Clinical trial NCT02500316
Conditions: Growth Hormone Deficiency (GHD)
Keywords: Growth hormone deficiency (GHD) r-hGH Long-acting
Sponsor: OPKO Health, Inc.
Start date: 2014-02-01; Completion date: 2023-11-01
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Protocol CP-4-004-OLE (Open Label Extension) is designed as a long-term, open-label extension using single patient use, multi-dose, disposable pre-filled pen.

Detailed description:

Arms: arm 1: Once weekly injection of long acting r-hGH (MOD-4023) provided as a solution for injection containing 20 or 50 mg/mL MOD-4023 in a single patient use, multi-dose, disposable pre-filled pen (PEN).
Interventions: intervention 1: MOD-4023
Intervention descriptions: intervention 1: Once weekly injection of long acting r-hGH (MOD-4023) provided as a solution for injection containing 20 or 50 mg/mL MOD-4023 in a single patient use, multi-dose, disposable pre-filled pen (PEN).

Protocol documents:
Prot_000.pdf: 
Signature Page for VV-TMF-53886 v1.0
Signature Page for 
Reason for signing: Approved
Name: R
l
Role: Regulatory Affairs
Date of signature: 08-Oct-2017 13:13:06
GMT+0000
Reason for signing: Approved
Name: 
Role: General Manager
Date of signature: 09-Oct-2017 10:06:54
GMT+0000
Reason for signing: Approved
Name: 
Role: Biostatistics
Date of signature: 09-Oct-2017 14:35:42
GMT+0000
Reason for signing: Approved
Name: 
Role: Clinical Operations
Date of signature: 12-Oct-2017 17:46:41 
GMT+0000
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Protocol for Clinical Study CP-4-004 
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Confidential Document 
Safety and dose finding study of different MOD-4023 dose levels 
compared to daily r-hGH therapy in pre-pubertal growth hormone 
deficient children 
 
EUDRACT NUMBER: 2011-004553-60 
 
Drug Code No.: 
MOD-4023 
Drug Class: 
Long Acting Human Growth Hormone 
Investigational Phase: 
Phase 2 
Protocol No.: 
CP-4-004 
Protocol Version/Date: 
Final 1.0/ 27 October 2011 
Protocol Version/Date: 
Final Version 2.0/ 15 May 2012, Global Amendment 1 
Protocol Version/Date: 
Final Version 3.0/ 26 June 2012, Global Amendment 2 
Protocol Version/Date: 
Final Version 4.0/ 20 March 2013, Global Amendment 3 
Protocol Version/Date: 
Final Version 5.0/ 23 July 2013, Global Amendment 4 
Protocol Version/Date: 
Final Version 6.0/ 01 September 2013, Global Amendment 5 
Protocol Version/Date: 
Final Version 7.0/ 26 January 2015, Global Amendment 6  
Protocol Version/Date: 
Final Version 8.0 / 3 April 2016, Global Amendment 7 
Protocol Version/Date: 
Final Version 9.0 / 25 April 2016, Global Amendment 8 
Protocol Version/Date: 
Final version 10.0 / 03 Oct 2017, Global Amendment 9 
 
 
 
 
OPKO Biologics Ltd. 
16 Ashlagan Str., Kiryat Gat, Israel  
 
________________________ 
 
CONFIDENTIALITY STATEMENT 
The information in this document is considered privileged and confidential, and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board/Ethics 
Committee approval, informed consent and the approval of local regulatory authorities as 
required by local law. 
 
 
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Confidential Document 
 
Signature Page 
 
Name and Position 
Signature 
Date 
OPKO Biologics General 
Manager: 
 
 
 
OPKO Biologics Director of 
Clinical Affairs:  
  
 
 
OPKO Biologics 
  
 
 
 
Coordinating Investigator:  
 
 
 
Statistician:  
 
 
 
 
 
PREVIOUS VERSIONS 
Version 1.0/ 27 October 2011 
Version 2.0/ 15 May 2012 
Version 3.0/ 26 June 2012 
Version 4.0/ 20 March 2013 
Version 5.0/23 July 2013 
Version 6.0 /01 September 2013 
Version 7.0 / 26 January 2015 
Version 8.0 / 3 April 2016 
Version 9.0 / 25 April 2016 
 
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Protocol Synopsis 
STUDY TITLE: 
Safety and dose finding study of different MOD-4023 dose levels compared to 
daily r-hGH therapy in pre-pubertal growth hormone deficient children. 
PROTOCOL 
NUMBER: 
CP-4-004 
CLINICAL STUDY 
LOCATION: 
The main study is conducted in 7 countries (Hungary, Bulgaria, Belarus, Ukraine, 
Russia, Greece and USA), and at 14 sites.  
The extension study is conducted in all countries except Bulgaria and Greece. 
STUDY PHASE: 
Phase 2 
THERAPEUTIC 
INDICATION: 
MOD-4023 is a long-acting modified recombinant human growth hormone which 
utilizes the C-terminal peptide (CTP) technology indicated for treatment of 
children with growth failure due to growth hormone deficiency. 
PRIMARY STUDY 
OBJECTIVES: 
The primary objective is: 
To compare the safety, efficacy, and tolerability of three MOD-4023 doses to that 
of a commercially available standard daily recombinant human growth hormone 
(r-hGH) formulation, in pre-pubertal children with growth failure due to 
insufficient secretion of endogenous growth hormone. 
SECONDARY STUDY 
OBJECTIVE: 
The secondary objectives are: 
1. To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles 
of 3 different doses of MOD-4023 in pre-pubertal growth hormone deficient 
(GHD) children. 
2. To select the optimal dose of MOD-4023 for the subsequent phase 3 study on 
the basis of safety and efficacy. 
NUMBER OF 
PATIENTS: 
Estimated recruitment will be up to 56 patients (up to 14 patients/cohort) into the 
Main Study. Patients will be divided into two subgroups: Up to 40 patients with 
peak serum GH levels after stimulation test 
 ng/ml and up to 16 patients with 
peak serum GH levels after stimulation test 
 and 
 ng/ml. 
Patients who completed 12 months of treatment in the Main Study and continued 
to the 12-month Open Label Extension (OLE) period will be eligible to continue 
into the Long-Term OLE (LT-OLE) period and Long-Term OLE PEN (LT-OLE-PEN) 
periods until marketing approval in their country, subject to an annual notification 
to local EC/IRB of continuation of study, where applicable. 
DURATION OF 
STUDY: 
The duration of the Main Study is expected to be 12 months for each patient.  
The OLE period duration will be based on the initial extension of 12 months of 
active treatment for all patients completing the Main Study which will be 
extended to LT-OLE and to LT-OLE-PEN on a yearly basis until marketing approval 
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in each country. The yearly extension notification will be submitted to local 
EC/IRB, where applicable 
TEST DRUG: 
MOD-4023 is a long-acting modified recombinant human growth hormone which 
utilizes the CTP technology.  
In the Main Study and OLE, MOD-4023 will be provided as a solution for 
subcutaneous (SC) injection containing 
 or 4  mg protein1/ml  
In the LT-OLE-PEN period, MOD-4023 will be provided as a solution for injection 
containing 
 or 
 mg/mL MOD-4023 in a single patient use, multi-dose, 
disposable pre-filled pen (PEN).   
REFERENCE DRUG 
(main study): 
Genotropin 5.3 mg is dispensed in a two-chamber cartridge. The front 
compartment contains recombinant somatropin, glycine, mannitol, sodium 
dihydrogen phosphate anhydrous, and disodium phosphate anhydrous. The rear 
compartment contains m-Cresol and mannitol in water for injections. 
A delivery device (Genotropin Pen) will be used for administration of the drug. 
Active comparator will only be administered in the Main Study. 
STUDY DRUG 
ADMINISTRATION: 
The investigational product will be administered preferably in the morning hours 
once a week and the comparator (Genotropin) will be administered in the evening 
hours once a day. Both drugs will be administered as a SC injection into the region 
of the upper arms, buttocks, thighs or abdomen. It is recommended that all 8 
injection sites are used successively, using a different injection site at each 
subsequent injection.  
STUDY DESIGN AND 
DOSE REGIMENS: 
This is a phase 2, safety and dose finding study of different MOD-4023 dose levels 
compared to daily r-hGH therapy in pre-pubertal growth hormone deficient 
children.  
The study consists of a Screening, Active Treatment periods (Main Study), an OLE 
period, LT-OLE period and LT-OLE-PEN period: 
1. Screening period will last up to 6 weeks 
2. Main Study (12 months) Active treatment period: 
a. Period I: 6 month repeated dose period including PK/PD sampling 
b. Period II: additional 6 month continuous repeated dosing period 
3.  OLE (Period III, 12 months) – 12 months continuous repeated dosing of 
MOD-4023 
4. LT-OLE (Period IV – from second year OLE) – long-term annual extension 
with repeated administration of MOD-4023 until transition to PEN device. 
During that period all patients will be switched to 0.66 mg/kg/week. 
5. LT-OLE-PEN (Period V) - long-term, open-label extension using single 
patient use, multi-dose, disposable pre-filled pen. Upon regulatory 
clearance and Sponsor's written approval, study patients should be 
                                                          
1 MOD-4023 concentration (mg protein/ml) refers to the protein backbone 
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switched to PEN device. Patient will continue with their current dose. 
Study duration will be until marketing approval; a yearly extension 
request will be submitted to local EC/IRB where it is required. An updated 
informed consent form (ICF) for the LT-OLE-PEN period treatment should 
be signed during the first PEN transition visit, prior to using the PEN or any 
other assessments related to the transition to PEN. 
SCREENING 
The Screening period will last up to 6 weeks.  
The following key tests and assessments must be performed and data obtained: 
1. Informed consent/assent signature.  
2. Data on growth history and current anthropometric measurements 
(Auxology). 
3. Body weight. 
4. Medical history, including a description of pituitary deficiencies, 
concomitant and previous medications. 
5. Overall health status assessments – complete physical examination, vital 
signs, and ECG. 
6. Pubertal status (according to Tanner stages). 
7. Bone age determination – with the method of Greulich-Pyle using a 
central bone age reader. 
8. Assessment of biochemical markers and stimulation tests: 
 
