ordinate with safety and PD assessments. 
- 
Drug (BIM23B065) and its major metabolite BIM23B133. 
3.2.6 
Biobanking Endpoints and Evaluations 
• 
To biobank whole blood samples for DNA at baseline pre-dose (Day -1), serum/plasma 
and whole blood samples for RNA at baseline pre-dose (Day -1), at Day 14 and Day 28 
(EoS/ED). 
3.3 
Subjects Managements 
3.3.1 
Study Visits and Procedures 
Study visits and procedures are described in the Study Schedule of Events (see Section 15.1). 
3.3.1.1 
Screening Period 
After a subject has received explanations and response(s) to his/her potential questions about 
the study by the Investigator (or designee) and has been given reasonable time to think about 
it, a signed and dated informed consent form will be obtained prior to any study procedures.   
Once informed consent is obtained, subjects will be allocated a study-specific subject number 
which must comply with formatting specifications provided by the Sponsor (see Section 
3.3.2). 
The screening tests and assessments will then be performed to check compliance with 
Inclusion/Exclusion criteria and study restrictions (Visit 1). The results must be obtained and 
confirm subject’s eligibility within 21 days prior to dosing on Day 1. 
In parallel of the completion of the initial screening assessments, subjects will undergo on an 
octreotide test dose to assess their response to somatostatin analogues (SSA) (Visit 2 
performed at the latest on Day -7). An octreotide responder is defined as having a >50% 
reduction from baseline in mean GH in the 6 hours after a single sub-cutaneous injection of 
100μg octreotide (sampling at -15 minutes, 1, 2, 3, 4, 5 and 6 hours). 
The subjects will be hospitalised 24h prior to first IMP administration and baseline control 
assessments will be performed on Day-1 (Visit 3). Subjects will be hospitalized at the latest in 
the morning of on Day -1 
If a subject has undergone pituitary surgery, and if the subject consents (subject will sign a 
separate and specific consent form), any paraffin-fixed tumour tissue will be analysed for 
SSTR2, SSTR5 and D2 receptor expression. This will either be done at the investigational site 
with a methodology protocol and reagents provided by Ipsen or at a central laboratory using 
the same methodology protocol. Given the difficulties in obtaining tumour blocks it is 
expected that very few will be retrieved and evaluated so this will be an exploratory objective. 
Subjects who do not have tumour tissue available are equally eligible for the study. 
 
Re-screening; due to the inherent variability of the assays for both GH and IGF-1 
measurement, a subject may be re-screened on one occasion should the GH or IGF-1 value (as 
measured by central laboratory) be outside of the inclusion criteria. The decision to rescreen is 
taken at the Investigator’s discretion and the Sponsor must be informed. 
Subject who participated to the stage 1 of the study (BID administration) cannot participate to 
the stage 2 (TID administration). 


 
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3.3.1.2 
Study Treatment Period 
Subjects will receive administration of the IMP on the morning of Day 1 (Visit 3). Subject 
will remain hospitalised at least until Day 2 post morning dose assessments. BIM23B065 will 
be administered twice a day or three times a day s.c. injection in the abdominal region with a 
rotation of injection sites between left and right sides. In addition to IMP administration, 
safety, PD and PK assessments will be performed during Visit 3. 
The first 6 days will be a titration of BIM23B065, with the aim of reducing the occurrence of 
known side-effects of dopamine agonists; primarily hypotension. Due to the need for all 
injections of BIM23B065 to be given by a healthcare professional (HCP) and for the close 
monitoring of side-effects and safety, subjects will have the option of either: 
• 
Being admitted to hospital for the whole duration of the treatment period of the study 
irrespective of the IMP administration regimen (i.e. BID or TID administration). 
• 
Only for the BID administration regimen: being admitted for the titration week (up to 
first dose of 1.0mg) and then having a HCP visiting them twice a day to administer 
subsequent doses in-between 3 further visits to the hospital for full study assessments. 
• 
Only for the BID administration regimen: being admitted for 24 hours on Day 1, 
returning to the site for the first injection of each dose increase (every 2 days) during 
the titration week (up to and including 1.0mg) and having a HCP visiting them twice a 
day to administer subsequent doses and complete study assessments. The subject would 
return to hospital for the remaining study visits. 
• 
For the TID administration regimen: due to the frequent injections, the subjects will be 
hospitalised for the treatment period duration. 
Titration of BIM23B065 will be in 4 steps with dose increases every 2 days until the target 
dose is reached at Day 7. The doses will be 0.4mg BID or TID (Day 1 and Day 2), 0.6mg BID 
or TID (Day 3 and Day 4), 0.8mg BID or TID (Day 5 and Day 6) and 1.0mg BID or TID 
(starting at Day 7). The concentration of BIM23B065 will be constant (1.0mg/ml) and the 
required dose will be achieved by adjusting the volume administered (0.4mL, 0.6ml, 0.8ml or 
1.0 ml). Study visits will occur every day that BIM23B065 is uptitrated (Visit 4 on Day 3, 
Visit 5 on Day 5 and Visit 6 on Day 7). Safety will be assessed at all visits, PD during Visits 6 
and 8 and PK assessments will be performed during Visits 6, 7 and 8. 
Subjects will be administered a target dose of 1.0 mg BID or TID from Day 7 until the 
morning of Day 14. The morning dose on Day 14 will be the final dose. Safety assessments 
will be performed during Visit 7 on Day 10. The criteria for either not increasing the dose or 
dose escalation are described in this protocol in Table 1 and Table 2. 
 
If during the study, a subject experiences any safety or laboratory events that meet the criteria 
in Table 1 on page 23, they may have their dose reduced to the prior dose.  
• 
For example, if the criteria for dose reduction are met when a subject is taking 1.0mg 
BID or TID, they may be dose reduced to 0.8mg BID or TID. 
• 
If the criteria for dose reduction are met when a subject is taking 0.8mg BID or TID, 
they may be dose reduced to 0.6mg BID or TID. 
• 
A subject may be dose reduced more than once and at anytime during the study. For 
example, from 1.0mg BID or TID to 0.8mg BID or TID and if safety/tolerability issues 
persist, they may be further dose reduced to 0.6mg BID or TID. 
• 
0.6mg BID or TID is the minimum allowable dose for the treatment period and if a 
subject is unable to tolerate 0.6mg BID or TID, they will be withdrawn from the study. 
 


 
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Last visit of the treatment period will be Visit 8 and will occur on Day 14. Safety, PD and PK 
assessments will be performed. 
As this is a first-in-patient study, the recruitment rate will be as follows for both IMP 
administration regimen parts (i.e. BID or TID); 
For the first 3 subjects for both BID and TID cohorts, no more than 1 subject per 8 days may 
be treated (perform Visit3 - Day1). The Data Review Committee (DRC) will review the first 7 
days safety data of the first 3 subjects including blood biochemistry, blood pressure and ECG 
data. Once the DRC has approved the study to continue, subjects may be enrolled at a rate of 
a maximum of 3 treated subjects per week (in other terms, a maximum of 3 subjects attending 
visit 3 per week). 
3.3.1.3 
End of Study/Early Discontinuation Visit 
Subjects will be discharged from the study after completion of the End of Study (EoS) visit 
(Visit 9) for follow-up assessments which will happen 2 weeks after the last dosing day (Visit 
8), or earlier in case of early treatment discontinuation. 
3.3.2 
Subjects Disposition 
At screening, subjects will be allocated an 11-digit subject number. It will consist of the 
combination of the country number (three digits), centre number (three digits) and the 
sequential order of entry of the subject in the unit (five digits).  
A minimum of 8 octreotide responders must be evaluable in the final analysis. If an octreotide 
responder withdraws prematurely, he/she will be replaced by another octreotide responder. If 
an octreotide non-responder withdraws, they can be replaced by either a responder or non-
responder.  
The minimum evaluable number of subjects is 12 per stage of either BID or TID 
administration. 
A subject is considered evaluable if he or she completes the 14-day treatment period (with 6 
hours GH samples collected). Subjects who withdraw from the study before reaching the 
point of being evaluable will be replaced except for withdrawal due to safety and tolerability 
reasons. If 12 evaluable subjects have already completed visit 8 (day 14) any subsequent 
withdrawn subjects will not be replaced. 
3.3.3 
Study Duration 
For each individual subject, the study is expected to last a maximum of 7 weeks, including up 
to 3 weeks for screening assessments, 2 weeks of study treatment and a 2 weeks safety 
follow-up. 
3.4 
Study Conduct  
All screened subjects must be identifiable throughout the study. The Investigator will 
maintain a list of subject numbers and names (i.e. Subject Identification Log – to be kept on 
site(s)) and a list of all subjects screened (and potentially enrolled) into the study (i.e. 
Screening and Enrolment Log – to be shared with the Sponsor or designee) to enable 
reconciliation of records at a later date if required. 
For screened failure subjects, data collection will be limited to demography, informed consent 
signature date, eligibility and visit status (that includes reason for screen failure). 
The study is planned to be conducted in more than one country. Depending on the recruitment 
rate, number of countries involved may vary. 


 
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3.5 
Rationale for the Study Design 
Discussion of Design 
This study will be the first in an acromegaly subject population with a planned 14-day 
treatment period which includes up-titration.  There will be a 2 week safety follow-up period 
during which the subject will not receive BIM23B065. The study treatment is this duration for 
a number of reasons; 
• 
Due to the short t1/2 (5-7 hours), steady state will be reached in a couple of days. This is 
true for both BIM23B065 and the major metabolite. This is sufficient time for the 
required PK analysis. 
• 
The primary endpoint is % subjects with a reduction of mean GH to mean GH≤2.5μg/l 
or a >50% reduction from mean baseline. GH can respond  rapidly to therapy and a 6-
day titration plus 8-day treatment is considered sufficient to see any GH response. 
• 
The 2-stage adaptive design of the trial permits to evaluate two dosage regimen (BID 
and TID) in a maximum of 24 subjects. During Stage 1, the BID regimen will be tested 
in up to 12 subjects. Futility analyses will occur several times during Stage 1. The BID 
regimen will be stopped for futility if it does not meet the primary objective. Then, a 
TID regimen will be initiated in a Stage 2 cohort. The same interim and final futility 
analyses will occur for Stage 2 as for Stage 1 cohort.  
• 
If the BID regimen meets the primary objective of the study at the end of Stage 1, Stage 
2 will not be initiated.  


 
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4 
POPULATION RECRUITMENT, ENROLMENT AND WITHDRAWAL 
4.1 
Definitions 
Screened Subject: 
A screened subject is a subject who signed the Informed Consent and could potentially be 
enrolled into the study. 
Screening Failure: 
A subject is considered as a screening failure when he/she is not enrolled in the study after 
signing the Informed Consent. 
Subject Enrolment: 
A subject is considered as enrolled in the study when he/she has received a least one IMP 
administration. 
Subject Drop-out: 
A subject will be considered as drop-out when, for any reason, he/she withdraws from the 
study after the 1st IMP administration. 
4.2 
Recruitment of Population  
The Study will start with the BID administration cohort (Stage 1). The first 3 subjects will 
have to be dosed at least 8 days apart. This is to ensure that safety data can be reviewed by the 
DRC after the titration period before the next subject receives their first dose. If no related 
SAE is reported or unless the first 3 subjects experienced at least one DLT, remaining 
subjects can be dosed at a maximum rate of 3 per week. After the stage 1, the study may 
continue with the TID administration cohort (please see next Section for more details). Again 
the first 3 subjects will have to be dosed at least 8 days apart. This is to ensure that safety data 
can be reviewed by the DRC after the titration period before the next subject receives their 
first dose. If no related SAE is reported or unless the first 3 subjects experienced at least one 
DLT, remaining subjects can be dosed at anytime. 
As described in Section 3.3.1, and for both IMP administration regimen (BID and TID), 
subjects will be screened within 3 weeks before dosing on a voluntary basis.  The criteria for 
enrolment must be followed explicitly.   
As illustrated in the Study Schedule of Events (see Section 15.1), eligibility of subjects in the 
study will be based on the results of a screening medical history (including any pre-existing 
conditions, and previous/concomitant medication(s)), physical examination, clinical 
laboratory tests (including PD assessments), GH levels, vital signs, electrocardiogram (ECG) 
and gallbladder echography. These tests / assessments may be performed at any time during 
the screening period (Day -21 to Day -7, included) after Informed Consent signature. Results 
of tests and assessments required at screening should be available to confirm subject’s 
eligibility prior D-7 – when octreotide test will be performed – and prior dosing on Day 1. 
4.3 
Interim Analyses during Stage 1 and Stage 2 
During Stage 1, one interim analysis is planned after 6 subjects complete the Day 14 GH 
assessment. The DRC will meet and review the number of GH responders on Day 14 (i.e. a 
GH responder is defined as a subject with GH ≤2.5µg/l or with at least  50% reduction from 
baseline GH after 6-day titration plus 8-day treatment with BIM23B065 measured by mean 
serum concentration of GH over 6 hours at Day 14) as well as the safety and tolerability data. 
Based on the safety and efficacy data of these subjects, the DRC will decide if the BID cohort 
may be continued or stopped, and if stopped, if a TID cohort (Stage 2) may be initiated, 
according to the following criteria (please see Figure 3 below).  


 
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• 
If there are less than 3 responders then the BID regimen (Stage 1) will be stopped for 
futility and Stage 2 will be initiated, where new enrolled subjects will follow the TID 
administration part (Option 1 in Figure 3). 
If there is at least 3 responders, then the Stage 1 will continue: the next 2 subjects will follow 
the BID administration part and DRC will review the safety and efficacy data once 8 subjects 
will have completed stage 1. 
• 
If there are less than 4 responders (out of 8 subjects) then the BID regimen (Stage 1) 
will be stopped for futility and Stage 2 will be initiated, where new enrolled subjects 
will follow the TID administration part (Option 2 in Figure 3). 
If there is at least 4 responders (out of 8 subjects), then the Stage 1 will continue: the next 4 
subjects will follow the BID administration part and DRC will review the safety and efficacy 
data once 12 subjects will have completed stage 1. 
• 
If there are less than 8 responders then the Stage 2 will be initiated, where new enrolled 
subjects will follow the TID administration part (Option 3 in Figure 3). 
If there is at least 8 responders, then no new subjects will be enrolled into the BID 
administration part, no TID administration part will be conducted and the study will be 
stopped. 
At any time of the stage 1 if at least 3 subjects experienced at least one DLT, then the DRC 
will stop the recruitment and no TID administration part will be conducted. 
During Stage 2, one interim analysis is planned after the first 6 subjects will have completed 
the GH Day 14 assessment. The DRC will review safety and efficacy data of these subjects in 
order to decide if the trial may be stopped early for futility or not (please see Figure 4 below).  
If there are less than 3 responders, then no new subjects will be enrolled into the TID 
administration part and the study will stop (Option 1 in Figure 4). 
If there is at least 3 responders (out of 6 subjects), then the next 2 subjects will follow the TID 
administration part and DRC will review the safety and efficacy data once 8 subjects will 
have completed stage 2. 
If there are less than 4 responders (out of 8 subjects) then the TID regimen (Stage 2) will be 
stopped for futility, no new subjects will be enrolled into the TID administration part and the 
study will stop (Option 2 in Figure 4). 
If there is at least 4 responders, then the Stage 2 will continue: the next 4 subjects will follow 
the TID administration part once 12 subjects will have completed stage 2 and the study will 
be stopped (Option 3 in Figure 4). 
Again, at any time of the stage 2 if at least 3 subjects experienced at least one DLT, then the 
DRC will stop the recruitment. 


 
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Figure 3 BID administration part 
 


 
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Figure 4 TID administration part 
 


 
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4.4 
Inclusion Criteria 
Potential study subjects may be entered in the study if they meet all of the following criteria: 
(1) 
Provided written informed consent prior to any study related procedures. 
(2) 
Subjects will have a documented diagnosis of acromegaly. 
(3) 
Subjects will have active acromegaly confirmed by a mean serum concentration of GH 
over 2 hours > 2.5 μg/l at screening analysed by central laboratory. 
(4) 
Subjects who have had pituitary surgery must be >8 weeks post-surgery. 
(5) 
18 to 75 years of age. 
(6) 
Negative pregnancy test (female subjects). 
(7) 
Female who is either of non-childbearing potential or who is not pregnant at screening 
and agrees to use highly effective contraception during whole duration of the study. 
Non-childbearing potential is defined as being postmenopausal for at least 1 year, or 
women with documented infertility (natural or acquired).   
(8) 
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 treatment period of the study. 
(9) 
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. 
4.5 
Exclusion Criteria 
Potential study subjects may not be entered into the study if any of the following apply: 
(1) 
The subject has received long-acting SSA within 12 weeks prior screening (e.g. 
octreotide long acting release (LAR), lanreotide Autogel, pasireotide LAR).  
(2) 
The subject has received short-acting SSA within 1 week (e.g. octreotide s.c.) prior to 
screening.  
(3) 
The subject has received a dopamine agonist within 6 weeks (e.g. bromocriptine or 
cabergoline) prior to screening. 
(4) 
The subject has received GH antagonist within 12 weeks prior to screening (e.g. 
pegvisomant). 
(5) 
The subject had undergone radiotherapy to the pituitary gland at any time prior to study 
entry. 
(6) 
It is anticipated that the subject will undergo pituitary surgery or radiation to the 
pituitary gland during the study, or will require additional medical therapy for 
acromegaly (including SSA, pegvisomant, or dopamine agonists) during the study. 
(7) 
The subject has unsubstituted/untreated adrenal insufficiency. 
(8) 
If the subject has any history of postural hypotension or evidence of postural 
hypotension at screening (>= 20 mm Hg decrease in SBP, >= 10 mm Hg decrease in 
DBP, or >=30 bpm increases in pulse rate, after standing for 2 minutes from resting 
supine position of at least 10 min). 
(9) 
Subject with poorly controlled diabetes mellitus (presence of ketoacidosis or a 
glycosylated haemoglobin level >10%). 
(10) Subject with diabetes treated with insulin for less than 6 weeks prior to study entry, or 
with an unstable insulin dose in the 6 weeks prior to study entry or Haemoglobin A1c 
(HbA1c) >10%. 


