Long-term Safety Follow-up After Growth Hormone Treatment (rhGH) of Short Children Born Small for Gestational Age (SGA)
Phase: NA
Conditions: Short Children Born Small for Gestational Age (SGA)
Sponsor: Sandoz

OMNITROPE®
Protocol number: EP00-402 / NCT01491854
EUDRACT number: 2007-001364-72
Long-term safety follow-up after growth hormone treatment (rhGH) 
of short children born Small for Gestational Age (SGA) 
Author(s):
Document type:
Clinical Study Protocol
Development phase:
IV
Sponsor:
Sandoz GmbH
Biochemiestr. 10
A-6250 Kundl
Austria
Document status:
Version 5.0 (Clean), including Amendment 1, 2, 3 and 4
Number of pages:
39
Release date:
14 July 2014
Property of Sandoz
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Sandoz

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Study No. EP00-402 
Protocol History
Document version (v) No
Released by
Comment
Protocol v 1.0
16. March 2007
Amendment 01
12. March 2012
incorporated into Protocol v 1.0, 
leading to protocol v 2.0
Protocol v 2.0
12. March 2012
Amendment 02
9. May 2012
incorporated into Protocol v 2.0, 
leading to protocol v3.0
Protocol v 3.0
9. May 2012
Amendment 03
06. June 2013
Incorporated into Protocol v3.0, 
leading to protocol v 4.0
Protocol v 4.0
06. June 2013
Amendment 04
14. July 2014
Incorporated into Protocol v4.0, 
leading to protocol v5.0
Protocol v 5.0
14. July 2014

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Study No. EP00-402 
Signature of Principal Investigator
Omnitrope®
EUDRACT number:2007-001364-72
Protocol EP00-402: Long-term safety follow-up after growth hormone treatment (rhGH) of 
short children born Small for Gestational Age (SGA)
Amended Clinical Study Protocol EP00-402, Version 5.0 from 14. July 2014, Clean and 
Track Changes to Clinical Study Protocol EP00-402.
I have read the amended protocol version and agree to conduct this trial in accordance with all 
stipulations of the protocol as amended, with applicable laws and regulations and in 
accordance with the ethical principles outlined in the Declaration of Helsinki.
Investigator Signature
Date
Print name:___________________________________________
Center name and address: 

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Study No. EP00-402 
Signature page for Sandoz
Omnitrope®
Protocol EP00-402: Long-term safety follow-up after growth hormone treatment (rhGH) of 
short children born Small for Gestational Age (SGA)  
(Clinical Study Leader)
Signature 
Date
(Trial Statistician)
Signature 
Date
(Clinical Program Leader /  
Scientific Expert)
Signature 
Date
The telephone and telefax number of the contact persons in the department of Global Clinical Safety 
Desk are listed in the investigator folder provided to each site

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Study No. EP00-402 
Table of Contents
Protocol History .................................................................................................................................................................................2
Table of Contents ...............................................................................................................................................................................6
List of abbreviations...........................................................................................................................................................................8
Amendment 4, 14. July 2014..............................................................................................................................................................9
Amendment 3, 06. June 2013...........................................................................................................................................................11
Amendment 2, 09. May 2012...........................................................................................................................................................12
Amendment 1, 12. March 2012........................................................................................................................................................14
Protocol synopsis..............................................................................................................................................................................15
Primary objective(s) .................................................................................................................................................................15
Secondary objectives................................................................................................................................................................15
Inclusion/exclusion criteria ......................................................................................................................................................16
Inclusion criteria.......................................................................................................................................................................17
Exclusion criteria......................................................................................................................................................................17
Flow Chart Follow up Period ...........................................................................................................................................................17
1.0
Background .................................................................................................................................................................18
1.1.
The indication SGA.............................................................................................................................................18
1.1.1.
Type 2 Diabetes and SGA...................................................................................................................................19
1.1.2.
Syndrome X and SGA.........................................................................................................................................19
1.1.3.
Metabolic effects of growth hormone treatment in patients born SGA ...............................................................20
2.0
Study Purpose..............................................................................................................................................................21
3.0
Objectives....................................................................................................................................................................21
3.1.
Primary objective(s) ............................................................................................................................................21
3.2.
Secondary objectives...........................................................................................................................................21
4.0
Study design................................................................................................................................................................21
5.0
Population ...................................................................................................................................................................22
5.1.
Inclusion/exclusion criteria .................................................................................................................................23
5.1.1.
Inclusion criteria..................................................................................................................................................23
5.1.2.
Exclusion criteria.................................................................................................................................................23
6.0
Treatment ....................................................................................................................................................................23
6.1.
Investigational drug.............................................................................................................................................23
6.1.1.
Concomitant treatment ........................................................................................................................................23
6.1.2.
Study discontinuation..........................................................................................................................................23
6.1.3.
Premature patient withdrawal..............................................................................................................................24
7.0
Visit Schedule and assessments...................................................................................................................................24
7.1.
Procedures by visits.............................................................................................................................................24
7.1.1.
Baseline visit (F0) ...............................................................................................................................................24
7.1.2.
6 months visit (F1) ..............................................................................................................................................25
7.1.3.
1 year visit (F2), 5 year visit (F3), 10 year visit (F4, final visit)..........................................................................25
7.2.
Patient compliance ..............................................................................................................................................25
7.3.
Safety ..................................................................................................................................................................25
7.3.1.
Methods and timing for assessing, recording and analysis of parameters ...........................................................25
7.3.2.
Weight measurements .........................................................................................................................................26
7.3.3.
Carbohydrate metabolism:...................................................................................................................................26
7.3.4.
Immunogenicity ..................................................................................................................................................26
7.3.5.
Physical examination...........................................................................................................................................27
7.3.6.
Vital signs............................................................................................................................................................27
7.3.7.
Laboratory evaluations........................................................................................................................................27
7.4.
Efficacy ...............................................................................................................................................................28
7.4.1.
Height measurements ..........................................................................................................................................28
7.4.2.
IGF-I and IGFBP-3 serum levels.........................................................................................................................28
7.5.
Tolerability/acceptability.....................................................................................................................................28
7.6.
Resource utilization.............................................................................................................................................28
8.0
Safety monitoring........................................................................................................................................................28
8.1.
Adverse events ....................................................................................................................................................28
8.2.
Serious adverse event reporting...........................................................................................................................29
8.3.
Pregnancies .........................................................................................................................................................30
8.4.
Data Monitoring Board .......................................................................................................................................30
9.0
Data review and database management.......................................................................................................................31
9.1.
Site monitoring....................................................................................................................................................31
9.2.
Data collection.....................................................................................................................................................31
10.0
Data analysis ...............................................................................................................................................................31
10.1.
Population for analysis ........................................................................................................................................31
10.2.
Patient demographics/other baseline characteristics............................................................................................32

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Study No. EP00-402 
10.3.
Treatments (study drug, rescue medication, other concomitant therapies, compliance)......................................32
10.3.1.
Study drug administration: ..................................................................................................................................32
10.3.2.
Concomitant medication:.....................................................................................................................................32
10.4.
Analysis of safety endpoints................................................................................................................................32
10.4.1.
Carbohydrate metabolism:...................................................................................................................................32
10.4.2.
Safety lab:............................................................................................................................................................33
10.4.3.
(Serious) Adverse events:....................................................................................................................................33
10.4.4.
Vital signs / weight:.............................................................................................................................................33
10.5.
Analysis of efficacy endpoints ............................................................................................................................33
10.5.1.
Pharmacodynamic endpoints:..............................................................................................................................33
10.5.2.
Height measurements: .........................................................................................................................................33
10.6.
Interim analysis ...................................................................................................................................................34
10.7.
Sample size calculation .......................................................................................................................................34
10.8.
Power for analysis of critical secondary variables...............................................................................................34
11.0
Discussion and rationale for study design features......................................................................................................34
12.0
Procedures and instructions: Administrative procedures.............................................................................................34
12.1.
Changes to the protocol.......................................................................................................................................34
12.2.
Protocol adherence ..............................................................................................................................................35
12.3.
Publication of study protocol and results.............................................................................................................35
12.4.
Signatory investigator for study report................................................................................................................35
12.5.
Ethics and Good Clinical Practice.......................................................................................................................35
12.5.1.
Institutional Review Board/Independent Ethics Committee................................................................................36
12.5.2.
Informed consent.................................................................................................................................................36
12.5.3.
Declaration of Helsinki .......................................................................................................................................36
13.0
References...................................................................................................................................................................37