Two different GH stimulation (provocation) tests (insulin tolerance 
test, with cortisol response to hypoglycemia if insulin stimulation test 
is chosen/arginine test/clonidine test/glucagon test (with or without 
propranolol)/L-dopa plus propranolol. Sex-hormone priming will be 
performed prior to GH-stimulation tests for girls over the age of 8 and 
for boys over the age of 10. If the patient requires sex hormone 
priming (due to the age), and both stimulation tests must be 
performed during the Screening (no historical samples kept, or test 
was without priming), it is recommended to perform stimulation tests 
in consecutive setting in one day, or in two consecutive days, to avoid 
priming the patient twice. Local historical tests without sex-steroid 
priming will not be accepted for patients that require sex steroid 
priming according to the protocol 
 
Standard Dose Short ACTH test (only if the patient was not previously 
assessed for the hypothalamus-pituitary-adrenal axis, or if there are 
clinical or laboratory signs of adrenal insufficiency) 
 
Assessment of insulin-like growth factor-I (IGF-I) and IGFBP-3 levels 
 
Assessment of anti-hGH antibody levels 
 
Assessments of routine safety biochemistry and hematology 
parameters 
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 
Assessment of hormones (TSH, Free T4,  Free T3 and cortisol) 
 
Assessment of glucose metabolism (fasting insulin, glucose and 
HbA1C) 
9. Head MRI. 
10. Fundoscopy. 
11. Assessment of karyotype in girls. 
12. SHOX (short stature homeobox) gene evaluation in all patients. 
Key data and all test results obtained during screening will be reviewed by the 
Sponsor Medical Monitor prior to randomization of each patient.  
Eligible patients will be randomized (central randomization) to one of the three 
different MOD-4023 doses or to the standard daily r-hGH control group prior to 
the first injection. The following stratification factors will be considered when 
adding patients to one of the four treatment groups: 
1. Provocation tests peak plasma GH level (patients with peak levels 
ng/ml and patients with peak levels 
 ng/ml and 
ng/ml). 
2. Patients with peak plasma GH level 
 ng/ml will additionally be stratified 
by:  
a. Chronological age (3-7, above 7) 
b. Height SDS - target height SDS (≤ -3 and > -3) 
c. Peak GH levels 
. Patients with peak GH levels 
 can be enrolled in the study. However, these patients have a 
separate randomization list 
 
PERIOD I: SIX MONTH REPEATED DOSE PERIOD 
During this period, which will last 6 calendar months, eligible patients will receive 
weekly doses of MOD-4023 or daily doses of r-hGH, according to the table below. 
Safety will be assessed throughout this period, and individual growth assessments 
for each patient will be completed at the end of the period as described below.  
TABLE 1: DOSE COHORTS 
Cohort 
MOD-4023/Genotropin Dose 
1 
0.25 mg MOD-4023 protein/kg/week equivalent to 0.18 mg 
hGH/kg weekly injection. 
2 
0.48 mg MOD-4023 protein/kg/week equivalent to 0.35 mg 
hGH/kg weekly injection. 
3 
0.66 mg MOD-4023 protein/kg/week equivalent to 0.48 mg 
hGH/kg weekly injection. 
4 
Genotropin: 0.034 mg/kg/day. 
In order to introduce naïve patients to the allocated MOD-4023 dose in a gradual 
manner, a stepwise dose increase will be implemented (see Table 2). All patients 
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randomized to receive one of the three MOD-4023 doses will start treatment for 
2 weeks with the low MOD-4023 dose (0.25 mg/kg). Based on the patient's dose 
allocation, this will be followed by a dose increase to the next dose level every two 
weeks until the final allocated dose is reached. 
Subsequent to the second dose administration of the targeted dose, limited 
(population based) PK and PD sampling will be performed as described in Table 2. 
TABLE 2: DOSE INCREASE SCHEME FOR MOD-4023 COHORTS 
Cohort 
Dosing Scheme 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Cohort 1 
0.25 mg 
protein/kg/week 
 
 
PK/PD 
sampling 
Cohort 2 
0.25 mg 
protein/kg/week 
0.48 mg 
protein/kg/week 
 
 
PK/PD 
sampling 
Cohort 3 
0.25 mg 
protein/kg/week 
0.48 mg 
protein/kg/week 
0.66 mg 
protein/kg/week 
 
PK/PD 
sampling 
During the first 6 weeks of the study, the visit schedule will be as follows: 
All Patients: 
Visit 1 (Week 1): This visit will take place in the medical center for all patients on 
the day of the first dose. The following procedures will be performed: physical 
examination, vital signs, adverse events (AEs), local tolerability, concomitant 
medications, parameters of glucose metabolism (fasting glucose, insulin, and 
HbA1C), other hormonal levels (TSH,  free T4,  free T3, cortisol), antigenicity (anti-
MOD-4023 antibodies for cohort 1-3 patients and anti-hGH antibodies for cohort 
4 patients), routine safety biochemistry and hematology, patient’s height and 
weight, parameters of lipid metabolism, pubertal status, IGF-I and IGFBP-3 serum 
levels, baseline MOD-4023 (cohorts 1-3) or hGH (cohort 4) levels, fundoscopy, and 
training for parents on drug administration. Patients allocated to the MOD-4023 
cohorts will be administered the first dose by the study staff in the morning hours. 
Patients allocated to the Genotropin cohort will be administered the first dose at 
home in the evening hours. 
MOD-4023 Dose Cohorts (Cohorts 1-3): 
V2(a-h) – Week 2, V3(a-h) – Week 4 and V4(a-h) – Week 6: Patients allocated to 
a MOD-4023 dose cohort will be randomized within the cohort into one of three 
blocks and undergo limited PK/PD sampling (4 samples per patient over a period 
of one week), according to Table 3 below.  
Patients allocated to Cohort 1 will undergo limited PK/PD sampling following the 
2nd dose of MOD-4023 (V2a-g – week 2) and return to the medical centers for a 
single visit 4 days after dosing during week 6 (V4h). 
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Patients allocated to Cohort 2 will come to the medical centers for a single visit 4 
days after dosing during week 2 (V2h), undergo limited PK/PD sampling following 
the 4th dose of MOD-4023 (week 4: the second dose at the allocated dose level; 
V3a-g) and return to the medical centers for a single visit, 4 days after dosing, 
during week 6 (V4h). 
Patients allocated to Cohort 3 will come to the medical centers for a single visit 4 
days after dosing during weeks 2 and 4 (V2h and V3h) and undergo limited 
sampling following the 6th dose of MOD-4023 (week 6: the second dose at the 
allocated dose level, V4a-g).  
TABLE 3: MOD-4023 POPULATION PK AND PD SAMPLING SCHEME 
Visit (V2, V3, V4) 
A 
b 
c 
d 
e 
F 
g 
Time 
after 
dosing(h)/ 
Block number 
0h 
6h 
12h 
24h 
48h 
72
h 
96
h 
120
h 
168
h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
 
The following procedures will be performed at visits 2a and 2h, 3a and 3h, and 4a 
and 4h: 
Physical examination, vital signs, AEs, local tolerability, concomitant medications, 
parameters of glucose metabolism (fasting glucose and insulin; HbA1C only at V4), 
other hormonal levels (TSH, free T4,  free T3, cortisol), routine safety biochemistry 
and hematology (visits 2a and 2h, 4a and 4h), patient’s height and weight, 
parameters of lipid metabolism, IGF-I and IGFBP-3 serum levels. 
Genotropin Cohort (Cohort 4): 
Patients allocated to the Genotropin cohort (cohort 4) will return to the medical 
centers for visits 2 and 4, during the 2nd and 6th week of treatment. The following 
procedures will be performed:  
Physical examination, vital signs, AEs, local tolerability, concomitant medications, 
parameters of glucose metabolism (fasting glucose and insulin; HbA1C only at V4), 
other hormonal levels (TSH, free T4, free T3, cortisol), routine safety biochemistry 
and hematology, patient’s height and weight, parameters of lipid metabolism, 
IGF-I and IGFBP-3 serum levels. 
In addition, after the 8th Genotropin dose (start of week 2 of dosing), the patients 
allocated to the Genotropin cohort will be randomized into one of three blocks 
and undergo limited PK/PD sampling (4 samples per patient over a period of 24 
hours), according to Table 4 below.  
 
 
 
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TABLE 4: GENOTROPIN POPULATION PK AND PD SAMPLING SCHEME (VISIT 2) 
Time 
after 
dosing(h)/ 
Block number 
0h 
1h 
2h 
4h 
6h 
12
h 
16
h 
20
h 
24
h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
 
All patients: 
Following the first 6 weeks of the study, all patients will visit the hospital on a 
monthly basis (weeks 10, 14, 18, 22 and 26). Patients allocated to the MOD-4023 
dose cohorts (cohorts 1-3) will be asked to return 4 days after MOD-4023 dosing 
in order to obtain MOD-4023, IGF-I and IGFBP-3 levels and conduct routine safety 
assessments. In addition, after 5 months of dosing, patients allocated to MOD-
4023 dosing will be asked to return to the medical center in the morning hours 
prior to dosing in order to obtain a trough level MOD-4023 and PD (IGF-I and 
IGFBP-3) samples. Patients allocated to the Genotropin dose cohort (cohort 4) will 
be asked to return on any day during the relevant dosing week. 
The following assessments will be performed at indicated time-points (detailed 
scheduling in section 5.1 of the protocol): 
Physical examination, vital signs, AEs, local tolerability, concomitant medications, 
parameters of glucose metabolism (fasting glucose, insulin and HbA1C), other 
hormonal levels (TSH, free T4, free T3, cortisol), antigenicity (anti MOD-4023 
antibodies for cohort 1-3 patients and anti hGH antibodies for cohort 4 patients), 
routine safety biochemistry and hematology, patient’s height and weight, 
parameters of lipid metabolism, pubertal status, IGF-I and IGFBP-3 serum levels, 
fundoscopy. 
During Period I, the dose of MOD-4023 and r-hGH will be adjusted to the patient’s 
body weight every three months. Doses may be decreased for safety reasons 
according to the pre-defined dose-adjustment criteria (which will be based on the 
severity of AEs or elevated levels of IGF-I). For patients on MOD-4023, the dose 
may be decreased based on repeated day 4 levels of IGF-I above +2.0 SDS. For 
patients on Genotropin, the dose may be decreased based on repeated IGF-I levels 
above +2.0 SDS. 
The study Medical Monitor shall review all AEs from entries in the e-CRF on a 
weekly basis and all SAE safety reports as received. The key safety data will be 
reviewed by an independent DSMB approximately every 6 months or on an ad-
hoc basis if any safety concerns arise. After completion of Period I each patient 
will be assessed separately for the growth progress and overall safety. If the 
growth meets the pre-defined criteria1 and there are no safety concerns, the 
                                                          
