Long-term Phase IV Multicentre Study on the Safety and Efficacy of Omnitrope® (rhGH) in Short Children Born Small for Gestational Age (SGA)
Phase: PHASE4
Conditions: Small for Gestational Age
Sponsor: Sandoz

Long-term Phase IV Multicentre Study on the Safety and Efficacy of Omnitrope® 
Official Title: 
NCT Number: 
NCT00537914 
Document Date: 
Clinical Study Protocol Version 6.0: 07 February 2020
(rhGH) in Short Children Born Small for Gestational Age (SGA) 

Omnitrope®
Study protocol EP00-401
Long-term phase IV multicentre study on the safety and 
efficacy of Omnitrope® (rhGH) in short children born Small 
for Gestational Age (SGA) 
Author(s):
Sandoz GmbH
Sponsor:
Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria
Date:
07-Feb-2020
Version:
6.0 incorporating amendment 5
Phase:
IV
EudraCT number
2006-002506-58
Number of pages:
55
Property of Sandoz 
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Sandoz

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Study No. EP00-401 
Protocol History
Document version (v) No
Released by
Comment
Protocol v 1.0
07 March 2007
Amendment 01
24 August 2007
incorporated into Protocol v 1.0, leading to
Protocol v 2.0
24 August 2007
Amendment 02
27 November 
2008
incorporated into Protocol v 2.0, leading to
Protocol v 3.0
27 November 
2008
Amendment 03
22 March 2012
incorporated into Protocol v3.0, leading to
Protocol v 4.0
22 March 2012
Amendment 04
24 August 2017 
incorporated into Protocol v4.0, leading to
Protocol v 5.0
24 August 2017
Amendment 05
07 February 2020
incorporated into Protocol v6.0, leading to
Protocol v 6.0
07 February 2020

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Study No. EP00-401 
Table of contents
Protocol History...................................................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Amendment 5 ......................................................................................................................8
Study status..........................................................................................................................8
Protocol synopsis...............................................................................................................10
Flow Chart Treatment Period ............................................................................................13
1
Background........................................................................................................................15
1.1
Investigational product ..........................................................................................15
1.2
The indication SGA...............................................................................................15
1.2.1
Type 2 Diabetes and SGA.....................................................................17
1.2.2
Syndrome X and SGA...........................................................................17
1.2.3
Growth Hormone therapy in SGA patients...........................................18
1.2.4
Metabolic effects of growth hormone treatment in patients born 
SGA.......................................................................................................20
2
Study Purpose....................................................................................................................20
3
Objectives..........................................................................................................................21
3.1
Primary objective(s)...............................................................................................21
3.2
Secondary objectives .............................................................................................21
4
Study design ......................................................................................................................21
5
Population..........................................................................................................................22
5.1.
Inclusion/exclusion criteria....................................................................................23
5.1.1
Inclusion criteria....................................................................................23
5.1.2
Exclusion criteria ..................................................................................23
6
Treatment...........................................................................................................................24
6.1
Investigational drug ...............................................................................................24
6.1.1
Omnitrope® 5 mg/ml powder and solvent for solution for injection ....24
6.1.2
Omnitrope® 5 mg/ 1.5 ml and Omnitrope® 10 mg/ 1.5 ml solution 
for injection...........................................................................................25
6.2
Treatment groups...................................................................................................25
6.3
Treatment assignment............................................................................................25
6.4
Treatment blinding.................................................................................................25
6.5
Treating the patient................................................................................................25
6.5.1
Dose.......................................................................................................25

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Study No. EP00-401 
6.5.2
Study drug administration.....................................................................25
6.5.3
Treatment duration................................................................................26
6.5.4
Permitted study drug dose adjustments.................................................26
6.5.5
Dose increase ........................................................................................26
6.5.6
Rescue medication ................................................................................26
6.5.7
Prohibited medication ...........................................................................27
6.5.8
Concomitant treatment..........................................................................27
6.5.9
Study drug discontinuation ...................................................................27
6.5.10
Premature patient withdrawal ...............................................................28
6.5.11
Emergency unblinding of treatment assignments .................................28
6.6
Contraception measures.........................................................................................29
7
Visit Schedule and assessments.........................................................................................30
7.1
Procedures by visits ...............................................................................................30
7.1.1
Screening Period (Visit 00)...................................................................30
7.1.2
Start of Treatment (Visit 01).................................................................31
7.1.3
3-Month Treatment Visit (Visit 02)......................................................31
7.1.4
6-Month Treatment Visit (Visit 03)......................................................32
7.1.5
9-Month Treatment Visit (Visit 04)......................................................32
7.1.6
12-Month Treatment Visit (Visit 05)....................................................32
7.1.7
15-Month Treatment Visit (Visit 06)....................................................33
7.1.8
18-Month Treatment Visit (Visit 07)....................................................33
7.1.9
21-Month Treatment Visit (Visit 08)....................................................33
7.1.10
24-Month Treatment Visit (Visit 09) and subsequent visits 
performed annually (Visit 11, Visit 13 etc) ..........................................34
7.1.11
30-Month Treatment Visit (Visit 10) and subsequent visits 
performed annually (Visit 12, Visit 14 etc) ..........................................34
7.1.12
Final Visit of treatment period..............................................................34
7.2
Treatment exposure and compliance .....................................................................35
7.3
Efficacy..................................................................................................................35
7.3.1
Methods and timing for assessing, recording and analysis of 
efficacy parameters ...............................................................................35
7.3.2
Anthropometric Measurements.............................................................35
7.3.3
Presentation and Calculation of Auxological Data...............................35
7.3.4
Weight measurements...........................................................................36
36
7.4
Safety.....................................................................................................................36
7.4.1
Carbohydrate metabolism .....................................................................36

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Study No. EP00-401 
7.4.2
Immunogenicity ....................................................................................37
7.4.3
Fundoscopy ...........................................................................................37
7.4.4
Physical examination ............................................................................37
7.4.5
Vital signs..............................................................................................37
7.4.6
Laboratory evaluations..........................................................................37
7.4.7
Adverse events ......................................................................................38
7.4.8
Serious adverse events ..........................................................................40
7.5
Tolerability/acceptability.......................................................................................41
7.6
Resource utilization ...............................................................................................41
8
Safety monitoring..............................................................................................................41
8.1
Serious adverse event reporting.............................................................................41
8.2
Reporting procedures for technical complaints .....................................................42
8.3
Reporting of study treatment errors including misuse/abuse ................................42
8.4
Pregnancy reporting...............................................................................................43
8.5
Data Monitoring Board..........................................................................................43
9
Data review and database management.............................................................................43
9.1
Site monitoring ......................................................................................................43
9.2
Data collection.......................................................................................................44
9.3
Medical Monitoring...............................................................................................44
10 Data analysis......................................................................................................................44
10.1
Analysis sets ..........................................................................................................44
10.1.1
Safety analysis set .................................................................................44
10.1.2
Full analysis set.....................................................................................44
10.2
Patient demographics/other baseline characteristics .............................................45
10.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................45
10.3.1
Study drug administration.....................................................................45
10.3.2
Concomitant medication .......................................................................45
10.3.3
Treatment compliance...........................................................................45
10.4
Analysis of safety endpoints..................................................................................45
10.4.1
Carbohydrate metabolism .....................................................................45
10.4.2
Immunogenicity ....................................................................................46
10.4.3
Safety lab / urine analysis .....................................................................46
10.4.4
(Serious) Adverse Events / Incidents ....................................................46
10.4.5
Vital signs / weight................................................................................46
10.4.6
Physical examination ............................................................................46
10.5
Analysis of efficacy endpoints...............................................................................46

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Study No. EP00-401 
10.5.1
Auxological endpoints ..........................................................................46
10.5.2
Pharmacodynamic endpoints ................................................................47
47
10.6
Interim analysis......................................................................................................47
10.7
Sample size calculation..........................................................................................47
10.8
Power for analysis of critical secondary variables ................................................47
10.9
Subgroup analyses .................................................................................................48
11 Discussion and rationale for study design features ...........................................................48
12 Procedures and instructions: Administrative procedures ..................................................49
12.1
Changes to the protocol .........................................................................................49
12.2
Ethics and Good Clinical Practice .........................................................................49
12.2.1
Institutional Review Board/ Independent Ethics Committee................49
12.2.2
Informed consent...................................................................................49
12.2.3
Declaration of Helsinki .........................................................................50
13 References .........................................................................................................................50
Appendices ........................................................................................................................54
Tanner Breast Stages .........................................................................................................54
Handling of elevated blood glucose levels and OGTT .....................................................54
Recommended Dosage of Omnitrope® ............................................................................55
List of tables
Table 4-1
Study Outline ........................................................................................22

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Study No. EP00-401 
List of abbreviations
AB
Antibody
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ANC
Absolute neutrophil count
BMI
Body Mass Index
BW
Body weight
CA
Calendar Age
CBC
complete blood count
CRF
Case report form
CRO
Contract research organization
EMEA
European Agency for the Evaluation of Medicinal Products
fT4
Free thyroxine 
GCP
Good clinical practice
GH
Growth hormone
HDL
High-density lipoproteins
hGH
Human growth hormone
HIV
Human immunodeficiency virus
HSDS
Height standard deviation score
HV
Height velocity
HVSDS
Height velocity standard deviation score
IEC
Independent ethics committee
IGFBP-3
Insulin-like growth factor binding protein 3
IGF-I
Insulin-like growth factor
IGT
Impaired glucose tolerance
IRB
Institutional review board
IUGR
Intrauterine growth retardation 
LDL
Low-density lipoproteins
LHRH
Luteinising hormone-releasing-hormone
OGTT
Oral glucose tolerance test
RBC
Red blood cell count
rhGH
Recombinant human growth hormone
SAE
Serious adverse event
SD
Standard deviation
SDS
Standard deviation score
SGA
Small for gestational age
SGOT
Serum-Glutamat-Oxalacetat-Transaminase
SGPT
Serum-Glutamat-Pyruvat-Transaminase
SmPC
Summary of medicinal Product Characteristics
SOP
Standard operating procedure
TSH
Thyroid stimulating hormone
WBC
White blood cell count
WHO
World Health Organization