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Study No. EP00-402 
List of abbreviations
AB
Antibody
AE
Adverse event
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
CRF
Case report form
CRO
Contract research organisation
DRL
Drug reference list
EMEA
European Medicines Agency
fT4
Free thyroxine 
GCP
Good clinical practice
GH
Growth hormone
hGH
Human growth hormone
IEC
Independent ethics committee
IGF-I
Insulin-like growth factor
IGFBP-3
Insulin-like growth factor binding protein 3
IGT
Impaired glucose tolerance
IRB
Institutional review board
ITT
Intention to treat
IUGR
Intrauterine growth retardation
MedDRA
Medical dictionary for regulatory activities
OGTT
Oral glucose tolerance test
PP
Per protocol
RBC
Red blood cell count
rhGH
Recombinant human growth hormone
SAE
Serious adverse event
SAF
Safety population
SD
Standard deviation
SDS
Standard deviation score
SGA
Small for gestational age
TSH
Thyroid stimulating hormone
WBC
White blood cell count
WHO
World health organisation

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Study No. EP00-402 
Amendment 4, 14. July 2014
Rationale for amendment
Patients who have received at least one dose of Omnitrope under the protocol EP00-401 shall 
be enrolled after the termination of growth hormone treatment in study EP00-402 for an 
additional 10 year follow up observation.
Amendment 4 is issued to implement changes to the safety data collection and reporting in 
order to comply with internal safety reporting standards, i.e. to report any serious events 
irrespective of causality throughout the study. So far, all SAE were collected within the first 
30 days after obtained informed consent for EP00-402. After that period, only SAE with 
suspected causality to study drug administered in EP00-401 study where to be reported.
Therefore, safety reporting is extended by this amendment to reporting of every serious 
adverse event (SAE), regardless of suspected causality, occurring after the patient has 
provided informed consent for EP00-402 study and until 30 days after the patient has stopped 
study participation in EP0-402 study within 24 hours of learning of its occurrence. 
At this occasion, the following is changed in addition:

To ensure consistency between EP00-401 and EP00-402 protocols, wording of inclusion 
criteria 2 regarding informed consent is changed in order to be identical with respective 
wording used in protocol EP00-401 study. Wording is updated to specify the case a 
patient is not able to read and write. 

Former protocol amendments 1, 2 and 3 are fully integrated into the protocol

Protocol is updated regarding publication of study protocol and results, signature of study 
report and protocol adherence in order to adhere to current standards.

Minor spelling errors are corrected.
Study Status
The Study is ongoing.
Changes to the protocol
The following sections of the protocol were amended:
Integration Amendment 1, 12. March 2012
Integration Amendment 2, 09. May 2012
Integration Amendment 3, 06. June 2013
Integration Amendment 4, 14. July 2014
Protocol synopsis
Section 5.0
“Population”
Section 8.0
“Safety monitoring”
Section 12.0
“Procedures and instructions: Administrative procedures
The changes of the protocol do not affect the Informed Consent.
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board

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Study No. EP00-402 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol are non-substantial and do not require IRB/IEC approval prior to 
implementation.

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Study No. EP00-402 
Amendment 3, 06. June 2013
Rationale for amendment
This study had been designed in accordance with the post-approval pharmacovigilance plan to 
extend the safety database of Omnitrope® and to address the EMA’s request to investigate the 
potential of Omnitrope® with regard to the development of diabetes after treatment cessation 
in short children born SGA. Further, the immunogenicity of Omnitrope® in short children 
born SGA treated with Omnitrope® under the protocol EP00-401 should be investigated. 
Patients fulfilling the diagnosis SGA who have received at least one dose of Omnitrope under 
the protocol EP00-401 shall be observed after termination of growth hormone treatment in 
this follow-up study for an additional time period of 10 years.  
This amendment aims to document changes regarding requirements for safety monitoring and 
harmonization of safety related sections in the protocol. In addition, the study synopsis which 
was created as a separate document earlier was integrated into the protocol.
Study Status
The Study is ongoing.
Changes to the protocol
The following sections of the protocol were amended:
Integration of study synopsis
Section 7.0
“Visit Schedule and assessments”
Section 8.0
“Safety monitoring”
Details of the changes are provided in the protocol amendment document. 
The changes of the protocol do affect the Informed Consent.

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Study No. EP00-402 
Amendment 2, 09. May 2012
Rationale for amendment
This study had been designed in accordance with the post-approval pharmacovigilance plan to 
extend the safety database of Omnitrope® and to address the EMA’s request to investigate the 
diabetogenic potential of Omnitrope® during treatment and the development of diabetes after 
treatment cessation in short children born SGA. Further, the immunogenicity of Omnitrope®
in short children born SGA treated with Omnitrope® under the protocol EP00-401 should be 
investigated. 
Patients fulfilling the diagnosis SGA who have received at least one dose of Omnitrope under 
the protocol EP00-401 shall be observed after termination of growth hormone treatment in 
this follow-up study for an additional time period of 10 years.  
This amendment aims to refrain from further assessment of host cell protein (HCP).The 
rationale of this change to the protocol is provided in the next section. 
Assessment of host cell protein (HCP)
The EP00-401 and EP00-402 study started after approval of Omnitrope® for marketing 
authorization. At that time the assessment of E.coli host cell protein (HCP) antibodies using 
the anti-HCP antibody western blot was voluntarily included by Sandoz to further monitor the 
development of anti-HCP antibodies in patients during treatment.
However, the low immunogenicity of Omnitrope (API Kundl) has meanwhile been confirmed 
in three phase III studies (see “legend” below). Therefore Sandoz regards the cessation of the 
assessment of E.coli host cell protein (HCP) antibodies as justified from the time of approval 
of this amendment.
The analysis of the HCP antibody results (tests performed until this amendment became 
effective) will be specified in the Statistical Analysis Plan (SAP) provided for each analysis.
Legend:  
The active pharmaceutical ingredient (API) manufacturing process was developed at Sandoz 
(formerly Biochemie) in Kundl, Austria, in the 1990s using standard E.coli technology used 
also for Genotropin® and most other GH products. Sandoz was familiar with all aspects of 
this process and kept close control of the impact of any changes on the quality of all 
intermediates as well as the purified bulk API. At that time for patent reasons, Sandoz had the 
first batches of API for early clinical trials manufactured at Covance in the US (API Covance) 
in 1999. This API was used to manufacture finished dosage forms (FDFs) for the first 9 
months of the initial Phase III studies in GHD children. Evaluation of the process and the 
resulting product quality continued in Sandoz’s development facilities. In this context, 
Sandoz performed an assay specifically developed to detect even slightest traces of HCPs in 
the API preparations. Using this new, more sensitive method, API Covance was found to 
contain high levels of HCPs. Investigations on the clinical consequences were initiated and it 
was found that this high level of HCPs was directly correlated to the occurrence of anti-HCP 
antibodies as well as non-neutralizing anti-rhGH antibodies. Sandoz reacted immediately and 
introduced two modifications into the API downstream purification process in 2000 leading to 
a significantly improved HCP clearance without changing any other product characteristics.  
In-depth physicochemical characterization and comparability exercises demonstrated that API 
Covance and API Kundl were fully comparable in all quality aspects with the sole exception 