1 Delta Height SDS at least 0.2  
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patient will continue with the same dose, otherwise dose modifications will be 
performed according to the pre-determined rules.  
PERIOD II: SIX MONTH CONTINUOUS DOSING PERIOD 
The purpose of Period II is to collect an additional 6 months of efficacy and safety 
data. During period II, patients will be kept whenever it is possible on the originally 
allocated dose levels; however, the dose may be adjusted for safety reasons 
throughout the study and/or for efficacy reasons after 6 months of dosing. 
Patients allocated to the r-hGH dose group will continue their doses as initiated 
earlier, up to the end of the 12-month treatment period.  
Patients will visit the clinic twice during Period II, at months 9 and 12. Period II 
assessments will include the following at each visit: physical examination, vital 
signs, AEs, local tolerability, concomitant medications, parameters of glucose 
metabolism (fasting glucose, insulin, and HbA1C), other hormonal levels (TSH, 
free T4,  free T3, cortisol), routine safety biochemistry and hematology, patient’s 
height and weight, parameters of lipid metabolism (month 12 only), pubertal 
status (month 12 only), IGF-I and IGFBP-3 serum levels, fundoscopy (month 12 
only or earlier if there are signs or symptoms indicative of benign intracranial 
hypertension), ECG (month 12 only), and bone age (month 12 only). 
PERIOD III: 12 Months OPEN LABEL EXTENSION (OLE) PERIOD 
All patients who completed 12 months of treatment in the Main Study will be 
eligible to continue to a 12-month Open Label Extension (OLE) period. After 
completion of Period II each patient will be assessed individually for the growth 
progress and overall safety. If the growth meets the pre-defined criteria1 and there 
are no safety concerns, the patient will continue on the same dose, otherwise 
dose modifications will be performed according to the pre-determined rules. 
Patients who received MOD-4023 in the Main Study (initial 12 months of active 
treatment) will continue with the same dose (mg/kg) of MOD-4023 they received 
in the Main Study. Study visits will take place every 3 months (i.e. every 13±2 
weeks, 4 days (or 3 days, when necessary) after dosing until the LT-OLE period. 
Patients who received active comparator, Genotropin, during the Main Study, will 
be switched to MOD-4023 (will be randomized to one of the three MOD-4023 
cohorts). Their visit schedule during the first three months of the OLE will be as 
follows: Visit 1/OLE for first MOD-4023 injection (week 52 +1 day, which is on 
Month 12 visit of the Main Study) in which the patient will be trained on 
medication administration, Visit 2/OLE will be 28 days + 4 (-1) days after the first 
MOD-4023 injection and Visit 3/OLE will be 3 months after the first MOD-4023 
injection (i.e. 13±2 weeks + 4 (-1) days after the first MOD-4023 injection). All 
subsequent visits will be every three months (i.e. every 13 weeks (±2 weeks), on 
day 4 or 3, when necessary post dosing) until the LT-OLE- period.  
Patients who are off treatment for 
 days between the last MOD-
4023/Genotropin dose in the Main Study and the first OLE dose (2nd year) will be 
allowed to continue into the OLE period after the following tests and assessments 
will be conducted:  
 
Parameters of glucose metabolism: fasting glucose, insulin, and HbA1c  
                                                          
1 Delta Height SDS at least 0.2  
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 
Antigenicity: anti MOD-4023 antibodies (only Genotropin group – 
baseline for future tests) 
 
Routine safety laboratory (biochemistry, hematology, and urinalysis)  
 
PD: IGF-I and IGFBP-3 baseline serum levels  
 
MOD-4023 baseline serum levels 
During the OLE period, the DSMB will review the data at month 12 or on an ad-
hoc basis, if any safety concern arises.  
During the 12-month OLE period, the following assessments will be conducted at 
each visit: physical examination, auxology measurements (actual height measured 
on a calibrated stadiometer and body weight measurement); Adjustment of dose 
for weight; vital signs, AEs, local tolerability, concomitant medications, 
parameters of glucose metabolism (fasting glucose, insulin, and HbA1C), other 
hormonal levels (TSH, free T4, free T3, cortisol), , routine safety laboratory 
(biochemistry, hematology and urinalysis), MOD-4023 serum level and IGF-I and 
IGFBP-3 serum levels, antigenicity: anti MOD-4023 antibodies (every 6 months 
only) and drug dispensing. 
The following assessments will be done after patient completes the 12-month OLE 
(unless otherwise specified):  parameters of lipid metabolism (Lp(a), pubertal 
status, ECG, bone age and fundoscopy (or earlier if there are signs or symptoms 
indicative of benign intracranial hypertension). 
The used study drug and filled patient diaries will be returned at the next visit. 
PERIOD IV: LONG-TERM OPEN LABEL EXTENSION (LT-OLE) PERIOD 
LT-OLE starts from the 2nd year of OLE (i.e. the 3rd year of treatment in the study) 
until transition to PEN (LT-OLE-PEN period).  Patients in Cohorts 1 and 2 entering 
the LT-OLE will be switched to the highest MOD-4023 dose 0.66 mg/kg/week after 
signing a separate informed consent (unless a different medical decision was 
made). In case patients from Cohorts 1 and 2 have already entered the 2nd year of 
OLE, the switch to 0.66 mg/kg/week will be done at their next study visit after 
signing a separate informed consent. Patients in Cohort 3 will continue receiving 
0.66 mg/kg/week. 
If the IGF-I value will be above +2.0 SDS, patients will be requested to return to 
the clinic within 4-6 weeks for another evaluation. If IGF-I level value will continue 
to be above +2.0 SDS, the dose will be reduced by 15% to 0.56 mg/kg/week. 
Patients with reduced dose will be required to return to the clinic within 4-6 weeks 
for another IGF-I evaluation. If IGF-I level value is still above 2.0 SDS, the dose will 
be reduced again by 15% to 0.48 mg/kg/week. Patients, who had their dose 
reduced twice and who still have IGF-I level above 2.0 SDS within 4-6 weeks of 
second dose reduction, will be required to have individual medical consultation 
with the Medical Monitor (with the assistance of the DSMB if necessary). 
Patients who are off treatment for 
 days between the last MOD-4023 in 
the OLE period and the first LT-OLE dose (3rd year) will be allowed to continue into 
the LT-OLE period after the following samples for testing  will be collected  
 
Parameters of glucose metabolism: fasting glucose, insulin, and HbA1c  
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 
Antigenicity –anti MOD-4023 antibodies   
 
Routine safety laboratory (biochemistry, hematology, and urinalysis)  
 
PD: IGF-I and IGFBP-3 baseline serum levels  
 
MOD-4023 baseline serum levels 
During LT-OLE, all patients will be assessed once every 3 months, as specified in 
the Schedule of Assessment, including: auxology measurements (actual height 
measured on a calibrated stadiometer and body weight measurement); 
adjustment of dose for weight; AEs; local tolerability; concomitant medication; 
and dispensing of drug. 
 
In addition, IGF-I, IGFBP-3 and MOD-4023 serum levels will be assessed every 6 
months on day 3 or 4 post dosing. Once a year, patients will be required to attend 
another visit on dosing day (in addition to the semi-annual visit on day 3 or 4 post 
dosing) where the following additional assessments will be conducted (on top of 
the three and six months assessments): antigenicity (anti MOD-4023 antibodies), 
MOD- 4023 serum levels, Physical examination, Vital signs, Parameters of glucose 
metabolism (fasting glucose, fasting insulin and HbA1c), Routine safety laboratory 
(biochemistry, hematology and urinalysis),  other hormonal levels (TSH,  free T4,  
free T3 and cortisol), lipid metabolism parameters, pubertal status, ECG, bone age, 
fundoscopy (if required), and for males that are 13 years old and above: LH, FSH 
and testosterone. For females that are 12 years old and above: LH, FSH and 
estradiol.  
All patients switching to 0.66 mg/kg/week (e.g. patients from cohort 1 &2 
treatment arms)  will be required to attend a site visit after 3 months (on day 3 or 
4 post-dosing) for the process following evaluations: physical examination and 
vital signs, patient’s height and weight, concomitant medications, glucose 
metabolism parameters (fasting glucose, insulin and HbA1c), antigenicity (anti 
MOD-4023 antibodies), routine safety laboratory (biochemistry, hematology and 
urinalysis) and IGF-I and IGFBP-3 serum levels.  
In case the switch to the 0.66 mg/kg/week dose is on month 9 visit, the 3 months 
follow up visit will take place on dosing day. Additional visit will take place 3-4 days 
post dosing in which only IGF-I, IGFBP-3 and MOD-4023 serum levels will be 
measured.  
Patients from cohort 3 should continue with their routine visit schedule. 
Patients will sign a separate informed consent to be eligible to enter OLE and LT-
OLE. Patients who have already entered OLE will be re-consented for LT-OLE. 
Patients from Cohorts 1 and 2 will be instructed by the investigator about the 
transition to the higher dose of MOD-4023 (0.66 mg/kg/week) and will also be re-
consented. 
Annual extension notification will be submitted to local EC/IRB. 
 
 
 
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Treatment Period V (LT-OLE-PEN) – until marketing approval 
First year of LT-OLE-PEN period 
Upon regulatory clearance of protocol amendment 9 and sponsor written 
approval, patients will be requested to come to the clinic for PEN Visit 1(PEN V1).  
PEN V1 will occur on a planned dosing day (sites should make any effort to 
schedule this visit according to the current visit schedule and consider to combine 
visits in order to minimize the burden on the patients), patients should arrive at 
the clinic prior to dosing. This visit will serve as the ‘baseline’ for the LT-OLE-PEN 
Period in which the consent/assent form for the LT-OLE-PEN period will be signed. 
Patients should return used and un used vials that were dispensed during the 
study and kept at patient home. Site staff should remind the patients to bring all 
vials dispensed during the study (used and unused) before the visit.   
During PEN V1, the patients will be trained on the use of the PEN, the PEN will be 
dispensed and the first PEN dose will be administered at the clinic by the 
parents/legal guardians. Patient will continue his/her treatment with the same 
dose level as before the switch to PEN. In addition to the PEN, the patients will be 
provided with updated patient diary, instructions for use and dosing instructions. 
If splitting the dose between 2 injections, the patient should complete new diary 
page for each injection. 
   