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Study No. EP00-401 
Amendment 5
Amendment rationale
Patients treated with rhGH in study EP00-401 were allowed to enter the post-treatment 
observation EP00-402 to monitor the occurrence of type 2 diabetes mellitus over a 10-years’ 
time span after treatment completion. According to the termination in 2018 of the 
complementary EP00-402 study: “A phase IV multicenter, long-term safety follow-up 
planned for 10 years after stopping growth hormone treatment in patients who have completed 
study EP00-401”, references to patients’ enrolment into the terminated EP00-402 study were 
removed from the EP00-401 protocol by this amendment.
This protocol amendment provides also further clarification of the lost to follow up definition. 
This clarification is implemented to limit protocol deviations resulting from prolonged
interruption(s) of Omnitrop dosing and to facilitate compliance to visit schedule.
Study status
A total of 278 patients had been enrolled in the study. The last subject was enrolled on 29-
Apr-2010. As of 31-Dec-2019, 32 patients, hereof 7 female patients, are still on Omnitrope 
therapy and will continue treatment until they reach their final height. So far, no case of 
pregnancy has been reported in the study. One hundred twenty seven female patients have 
already completed the study. Clinical Study Report with the final results for the long-term 
observation study EP00-402 was submitted to EMA on the 18-April-2019.
Changes to the protocol will allow to limit protocol deviations due to prolonged interruptions 
of Omnitrop treatment. 
Changes to the protocol
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.
List of changes made in this amendment are:
Section Protocol synopsis 

Reference to inclusion into EP00-402 study removed
Section 2 Study Purpose

Reference to inclusion into EP00-402 study removed
Section 6.5.9 Study drug discontinuation Reference to inclusion into EP00-402 study 
removed
Section 6.5.10 Premature withdrawal Reference to inclusion into EP00-402 study removed

Definition of lost to follow up clarified
Section 11 Discussion and rationale for study design features

Reference to inclusion into EP00-402 study removed
The changes described in this amended protocol are considered non-substantial.

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Study No. EP00-401 
This amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committees (IECs) and Health Authorities (HA) for approval or notification as 
required according to local regulations.
The changes herein do not affect the Informed Consent Form.

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Study No. EP00-401 
Protocol synopsis
Title of study: 
Long-term phase IV multicentre study on the safety and efficacy of Omnitrope® (rhGH) in short 
children born Small for Gestational Age (SGA) 
Study Purpose:
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). In addition, 
within a supplemental follow-up study (Protocol number EP00-402) Sandoz was documenting the 
long-term safety during a follow-up period of 10 years after stopping growth hormone treatment and till 
closure of the study.
Objectives:
The primary objective of this study is to evaluate the long-term effect of growth hormone treatment on 
the development of diabetes during the treatment period in short children born SGA. The secondary 
objectives of this study are: 

to report the incidence of anti-rhGH antibodies (ABs) during treatment

to evaluate the efficacy (with respect to changes in height parameters) of Omnitrope®
treatment in short children born SGA

to evaluate IGF-I and IGFBP-3 levels during treatment 

to evaluate incidence and severity of adverse events
Inclusion/Exclusion criteria
Inclusion criteria:
1.
Pre-pubertal (Tanner stage I) children born SGA 
Boys: > 4 years of age (bilateral testicular volume <4 ml) (Marshall 1979)
Girls: > 4 years of age (bilateral Tanner breast stage 1) (Marshall 1969)
2.
Growth disturbance defined as current height SDS < -2.5 (and parental adjusted SDS < -1) 
for chronological age and sex according to country specific references. If country specific 
references are not available, pre-defined published references will be used.
3.
Birth weight and/or length below -2 SD for gestational age (according to country specific 
references). For the evaluation of gestational age, the date of the last menstrual period or 
ultrasonographic data obtained during the pregnancy should be used. If country specific 
references are not available, pre-defined procedures / published references will be used.
4.
Height records  between 18 months and 6 months prior to the start of GH treatment must be 
available
5.
Calculated height velocity SDS < 0 during the last year according to Prader (1989).
6.
Written informed consent of patient (for children who can read and write) and parent or legal 
guardian
Exclusion criteria:
1.
Onset of puberty
2.
Closed epiphyses
3.
Diabetes mellitus type I or type II 
4.
Fasting blood glucose > 100 mg/dl or > 5.6 mmol/l measured in venous blood sample
5.
Abnormal findings in OGTT defined by > 140 mg/dl or > 7.8 mmol/l after 120 minutes 
6.
Known IGF-I level above +2SD for sex and age

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Study No. EP00-401 
7.
Acute critical illness e.g. suffering complications following open heart surgery, abdominal 
surgery, multiple accidental trauma, acute respiratory failure 
8.
Known to be hepatitis B or hepatitis C positive or HIV-positive, known to have advanced 
diseases such as AIDS or tuberculosis 
9.
Any other disease, genetic disorder or malformation or treatment known to be associated with 
growth retardation, e.g. Turner or Noonan syndrome, Laron syndrome, Russell-Silver 
syndrome, Prader-Willi syndrome, skeletal dysplasias, chronic renal failure, cystic fibrosis, 
heart and liver diseases, malabsorption (coeliac disease), malnutrition, patients receiving 
radiation therapy of head or spinal cord
10. History of malignancy of any organ system, treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases, with the exception of 
localized basal cell carcinoma of the skin
11. Known or suspected hypersensitivity to rhGH or any of the excipients (e.g. benzyl alcohol)
12. Previous treatment with any hGH preparation
13. Oral, inhalative or parenteral treatment with glucosteroids, except for physiological 
replacement, or hypothyroidism which has been left untreated, or was inadequately treated, 
or treated for less than 3 months 
14. Treatment with LHRH / gonadotropin releasing hormone (GnRH) analoga (e.g. triptorelin)
15. Treatment with antidiabetic medication (e.g. metformin, insulin)
16. Drug abuse, substance abuse, or alcohol abuse
17. Known to be immunocompromised
18. Intake of growth promoting medication, e.g. anabolic steroids
19. Use of other investigational drugs within 30 days of enrolment 
20. Patients unwilling and/or parents/guardians who are not capable of ensuring compliance with 
the provisions of the study protocol
Investigational therapy:
Omnitrope® (rhGH) supplied as Omnitrope® 5 mg/ 1.5 ml and 10mg / 1.5 ml solution for injection. 
These formulations will be referred to as Omnitrope® throughout this document. 
A dose of 0.035 mg/kg body weight (BW) per day will be administered by daily subcutaneous injection 
in the evening. Dose adjustments will be allowed during therapy consistent with label 
recommendations.
Study design:
Phase IV, prospective, open label, non-comparative, multicentre trial. Omnitrope® treatment will 
continue until final height is reached. Treatment should be discontinued after the first year of treatment 
if the height velocity SDS is below +1. Treatment should be discontinued if height velocity is below 2 
cm/year
 
 
Measurements of carbohydrate metabolism (in terms of fasting plasma glucose, insulin and HbA1c
levels) will be performed throughout treatment. Anti-rhGH antibodies (ABs) will be measured during 
Omnitrope® treatment. Patients will be monitored for safety and efficacy throughout treatment. 
Efficacy assessments:
Height, standardised height (HSDS), height velocity (HV) and standardised HV (HVSDS) will be 
assessed at baseline, every 3 months during the first two years of GH treatment and semi-annually 
thereafter until final height is reached (end of treatment). 
 
 

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Study No. EP00-401 
IGF-I and IGFBP-3 serum levels will be assessed by a central laboratory at baseline, at 3, 6, 9 and 12 
months, then biannually during treatment, and at the end of treatment. 
Safety assessments:
Carbohydrate metabolism: Fasting plasma glucose and insulin levels will be measured at baseline, 
at 6 and 12 months, then annually during GH treatment, and at the end of treatment. Glycosylated 
haemoglobin (HbA1C) will be measured at baseline, at 6 and 12 months, then annually during GH 
treatment and at the end of treatment. An oral glucose tolerance test (OGTT) will be performed at 
baseline, at 6 and 12 months and then annually during GH treatment, and at the end of treatment. 
Immunogenicity: Subjects will be screened for anti-rhGH antibodies (ABs) at baseline, at 3, 6, 9, 12, 
18 and 24 months, then annually during GH treatment and the end of treatment. Antibody-induced lack 
or loss of efficacy will be examined by comparing height outcome data between antibody-positive and 
antibody-negative subjects.
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. Fundoscopy will be performed if intracranial 
hypertension is suspected (severe or recurrent headache, visual problems, nausea and/or vomiting). 
Adverse events, body weight and physical condition will be assessed at every study visit during 
Omnitrope® treatment. Laboratory tests for safety will be performed at baseline, at 6 and 12 months, 
then annually thereafter for the remainder of GH treatment, unless more frequent assessment is 
clinically indicated. 