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Study No. EP00-402 
of the decreased HCP content. Based on HCP data of API Kundl the limit for E. coli host cell 
proteins was tightened from 
. API manufactured at Covance was not 
used for further development. 
Consequently, the FDFs using API Kundl were then introduced into the ongoing Phase III 
study (after month 9 of overall GH therapy) and immediately thereafter, antibody titers started 
to drop while all other safety and efficacy parameters remained unchanged. The FDFs using 
API Kundl were evaluated in two additional clinical phase III studies. In all of these three 
studies the low immunogenicity of API Kundl has been demonstrated. Finally, efficacy 
analyses carried out in defined subgroups of the study patients revealed that growth 
parameters in patients with a positive anti-HCP and anti-rhGH test were not affected and none 
of the patients showed antibody-related growth attenuation.
In summary, only API manufactured at Sandoz Kundl was used from late clinical 
development (Phase III) up to process validation and registration.  
Commercial manufacturing is controlled using the tight HCP limit of 
.  
Study Status
The Study is ongoing.
Changes to the protocol
The following sections of the protocol were amended:
Section 2.0 
“Study purpose”
Section 3.0
“Objectives”
Section 4.0
“Study design”
Section 7.0
“Visit Schedule and assessments”
Section 10.0
“Data analysis”
Section 11.0
“Discussion and rationale for study design features”
Details of the changes are provided in the protocol amendment document. 
The changes of the protocol do not affect the Informed Consent.

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Study No. EP00-402 
Amendment 1, 12. March 2012
Rationale for amendment
This study had been designed in accordance with the post-approval pharmacovigilance plan to 
extend the safety database of Omnitrope® and to address the EMA’s request to investigate the 
diabetogenic potential of Omnitrope® during treatment and the development of diabetes after 
treatment cessation in short children born SGA. Further, the immunogenicity of Omnitrope®
in short children born SGA treated with Omnitrope® under the protocol EP00-401 should be 
investigated. 
Patients fulfilling the diagnosis SGA who have received at least one dose of Omnitrope®
under the protocol EP00-401 shall be observed after termination of growth hormone treatment 
in this follow-up study for an additional time period of 10 years.  Due to the duration of the 
study and length of time between the planned follow-up visits, patients and their 
parents/guardians will be asked to enroll in a study retention program. This program has been 
designed to maintain contact with and engage patients and their parents/guardians in order to 
maximize study compliance. The program will include regular contact, interaction and 
engagement of patients and parents/guardians during each year of the follow-up until study 
completion. Additionally the inclusion criteria and the procedure of obtaining written 
informed consent are described more precisely.
Additionally some minor administrative changes are made.
Study Status
The Study is ongoing.
Changes to the protocol
The following sections of the protocol were amended:
Section 5.0 
“Population”
Section 7.0 
“Visit Schedule and Assessments”
Section 12.0
“Procedures and instructions: Administrative procedures”
Administrative changes
Details of the changes are provided in the protocol amendment document. 
The changes of the protocol affect the Informed Consent.

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Study No. EP00-402 
Protocol synopsis
Title of study: 
Long-term safety follow-up after growth hormone treatment (rhGH) of short children born 
Small for Gestational Age (SGA) 
Study Purpose
Epidemiological evidence suggests that children born SGA may be at an increased risk of 
insulin resistance and type 2 diabetes in later life. Given that GH therapy has been shown to 
induce transient resistance to the actions of insulin in children, concerns over the diabetogenic 
potential of GH therapy in individuals predisposed to metabolic abnormalities, such as 
children born SGA, have been raised. 
This study is performed as part of the Marketing Authorisation Holder’s post-marketing 
pharmacovigilance plan to investigate the long-term safety, in particular the diabetogenic 
potential and immunogenicity of rhGH therapy in short children born small for gestational 
age (SGA). The purpose of this study is 
(a) to monitor short children born SGA who participated in study EP00-401 for the 
development of diabetes for a further 10 years after termination of growth hormone treatment 
and 
(b) to report the incidence of anti-rhGH antibodies for 6 months after termination of GH 
treatment.
Objectives
Primary objective(s)
The primary objective of this study is to evaluate the long-term effect of growth hormone 
treatment on the development of diabetes in short children born SGA for 10 years after the 
end of treatment.
Secondary objectives
The secondary objectives of this study are: 
•
to report the incidence of anti-rhGH antibodies 6 months after termination of growth 
hormone treatment.
•
to evaluate final height in follow-up period
•
to evaluate IGF-1 and IGFBP-3 levels for 10 years  after end of growth hormone 
treatment
•
to evaluate incidence and severity of adverse events
Study design
Long term safety follow-up study of patients that were included in the Phase IV study (EP00-
401). Patients will be monitored for safety. 

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Study No. EP00-402 
The baseline visit equals the final visit of the study EP00-401. Examinations and laboratory 
values from the final visit will be transferred to the baseline visit.
Safety assessments:
Carbohydrate metabolism: Fasting plasma glucose and insulin levels will be measured 
6 months, 1, 5 and 10 years after the end of treatment. Glycosylated haemoglobin (HbA1C)
will be measured at 6 months, 1, 5 and 10 years after the end of treatment. An oral glucose 
tolerance test (OGTT) will be performed 6 months, 1, 5 and 10 years after the end of 
treatment. 
Immunogenicity: Subjects will be screened for anti-rhGH antibodies 6 months after treatment. 
Only in case of positive antibodies measurements in previous visit follow-up measurements 
are planned after 1 year, 5 years and 10 years.
Additional safety criteria: Additional criteria for assessing safety will consist of monitoring 
and recording all adverse events, vital signs and body weight, physical condition, 
haematology, blood chemistry, thyroid function tests, lipids and urinalysis. Adverse events, 
body weight and physical condition will be assessed at every study visit. Laboratory tests for 
safety will be performed, 6 months, 1, 5 and 10 years after the end of treatment.  
Efficacy assessments:
The patients’ height will be measured at each visit and IGF-1 and IGFBP-3 serum levels will 
be assessed by a central laboratory 6 months, 1, 5 and 10 years after the end of treatment.
A summary of the study plan is given below.
Study Outline
PHASE
Follow-up
TIME
0
6
1
5
10
POINT
mo
mo
yr
yrs
yrs
VISIT
F0
F1
F2
F3
F4
THERAPY
None
Population
All patients who participated in the EP00-401 study and received at least one dose of study 
medication will be asked to enter this safety follow-up period of 10 years. The study will be 
performed in approximately 40 centres in Europe (incl. one site in 
 Asia). The 
treating physicians shall be appropriately qualified and experienced in conducting clinical 
trials. About 200 subjects are planned to enter the long-term follow-up period. The patients 
participating in this study are out-patients.
Inclusion/exclusion criteria
The investigator must ensure that all patients who meet the following inclusion and none of 
the exclusion criteria are offered enrolment in the study. No additional exclusions can be 
applied by the investigator, in order for the study population to be representative of all 
eligible patients.