 
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(11) Subject is taking beta-blockers (which can inhibit compensatory increases in HR during 
hypotensive episodes). 
(12) Subject is taking Clonidine, Alpha-blockers, Verapamil and Diltiazem, Amiodarone, 
Ivabradine and Anti-cholinesterase drugs. 
(13) Subject is being treated for hypertension and in the opinion of the Investigator their 
antihypertensive medication puts them at increased risk of postural hypotension. 
(14) Subject is hypotensive at screening as defined as systolic < 90 mmHg and/or diastolic 
<60 mmHg. 
(15) Subject has clinically significant hepatic abnormalities and/or ALT and/or AST 
≥2 x ULN and/or alkaline phosphatase (ALP) ≥2 x ULN and/or total bilirubin 
≥1.5 x ULN and gamma-glutamyl transferase (GGT) ≥2.5 x ULN during the screening 
period (local laboratory results). 
(16) Subject has a compression of the optic chiasm causing visual-field defects. 
(17) Subject with a life expectancy of < 1 year.  
(18) Subject is receiving any oestrogen-containing Hormone Replacement Therapy (HRT). 
(19) Subject is receiving neuroleptic antipsychotic/antiemetic drugs. 
(20) Subject has clinically significant pancreatic abnormalities and/or amylase and/or lipase 
≥2 x ULN during the Screening period (local laboratory results). 
(21) Any significant renal abnormalities, including confirmed proteinuria and/or creatinine 
≥1.5x ULN during screening assessed by the local laboratory.  
(22) Subject has any known uncontrolled cardiovascular disease or any of the following 
within 6 months of Screening: ventricular or atrial dysrhythmia ≥ common terminology 
criteria for adverse event (CTCAE) grade 2, bradycardia ≥ CTCAE grade 2, 
electrocardiogram (ECG), QTc prolonged ≥ CTCAE 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. 
(23) Subject with history of, or known current, problems with alcohol or drug abuse. 
(24) Subject with 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. 
(25) Subject with uncontrolled hypothyroidism. 
(26) Subject with abnormal coagulation. 
(27) Subject with previously known immune compromise. 
(28) Subject with history of gallstones or any gallstones/sludge observed at screening 
gallbladder echography (local assessment). 
(29) Subject has been treated with any other IMP prior to the first study visit without 
undergoing a washout period of seven times the elimination t1/2 of the investigational 
compound. 
(30) Subject has a known hypersensitivity to any of the test materials or related compounds. 
(31) Subject had 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 or ability to complete the study. 
(32) Blood donation within the last 3 months. 


 
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4.6 
Randomisation 
No randomisation list will be required for this open-label study. Subjects will be identified 
throughout the study with the subject number assigned at screening (see Section 3.3.2). 
4.7 
Discontinuation of an Individual Subject 
4.7.1 
Discontinuation / Withdrawal Criteria 
All subjects are free to interrupt or withdraw their consent to participate in the study at any 
time, for any reason, specified or non-specified, and without penalty. 
A subject may also be discontinued from the study upon Sponsor’s and/or Investigator’s 
decision for any appropriate reason, such as safety related to an adverse event or concomitant 
therapy, major protocol violation or deviation, noncompliance with protocol restrictions, etc. 
The Sponsor and its representatives must be informed of all cases of discontinuation.   
The criteria described in Table 3 on page 23 are for the discontinuation of study drug 
administration for reasons of safety. 
For studies, with optional biobanking Subjects participating to the optional research 
biobanking program 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 at this time, the Investigator must inform the study 
monitor in writing of the subject’s decision and destroy the samples. The study monitor will 
forward confirmation of the destruction to the repository leader in the Biomarker team.  
If the samples are at the Sponsor’s repository (central lab or the biobanking vendor), the 
Investigator must inform directly the Sponsor using following e-mail address 
 who will ensure destruction of the samples and all 
corresponding aliquots and issue confirmation of the withdrawal, which will be forwarded to 
the Investigator. 
4.7.2 
Follow-up Procedures for Drop-out Subjects 
In case a subject who has already taken study medication(s) drops out or is discontinued from 
the study earlier than study end, the end of study/early discontinuation (ED) visit (Visit 9) 
should preferably be done within 14 days of the last IMP administration. It is preferred not for 
it to be done on the day of discontinuation so that all safety events are captured that occur in 
the days after the last IMP administration and before the EoS/ED visit. However, if there is no 
option but to complete the EoS/ED visit on the day of discontinuation, then this is acceptable.  
The reason and date for drop-out should be documented. 
Drop-out subjects will have completed their study participation when they have undergone all 
assessments of this last study visit (EoS/ED), and electronic case report form (eCRF) should 
be completed up to these last assessments. 
Data collected prior to subject discontinuation may be kept in study records and shared with 
the Sponsor for study analyses (see Section 9) unless a subject formally specifies his/her 
decision to withdraw his consent for using data already collected before discontinuation.  
4.7.3 
Replacement Strategy 
Subjects who drop-out from the study after IMP administration but before reaching last IMP 
administration on day 14 and its associated assessments will be replaced. The exception is if 
the drop-out is due to a safety or tolerability reason. As soon as 12 subjects (out of which at 
least 8 are Octreotide responders) reach Visit 8, withdrawn subjects will not be replaced. 
PPD


 
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4.8 
Discontinuation of Study Site(s) 
Study site participation may be discontinued if the Sponsor, the Investigator, or the ethics 
committee (EC) of the study site judges it necessary for any reason. 
4.9 
Discontinuation of Subject's Recruitment 
Subjects’ recruitment in the study may be stopped at any time upon Sponsor’s decision, e.g. if 
actual data indicate that a sufficient number of subjects have already been enrolled in the 
study or for any other appropriate reason. 
4.10 
Study Termination 
The study can be discontinued prematurely at any time if the Sponsor judges it for any 
appropriate reason. In that case, all scheduled procedures and assessment for subjects who are 
still in the study will be performed. 


 
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5 
STUDY TREATMENT 
5.1 
Study Drug and Treatment of Subjects 
5.1.1 
Investigational Drug Formulation 
Chemical Identity 
BIM23B065 consists of one molecule of dopamine bound to one molecule of a peptidic SST 
analogue. It is a chimera of a D2 and an SST2 receptor agonist. 
Laboratory code:  
BIM23B065 
INN:   
 
Not Applicable 
Chemical formula:  
D-6-methyl-8β-Ergolinylmethyl)-thioethyl-cyclic [DLysyl-Arginyl-
Phenylalanyl-4-Aminophenylalanyl-DTryptophyl-Lysyl-Threonyl-Tyrosyl] 
Empirical formula:  C77H101N17O10S 
Molecular weight:  
1456.8 g/mol 
Dosage Form and Strength of BIM23B065 
The IMP, BIM23B065, is an immediate release formulation to be administered by a bolus s.c. 
injection. The drug product is a clear to slightly opalescent and colourless to slightly coloured 
sterile solution filled in a clear glass vial with a rubber stopper. 
The dosage strength is 1.0 mg/ml. 
Investigational Medicinal Product Packaging and Release and Labelling 
The Investigational Medicinal Product BIM23B065 will be packaged and released by the 
Beaufour Ipsen Industrie, Chemistry, Manufacturing and Control Supply Chain (CMC-SC) 
and delivered to the investigational sites or deposited in an Interim Storage Facility (ISF). A 
sufficient quantity of BIM23B065 will be supplied as well as an acknowledgement of receipt 
form. The Sponsor’s representative will receive a Certificate of Analysis for the IMP batches 
of the study, and the Certificate of Compliance which reflects the product release statement 
and will provide them to the sites according to local requirements. 
The core text for all packaging units will be translated and/or adjusted, to be in compliance 
with applicable regulatory requirements (e.g. Good Manufacturing Practice guidelines 
(Volume 4 Annex 13)), national laws in force and in accordance with the local languages. A 
non-exhaustive description of the core text of the IMP labels is displayed below: 
• 
Sponsor name, address and telephone number (the main contact for information on the 
product and the clinical study), 
• 
Study Number, 
• 
Pharmaceutical dosage form, 
• 
Route of administration, 
• 
Quantity of dose units, 
• 
Batch number, 
• 
Treatment number, 
• 
Subject Number, 
• 
Investigator Name, 
• 
Direction for use, 
• 
“Keep out of reach of children”, 
• 
“For clinical trial use only”, 
• 
Storage conditions, 
• 
Expiry date. 


 
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Storage 
The Investigator, or designee (e.g. Pharmacist), will ensure that IMPs will be stored, and 
returned or destroyed according to applicable regulations.  The IMP will be stored in a 
secured and locked area, under monitored conditions and at the recommended temperature 
(between +2°C and +8°C), in accordance with applicable regulatory requirements and any 
other specific instructions provided by the Sponsor. If IMP is taken home by the subjects, they 
will be instructed to keep the IMP in a refrigerator. All IMP will be administered by qualified 
staff members at the investigational site, or by a HCP outside the investigational site. 
Supplies for this study will not be stored in such a way that they may be confounded with 
supplies being used for another study. 
Investigational Drug Accountability 
BIM23B065 will be provided to the Investigator, or designee (e.g. Pharmacist), and 
administered to subjects by appropriately trained study staff as described in Section 5.1.2. 
The Pharmacist or assignee will record drug movement and accountability on specific drug 
accountability forms/logs.  Study medication allocation, preparation and disposition records, 
as well as shipping, dispensing and returned drug records, and inventory logs must be 
maintained at the investigational site.  
The dispensing for each subject will also be documented in the eCRF. 
It is essential that all used and unused supplies are retained for verification by the Sponsor or 
designee who will ensure that BIM23B065 administration in the eCRF, the accountability 
forms/logs and the number of remaining used/unused treatments are consistent.  
At the end of the study, all remaining IMPs will be preferably destroyed at the investigational 
site or return to CMC-SC (Beaufour Ipsen Industry – Dreux) for destruction (only if site is not 
able to do it). The destruction of used and unused BIM23B065 should be carried out only 
after any discrepancies have been investigated and satisfactorily explained and the 
reconciliation has been accepted by the Sponsor or designee. 
5.1.2 
Study Drug Administration 
The Investigator, or designee, will only administer BIM23B065 to subjects enrolled in this 
study. 
Each dose of IMP will be prepared and allocated to subject(s) according to the pre-determined 
dosing schedule agreed upfront with the Sponsor or designee. 
Preparation Procedure 
BIM23B065 will be supplied as a sterile solution in vials for s.c. injection, in one dosage 
strength at 1.0 mg/ml. 
Administration Procedure 
The Investigator, or an approved representative (e.g. pharmacist), will ensure that all 
BIM23B065 is administered by qualified staff members. 
The study drug will be administered to the subject via s.c. injection in the abdominal region 
(intended volume of administration will be 0.4 ml, 0.6 ml, 0.8 ml and 1.0 ml). There will be a 
rotation of the injection sites in the abdomen between the left and right sides.  BIM23B065 
will be administered BID (morning dose and evening dose) or TID (morning dose, mid-day 
dose and evening dose) for the whole duration of the treatment period except on Day 14 when 
only the morning dose will be administered.  
When the IMP is administered twice a day, there should be an interval of 12 hours (± 1 hour) 
between the morning and the evening doses. 


 
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When the IMP is administered three times a day, IMP should be administered every 8 hours ± 
1 hour. First IMP administration in the morning should be around 8 a.m., second IMP 
administration should be around 4 pm and third IMP administration will be around midnight. 
Section 6.1 has details of when BIM23B065 should be administered regarding food intake. 
5.2 
Blinding  
Not applicable (open label study). 
5.3 
Product Complaint 
Sponsor collects product complaints on study drugs used in clinical trials in order to ensure 
the safety of study participants, monitor quality, and to facilitate process and product 
improvements. 
The Investigator is responsible for handling the following aspects of the product complaint 
process in accordance with the instructions provided for this study: 
• 
Recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose. 
• 
Faxing the completed product complaint form within 24 hours to Sponsor or designee. 
If the Investigator is asked to return the product for investigation, they will return a copy of 
the product complaint form with the product. 


 
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6 
STUDY RESTRICTIONS 
6.1 
Study Drug Administration 
No food effect on IMP exposure has been demonstrated so far in the development of 
BIM23B065. In the interest of keeping food intake constant in case of effect on GH 
secretion/levels, breakfast is to be eaten within 1 hour of the morning dose – either 1 hour 
before or 1 hour after. Nevertheless, for each subjects, breakfast intake with regards to 
morning dosing should remain the same for the whole treatment period. 
For the evening dose (BID administration) and for the afternoon and night dose (TID 
administration), there are no specific restrictions regarding food intake related to IMP 
administration. In the phase I healthy volunteer study, there were reports of abdominal pain in 
some subjects after the evening dose which was given in a fed state. There was less abdominal 
pain reported after the morning dose which was given in a fasted state. As a result, if a subject 
reports abdominal pain post-administration of BIM23B065, the evening injection (BID 
administration) or the afternoon and the night injection (TID administration) can be given 
when the subject is in a fasted state.   
Episodes of hypotension were reported after IMP administration during the phase I study in 
healthy volunteers. It is recommended to ask the subject to remain lying down or sitting in a 
reclined chair for approximately 30 minutes after each dose before standing in order to 
minimise the risk of episodes of dizziness or syncope. After 30 minutes in supine/reclined 
position, the subject should be sitting for at least two minutes before standing. 
6.2 
Concomitant Therapy(ies) 
Concomitant drugs or therapies are to be avoided during the study unless required to treat an 
AE or an ongoing medical condition. 
Concomitant administration of bradycardia inducing drugs (e.g. beta-blocker) is not allowed, 
as it may inhibit compensatory increases in HR during any hypotensive episodes. 
Clonidine, Alpha-blockers, Verapamil and Diltiazem, Amiodarone, Ivabradine and Anti-
cholinesterase drugs should also not be allowed. 
During the study, the Investigator should regularly check if the subject has received any 
concomitant medication/therapy that is not permitted at study entry.   
Subjects will provide information about all previous medication taken over the last 3 months 
and investigational drug taken over the last year, and this information will be recorded on the 
appropriate eCRF. 
Contraception 
The inclusion of Women Of ChildBearing Potential (WOCBP) requires use of a highly 
effective contraceptive measure (5) 
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Such methods include: 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation: 
- 
oral 
- 
injectable 
- 
implantable 
- 
intravaginal 
- 
transdermal 
• 
intra-uterin device (IUD) 
• 
Intra-uterin hormone-releasing system (IUS) with no oestrogen 


 
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• 
bilateral tubal occlusion 
• 
vasectomised partner1 
• 
sexual abstinence2 
One of the contraceptive methods is required for women with childbearing potential for the 
duration of the study, i.e. from enrolment until discharge from the study. In addition, subject 
will be asked to continue to use contraceptive method 3 months following the last dose of 
study drug. 
6.3 
Lifestyle Restrictions 
Non Applicable for this study 
                                                 
 
 
 
1 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success. 
2 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. 


 
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7 
STUDY ASSESSMENTS 
Timing of safety assessments, PD and PK sampling collection, and any other tests is specified 
in the attached study schedule of events table. Maximum blood volume for all tests and assays 
is also documented for each of the tests in the attached summary of blood collection volumes 
(See Section 15.3).   
7.1 
 Safety Assessments 
The Investigator is responsible for monitoring the safety of the subjects who have entered the 
study and to take appropriate action during the study concerning any event that seems 
unusual, as well as to alert the Sponsor or its assigned representative. 
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that caused the subject to discontinue before completing the study.  
The subject should be followed until the event is resolved or explained. Frequency of follow-
up evaluation is left to the discretion of the Investigator. 
The Investigator will be responsible for a clinical assessment of the study participants before 
discharge from the study, and for the set up of a discharge plan if needed. 
In addition to records of observations made at specific times, unexpected signs and symptoms 
and concomitant medications will be recorded in the clinical study records throughout the 
study. 
Safety Parameters 
The following safety parameters will be collected during this study at specific time points 
described in the study schedule of events: 
• 
Adverse events; 
• 
Physical examination with oral/body temperature and body weight/height 
• 
Vital signs, including HR, SBP and DBP  
• 
12-Lead ECG and 3-lead Holter 
• 
Clinical safety laboratories, including clinical chemistry, haematology, HbA1c, insulin, 
glucagon and concurrent glucose. 
• 
Endocrine parameters including, ACTH, Cortisol, LH, FSH, FT4, TSH and 
Testosterone (for male subjects only); 
• 
Gallbladder echography, 
• 
Anti-BIM23B065 Antibodies. 
Further routine medical assessments or any additional safety procedures may be performed 
during the study, if warranted and agreed upon between the Sponsor and Investigator, or when 
clinically indicated. 
Any clinically significant findings that result in a diagnosis should be recorded and 
commented on appropriate document. 
7.1.1 
Adverse Events  
7.1.1.1 
Definition 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition, 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). 


 
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An AE can include an undesirable medical condition occurring at any time, even if no IMP 
has been administered. 
This definition includes events occurring from the time of the subject giving informed consent 
until the EoS/ED. 
7.1.1.2 
Adverse Event Collection 
AEs will be monitored from the time that a subject gives informed consent and throughout the 
study, and will be elicited by direct, nonleading questioning or by spontaneous reports. 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the eCRF.  
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered as clinically significant by the Investigator. 
• 
The management of elevations in AST/ALT and/or bilirubin is detailed in the algorithm 
in Attachment 4 (Section 15.4). Should such elevations be detected during the study, 
the subject management algorithm is to be followed. The parameters in the algorithm in 
Attachment 4 correlate with the guidance in Table 3 in Section 3.1. 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the Investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the Investigator as clinically significant (e.g. 
electrocardiogram changes) that result in a change in IMP dosage or administration schedule, 
or in discontinuation of the IMP, or require intervention or diagnostic evaluation to assess the 
risk to the subject, should be recorded as AEs.  
7.1.1.3 
Adverse Events Assessment 
For all AEs, sufficient information should be obtained by the Investigator to determine the 
causality of the AE (i.e. IMP or other illness). The Investigator is required to assess causality 
and record that assessment in the eCRF. 
Adverse events will be classified by the Investigator as mild, moderate or severe according to 
the following criteria: 
• 
Mild: Symptoms do not alter the subject’s normal functioning, 
• 
Moderate: Symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject, 
• 
Severe: Symptoms definitely hazardous to well-being, significant impairment of 
function or incapacitation. 
If in the duration of an AE there is a change in intensity, each change will be recorded as a 
new episode of the AE. 
The relationship of an AE to IMP administration will be classified by the Investigator 
according to the following: 


 
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• 
Related: Reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose-response relationship, pharmacology) to assume a causal relationship 
with IMP 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 IMP administration. 
The expectedness of an AE shall be determined by the Sponsor according to the current 
version of the IB. 
Any AEs already recorded and designated as “continuing” should be reviewed at each 
subsequent assessment. 
If a subject's treatment is discontinued or changed as a result of an AE, study site personnel 
must clearly report to the Sponsor or its designee the circumstances and data leading to such 
decision. 
7.1.1.4 
Adverse Event Follow-up 
If an AE is still present at the end of the study, reasonable follow-up clinical monitoring 
should be managed by the Investigator or any appropriate physician until event is resolved or 
stabilised at an acceptable level, as judged by the Investigator.  The frequency of follow-up 
evaluation is left to his/her discretion. 
7.1.1.5 
Clinical Evaluation of Safety 
All study drug and protocol procedure AEs will be listed, and if the frequency of events 
allows, safety data will be summarised using descriptive methodology. 
The incidence of symptoms for each treatment will be presented by severity and by 
association with study drug as perceived by the Investigator.  Symptoms reported to occur 
prior to dosing will be distinguished from those reported as new or increased in severity 
during or after IMP administration.  Each symptom will be classified by the most suitable 
term from a version of a medical regulatory dictionary agreed by the Sponsor and other 
parties involved in the study. 
7.1.1.6 
Serious Adverse Event Assessment 
Definition 
A SAE is defined as any adverse event that either: 
(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 occurs. 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, 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person's ability to conduct normal life functions, 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received 
the IMP, 
(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, 


 
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blood dyscrasias or convulsions that do not result in in-patient hospitalisation, or the 
development of drug dependency or drug abuse. 
(7) 
Other medically important conditions 
In addition to the above criteria, any additional AE that the Sponsor or an Investigator 
considers serious should be immediately reported to the Sponsor and included in the corporate 
SAEs database system. 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the Investigator or treating physician. For 
protocol-specified hospitalisation in clinical 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 criteria 
for "seriousness" but is not an adverse experience and thus is not subject 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 which 
meet the criteria for seriousness described above. 
SAE Collection and Reporting 
Study site personnel must immediately (within 24 hours) report any SAE to the Sponsor using 
the contact details specified on the front page of the current document, independent of the 
circumstances, together with the Investigator's opinion of causality, as soon as it occurs or 
comes to the attention of the Investigator at any time during the study period. 
Any SAE with a suspected causal relationship to IMP 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: 
• 
Study number, 
• 
Investigational site identification, 
• 
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 which occurred as complications. 
7.1.1.7 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not 
listed in the IB and that the Investigator identifies as related to IMP or procedure. 