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Study No. EP00-401 
Flow Chart Treatment Period
Treatment Period
TIME POINT
Screening
Start
3 mo
± 
3wks
6 mo
± 
3wks
9 mo
± 
3wks
12 
mo
± 
3wks
15 
mo
± 
3wks
18 mo
± 3wks
21 
mo
± 
3wks
24 
mo
± 
3wks
30 
mo
± 
3wks
36 
mo
± 
3wks
42 mo, 54 
mo etc…
± 3wks
48 mo, 60 
mo, etc…
± 3wks
End
± 3wks
VISIT
00
01
02
03
04
05
06
07
08
09
10
11
12, 14 etc…
annual visits
13, 15 etc…
annual visits
Final visit
Written Informed 
consent
X
Demographic data
X
Medical History 
X
SGA Diagnosis
X
Physical examination, 
weight (kg) and height 
(cm), pubertal status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
X
X
Blood chemistry incl. 
fT4, TSH, HbA1C, 
fasting plasma glucose 
and insulin levels
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Pregnancy test
X1
X1
X1
X1
X1
X1
Anti-hGH AB
X
X
X
X
X
X
X
X
X
X
IGF-I, IGFBP-3
X
X
X
X
X
X
X
X
X
X
X
X
OGTT 
X
X
X
X
X
X
X

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Study No. EP00-401 
Treatment Period
TIME POINT
Screening
Start
3 mo
± 
3wks
6 mo
± 
3wks
9 mo
± 
3wks
12 
mo
± 
3wks
15 
mo
± 
3wks
18 mo
± 3wks
21 
mo
± 
3wks
24 
mo
± 
3wks
30 
mo
± 
3wks
36 
mo
± 
3wks
42 mo, 54 
mo etc…
± 3wks
48 mo, 60 
mo, etc…
± 3wks
End
± 3wks
VISIT
00
01
02
03
04
05
06
07
08
09
10
11
12, 14 etc…
annual visits
13, 15 etc…
annual visits
Final visit
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fundoscopy
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
X3
Drug dispensing and 
recording
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug return 
(accountability) and 
recording
X
X
X
X
X
X
X
X
X
X
X
X
X
1: urine pregnancy test only in female patients after onset of menarche 
3: Fundoscopy will be performed only if intracranial hypertension is suspected

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Study No. EP00-401 
1
Background
1.1
Investigational product
The active substance of Omnitrope® is somatropin, a growth hormone produced by a 
genetically modified strain of Escherichia coli. Omnitrope® is a biological medicinal product 
authorized in the EU. Omnitrope® , 1.3 mg/ml and 5 mg/ml, powder and solvent for solution 
for injection, Omnitrope® 5 mg/ 1.5 ml solution for injection and Omnitrope® 10mg/ 1.5 ml 
solution for injection, obtained marketing authorization in the following indications:
Children

Growth disturbance due to insufficient secretion of growth hormone (GH) and growth 
disturbance associated with Turner syndrome and chronic renal insufficiency.

Growth disturbance (current height standard deviation score (SDS) < -2.5 and parental 
adjusted SDS < -1) in short children born small for gestational age (SGA), with a birth 
weight and/or length below -2 standard deviation (SD), who failed to show catch-up 
growth (height velocity (HV) SDS <0 during the last year) by 4 years of age or later.

Prader-Willi syndrome (PWS) for improvement of growth and body composition. The 
diagnosis PWS should be confirmed by appropriate genetic testing.
Adults

Replacement therapy in adults with pronounced growth hormone deficiency. 
Detailed conditions for the use of Omnitrope® are described in the Summary of Product 
Characteristics (SmPC).
1.2
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) (Lee et al 2003). The standards 
for neonatal growth were established by Usher and McLean (Usher and McLean 1969). 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.
Impaired foetal growth may be due to placental, foetal and maternal causes. Placental factors 
include any mismatch between placental perfusion and foetal oxygenation. Placental 

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Study No. EP00-401 
insufficiency, placental abruption, infarction, and vascular abnormalities are the most 
common contributors to foetal growth impairment. 
15% - 20% of SGA cases may be a result of foetal factors, including genetic and 
chromosomal abnormalities, congenital malformations, innate metabolic problems, infections, 
and multiple gestations (Lin and Santolaya-Forgtas 1998). Maternal factors include medical 
conditions (such as hypertension, diabetes mellitus, systemic lupus erythematosus, renal 
disorders, collagen vascular diseases, infections), demographic factors (age, height, weight, 
maternal and paternal ethic origin, parity), nutritional status, cigarette smoking, illicit drug use, 
alcohol abuse, and the use of certain therapeutic drugs (Lee et al 2001). 
Ultrasound criteria are used as a diagnostic standard in the identification of SGA. 
Ultrasonographic 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 (Degani 2001).
Between 3% and 10% of all live births each year are described as SGA (Rosenfeld and Cariati 
2002). 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 (Ventura et al 
1999)). In 2000, 4,058,814 infants were born in the United States according to the data from 
the National Centre for Health Statistics (Rosenfeld and Cariati 2002). 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 (Albertsson-Wikland and Karlberg 1997).
Endocrine and metabolic outcomes may be related to failure to achieve catch-up. While GH 
levels have a relatively small effect on in utero growth, insulin and insulin-like growth factors 
(IGFs) are key modifiers of foetal growth and development. Endocrine studies in utero show 
that growth retarded foetuses have reduced insulin (Economides et al 1989) and IGF-I 
(Lassarre et al 1991) levels and in the neonatal period, babies born SGA have low IGF-I 
levels and IGFBP-3 levels despite elevated GH secretion (Cance-Rouzaud et al 1998). Failure 
of catch-up growth is associated with persistent low IGF-I and IGFBP-3 levels (Boguszewski 
et al 1997), 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 

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(Boguszewski et al 2000). 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 (Lundgren 2001).
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, polycythemia.
There is also convincing evidence that SGA is a predisposing factor for the development of 
hypertension (Barker et al 1990), diabetes (Hales et al 1991) and cardiovascular disease 
(Barker et al 1993) in adult life.
1.2.1
Type 2 Diabetes and SGA
Studies in Europe, North America, and the developing world (Reynolds and Phillips 1998, 
Phillips 1996, Boyko 2000, Curhan et al 1996, Lithell et al 1996, McCance et al 1994, Rich-
Edwards et al 1999) 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 colleagues (Rich-Edwards et al 1999) 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. Alternatively, 
insulin resistance may be controlled by the same genetic factors that regulate foetal growth 
(Stern et al 2000, Rich-Edwards et al 1997). Hattersley and colleagues (Hattersley and Tooke 
1999) 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.
1.2.2
Syndrome X and SGA
Certain chronic and metabolic disorders including hypertension, glucose intolerance, central 
obesity, and dyslipidemia 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 SGA 
(Valdez et al 1994, Li et al 2001, Ong and Dunger 2002, Yarbrough et al 1998). Moreover, 
adult overweight and obesity increase the risk of syndrome X, and studies show adults born 

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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 colleagues (Yarbrough et al 1998) 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, 
dyslipidemia, 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 (Leger et al 1997) 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.
1.2.3
Growth Hormone therapy in SGA patients
Growth Hormone (GH) therapy is indicated for children who were born SGA and have 
persistent short stature (below - 2 SD); are at least 2 years of age; and are growing at an 
average or subnormal rate of age, provided that other causes for short stature such as growth
inhibiting medication, chronic disease, endocrine disorders, emotional deprivation or 
syndromes (except Silver Russell syndrome) have been ruled out (Lee et al 2001).
The aims for GH therapy in children born SGA who fail to catch up are to:

Increase height during childhood,

Sustain the height gain in adolescence, and

Normalise final adult height.
Results of several trials indicate that high-dose GH therapy accelerates short-term height 
velocity in short children born SGA.
In the first studies examining the effects of GH therapy in children with insufficient catch-up 
growth, GH was given with low frequency or in substitution doses. Since the growth 
responses were inconsistent, researchers began to evaluate high-dose GH schedules.
De Zegher et al (2002) evaluated the effects of daily high-dose GH therapy over 2 years in 50 
short, prepubertal, non-GH-deficient children born SGA in an open-label, controlled, 
multicentre trial. Catch-up growth was observed in none of the untreated and in all of the 
treated children. Both treatment groups experienced significantly greater height velocity 
(P < 0.001), height velocity SDS (P < 0.001), and height gain SDS (P < 0.001) compared with 
the control group. There were, however, no significant differences between the two GH doses. 
Height velocity was greater in the first year of treatment compared with the second. The mean 
gain in height for the treatment groups was 2.3 SDS. GH-induced catch-up growth was 

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associated with an acceleration of bone maturation. There were associated elevations in serum 
concentrations of insulin, IGF-I and IGFBP-3.
In a follow-up study, De Zegher et al (1999) reported on the further prepubertal growth of the 
children treated in the previous study after withdrawal of the high-dose GH treatment. Of the 
38 treated children, none developed precocious puberty and 22 remained prepubertal. Height 
increased by an average of 2.5 SD over the 2-year treatment period and decreased by 0.4 SD 
during the first and 0.3 SD in the second year after GH withdrawal. No further GH treatment 
was given to those children (n=13) whose mean adjusted height stabilised at an SDS of 
around -1.0 after completion of the first treatment phase. When stature was very short at the 
completion of the first phase (mean adjusted height = -3.3 SD score; n=9), a second course of 
GH treatment of 0.2 IU/kg/day was initiated either 2 years (n=5) or 3 years (n=4) after initial 
GH withdrawal. 
This second treatment phase was associated with further growth and also resulted in a mean 
adjusted height of -1.0 SD score.
De Zegher et al (2000) also reported the data of four randomized, multicentre studies 
examining the effects of continuous and discontinuous GH therapy in a total of 49 untreated 
and 139 treated children born SGA. At the start of the study, the average age of the children 
was 5.2 years. Two studies examined the effects of continuous GH treatment at a dose of 
0.033 or 0.067 mg/kg/day over a 6-year period. The other 2 studies examined the impact of 
discontinuous GH treatment at a range of 0.033-0.10 mg/kg/day. In the discontinuous regimen, 
the initial treatment period of 2 to 3 years was followed by a withdrawal phase of 1 to 2 years 
and then either none, one, or more additional treatment phases at the same dose. Continuous 
GH treatment for 6 years was associated with mean increases in height of 2.0 SD for the low-
dose and 2.7 SD for the high-dose regimens. Discontinuous GH treatment, with an average 
dose of 0.032 mg/kg/day over the course of 6 years, resulted in a mean height increase of 1.6 
SD. Patients in the untreated group, on the other hand, increased their height by a mean of 
only 0.2 SD. Bone maturation progressed similarly in all treatment groups. The average GH 
doses over the 6 year period, parental-adjusted height SD scores, and age at start of treatment 
were the prime predictors of the growth response.
Sas et al (1999) began a randomized, double-blind, dose-response, multicentre trial on the 
long-term effects of continuous GH therapy (five years) in 79 prepubertal children with short 
stature born SGA. Twenty-two patients with GH deficiency were included in the study and 
there was no untreated control group. Patients were randomized to receive 3 IU/m2 body 
surface per day or 6 IU/m2 body surface per day. Five of the 79 children dropped out of the 
study for such reasons as poor compliance, concomitant treatment, and possible GH 
insensitivity. Their data were not included in the analysis. After 5 years of treatment, the mean 
height SD for chronological age was increased significantly over baseline (P < 0.001). In 
addition, almost every subject had reached a height within the normal range after the 
treatment period. Except for the children who remained prepubertal over the course of the 5 
years, there was no significant growth difference in response to the 2 doses. GH treatment was 
associated with an acceleration of bone maturation, increase in bone age, and increase in 
predicted adult height regardless of the GH dose.
On the basis of efficacy data but taking into account the concerns of long-term safety, the 
Committee for Proprietary Medicinal Products (CPMP) of EMEA recommended that the 