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Study No. EP00-402 
Inclusion criteria
1. All patients who fulfilled the diagnosis SGA, participated in study EP00-401, and 
received at least one dose of study medication
2. Written informed consent of patient (for children who can read and write) and parent or 
legal guardian
Exclusion criteria 
1. Patients unwilling and/or parents/guardians who are not capable of ensuring compliance 
with the provisions of the study protocol
Flow Chart Follow up Period
Follow-up Period
Time Point
baseline = 
final visit of 
EP00-401
6 mo ± 4 wks
1 yr  ± 4 wks
5 yrs ± 4 wks
10 yrs ± 4 wks
Final Visit
Visit
F01
F1
F2
F3
F4
Written Informed Consent
X
Physical examination incl. 
weight (kg),  height (cm) and 
pubertal status (if applicable)
X
X
X
X
Vital signs
X
X
X
X
Haematology
X
X
X
X
Blood chemistry inc. fT4, 
TSH, HbA1C,  fasting plasma 
glucose and insulin levels
X
X
X
X
Urinalysis
X
X
X
X
Anti-hGH 
X
X2
X2
X2
IGF-1, IGFBP-3
X
X
X
X
OGTT 
X3
X3
X3
X3
Concomitant medication
X4
X
X
X
X
Adverse events 
X4
X
X
X
X
1: equals the final visit of study EP00-401
2: only if positive anti-hGH antibodies in previous visit
3: contraindicated in patients with overt diabetes mellitus
4: documentation of all adverse events / concomitant medications ongoing at the final visit of study EP00-401

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Study No. EP00-402 
1.0
Background
This study is performed as part of the Marketing Authorisation Holder’s post-marketing 
pharmacovigilance plan to investigate the long-term safety, in particular the diabetogenic 
potential and immunogenicity of rhGH therapy in short children born small for gestational 
age (SGA). Children born SGA who were treated in study EP00-401 with growth hormone 
due to short stature will be followed up for 10 years after stop of rhGH treatment. 
1.1.
The indication SGA 
The most common definition of the term “small for gestational age” (SGA) is a birth weight 
and/or length of ≥ 2 standard deviations (SD) below the mean for the infant’s gestational age 
and sex (based on data derived from a reference population).1 The standards for neonatal 
growth were established by Usher and McLean.2 These decades-old growth curves are based 
upon measurement of intrauterine growth between 25 and 44 weeks of gestation of white 
infants born at sea level. Given that the race and ethnicity are known to be important 
modifiers of foetal growth patterns and that improvements in prenatal care and nutrition as 
well as the identification of factors that adversely affect the foetus may have resulted in a 
trend toward larger neonates, efforts should be made to improve the existing reference data.
The term SGA does not refer to foetal growth but to the size of the infant at birth. Intrauterine 
growth retardation (IUGR), while not a synonym, is commonly used interchangeably with 
SGA. Technically, IUGR implies a pathophysiological cause for the inhibition of normal 
growth in utero. Not all SGA infants have suffered from IUGR, while certain infants born 
after a period of IUGR are not necessarily SGA.
Ultrasound criteria are used as a diagnostic standard in the identification of SGA. Ultrasonic 
foetal indices such as crown-rump length during the first trimester correlate well with 
gestational age, but they must be recorded accurately and birth length must subsequently be 
measured precisely for a correct diagnosis of SGA.3
Between 3% and 10% of all live births each year are described as SGA.4 More than 90% of 
these children catch up to normal height by 2 to 3 years of age. According to data from the 
National Centre for Health Statistics (in the US), approximately 91,000 infants were born 
SGA in 1999 in the United States (the most recent year for which adult birth data are 
available from the National Centre for Health Statistics.5 In 2000, 4,058,814 infants were 
born in the United States according to the data from the National Centre for Health Statistics.4
Using this figure and defining SGA as the ≤2.3 percentile, approximately 93,400 SGA 
infants are born annually in the United States. Extrapolating from that figure, the number of 
SGA children in the United States between the ages of 2 and 16 years with persistent short 
stature is estimated to be 146,000.
Catch-up growth of an infant born SGA is defined as accelerated growth that results in the 
attainment of length and weight within 2 SD of the mean for corresponding sex and age. This 
surge in growth generally begins immediately after birth, with the largest increases occurring 
by 6 months of age. SGA babies who fail to display catch-up growth by 2 years of age, are at 
increased risk of adult short stature.1,6
Endocrine and metabolic outcomes may be related to failure to achieve catch-up. While GH 
levels have a relatively small effect on in uteri growth, insulin and insulin-like growth factors 
(IGFs) are key modifiers of foetal growth and development. Endocrine studies in uteri show 
that growth retarded foetuses have reduced insulin7 and IGF-I8 levels and in the neonatal 

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period, babies born SGA have low IGF-I levels and IGFBP-3 levels despite elevated GH 
secretion.9
Failure of catch-up growth is associated with persistent low IGF-I and IGFBP-3 levels,10
suggesting ongoing dysfunction of the GH/IGF-I axis. In contrast to their high neonatal GH 
levels, older SGA children may have reduced GH secretion.
In addition to short stature, SGA infants may be predisposed to a number of developmental 
problems. Infants born with SGA usually have less body fat than those who are born adequate 
for gestational age. Serum concentrations of leptin, a protein produced by adipose tissue and 
involved in the regulation of the appetite and body weight are reduced in short children born 
SGA, possibly leading to lack of appetite and inadequate consumption of calories.1,11 SGA 
can have adverse effects on the health of children during infancy and childhood, including 
slower physical growth, possibly slower mental development and higher morbidity. Some 
evidence suggests that SGA may affect brain development, leading to an increased risk of 
slight yet significant cognitive and neurodevelopmental impairment. For example, one study 
showed that absence of catch-up growth among male infants who were born SGA was the 
most important predictor of subnormal performance in standard psychological tests.12
SGA children are also more likely to have congenital abnormalities. Severely growth-retarded 
infants are at markedly increased risk for foetal and neonatal death, hypoglycaemia, 
hypocalcaemia, polycythaemia.
There is also convincing evidence that SGA is a predisposing factor for the development of 
hypertension13, diabetes14 and cardiovascular disease15 in adult life.
1.1.1.
Type 2 Diabetes and SGA
Studies in Europe, North America, and the developing world16,17,18,19,20,21,22 have shown that 
low birth weight in babies born at term is associated with a higher prevalence of glucose 
intolerance and type 2 diabetes in adult life. For example, Rich-Edwards and colleagues22
investigated the relationship between birth weight and type 2 diabetes in more than 69,000 
adult women as part of the Nurses Health Study. There was an inverse association between 
the risk of type 2 diabetes in adulthood and the entire range of birth weight. The trend was 
strong and statistically significant with adults who weighed < 5 pounds at birth, who had 1.8 
times the risk of developing type 2 diabetes compared with their normal birth weight 
counterparts. Similar results have been found among men and women across a variety of 
populations.
As with the association between SGA and adult cardiovascular disease, the “foetal origins” 
hypothesis focuses on the intrauterine environment as the etiologic agent.23 Alternatively, 
insulin resistance may be controlled by the same genetic factors that regulate foetal 
growth.24,25 Hattersley and colleagues26 theorize that genetically determined insulin resistance 
results in impaired insulin-mediated growth in the foetus as well as insulin resistance in adult 
life. These researchers propose that there is an insulin-resistant genotype that may predispose 
to low birth weight, insulin resistance, diabetes, and hypertension.
1.1.2.
Syndrome X and SGA
Certain chronic and metabolic disorders including hypertension, glucose intolerance, central 
obesity, and dyslipidaemia tend to cluster in the same individuals, leading to an increased risk 
of mortality from cardiovascular disease. This syndrome is referred to by several names, 
including syndrome X, the metabolic syndrome, and insulin resistance syndrome. Several 
studies have demonstrated an increased prevalence of syndrome X among adults born 