 
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7.1.1.8 
Pregnancy 
Pregnancy tests will be performed in all female subjects of childbearing potential as specified 
in the schedule of assessments (See Section 15.1). 
Information regarding pregnancies with a conception date either during the study period or 
within 3 months after dosing must be collected in the eCRF and reported to the Sponsor on a 
Standard Pregnancy Outcome Report Form. 
The Investigator must instruct all female subjects to inform him/her immediately should they 
become pregnant. The Investigator should counsel the subject, discuss the risks of continuing 
with the pregnancy and the possible effects on the foetus. Monitoring of the subject should 
continue until conclusion of the pregnancy. The Sponsor will request further information from 
the Investigator as to the course and outcome of the pregnancy using a Standard Pregnancy 
Outcome Report Form. Adverse consequences of a pregnancy will be regarded as SAEs. 
If the Investigator becomes aware of a pregnancy occurring in the partner of a subject 
participating in the study, this should be reported to the Sponsor. After the partner has given 
informed consent, she should be counselled and monitored until conclusion of the pregnancy. 
7.1.1.9 
Death 
All AEs resulting in death either during the study period or within 1 months after dosing must 
be reported as a SAE. 
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”. 
7.1.1.10 Reporting to Competent Authorities, IECs/IRBs and other Investigators 
The Sponsor will ensure that processes are in place for submission of reports of SUSARs 
occurring during the study to the Competent Authorities (CAs), Independent Ethics 
Committees (IECs)/Institutional Review Boards (IRBs) and other Investigators concerned by 
the IMP. 
Reporting will be done in accordance with the applicable regulatory requirements. The 
Sponsor must report all SUSARs to EMA’s EudraVigilance database within 15 days. 
Fatal and life-threatening SUSARs should be reported within 7 calendar days, with another 8 
days for completion of the report. 
The Sponsor can prepare additional reports for other authorities (e.g. Food and Drug 
Administration (FDA)). 
7.1.2 
Physical Examination 
Physical examinations will be conducted as presented in the Study Schedule of Events (see 
Section 15.1). 
Clinically significant changes, in the judgement of the Investigator, in physical examination 
findings will be recorded as AEs. Any physical examination findings (abnormalities) 
persisting at the end of the study will be followed by the Investigator until resolution or until 
reaching a clinically stable endpoint. 
7.1.3 
Vital Signs Assessments 
Systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) will be assessed 
with an automated device so that measurements are independent of the observer. Body 


 
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Weight and body temperature will also be assessed and recorded as part of vital signs 
assessments. Height will be measured at Screening Visit only. 
Blood pressures and HR will be measured as follows: 
 
Automated blood pressure (ABP) will consist of a 5-hour post-dose period recording and 
should be started at least 1 hour pre-dose in the morning of the visit (recordings every 30 
minutes). Recordings should be taken every 30 minutes for the first hour post-dose, then 
every 15 minutes for the second hour post-dose and every 30 minutes for the next 2 hours. 
ABP will be taken at visit 3 (Day -1 as baseline assessment and Day 1: to include the morning 
dose), visit 4 (Day 3: to include the morning dose), visit 5 (Day 5: to include the morning 
dose), visit 6 (Day 7: to include the morning dose), visit 7 (Day 10: to include the morning 
dose) and visit 8 (Day 14: to include the morning dose).  The machine used for ABP 
measurements will be standardised across study sites with evidence of recent calibration. 
Recordings will be stored with the ABP machine and will be transferred to central reader as 
specified in a specific study manual. 
At the times stipulated in the Study Schedule of Events (see Section 15.1), single 
measurement of supine blood pressure will be recorded on the hospital subject file and 
reported onto the eCRF. Single BP measurement will be obtained with the same machine used 
for ABP measurement. All BP assessments will be taken in triplicate. 
Measurements of orthostatic blood pressure will consist of BP measurements of subject being 
standing for 2 minutes after at least 10 minutes supine. Orthostatic blood pressure timepoints 
are stipulated in the Study Schedule of Events (see Section 15.1). 
Orthostatic hypotension will be defined as a decrease of 20 mmHg or more in SBP or 10 
mmHg or more in diastolic blood pressure (DBP) from supine to standing or more than 30 
bpm increases in pulse rate, after standing for 2 minutes from resting supine position of at 
least 10 minutes. 
7.1.4 
Electrocardiograms Assessments 
A 3 lead Holter device will be used at visit 3 (Day -1 as baseline assessment and Day 1), visit 
6 (Day 7) and visit 7 (Day 10). A continuous 24-hour post-dose period will be recorded and 
should be started at least 15 minutes pre-dose in the morning of the visit. The 24-hour period 
will cover two or three administrations of IMP (except for Day -1 where there will be no IMP 
administration, this assessment will be the baseline assessment). The Holter device can be 
removed immediately prior to the third (when BID administration) or fourth (when TID 
administration) scheduled administration of IMP. 
At the times stipulated in the Study Schedule of Events (see Section 15.1), , 3 consecutive 
twelve-lead computerised standard ECGs, with paper printout, will be obtained  whilst the 
subject is in resting supine position for at least 10 minutes. At Visits when IMP is 
administered, this assessment will be performed post-dose. ECG machines will be 
standardised between sites and ECG data analysed by a central reader in addition to the local 
analysis described below. All assessments will be performed in triplicate. 
For each timepoint, computerised standard ECGs will be recorded so that the following 
parameters can be automatically calculated and reported on the ECG paper printout: 
• 
Sinus rhythm, 
• 
RR interval duration or HR, 
• 
PR interval duration, 
• 
QRS interval duration, 


 
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• 
QT interval duration, 
• 
QT interval corrected by the Fridericia correction method. 
Automated ECG interval data will be interpreted by a qualified physician at the site as soon 
after the time of ECG collection as possible, and ideally while the subject is still present, for 
immediate subject management. The qualified physician will document his/her review and 
interpretation (including evaluation of clinical significance in case of abnormality) on every 
ECG printout.  
The paper printouts will be kept in the source documents at site. Only the interpretation and 
abnormalities after central review will be reported in the eCRFs for integration with other 
clinical study data.  These paper ECGs may be subject to further review, if appropriate. 
ECG analysis will be included as a safety evaluation/endpoint in this study. 
Any clinically significant abnormalities will be recorded as AEs. 
7.1.5 
Clinical Safety Laboratory Tests  
Blood will be collected for standard clinical laboratory tests, including biochemistry, 
haematology, as well as specific tests such as urine/serum pregnancy tests for women of 
childbearing potential) at timepoints indicated in the Study Schedule of Events (see Section 
15.1).  
The exact lists of parameters to be assessed are given in Section 15.2. 
7.1.5.1 
Urinalysis 
Freshly voided urine samples (at least 10 mL) will be collected to perform a dipstick 
assessment of the parameters described in Section 15.2.  
Microscopy will be performed, if indicated. If in the opinion of the Investigator there are any 
clinically significant abnormalities in microscopy, they will be recorded as an AE in the 
eCRF.  
7.1.5.2 
Pregnancy Test 
Human chorionic gonadotrophin (HCG) urine test will be performed for all female subjects of 
childbearing potential at Screening (visit 1), pre-dose (visit 3) and EoS (visit 9). It may be 
repeated at any time during the study according to Investigator’s judgement. 
In case of a positive urine test, a Beta-human chorionic gonadotrophin (ßHCG) serum test will 
be performed and if clinically indicated thereafter. 
Any subject becoming pregnant during the study will be withdrawn from treatment. All 
pregnancies that occur during the study are to be reported as described in Section 7.1.1.8. 
7.1.5.3 
Investigator’s Review 
Investigators must document their review of each laboratory report by signing or initialling 
and dating each report.  Laboratory values that fall outside a clinically accepted reference 
range or values that differ significantly from previous values will be evaluated. 
When multiple laboratory values are out of range but not clinically significant, “all labs NCS” 
or a general comment may be written on the laboratory page.  However, all clinically 
significant laboratory values must be individually marked with CS. 
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 7.1.1 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 


 
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Investigator and the Sponsor’s clinical monitor (or his/her designated representative) or until 
the abnormality is explained by an appropriate diagnosis.  
7.1.5.4 
Sample Handling, Storage and Destruction 
Full details related to the samples processing, labelling, storage, shipment, destruction 
procedures, methodology and reference ranges will be provided to the Investigator via 
separate instructions and archived in the Trial Master File (TMF). 
Tests are run and confirmed promptly whenever scientifically appropriate. When scientific 
circumstances warrant, however, it is acceptable to retain samples to batch the tests run, or to 
retain the samples until the end of the study to confirm that the results are valid.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards. Clinical laboratory tests will be performed 
by local laboratories (apart for urine pregnancy test). 
7.1.6 
Additional Definitions or Special Procedures  
7.1.6.1 
Gallbladder Echography 
A Gallbladder echography will be conducted according to study site procedures for the 
evaluation of presence or absence of lithiasis or sludge as illustrated in the Study Schedule of 
Events (see Section 15.1). The results will be recorded in the eCRF specifically the presence 
or absence of biliary sludge or stones. 
7.1.6.2 
Anti-BIM23B065 Antibodies 
Blood samples will be collected for the assay of anti-BIM23B065 antibodies timepoints 
illustrated in the Study Schedule of Events (see Section 15.1).  
• 
Collect 2 mL of blood into a Silica clot activator collection tube at each time point. 
• 
Allow the blood to clot for at least 30 minutes but no longer than 60 minutes at room 
temperature. 
• 
Centrifuge blood samples at room temperature within 60 minutes of collection at 1300g 
for 10 minutes 
• 
Transfer 2 times 500μl of separated serum immediately to 2x 1 ml Sarstedt-storage 
tube Store the samples within 1 hour at -20°C or below 
• 
All study samples will be collected by a central laboratory and sent to BERTIN 
PHARMA. 
Full details regarding the requirements for processing, labelling and shipment of these 
samples will be provided in separate instructions and archived in the TMF. 
All samples collected for anti-BIM23B065 antibodies assessment may be stored for up to 3 
months following the finalisation of the Clinical Study Report at the Sponsor designated 
laboratory in Europe.  Any samples left 5 years after all subjects have finished the study will 
be destroyed with prior approval by the Sponsor. 
7.2 
Efficacy Assessment(s) 
For this study, the primary PD and efficacy parameter will be GH. 
Blood samples will be collected at timepoints indicated in the Study Schedule of Events (see 
Section 15.1). 
Mean serum concentration of GH over 6 hours at Day -1, Day 7 and Day 14 will be 
calculated. 


 
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7.3 
Pharmacokinetics Assessments 
7.3.1 
Pharmacokinetics Sampling Schedule 
BIM23B065 and BIM23B133 serum concentrations at timepoints illustrated in the Study 
Schedule of Events (see Section 15.1). 
7.3.2 
Sampling Method for Pharmacokinetic Measurements 
Sampling method will be as follow: 
• 
Collect 7 mL of blood into a Li-Heparin containing collection tube at each time point. 
• 
Blood samples will be placed immediately on melting ice. 
• 
Centrifuge blood samples at 4°C within 60 minutes of collection at 2000g for 15 
minutes at 4°C. 
• 
Transfer 3 times at least 900μl of separated plasma immediately to 3x 2 ml Sarstedt-
storage tube. 
• 
Store plasma samples at -80°C. 
• 
Sarstedt tube will be collected by a central laboratory and sent to Kymos 
• 
There will be 2 separate shipments for primary (2 tubes) and backup (1 tube). The 
backup will be sent after the main have been received. 
Specific details of labelling, sampling, storing and shipping procedures will be described in 
separate documentation, and provided by the Sponsor. 
7.3.3 
Bio-analytical Method 
Plasma samples will be analysed to determine concentrations of BIM23B065 and 
BIM23B133 using a validated, specific and sensitive LC-MS/MS methods.  
7.3.4 
Pharmacokinetic Parameter Estimation 
Analysis of PK data by noncompartmental approach will be documented by a separate 
analysis plan. Individual plasma concentrations for BIM23B065 and BIM23B133 will be 
listed and summarised by timepoints and dose level using descriptive statistics for continuous 
variables (number of available observations, mean, median, standard deviation, minimum, 
maximum, geometric mean, and geometric coefficient of variation assuming log-normally 
distributed data). Linear and semilogarithmics- plots of individual and mean plasma 
concentration-time profiles as well as spaghetti plots will be reported. 
 
The following, but not limited to, PK parameters may be calculated on Day 7 and Day 14: 
• 
Cmax: Empirical peak plasma concentration after first dose. 
• 
tmax: Empirical time of Cmax. 
• 
AUCt: Area under the plasma concentration time curve within a dosage interval (0 to 
last measurable concentration) after the first dose. 
• 
AUCτ: Area under the plasma concentration time curve within a dosage interval (0 to 
24 hours) after the first dose. 
• 
AUCinf: Area under the plasma concentration time curve extrapolated to infinity. 
• 
AUC%ext: Percentage of AUC extrapolated. 
• 
t½: Terminal elimination half-life. 
• 
λz: Elimination rate constant. 
• 
CL/F: Apparent total clearance of the drug from plasma after s.c. administration. 
• 
Vz/F: Apparent volume of distribution during terminal phase after s.c. administration. 


 
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Additional exploratory model-based analysis using non-linear mixed effects model 
(population PK analysis) might also be conducted using specific software (e.g. NONMEM). 
7.4 
Pharmacodynamic Assessment(s) 
For this study, the primary PD parameter will be GH. 
The other PD parameters, IGF-1 and PRL concentrations will be regarded as secondary 
endpoints and used as supportive information to complete the efficacy evaluation. 
Blood samples will be collected at timepoints indicated in the Study Schedule of Events (see 
Section 15.1). 
All PD parameters will be assessed in a central laboratory. All details of sample collection, 
handling and shipment will be provided in the laboratory manual. Details of methodology and 
reference ranges will be provided in the TMF. 
7.5 
Pharmacokinetics/Pharmacodynamics Evaluation 
To investigate the relationship between PD/safety variables (GH, IGF-1, PRL, blood pressure, 
HR) and PK exposure, exploratory PK/PD modeling might be performed if a relationship 
between BIM23B065 exposure and PD effect can be defined. Details regarding PK and 
PK/PD modeling will be described in a separate Pharmacometric Analysis Plan and results 
will be reported in a standalone report. 
7.6 
Optional Exploratory Assessment(s) 
7.6.1 
Tumour Tissue Receptors Profile 
For subjects who have undergone pituitary surgery and who consent (on a separate and 
specific consent) paraffin-fixed tumour tissue (when available and in accordance with local 
regulations) will be collected for further analyses on correlation of the GH, IGF-1 and PRL 
responses with the expression of SSTR2, SSTR5 and D2. 
7.6.2 
Biobanking 
Analysis of biobank samples will be performed outside the scope of the main study and 
reported separately. 
Serum and plasma, whole blood samples for RNA and whole blood samples for DNA, are 
biobanked for future analysis of circulating markers, including proteins, pharmacogenetic and 
pharmacogenomic biomarkers and will only be collected for those subjects who have agreed 
to it by signing the specific informed consent form for the optional exploratory part of the 
study. 
The biobanked samples will be stored for up to 15 years from the end of the study, to be made 
available for future research towards further understanding of (i) treatment response 
including, but not limited to, the safety profile, (ii) drug treatment mode of actions and (iii) 
disease understanding. 
Instructions for collection, processing, handling and shipment of the samples banking are 
outlined in Section 15.5 and will be detailed in the laboratory manual.  
Samples to be used for serum, plasma and whole blood for DNA, and whole blood for RNA, 
will be at timepoints indicated in the Study Schedule of Events (see Section 15.1). 
Serum/Plasma Biobank for Biomarker Assessment 
Total blood will be collected on specific dry tubes for serum isolation and frozen for storage. 
Further details of sample collection, coding and analysis will be provided in a laboratory 
manual. 
Blood for DNA and RNA for Biobank 


 
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Blood will be collected in PAXgene DNA and RNA tubes, which have proprietary materials 
in them to preserve the integrity of the nucleic acids so only the recommended volume should 
be collected. 
Further details of sample collection, coding and analysis will be provided in a laboratory 
manual. 
7.7 
Compliance to Study Procedures 
7.7.1 
Compliance to Protocol 
Every attempt will be made to select subjects who have the ability to understand and comply 
with instructions.  Noncompliant subjects may be discontinued from the study.  The time and 
day of drug administration may be recorded.  Drug accountability records will be maintained 
by the study site. 
7.7.2 
Compliance to Timing of Procedures 
The specifications in this protocol for the timings and dates of primary tests are given as 
targets, to be achieved within reasonable limits. The scheduled time points may be subject to 
minor deviations within the allowed time windows specified in the Study Schedule of Events 
(see Section 15.1); however, the actual time must always be correctly recorded in the eCRF 
and other relevant source documents. Any excursion outside of these allowed time windows 
might be regarded as protocol violation. 
Modifications may be made by the Sponsor to the time points based upon the 
safety/tolerability and PK information obtained.  Any major modification that might affect the 
conduct of the study, subject safety, and/or data integrity will be detailed in a protocol 
amendment. 