Weekly dose 
Number 
of 
patient 
Diary pages 
1 injection 
1 
2 injections from the same 
pen 
2 
2 injections from 2 different 
pens 
2 
 
The following assessments will be conducted at PEN V1 (dosing day) pre-dose: 
auxology measurements (actual height measured on calibrated stadiometer); 
body weight measurement; adjustment of dose for weight; AEs; urine pregnancy 
test for female of child bearing potential (In case of positive result please refer to 
section 7.4); local tolerability; concomitant medication; dispensing of drug; 
patients should return completed diaries and will be provided with new diaries; 
IGF-I, IGFBP-3 and MOD-4023 serum levels; anti MOD-4023 antibodies; Physical 
examination; Vital signs; Parameters of glucose metabolism (fasting glucose, 
fasting insulin and HbA1c); Routine safety laboratory (biochemistry, hematology 
and urinalysis);  other hormonal levels (TSH,  free T4 and cortisol); lipid 
metabolism parameters; pubertal status;  fundoscopy (if required); return of 
used and unused vials; bone age assessment 1; for males that are 13 years old 
and above: LH, FSH and testosterone, for females that are 12 years old and 
above: LH, FSH and estradiol; training on PEN. 
  
                                                          
1 Bone age measurement will be performed in case the previous assessment was done more than 6 months prior to this 
visit. 
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Four weeks (+1 week) after PEN visit 1, the patient will be required to come for 
PEN visit 2 (PEN V2).  This visit should occur on Day 4 (-1) post dose. 
The following assessments will be conducted at PEN V2, Day 4(-1):  
 
Completed patient diary and used PENs should be returned at this visit. 
If necessary, the patient will be re-trained on the PEN   
 
Body weight measurements; adjustment of dose for weight; AEs; urine 
pregnancy test for females of child bearing potential (In case of positive 
result please refer to section 7.4); local tolerability; concomitant 
medication; dispensing of drug; IGF-I, IGFBP-3 and MOD-4023 serum 
levels; anti MOD-4023 antibodies; Physical examination; Vital signs; 
fundoscopy (if required); provide patient diary. 
 
For the following visits, patients will come to the clinic 4 days (-1) post dose every 
3 months (±2 weeks), counting from PEN V1.  
 
In months 3 and 6 visits (counting from PEN V1) the patient will be assessed as 
specified in the schedule of assessment. The following assessments will be 
conducted on those visits: Auxology measurements (actual height measured by 
calibrated stadiometer); body weight measurement;  adjustment of dose for 
weight; AEs; urine pregnancy test for females of child bearing potential (In case of 
positive result please refer to section 7.4); local tolerability; concomitant 
medication;  dispensing and return of used drug; anti MOD-4023 antibodies;  IGF-
I, IGFBP3; MOD-4023 serum levels; fundoscopy (if required); physical examination 
and vital signs; Parameters of glucose metabolism (fasting glucose, fasting insulin 
and HbA1c); other hormonal levels (TSH,  free T4 and cortisol); lipid metabolism 
parameters; Routine safety laboratory (biochemistry, hematology and urinalysis); 
pubertal status; patients should return completed patient diaries and will be 
provided with new diaries.  
 
In month 9 (counting from PEN V1) visit the patient will be assessed as specified 
in the schedule of assessment. The following assessments will be conducted on 
this visit: Auxology measurements (actual height measure measured by calibrated 
stadiometer); Body weight measurement; adjustment of dose for weight; AEs; 
urine pregnancy test for females of child bearing potential (In case of positive 
result please refer to section 7.4); local tolerability; concomitant medication;  
Fundoscopy (if required); IGF-I and IGFBP-3; MOD-4023 serum levels; anti MOD-
4023 antibodies; physical examination and vital signs; dispensing and return of 
used drug; pubertal status; patients should return completed patient diaries and 
will be provided with new diaries.  
 
On month 12 (±2 weeks) counting from PEN V1, two visits will be conducted, one 
on dosing day and one on day 4 (-1) post injection. 
 
On month 12 (±2 weeks) dosing day visit, the following procedures will take 
place (pre dose): Auxology measurements (actual height measure measured by 
calibrated stadiometer); body weight measurement; adjustment of dose for 
weight; AEs; local tolerability; concomitant medications; return and dispense of 
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drug; anti MOD-4023 antibodies; MOD- 4023 serum levels; Physical examination; 
Vital signs; Parameters of glucose metabolism (fasting glucose, fasting insulin 
and HbA1c); Routine safety laboratory (biochemistry, hematology and 
urinalysis);  other hormonal levels (TSH,  free T4 and cortisol); lipid metabolism 
parameters; pubertal status; bone age; fundoscopy (if required); urine pregnancy 
test for females of child bearing potential (In case of positive result please refer 
to section 7.4); patients should return completed diaries and will be provided 
with new diaries; for males that are 13 years old and above: LH, FSH and 
testosterone, for females that are 12 years old and above: LH, FSH and estradiol; 
ECG around Tmax (7-12 hours post dose). 
 
In case not possible to conduct the ECG around Tmax at this 12 month visit, it 
can be performed on month 12 ± 3 weeks (7-12 hours post dose).  
 
The second visit on month 12 (±2 weeks) will be conducted on day 4 (-1) post 
injection and IGF-I and IGFBP-3 will be assessed.  
 
Second year of LT-OLE_PEN period until marketing approval 
From the second year of the LT-OLE-PEN period and until marketing approval, 
visits will be conducted every 3 months (months 3, 6, 9 and 12), ±2 weeks, on day 
4 (-1) post injection.  
 
The following assessments will be conducted on each visit: Auxology 
measurements (actual height measure measured by calibrated stadiometer); 
body weight measurement; adjustment of dose for weight; AEs; local tolerability; 
concomitant medications; return and dispensing of drug; fundoscopy (if required); 
IGF-I and IGFBP-3; physical examination and vital signs; urine pregnancy test for 
females of child bearing potential (In case of positive result please refer to section 
7.4); pubertal status; patients should return completed patient diaries and will be 
provided with new diaries.  
 
In addition, the following assessments will be added every 6 months, on month 6 
and month 12 visits: MOD-4023 serum levels; anti MOD-4023 antibodies; 
parameters of glucose metabolism (fasting glucose, fasting Insulin, HbA1c); Lipid 
parameters; routine safety laboratory (biochemistry, hematology and urinalysis); 
other hormonal levels (TSH,  free T4 and cortisol. 
 
In addition, the following assessments will be conducted ones a year on month 12 
visit: ECG; Bone age; for males that are 13 years old and above: LH, FSH and 
testosterone and for females that are 12 years old and above: LH, FSH and 
estradiol,  
The investigator may conduct unscheduled visits, for safety reasons, or any other 
reason per investigator medical judgment. 
Throughout the LT-OLE-PEN period, patients will continue to complete a patient 
diary at home to collect dosing and safety data.  
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INCLUSION 
CRITERIA: 
1. Pre-pubertal child aged ≥ 3 years old and not above 10 years for girls or 
11 years for boys with either isolated GHD, or GH insufficiency as part of 
multiple pituitary hormone deficiency. 
2. Confirmed diagnosis of GHD by two different GH provocation tests 
defined as a peak plasma GH level of 
 ng/ml1, determined by central 
laboratory using a validated assay2. If the patient has already been tested 
locally and reserve samples that were taken at appropriate time-points 
are available, these will be reanalyzed by the central laboratory3. 
Historical tests missing the -30 minutes time point will be accepted. If no 
reserve samples are kept (only for tests performed prior to site initiation), 
then the details of the locally performed tests will be reviewed by the 
Coordinating Investigator: if the results cannot be accepted, the patient 
will undergo both stimulation tests during the screening period and the 
samples will be analyzed by the central laboratory. At least one of the two 
stimulation tests (and preferably both) will be analyzed by the central 
laboratory. If the patient requires sex hormone priming (due to the age), 
and both stimulation tests must be performed during the Screening (no 
historical samples kept, or test was without priming), it is recommended 
to perform stimulation tests in consecutive setting in one day, or in two 
consecutive days, to avoid priming the patient twice. Local historical tests 
without sex-steroid priming will not be accepted for patients that require 
sex steroid priming according to the protocol. 
3. Bone age (BA) is not older than chronological age and should be no greater 
than 9 years for girls and 10 years for boys. 
4. Without prior exposure to any r-hGH therapy. 
5. Impaired height and height velocity defined as: 
a. Height (HT) of at least 2.0 standard deviations (SD) below the 
mean height for chronological age (CA) and gender according to 
the standards from Prader et al, 1989, (HT SDS ≤ -2.0). 
b. Annualized height velocity (HV) below the 25th percentile for CA 
(HV <-0.7 SDS) and gender according to the standards of Prader 
et al (1989). The interval between two height measurements 
should be at least 6 months, but should not exceed 18 months 
prior to inclusion.  
6. BMI must be within ±2 SD of mean BMI for the chronological age and sex 
according to the 2000 CDC standards. 
                                                          