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treatment with GH of the children with growth disturbance (current height SDS <-2.5 and 
parental adjusted height SDS <-1) born SGA, who failed to show catch-up growth by 4 years 
of age or later, should be initiated at a dose of 0.035 mg/kg/day and continued until final 
height is reached (CPMP/3477/03).
1.2.4
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 (2000) evaluated the changes in body metabolism, blood pressure and lipid 
metabolism in 79 GH-treated children (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 (Hokkon-Koelega et al 2004, Sas et al 2001), 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 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
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. However in most recent investigations which followed-

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up SGA patients after treatment completion no increased risk of insulin resistance or type 2 
diabetes could be observed in the long-term perspective (van der Steen et al 2017, Poidvin et 
al 2017, Poidvin et al 2017).
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). Within an additional study EP00-402, Sandoz was documenting the long-term safety 
during a follow-up period of 10 years after stopping growth hormone treatment till study 
closure.
The purpose of this study is 
(a) to monitor short children born SGA for the development of diabetes during Omnitrope®
treatment and 
(b) to report the incidence of anti-rhGH antibodies (ABs) during treatment GH treatment.
3
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 during treatment. 
3.2
Secondary objectives
The secondary objectives of this study are: 

to report the incidence of anti-rhGH antibodies (ABs) during Omnitrope® treatment

to evaluate the efficacy (with respect to changes in height parameters) of Omnitrope® 
treatment in short children born SGA

to evaluate IGF-I and IGFBP-3 levels during treatment 

to evaluate incidence and severity of adverse events
4
Study design
This study is designed as a phase IV, prospective, open label, non-comparative, multicentre 
trial. Safety and efficacy will be assessed periodically during treatment. 
Treatment should be discontinued after the first year of treatment if the height velocity SDS is 
below +1. Treatment will continue until final height (height velocity < 2 cm/year, 
 
 
 is reached but will be discontinued earlier if medically indicated or if 
there is inadequate response to treatment.
A summary of the study plan is given below.

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Table 4-1
Study Outline
PHASE
Treatment
TIME
POINT
Start
3
mo
6
mo
9
mo
12
mo
Study visits until final height
End
VISIT
01
02
03
04
05
  06, 07, 08, 09, etc.
End of treatment
THERAPY
0.035 mg/kg BW/day
5
Population
The study population will consist of a representative group of children of both sexes, aged ≥4, 
with short stature born small for gestational age (SGA).
SGA is defined as per the label indication authorised by the EMEA:
“Growth disturbance (current height standard deviation score (SDS) < -2.5 and parental 
adjusted SDS < -1) in short children born small for gestational age (SGA), with a birth weight 
and/or length below -2 standard deviation (SD), who failed to show catch-up growth (height 
velocity (HV) SDS < 0 during the last year) by 4 years of age or later.”
Standardized and controlled Enrolment Authorization:
To assist Investigators to avoid errors in the local calculation of the auxological parameters by 
applying different ways of calculation and to ensure that only patients in strict adherence to 
the SGA definition in the study protocol are enrolled, a standardized and controlled procedure 
for patient enrolment authorization (“Enrolment Authorization Fax”) was implemented after 
the first 60 patients were enrolled in the study (by November 2008).
For the patients enrolled before implementation of the “Enrolment Authorization Fax” a 
standardized approach for the recalculation of growth indication for inclusion according to 
inclusion criteria 2, 3 and 5 was implemented in March 2009. 
Historical data will be used to screen the subjects for eligibility, i.e. records of birth length 
and weight, as well as height and weight measurements taken 1 year (between 18 months and 
6 months) before the start of GH treatment for calculation of HVSDS. For the evaluation of 
gestational age, the date of the last menstrual period will be used, however, if this is not 
known, ultrasonographic data obtained during the pregnancy may be used. 
The study will be performed in approximately 40 centres in Europe. The treating physicians 
shall be appropriately qualified and experienced in the diagnosis and management of SGA. 
The patients will be treated as out-patients.
 Subjects dropping out before 
completing 1 year of treatment will be replaced.
 
 
 

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Study No. EP00-401 
 
 
Patients who have started their treatment with Omnitrope® 5 mg/ml powder and solvent for 
injection will continue with Omnitrope® 5 mg/1.5 ml solution for injection from Visit 5 on (i.e. 
after 12 months of treatment with Omnitrope® 5 mg/ml powder and solvent for injection). 
Depending on the weight and corresponding injection volume patients may also switch to 
Omnitrope® 10 mg/ 1.5 ml solution for injection. 
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. Pre-pubertal (Tanner stage I) children born SGA 
Boys: > 4 years of age (bilateral testicular volume < 4 ml) 
Girls: > 4 years of age (bilateral Tanner breast stage 1)
2. Growth disturbance defined as current height SDS < -2.5 (and parental adjusted SDS < -1) 
for chronological age and sex according to country specific references. If country specific 
references are not available, pre-defined published references will be used.
3. Birth weight and/or length below -2 SD for gestational age (according to country specific 
references). For the evaluation of gestational age, the date of the last menstrual period or 
ultrasonographic data obtained during the pregnancy should be used. If country specific 
references are not available, pre-defined procedures / published references will be used.
4. Height records between 18 months and 6 months prior to the start of GH treatment must 
be available
5. Calculated height velocity SDS < 0 during the last year according to Prader (1989). 
6. Written informed consent of patient (for children who can read and write) and parent or 
legal guardian
5.1.2
Exclusion criteria 
1. Onset of puberty
2. Closed epiphyses
3. Diabetes type I or type II
4. Fasting blood glucose > 100 mg/dl or > 5.6 mmol/l measured in venous blood sample
5. Abnormal findings in OGTT defined by > 140 mg/dl or > 7.8 mmol/l after 120 minutes 
6. Known IGF-I level above +2SD for sex and age
7. Acute critical illness e.g. suffering complications following open heart surgery, abdominal 
surgery, multiple accidental trauma, acute respiratory failure. 
8. Known to be hepatitis B or hepatitis C positive or HIV-positive, known to have advanced 
diseases such as AIDS or tuberculosis 

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9. Any other disease, genetic disorder or malformation or treatment known to be associated 
with growth retardation, e.g. Turner or Noonan syndrome, Laron syndrome, Russell-Silver 
syndrome, Prader-Willi syndrome, skeletal dysplasias, chronic renal failure, cystic fibrosis, 
heart and liver diseases, malabsorption (coeliac disease), malnutrition, patients receiving 
radiation therapy of head or spinal cord
10. History of malignancy of any organ system, treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases, with the exception of 
localized basal cell carcinoma of the skin
11. Known or suspected hypersensitivity to hGH or any of the excipients (benzyl alcohol)
12. Previous treatment with any hGH preparation
13. Oral, inhalative or parenteral treatment with glucosteroids, except for physiological 
replacement, or hypothyroidism which has been left untreated, or was inadequately treated, 
or treated for less than 3 months 
14. Treatment with LHRH / gonadotropin releasing hormone (GnRH) analoga (e.g. 
triptorelin)
15. Treatment with antidiabetic medication (e.g. metformin, insulin)
16. Drug, substance, or alcohol abuse
17. Known to be immunocompromised
18. Intake of growth promoting medication, e.g. anabolic steroids 
19. Use of other investigational drugs within 30 days of enrolment 
20. Patients unwilling and/or parents/guardians who are not capable of ensuring compliance 
with the provisions of the study protocol
6
Treatment
6.1
Investigational drug
6.1.1
Omnitrope® 5 mg/ml powder and solvent for solution for injection
Omnitrope® 5 mg/ml is supplied with 1 vial containing somatropin as a powder and a 
cartridge containing diluent (bacteriostatic water for injection containing 1.5% benzyl alcohol 
as preservative). Omnitrope® is to be stored refrigerated at 2ºC to 8ºC and protected from light. 
Freezing must be avoided. 
After reconstitution by means of a specifically designed reconstitution set (“Transfer Set“) 
provided by Sandoz, one cartridge contains 5.0 mg (15 IU) somatropin per ml. 
The reconstituted Omnitrope® solution for injection can be stored up to 21 days at 2ºC to 8ºC 
in the refrigerator. The cartridges are designed to be used in a pen injection device, the 
Omnitrope® Pen, which will be provided by Sandoz. 
Parents and patients, if appropriate, will be sufficiently trained on the use of the Transfer set 
and the dose and injection technique by means of the Omnitrope® Pen.

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6.1.2
Omnitrope® 5 mg/ 1.5 ml and Omnitrope® 10 mg/ 1.5 ml solution for 
injection
Omnitrope®  5 mg/ 1.5 ml (injection containing 0.9 % benzyl alcohol as preservative) and
Omnitrope® 10mg/ 1.5 ml are supplied in cartridges containing solution for injection. 
Omnitrope® is to be stored refrigerated at 2ºC to 8ºC and protected from light. Freezing must 
be avoided.
The cartridges are designed to be used in a pen injection device, the Omnitrope® Pen will be 
provided by Sandoz. After opening and first injection the cartridge should remain in the pen 
and has can be stored up to 28 days at 2ºC to 8ºC in the refrigerator. 
Parents and patients, if appropriate, will be sufficiently trained on the dose and injection 
technique by means of the Omnitrope® Pen.
6.2
Treatment groups
There will only be one treatment group.
6.3
Treatment assignment 
This study is not randomized.
Each patient is uniquely identified in the study by a combination of his/her centre number and 
patient number. The centre number is assigned by Sandoz to the investigative site. Upon 
signing the informed consent form, the first patient is assigned patient number 001 per site, 
and subsequent patients are assigned consecutive numbers (e.g., the second patient is assigned 
patient number 002, the third patient is assigned patient number 003). Once assigned to a 
patient, a patient number will not be reused. If the patient fails to start treatment for any 
reason, the reason for not being started on treatment will be entered on the Screening Log, and 
the Demography CRF should also be completed.
Only this unique identifier number will be used to identify the enrolled patients.
6.4
Treatment blinding
Treatment during this study is open-label.
6.5
Treating the patient
6.5.1
Dose
A daily dose of 0.035 mg/kg per day will be administered by subcutaneous injection in the 
evening. A table is provided in the appendix for calculation of the individual dose according 
to the individual body weight.
6.5.2
Study drug administration
Each study site will be supplied, by Sandoz, with study drug in country specific packaging 
identifying the medication as study drug. Investigator staff will identify the study drug for 
dispensing to the patient using the centre and patient code number. Prior to dispensing study 

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drug to the patient, investigator staff shall transfer the tear-off label with the serial number of 
the vials to the respective CRF page. 
A daily dose of 0.035 mg/kg per day will be administered by subcutaneous injection in the 
evening. The injection site should be varied to prevent lipoatrophy. 
The investigator should instruct the patient to administer the study drug exactly as prescribed 
(promote compliance). All doses dispensed to the patient and all dose changes during the 
study must be recorded on the Dose Administration Record CRF. 
For handling of study medication please refer to section 6.1.
6.5.3
Treatment duration
Omnitrope® treatment will continue until final height is reached. Treatment should be 
discontinued after the first year of treatment if the height velocity SDS is below +1 (see also 
6.5.9 Study drug discontinuation). 
 