 
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8 
STATISTICAL ANALYSES 
8.1 
Data Analysis Plan 
8.1.1 
General Considerations 
Statistical analysis will be performed by the Sponsor or designee selected Contract Research 
Organisation (CRO) according to ICH E9 guidelines  and using SAS version 9.3 or higher. 
Further details of the statistical analyses will be available in a Statistical Analysis Plan 
developed by the CRO per Sponsor agreement and approval. All data will be listed and 
summarised for the BID (Stage 1) and TID (Stage 2) treatment regimen separately. 
8.1.2 
Analyses Population 
The following populations will be used during statistical analyses: 
• 
Safety population/Intent to treat (ITT): All subjects with at least one IMP 
administration 
• 
Modified Intent to treat (mITT) population: All subjects in the Safety population with 
available pharmacodynamic data and no protocol deviations with relevant impact on 
PD data. 
• 
Efficacy Evaluable population: All subjects in the mITT population with non missing 
evaluations of the primary efficacy criterion (mean concentration of GH over 6 hours) 
at baseline and V8 (+14 days post baseline). 
• 
Per protocol (PP) population: All subjects in the efficacy evaluable population who 
complete the study and for whom no major protocol violations/deviations occurred. 
8.1.3 
Determination of Sample Size 
The maximum sample size will be 24 evaluable subjects (12 per stage). Enrolled subjects who 
drop out of the study prior to Day 14 GH evaluation may be replaced. If 12 evaluable subjects 
have already completed visit 8 (Day 14) any subsequent withdrawn subjects will not be 
replaced. 
A minimum of 8 of the 12 evaluable subjects must be responsive to a single test dose of 
octreotide pre-study defined as a >50% reduction in GH. 
Per the primary endpoint, a subject is defined as a responder if the median concentration of 
GH over 6 hours is ≤2.5µg/l or if there is at least 50% reduction from mean baseline in GH at 
Day 14 (after 6 days titration plus 8 days treatment).  
Based on the exact test for single proportion, twelve evaluable subjects per stage would be 
sufficient to have over 84% power, at a significance level of 0.05 (one sided) to reject the  
• 
null hypothesis that there is no indication of efficacy of BIM23B065 if the GH 
responder rate is at most 33%, assuming that the GH responder rate is equal to 75%.  
8.1.4 
Primary Analysis 
The primary efficacy variable is the percentage of subjects with mean GH ≤ 2.5 μg/l at V8 or 
at least 50% reduction in the mean change from baseline at V8 (14 days after first IMP 
administration) i.e. % GH responders. The mean serum concentration of GH is obtained for 
baseline and V8 from the non-missing serum concentrations of GH recorded over 6 hours on 
these days. The proportion of GH responders will be reported with its 90% confidence 
interval calculated using the exact Clopper-Pearson method. The null hypothesis that the GH 
responder rate is not clinically relevant will be rejected if the lower 90% confidence boundary 
is larger than 33%. Primary efficacy analysis will be based on the Efficacy evaluable 
population. 


 
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8.1.5 
Study Participant Disposition 
The numbers and percentages of subjects enrolled and included in the safety, ITT, mITT and 
efficacy evaluable populations will be tabulated. The reasons for subject exclusions from the 
populations will also be tabulated. In addition, the numbers of subjects who were treated, 
discontinued and completed will be tabulated. 
Primary reasons for discontinuation of study treatment will be tabulated. 
8.1.6 
Study Participant Characteristics 
Descriptive summary statistics (n, mean, standard deviation (SD), median, minimum, 
maximum) or frequency counts of demographics including age categories 18-64 yrs and 65-
75 yrs and baseline data (medical history, concomitant medications, etc.) will be presented by 
overall for the safety population(s). 
8.1.7 
Statistical Evaluation of Safety 
Safety analyses and summary tables will be based on the safety population. Adverse events 
reported by investigators will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA 19 or higher Version). 
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 as well as whether the AE occurred during 
up titration or after and the corresponding dose at the time of AE occurrence. 
All AEs and SAEs occurring during the Screening period will be reported;  
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 BIM23B065, or 
• 
it was present prior to receiving the dose of BIM23B065 but the intensity increased 
during the active phase of the study. 
All TEAEs will be flagged in the AEs listings. The incidence of all reported TEAEs and SAEs 
as well as non SAEs will be tabulated. In addition, summary tables will be presented by 
maximum intensity, drug relationship and TEAEs associated with premature withdrawal of 
study medication. 
Concomitant medication will be coded by using the World Health Organisation (WHO) Drug 
Dictionary (December 2015 Version or higher) and will be summarised 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) will be presented for vital 
signs (blood pressure and HR) 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. 
8.1.8 
Pharmacokinetic Analyses and Statistical Inference 
The PK data analysis will be performed independently by a CRO under the supervision of 
Ipsen’s Pharmacokinetics and Drug Metabolism (PDM) Department as described in Section 
7.3.4. 
Individual listings and summary tables of BIM23B065 concentrations will be provided. 
8.1.9 
Pharmacodynamics Analysis 
All PD data will be included in the subject data listings and summarised separately for the 
BID and TID regimen in the mITT set.  


 
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The following secondary response criteria will be defined on Day 7 and Day 14 based on the 
GH and IGF-1 profiles and their change from baseline: 
• 
Mean GH ≤ 1.0 µg/l  
• 
Mean GH ≤ 2.5 µg/l  
• 
Mean GH reduction from baseline ≥ 50% 
• 
Mean IGF-1 to <ULN (age normalised) 
For all secondary responses, the number and proportion of responders will be summarised 
over time by BIM23B065 actual dose level and overall.   
Individual profiles of GH, IGF-1 and PRL over time and their percent change from baseline 
will be summarised for each day separately in tabular and graphical formats. 
Individual profiles and % change from baseline in other PD parameters such as ACTH, 
Cortisol, LH, FSH, FT4 TSH and testosterone will be also be summarised. 
8.2 
Preliminary and/or Interim Analysis 
During each stage, interim and final analyses will occur after the number of subjects as 
presented in the table below complete their GH assessment on Day 14. The corresponding 
dosing arm (i.e. BID or TID) will be stopped for futility if the number of GH responders is not 
superior to the preset maxima, as defined in the Table 4. 
Table 4 Maximum Number of GH responders to declare futility 
Analysis occurs after # 
subjects with evaluable 
GH responder endpoint 
Maximum number of 
GH 
responders 
to 
declare futility 
6 (interim1) 
2 
8 (interim2) 
3 
12 (final) 
7 
 
If Stage 1 (BID) arm is stopped for futility, Stage 2 (TID) arm may be initiated, if warranted 
based on safety and tolerability. If final Stage 1 (BID) data show efficacy, Stage 2 will not be 
initiated. If Stage 2 arm is stopped for futility, the study will be terminated. 
The maximum threshold of 2 for the interim futility stop after 6 subjects and the threshold of 
3 after 8 subjects were determined based on the calculation of the predictive probability of 
failure at study end (6). Indeed, given the observed responders at interim time, we calculate 
the probability that the study will be a failure at the end of the stage, when 12 subjects will be 
available. Failure is when the lower bound for the Clopper-Pearson 90% confidence interval 
on GH responder rate does not exceed 33%. The distribution of responder rates for the 6 or 4 
subjects yet to be recruited after the interim analysis 1 and 2, respectively, was estimated 
using a beta-binomial distribution with probability equal to the observed responder rate in the 
interim set and beta prior with parameters (a=0.5, b=0.5). The predictive probability of failure 
was at least 95% at both interims. 
After 12 subjects, the threshold of 7 was set to the maximum number of responders so that the 
test would not be significant at the one-sided 5% level. 
Ongoing DRC are planned during the study. Data review will be documented in a 
data/medical review plan. See description of DRC in Section 12.3. 


 
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9 
DATA HANDLING AND RECORD KEEPING 
9.1 
Data Capture 
The following source data may be generated and handled for further data basing process: 
• 
Paper-based or electronic data captured in Case Report Forms 
• 
Paper-based or electronic data captured systems, other than the case Report Forms 
• 
Paper or electronic data from local or external vendors. 
To ensure accurate, complete, and reliable data, the Sponsor or its representative will provide 
instructional material to the study site(s), as appropriate. Training session will be given during 
a start-up/initiation meeting for instructions on the completion/data entry of any source data 
documents and Case Report Forms. 
The Investigators or their designees must verify that all data entries in the eCRFs are accurate 
and correct.  If certain information is not available for a particular timepoint and/or subject, 
specific instructions should be followed, e.g. to document that the procedure was either not 
done (ND) or not applicable (NA). 
Every effort should be made to ensure that all safety evaluations are completed by the same 
individual who made the initial baseline determination. 
9.2 
Data Handling 
All or part of the data will be monitored at periodic visit to the study site, according to a 
monitoring plan.  All entries in the eCRFs, corrections and alterations are to be made by the 
responsible Investigator or his/her designee. 
Once monitored and cleaned, the paper-based data (either source or transcribed data) that 
have been selected for populating the database will follow a single entry process.  Electronic 
data will be directly entered in the database. 
Details of all data management procedures, from the initial planning to the archiving of final 
datasets / documents following database freeze/lock will be documented in appropriate data 
management and validation plan(s). Among others, these procedures will also describe quality 
control (QC) checks, data handling process for any missing, unused or spurious data, as well 
as coding procedures for AE’s, medical history, non drug therapy and medications. 
9.3 
Record Keeping 
The Investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes. 
Depending on the data collected and the type(s) of data, records will be kept following 
storage, and archiving procedures agreed by the Sponsor/Investigator site involved in this 
study, and in accordance to any regulations that are applicable in the country(ies) where the 
study is conducted. 


 
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10 
REGULATORY AND ETHICAL CONSIDERATIONS 
The study will be conducted in compliance with 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.  
10.1 
Subject Information Sheet and Consent 
The Investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering, orally and/or in writing, to any 
questions the subject may have throughout the study and sharing any new information that 
may be relevant to the subject’s willingness to continue his or her participation in the study in 
a timely manner. 
The subject information sheet and consent document will be used to explain the potential risks 
and benefits of study participation to the subject in simple terms before the subject is entered 
into the study, and to document that the subject is satisfied with his or her understanding of 
the study and desires to participate.   
The Investigator is ultimately responsible for ensuring that the EC-approved informed consent 
is appropriately signed and dated by each subject prior to the performance of any study 
procedures. Informed consent obtained under special circumstances may occur only if 
allowed by local laws and regulations. 
10.2 
Ethical Review Considerations 
The following documents should be submitted to the relevant Ethics Committee(s) (EC’s) for 
review and approval to conduct the study (this list may not be exhaustive): 
• 
Protocol/amendment(s) approved by the Sponsor, 
• 
Currently applicable IB or package labelling, 
• 
Relevant Investigator’s curriculum vitae, 
• 
Subject information and ICD(s) and form(s), 
• 
Subject emergency study contact cards 
• 
Recruitment procedures/materials (advertisements), if any. 
The EC(s) will review all submission documents as required, and a written favourable opinion 
for the conduct of the study should be made available to the Investigator before initiating the 
study. This document must be dated and clearly identify the version number(s) and date(s) of 
the documents submitted/reviewed and should include a statement from the EC that they 
comply with GCP requirements. 
The study may begin at the Investigator site(s) only after receiving this dated and signed 
documentation of the EC approval or favourable opinion. 
During the study, any update to the following documents will be sent to the EC either for 
information, or for review and approval, depending on how substantial the modifications are: 
(1) IB; (2) reports of SAEs; (3) all protocol amendments and revised informed consent(s), if 
any. 
At the end of the study, the Ethics Committee will be notified about the study completion. 


 
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10.3 
Regulatory Considerations 
This study will be conducted in accordance with applicable laws and regulations, GCPs, and 
the ethical principles that have their origin in the Declaration of Helsinki. 
All or some of the obligations of the Sponsor will be assigned to a (CRO).  
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other trial-related data. 
10.4 
Final Report Signature 
The Investigator or designee will proposed to review and sign the clinical study report for this 
study, indicating agreement with the analyses, results, and conclusion of the report. 


 
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11 
INSURANCE AND FINANCE 
11.1 
Insurance 
The Sponsor declares that it has taken out a product liability insurance covering all subjects 
screened and enrolled in this study in respect to risks involved in the study.  
11.2 
Financial Agreement 
Since this study is to be performed in partnership with a Contract Research Organisation (the 
CRO) in charge of project management and other CROs (third parties), separate financial 
agreements between the Sponsor and the CRO on one side, the CRO and third parties and the 
Investigator site(s) and the third party on the other side, will be signed prior to initiating the 
study, outlining overall Sponsor and Investigators responsibilities in relation to the study. 


 
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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will provide 
instructional material to the study sites, as appropriate.  A start-up training session will be 
done prior to screening start to instruct the Investigators and investigational site staff.  This 
session will give instruction on the protocol, the completion of the eCRFs, and all study 
procedures. 
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 and Exceptions 
Protocol deviations are defined and classified either Major or Minor for a given study. Major 
deviations (or combination of minor becoming major) may impact or not the analysis 
Population. All minor and major protocol deviations will be identified and recorded by 
clinical unit personnel and should be traceable 
 
Major Protocol Deviation definition: 
Any changes in the study design, study conduct and/or procedures that are not in accordance 
with the protocol and any study materials originally approved by the IEC/IRB and which may 
affect the subject’s rights, safety or well-being, or the completeness, accuracy and reliability 
of the study data.  
Minor Protocol Deviation definition 
Any changes in the study design, study conduct and/or procedures that are not in accordance 
with the protocol and any study materials originally approved by the IEC/IRB but do not have 
a major impact on the subject’s rights, safety or well-being, or the completeness, accuracy and 
reliability of the study data. 
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 is required before the subject will be 
allowed to enter the study. 
If investigative clinical unit personnel learn that a subject who did not meet protocol 
eligibility criteria was entered in a study (Eligibility criteria deviation), they must immediately 
inform the Sponsor. Such subjects will be discontinued from the study treatment, except in an 
exceptional instance, following review and written approval by the Sponsor and the 
responsible IRB/IEC. 
12.1.3 
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 


 
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must be listed on the clinical unit 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. 
12.2 
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 well-being 
of subjects are protected, 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. 
Before the study initiation visit, the Sponsor assigned CRO will write a monitoring plan 
indicating the monitoring procedures and at which occasions during the study monitoring 
visits will be performed. 
Periodic visits will be made to the study site throughout the study at mutually agreeable times.  
Any appropriate communication tools will be set up to ensure the Sponsor and/or its 
representative is/are available for consultation, so they can stay in contact with the study site 
personnel. 
Adequate time and space for monitoring visits should be made available by the Investigator. 
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 activities, if requested. 
Quality of the paper-based or electronic data will be reviewed to detect errors in data 
collection and, if necessary, to verify the quality of the data. 
The eCRF is expected to be completed an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The study monitor 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’s personal data (e.g. name, address, phone…) is present on a document 
required by the Sponsor (e.g. laboratory print outs) these data must be blacked out 
permanently by the site personnel, leaving the date of birth visible (or only the year of birth 
depending on local regulation), and annotated with the subject number as identification. 
12.3 
Data Review Committee 
The DRC will be composed of the coordinating Investigator, the Sponsor drug safety 
physicians, the Sponsor medical director, the Sponsor clinical pharmacology representant and 
a statistician. Ad hoc members may be part of the DRC if required by the permanent 
members. A specific charter will be developed to define roles and responsibilities. Safety and 
efficacy data will be summarised and presented to the DRC. 
For both the BID and the TID cohorts and for the first 3 subjects, the DRC will review the 
first 7 days safety data including blood biochemistry, blood pressure and ECG data. Once the 
DRC has approved the study to continue, subjects may be enrolled at a rate of a maximum of 
3 subjects completing visit 3 per week. 
During each stage (i.e. BID and TID cohorts), DRC will meet for interim and final analyses 
after the 6, 8 and 12 subjects have completed their GH assessment on Day 14.  


 
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Details of the DRC set up, membership, management and responsibilities will be provided in 
the DRC charter and archived in the TMF. 
12.4 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP rules.  This includes 
that the study may be audited at any time by a Quality Assurance (QA) personnel designated 
by the Sponsor, or by regulatory bodies. The Investigator must adhere to the GCP principles 
in addition to any applicable local regulations.   
If requested, the Investigator will provide the Sponsor, applicable regulatory agencies, and 
applicable Ethics Committee with direct access to any original source documents. 
The Investigator(s) should demonstrate due diligence in recruitment and screening of potential 
study subjects. The enrolment rate should be sufficient to complete the study as agreed with 
the Sponsor. The Sponsor should be notified of any projected delays, which may impact the 
completion of the study. 
12.4.1 
Audit and Inspection 
Authorised personnel from external CAs and the Sponsor’s authorised QA personnel may 
carry out inspections and audits. 
12.4.2 
Data Quality Assurance 
All data Monitored will be reviewed (secondary monitoring) for completeness, consistency, 
and protocol compliance by the assigned data management group. 
Reasons should be given in 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 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 
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. 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 65 of 78 
 
14 
REFERENCES 
 
1. 
Alexandru Saveanu, Rakesh Datta, Shengwen Zhang, Yeelana Shen, Jesse Z Dong, 
Thomas Graillon, Celine Desfilles, Tanya Landsman, Heather A Halem, Alain 
Enjalbert, Anne Barlier and Michael D Culler. Novel Somatostatin-Dopamine Chimeric 
Compound Demonstrates Superior Efficacy in Suppressing Growth Hormone Secretion 
from Human Acromegalic Tumors Partially Responsive to Current Somatostatin and 
Dopamine Therapies. Poster Endocrine Society's 98th Annual Meeting and Expo, April 
1–4, 2016. 
2. 
Heather A. Halem, Shengwen Zhang, Rakesh Datta, Amy Bastille, Jeremy Beech, 
Marilyn Marques, Shraddha Patel, Yeelana Shen, Jesse Z. Dong and Michael D. Culler. 
A Novel Somatostatin-Dopamine Chimeric Compound Induces Dose-Related 
Suppression of GHRH-Stimulated Growth Hormone Secretion and Increases Insulin 
Sensitivity in Normal Rats. Poster Endocrine Society's 98th Annual Meeting and Expo, 
April 1–4, 2016. 
3. 
Baragli A, Alturaihi H, Watt HL, Abdallah A, Kumar U. Heterooligomerisation of 
human dopamine receptor 2 and somatostatin receptor 2 Co-immunoprecipitation and 
fluorescence resonance energy transfer analysis. Cell Signal. 2007 ;19(11): 2304-16. 
4. 
Investigator’s Brochure BIM23B065, Final Version No. 2.0, Dated 08 April 2016. 
5. 
Guidance Clinical Trial Facilitation Group, Recommendations related to contraception 
and pregnancy testing in clinical trials, September 2014. 
6. 
J Jack Lee and Diane D Liu. A predictive probability design for phase II cancer clinical 
trials. Clinical Trials 2008; 5: 93–106. 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 66 of 78 
 
15 
ATTACHMENTS 
15.1 
Attachment 1 – Study Schedule 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 67 of 78 
 
Study Schedule of Events - Protocol D-FR-10380-002 
 
 
Screening 
Treatment 
End of Study 
 
V1 
V2 
V3 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Procedures and assessments 
Screening 
Octreotide 
test dose 
Baseline 
Pre-dose 
Post-1st 
dose 
Up-titration 
Up-titration 
Up-
titration 
 
Primary endpoints 
EOS/ED 
 
Week 
-3 to -1 
-3 to -1 
-1 
1 
1 
1 
2 
2 
2 
4 
Day 
-21 to -7 
-21 to -7 
-1 
1 and 2 
3 
5 
7 
10 
14 
28 ± 2 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
x 
 
x 
 
 
 
 
 
 
x 
Hospitalisation1 
 
 
x 
x 
 
 
 
 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
x 
x 
x 
 
 
 
 
 
 
 
Octreotide test dose 
 
x2 
 
 
 
 
 
 
 
 
IMP administration3 
 
 
 
x4 
x5 
x5 
x5 
x5 
x6 
 
Gallbladder echography 
x7 
 
 
 
 
 
 
 
 
x 
Physical exam8 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
12-lead ECG9 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
3-lead Holter ECG10 
 
 
x 
x 
 
 
x 
x 
 
 
Vital signs 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Body Temperature 
 
 
x 
 
 
 
 
 
 
 
Body Height, Body Weight11 
x 
 
x 
 
 
 