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SGA.27,28,29,30,31,32 Moreover, adult overweight and obesity increase the risk of syndrome X, 
and studies show adults born SGA may have an increased risk of obesity. 
Thus, close clinical follow-up of weight, height, and body mass index (BMI) in patients born 
SGA is particularly important.
Yarbrough and colleagues32 studied 303 postmenopausal white women aged 50-84 years to 
examine the relationship between birth weight and the metabolic syndrome. The metabolic 
syndrome was defined as the grouping of hypertension, dyslipidaemia, and abnormal glucose 
tolerance in an individual. The metabolic syndrome was present in 7.9% of this study 
population. Compared with women in the highest birth weight group, those in the lowest birth 
weight group (mean =5.51) had a significantly increased prevalence (12.0% vs 4.3%, P 
< 0.05) and 2.41 times the risk (95% CI = 1.06 - 5.51) of developing the metabolic syndrome. 
In addition, women in the lowest birth weight group who became adults in the highest BMI 
group had the highest prevalence of the metabolic syndrome (approximately 30%).
Leger and associates 33 conducted a similar study in young adults. The regional cohort 
comprised 236 subjects born SGA and 281 subjects born adequate for gestational age with a 
mean age of 20.6 years. After adjusting for sex and BMI, mean plasma glucose concentration 
30 minutes after a glucose load was significantly higher in subjects born SGA compared with 
subjects born adequate for gestational age, as were insulin and pro-insulin concentrations 30 
and 120 minutes after a glucose load.
1.1.3.
Metabolic effects of growth hormone treatment in patients born SGA
In view of the fact that several studies have found an association between low birth weight 
and impaired insulin sensitivity, type 2 diabetes, hypertension and cardiovascular disease in 
later life, and because growth hormone is known to increase fasting and postprandial insulin 
levels, concern has been expressed regarding the possible detrimental effects of GH therapy 
in children born SGA.
Sas et al.34 evaluated the changes in body metabolism, blood pressure and lipid metabolism in 
79 GH-treated children therapy (2 dose groups, 1 mg/m2/day and 2 mg/m2/day). The authors 
measured skin fold thickness, systemic blood pressure, and blood lipids in the 79 subjects. 
Compared with normal children, the short children born SGA had significantly lower BMI, 
higher systolic blood pressure, and normal lipids. During GH treatment, BMI increased 
significantly over baseline values with no overall changes in body fat percentage compared 
with age-matched healthy controls. These findings demonstrated that GH therapy decreases 
adipose tissue mass and increases muscle mass in this group of patients. Both systolic and 
diastolic blood pressure SDS also decreased significantly (P < 0.05) during therapy. After 6 
years of therapy, there were no differences in blood pressure measurements between the 
treatment group and age-matched controls. While pre-treatment mean lipid values were 
normal, GH treatment was associated with significant changes in the lipid profiles during the 
first year of therapy; total cholesterol (P < 0.001) and LDL cholesterol (P < 0.001) decreased 
significantly and stabilised thereafter.
In the same study,35, 36 all 79 children underwent standard oral glucose tolerance tests at 
baseline, after 1 and 6 years of GH treatment and 6 months after discontinuation of GH 
therapy. Before GH therapy 8% of the children had impaired glucose tolerance (IGT) 
according to WHO criteria. IGT was found in 4% of children after 6 years of therapy and in 
10% of children after stopping GH treatment. GH therapy induced considerably higher fasting 
and glucose-stimulated insulin levels, indicating insulin resistance. After discontinuation of 
GH therapy the mean serum glucose levels remained normal and the mean serum insulin 

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levels decreased significantly, to normal age-matched reference values. HbA1C levels were 
always in the normal range and none of the children developed diabetes mellitus. 
2.0
Study Purpose
Epidemiological evidence suggests that children born SGA may be at an increased risk of 
insulin resistance and type 2 diabetes in later life. Given that GH therapy has been shown to 
induce transient resistance to the actions of insulin in children, concerns over the diabetogenic 
potential of GH therapy in individuals predisposed to metabolic abnormalities, such as 
children born SGA, have been raised. 
This study is performed as part of the Marketing Authorisation Holder’s post-marketing 
pharmacovigilance plan to investigate the long-term safety, in particular the diabetogenic 
potential and immunogenicity of rhGH therapy in short children born small for gestational 
age (SGA). The purpose of this study is 
(a) to monitor short children born SGA who participated in study EP00-401 for the 
development of diabetes for a further 10 years after termination of growth hormone treatment 
and 
(b) to report the incidence of anti-rhGH antibodies (ABs) for 6 months after termination of 
GH treatment.
3.0
Objectives
3.1.
Primary objective(s)
The primary objective of this study is to evaluate the long-term effect of growth hormone 
treatment on the development of diabetes in short children born SGA for 10 years after the 
end of treatment.
3.2. Secondary objectives
The secondary objectives of this study are: 
•
to report the incidence of anti-rhGH antibodies (ABs) 6 months after termination of 
growth hormone treatment.
•
to evaluate final height in follow-up period
•
to evaluate IGF-I and IGFBP-3 levels for 10 years  after end of growth hormone 
treatment
•
to evaluate incidence and severity of adverse events
4.0
Study design
Follow-up, observational study of patients that were included in the Phase IV study (EP00-
401). Patients will be monitored for safety. 
The baseline visit equals the final visit of the study EP00-401. Examinations and laboratory 
values from the final visit will be transferred to the baseline visit.

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Safety assessments:
Carbohydrate metabolism: Fasting plasma glucose and insulin levels will be measured 6 
months, 1, 5 and 10 years after the end of treatment. Glycosylated haemoglobin (HbA1C) will 
be measured at 6 months, 1, 5 and 10 years after the end of treatment. An oral glucose 
tolerance test (OGTT) will be performed 6 months, 1, 5 and 10 years after the end of 
treatment. 
Immunogenicity: Subjects will be screened for anti-rhGH antibodies (ABs) 6 months after 
treatment. Only in case of positive antibodies measurements in previous visit follow-up 
measurements are planned after 1 year, 5 years and 10 years. 
Additional safety criteria: Additional criteria for assessing safety will consist of monitoring 
and recording all adverse events, vital signs and body weight, physical condition, 
haematology, blood chemistry, thyroid function tests, lipids and urinalysis. Adverse events, 
body weight and physical condition will be assessed at every study visit. Laboratory tests for 
safety will be performed, 6 months, 1, 5 and 10 years after the end of treatment.  
Efficacy assessments:
The patients’ height will be measured at each visit and IGF-I and IGFBP-3 serum levels will 
be assessed by a central laboratory 6 months, 1, 5 and 10 years after the end of treatment.
A summary of the study plan is given below.
Study Outline
PHASE
Follow-up
TIME
0
6
1
5
10
POINT
mo
mo
yr
yrs
yrs
VISIT
F0
F1
F2
F3
F4
THERAPY
None
Interim analyses are planned at the following time points:
•
2022 with data of patients who completed 1 year of follow-up
•
2026 with data of patients who completed 5 years of follow-up
•
2031 with data of patients who completed 10 years of follow-up
5.0
Population
All patients who participated in the EP00-401 study and received at least one dose of study 
medication will be asked to enter this observational period of 10 years. The study will be 
performed in approximately 40 centres in Europe (incl. one site in 
 Asia). The 
treating physicians shall be appropriately qualified and experienced in conducting clinical 
trials. About 200 subjects are planned to enter the long-term follow-up period. The patients 
participating in this study are out-patients.