 
A standardized controlled procedure for the calculation of the treatment response (“Treatment 
Response Control Fax”) was implemented.
6.5.4
Permitted study drug dose adjustments
Dose adjustments will be allowed during therapy consistent with label recommendations to 
take individual responsiveness into consideration. This dose may be adjusted at subsequent 
study visits; investigators are requested to adapt the dose at every study visit according to the 
changing body weight after initiation of therapy. 
For patients who are unable to tolerate the protocol-specified dose scheme, dose adjustments 
and interruptions up to 3 weeks are permitted in order to keep the patient on study drug. This 
may for instance be required if transient labelled side effects occur. Please also refer to section 
6.5.10. 
All changes must be recorded on the Dose Administration Record CRF.
6.5.4.1
Dose reduction
If IGF-I exceeds +2SD compared to references for age and pubertal status, the IGF-I/IGFBP-3 
ratio will be determined. If IGF-I/IGFBP-3 ratio also exceeds +2SD, a dose reduction is 
recommended. The extent of the dose reduction will be at the discretion of the investigator. 
6.5.5
Dose increase
An increase of recommended dose of 0.035 mg/kg per day is not allowed, especially if based 
on concomitant treatment e.g. treatment with LHRH/GnRH analoga. In case an increase of the 
dose is required for obtaining increased growth velocity, the patient has to discontinue the 
study.
6.5.6
Rescue medication
Not applicable

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6.5.7
Prohibited medication
Treatment with antidiabetic medication (e.g metformin, insulin) is not allowed during the 
study. If treatment with antidiabetics becomes necessary, the patient has to discontinue the 
study.
6.5.8
Concomitant treatment
Other medication which is considered necessary for the patient’s welfare may be given at the 
discretion of the investigator. Administration of all such 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.
6.5.9
Study drug discontinuation
Treatment can be terminated at any time, at the discretion of the investigator or the Sponsor, 
or at the patient’s request, in the event of an AE or due to treatment failure. 
Study drug treatment has to be discontinued in the following cases during treatment period:

Occurrence of overt diabetes mellitus; defined as fasting blood glucose >126 mg/dl or 
> 7.0 mmol/l and abnormal findings in OGTT defined by > 200 mg/dl or > 11.1 mmol/l 
after 120 minutes. For further instruction see appendix 

Requirement of an increase of the recommended dose to obtain increased growth velocity

Renal transplantation

Diagnosis of benign intracranial hypertension 

Malignancy

Pregnancy

Withdrawal of informed consent

Treatment failure
Treatment failure is defined as: Inadequate response to treatment, e.g. height velocity standard 
deviation score (HVSDS) below +1 in the first year. 
Furthermore a standardized controlled procedure for the calculation of the treatment response 
(via “Treatment Response Control Fax”) was implemented (see also 6.5.3 treatment duration) 
to ensure a unified flawless computation and to authorize treatment continuation, if applicable 
(managed by Data Management at Metronomia). In case the Investigator does not agree with 
the assessment by Data Management, Sandoz is informed and initiates the re-assessment of 
the treatment response data via an independent specialist reader.
Patients who are withdrawn from the study before completing at least one year of treatment 
with Omnitrope® will be replaced.
Study drug must be discontinued if the investigator concludes that continuation would result 
in significant safety risk for that patient and in the event of pregnancy.

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Patients who discontinue study drug before completing the study should not be considered 
withdrawn from the study and should be scheduled for a final visit as soon as possible, at 
which time all of the assessments for the final visit will be performed. 
A Study Drug Discontinuation form should be completed, giving the date and reason for 
stopping the study drug. All patients who discontinue study drug, including those who refuse 
to return for a final visit, will be contacted for safety evaluations during the 4 weeks following 
the last dose of the study drug.
Patients who discontinued this study for any reason will not be able to re-enter the study.
6.5.10
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.
A patient is considered to be lost to follow up in case patient status is unclear because they fail 
to appear for study visit within visit window without stating an intention to withdraw and the 
patient does not react to at least three attempts of the investigator to schedule the visit within 
visit window (the investigator should show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, 
etc.)
A patient who does not attend the visit during visit window is considered as lost to follow up, 
unless
-
(s)he experiences medical condition, which prevents her/him from appearing to the 
visit within visit window and
-
patient notifies the investigator about this condition during visit window or earlier and
-
before or during visit window sponsor grants upfront written approval for the visit 
outside of visit window.
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. For lost to follow up patients the termination fax specifying the reason of 
withdrawal should be provided to DM within 4 weeks of calculated visit date.
6.5.11
Emergency unblinding of treatment assignments
Not applicable.

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6.6
Contraception measures
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric patients who are menarchal or who 
become menarchal during the study. 
All menarchal girls and their parents/caregivers should be informed about the potential risks 
of pregnancy and the need to prevent pregnancy during the study. It is important to be 
sensitive in introducing this issue, as understanding and comprehension of puberty, sexual 
activity, pregnancy and contraception is influenced by age, as well as factors such as precocity, 
socio(educational) economic and familial background. These discussions with the patient and 
her parents/caregivers are therefore best performed by investigators familiar with the pediatric 
subject and her family and should be guided by requirements of the local regulatory 
authorities. These discussions should take into account the socio-economic, cultural factors 
and religious beliefs of the adolescent participant and her family. The investigator should also 
discuss the management of the pregnancy test results with the patient and her 
parents/caregivers. The privacy of the patient should be considered in accordance with the 
local law and ethics.
Urine pregnancy tests will be performed for all females of child-bearing potential according to 
the schedule in the Flow Chart. Additional pregnancy tests may be performed at the 
investigator’s discretion during the study. Patients becoming pregnant must be discontinued 
from study drug.
All female patients of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant must use effective methods of contraception during dosing of study 
treatment. Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation. In case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment 

Male sterilization. For female subjects participating in the study, the vasectomized 
male partner must be the sole partner for that subject 

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception it is recommended that the female patients of childbearing 
potential is exerting abstinence for a period of 3 months until safe onset of action of the oral 
contraception.

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7
Visit Schedule and assessments
The Flow Chart (synopsis) lists 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 +/- three weeks will be allowed.
All data obtained from the assessments listed in the Flow-Chart and described in detail in the 
subsections below must be supported in the patient’s source documentation. 
The study visit schedule consists of screening period for up to 8 weeks prior to the initiation 
of therapy followed by an open treatment period until final height is reached. The study plan 
timetable (please refer to the Flow Chart Treatment Period) indicates the number and timing 
of the planned visits. During these visits, the mentioned efficacy and safety parameters will be 
assessed. It is important to maintain the visit schedule during the treatment period 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 
treatment period.
The clinical and laboratory investigational plan per visit is summarized in the Flow Chart 
Treatment Period.
7.1
Procedures by visits
7.1.1
Screening Period (Visit 00)
At the screening visit (to be performed within 8 weeks prior to visit 1), all data to confirm the 
diagnosis SGA will be collected in addition to demographic and baseline data to determine the 
patient’s eligibility for study participation.

Demographics (date of birth, sex, ethnic origin) 

Medical and surgical history

Prenatal history 

Placental dysfunction (eclampsia, infarcts), genetic causes

Maternal disease

Gestational age

Birth history

Vaginal/caesarean, Apgar-score, blood pH, body weight, body length, neonatal 
complications (need for glucose, respiratory support)

Infant growth data

Retrospective weight, length, feeding mode

Pre-treatment growth data

Height measurement between 18 months and 6 months prior to the start of 
Omnitrope® treatment to enable calculation of pre-treatment height velocity

Current standing height

Physical examination, puberty stage and vital signs

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
Body mass index

Parental height and weight

Growth hormone secretion

Collection of historical data with regard to growth hormone secretion

Written informed consent will be obtained before any measurements are made. 