 
 
 
x 
ABP12 
 
 
x13 
x 
x 
x 
x 
x 
x 
 
Blood Pressure (non automated) and 
HR 
x 
 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x 
Orthostatic BP 
x 
 
x15 
x15 
x15 
x15 
x15 
x15 
x15 
 
Clinical Laboratory tests 
x 
 
x 
 
x16 
x16 
x17 
x16 
x16 
x 
PK assessments 
 
 
 
 
 
 
x18 
x 
x18 
 
PD assessments 
 
 
 
 
 
 
 
 
 
 
GH and PRL cycle 
x19 
 
x20 
 
 
 
x20 
 
x20 
 
IGF-1 
x 
 
x 
 
 
 
 
 
x 
x 
Safety endocrine assessments 
 
 
 
 
 
 
 
 
 
 
ACTH, Cortisol23, FSH, FT4, 
TSH, LH, Testo21
 
 
x22 
x22 
 
 
x22 
 
x22 
x 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 68 of 78 
 
 
Screening 
Treatment 
End of Study 
 
V1 
V2 
V3 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Procedures and assessments 
Screening 
Octreotide 
test dose 
Baseline 
Pre-dose 
Post-1st 
dose 
Up-titration 
Up-titration 
Up-
titration 
 
Primary endpoints 
EOS/ED 
 
Week 
-3 to -1 
-3 to -1 
-1 
1 
1 
1 
2 
2 
2 
4 
Day 
-21 to -7 
-21 to -7 
-1 
1 and 2 
3 
5 
7 
10 
14 
28 ± 2 
HbA1c 
x 
 
x 
 
 
 
 
 
x 
x 
Insulin, glucagon and concurrent 
glucose24 
 
 
x 
x 
 
 
 
 
x 
 
Pituitary tumour tissue collection25 
x 
 
 
 
 
 
 
 
 
 
Biobanking26 
 
 
x 
 
 
 
 
 
x 
x 
Antibodies anti-BIM23B065 
 
x27 
 
 
 
 
 
 
 
x 
 
1. 
Hospitalisation for 24 hours to include at a minimum pre-first dose baseline assessments up to the morning dose on Day 2 and post-dose assessments. For TID cohort 
hospitalisation will last the whole treatment period 
2. 
Octreotide test dose with 100μg octreotide with 6 hours with GH sampling at -15 min, 1, 2, 3, 4, 5 and 6 hours post-octreotide dose 
3. 
IMP will be administered twice a day (with an interval of 12 hours ± 1 hour between the morning and the evening administration) or three times a day (every 8 hours ± 
1hour with first IMP administration around 8 am, second one around 4 pm and third one around midnight)  
4. 
Both doses on Day 1 and morning dose on Day 2 (for BID regimen, if the subject returns home, evening dose of Day 2 to be administered by HCP at subject’s home) 
5. 
For BID regimen, morning dose only during visit and evening dose at home (if the subject returns home). For TID regimen all doses will be performed at hospital. 
6. 
Final study IMP dose to be given in the morning at study visit. No evening dose will be administered (BID) nor the afternoon and the night dose for TID 
7. 
Gallbladder echography performed at screening between Day -21 and Day -7 
8. 
Physical examinations are to be performed prior to IMP injection 
9. 
Twelve-lead computerised standard ECG whilst the subject is in resting supine position for at least 10 minutes. 3 consecutive ECGs will be obtained. At Visit 3 (at 
Day -1 and at Day 1), Visit 4, Visit 5, Visit 6, Visit 7 and Visit 8, ECGs will be performed within 1 hour pre-dose and 30 minutes and 2 hours post-dose. At Visit 1 
and Visit 9, only 1 set of 3 consecutive ECG will be obtained. 
10. 
Three lead holter ECG will be recorded for 24 hour period starting at least 15 minutes pre-dose. The 24 hour period will cover two or three IMP administrations (BID 
in stage 1 and TID in stage 2). Assessment to be performed at Day -1 (for baseline assessment) Day 1, Day 7 and Day 10. 
11. 
Body height only at screening. Body weight at screening, Day 1 pre-dose and Day 28. 
12. 
Automated blood pressure will be taken starting at least 1 hour before the morning dose and will last for 4 hours post dose. Recordings should be taken every 30 
minutes for the first hour pre and post-dose, then every 15 minutes for the second hour post-dose and every 30 minutes for the next 2 hours post-dose. 
13. 
Automated blood pressure will be performed twice at Visit 3 at Day -1 (as baseline assessment) and at Day 1. 
14. 
Supine blood pressure. At Visit 3 (both at Day -1 as baseline assessment and at Day 1), Visit 4, Visit 5, Visit 6, Visit 7 and Visit 8, Blood pressure will be recorded 1 
hour pre-dose then post-dose at : 30 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, 1 hour 45 minutes and 2 hours. 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 69 of 78 
 
15. 
Orthostatic BP At Visit 3, Visit 4, Visit 5, Visit 6, Visit 7 and Visit 8, Blood pressure will be recorded 1 hour pre-dose then post-dose at : 30 minutes, 1 hour, and 2 
hours. For Visit 5 and Visit 6 additional Orthostatic BP will be recorded on Day 4 and Day 6 respectively at the following timepoints; 1 hour pre and post evening (for 
BID) or 1 hour pre and post night (for TID) dose of Day 4 and Day 6 
16. 
Clinical laboratory tests (including urine samples) at visits 4, 5, 7 and 8 should be done pre-dose in the morning 
17. 
Clinical laboratory tests (including urine samples) at visits 6 should be done pre-dose in the morning and 6 hours post-dose (morning dose) 
18. 
PK samples for BIM23B065 will be taken at visits 6 and 8 at pre-dose (-15 minutes), 0.5h, 1h, 2h, 4h and 6h post-morning IMP dose 
19. 
PRL and Mean concentration of GH over 2 hours (5 samples at T0 then every half an hour up to 2 hours) 
20. 
PRL and Mean concentration of GH over 6 hours means will be obtained with PRL and GH samples pre-dose (-15 minutes) and at 0.5h, 1h, 2h, 4h and 6h. For Visit 3 
PRL and mean GH over 6 hours will be obtained at Day -1 (as baseline assessment) 
21. 
Testosterone will be assessed for males only 
22. 
Blood samples for ACTH, FT4, TSH, LH, FSH and testosterone will be taken at baseline pre-dose on Day -1, 1 hour post dose in the morning of Day 2 and 1 hour 
post. dose in the morning of Day 7 and Day 14. 
23. 
Serum Cortisol will be assessed at baseline on Day -1 and and at Visit 9 (EOS/ED). Samples should be withdrawn at 8 am. 
24. 
Samples at morning pre-dose in fasting condition, 2 h after first dose, 1 sample just before lunch and 1 sample 1h and 2h after lunch on Day -1, Day 1 and Day 14. 
25. 
If tumour tissue is available and subject consents 
26. 
Serum/plasma and whole blood for RNA (at Baseline (Day-1), Visit 8 (Day 14) and Visit 9 (Day 28) and whole blood for DNA (only at Baseline (Day -1)) 
27. 
Antibody sample to be taken prior to octreotide test dose 
 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 70 of 78 
 
15.2 
Attachment 2 –Clinical Laboratory Tests 
 
 
Scre 
Main 
 
Scre 
Main 
Haematology 
 
 
Clinical Chemistry 
 
 
Haematocrit 
x 
x 
Sodium 
x 
x 
Haemoglobin 
x 
x 
Potassium 
x 
x 
Erythrocyte count (RBC) 
x 
x 
Bicarbonate 
x 
x 
Mean cell volume (MCV) 
x 
x 
Chloride 
x 
x 
Mean cell haemoglobin (MCH) 
x 
x 
Calcium 
x 
x 
Mean cell haemoglobin concentration (MCHC) 
x 
x 
Phosphorus 
x 
x 
Leukocytes (WBC) 
x 
x 
Glucose (fasting) a 
 
 
Absolute counts of: 
 
 
Amylase 
x 
x 
Neutrophils 
x 
x 
Lipase 
x 
x 
Lymphocytes 
x 
x 
Urea 
x 
x 
Monocytes 
x 
x 
Total cholesterol 
x 
x 
Eosinophils 
x 
x 
Total protein 
x 
x 
Basophils 
x 
x 
Albumin 
x 
x 
Platelets 
x 
x 
Total bilirubin 
x 
x 
 
 
 
Conjugated bilirubin 
x 
x 
Coagulation 
 
 
Alkaline phosphatase (ALP) 
x 
x 
Activated partial thromboplastin time 
x 
x 
Aspartate aminotransferase 
(AST) 
x 
x 
Prothrombin time and derived measures of 
prothrombin ratio 
x 
x 
Alanine aminotransferase 
(ALT) 
x 
x 
International normalised ratio (INR) 
x 
x 
Creatinine 
x 
x 
 
 
 
Gamma-glutamyl transferase 
(GGT) 
x 
x 
Urinalysis f 
 
 
Triglycerids (TG) 
x 
x 
pH 
x 
x 
Total creatine kinase 
x 
x 
Protein 
x 
x 
Glycated Haemoglobin (A1C) 
x 
x 
Glucose 
x 
x 
Insulin, concurrent Glucose 
and Glucagon 
x 
x 
Ketones 
x 
x 
 
 
 
Bilirubin 
x 
x 
Endocrine 
 
 
Urobilinogen 
x 
x 
TSH 
x 
x 
Blood 
x 
x 
FT4 
x 
x 
Nitrite 
x 
x 
FSH 
x 
x 
Microscopic examination of sediment (if 
indicated) b 
Opt. 
Opt. 
ACTH 
x 
x 
Pregnancy testc 
 
 
Testosterone g 
x 
x 
 
 
 
Cortisol 
 
 
 
 
 
LH 
x 
x 
Scre = Screening visit(s), Main = Treatment Study Part and EoS/ED, Opt. = Optional 
a 
Glucose measured in fasting  
b 
will not be collected in the eCRF unless abnormal 
c 
Urine pregnancy test at least at screening, predose and discharge from the study (EoS/ED). Serum 
pregnancy test will be performed only in case of positive urine pregnancy test. 
f 
Urinalysis performed via dipstick.  
G 
Only male 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 71 of 78 
 
15.3 
Attachment 3 – Blood Sampling Summary 
This table summarises the maximum number of (veni) punctures and blood volumes for all 
blood sampling (screening, safety laboratories and bio-analytical assays) during the study.   
Fewer venipunctures and blood draws may actually occur if needed for safety purposes, but 
this will not require a protocol amendment. 
 
Category 
Description 
Volume tube 
(mL) 
Number of 
Samples 
Total Volume 
(mL) 
Safety 
Haematology 
4 
9 
36 
Biochemistry 
8.5 
9 
76.5 
Coagulation 
4.5 
9 
40.5 
HbA1c 
3 
4 
12 
ACTH 
2 
5 
10 
Cortisol, FT4, TSH, FSH, LH, 
Testosterone 
3 
5 
15 
Insulin, glucose 
2 
15 
30 
Glucagon 
2 
15 
30 
BIM23B065 Antibodies 
2 
2 
4 
Biobank 
Biobank serum 
5 
3 
15 
Biobank DNA 
8.5 
1 
8.5 
Biobank RNA 
2.5 
6 
15 
PK 
PK 
7 
13 
91 
PD 
GH, PRL 
2 
30 
60 
IGF-1 
2 
4 
8 
Total 
volume 
  
  
  
451.5 
HbA1c = Haemoglobin A1c, FT4 = Free thyroxine, TSH = thyroid stimulating hormone, FSH = follicular stimulating 
hormone, LH = luteinising hormone, DNA = Deoxyribonucleic acid, RNA = Ribonucleic acid, PK = Pharmacokinetics, 
GH = Growth Hormone, IGF-1 = Insulin-like Growth Factor 1, PRL = Prolactin, ACTH = Adrenocorticotropic hormone 
 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 72 of 78 
 
15.4 
Attachment 4 – Liver Safety Algorithm 
 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 73 of 78 
 
15.5 
Attachment 5 - Biobanking 
Biobanking involves the collection of blood samples. Blood samples will be collected only in 
subjects who have signed consent for the exploratory part, particularly for the biobank 
samples, during specific time points described in Section 15.1 (Attachment 1 – Study 
Schedule). One of the four blood samples will be centrifuged (serum sample); the three others 
will not be centrifuged (two blood samples in RNA PAXgene and one blood sample in DNA 
PAXgene tubes). The samples should be clearly and appropriately labelled with the following 
minimum information: study code, subject number, and visit name. 
The samples will be stored at -80°C at the site or a central laboratory. The samples will then 
be shipped regularly to the biobanking central laboratory, FISHER, on dry ice. Upon receipt 
of each shipment with samples, an acknowledgment of receipt made out by the contact person 
will be sent to the site or the central laboratory. The samples will then be stored at the 
biobanking central laboratory, FISHER, for future exploratory biomarker analysis. 
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 programme. 
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: 
 
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CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 74 of 78 
 
15.6 
Attachment 6 – Protocol Amendment Summary 
All additions have been identified by the use of underline and all deletions by strikethroughs. 
 
Front page 
Pharmacovigilance contact details:  
, Ipsen 
Biopharm Ltd 
EU Qualified Person for Pharmacovigilance 
102 Park Drive, Milton Park, Oxfordshire, OX14 4RY, England 
Tel: 
 
Mob: 
 
 
Synopsis 
 
 
Endocrine parameters: Adrenocorticotrophic Hormone (ACTH), Cortisol, Luteinizing Hormone (LH), 
Follicle Stimulating Hormone (FSH), Free Thyroxine (FT4), Thyroid Stimulating Hormone (TSH) and 
Testosterone (for males only). 
 
3.2.4 Safety Endpoints and Evaluations 
• 
Endocrine parameters: Adrenocorticotrophic Hormone (ACTH), Cortisol, Luteinizing 
Hormone (LH), Follicle Stimulating Hormone (FSH), Free Thyroxine (FT4), Thyroid 
Stimulating Hormone (TSH) and Testosterone (for males only). 
 
4.5 
Exclusion Criteria 
Potential study subjects may not be entered into the study if any of the following apply: 
… 
(6) 
It is anticipated that the subject will undergo pituitary surgery or radiation to the 
pituitary gland during the study, or will require additional medical therapy for acromegaly 
(including SSA, pegvisomant, or dopamine agonists) during the study. 
(7) 
The subject has unsubstituted/untreated adrenal insufficiency. 
(8) 
If the subject has any history of postural hypotension or evidence of postural 
hypotension at screening (>= 20 mm Hg decrease in SBP, >= 10 mm Hg decrease in DBP, or 
>=30 bpm increases in pulse rate, after standing for 2 minutes from resting supine position of 
at least 10 min). 
 
7.1 
Safety Assessments 
… 
• 
Clinical safety laboratories, including clinical chemistry, haematology, HbA1c, 
insulin, glucagon and concurrent glucose. 
• 
Endocrine parameters including, ACTH, Cortisol, LH, FSH, FT4, TSH and 
Testosterone (for male subjects only); 
• 
Gallbladder echography, 
 
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Page 75 of 78 
 
8.1.9 Pharmacodynamics Analysis 
… 
For all secondary responses, the number and proportion of responders will be summarised 
over time by BIM23B065 actual dose level and overall.   
Individual profiles of GH, IGF-1 and PRL over time and their percent change from baseline 
will be summarised for each day separately in tabular and graphical formats. 
Individual profiles and % change from baseline in other PD parameters such as ACTH, 
Cortisol, LH, FSH, FT4 TSH and testosterone will be also be summarised. 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 76 of 78 
 
Study Schedule of Events - Protocol D-FR-10380-002 
 
 
Screening 
Treatment 
End of Study 
 
V1 
V2 
V3 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Procedures and assessments 
Screening 
Octreotide 
test dose 
Baseline 
Pre-dose 
Post-1st 
dose 
Up-titration 
Up-titration 
Up-
titration 
 
Primary endpoints 
EOS/ED 
 
Week 
-3 to -1 
-3 to -1 
-1 
1 
1 
1 
2 
2 
2 
4 
Day 
-21 to -7 
-21 to -7 
-1 
1 and 2 
3 
5 
7 
10 
14 
28 ± 2 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
x 
 
x 
 
 
 
 
 
 
x 
Hospitalisation1 
 
 
x 
x 
 
 
 
 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
x 
x 
x 
 
 
 
 
 
 
 
Octreotide test dose 
 
x2 
 
 
 
 
 
 
 
 
IMP administration3 
 
 
 
x4 
x5 
x5 
x5 
x5 
x6 
 
Gallbladder echography 
x7 
 
 
 
 
 
 
 
 
x 
Physical exam8 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
12-lead ECG9 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
3-lead Holter ECG10 
 
 
x 
x 
 
 
x 
x 
 
 
Vital signs 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Body Temperature 
 
 
x 
 
 
 
 
 
 
 
Body Height, Body Weight11 
x 
 
x 
 
 
 
 
 
 
x 
ABP12 
 
 
x13 
x 
x 
x 
x 
x 
x 
 
Blood Pressure (non automated) and 
HR 
x 
 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x 
Orthostatic BP 
x 
 
x15 
x15 
x15 
x15 
x15 
x15 
x15 
 
Clinical Laboratory tests 
x 
 
x 
 
x16 
x16 
x17 
x16 
x16 
x 
PK assessments 
 
 
 
 
 
 
x18 
x 
x18 
 
PD assessments 
 
 
 
 
 
 
 
 
 
 
GH and PRL cycle 
x19 
 
x20 
 
 
 
x20 
 
x20 
 
IGF-1 
x 
 
x 
 
 
 
 
 
x 
x 
Safety endocrine assessments 
 
 
 
 
 
 
 
 
 
 
ACTH, Cortisol23, FSH, FT4, 
TSH, LH, Testo21 
 
 
x22 
x22 
 
 
x22 
 
x22 
x 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 77 of 78 
 
 
Screening 
Treatment 
End of Study 
 
V1 
V2 
V3 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Procedures and assessments 
Screening 
Octreotide 
test dose 
Baseline 
Pre-dose 
Post-1st 
dose 
Up-titration 
Up-titration 
Up-
titration 
 
Primary endpoints 
EOS/ED 
 
Week 
-3 to -1 
-3 to -1 
-1 
1 
1 
1 
2 
2 
2 
4 
Day 
-21 to -7 
-21 to -7 
-1 
1 and 2 
3 
5 
7 
10 
14 
28 ± 2 
HbA1c 
x 
 
x 
 
 
 
 
 
x 
x 
Insulin, glucagon and concurrent 
glucose24 
 
 
x 
x 
 
 
 
 
x 
 
Pituitary tumour tissue collection25 
x 
 
 
 
 
 
 
 
 
 
Biobanking26 
 
 
x 
 
 
 
 
 
x 
x 
Antibodies anti-BIM23B065 
 
x27 
 
 
 
 
 
 
 
x 
 
…. 
23. 
Serum Cortisol will be assessed at baseline on Day -1 and and at Visit 9 (EOS/ED). Samples should be withdrawn at 8 am. 
 