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5.1.
Inclusion/exclusion criteria
The investigator must ensure that all patients who meet the following inclusion and none of 
the exclusion criteria are offered enrolment in the study. No additional exclusions can be 
applied by the investigator, in order for the study population to be representative of all 
eligible patients.
5.1.1.
Inclusion criteria
1. All patients who fulfilled the diagnosis SGA, participated in study EP00-401, and 
received at least one dose of study medication
2. Written informed consent of patient (for children who can read and write) and parent or 
legal guardian
5.1.2.
Exclusion criteria 
1. Patients unwilling and/or parents/guardians who are not capable of ensuring compliance 
with the provisions of the study protocol
6.0
Treatment
6.1.
Investigational drug
Not applicable. This is an observational follow-up study without intake of any investigational 
drug. 
6.1.1.
Concomitant treatment
All kind of medications, except investigational medicinal products, are allowed. 
Administration of all drugs must be reported in the appropriate section of the Case Report 
Forms (CRFs), along with dose information, dates of administration and reason for use. 
Any diagnostic, therapeutic or surgical procedure should be recorded, including the date, 
indication, descriptions of the procedure and clinical findings.
6.1.2.
Study discontinuation
Study must be discontinued if the investigator concludes that continuation would result in 
significant safety risk for that patient.
Patients who discontinue study before completing the study should not be considered 
withdrawn from the study, and should be scheduled for a visit as soon as possible, at which 
time all of the assessments for the final visit will be performed. A Study Discontinuation form 
should be completed, giving the date and reason for stopping the study. At a minimum, all
patients who discontinue, including those who refuse to return for a final visit, will be 
contacted for safety evaluations during the following 30 days.

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6.1.3.
Premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients should also be withdrawn at any time if the investigator 
concludes that it would be in the patient’s best interest. Patients must be withdrawn from the 
study if any of the following occur:

Withdrawal of informed consent
Protocol violations should not lead to patient withdrawal unless they indicate a significant 
risk to the patient’s safety. Patients may be considered withdrawn if they state an intention to 
withdraw, or fail to return for visits, or become lost to follow-up for any reason. For patients 
who are lost to follow-up (i.e. those patients whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw), the investigator should show 
“due diligence” by documenting in the source documents steps taken to contact the patient: 

at least one telephone call and

at least one registered letter.
If premature withdrawal occurs for any reason, the investigator must determine the primary 
reason for the patient’s premature withdrawal from the study and record this information on 
the CRF.
7.0
Visit Schedule and assessments
The flowchart lists all assessments and indicates with an “X” the visits during which they are 
performed. Patients should be seen for all visits at the designated time-point or as close to it 
as possible. A time window for the visits of up to +/- four weeks will be allowed.
All data obtained from the assessments listed in the flowchart and described in detail in the 
subsections below must be supported in the patient’s source documentation. 
The study visit schedule consists of 5 visits within 10 years. The study plan timetable (see 
flow chart) indicates the number and timing of the planned visits. During these visits, the 
mentioned safety parameters will be assessed. It is important to maintain the visit schedule as 
accurately as possible. If any individual visit date does not conform to the planned schedule, 
the subsequent visit should be realigned to maintain the schedule relative to the start of the 
follow-up period. As part of the retention program, patients and/or parents/guardians as 
appropriate will receive reminders about attending their study visits to help maximize study 
compliance.
The clinical and laboratory investigational plan per visit is summarized in the flow-chart.
7.1.
Procedures by visits
7.1.1.
Baseline visit (F0)
This visit equals the final visit of EP00-401. Examinations and laboratory values from the 
final visit will be transferred to the baseline visit
•
Written informed consent will be obtained

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•
Concomitant medication recording
•
Adverse Events recording including all events from study EP00-401 which are 
ongoing at the time of start of the follow-up phase
7.1.2.
6 months visit (F1)
This visit has to be performed 6 months after termination of growth hormone treatment. The 
following investigations and assessments will be performed during clinical examination: 
•
Physical examination including height, body weight and pubertal status
•
Vital signs (blood pressure and heart rate)
•
Blood sampling for laboratory testing: Haematology and clinical chemistry including 
thyroid function, fasting plasma glucose, fasting plasma insulin and HbA1C
•
Urinalysis
•
IGF-I and IGFBP-3 determination
•
Blood sampling for anti-hGH antibodies
•
OGTT 
•
Concomitant medication recording
•
Adverse Events recording
7.1.3.
1 year visit (F2), 5 year visit (F3), 10 year visit (F4, final visit)
The following investigations and assessments will be performed during clinical examination: 
•
Physical examination including height, body weight and pubertal status
•
Vital signs (blood pressure and heart rate)
•
Blood sampling for laboratory testing: Haematology and clinical chemistry including 
thyroid function, fasting plasma glucose, fasting plasma insulin and HbA1C
•
Urinalysis
•
IGF-I and IGFBP-3 determination
•
Only if positive antibodies in previous visit: Blood sampling for anti-hGH antibodies
•
OGTT 
•
Concomitant medication recording
•
Adverse Events recording
7.2.
Patient compliance
Patient compliance will be assessed corresponding to visit schedule. 
7.3.
Safety
7.3.1.
Methods and timing for assessing, recording and analysis of parameters
At each visit, which should take place preferably in the morning, patient’s height and weight 
will be assessed and noted. If applicable, pubertal status should be assessed by the 
investigator and expressed in stages as described by Tanner and Whitehouse37.
Patients will also undergo a general physical examination and will also be questioned about 
and examined for any adverse events

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7.3.2.
Weight measurements
Weight will be measured according to the usual clinical practice.
7.3.3.
Carbohydrate metabolism: 
Fasting plasma glucose and insulin levels will be measured 6 months, 1, 5 and 10 years after 
the end of treatment. In case of elevated fasting blood glucose (> 100 mg/dl or > 5.6 mmol/l) 
a second sample for fasting blood glucose will be measured within 2 weeks. 
After an overnight fast, venous blood samples will be taken to assay fasting glucose and 
insulin levels. Insulin resistance will be estimated using both the homeostasis model 
assessment (HOMA)38 and quantitative insulin sensitivity check index (QUICKI).39 40
*
405
(mg/dl)
glucose
fasting
U/ml)
(
insulin
fasting
HOMA



*use constant 22.5 instead of 405 if glucose concentration is reported in mmol/L
(mg/dl)
glucose
fasting
log
U/ml)
(
insulin
fasting
log
1
QUICKI



Glycosylated haemoglobin (HbA1C) will be measured at 6 months, 1, 5 and 10 years after the 
end of treatment. 
An oral glucose tolerance test (OGTT) will be performed at 6 months, 1, 5 and 10 years after 
the end of treatment. 
The OGTT is a provocation test to examine the efficiency of the body to metabolise glucose. 
The OGTT provides information on latent diabetes states. The OGTT will be carried out 
according to WHO criteria (2002). After 3 days of an unrestricted, carbohydrate–rich diet, 
and after overnight fasting, 75 grams of glucose (for children: 1.75 grams of glucose per kg 
body weight (up to a maximum of 75 g) will be administered orally after being dissolved in 
250-300 ml of water. Blood samples will be taken 10 minutes before, and 120 minutes after 
the glucose load. Diabetes mellitus is defined by > 200 mg/dl or > 11.1 mmol/L blood 
glucose after 120 minutes.
OGTT is contraindicated in patients with overt diabetes mellitus.
7.3.4.
Immunogenicity
Subjects will be screened for anti-rhGH antibodies (ABs) at baseline and visit F1. Only in the 
case of development of anti-rhGH antibodies (ABs) in the previous visit follow-up 
measurements will be made 1, 5 and 10 years after the end of treatment.