1 Patients will be divided into two subgroups:  Patients with peak serum GH levels after stimulation test 
ng/ml and 
patients with peak serum GH levels after stimulation test 
 and 
 ng/ml. 
2 Insulin tolerance test, with cortisol response to hypoglycemia if insulin stimulation test is chosen / Arginine test / 
Clonidine test / Glucagon test (plus or without propranolol) / L-dopa plus propranolol. 
3 Central laboratory results will be used for eligibility confirmation. 
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7. Baseline IGF-I level of at least 1 SD below the mean IGF-I level 
standardized for age and sex (IGF-I SDS ≤ -1.0) according to the central 
laboratory reference values. 
8. Children with normal fundoscopy (ophthalmoscopy) at screening (without 
signs/symptoms of intracranial hypertension as assessed by fundoscopy). 
9. Children with multiple hormonal deficiencies must be on stable 
replacement therapies for other hypothalamo-pituitary-organ axes for at 
least 3 months and 6 months for thyroid replacement therapy prior to the 
first study drug administration. 
10. Normal 46 XX karyotype for girls. 
11. Written informed consent of the parent or legal guardian of the patient 
and assent of the patient (if the patient can read) for the Main Study and 
for the OLE. 
Specific Inclusion criteria for Period V (LT-OLE –PEN): 
12. Continuing participation in the LT-OLE-PEN Period.  
13. Signed consent and assent (when applicable) form for the LT-OLE-PEN 
Period. 
14. Investigator’s assessment and confirmation of the patient anticipated 
compliance to the protocol procedures. 
15. Agreement to refrain from sexual activity during the study i.e. observe 
complete sexual abstinence as the only acceptable contraceptive measure 
in this study. 
EXCLUSION 
CRITERIA: 
1. Children with past or present intracranial tumor growth as confirmed by 
an MRI scan (with contrast). 
2. History of radiation therapy or chemotherapy. 
3. Malnourished children defined as:  
a. Serum albumin below the lower limit of normal (LLN) according 
to the reference ranges of central laboratory; AND 
b. Serum iron below the lower limit of normal (LLN) according to the 
reference ranges of central laboratory; AND 
c. BMI < -2 SD for age and sex; 
4. Children with psychosocial dwarfism. 
5. Children born small for gestational age (SGA – birth weight and/or birth 
length < -2 SD for gestational age).  
6. Presence of anti-hGH antibodies at screening. 
7. Any clinically significant abnormality likely to affect growth or the ability to 
evaluate growth, such as, but not limited to, chronic diseases like renal 
insufficiency, spinal cord irradiation, etc. 
8. Patients with diabetes mellitus. 
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9. Patients with impaired fasting sugar (based on WHO; fasting blood sugar 
>110 mg/dl or 6.1 mmol/l) after repeated blood analysis. 
10. Chromosomal abnormalities and medical “syndromes” (Turner’s 
syndrome, Laron syndrome, Noonan syndrome, Prader-Willi Syndrome, 
Russell-Silver 
Syndrome, 
SHOX mutations/deletions 
and 
skeletal 
dysplasias), with the exception of septo-optic dysplasia. 
11. Closed epiphyses. 
12. Concomitant administration of other treatments that may have an effect 
on growth such as anabolic steroids and methylphenidate for attention 
deficit hyperactivity disorder (ADHD), with the exception of hormone 
replacement therapies (thyroxin, hydrocortisone, desmopressin (DDAVP)). 
13. Children requiring glucocorticoid therapy (e.g. asthma) that are taking a 
dose greater than 400 µg/d of inhaled budesonide or equivalents1 for 
longer than 1 month during a calendar year. 
14. Major medical conditions and/or presence of contraindication to r-hGH 
treatment. 
15. Known or suspected HIV-positive patient, or patient with advanced 
diseases such as AIDS or tuberculosis. 
16. Drug, substance, or alcohol abuse. 
17. Known hypersensitivity to the components of study medication. 
18. Other causes of short stature such as coeliac disease, hypothyroidism and 
rickets. 
19. The patient and/or the parent/legal guardian are likely to be non-
compliant in respect to study conduct. 
20. Participation in any other trial of an investigational agent within 30 days 
prior to Screening. 
Specific exclusion criteria for Treatment Period V (LT-OLE-PEN): 
21. Unresolved drug related SAE from previous treatment periods. 
22. Diagnosis of cancer.  
23. Patients who, based on the investigator’s judgment, have a clinically 
significant or unstable medical or surgical condition that may preclude safe 
and complete study participation. Conditions may include cardiovascular, 
peripheral vascular, pulmonary, hepatic, renal, neurological or metabolic 
disease.  
24. Concomitant administration of other treatments that may have an effect 
on growth such as anabolic steroids or replacement of sex hormones, with 
the exception of ADHD drugs or hormone replacement therapies (thyroxin, 
hydrocortisone, desmopressin [DDAVP]). 
                                                          
1 Approximately equivalent doses: Fluticasone: 264 µg/d; Beclomethasone: 504 µg/d; Flunisolide 1,000 µg/d; 
Triamcinolone: 1,000 µg/d. 
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25. Unsatisfactory treatment response defined as improvement of height SDS 
of less than 0.2 SDS in a 6-month treatment interval if dose increase at this 
time point is not feasible.  
EFFICACY 
ENDPOINTS 
(Main and OLE) : 
Primary endpoints (Main Study): 
 
Annual Height Velocity in cm/year at 12 months (Baseline Visit – Visit 1). 
Secondary endpoints (Auxology/Clinical) (Main Study): 
 
Height velocity at 6 months (Baseline Visit – Visit 1). 
 
Delta height SDS at 6 and 12 months (compared to Visit 1/Baseline value). 
Secondary endpoints (Biochemical)  (All study periods): 
 
Absolute IGF-I levels on day 4 after MOD-4023 dosing. 
 
IGF-I SDS on day 4 after MOD-4023 dosing. 
 
 
 
OLE endpoints (including LT-OLE and LT-OLE-PEN) 
 
Annual Height Velocity in cm/year at  each 12 months interval. 
 
Delta height SDS every 12 months (compared to the previous value). 
SAFETY ENDPOINTS: 
(Main and OLE) 
 
Incidence of adverse events; 
 
Incidence 
of 
anti-MOD-4023 
antibody 
formation 
(including 
characterization of the antibodies and neutralizing properties); 
 
Local injection site assessment; 
 
IGF-I levels; 
 
Parameters of glucose metabolism: blood glucose, fasting insulin level, 
HbA1c; 
 
Thyroid status; 
 
Lipid parameters;  
 
Cortisol levels; 
 
All other hematology and biochemical parameters; 
 
Physical examination; 
 
Vital signs. 
PK/PD ENDPOINTS: 
Population based PK/PD profile of MOD-4023 after 2nd dose administration at final 
allocated dose (AUC, MRT, Cmax, Ctrough, Tmax, T1/2). 
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STATISTICAL 
ANALYSIS: 
Details of applicable statistical methods will be provided in a Statistical Analysis 
Plan.  
Data from all clinical assessments will be listed and, where appropriate, 
summarized by cohorts using descriptive statistics. Endpoints will be summarized 
by cohorts and stratifying variables as well.  
Summary statistics (arithmetic mean, standard deviation, minimum value, 
maximum value, number of non-missing values) will be presented for continuous 
variables (absolute values at each time point and changes from baseline if 
applicable). Frequency statistics (counts and percentages) will be presented for 
categorical variables. Where appropriate, the presentation of results will include 
shift tables, plots, or confidence intervals.  
All statistical evaluations, including efficacy analysis, will be purely exploratory; no 
hypothesis tests will be conducted, hence this pilot study is not powered. 
The assessment of safety will be based mainly on the frequency of AEs, frequency 
of patients developed anti-MOD-4023 antibody, IGF-I serum levels and on the 
number of laboratory values that fall outside of pre-determined ranges. Data of 
all safety endpoints will be listed and tabulated. 
When all patients complete the Main Study a full statistical analysis will be 
performed for the Main Study based on the applicable approved SAP. The results 
will be presented and discussed in a full Clinical Study report. 
2nd year, 3rd year and subsequent analysis will be conducted periodically for 
efficacy and safety updates. 
PK/PD evaluations: 
PK/PD parameters will be calculated utilizing a population PK modelling approach, 
based on limited sampling in each patient.  
The proposed analysis strategy will include the following steps: 
1. Estimate the Population PK/PD means and variances using the Population 
PK/PD analysis.  
2. Perform an Empirical Bayesian estimation to retrieve the individual PK/PD 
model Parameters.  
3. Use these individual PK/PD estimates to generate individual concentration 
time profile using rich sampling to cover the entire desired time range for 
non-compartmental analysis calculation. 
4. Perform Non compartmental Analysis for estimation of AUC and Cmax. 
PATIENT 
DISCONTINUATION 
RULES (all study 
periods) : 
The patient's participation in this study may be discontinued due to the following 
reasons: 
1. Request from regulatory agency, sponsor, primary care physician, or 
Investigator. 
2. Patient (or parent/legal guardian) withdraws consent. 
3. Adverse event (AE): 
o Occurrence of a malignancy during the course of study. 
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o Evidence of growth of an intracranial tumor during the course of 
the study. 
o Development of benign intracranial hypertension, if the 
symptoms return following resumption of drug (after a temporary 
stop). 
o Occurrence of AE's following which the Investigator or the patient 
wishes to discontinue treatment (such as, but not limited to, 
slipped capital femoral epiphysis, scoliosis, avascular necrosis and 
development of lipoatrophy, etc.).  
o Development of a serious inter-current critical illness. 
o Abnormal laboratory values that affect the patient’s safety (if 
discontinuation is considered necessary by the Investigator or the 
Sponsor Medical Monitor).  
o A severe adverse drug reaction (if discontinuation of study 
medication is desired by the patient or considered necessary by 
the investigator or the Sponsor Medical Monitor).  If the 
Investigator decision is made because of a SAE or clinically 
significant laboratory value, the Medical Monitor is to be alerted 
immediately 
4. Intake of prohibited concomitant medication.  
5. Unsatisfactory treatment response defined as improvement of height SDS 
of less than 0.2 SDS in a 6-month treatment interval if dose increase at 
this time point is not feasible (Applicable for periods I-IV)  
6. Patient is unwilling or unable to continue the study or is lost-to-follow-up. 
7. Patient is non-compliant with study procedures/ study protocol. 
8. Investigator decides that withdrawal from the study is in the best interest 
of the patient: 
o Occurrence of neutralizing antibodies which, in the opinion of the 
Investigator, requires discontinuation of the patient.   
o Lack of patient compliance (if discontinuation is desired or 
considered necessary by the investigator or the Sponsor Medical 
Monitor).  
o A serious protocol deviation that affects the patient’s safety or 
the accuracy and/or validity of data. 
9. Patient meets one of the exclusion criteria during the study. 
10. Any clinically significant change in the patient’s medical condition. 
Discontinuation rules specific to the LT-OLE-PEN period: 
11. Positive urine pregnancy test or confirmed pregnancy. In case of 
confirmed pregnancy, the study drug should be discontinued and the 
Medical Monitor be alerted immediately. 
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12. When the patient reaches a growth rate of cm/12 months (the interval 
between two height measurements should be at least 6 months). 
 