 
CONFIDENTIAL – Protocol n°: D-FR-10380-002 v2.0  Date: 14-SEPTEMBER-2016 
Page 78 of 78 
 
15.2 
Attachment 2 –Clinical Laboratory Tests 
 
… 
Microscopic examination of sediment (if 
indicated) b 
Opt. 
Opt. 
ACTH 
x 
x 
Pregnancy testc 
 
 
Testosterone g 
x 
x 
 
 
 
Cortisol 
 
 
 
 
 
LH 
x 
x 
 
 
15.3 
Attachment 3 – Blood Sampling Summary 
 
Category 
Description 
Volume tube 
(mL) 
Number of 
Samples 
Total Volume 
(mL) 
Safety 
Haematology 
4 
9 
36 
Biochemistry 
8.5 
9 
76.5 
Coagulation 
4.5 
9 
40.5 
HbA1c 
3 
4 
12 
ACTH 
2 
5 
10 
Cortisol, FT4, TSH, FSH, LH, 
Testosterone 
3 
5 
15 
Insulin, glucose 
2 
15 
30 
Glucagon 
2 
15 
30 
BIM23B065 Antibodies 
2 
2 
4 
Biobank 
Biobank serum 
5 
3 
15 
Biobank DNA 
8.5 
1 
8.5 
Biobank RNA 
2.5 
6 
15 
PK 
PK 
7 
13 
91 
PD 
GH, PRL 
2 
30 
4660 
IGF-1 
2 
4 
8 
Total 
volume 
  
  
  
437.5451.5 
HbA1c = Haemoglobin A1c, FT4 = Free thyroxine, TSH = thyroid stimulating hormone, FSH = follicular stimulating 
hormone, LH = luteinising hormone, DNA = Deoxyribonucleic acid, RNA = Ribonucleic acid, PK = Pharmacokinetics, 
GH = Growth Hormone, IGF-1 = Insulin-like Growth Factor 1, PRL = Prolactin, ACTH = Adrenocorticotropic hormone 
 
 

SAP_001.pdf: 
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Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 1 of 37 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
A phase IIA, open-label, single-arm, two stage, multi-centre study to investigate the 
pharmacodynamics, pharmacokinetics, safety and tolerability of repeated subcutaneous 
administration of BIM23B065 in subjects with acromegaly  
Protocol version 2.0 
 
 
 
Signature 
 
Date 
Author: 
  
Biostatistician II 
 
  
 
 
 
  
Reviewed by: 
 
Manager, Biostatistics 
 
  
 
 
 
Project Statistician, ClinBAY 
Limited 
 
 
  
Approved by: 
 
Chief Scientific Officer, Scientific 
Strategy 
 
  
 
 
 
 
  
 
Clinical Statistics Manager, IPSEN 
Pharma, SAS 
 
  
 
 
 
 
 
 
 
 
 
Effective Date: 10-FEB-2017 
 
Version: 
1.0 
PPD
PPD
PPD
PPD
PPD


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 2 of 37 
 
TABLE OF CONTENTS      
 
1. 
HISTORY OF CHANGES .......................................................................................................5 
2. 
ABBREVIATIONS ....................................................................................................................6 
3. 
GENERAL .................................................................................................................................9 
3.1. Distribution list ..........................................................................................................................9 
3.1.1. Contact Details of Accelsiors Biostatistics team ..................................................................9 
3.1.2. Contact Details of Vendors ..................................................................................................9 
3.2. Scope .......................................................................................................................................11 
3.3. Purpose ....................................................................................................................................11 
3.4. Preparation, Review and Changes to the SAP ........................................................................11 
3.5. Changes to the Protocol ...........................................................................................................12 
4. 
PREFACE ................................................................................................................................12 
5. 
STUDY OBJECTIVES AND ENDPOINTS .........................................................................12 
5.1. Study Objectives .....................................................................................................................12 
5.1.1. Primary Objective ..............................................................................................................12 
5.1.2. Secondary Objectives .........................................................................................................13 
5.1.3. Exploratory Objectives .......................................................................................................13 
5.1.4. Biobanking .........................................................................................................................13 
5.2. Study Endpoints ......................................................................................................................13 
5.2.1. Primary Endpoints and Evaluations ...................................................................................13 
5.2.2. Secondary Endpoints and Evaluations ...............................................................................13 
5.2.3. Exploratory Endpoints and Evaluations .............................................................................14 
5.2.4. Safety Endpoints and Evaluations ......................................................................................14 
5.2.5. Pharmacodynamics and Pharmacokinetics Endpoints and Evaluations .............................14 
5.2.6. Biobanking Endpoints and Evaluations .............................................................................15 
6. 
STUDY METHODS ................................................................................................................15 
6.1. Overall Study Design and Plan ...............................................................................................15 
6.2. Selection of Study Population .................................................................................................16 
6.3. Method of Treatment Assignment and Randomization ...........................................................16 
7. 
SEQUENCE OF PLANNED ANALYSIS .............................................................................16 
7.1. Data Review Committee (DRC)..............................................................................................16 
7.2. Interim Analysis ......................................................................................................................17 
7.3. Monthly blood pressure and 12-lead ECG report....................................................................20 
7.4. Final Analyses .........................................................................................................................21 
8. 
SAMPLE SIZE DETERMINATION ....................................................................................21 
9. 
ANALYSIS POPULATIONS .................................................................................................21 
9.1. Use of analysis populations in different analyses....................................................................22 
10. GENERAL ISSUES FOR STATISTICAL ANALYSIS ......................................................22 
10.1. Definition of Treatment Arms .................................................................................................22 
10.2. Definition of Baseline .............................................................................................................22 
10.3. Definition of Visit Windows ...................................................................................................23 
10.4. Multicentre Study ....................................................................................................................23 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 3 of 37 
 
10.5. Planned Subgroup Analyses ....................................................................................................24 
10.6. Analysis Software ...................................................................................................................24 
10.7. Derived and Computed Variables ...........................................................................................24 
11. STUDY SUBJECTS ................................................................................................................26 
11.1. Disposition of Subjects and Withdrawals ...............................................................................26 
11.2. Protocol Deviations .................................................................................................................26 
11.3. Study Participant Disposition ..................................................................................................27 
12. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ............................27 
12.1. Demographics..........................................................................................................................27 
12.2. Drug Exposure.........................................................................................................................27 
12.3. Prior and Concomitant Medications ........................................................................................27 
12.4. Baseline and Screening Conditions .........................................................................................28 
12.4.1. Baseline Medical History ...................................................................................................28 
12.4.2. Baseline Octreotide Test ....................................................................................................28 
12.4.3. Baseline Body Temperature, Height and Weight ...............................................................28 
12.5. Measurement of Treatment Compliance .................................................................................28 
13. EFFICACY ANALYSIS .........................................................................................................29 
13.1. Primary Efficacy Variable Analyses .......................................................................................29 
13.1.1. Sensitivity and Supportive Analyses for the Primary Efficacy Variable ...........................29 
13.1.2. Subgroup Analyses .............................................................................................................29 
13.2. Secondary Efficacy Variable Analysis ....................................................................................29 
13.2.1. GH responders ....................................................................................................................30 
13.2.2. PD endpoints ......................................................................................................................30 
14. SAFETY AND TOLERABILITY ANALYSES ....................................................................30 
14.1. Adverse Events ........................................................................................................................30 
14.1.1. Summary of AEs ................................................................................................................31 
14.1.2. Deaths .................................................................................................................................31 
14.1.3. AE listings ..........................................................................................................................31 
14.1.4. AE tables ............................................................................................................................31 
14.2. Cardiovascular Vital Signs ......................................................................................................32 
14.2.1. Blood Pressure and Heart Rate ...........................................................................................32 
14.2.2. Orthostatic hypotonia .........................................................................................................32 
14.2.3. 12-lead ECG .......................................................................................................................32 
14.2.4. 3-lead Holter .......................................................................................................................33 
14.3. Clinical Laboratory Assessments ............................................................................................33 
14.3.1. Haematology, Clinical Chemistry, Coagulation, Urinalysis ..............................................33 
14.3.2. Parameters of the Glucose Metabolism ..............................................................................34 
14.3.3. Antibodies to BIM23B065 .................................................................................................34 
14.3.4. Endocrine Parameters .........................................................................................................34 
14.4. Gallbladder Echocardiography ................................................................................................35 
14.5. Physical Examination ..............................................................................................................35 
14.6. Pregnancies..............................................................................................................................35 
15. OTHER PLANNED ANALYSIS ...........................................................................................35 
15.1. Pharmacometrics .....................................................................................................................35 
15.2. Tumour tissue receptor expression and drug response ............................................................35 
15.3. Biobanking ..............................................................................................................................35 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 4 of 37 
 
16. DEPARTURES FROM THE ANALYSIS PLANNED IN THE PROTOCOL .................36 
17. LIST OF APPLICABLE QUALITY DOCUMENTS ..........................................................36 
17.1. List of Relevant SOPs and WINs ............................................................................................36 
18. REFERENCES ........................................................................................................................36 
 
 
 
                                                     
 
 
 
 
      1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 5 of 37 
 
1. 
HISTORY OF CHANGES 
 
All versions of the document have to be documented in the table of history of changes. 
The owner of the document has to act in accordance with the latest version of the document.  
 
Status 
Version 
Effective Date 
(10-FEB-2017) 
Change description 
Current version 
1.0 
 
First version 
 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 6 of 37 
 
2. 
ABBREVIATIONS 
 
Acronyms, 
Abbreviations, Initials 
Description / Explanation 
ACC 
Accelsiors CRO and Consultancy Services 
ACTH 
Adrenocorticotrophic Hormone 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
BID 
Bis in die (twice a day) 
BP 
Blood Pressure 
BS 
Biostatistics 
CBC 
Complete Blood Count 
Core Review Team 
Consists of Project Manager, Head of Drug Safety Unit, Clinical 
Data Manager, Biostatistician 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DLT 
Dose Limiting Toxicities 
DM 
Data Management 
DMP 
Data Management Plan 
DNA 
Deoxyribonucleic acid  
DRC 
Data Review Committee 
DSMB 
Data and Safety Monitoring Board  
D2 
Dopamine Receptor Sub-type 2 
ED 
Early Discontinuation 
EE 
Efficacy Evaluable 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 7 of 37 
 
Acronyms, 
Abbreviations, Initials 
Description / Explanation 
EoS 
End of Study 
FDA 
United States Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
FT4 
Free Thyroxine 
FU 
Follow Up 
GCP 
Good Clinical Practice 
GH 
Growth Hormone 
HR 
Heart Rate 
ICU 
Intensive Care Unit 
IGF-1 
Insulin-like Growth Factor-1 
IMP 
Investigational Medicinal Product 
ITT 
Intent-To-Treat Population 
LH 
Luteinizing Hormone 
mITT 
Modified Intent to Treat 
NA 
Not Applicable 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PM 
Project Manager 
PP 
Per-Protocol Population 
PRL 
Prolactin 
QA 
Quality Assurance 
QC 
Quality Control 
RA 
Regulatory Authority 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 8 of 37 
 
Acronyms, 
Abbreviations, Initials 
Description / Explanation 
RNA 
Ribonucleic Acid 
SBP 
Systolic Blood Pressure 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIV 
Site Initiation Visit 
SMP 
Study Management Plan 
SOP 
Standard Operating Procedure 
SSTR2 
Somatostatin Receptor 2 
SSTR5 
Somatostatin Receptor 5 
TEAE 
Treatment-emergent AE 
TID 
Ter in die (Three times a day) 
TSH 
Thyroid Stimulating Hormone 
WIN 
Work Specific Instruction 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 9 of 37 
 
3.
GENERAL 
 
3.1.
Distribution list 
Statistical Analysis Plan is an Accelsiors confidential document. 
Accelsiors: Complete SAP is distributed to Project Management.  
IPSEN/Aepodia: Complete SAP is made available for Aepodia S.A. and Ipsen Pharma SAS for 
internal distribution. 
3.1.1.
Contact Details of Accelsiors Biostatistics team 
Biostatistician  
  
Háros u. 103. 
1222 Budapest 
Hungary 
Phone: 
 
Fax: 
 
E-Mail: 
 
SAS Programmer  
 
Háros u. 103. 
1222 Budapest 
Hungary 
 
Phone: 
Fax: 
E-Mail: 
 
 
 
3.1.2.
Contact Details of Vendors 
Laboratory for PD 
Parameters  
 
Institut für 
Laboratoriumsmedizin, 
Klinische Chemie und 
Molekulare Diagnostik 
Paul-List-Str. 13/15 
04103 Leipzig 
 
Phone: 
 
Fax: 
 
 
Laboratory for PK 
Parameters 
Kymos Pharma Services S.L. 
Parc Tecnològic del Vallès 
Ronda Can Fatjó, 7B 
 08290 - Cerdanyola del 
Vallès Barcelona 
Phone: 
 
Laboratory for 
Immunogenicity 
Testing 
Bertin Pharma  
Parc d’Activités du Pas du  
Lac 10 bis avenue Ampère 
78180 Montigny le Bretonne
- France 
Phone: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 10 of 37 
 
Supporter of Cardiac 
Safety Assessments 
Biomedical Systems SA/NV 
Waversesteenweg 1945 
Chaussée de Wavre 
1160 Brussels, Belgium 
Phone: 
 
Fax: 
 
PPD
PPD


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 11 of 37 
 
3.2. 
 Scope 
This SAP applies to all planned statistical analyses performed by Accelsiors Biometrics. Details 
regarding PK and PK/PD modelling will be described in a separate Pharmacometric Analysis 
Plan. Any other statistical tasks, which are not analysis-related (e.g. Protocol and CRF Review) 
are out of the scope of this plan. These tasks are described in detail in the applicable BS SOPs 
and WINs. 
Activity/Task 
Sponsor/ 
3rd Party 
Vendor 
ACC 
N/A 
Interim statistical analyses 
 
X 
 
Final statistical analyses 
 
X 
 
PK analysis 
X 
 
 
PK/PD analysis 
X 
 
 
 
3.3. 
Purpose 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
completion of the Clinical Study Report (CSR) for protocol D-FR-10380-002. The planned 
analyses identified in this SAP will be included in regulatory submissions and/or future 
manuscripts. Also, exploratory analysis not necessarily identified in this SAP may be performed 
to support the clinical development program. Any post-hoc, or unplanned analysis not 
identified in this SAP will be clearly identified in the respective CSR. 
3.4. 
Preparation, Review and Changes to the SAP 
The SAP will be prepared by ACC Biostatistician for submission to ACC PM and to the Aepodia 
S.A. and Ipsen Pharma SAS study team for review and input. Final approval is given by the ACC 
Chief Scientific Officer and by the head of statistics of Ipsen Pharma SAS. The SAP needs to be 
finalized before the first patient first visit. 
SAP is subject to the periodic review as appropriate in relation to the trial status. The 
authoring, review and approval of SAP revisions will follow the same process as for the initial 
version. Review may result in possible extension, modification or replacement in the form of 
an Appendix, Amendment, or Revision.  


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 12 of 37 
 
 The core review team is responsible for ensuring that after any changes all sections of the 
Statistical Analysis Plan will be harmonised.  
3.5. 
Changes to the Protocol 
In case the clinical study protocol undergoes a major amendment affecting statistical analyses 
procedures then a new version of the SAP will be issued. 
Authoring, review and approval process of new SAP versions will be the same as for the 
initial version.  
 
4. 
PREFACE 
 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Ipsen 
Pharma SAS protocol D-FR-10380-002 (A phase IIA, open-label, single-arm, two stage, multi-
centre study to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability 
of repeated subcutaneous administration of BIM23B065 in subjects with acromegaly). This 
phase IIA study is being carried out to assess pharmacodynamics, safety and tolerability of 
BIM23B065 for the treatment of acromegaly. The structure and content of this SAP provides 
sufficient details to meet the requirements identified by the FDA and International Conference 
on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH): Guidance on Statistical Principles in Clinical Trials. The following documents were 
reviewed in preparation of this SAP: 
x Clinical Study Protocol D-FR-10380-002 issued 27 July 2016. 
x Clinical Study Protocol version 2, D-FR-10380-002 issued 14 September 2016. 
x CRF Module Plan 1.1. for Protocol D-FR-10380-002. 
 
5. 
STUDY OBJECTIVES AND ENDPOINTS 
 
5.1. 
Study Objectives 
5.1.1. 
Primary Objective 
x To assess the pharmacodynamics (PD) of repeated administration of BIM23B065 in 
reducing growth hormone (GH) in subjects with acromegaly. 
 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 13 of 37 
 
5.1.2. 
Secondary Objectives 
x To assess the safety and tolerability of repeated administration of BIM23B065 in 
subjects with acromegaly.  
x To assess the pharmacokinetics (PK) and PD of repeated administration of BIM23B065. 
x To investigate the PK of BIM23B133 which is the major metabolite of BIM23B065.  
x To assess the correlation of BIM23B065 exposure with blood pressure (BP) and heart 
rate (HR). 
 
5.1.3. 
Exploratory Objectives 
x To correlate GH, Insulin-like Growth Factor-1 (IGF-1) and Prolactin (PRL) responses 
with expression of Somatostatin Receptor 2 (SSTR2), Somatostatin Receptor 5 (SSTR5) 
and Dopamine receptor sub-type 2 (D2) in pituitary tumour tissues, when available.  
x To assess anti-drug antibodies (ADA). 
 
5.1.4. 
Biobanking 
x To explore potential utility of biomarkers for association with drug activity, adverse 
events (AEs), to explore drug mechanism of action and/or disease understanding. 
Serum/plasma, whole blood samples will be collected for deoxyribonucleic acid (DNA) 
and whole blood samples for ribonucleic acid (RNA). 
 
5.2. 
Study Endpoints 
PD endpoints are primary and PK and safety are secondary endpoints in this study. PD and 
safety endpoints are further described below. PK endpoints, PK and PK/PD analyses are 
detailed in a separate Pharmacometrics Analysis Plan document. 
5.2.1. 
Primary Endpoints and Evaluations 
x The proportion of subjects with GH ื2.5μg/l or >50% reduction from mean baseline 
GH (measured over 6 hours on Day -1) after 6-day titration plus 8-day treatment with 
BIM23B065 measured by mean serum concentration of GH over 6-hours on Day 14.  
 
5.2.2. 
 Secondary Endpoints and Evaluations 
x Assessment of safety and tolerability.  
x Assessment of the proportion of subjects with GH <1.0μg/l after 6-day titration plus 8-
day treatment with BIM23B065 measured by mean serum concentration of GH over 
6-hours at Day 14.  
x Determination of the efficacy of BIM23B065 in reducing IGF-1 to <ULN (age 
normalised) after 6 day-titration and 8-day treatment period at Day 14 and Day 28.  


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 14 of 37 
 
 
5.2.3. 
Exploratory Endpoints and Evaluations  
x Assessment of ADA.   
x Exploration of the relationship between response to BIM23B065 and the expression of 
SSTR2, SSTR5 and D2 in those subjects with available tumour tissue.  
 