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7.3.5.
Physical examination
At each scheduled visit (at baseline, 6 months, 1, 5 and 10 years after treatment), a thorough 
physical examination including of the following will be made: head (external), eyes, ears, 
nose and throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph 
nodes, central nervous system and, where appropriate, others. Additionally if applicable, pre-
pubertal or pubertal status will be documented by physical examination.
7.3.6.
Vital signs
Vital signs (blood pressure and pulse rate) will be recorded at each visit in a standardised 
manner, i.e., after the patient has rested for five minutes in the sitting position.
7.3.7.
Laboratory evaluations
7.3.7.1.
Local Laboratories
Local laboratories will be responsible for performing haematology including complete blood 
count (automated 5-part differential recommended) and platelet counts, biochemistry, thyroid 
function and urinalysis. All supernatants of these samples are destroyed after analysis.
The following laboratory safety tests will be performed 6 months, 1, 5 and 10 years after 
termination of treatment, unless more frequent assessment is clinically indicated. 
Haematology:
Haemoglobin, haematocrit, white blood cell count (total and 
differential) (WBC), red blood cell count (RBC), platelet count, mean 
cell volume (MCV), mean cell haemoglobin (MCH), mean cell 
haemoglobin concentration (MCHC), HbA1C, erythrocyte sedimentation 
rate (ESR). 
Biochemistry:
Thyroid function:
Creatinine, urea, aspartate aminotransferase (SGOT/AST), alanine 
aminotransferase (SGPT/ALT), gamma-glutamyltransferase (gamma-
GT), alkaline phosphatase, total bilirubin, albumin, total protein, HDL, 
LDL, sodium, potassium, chloride, glucose*, insulin*, uric acid, total 
cholesterol*, triglycerides*, calcium, phosphorus.
Free thyroxine (fT4) and thyroid stimulating hormone (TSH).
Urinalysis:
pH, glucose, ketones, bilirubin, protein..
*fasting serum levels; fasting is defined as no caloric intake for at least 8h
7.3.7.2.
Central Laboratory
Central laboratory will process samples for antibody analysis, IGF-I and IGFBP-3. 
Instructions on preparation and shipment of samples will be provided in the corresponding 
Manual. Serum samples have to be stored deep frozen between -20°C and -70°C for central 
determination of IGF-I, IGFBP-3 and anti-hGH antibodies. For central laboratory details 
please refer to Investigator File. All supernatants of samples will be destroyed after analysis 
with exemption of samples for antibody analyses which will be stored by the sponsor 
according Good Laboratory Practice (GLP) Guidelines in order to potentially re-analyze anti-
hGH antibodies at a later stage, if needed.

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7.4.
Efficacy
7.4.1.
Height measurements
Height will be measured according to the usual clinical practice
7.4.2.
IGF-I and IGFBP-3 serum levels
IGF-I and IGFBP-3 serum levels will be assessed 6 months, 1, 5 and 10 years after the end of 
treatment. 
7.5.
Tolerability/acceptability
Not applicable
7.6.
Resource utilization
Not applicable
8.0
Safety monitoring
8.1.
Adverse events
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug. Study drug includes the investigational drug under evaluation and 
the comparator drug or placebo that is given during any phase of the study. Medical 
conditions/diseases present before starting study drug are only considered adverse events if 
they worsen after starting study drug. Abnormal laboratory values or test results constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy.
Despite the above definition any appearance or worsening of any undesirable sign, symptom, 
or medical condition observed after start of the study and associated with study conduct (e.g. 
blood sample drawing) must also be recorded on the Adverse Event page of the patient’s CRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. All adverse events must be recorded on the Adverse Events CRF with the 
following information:
1. the severity grade 

Mild: No effect on normal daily activities/ awareness of symptoms but easily 
tolerated

Moderate: Effect on normal daily activities

Severe: Inability to perform daily activities
2. its relationship to the study drug(s) (suspected/not suspected)

Not suspected: The temporal relationship of the clinical event to trial drug 
administration makes a causal relationship unlikely, or other drugs, therapeutic 

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interventions or underlying conditions provide a sufficient explanation for the 
observed event.

Suspected: The temporal relationship of the clinical event to trial drug administration 
makes a causal relationship possible, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed event.
3. its duration (start and end dates or if continuing at final exam)
4. whether it constitutes a serious adverse event (SAE)
An SAE is defined as an event which:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
o
routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition
o
elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since the start of study drug
o
treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
o
social reasons and respite care in the absence of any deterioration in the 
patient’s general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 8.2.
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); concomitant medication given; non-
drug therapy given, patient hospitalized/patient’s hospitalization prolonged. The action taken 
to treat the adverse event should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
8.2.
Serious adverse event reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent for EP00-402 study and until 30 days after the patient 
has stopped study participation in EP00-402 study, must be reported to the sponsor within 24 
hours of learning of its occurrence.

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Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study drug given in the EP00-401 study, 
complete the SAE Report Form in English, and send the completed, signed form by fax 
within 24 hours to the sponsor. The telephone and fax number of the contact persons, specific 
to the site, are listed in the investigator folder provided to each site.
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the case report form documentation at the study site.
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE. The follow-up information should describe whether the event has resolved or continues, 
if and how it was treated, and whether the patient continued or withdrew from study 
participation. 
If the SAE is not previously documented in the Summary of Product Characteristics (SmPC) 
or Package Insert (new occurrence) and is thought to be related to the study drug taken in the 
EP00-401 study, the sponsor may urgently require further information from the investigator 
for Health Authority reporting. The sponsor may need to issue an Investigator Notification 
(IN) to inform all investigators involved in any study with the same drug that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries.
8.3.
Pregnancies
To ensure patient safety, each pregnancy in a patient who received study drug in EP00-401 
study must be reported to the sponsor within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the sponsor. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship of any pregnancy outcome to the 
sponsor study drug taken in EP00-401 study. Any SAE experienced during pregnancy must 
be reported on the SAE Report Form. 
8.4.
Data Monitoring Board
Not applicable

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9.0
Data review and database management
9.1.
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Sandoz 
representative or designee will review the protocol and CRFs with the investigators and their 
staff. During the study, the monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to 
Good Clinical Practice as well as the progress of enrollment. Key trial personnel must be 
available to assist the monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the patient's file. Data not requiring a 
written or electronic record will be defined before study start and will be recorded directly on 
the CRFs, which will be documented as being the source data. The investigator must also 
keep a copy of the signed informed consent form. 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Sandoz monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed. 
9.2.
Data collection
Designated investigator staff must enter the information required by the protocol onto the 
Sandoz CRFs that are printed on 2-part, non-carbon-required paper. Study monitors will 
review the CRFs for completeness and accuracy and instruct site personnel to make any 
required corrections or additions. The original CRFs are forwarded to the CRO by monitors 
or by the investigational site, the copy is being retained at the investigational site. Once the 
CRFs are received by the CRO, their receipt is recorded, the original copy is scanned and 
forwarded to the responsible data management staff for processing. After scanning the 
original copy is placed in Central Files.
10.0
Data analysis
The analyses will be described in more detail in Statistical Analysis Plans which will be 
written for each of the interim analyses as well as for the final analysis.
10.1.
Population for analysis
The safety population (SAF) will comprise all subjects who enter the observational period. 
The SAF population will be the basis for all safety analyses. Efficacy analyses will 
additionally be carried out for the ITT and PP populations as defined for the final analysis of 
study EP00-401.