 
 
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Table of Contents 
PROTOCOL SYNOPSIS ....................................................................................................... 3 
1. BACKGROUND AND RATIONALE .................................................................................. 30 
1.1 INTRODUCTION ................................................................................................................ 30 
1.1.1 Aetiology ........................................................................................................... 30 
1.2 THE INVESTIGATIONAL PRODUCT ......................................................................................... 32 
1.3 RISK-BENEFIT ANALYSIS ..................................................................................................... 33 
1.4 DOSE SELECTION RATIONALE .............................................................................................. 33 
1.4.1 Justification for Switching All Patients to MOD-4023 Dose of 0.66 
mg/kg/week in OLE 2nd year ........................................................................ 34 
2. STUDY OBJECTIVES AND ENDPOINTS ........................................................................... 34 
2.1 STUDY OBJECTIVES ........................................................................................................... 34 
2.1.1 Primary Objectives ............................................................................................ 34 
2.1.2 Secondary Objectives ....................................................................................... 34 
2.2 STUDY ENDPOINTS ........................................................................................................... 35 
3. OVERALL STUDY DESIGN ............................................................................................. 36 
4. STUDY POPULATION ................................................................................................... 40 
4.1 INCLUSION CRITERIA ......................................................................................................... 41 
4.2 EXCLUSION CRITERIA ......................................................................................................... 42 
4.3 PATIENT IDENTIFICATION ................................................................................................... 44 
4.4 SCREENING FAILURES ........................................................................................................ 44 
4.5 RANDOMIZATION ............................................................................................................. 44 
4.6 REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT . 45 
4.6.1 Handling of Withdrawals .................................................................................. 46 
5. STUDY PROCEDURES AND ASSESSMENTS .................................................................... 47 
5.1 MAIN STUDY ................................................................................................................... 47 
5.1.1 Screening .......................................................................................................... 47 
5.1.2 Visit 1 – All Patients .......................................................................................... 48 
5.1.3 PK/PD Visits (V2 - Week 2; V3 - Week 4; V4 -Week 6) ..................................... 49 
5.1.3.1 Week 2: V2 (a-h) – MOD-4023 Dose Cohorts ............................................ 50 
5.1.3.2 Week 4: V3 (a-h) – MOD-4023 Dose Cohorts ............................................ 51 
5.1.3.3 Week 6: V4 (a-h) - MOD-4023 Dose Cohorts ............................................. 53 
5.1.3.4 Week 2 and 6: Visits 2 and 4 for Genotropin Cohort (Cohort 4)................ 54 
5.1.4 Monthly Follow Up Visits: Visit 5 (wk10), Visit 6 (wk14), Visit 7 (wk18), 
Visit 8 (wk22) - All Patients .......................................................................... 55 
5.1.5 Visit 9 (wk23) – Only MOD-4023 Dose Cohorts ................................................ 55 
5.1.6 Visit 10 (wk26) – All Cohorts ............................................................................. 56 
5.1.7 V11 (month 9), V12 (month 12) – All Cohorts – PERIOD II ............................... 56 
5.2 12-MONTH OPEN LABEL EXTENSION (OLE)   PERIOD III.......................................................... 57 
5.3 LONG-TERM OPEN LABEL EXTENSION (LT-OLE) PERIOD IV ................................................... 59 
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5.4 LONG-TERM OPEN LABEL EXTENSION PEN (LT-OLE-PEN) PERIOD V- UNTIL MARKETING APPROVAL
 ............................................................................................................................... 60 
5.4.1 First year of LT-OLE-PEN period ........................................................................ 60 
5.4.1.1 PEN Visit 1 (PEN V1) – Dosing Day ............................................................. 60 
5.4.1.2 PEN Visit 2 (PEN V2) - Week 4 (+1 weeks) counting from PEN V1 ............. 62 
5.4.1.3 Months 3 and 6 (±2 week) visits counting from PEN V1 ............................ 62 
5.4.1.4 Month 9 (±2 week) visit counting from PEN V1 ......................................... 63 
5.4.1.5 Months 12 (±2 week) visit counting from PEN V1 ..................................... 64 
5.4.2 Second year of LT-OLE-PEN until marketing approval ..................................... 65 
5.5 UNSCHEDULED AND EARLY TERMINATION VISITS .................................................................... 66 
5.5.1 Unscheduled Visits ............................................................................................ 66 
5.5.2 Early Termination and End of Study Visits – Main Study, OLE, LT-OLE and 
LT-OLE-PEN Periods ..................................................................................... 66 
5.6 EFFICACY ASSESSMENTS..................................................................................................... 67 
5.7 SAFETY ASSESSMENTS ....................................................................................................... 67 
5.7.1 Laboratory Safety Assessments ........................................................................ 67 
5.7.1.1 IGF-I ............................................................................................................ 68 
5.7.1.2 Assessment of glucose metabolism ........................................................... 68 
5.7.1.3 Indicators of lipid metabolism ................................................................... 68 
5.7.1.4 Hormonal status with special attention on thyroid and adrenal status .... 69 
5.7.1.5 Assessment of antigenicity ........................................................................ 69 
5.7.1.6 MOD-4023 hGH Concentrations ................................................................ 69 
5.7.1.7 Blood biochemistry .................................................................................... 70 
5.7.2 Vital signs and Physical Examination ................................................................ 70 
5.7.3 Local Injection Site Reactions ........................................................................... 70 
5.7.4 Fundoscopy and MRI ........................................................................................ 71 
5.7.5 ECG .................................................................................................................... 71 
5.8 DOSE MODIFICATION AND DISCONTINUATION ....................................................................... 72 
5.8.1 Dose Modifications Based on Adverse Effects (main study) ............................ 73 
5.8.2 Overdose with the Study Medication ............................................................... 73 
5.8.3 Dose adjustment paradigm .............................................................................. 74 
6. INVESTIGATIONAL PRODUCT ...................................................................................... 76 
6.1 INVESTIGATIONAL THERAPY AND REFERENCE THERAPY ............................................................. 76 
6.1.1 MOD-4023 ........................................................................................................ 76 
6.1.2 MOD-4023 Administration (all study periods) ................................................. 76 
6.1.3 Reference Non-Investigational Medicinal Product (Non-IMP): Genotropin 
(Period I) ...................................................................................................... 79 
6.1.4 Genotropin Administration (Period I) ............................................................... 79 
6.2 PACKAGING AND LABELING OF STUDY MEDICATION ................................................................ 79 
6.2.1 MOD-4023 vials (Periods I to IV)....................................................................... 79 
6.2.2 MOD-4023 PEN (Period V) ................................................................................ 80 
6.2.3 The PENs will be packed and labelled in compliance with the FDA, EU 
and ICH guidelines. Genotropin (Periods I) ................................................. 80 
6.3 DISTRIBUTION AND SHIPMENT OF STUDY MEDICATION ............................................................ 80 
6.4 STORAGE, DISPENSING AND RETURN OF THE INVESTIGATIONAL PRODUCT .................................... 80 
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6.4.1 MOD-4023 (all study periods) .......................................................................... 81 
6.4.2 Genotropin (Period I) ........................................................................................ 81 
6.5 ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL PRODUCT .......................................... 82 
6.6 BLINDING ....................................................................................................................... 83 
6.7 PRIOR AND CONCOMITANT THERAPY.................................................................................... 83 
6.7.1 General Guidelines ........................................................................................... 83 
6.7.2 Allowed Medications ........................................................................................ 83 
6.7.3 Prohibited Concomitant Medication ................................................................ 84 
7. SAFETY AND PHARMACOVIGILANCE............................................................................ 84 
7.1 ADVERSE EVENTS ............................................................................................................. 84 
7.2 SERIOUS ADVERSE EVENTS ................................................................................................. 88 
7.2.1 Notification of Serious Adverse Events ............................................................ 89 
7.2.1.1 Reporting responsibility ............................................................................. 89 
7.2.1.2 Reporting procedures ................................................................................ 89 
7.2.1.3 Contact persons and numbers ................................................................... 90 
7.2.1.4 Information to include on SAE form .......................................................... 90 
7.3 ANTICIPATED ADVERSE EVENTS ........................................................................................... 91 
7.4 PREGNANCY REPORTING AND FOLLOW-UP ............................................................................ 91 
7.5 PEN DEVICE COMPLAINT REPORTING REQUIREMENTS ............................................................ 92 
8. STATISTICAL ANALYSIS ................................................................................................ 92 
8.1 STATISTICAL METHODS ...................................................................................................... 92 
8.2 SAMPLE SIZE ................................................................................................................... 93 
8.3 POPULATION ANALYSIS ...................................................................................................... 94 
8.3.1 Background and Demographic Characteristics ................................................. 94 
8.3.2 Study Medication .............................................................................................. 94 
8.3.3 Concomitant Therapy ....................................................................................... 95 
8.4 EFFICACY EVALUATION ...................................................................................................... 95 
8.4.1 Methods of Efficacy Analysis ............................................................................ 96 
8.5 SAFETY EVALUATION ......................................................................................................... 96 
8.6 PK/PD EVALUATION ........................................................................................................ 97 
9. ETHICS ........................................................................................................................ 98 
9.1 ETHICS AND GOOD CLINICAL PRACTICE (GCP) ....................................................................... 98 
9.2 INSTITUTIONAL REVIEW BOARD (IRB) /INDEPENDENT ETHICS COMMITTEE (IEC) ......................... 98 
9.3 INFORMED CONSENT......................................................................................................... 98 
9.4 DECLARATION OF HELSINKI ................................................................................................. 99 
9.5 INSURANCE ..................................................................................................................... 99 
9.6 DATA SAFETY MONITORING BOARD (DSMB) ........................................................................ 99 
9.7 PROTOCOL AMENDMENTS, OTHER CHANGES IN STUDY CONDUCT ........................................... 100 
9.7.1 Protocol Exceptions and Deviations ............................................................... 100 
9.7.2 Protocol Amendments .................................................................................... 100 
9.7.3 Other Changes in Study Conduct .................................................................... 100 
10. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 100 
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10.1 AUDITS AND INSPECTIONS .............................................................................................. 100 
10.2 STUDY MONITORING .................................................................................................... 101 
10.3 QUALITY LABORATORY STANDARDS ................................................................................. 101 
10.4 STUDY DOCUMENTATION ............................................................................................... 102 
10.5 SOURCE DOCUMENTS ................................................................................................... 102 
10.6 RECORDING OF DATA ON ELECTRONIC CASE REPORT FORMS (ECRFS) .................................... 102 
10.7 INVESTIGATOR SITE FILE................................................................................................. 103 
10.8 CLINICAL TRIAL SUPPLIES ............................................................................................... 103 
10.9 DATA MANAGEMENT .................................................................................................... 104 
10.9.1 Coding Dictionaries ....................................................................................... 104 
11. STUDY ADMINISTRATION ........................................................................................ 104 
11.1 REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION .......................................................... 104 
11.2 STUDY COMPLETION ..................................................................................................... 105 
11.3 SPONSOR'S TERMINATION OF STUDY ................................................................................ 106 
11.4 CLINICAL STUDY REPORT ................................................................................................ 106 
11.5 RETENTION OF DOCUMENTS ........................................................................................... 106 
11.6 PUBLICATION OF RESULTS .............................................................................................. 106 
11.7 DISCLOSURE AND CONFIDENTIALITY ................................................................................. 107 
12. INVESTIGATOR'S STATEMENT OF RESPONSIBILITY ................................................... 108 
13. REFERENCES ........................................................................................................... 133 
 