5.2.4. 
Safety Endpoints and Evaluations  
x Adverse Events.   
x Vital signs (supine and standing BP and HR).  
x 12-lead ECG and ECG monitoring by 3-lead Holter device at specific timepoints, QTc 
interval will be calculated using Fridericia methodology.  
x Clinical laboratory assessments: haematology, coagulation, clinical biochemistry 
including glucose, glucagon and insulin measurements, urinalysis.  
x Putative antibodies to BIM23B065.  
x Endocrine parameters: Adrenocorticotrophic Hormone (ACTH), Cortisol, Luteinizing 
Hormone (LH), Follicle Stimulating Hormone (FSH), Free Thyroxine (FT4), Thyroid 
Stimulating Hormone (TSH) and Testosterone (for males only), .  
x Gallbladder echography.   
 
5.2.5. 
Pharmacodynamics and Pharmacokinetics Endpoints and Evaluations  
•  
PD Assessments:  
- Mean serum concentration of GH over 6 hours at baseline (Day -1), Day 7 and Day 14.  
- IGF-1 levels at baseline, Day 14 and Day 28.   
- PRL levels over 6 hours at baseline, Day 7 and Day 14.  
• PK Assessments:  
- Time points will follow a sparse PK sampling approach. On day 7 (first day of 1.0mg) 
pre-dose, 0.5h, 1h, 2h, 4h and 6h post-morning dose. On day 14 (last day of 1.0mg) 
pre-dose, 0.5h, 1h 2h, 4h and 6h post-morning dose.  
- One random sampling for PK analysis will also be taken at further routine study visits 
(Day 10) to co-ordinate with safety and PD assessments.  
- Drug (BIM23B065) and its major metabolite BIM23B133.  


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 15 of 37 
 
5.2.6. 
Biobanking Endpoints and Evaluations  
To biobank whole blood samples for DNA at baseline pre-dose (Day -1), serum/plasma and 
whole blood samples for RNA at baseline pre-dose (Day -1), at Day 14 and Day 28 (EoS/ED).  
 
6. 
STUDY METHODS 
 
6.1. 
Overall Study Design and Plan 
This is an open-label, non-randomised, multi-centre, adaptive two-stage phase II study. 
During Stage 1, up to 12 subjects will be enrolled to receive BIM23B065 BID for two 
weeks. The primary endpoint will be the proportion of subjects with GH ≤2.5 μg/l or >50% 
reduction from baseline GH on Day 14. The mean serum concentration of GH collected over 6 
hours will be used for the baseline (Day -1) and endpoint (Day 14) GH determination.  
Several sequential analyses will occur during Stage 1. The Stage 1 arm (BID 
administration) may be terminated early for futility during each of these interim analyses if 
the responder rate does not exceed the pre-determined minimum efficacy criteria. In that 
case, a Stage 2 arm will be initiated during which up to 12 subjects will be recruited to receive 
BIM23B065 three times a day (TID) for 14 days. The same sequential analysis and early 
termination rule for futility will apply during Stage 2 as for Stage 1. 
Any subjects who withdraw prior to the Day 14 end of treatment visit may be replaced 
except for early withdrawal due to safety and tolerability reasons. As soon as 12 subjects (out 
of which at least 8 are Octreotide responders as tested during the screening period) reach 
Visit 8, withdrawn subjects will not be replaced.  
Both the BID and TID regimen parts will consist of 3 periods (See Figure 1):  
• 
A screening period of 21 days maximum during which the eligibility criteria will be 
assessed. An Octreotide test will be also performed at the latest 7 days prior to first IMP 
administration. 
• 
A treatment period that will consist of twice or three times daily administrations of 
BIM23B065. This period will last for 14 days. The first 6 days will be a titration of 
BIM23B065 (0.4 mg/0.6 mg/0.8 mg BID or TID). Then a stable target dose (1.0 mg) of 
BIM23B065 will be BID or TID administered from Day 7 to Day 14.  
• 
If during the study, a subject experiences any safety or laboratory events (for detailed 
description see Table 1 of the Protocol), they may have their dose reduced to the prior 
dose. The minimum dose allowed for the treatment period is 0.6mg BID or TID. 
• 
If during the titration period, the subject experiences any cardiovascular events that 
meet the protocol determined criteria (for detailed description see Table2 of the 
Protocol), they must remain on their current dose and not be dose escalated. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 16 of 37 
 
• 
A follow up period that will last for 14 days during which the subjects will not be 
administered BIM23B065. 
 
Figure 1 Study Schema
 
 
6.2. 
Selection of Study Population 
The detailed description of the inclusion and exclusion criteria can be found in the study 
Protocol. 
6.3. 
Method of Treatment Assignment and Randomization 
No randomisation list will be required for this open-label study. Enrolled subjects will be 
identified throughout the study with the unique subject number assigned at screening. 
 
7. 
SEQUENCE OF PLANNED ANALYSIS 
 
7.1. 
Data Review Committee (DRC) 
Details of the DRC set up, membership, management and responsibilities will be provided in 
the DRC charter and archived in the TMF. Safety and efficacy data will be summarised and 
presented to the DRC according to analyses planned in the DRC charter. 
Day 
21
Day 
7
Day 
1
Day 
7
Day 
14
Day 
28
Octreotide 
T
t
14 days 
F ll
U
14 days 
Treatment 
21 days 
Screening 
Titration 
Stable 
dose 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 17 of 37 
 
7.2. 
Interim Analysis  
During Stage 1, two interim analyses are planned after 6 and 8 subjects complete the Day 14 
GH assessment. The DRC will meet and review the number of GH responders on Day 14 (i.e. a 
GH responder is defined as a subject with GH ≤2.5μg/l or with at least 50% reduction from 
baseline GH after 6-day titration plus 8-day treatment with BIM23B065 measured by mean 
serum concentration of GH over 6 hours at Day 14) as well as the safety and tolerability data 
defined in the DRC charter.  
Based on the safety and efficacy data of these subjects, the DRC will decide if the BID cohort 
may be continued or stopped, and if stopped, if a TID cohort (Stage 2) may be initiated, 
according to the following criteria (please see  
Figure 2 below).  
• 
If there are less than 3 out of 6 (3/6) responders then the BID regimen (Stage 1) will be 
stopped for futility and Stage 2 will be initiated, where new enrolled subjects will follow 
the TID administration part (Option 1 in  
• 
Figure 2). 
If there is at least 3/6 responders, then the Stage 1 will continue: the next 2 subjects will follow 
the BID administration part and DRC will review the safety and efficacy data once 8 evaluable 
subjects will have completed Stage 1. 
• 
If there are less than 4 responders (out of 8 subjects) then the BID regimen (Stage 1) 
will be stopped for futility and Stage 2 will be initiated, where new enrolled subjects will 
follow the TID administration part (Option 2 in  
• 
Figure 2). 
If there are at least 4 responders (out of 8 subjects), then the Stage 1 will continue: the next 4 
subjects will follow the BID administration part and DRC will review the safety and efficacy 
data once 12 subjects will have completed Stage 1. 
• 
If there are less than 8 responders (out of 12 subjects) then the Stage 2 will be initiated, 
where new enrolled subjects will follow the TID administration part (Option 3 in  
• 
Figure 2). 
If there are at least 8/12 responders, then no new subjects will be enrolled into the BID 
administration part, no TID administration part will be conducted and the study will be 
stopped as the primay objective is met with the BID regimen. 
At any time during Stage 1 if at least 3 subjects experienced at least one dose limiting 
toxicity (DLT) (the definition of DLT can be found in the study protocol Table 3.) then the DRC 
will stop the recruitment and no TID administration part will be conducted. 
During Stage 2, two interim analyses are planned after the first 6 and 8 subjects will 
have completed the GH Day 14 assessment. The DRC will review safety and efficacy data of 
these subjects in order to decide if the trial may be stopped early for futility or not (please see 
Figure  below).  


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 18 of 37 
 
If there are less than 3/6 responders, then no new subjects will be enrolled into the 
TID administration part and the study will stop (Option 1 in Figure ). 
If there are at least 3 responders (out of 6 subjects), then the next 2 subjects will follow 
the TID administration part and DRC will review the safety and efficacy data once 8 subjects 
will have completed Stage 2. 
If there are less than 4 responders (out of 8 subjects) then the TID regimen (Stage 2) 
will be stopped for futility, no new subjects will be enrolled into the TID administration part 
and the study will stop (Option 2 in Figure ). 
If there are at least 4 responders, then Stage 2 will continue: the next 4 subjects will 
follow the TID administration part once 12 subjects will have completed Stage 2 and the study 
will be stopped (Option 3 in Figure ). 
Again, at any time during Stage 2 if at least 3 subjects experienced at least one DLT, 
then the DRC will stop the recruitment. 
 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 19 of 37 
 
Figure 2 BID administration part (Stage 1)
 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 20 of 37 
 
Figure 3 TID administration part (Stage 2)
 
 
7.3. 
Monthly blood pressure and 12-lead ECG report 
On the second week of each month a report will be created presenting the blood pressure 
and ECG parameters for all subjects enrolled until the beginning of the month.  
Systolic blood pressure, diastolic blood pressure and heart rate will be listed with visit 
days and time-points. The time-matched change from baseline (the same time-point on Day 
-1) will be calculated, and listed. Descriptive statistics (n, mean, SD, median, minimum and 
maximum) will be provided for the scheduled values and changes from baseline at each time 
point. 
ECG parameters (RR interval, PR/PQ interval, QRS interval, QT interval, QTc interval 
(calculated according to the Fridericia method), and HR) will be listed at each visit and time 
point, along with their change from the time-matched baseline of Day-1. Descriptive statistics 
will be provided about the measured values and the calculated change of baseline. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 21 of 37 
 
 
Number and proportion of subjects with absolute QTc values above 460, 480 and 500 
msec and subjects with a QTc change more than 30 and 60 msec from baseline will be 
presented at each time point.  
7.4. 
Final Analyses 
The study can be discontinued prematurely at any time if the Sponsor judges it for any 
appropriate reason, and for safety reasons, patients will not be dosed further.  
In the final analyses all data will be listed for the BID (Stage 1) and TID (Stage 2) treatment 
regimen separately and summary tables will be created including the results of both stages. 
 
8. 
SAMPLE SIZE DETERMINATION 
 
A sufficient number of subject will be enrolled so that there is a maximum of 24 evaluable 
subjects for the primary analysis (12 per stage). Enrolled subjects who drop out of the study 
prior to Day 14 GH evaluation may be replaced so that 12 are evaluable per Stage. 
(Replacement strategy is detailed in Section 10.1.). 
A minimum of 8 of the 12 evaluable subjects must be responsive to a single test dose 
of octreotide pre-study defined as a >50% reduction in GH. 
Per the primary endpoint, a subject is defined as a responder if the mean concentration 
of GH over 6 hours is ≤2.5μg/l or if there is at least 50% reduction from mean baseline in GH 
at Day 14 (after 6 days titration plus 8 days treatment).  
Based on the exact test for single proportion, twelve evaluable subjects per stage would 
be sufficient to have over 84% power, at a significance level of 0.05 (one sided) to reject the 
null hypothesis that there is no indication of efficacy of BIM23B065 if the GH responder rate 
is at most 33%, assuming that the GH responder rate is equal to 75%.  
 
9. 
ANALYSIS POPULATIONS 
 
The following populations will be used during statistical analyses: 
• 
Safety population/Intent to treat (ITT): All subjects with at least one IMP administration 
• 
Modified Intent to treat (mITT) population: All subjects in the Safety population with 
available pharmacodynamic data and no protocol deviations with relevant impact on 
PD data. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 22 of 37 
 
• 
Efficacy Evaluable (EE) population: All subjects in the mITT population with an evaluable 
primary efficacy endpoint (mean concentration of GH over 6 hours) at baseline and V8 
(+14 days post baseline). 
• 
Per protocol (PP) population: All subjects in the efficacy evaluable (EE) population who 
complete the study and for whom no major protocol violations/deviations occurred. 
9.1. 
Use of analysis populations in different analyses 
Analyses 
 
Safety 
population/ 
Intent to 
Treat 
Population 
Modified 
Intent to 
Treat 
Population 
Efficacy 
Evaluable 
Population 
Per 
Protocol 
Population 
Baseline Assessments  
(including demographics, disease 
characteristics, prior therapies) 
9 
 
9 
 
Compliance and exposure 
9 
9 
9 
9 
PD Assessments 
 
9 
9 
 
Efficacy: Primary endpoint 
 
 
9 
9 
Efficacy: Secondary endpoints 
 
 
9 
9 
Safety (including concomitant 
therapies) 
9 
 
 
 
 
10. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS 
 
10.1. 
Definition of Treatment Arms 
It is a single-arm study, all subjects will receive the same IMP, BIM23B065. Patients with the 
different dosing regimens (BID and TID) will be presented as “BID” and “TID” subjects. 
10.2. 
Definition of Baseline 
Most baseline assessments will be performed on Day -1 (Visit 3) with some exceptions. In 
case the data of the planned baseline assessment is not available, the last assessment which 
precedes the first administration of the IMP will be used as a baseline. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 23 of 37 
 
x For the GH and PRL calculations the mean serum concentration will be used as 
baseline, collected over 6 hours on the Day -1. The baseline IGF-1 will be measured on 
Day -1.  
x For antibodies anti-BIM23B065 the baseline will be the serum concentration taken 
prior to octreotide test dose, on V2. 
x For other laboratory assessments (all endocrine and clinical laboratory assessments, 
parameters of glucose metabolism etc.) baseline will be the measurement of Day -1. 
At the parameters of glucose metabolism more baseline values will be used in 
accordance to the fasting condition or the relative time from meals (the fasting 
condition on Day -1 will be compared with the fasting condition of the studied day, 
while the assessment one hour after meal will be compared to the baseline (Day -1) 
one hour after meal measurement etc.). 
x For BP and HR, orthostatic hypotonia, and ECG, the baseline will be the corresponding 
measurements on Day -1 at the same time points (i.e. time-matched). For Holter the 
baseline will be the assessment on Day -1. 
x For gallbladder echography, the baseline will be the assessment during the screening 
period. 
x For other results of the physical examination (body weight, body temperature etc.) the 
D-1 assessments will be the baseline. 
 
10.3. 
Definition of Visit Windows 
There will be two stages. During Stage 1, the subjects will be enrolled to receive BIM23B065 
BID, and during Stage 2, TID. 
Both the BID and TID regimen parts will consist of 3 periods: screening, treatment, and follow 
up. 
Screening period will start on the date of signing the informed consent and ends on 
the Day -1, the day preceding the first dose of IMP on Day 1. Treatment phase will start on 
Day 1 and ends with the Visit 8. Follow up phase starts on the following day of the Visit 8 and 
ends with the End of Study/Early Discontinuation visit.  
Throughout the study 9 visits are planned (please see Study Schedule of Events in the 
Protocol). During the analysis visits will not be re-defined, eCRF visits will be used. Visits will 
be presented with the following labels: SCR (screening) D-1 (first day of Visit 3, pre-dose day), 
D1 – D14 (Day 1 is the first dosing day), EOS (End of Study day), ED (Early Discontinuation).   
10.4. 
Multicentre Study 
This is a multicentre study planned to be conducted in multiple centres from approximately 6 
countries. No subgroup analyses are planned by country, the data of the sites will be pooled. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 24 of 37 
 
 
10.5. 
Planned Subgroup Analyses 
Two age categories will be defined: subjects with 18-64 years age at baseline, and subjects 
with 65-75 years age at baseline. Descriptive statistics for the disposition, demographics, 
baseline characteristics, AE, primary and secondary endpoints will be prepared by age 
category and by octreotide responder category (responders/non responders).  
10.6. 
Analysis Software 
All analysis will be performed using SAS® Software version 9.3 or above.  
10.7. 
Derived and Computed Variables 
The following derived and computed variables have been initially identified. It is expected that 
additional variables could be required. The SAP will not be amended for additional variables 
unless they are directly related to the primary endpoint or key secondary efficacy variables. 
Any additional derived or computed variables will be identified and documented in the ADaM 
requirement documentation and/or in the footnotes of the outputs, where appropriate. 
Variable Name 
Description 
Valid 
values 
(Ranges) 
Computation methods, Notes or 
equation(s) 
OTPDMEN 
Mean GH over 6 
hours after octreotide 
dosing during 
Octreotide Test 
0-200 
ug/L 
= [SUM(GH measurements 1, 2, 3, 
4, 5, 6 hours post octreotide 
dose)]/number of valid GH 
measurements 
OTRBL 
Reduction from 
Baseline in GH level 
during Octreotide 
Test 
0-100 %  
= [1- (OTPDMEN/ Baseline GH 
level)] x 100 
GHMDX 
Mean GH over 6 
hours measured on 
DayX 
0-
200ug/L 
= [SUM(GH measurements 1, 2, 3, 
4, 5, 6)]/number of valid GH 
measurements over 6 hours on 
DayX] 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 25 of 37 
 
Variable Name 
Description 
Valid 
values 
(Ranges) 
Computation methods, Notes or 
equation(s) 
GHRGL 
Reduction from 
Baseline in GH level 
on DayX 
0-100 %  
= [1- (GHMDX/GHM(D-1))] x 100 
 
As a general rule mean will be calculated by summarizing the available valid (non-missing) 
measurements and divided by the number of measurements. Percent change from baseline 
will be calculated according to the following: [1- (present value/baseline value)] x 100. 
10.1. Methods for Missing Data  
A subject is considered evaluable if he or she completes the 14-day treatment period (with 6 
hours GH samples collected). Subjects who withdraw from the study before reaching the point 
of being evaluable may be replaced. If the withdrawal is due to safety and tolerability reasons 
no replacement will be performed, but otherwise the subject will be replaced. If 12 evaluable 
subjects have already completed visit 8 (day 14) any subsequent withdrawn subjects will not 
be replaced. 
A minimum of 8 octreotide responders must be evaluable in the final analysis. If an 
octreotide responder withdraws prematurely, he/she will be replaced by another octreotide 
responder. If an octreotide non-responder withdraws, they can be replaced by either a 
responder or non-responder. 
No substitution of missing values will be performed, an observed case approach will 
be used.  
In all listings, missing or incomplete dates will be left as they have been recorded. 
However, for calculation / sorting / assignation based on dates, the following methods will be 
used: 
x The most conservative approach will be systematically considered. For example, if 
the onset date of an AE/concomitant medication is missing / incomplete, it is 
assumed to have occurred during the study treatment phase (i.e. a TEAE for AEs) 
except if the partial onset date or other data (e.g. stop date) indicates differently. 
x A missing/incomplete date of medical history or disease diagnosis will be assumed 
to have occurred before any study treatment. 
Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the  administration performed on 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 26 of 37 
 
31JAN2004, the days since last dose will be “≥2”, similarly the duration of ongoing AEs or 
medication will be“≥xx” according to the start and last visit dates). 
If the severity or the relationship to the IMP is not available for an AE it will be marked 
as ‘unknown’. 
 