Recording of patient’s and parents’ data in the respective CRF

Patients history and details of concomitant medications

Recording of historical X-ray radiograph of the patient’s left hand and wrist
7.1.2
Start of Treatment (Visit 01)
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 and fasting plasma insulin 

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

OGTT 

Urinary analysis (dip stick)
 

Concomitant medication recording

Adverse Events recording

Drug dispensing and recording
At this visit, patients/parents will be carefully instructed by the investigator/clinical staff on 
the use of the pen injector, the pen needle, and the appropriate injection technique including 
cleaning of the injection site and discharging of the used needle. The first injection of 
Omnitrope® will be administered. Patients will receive a three months supply of study drug 
packed in a cool box and will be instructed to place the study medication in the refrigerator at 
home as soon as possible. The dispensed study drug will also be recorded in the Drug 
Accountability Form.
7.1.3
3-Month Treatment Visit (Visit 02)
At visit 02, the following investigations will be performed: 

Physical examination including height, weight and pubertal status

Vital signs (blood pressure and heart rate)

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

Concomitant medication recording

Adverse Events recording 

Fundoscopy, if needed

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
Drug dispensing, drug accountability and recording
7.1.4
6-Month Treatment Visit (Visit 03)
At visit 03, the following investigations will be performed: 

Physical examination including height, 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 and fasting plasma insulin 

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

OGTT 

Urinary analysis (dip stick)

Pregnancy test (only in female patients after onset of menarche)

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug dispensing, drug accountability and recording
7.1.5
9-Month Treatment Visit (Visit 04)
At visit 04, the following investigations will be performed: 

Physical examination including height, weight and pubertal status

Vital signs (blood pressure and heart rate)

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug dispensing, drug accountability and recording
7.1.6
12-Month Treatment Visit (Visit 05)
At visit 05, the following investigations will be performed: 

Physical examination including height, 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 and fasting plasma insulin 

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

OGTT 

Urinary analysis (dip stick)

Pregnancy test (only in female patients after onset of menarche)
 

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
Concomitant medication recording

Adverse Events recording 

Fundoscopy, if needed

Drug dispensing, drug accountability and recording
7.1.7
15-Month Treatment Visit (Visit 06)
At visit 06, the following investigations will be performed: 

Physical examination including height, weight and pubertal status

Vital signs (blood pressure and heart rate)

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug dispensing, drug accountability and recording
7.1.8
18-Month Treatment Visit (Visit 07)
At visit 07, the following investigations will be performed: 

Physical examination including height, weight and pubertal status

Vital signs (blood pressure and heart rate)

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug dispensing, drug accountability and recording
7.1.9
21-Month Treatment Visit (Visit 08)
At visit 08, the following investigations will be performed: 

Physical examination including height, weight and pubertal status

Vital signs (blood pressure and heart rate)

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug dispensing, drug accountability and recording

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Study No. EP00-401 
7.1.10
24-Month Treatment Visit (Visit 09) and subsequent visits performed 
annually (Visit 11, Visit 13 etc) 
The following investigations will be performed: 

Physical examination including height, 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 and fasting plasma insulin 

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

OGTT

Urinary analysis (dip stick)

Pregnancy test (only in female patients after onset of menarche)
 

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug dispensing, drug accountability and recording
7.1.11
30-Month Treatment Visit (Visit 10) and subsequent visits performed 
annually (Visit 12, Visit 14 etc)
The following investigations will be performed: 

Physical examination including height, weight and pubertal status

Vital signs (blood pressure and heart rate)

Blood sampling for IGF-I and IGFBP-3 determination

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug dispensing, drug accountability and recording
7.1.12
Final Visit of treatment period
At final visit of treatment period, the following investigations will be performed: 

Physical examination including height, 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 and fasting plasma insulin 

Blood sampling for anti-hGH antibodies, IGF-I and IGFBP-3 determination

OGTT 

Urinary analysis (dip stick)

Pregnancy test (only in female patients after onset of menarche)

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Study No. EP00-401 
 

Concomitant medication recording

Adverse Events recording

Fundoscopy, if needed

Drug accountability and recording
7.2
Treatment exposure and compliance
Patient compliance will be assessed by the collection of used, partly used and unused vials as 
well as cartridges at each visit. The number of returned vials and the quantity of unused 
treatment remaining in the vials will provide information on treatment compliance, which will 
be recorded in the source document at each visit. Patients must comply with the dose schedule. 
The daily dose should be maintained in the range between 80% and 120% of the 
recommended daily dose of 0.035 mg/kg BW depending on the patient’s responsiveness. 
7.3
Efficacy
7.3.1
Methods and timing for assessing, recording and analysis of efficacy 
parameters
At each visit, which should take place preferably in the morning, patient’s height and weight 
will be assessed and noted. 
7.3.2
Anthropometric Measurements
Height measurements will be performed using a wall-mounted stadiometer. Whenever 
possible, a patient will be measured at each visit at a similar daytime by the same trained 
person to minimise observer bias. The technique as described by Tanner et al (1966) should 
be used.
7.3.3
Presentation and Calculation of Auxological Data
Height velocity (HV) will be calculated in cm/year as the difference between two height 
measurements divided by the time interval in days between these two measurements 
multiplied by 365.25.
Height and height velocity will not only be expressed in cm and cm/year, respectively, but 
also in Standard Deviation Scores (SDS), the relative deviation from the mean value of 
normally growing children of same sex and chronological age or bone age. The SDS values 
for height and HV will be calculated according to the following formula SDS= (X1-X2)/SD, 
where X1 means the measured value, X2 the mean value for the relevant chronological age 
(or bone age, where appropriate), and SD stands for the standard deviation for the mean of 
relevant age. For the calculation of HVSDS, the mean between the CA at the two height 
measurements should be considered as the relevant CA.
Since the formula for the calculation of SDS is not common practice in all countries 
(especially for the calculation of height SDS) the inclusion of a patient is evaluated according 

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Study No. EP00-401 
to national common practice. The following formula is widely used and allowed for inclusion 
instead of the formula used for the statistical analysis of the study cited above:
)
percentile
3rd
-
(median
*
0.5
S
median
lue
measuredva
DS


All standardized controlled procedures and methods applied for the calculation of auxological 
data (with reference to Inclusion Criteria No. 2, 3 and 5) to ensure a common basis and 
comparability of data derived from the different countries will be filed in the Trial Master File 
and described in the Clinical Study Report.
7.3.4
Weight measurements
Weight will be measured according to the usual clinical practice.
 
 
 
7.4
Safety
7.4.1
Carbohydrate metabolism 
Fasting plasma glucose and insulin levels will be measured at baseline, at 6 and 12 months, 
then annually during GH treatment, and at the end of treatment. 
After an overnight fast, venous blood samples will be taken to assess fasting glucose and 
insulin levels. Insulin resistance will be estimated using both the homeostasis model 
assessment (HOMA) (Matthews et al 1985) and quantitative insulin sensitivity check index 
(QUICKI) (Katz et al 2000, WHO 2002).
*
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 baseline, at 6 and 12 months and then 
annually during GH treatment, and at the end of treatment. 

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An oral glucose tolerance test (OGTT) will be performed at baseline, at 6 and 12 months and 
then annually during GH treatment, and at 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, 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.
7.4.2
Immunogenicity
Subjects will be screened for anti-rhGH antibodies (ABs) at baseline, at 3, 6, 9, 12, 18 and 24 
months, then annually during GH treatment and at the end of treatment. Antibody-induced 
lack or loss of efficacy will be examined by comparing height outcome data between 
antibody-positive and antibody-negative subjects.
7.4.3
Fundoscopy
Fundoscopy will be performed only if intracranial hypertension is suspected (severe or 
recurrent headache, visual problems, nausea and/or vomiting).
7.4.4
Physical examination
Patients will undergo a general physical examination and will also be questioned about and 
examined for any local or systemic adverse events. At each scheduled visit during 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. Prepubertal or pubertal 
status should be assessed by the investigator and expressed in stages as described by Tanner 
and Whitehouse (1976).
7.4.5
Vital signs
Vital signs (blood pressure and pulse rate) will be recorded at each visit during treatment in a 
standardised manner, i.e., after the patient has rested for five minutes in the sitting position.
7.4.6
Laboratory evaluations
7.4.6.1
Local Laboratories
Local laboratories will be responsible for performing blood serum and urine determinations; 
clinical chemistry and complete blood count (CBC) (automated 5-part differential 
recommended), absolute neutrophil count (ANC) and platelet counts.
All supernatants of samples are destroyed after analysis.
The following laboratory safety tests will be performed at baseline, at 6 and 12 months and 
annually thereafter for the remainder of GH treatment, and at the end of treatment, unless 
more frequent assessment is clinically indicated.

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Study No. EP00-401 
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:
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.
Thyroid function:
Free thyroxine (fT4) and thyroid stimulating hormone (TSH).
Urinalysis:
pH, glucose, ketones, bilirubin, protein. Pregnancy test only in girls 
after onset of menarche.
*fasting serum levels; fasting is defined as no caloric intake for at least 8h
7.4.6.2
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 stored deep frozen at –70°C for central determination of IGF-I, 
IGFBP-3 and anti-hGH antibodies. For central laboratory details please refer to lab manual. 
7.4.6.2.1 Anti-hGH antibodies 
Anti-hGH antibodies serum levels will be assessed at baseline, at 3, 6, 9, 12, 18 and 24 
months, then annually during treatment, and at the end of treatment. 
Samples will be stored by the sponsor according currently applicable guidelines in order to 
potentially re-analyze anti-hGH antibodies at a later stage, if needed.
7.4.6.2.2 IGF-I and IGFBP-3 serum levels
IGF-I and IGFBP-3 serum levels will be assessed at baseline, at 3, 6, 9 and 12 months, then 
every 6 months during treatment, and at the end of treatment. All supernatants of samples are 
destroyed after analysis.
7.4.7
Adverse events
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign, including abnormal laboratory findings, symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
investigational medicinal product.

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Study No. EP00-401 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be identified when they are 
volunteered by the subject during or between visits or through physical examination, 
laboratory test, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

the investigator considers them to be clinically relevant,

they require therapy.
Clinically relevant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, relevant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease. 
Adverse events must be recorded on the adverse events CRF with the following information 
within 10 days of learning of its occurrence (if the event is serious (refer to Section 7.4.8) it 
must be recorded in the CRF within 24 hours of learning of its occurrence):

the severity grade (indicating most severe grade during the course of the adverse event) 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

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 
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.
If the event is due to lack of efficacy or progression of underlying illness (i.e. 
progression of the study indication) the assessment of causality will usually be ‘Not 
suspected’. The rationale for this guidance is as follows:

the symptoms of a lack of efficacy or progression of underlying illness are not 
caused by the trial drug, they happen in spite of its administration

both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single subject

its duration (start and end dates) or ‘ongoing’ at the 30 day safety follow-up /end of study 
visit

whether it constitutes a serious adverse event (SAE) (see Section 7.4.8 for the definition of 
SAE)

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Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 8.1

action taken: All adverse events must be treated appropriately. Treatment may include one 
or more of the following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given, subject 
hospitalized/subject’s hospitalization prolonged. 