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10.2.
Patient demographics/other baseline characteristics
Descriptive statistics will be used to describe background and demographic variables such as 
age, weight, and height, and frequency tables will be used to describe the gender and race of 
the patients.
10.3.
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
10.3.1.
Study drug administration:
The extent of exposure in the EP00-401 study will be analyzed using descriptive statistics.
Tables showing descriptive statistics for the total dose per kg body weight will be presented.
10.3.2.
Concomitant medication:
Concomitant medication will be coded according to WHO-DRL and the medications will be 
tabulated by ATC term. 
10.4.
Analysis of safety endpoints
10.4.1.
Carbohydrate metabolism: 
Fasting plasma glucose and insulin levels will be measured at baseline, 6 months, 1, 5 and 10 
years after the end of treatment. For each of these visits descriptive statistics will be 
calculated and presented together with the absolute and relative changes as compared to 
baseline.

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Insulin resistance will be estimated using both the homeostasis model assessment (HOMA)38
and quantitative insulin sensitivity check index (QUICKI).39 The effect of Omnitrope®
treatment on HOMA and QUICKI scores, calculated subsequent for each plasma glucose and 
insulin measurement, will be evaluated at each visit using descriptive statistics for the 
observed values along with the changes from baseline.
Glycosylated haemoglobin (HbA1C) will be measured at baseline, 6 months, 1, 5 and 10 years 
after the end of treatment. The effect of treatment on the HbA1C levels will also be displayed 
using descriptive statistics.
An oral glucose tolerance test (OGTT) will be performed at baseline, 6 months, 1, 5 and 10 
years after the end of treatment. 
Immunogenicity
Subjects will be screened for anti-rhGH antibodies (ABs) at baseline and 6 months after the 
end of treatment. For each time point the number and percentage of patients with anti-rhGH 
antibodies (ABs) will be tabulated.
Antibody-induced lack or loss of efficacy will be examined by comparing height outcome 
data between antibody-positive and antibody-negative subjects.
10.4.2.
Safety lab:
Haematology and blood chemistry results will be displayed by visit using descriptive statistics 
and/ or frequency tables depending on the type of variable (continuous or discrete). Shift 
tables for the number and percentage of clinically significant results will also be provided.
10.4.3.
(Serious) Adverse events:
Adverse events will be coded using MedDRA (Version to be determined depending on the 
time of the analysis). The number and percentage of patients having at least one (serious) 
adverse event will be tabulated separately for the treatment and for the follow-up period. The 
(serious) adverse events will be displayed by system organ class and preferred term and the 
relationship to the study drug and the intensities will be shown in corresponding frequency 
tables. 
10.4.4.
Vital signs / weight:
The development of the vital signs (blood pressure, pulse) as well as weight and BMI will be 
analyzed using descriptive statistics for each visit. 
10.5.
Analysis of efficacy endpoints
10.5.1.
Pharmacodynamic endpoints:
These are IGF-I and IGFBP-3 serum levels, which will be assessed at baseline, 6 months, 1, 5 
and 10 years after the end of treatment.
The effect of treatment on serum IGF-I and IGFBP-3 levels will be evaluated using 
descriptive statistics for the observed values at each visit together with the absolute and 
relative changes as compared to baseline.
10.5.2.
Height measurements:
The patients' height will be tabulated for each visit using descriptive statistics.

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10.6.
Interim analysis 
Interim analyses are planned at the following time points:
•
2022 with data of patients who completed 1 year of follow-up
•
2026 with data of patients who completed 5 years of follow-up
•
2031 with data of patients who completed 10 years of follow-up
10.7.
Sample size calculation
All patients who participated in the EP00-401 study and received at least one dose of study 
medication are intended to enter the observational period.
10.8.
Power for analysis of critical secondary variables
Not applicable 
11.0
Discussion and rationale for study design features
This study has been designed in accordance with the post-approval pharmacovigilance plan to 
extend the safety database of Omnitrope® and to address the EMEA’s request:
•
to investigate the diabetogenic potential of growth hormone in short children born 
SGA, and
•
to further investigate the immunogenicity of growth hormone in short children born 
SGA.
More specifically, the primary objective of this study is:
•
to monitor the development of diabetes during a long-term follow-up period (10 years) 
after treatment cessation.
The secondary objectives of this study are:
•
to monitor the development of anti-hGH for 6 months after treatment cessation,
•
to evaluate the safety (incidence and occurrence of adverse events) for 10 years after 
treatment cessation 
To address concerns regarding the risk of developing diabetes mellitus in GH-treated children 
born SGA, specific parameters such as fasting plasma glucose and insulin levels will be 
measured for a number of years after the end of treatment.
Subjects will be monitored for safety throughout the observational period. 
12.0
Procedures and instructions: Administrative procedures
12.1.
Changes to the protocol
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Sandoz and the international Coordinating Investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or 
the scientific quality of the study, require additional approval by the IRB/IEC of all centers, 
and, in some countries, by the regulatory authority. A copy of the written approval of the 
IRB/IEC and the regulatory authority, where applicable, must be given to the study monitor.

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12.2.
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol violations. Under no 
circumstances should the investigator contact the sponsor or its agents, if any, monitoring the 
trial to request approval of a protocol violation, as no authorized violations are permitted. If 
the investigator feels a protocol violations would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by the 
sponsor and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol violations will be recorded and reported in the CSR.
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the sponsor, Health Authorities where required, and the 
IRB/IEC/REB. Only amendments that are required for patient safety may be implemented 
prior to IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, the sponsor should be notified of this action and the IRB/IEC/REB at 
the study site should be informed within 10 working days.
12.3.
Publication of study protocol and results
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the CSR the results of this trial will be either submitted for publication and/or 
posted in a publicly accessible database of clinical trial results.
12.4.
Signatory investigator for study report
ICH E3 guidelines recommend, and EMEA Directive 2001/83/EC requires that a CSR which 
forms part of a marketing authorization application is signed by a Coordinating Investigator. 
The Coordinating Investigator will have the responsibility to review the study results and 
CSR, and to confirm to the best of his/her knowledge it accurately describes the conduct and 
results of the study. 
12.5.
Ethics and Good Clinical Practice
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice:
ICH 
Harmonized 
Tripartite 
Guidelines 
for 
Good 
Clinical 
Practice 
1996.
Directive 91/507/EEC, US 21 Code of Federal Regulations dealing with clinical studies 
(including parts 50 and 56 concerning informed consent and IRB regulations).
Declaration of Helsinki, Directive 2001/20/EC, EU Clinical trials Directive, Directive 
2005/28/EC, EU GCP Directive 91/507/EEC and amendments, concerning medical research 
in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects).
The investigator agrees when signing the protocol to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it 
conforms to.

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12.5.1.
Institutional Review Board/Independent Ethics Committee
Before implementing this study, the protocol, the curriculum vitae of the investigators, the 
proposed informed consent form and other information to subjects, will be submitted to a 
properly constituted Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
according to national law. The study will only be performed at a study site if a full approval 
of the protocol has been obtained by the IRB/IEC.
12.5.2.
Informed consent
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. To cover adolescence of the patients with adequate 
patient information/ informed consent documents, three different types of documents, one for 
children between 4 and 6 years of age, one for children between 6 and 12 years of age, and 
one for children above 12 years of age should be used for this follow-up study. At all events, 
written informed consent has to be obtained from the patients’ parents or legal guardian. 
Additionally, children who can read and write should also sign the informed consent 
document corresponding to their relevant age group.  
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC approval. 
12.5.3.
Declaration of Helsinki
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki which can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/b3.htm.
[The Declaration of Helsinki (Document 17.C) is an official policy document of the World 
Medical Association, the global representative body for physicians. It was first adopted in 
1964 (Helsinki, Finland) and revised in 1975 (Tokyo, Japan), 1983 (Venice, Italy), 1989 
(Hong Kong), 1996 (Somerset-West, South Africa) and 2000 (Edinburgh, Scotland). Note of 
clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002. Note 
of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004]

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13.0
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