11. 
STUDY SUBJECTS 
 
Information on subjects of Stage BID and Stage TID will be presented in separately in lists and 
in the same tables. 
11.1. 
Disposition of Subjects and Withdrawals 
Disposition data will be listed for all subjects who entered this study.  
A frequency table will be created displaying disposition of patients including:  
x Total number of subjects entered (subjects who gave informed consent); 
x Number of screening failures/withdrawals before enrolment 
x Number of enrolled subjects  
x Number of subjects in the ITT set (subjects who received at least one IMP 
administration); 
x Number of subjects withdrawn after the treatment start date; 
x Number of subjects completed the treatment phase; 
x Number of subjects completing the study (including follow up); 
 
Withdrawals/Discontinuations during the treatment period will be summarized by the 
coded term for main reason of withdrawal (patients with a reason recorded as “other” will 
have an own category). Subjects withdrawn will be listed along with the reason and date of 
discontinuation. 
11.2. 
Protocol Deviations 
Protocol deviations will be assessed from medical aspect during a data review meeting before 
database lock in order to decide on subject’s eligibility to PP, EE and mITT populations. 
Protocol deviations will be classified as either minor or major. Details of protocol deviation 
evaluation will be provided in the study specific Protocol Deviation Handling Plan. 
Protocol deviations per subjects will be listed along with the description of the deviation 
and ‘minor’ or ‘major’ evaluation flags. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 27 of 37 
 
11.3. 
Study Participant Disposition 
The numbers and percentages of enrolled subjects included in the ITT, mITT, EE and PP 
populations will be tabulated. The reasons for subject exclusions from the populations will 
also be listed. 
 
12. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
 
12.1. 
Demographics  
Demographics will be presented descriptively for the ITT set.  
Descriptive statistics for continuous variable (age at baseline in years) will comprise N, 
arithmetic mean, standard deviation, minimum value, median, maximum value and number 
of non-missing values. Age (in integer, years) will be calculated from the difference between 
the recorded exact or rounded date of birth and the date of informed consent.  
Descriptive statistics for categorical variables (gender, race, ethnicity, age category) will 
comprise numbers of subjects and percentages in each category. 
12.2. 
Drug Exposure 
Incidence tables will present the actual doses per day. The descriptive statistics of the final 
and cumulative doses at the end of the titration and treatment periods will be presented. 
Total daily doses will be summarized and tabulated by day. 
The administered and planned total daily doses of each day will be listed with the 
cumulative doses at the end of the titration and treatment periods. 
Exposure time being the number of days when the subject received IMP will be 
summarized.  
12.3. 
Prior and Concomitant Medications 
Prior/concomitant medications will be coded using WHO Drug Dictionary (June 2016 Version 
or higher). These therapeutics will be listed by subject and by the second level of Anatomical 
Therapeutic Chemical (ATC) classification system code and ATC4 terms. Prior medication is 
defined as medication with a start date prior to the date of the first administration of the study 
medication. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 28 of 37 
 
12.4. 
Baseline and Screening Conditions 
Ideally, in general, baseline control assessments will be performed on Day -1 (Visit 3), for 
detailed description please see Section 10.2.  
12.4.1. Baseline Medical History 
Medical history/current medical condition events will be coded using MedDRA 19.1 or higher. 
These events will be listed by subject and by system organ class (SOC) and preferred terms 
(PT).  
The history of acromegaly will be detailed. Subjects will be listed with the date of 
acromegaly diagnosis, disease duration, the number of pituitary surgeries, the date, time since 
and the type of the last surgery and whether the patient is treatment naïve or not. Descriptive 
summaries will be presented for the main acromegaly characteristics. 
12.4.2. Baseline Octreotide Test 
Number and percentage of enrolled octreotide responders and non-responders will be 
presented. 
All enrolled subjects will be listed along with their octreotide test results. The baseline 
GH level, the mean GH in the 6 hours after a single sub-cutaneous injection of 100ug 
octreotide, the reduction from baseline (in %) and the responder status will be presented. An 
octreotide responder is defined as having a >50% reduction from baseline in mean GH in the 
6 hours. 
12.4.3. Baseline Body Temperature, Height and Weight 
Descriptive statistics for baseline vital signs (body weight, body height, body temperature 
along with the location of the measurement and D1 (predose) will be presented and the 
results will be listed. 
12.5. 
Measurement of Treatment Compliance 
Compliance factor will be determined for BIM23B065 on each day according to the following 
equation: 
Compliance (%) (on a day)= 
୅୫୭୳୬୲୭୤୆୍୑ଶଷ୆଴଺ହ୅ୢ୫୧୬୧ୱ୲ୣ୰ୣୢ
୅୫୭୳୬୲୭୤୆୍୑ଶଷ୆଴଺ହ୉୶୮ୣୡ୲ୣୢ୲୭ୠୣ୅ୢ୫୧୬୧ୱ୲ୣ୰ୣୢͳͲͲ 
Overall compliance (%) = 
େ୳୫୳୪ୟ୲୧୴ୣୟୢ୫୧୬୧ୱ୲ୣ୰ୢ୆୍୑ଶଷ୆଴଺ହ
େ୳୫୳୪ୟ୲୧୴ୣ୆୍୑ଶଷ୆଴଺ହ୉୶୮ୣୡ୲ୣୢ୲୭ୠୣ୅ୢ୫୧୬୧ୱ୲ୣ୰ୣୢͳͲͲ 
A subject will be considered as compliant on a day if its compliance rate is between 80 and 
120%. It will be overall compliant if the overall compliance rate is within 80-120%.  


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 29 of 37 
 
The descriptive statistics of the compliance percentages and rates on each day and overall will 
be presented. 
A by-patient listing will be created to display the compliance on each day and overall 
along with the presentation of any specific action that was applied during the dosing and the 
description of the reason for dose administration not occurred as planned. 
 
13. 
EFFICACY ANALYSIS 
 
13.1. 
Primary Efficacy Variable Analyses 
The primary efficacy variable is the percentage of subjects who are GH responders on Day 14. 
GH response is defined as having a mean GH ≤ 2.5 μg/l at Visit 8 (Day 14, after 6-day titration 
plus 8-day treatment with BIM23B065) or at least a 50% reduction in the mean GH change 
from baseline on Day 14. The mean serum concentration of GH is calculated at baseline and 
on Day14 from the non-missing serum concentrations of GH recorded over 6 hours on these 
days. The number and proportion (%) of GH responders will be reported with its 90% 
confidence interval calculated using the exact Clopper-Pearson method. The null hypothesis 
that the GH responder rate is not clinically relevant (i.e. <=33%) will be tested at the one-sided 
5% significance level. The exact p-value will be reported. The test will be rejected if the lower 
90% confidence limit is larger than 33%. Primary efficacy analysis will be based on the Efficacy 
Evaluable population. 
13.1.1. Sensitivity and Supportive Analyses for the Primary Efficacy Variable 
The primary efficacy analysis will be repeated on the Per Protocol Population, if the 
populations are different. 
13.1.2. Subgroup Analyses 
The number and proportion (%) of GH responders will be presented by age categories and by 
octreotide responders/non-responders. Confidence intervals will only be calculated for 
subgroups where the sample size N>2. 
13.2. 
Secondary Efficacy Variable Analysis 
The secondary efficacy endpoint analyses will be based on the Efficacy Evaluable and on the 
Per Protocol population. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 30 of 37 
 
13.2.1. GH responders 
The following secondary GH response criteria will be defined on Day 7 and Day 14 based on 
the GH profiles: 
x Mean GH ≤ 1.0 ug/l 
x Mean GH ≤ 2.5 ug/l 
x Mean GH reduction from baseline ≥ 50% 
 
The GH measurements, their mean by visit, the mean percent changes from baseline and the 
various GH responder criteria will be listed by patient and visit. The number and proportion 
(90% CI calculated by the Clopper-Pearson method) of GH responders on Day 7 and Day14 will 
be reported. 
 
Descriptive summaries will be presented for the measured GH values and for the 
calculated percent changes from baseline. Mean (+ SE) profiles over time will be displayed 
graphically. 
13.2.2. PD endpoints 
The IGF-1 and PRL measurements and the mean of the PRL concentration will be listed by 
patients and by visits along their change from baseline in percent.  
Descriptive summaries will be presented for the measured concentration values and 
for the calculated percent change from baseline in the mITT set. Mean (+ SE) profiles over time 
will be displayed graphically. 
The number and proportion (%) of subjects with IGF-1 < age normalized ULN, will be 
presented by visit along with the 90% Clopper-Pearson CI.  
 
14. 
SAFETY AND TOLERABILITY ANALYSES 
 
The safety analyses will be performed based upon the ITT population. 
14.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
central coding dictionary, version 19.1 or higher version. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 31 of 37 
 
Only treatment-emergent AEs (i.e. AEs which occurred or worsened in severity during 
or after the first administration of a study drug) will be presented in tables. AEs occurred 
before the first administration of the study drug will be listed separately. 
14.1.1. Summary of AEs 
An overview AE summary table will be prepared presenting the number and proportion of 
subjects in the following categories:  
x subjects reporting any adverse events 
x subjects with Serious AEs (SAEs) 
x deaths 
x subjects with AEs leading to early withdrawal 
x subject with severe AEs 
x subjects with IMP-related AEs 
 
A data listing of SAEs will be provided, displaying details of the event(s) captured on the 
eCRF. Serious adverse event narratives will be written by Accelsiors PV team and reviewed 
then by Aepodia S.A. and Ipsen Pharma SAS prior to be inserted in the CSR. 
14.1.2. Deaths  
The details of the event(s) captured on the eCRF will be supplied and narratives will be written 
by Accelsiors PV team and reviewed the by Aepodia S.A. and Ipsen Pharma SAS.  
14.1.3. AE listings 
All treatment-emergent AEs (TEAEs) will be listed by subject ID, presenting the start and end 
date of AE, the duration, as well as the period in which it occurred (titration/treatment), the 
last dose received prior to AE occurrence, classification by SOC and PT, severity, outcome, 
concomitant treatment, relationship to study medication (i.e. related or not related) and 
action taken. 
AEs occurred before the first study drug administration will be listed separately. 
A listing of AEs leading to withdrawal, SAEs, deaths will be provided, displaying details 
of the event(s) captured on the eCRF.  
14.1.4. AE tables 
Summary tables of number of subjects with TEAEs will be provided by PT in decreasing 
frequency, by SOC and PT and by SOC, PT and maximum severity. If a patient experiences more 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 32 of 37 
 
than one AE within a preferred term, only the AE with the greatest intensity will be included 
in the summaries.  
14.2. 
 Cardiovascular Vital Signs 
14.2.1. Blood Pressure and Heart Rate 
All available measurements (i.e. systolic blood pressure, diastolic blood pressure and heart 
rate) will be listed with visit days and time-points. Abnormal values will be marked by bolding. 
The normality range for systolic blood pressure is 100-140mmHg, for diastolic blood pressure 
60-90mmHg and for the heart rate from blood pressure measurements 60-100mmHg 
(inclusive of the borders). 
The time-matched change from baseline will be calculated for all post-baseline 
scheduled measurements after D1 T0 that has corresponding measurement at the same time 
point on Day -1.  
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be provided 
for the scheduled values and changes from baseline at each time point.  
14.2.2. Orthostatic hypotonia 
The diagnosis of orthostatic hypotension can be set if there is a decrease between the 
measurement in a supine position and standing position of ≥20 mmHg in SBP or a ≥10 mmHg 
in DBP or an increase ≥30 bpm in heart rate. By patient listing will be provided with the 
measurement pairs (supine – standing), the position how they were measured, the calculated 
difference between the supine and standing measurement. The values will be flagged if any 
criteria of orthostatic hypotonia was fulfilled.  
 
Frequency tables will be created to present the proportion of subjects with orthostatic 
hypotension by visit, for each time point and overall. The number and proportion of 
orthostatic hypotension episodes will be summarized by visit.  
14.2.3. 12-lead ECG 
Detailed listing will be provided with all available data at each time point. Abnormal values 
will be marked by bolding, based on the normality ranges, provided by BMS. Normality range 
is 60-100 beat/minutes for heart rate, 120-200 ms for PR, ≤ 110 ms for QRS. For males the 
normal value for QTcF is between 360 and 450 ms, while for females 360 and 470 ms. 
The mean of the ECG assessments will be calculated from the triplicates. The time-
matched and predose changes from baseline will be calculated as follows: 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 33 of 37 
 
x Time-matched changes: The time-matched mean replicated measurements of the 
Day-1 will be used as baseline.  
x Predose changes: the mean of the triplicates of the pre-dose measurements (time 
point -1hour) on Day 1 will be used as baseline. 
 
 
Descriptive summaries will be presented for the each ECG parameter on the mean 
replicated values and the changes from baseline (time-matched and predose)  of RR interval, 
PR/PQ interval, QRS interval, QT interval, QTc interval (calculated according to the Fridericia 
method), and HR at each visit and time point. 
A listing will be prepared for the interpretation of the ECG measurements recorded on 
the eCRF by visits and time points. 
 
Subjects with clinically significant findings will be listed additionally along with the 
critical ECG parameter. 
 
Number and proportion of subjects with absolute QTc values above 460, 480 and 500 
msec and subjects with a QTc change more than 30 and 60 msec from baseline will be 
presented at each time point.  
14.2.4. 3-lead Holter 
All provided data (the start and stop time of the assessments, the recorded 
electrocardiographic measurements (ventricular rate, number of single VE beats, number of 
paired VE beats, number of VE runs of 3+ beats, total number of VE beats, number of single 
SVE beats, number of paired SVE beats, number of SVE runs of 3+ beats, total number of SVE 
beats, pauses (total pauses > 2 seconds) atrial fibrillation – Atrial Flutter, Second degree AV-
block, Third degree AV-block), interpretation of clinical significance provided by the 
investigator) will be listed by patients and visit days. The interpretation will be summarized 
and presented in frequency tables by visit days, and in a shift table to present the change from 
baseline. 
14.3. 
Clinical Laboratory Assessments 
14.3.1. Haematology, Clinical Chemistry, Coagulation, Urinalysis 
By patient lists will be provided with all measurements along with the unit, normal range, any 
deviation from it (High/Low/Abnormal values), and the relevance of being outside the normal 
range, identified by the investigator. Measurement results will only be presented in standard 
units. 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 34 of 37 
 
Descriptive summaries will be presented for continuous clinical laboratory values. 
Categorical laboratory parameters will be summarized in frequency tables.  
Laboratory measurements of patients with clinically significant abnormalities will be 
listed separately. 
14.3.2. Parameters of the Glucose Metabolism 
By patient lists will be provided with all measurements (HbA1c, insulin, glucagon, concurrent 
glucose) along with the unit, normal range, any deviation from it, and the relevance of being 
outside the normal range, identified by the investigator. Visit labels will be provided describing 
the timing of the sampling to the dosing and to the meals. 
Descriptive statistics will be presented (mean, SD, median, minimum, and maximum) 
by time points. 
The change from the baseline value, measured pre-dose on Day-1 will be calculated 
and summarized in tabular and graphical formats for HbA1c. 
The time- and food status-matched change from baseline at insulin, glucagon and 
concurrent glucose will be calculated in the following way: every time point on Day 1 and Day 
14 will have the own baseline value from Day -1, considering fasting conditions or their timing 
to meals.  
 
Additional list will be created of patients with clinically significant abnormal values 
along with the abnormal parameter. 
14.3.3.  Antibodies to BIM23B065 
A by-patient listing will be created containing the results of antibody assessments by visits. 
A frequency table will be created to present the number and percentage of subjects 
developing antibodies, by visits.  
14.3.4.  Endocrine Parameters 
By patient lists will be provided with all measurements along with the unit, normal range, any 
deviation from it, and the relevance of being outside the normal range, identified by the 
investigator.  
Descriptive summaries will be presented from the measured values and from the 
calculated change from baseline (Day -1).  


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 35 of 37 
 
Additional list will be created of patients with clinically significant abnormal values 
along with the abnormal parameter. 
14.4. 
Gallbladder Echocardiography 
By patient list will be provided with all assessments and all time points. The presence of 
lithiasis and sludge, the result and the description of abnormality will be presented. The 
number and percentage of patient with lithiasis and sludge will be.  
14.5. 
Physical Examination  
Physical examination data will be presented in a by-patient listing along the reason if it was 
not done at each time point.  
14.6. 
Pregnancies 
Pregnancy data will be shown in a data listing. No special analysis will be performed on the 
pregnancy data. Subjects are to be discontinued from the study if they become pregnant. 
 
  
15. 
OTHER PLANNED ANALYSIS 
 
15.1. 
Pharmacometrics 
Details regarding PK, and PK/PD modelling will be described in a separate Pharmacometric 
Analysis Plan.  
15.2. 
Tumour tissue receptor expression and drug response 
Subjects with available tumour tissue specimen will be categorized according to the SSTR2, 
SSTR5 and D2 receptor expression status. Incidence tables for tumour tissue categories will be 
presented.  
The number and proportion of GH responders, subjects with an IGF-1<ULN (age normalized) 
on Day 14, and subjects with a PRL<ULN (gender normalized) on Day 14 will be presented by 
the receptor expression status.  
15.3. 
Biobanking 
Subjects who consented for biobanking will listed along the blood sampling date, time and 
type of collected sample (serum, DNA, RNA). 
 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 36 of 37 
 
16. 
DEPARTURES FROM THE ANALYSIS PLANNED IN THE PROTOCOL  
 
As a per protocol secondary endpoint the efficacy of BIM23B065 in reducing IGF-1 to <ULN 
(age normalized) will be assessed after 6 day-titration and 8-day treatment period at Day 14. 
A minor change will be implemented in SAP in the IGF-1 profile assessment, since it won’t be 
assessed on Day 7. As a secondary response criteria IGF-1 profiles will be defined on Day 14 
to be in accordance with the per protocol determined endpoints and with the collected 
laboratory data determined in the Study Schedule of Events.  
 
17. 
LIST OF APPLICABLE QUALITY DOCUMENTS  
17.1. 
List of Relevant SOPs and WINs 
 
Document Code 
Title 
Effective Date 
SOP-BS-004 
Sample Size Determination 
03Dec2014 
SOP-BS-005 
Statistical Analysis Plan 
12Nov2015 
SOP-BS-008 
Statistical Analysis and Programming 
12Nov2015 
WIN-BS-030 
Conventions for Statistical Programming 
03Dec2014 
 
18. 
REFERENCES 
 
No. Designation/ 
Code/Appendix 
Title 
1. 
ICH E9 
ICH Harmonised tripartite Guideline: STATISTICAL 
PRINCIPLES FOR CLINICAL TRIALS E9 
2. 
ICH E3 
ICH Harmonised tripartite Guideline: STRUCTURE AND 
CONTENT OF CLINICAL STUDY REPORTS E3 


Protocol code: D-FR-10380-002 
 
Protocol Title: A phase IIA, open-label, single-arm, two stage, 
multi-centre study to investigate the pharmacodynamics, 
pharmacokinetics, safety and tolerability of repeated 
subcutaneous administration of BIM23B065 in subjects with 
acromegaly 
 
Statistical Analysis Plan 
SD-BS-014, version 1.0 
Parent documen: SOP-BS-005 
Page: 37 of 37 
 
No. Designation/ 
Code/Appendix 
Title 
3. 
ICH E14 
ICH Harmonised tripartite Guideline: The clinical 
evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs 
4. 
ASA 
Ethical Guidelines for Statistical Practice. Prepared by the 
Committee on Professional Ethics, August 7, 1999 
http://www.amstat.org/committees/ethics/index.html 
5. 
RSS 
The Royal Statistical Society: Code of Conduct, August 
1993. 
http://www.rss.org.uk/main.asp?page=1875 
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