Its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is identified, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must 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.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the subject 
informed consent form and must be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding report. New information might require an update 
to the informed consent form and has then to be discussed with the subject.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to the sponsor.
7.4.8
Serious adverse events
A SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

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:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

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

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 

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

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
is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Death without known medical event must always be reported as SAE.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Medical and scientific judgment must be exercised in deciding whether other situations should 
be considered serious AEs, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization or development of drug 
dependency or abuse.
Any suspected transmission of an infectious agent via a medicinal product is also considered a 
serious adverse event.
7.5
Tolerability/acceptability
Not applicable
7.6
Resource utilization
Not applicable
8
Safety monitoring
8.1
Serious adverse event reporting
To ensure subject safety, the investigator has to report every SAE, regardless of suspected 
causality, occurring after the subject has provided informed consent and until 30 days after 
following the last administration of study treatment must be reported to the sponsor (or 
designated CRO) within 24 hours of learning of its occurrence using the SAE reporting form, 
and recorded in the CRF.
Any SAEs experienced after this 30 day period should only be reported to the sponsor (or 
designated CRO) if the investigator suspects a causal relationship to the study drug.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. Likewise, queries 
issued by the sponsor regarding the SAE must be responded to within 24 hours.
An SAE that is considered completely unrelated to a previously reported one must be reported 
separately as a new event.

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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study drug, complete the SAE Report 
Form in English, and send the completed, signed form within 24 hours to the sponsor. The 
contact details for SAE reporting 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 at the 
study site.
Follow-up information must be provided using a new SAE Report Form stating that this is a 
follow-up to the previously reported SAE. The follow-up information must describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the subject continued or withdrew from study participation. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study drug, the sponsor may urgently 
require further information from the investigator for Health Authority reporting. The sponsor 
may need 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 EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
8.2
Reporting procedures for technical complaints
Any technical complaint about the study drug needs to be reported to the sponsor within 24 
hours of identification of the defect (for details refer to the study drug handling manual). 
Technical complaints are complaints about an optical, organoleptic, qualitative, quantitative, 
mechanical or functional defect of a pharmaceutical product or medical device. This may 
include:

Any fault of quality and/or effectiveness e.g. particles

Any fault of the containers and outer packages e.g. surface imperfection, container leakage, 
broken syringe/plunger, missing contents, device malfunction

Any fault of the labeling e.g. missing or illegible label

Any falsification of the medicinal product or device e.g. suspected product mix-up, or 
tampering.
For reporting of adverse events caused by the defect (if applicable) refer to Section 7.4.7.
8.3
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.

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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors, misuse or abuse will be collected and reported in the CRF AE page 
irrespective of it being associated with an AE/SAE.
8.4
Pregnancy reporting
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Sandoz within 24 hours of learning of its occurrence. The pregnancy must 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 must be recorded on a Pregnancy Form and reported by the investigator to the 
sponsor. Pregnancy follow-up must be recorded on the same form and must include an 
assessment of the possible relationship to the Sandoz study drug of any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
8.5
Data Monitoring Board
Not Applicable
9
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, the progress of enrollment, and to ensure that study drug is being 
stored, dispensed, and accounted according to specifications. 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. 

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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. 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.
9.3
Medical Monitoring
Medical Monitoring is the summary of all Medical Review activities performed throughout 
the entire conduct of the study on different levels by different parties. This is to ensure 
patients’ safety and welfare and consistency of data. Medical Review is performed by CRAs 
during the Monitoring Visit (PRA), at Data Management/Data Validation (Metronomia), and 
at the sponsor (Study and Program Management at Sandoz). All tasks comprised to warrant a 
common understanding of duties and schedules of the respective parties in charge have been 
laid down in writing and filed in the Trial Master File. 
10
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
Analysis sets
10.1.1
Safety analysis set
The safety analysis set (SAF) will comprise all subjects who receive at least one dose of study 
medication and had at least one post-baseline safety assessment. 
10.1.2
Full analysis set
The full analysis set (FAS) will follow the intent-to-treat-principle and therefore consists of 
all patients who received at least one dose of study medication. 
The assignment of the patients to the respective analysis set will be done prior to each interim 
and to the final analysis during a specific data review meeting. 

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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.
Relevant medical history and current medical conditions, previous medication, results of 
laboratory screens, drug tests, and any other relevant information will be listed and 
summarized using descriptive statistics or frequency tables depending on the type of variable 
(continuous or discrete).
10.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
10.3.1
Study drug administration
The extent of exposure will be analyzed using descriptive statistics. Tables showing 
descriptive statistics for the dose per kg body weight will be presented by visit to assess the 
appropriateness of the applied doses.
10.3.2
Concomitant medication
Concomitant medication will be coded according to WHO-DRL and the medications will be 
tabulated by ATC term. 
10.3.3
Treatment compliance
The percentage of medication used compared to the amount prescribed will be analyzed for 
each visit and the frequency of non-compliant patients (daily dose range <80% or >120%) 
will be tabulated. 
10.4
Analysis of safety endpoints
10.4.1
Carbohydrate metabolism
Fasting plasma glucose and insulin levels will be measured at baseline, at 6 and 12 months, 
then annually during GH treatment, and at 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.
Insulin resistance will be estimated using both the homeostasis model assessment (HOMA)  
(Matthews et al 1985) and quantitative insulin sensitivity check index (QUICKI) (Katz et al 
2000, WHO 2002). The effect of Omnitrope® treatment on HOMA and QUICKI scores, 
calculated subsequent to 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, at 6 and 12 months and then 
annually during GH treatment, and at the end of treatment. The effect of treatment on the 
HbA1C levels will also be displayed using descriptive statistics.

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An oral glucose tolerance test (OGTT) will be performed at baseline, at 6 and 12 months and 
then annually during GH treatment, and at the end of treatment. 
10.4.2
Immunogenicity
Subjects will be screened for anti-rhGH antibodies (ABs) at baseline, at 3, 6, 9, 12, 18 and 24 
months, then annually during treatment, and at 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.
10.4.3
Safety lab / urine analysis
Haematology, blood chemistry and urine analysis 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.
10.4.4
(Serious) Adverse Events / Incidents
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. The (serious) adverse events will be displayed by system 
organ class and preferred term and the relationship to the study drug, intensities and outcome 
will be shown in corresponding frequency tables. 
Since incidents are qualified as clinical SAEs they are handled in the same way as all other 
clinical SAEs. A near incident is handled as a clinical SAE in case of seriousness, otherwise 
as an adverse event.
10.4.5
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. 
10.4.6
Physical examination
Shift tables for normal / abnormal findings will be presented by body system for each visit 
versus baseline. 
10.5
Analysis of efficacy endpoints
10.5.1
Auxological endpoints
These are height, height SDS, height velocity and height velocity SDS. These parameters will 
be monitored at baseline, at every 3 months during GH treatment and at the end of treatment. 
The effectiveness of treatment in inducing growth will be determined by descriptive statistics 
of the height at each scheduled visit including a comparison to the height at baseline. Similar 
analyses will be conducted for the height SDS.

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The effectiveness of treatment in accelerating linear growth rate will be determined by 
analyzing the annual height velocity in cm/year (the difference between two height 
measurements divided by the time interval between these two measurements multiplied by 
365.25) at each scheduled visit and by comparing it to the height velocity determined at 
baseline using historical data. Similar analyses will be conducted for the height velocity SDS.
Treatment will be considered to be ineffective (leading to drug discontinuation) if HVSDS 
remains below +1 in the first year of treatment.
10.5.2
Pharmacodynamic endpoints
These are IGF-I and IGFBP-3 serum levels, which will be assessed at baseline, at 3, 6, 9 and 
12 months, then bi-annually during treatment, and at 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.
 
 
10.6
Interim analysis 
Interim analyses are planned at the following time points:

Q4/2011 with data of patients who completed 1 year of treatment

Q4/2012 with data of patients who completed 2 years of treatment

Q4/2020 with data of patients who finished treatment
Additional ad-hoc interim analyses will be performed in case needed for interactions with 
health authorities.
10.7
Sample size calculation
There was no formal sample size calculation for this study which is intended to exploratorily 
investigate the long-term effect of the treatment with respect to the development of diabetes. 
No such incidences are currently available to allow for a rigorous sample size estimation. 
Results obtained in this study will be compared to data published in the literature.
200 subjects were agreed upon during the discussion with the EMEA. Taking into account a 
drop-out rate of 20%, 240 patients will be included in the study. Subjects dropping out before 
completing 1 year of treatment will be replaced.
10.8
Power for analysis of critical secondary variables
Not applicable 

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10.9
Subgroup analyses
Since the study population will consist of subjects treated with Omnitrope® 5 mg/ml powder 
for the first twelve months and with Omnitrope® 5 mg/1.5 ml solution for injection thereafter 
as well as of subjects treated continuously with Omnitrope® 5 mg/1.5 ml solution for injection, 
a corresponding subgroup analysis will be performed. The main focus of such subgroup 
analysis will be on the comparison of the safety profiles during the first twelve months of 
treatment as well as on the effects on the growth related parameters for the first twelve months 
of treatment and also for the whole treatment period.
Further subgroup analysis will be done for an overweight population with international cut-
off points for BMI for overweight by sex and age as defined by the percentile that passes 
through BMI of 25 at age 18. 
All comparisons will be performed descriptively using adequate frequency tables and 
descriptive statistics. Details of the analyses will be laid down in the statistical analysis plans 
for the respective (interim) analyses.
11
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 Omnitrope® in short children born SGA, and

to further investigate the immunogenicity of Omnitrope® in short children born SGA.
More specifically, the primary objective of this study is:

to monitor the development of diabetes during Omnitrope® treatment.
The secondary objectives of this study are:

to monitor the development of anti-hGH antibodies during Omnitrope® treatment,

to evaluate the safety (incidence and occurrence of adverse events) of Omnitrope® 
treatment in short children born SGA, and

to evaluate the efficacy (with respect to changes in height parameters, serum IGF-I and 
IGFBP-3 levels) of Omnitrope® treatment in short children born SGA.
All included subjects will receive Omnitrope® 0.035 mg/kg/day as per recommended dose for 
short stature secondary to SGA. Dose adjustments will be allowed during therapy consistent 
with label recommendations. Omnitrope® treatment will continue until final height is reached 
but will be discontinued earlier if there is inadequate response to treatment (e.g., height 
velocity standard deviation score (HVSDS) remains below +1 in the first year).
To address concerns regarding the risk of developing diabetes mellitus in GH-treated short 
children born SGA, specific parameters such as fasting plasma glucose and insulin levels will 
be measured at pre-defined time points throughout treatment with Omnitrope®. 
Subjects will be monitored for safety throughout treatment. Height, height SDS, HV and 
HVSDS will be determined until final height is reached. 