List of Appendices 
Appendix 1: Schedule of Assessments – Main Study .......................................................................... 109 
Appendix 2: Schedule of Assessments – 12-Month Open Label Extension (Ole) – Period III ............. 113 
Appendix 3: Schedule of Assessments – Long-Term OLE (LT-OLE) Period IV from Second Year of 
OLE/Third Year of Treatment until switch to LT-OLE-PEN period ............................... 114 
Appendix 4: Schedule of Assessments – Long-Term OLE PEN (LT-OLE-PEN) Period V first year ........ 116 
Appendix 5: Schedule of Assessments – Long-Term OLE PEN (LT-OLE-PEN) Period V from 2nd year 
until marketing approval ............................................................................................. 118 
Appendix 6: World Medical Association Declaration of Helsinki ........................................................ 119 
Appendix 7: Growth Hormone Stimulation Tests and Other Assessments ........................................ 125 
Appendix 8: Injection Site Assessment Table (Local Reactions) ......................................................... 128 
Appendix 9: Instructions for Obtaining Height Measurements .......................................................... 130 
Appendix 10: Instructions for Obtaining X-Ray Films ......................................................................... 131 
Appendix 11: List of Central Technical Facilities ................................................................................. 132 
 
 
 
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List of Tables 
TABLE 1: DOSE COHORTS ........................................................................................................................ 6 
TABLE 2: DOSE INCREASE SCHEME FOR MOD-4023 COHORTS .............................................................. 7 
TABLE 3: MOD-4023 POPULATION PK AND PD SAMPLING SCHEME ...................................................... 8 
TABLE 4: GENOTROPIN POPULATION PK AND PD SAMPLING SCHEME (VISIT 2) ................................... 9 
TABLE 5: DOSE INCREASE SCHEME FOR MOD-4023 COHORTS ............................................................ 37 
TABLE 6: MOD-4023 POPULATION PK AND PD SAMPLING SCHEME .................................................... 50 
TABLE 7: GENOTROPIN POPULATION PK AND PD SAMPLING SCHEME (VISIT 2) ................................. 50 
TABLE 8: MAIN STUDY WEEKLY DOSE REGIMENS................................................................................. 76 
 
List of Figures 
FIGURE 1: OVERALL STUDY DESIGN ...................................................................................................... 40 
FIGURE 2: OVERALL DOSE ADJUSTMENT SCHEME ............................................................................... 75 
FIGURE 3: INJECTION SITES AND RECOMMENDED ROTATION FOR MOD-4023 .................................. 77 
 
 
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List of Abbreviations 
Terms 
Descriptions 
ACTH  
Adrenocorticotropic hormone (corticotrophin) 
AE  
Adverse event 
ANOVA 
Analysis of variance 
BA  
Bone age 
BMI  
Body mass index  
CA  
Chronological age 
CRF  
Case Report Form 
CRO  
Contract Research Organisation 
CTP 
Carboxyl-terminal peptide 
DSMB 
Data Safety Monitoring Board 
ECG  
Electrocardiogram 
EU  
European Union 
GCP  
Good Clinical Practice 
GGT  
Gamma-glutamyl transferase 
GH  
Growth hormone  
GHD  
Growth hormone deficiency 
GMP  
Good Manufacturing Practice 
HDL  
High density lipoprotein 
hGH  
Human growth hormone 
HIV  
Human immunodeficiency virus 
HT  
Height  
HV 
Height velocity  
i.m. 
Intramuscular 
i.v. 
Intravenous 
ICF 
Informed consent form 
ICH  
International Committee on Harmonisation  
IEC  
Independent Ethics Committee  
IGF-I  
Insulin-like growth factor- I 
IRB 
Institutional Review Board  
ITT  
Intention-to-treat  
IU  
International units 
LDH  
Lactate dehydrogenase 
LDL  
Low density lipoprotein 
LLN  
Lower limit of normal 
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LP 
Lumbar puncture 
LT-OLE 
Long-term Open Label Extension 
OLE 
Open Label Extension 
MCH  
Mean corpuscular hemoglobin 
MCHC  
Mean corpuscular hemoglobin concentration 
MCV  
Mean corpuscular volume 
PD 
Pharmacodynamics 
PEN 
Single patient use, multi-dose, disposable pre-filled pen 
containing 20 or 50 mg/mL 
PK 
Pharmacokinetics  
PP 
Per-protocol  
SC  
Subcutaneous 
SAE  
Serious adverse event 
SD  
Standard deviation 
SDS  
Standard deviation score 
SGOT  
Serum glutamic oxaloacetic transaminase 
SGPT  
Serum glutamic pyruvic transaminase 
SHOX 
Short stature homeobox  
T3 
Triiodothyronine 
T4 
free thyroxin 
TEAE 
Treatment-emergent adverse event 
TSH  
Thyroid stimulating hormone 
ULN  
Upper limit of normal 
WHO 
World Health Organisation 
WHO-DRL 
WHO-Drug Reference List 
 
 
 
 
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1. Background and Rationale 
1.1 INTRODUCTION 
Human growth hormone (hGH) deficiency is the consequence of low or absent secretion of 
growth hormone from the pituitary gland.  hGH is a 191-amino-acid pituitary protein that 
stimulates the hepatic production and release of insulin-like growth factor-I (IGF-I) into the 
systemic circulation. IGF-I is instrumental in the promotion of linear growth in children, and 
in the control of metabolism and body-mass composition in adults.  It is regulated through 
complex feedback mechanisms involving hGH, insulin-like growth factor-I binding protein 3 
(IGF-BP3) and their complexes. The somatotroph cells of the anterior pituitary gland produce 
growth hormone.  Secretion of hGH is under strict hormonal homeostatic control.  Growth 
hormone-releasing hormone (GHRH) and ghrelin are the most significant stimulators of its 
production while somatostatin produces the strong inhibitory action.  Both GHRH and 
somatostatin are released into the portal system from the hypothalamus.  hGH has a pulsatile 
and mainly nocturnal pattern of secretion, occurring especially during REM (rapid eye 
movement) sleep.  The frequency and amplitude of pulses increase during the growth spurt 
in adolescence and decline thereafter.  Both acute stress and hypoglycemia stimulate hGH 
release, while hyperglycemia produces the opposite.  
 
hGH is considered to be the most important endogenous factor responsible for body growth.  
It is also under the inhibitory control of IGF-I, its major protein effector, synthesized in the 
liver in response to hGH. The bone and connective tissue, in which hGH stimulates collagen 
synthesis and increases the activity of chondroblasts and chondrocytes, are the effector 
tissues of GH/IGF-I.  GH is not only the hormone of growth; but it shows various effects on 
almost every tissue in the human organism.  It is one of the most important anabolic agents 
enhancing whole body protein synthesis, increasing plasma glucose level and lipolysis via the 
direct effect on adipocytes as well as lipid oxidation by increasing substrate availability. New 
research continues to reveal other potential roles of hGH, including regulation of cardiac and 
immune function, mental agility and aging. The far reaching influence of these interactions is 
quite consistent with the very significant pleiotropic consequences for growth and 
metabolism when the system is imbalanced, as in the case of GHD. 
 
In children, GHD results in inadequate circulating IGF-I levels and is manifested as abnormal 
linear growth.   
 
In adults, GHD results in decreased lean body mass, increased fat mass, weakness, reductions 
in exercise capacity, muscle mass/strength, cardiac performance, and bone density, and in 
neuropsychological disturbances.   
1.1.1 Aetiology 
Childhood GHD can be congenital, acquired, or idiopathic.  Underlying causes of two of these 
three types of GHD in children have been identified: 
 Congenital  
o Defective pituitary development that leads to pituitary aplasia 
o Empty sella 
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o Encephalocoele 
o Midline defects 
o Septo-optic dysplasia 
o Panhypopituitarism 
o Genetic abnormalities; autosomal-recessive, autosomal-dominant, or X-linked 
defects or a mutation or deletion in the growth hormone gene or in the GHRH. 
 Acquired  
o Tumours of the hypothalamic-pituitary region - Craniopharyngioma is the most 
common tumor 
o Cranial irradiation, surgical intervention 
o Infiltrative diseases, including sarcoidosis, tuberculosis, histiocytosis X, 
haemochromatosis, and lymphocytic hypophysitis 
o Trauma (specifically traumatic brain injury) 
o Hypoxic insult 
 Idiopathic  
In most cases, no clear aetiology can be identified. 
 