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12
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, the Coordinating Investigator as well as the Principal Investigator(s) 
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.
12.2
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, The Rules Governing Medicinal Products in the European Community.
Directive 2001/20/EC, EU Clinical Trials Directive
Directive 2005/28/EC, EU GCP Directive
91/507/EEC, The Rules Governing Medicinal Products in the European Community
MEDDEV 2.12-1 rev 5, Guidelines on a Medical Devices Vigilance System
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations).
Declaration of Helsinki 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.
12.2.1
Institutional Review Board/ Independent Ethics Committee
Before implementing this study, the protocol, the investigator brochure, 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.
12.2.2
Informed consent
The investigator must explain to each patient (and/ 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 

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time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
To cover adolescence of the patients with adequate patient information documents, three 
patient information documents, one for children between 4 and 6 years of age, one for 
children between 7 and 12 years of age, and one for children > 13 years of age are used within 
this clinical trial. Children who can read and write should sign the informed consent on the 
basis of the patient information document according to their relevant age group. At all events 
written informed consent has to be obtained from the patients’ parents or legal guardian. 
These informed consent(s) should be given by means of a standard written statement, written 
in non-technical language. The subject/parents or legal guardian 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 and 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.
Female patients of child bearing potential must be informed that taking the study drug may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
must discontinue the study.
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. 
12.2.3
Declaration of Helsinki
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki.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.
13
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Lancet; 341:938-41
Boguszewski M et al (1997). Hormonal status of short children born small for gestational age. 
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thrifty phenotype, or surviving small baby genotype? BMJ; 308:942-5
Ong KK and Dunger DB (2002). Perinatal growth failure: the road to obesity, insulin 
resistance and cardiovascular disease in adults. 
Best Pract Res Clin Endocrinol Metab; 16:191-207
Phillips DI. Insulin resistance as a programmed response to fetal undernutrition. 
Diabetologia 1996; 39:1119-22
Poidvin et al (2017) Risk of Diabetes Treated in Early Adulthood After Growth Hormone 
Treatment of Short Stature in Childhood J Clin Endocrinol Metab, 102(4):1291–8
Prader A, Largo RH, Molinari L, Issler C (1989). Physical growth of Swiss children from 
birth to 20 years of age. First Zurich longitudinal study of growth and development. 
Helv Paediatr Acta Suppl; 52:1-125
Reynolds RM and Phillips DI (1998). Long-term consequences of intrauterine growth 
retardation. Horm Res; 49 (Suppl 2):28-31

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Study No. EP00-401 
Rich-Edwards JW et al (1997). Birth weight and risk of cardiovascular disease in a cohort of 
women followed up since 1976. BMJ; 315:396-400.
Rich-Edwards JW et al (1999). Birthweight and the risk for type 2 diabetes mellitus in adult 
women. Ann Intern Med; 130:278-84
Rosenfeld R and Cariati S (2002). The role of growth hormone therapy in short children born 
small for gestational age. Medscape CME 
Sas T et al (1999). Growth hormone treatment in children with short stature born small for 
gestational age: 5-year results of a randomized, double-blind dose-response trial. 
J Clin Endocrinol Metab; 84:3064-70
Sas T et al (2000). Body composition, blood pressure, and lipid metabolism before and during 
long-term growth hormone (GH) treatment in children with short stature born small for 
gestational age either with or without GH deficiency. J Clin Endocrinol Metab; 85:3786-92
Sas T et al (2001). Carbohydrate metabolism during long-term growth hormone treatment in 
children with short stature born for small for gestational age. Clin Endocrin; 54:243-51
Stern MP et al (2000). Birth weight and the metabolic syndrome: thrifty phenotype or thrifty 
genotype? Diabetes Metab Res Re; 16:88-93
Tanner JM, Whitehouse RH (1976). Clinical longitudinal standards for height, height velocity, 
and weight velocity and the stages of puberty. Arch Dis Child; 51:170-9
Tanner JM, Whitehouse RH, Takaishi M (1966). Standards from birth to maturity for height, 
weight, height velocity, and weight velocity for British children, 1965, Part I Arch Dis Child; 
41:454-71
Usher R and McLean F (1969). Intrauterine growth of live-born Caucasian infants at sea 
level: standards obtained from measurements in 7 dimensions of infants born between 25 and 
44 weeks of gestation. J Pediatr; 74:901-10
Valdez R et al (1994). Birthweight and adult health outcomes in a biethnic population in the
USA. Diabetologia; 37:624-31
Van der Steen et al. (2017). Metabolic health of young adults who were born small for 
gestational age and treated with growth hormone, after cessation of growth hormone 
treatment: a 5-year longitudinal study. Lancet Diabetes Endocrinol; 5(2):106-16
Ventura SJ et al (2001). Births: final data for 1999. Natl Vital Stat Rep; 49:1-100
WHO 2002: Laboratory Diagnosis and Monitoring of diabetes mellitus 
Yarbrough DE et al (1998). Birth weight, adult weight, and girth as predictors of the 
metabolic syndrome in postmenopausal women: the Rancho Bernardo Study. 
Diabetes Care; 21:1652-8

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Study No. EP00-401 
Appendices
Tanner Breast Stages
Stage 1
Pre-adolescent; elevation of papilla only.
Stage 2
Breast bud stage; elevation of breast and papilla as a small
mound, enlargement of areola diameter.
Stage 3
Further enlargement of breast and areola, with no separation of 
their contours.
Stage 4
Projection of areola and papilla to form a secondary mound above 
the level of the breast.
Stage 5
Mature stage; projection of papilla only, due to recession of the 
areola to the general contour of the breast.
Source: Marshall WA, Tanner JM: Variations in Pattern of Pubertal Changes in girls. 
Arch Dis Childh 1969; 44: 291-303
Handling of elevated blood glucose levels and OGTT 
Fasting blood 
glucose levels
OGTT
Patient outcome
impaired
impaired
Ongoing
overt
impaired
Ongoing
overt
overt
Discontinuation
As the OGTT is more sensitive than fasting blood glucose assessment, the final decision with 
regards to discontinuation will be eventually based on the result of the OGTT. 
In case of the unlikely situation that fasting blood glucose levels = normal/impaired and 
OGTT=overt, patient outcome = discontinuation.
Overt levels are defined as:

Fasting blood glucose >126 mg/dl or > 7.0 mmol/l 

OGTT > 200 mg/dl or > 11.1 mmol/l after 120 minutes

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Study No. EP00-401 
Recommended Dosage of Omnitrope®
5 mg / 1.5 ml cartridge
10 mg / 1.5 ml cartridge
Weight in kg 
Dose dialed 
in mg
Weight in kg 
Dose dialed 
in mg
Weight in kg 
Dose dialed 
in mg
5.0 – 6.4
0.20
45.0 – 46.4
1.60
5.0 - 7.8
0.2
6.5 – 7.8
0.25
46.5 – 47.8
1.65
7.9 – 10.7
0.3
7.9 – 9.2
0.30
47.9 – 49.2
1.70
10.8 – 13.5
0.4
9.3 – 10.7
0.35
49.3 – 50.7
1.75
13.6 – 16.4
0.5
10.8 – 12.1
0.40
50.8 – 52.1
1.80
16.5 – 19.2
0.6
12.2 – 13.5
0.45
52.2 – 53.5
1.85
19.3 – 22.1
0.7
13.6 – 14.9
0.50
53.6 – 54.9
1.90
22.2 – 24.9
0.8
15.0 – 16.4
0.55
55.0 – 56.4
1.95
25.0 – 27.8
0.9
16.5 – 17.8
0.60
56.5 – 57.8
2.00
27.9 – 30.7
1.0
17.9 – 19.2
0.65
57.9 – 59.2
2.05
30.8 – 33.5
1.1
19.3 – 20.7
0.70
59.3 – 60.7
2.10
33.6 – 36.4
1.2
20.8 – 22.1
0.75
60.8 – 62.1
2.15
36.5 – 39.2
1.3
22.2 – 23.5
0.80
62.2 – 63.5
2.20
39.3 – 42.1
1.4
23.6 – 24.9
0.85
63.6 – 64.9
2.25
42.2 – 44.9
1.5
25.0 – 26.4
0.90
65.0 – 66.4
2.30
45.0 – 47.8
1.6
26.5 – 27.8
0.95
66.5 – 67.8
2.35
47.9 – 50.7
1.7
27.9 – 29.2
1.00
67.9 – 69.3
2.40
50.8 – 53.5
1.8
29.3 – 30.7
1.05
69.4 – 70.7
2.45
53.6 – 56.4
1.9
30.8 – 32.1
1.10
70.8 – 72.1
2.50
56.5 – 59.2
2.0
32.2 – 33.5
1.15
72.2 – 73.5
2.55
59.3 - 62.1
2.1
33.6 – 34.9
1.20
73.6 – 75.0
2.60
62.2 – 64.9
2.2
35.0 – 36.4
1.25
75.1 – 76.4
2.65
65.0 – 67.8
2.3
36.5 – 37.8
1.30
76.5 – 77.8
2.70
67.9 – 70.7
2.4
37.9 – 39.2
1.35
77.9 – 79.3
2.75
70.8 – 73.5
2.5
39.3 – 40.7
1.40
79.4 – 80.7
2.80
73.6 – 76.4
2.6
40.8 – 42.1
1.45
80.8 – 82.1
2.85
76.5 – 79.3
2.7
42.2 – 43.5
1.50
82.2 – 83.5
2.90
79.4 – 82.1
2.8
43.6 – 44.9
1.55
83.6 – 85.0
2.95
82.2 – 85.0
2.9