The idiopathic origin of GHD is poorly understood but it appears to be multifactorial.  
Retrospective analyses have considered familial traits (such as parental height) and perinatal 
risk factors (such as gestational age and birth size and weight) as possible predictors.  
Similarly, correlates of idiopathic GHD with untoward events during pregnancy and 
complications during birth have been examined. There are non-random effects evident in the 
frequency of GHD (and multiple pituitary hormone deficiency) dependent on some of these 
apparently extraneous influences, notably traumatic birth experience. The evidence suggests 
a model of causality in which there are ill-defined underlying familial and gender (males 
predominate 3-4:1) predispositions which are exacerbated by early life “adverse” events and 
result in deficiency, the degree of which (isolated GHD or multiple pituitary hormone 
deficiency) is determined by the severity of the “adverse” early life event.  
Most morbidity in children with GHD relates to short stature. Average adult height for 
untreated patients with severe isolated growth hormone deficiency is 143 cm in men and 130 
cm in women. The inability to achieve normal height leads to early onset of severe 
psychosocial problems directly related to short stature. This is compounded by delayed 
puberty and deficits in facial, dental and (in males) genital development. Approximately 5% 
of children with GHD have episodes of hypoglycemia, particularly in infancy. 
Human GH (somatropin) has been in clinical use for over 50 years primarily for treating GHD 
in children.  In 1985, hGH from recombinant DNA origin replaced the cadaveric pituitary hGH, 
which was the only source available until then. hGH replacement therapy has been the 
standard of care for tens of thousands of adult and pediatric GHD patients and has proved to 
be safe and effective. The safety profile of daily dosing of hGH preparations in pediatric and 
adult populations is well established in clinical trials. Adverse events of injection site reactions 
do occur but are not deemed serious and resolve spontaneously.  Safety is invariably 
concluded to be satisfactory in clinical trials.   
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The majority of currently available hGH products require daily or every other day 
subcutaneous or intramuscular injections in order to maintain hGH blood levels within the 
effective therapeutic window. Hence, compliance can be a problem, especially in self-
administering patients. Daily administration and its concomitant side effects (e.g., injection 
site discomfort, transient oedema and arthralgia) can limit the therapeutic utility of existing 
formulations. A long-acting form of GH has the potential to reduce discomfort by requiring 
fewer injections and possibly by minimizing the adverse events associated with peaks and 
troughs in plasma concentration that occur with daily injection. With a baseline of non-
compliance which has been shown to undermine the intended clinical effect of daily dosing, 
at least in the pediatric population, there is a strong imperative to enhance compliance in GH 
replacement therapy. In addition, in pediatric patients, psychological trauma related to years 
of regular injections is one of the major stressors reported by diabetic patients related to their 
medical treatment. The repeated injections required for daily r-hGH treatment may actually 
serve to enhance the negative self-image and stigmatization that already exist for many of 
these children. Patients receiving GH therapy less frequently may experience a benefit from 
such treatment, improving their quality of life. 
At the present time there are no commercially available sustained-release or long-acting GH 
preparations. However, their proof of principle and effectiveness has been extensively 
demonstrated both in clinical trials and in routine clinical use in childhood and adult GHD 
populations.  
CTP technology has enabled the production of a long-acting hGH (MOD-4023), which may 
obviate the need for the numerous injections now required for the treatment of GHD. This 
technology is based on a natural peptide, the C-terminal peptide (CTP) of the beta chain of 
hCG, which provides hCG with the required longevity to maintain pregnancy (initial T1/2 ~10 
hours, terminal T1/2 ~37 hours). The beta chain of luteinizing hormone (LH), a gonadotropin 
that triggers ovulation, is almost identical to hCG but does not include the CTP. As a result, LH 
has a significantly shorter half-life in blood (initial T1/2 ~1 hour, terminal T1/2 ~10 hours). 
MOD-4023 is an hGH molecule fused to 3 copies of CTP; one at the N-terminus and two at the 
C-terminus. Therefore, adding CTP to protein other than hCG will enable to increase their 
longevity. 
As demonstrated in animal models, healthy subject (Phase I) and GHD adult patients (Phase 
2), MOD-4023 may have the potential to be injected once per week to once every two weeks, 
resulting in similar clinical efficacy to daily injections of r-hGH. 
1.2 THE INVESTIGATIONAL PRODUCT 
MOD-4023 is a long acting hGH under development which utilizes the CTP technology. 
MOD-4023 consists of hGH fused to three copies of the C-terminal peptide (CTP) of the beta 
chain of human chorionic gonadotropin (hCG); one copy at the N-terminus and two copies (in 
tandem) at the C-terminus. Each CTP peptide contains up to four O-glycosylation sites, and 
has a theoretical molecular weight of 30,469 Daltons (Da) for the protein backbone and 
~38,500 Da for the entire molecule including the O-glycans. MOD-4023 is expressed in CHO 
cells grown in protein-free, serum-free medium. The protein is purified using a series of 
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chromatographic separation steps. The final material is formulated in 
 
 
Unlike other investigational long-acting/sustained-release hGH products, the liquid 
formulation of the MOD-4023 drug product is non-viscous (viscosity at 20 mg protein/ml is 
similar to saline).  Therefore the material can be administered using thin needles of 30-33 G. 
1.3 RISK-BENEFIT ANALYSIS 
Each of the study patients requires GH replacement, and may potentially be advantaged by 
approval of a safe and effective long acting growth hormone.  
Adverse events (AEs) in children seem to be mostly mild in nature (reported for up to a 
maximum of 10% of the patients participating in clinical trials). Side effects which have to be 
primarily considered when using hGH preparations include: symptoms of fluid retention 
(edema), arthralgia/myalgia, symptoms of carpal tunnel syndrome and transient local skin 
reactions at the injection site. In addition, symptoms of hypothyroidism, insulin resistance, 
nausea, increase of leukocytes and plasma free fatty acids, disturbance of blood lipids, benign 
intracranial hypertension, headache, muscle and joint pain, weakness, tiredness, 
hyperglycemia, glucosuria, and lipoatrophy (at the injection site) might occur. 
As with any other protein, treatment with a growth hormone preparation may induce 
immune responses, including the formation of anti- hGH antibodies. While growth response 
in children or change of body composition in adults may or may not considerably be affected 
by formation of such antibodies, it has been a concern with respect to the safety as well as 
the efficacy of such products. Although this concern historically arose following the use of 
human pituitary-derived hGH, earlier impure recombinant hGH preparations, and of 
methionylated-r-hGH, assessment of the potential antigenicity of current r-hGH products is 
still justified. 
On the basis of the preclinical studies and clinical studies conducted in adult GHD patients 
(see Investigator's Brochure), serious toxicological reactions are not to be expected in patients 
upon the injection of the study substance at the envisaged dose and route of administration. 
1.4 DOSE SELECTION RATIONALE 
The Phase 2 pediatric study will evaluate three dose levels of MOD-4023, intended to be 
equimolar to the dose level for cumulative weekly r-hGH treatment, or a multiple thereof.  All 
dose levels tested are supported by a significant safety margin derived from the “no observed 
adverse effect level” (NOAEL) established in nonclinical toxicology studies. The low dose 
administered to Cohort 1 (0.25 mg MOD-4023 protein/kg/week) is a weekly molar equivalent 
to a standard daily dose of r-hGH of 0.025 mg/kg/day or 0.18 mg/kg/week (after adjusting for 
the 1.38-fold difference in mass between the two proteins). Cohort 2 will be administered the 
weekly molar equivalent of the maximal recommended dose for GHD treatment (0.05 
mg/kg/day, based on the Growth Hormone Society Consensus Guideline on the Diagnosis and 
Treatment of GHD in Childhood and Adolescence published in 2000) and Cohort 3 will 
be administered the weekly molar equivalent of the maximal approved dose for other 
pediatric indications (equivalent to 0.068 mg/kg/day). 
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During the 12-month Open-Label Extension (OLE), patients will continue with the same dose 
(mg/kg) as in the Main Study. 
Patients who received active comparator, Genotropin®, during the Main Study, will be 
switched to MOD-4023; they will be randomized to one of the three MOD-4023 cohorts. 
In the Long-term OLE (LT-OLE) period, patients in the lower dose cohorts (cohorts 1 and 2) 
will be switched to 0.66 mg/kg/week as specified in this protocol. 
In the LT-OLE-PEN period, patients should continue with the same dose.  
1.4.1 Justification for Switching All Patients to MOD-4023 Dose of 0.66 mg/kg/week in OLE 
2nd year 
Based on favorable outcome of the 12-month data of this phase 2 pediatric dose range study 
(Main Study CP-4-004), it was decided to switch all patients from Cohorts 1 and 2 entering the 
LT-OLE (2nd year of the OLE) to MOD-4023 0.66 mg/kg/week. At 12-months (end of Main 
Study), patients on MOD-4023 at a dose of 0.66 mg/kg/week had comparable efficacy and 
safety outcome to patients on daily hGH (Genotropin) at a dose of 34 µg/kg/day (equivalent 
to 0.24 mg/kg/week).  Specifically, MOD-4023 at 0.66 mg/kg/week elicited comparable 
auxology outcome (HV SDS and Ht SDS) and IGF-I and IGFBP-3 profiles to daily hGH while 
maintaining optimal IGF-I serum levels, with values that were in the middle part of the gender 
and age-adjusted normal range (~0 SDS).  The 0.66 mg/kg/week dose of MOD-4023 was also 
associated with a satisfactory safety and tolerability profile which is consistent with known 
properties of r-hGH products.  No patients withdrew from the study due to an AE associated 
with MOD-4023. 
Based on these results, the Sponsor proposes that the dose of 0.66 mg/kg/week of MOD-4023 
has the highest probability to successfully demonstrate non-inferior efficacy to Genotropin in 
a subsequent Phase 3 pediatric GHD study with a comparable safety profile, and is the 
preferable therapeutic dose considering benefit/risk to the pediatric GHD patients. 
2. Study Objectives and Endpoints 
2.1 STUDY OBJECTIVES 
2.1.1 Primary Objectives 
The primary objectives are to compare the safety, efficacy and tolerability of three MOD-4023 
doses to that of a commercially available standard daily r-hGH formulation, in pre-pubertal 
children with growth failure due to insufficient secretion of endogenous growth hormone. 
2.1.2 Secondary Objectives 
The secondary objectives are: 
1. To evaluate the PK and PD profiles of 3 different doses of MOD-4023 in pre-pubertal GHD 
children. 
2. To select the optimal dose of MOD-4023 for the subsequent phase 3 study on the basis 
of safety, efficacy.  
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2.2 STUDY ENDPOINTS 
EFFICACY ENDPOINTS: 
Primary endpoints (Main study): 
 Annual Height Velocity in cm/year at 12 months (Baseline Visit – Visit 1). 
Secondary endpoints (Auxology/Clinical) (Main study): 
 Height velocity at 6 months (Baseline Visit – Visit 1); 
 Delta height SDS at 6 and 12 months (compared to Visit 1/Baseline value). 
Secondary endpoints (Biochemical) (all study periods): 
 Absolute IGF-I levels on day 4 after MOD-4023 dosing. 
 IGF-I SDS on day 4 after MOD-4023 dosing. 
 
 
 
OLE endpoints (including LT-OLE and LT-OLE-PEN) 
 Annual Height Velocity in cm/year at each 12 months interval. 
 Delta height SDS every 12 months (compared to the previous value). 
 
SAFETY ENDPOINTS: (all study periods) 
 Incidence of adverse events; 
 Incidence of anti-MOD-4023 antibody formation (including characterization of the 
antibodies and neutralizing properties); 
 Local injection site assessment; 
 IGF-I levels; 
 Parameters of glucose metabolism: blood glucose, fasting insulin level, HbA1c; 
 Thyroid status; 
 Lipid parameters;  
 Cortisol levels; 
 All other hematology and biochemical parameters; 
 Physical examination; 
 Vital signs. 
 
 
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PK/PD ENDPOINTS: 
Population based PK/PD profile of MOD-4023 after 2nd dose administration at final allocated 
dose (AUC, MRT, Cmax, Ctrough, Tmax, T1/2). 
3. Overall Study Design 
This is a phase 2, safety and dose finding study of different MOD-4023 dose levels compared 
to daily r-hGH therapy in pre-pubertal growth hormone deficient children.  
Eligible patients will undergo the following treatment schedule consisting of a Screening 
period, 2 Active Treatment Periods (Main Study), an Open Label Extension (OLE) period, a 
Long-term OLE (LT-OLE) period and a long-term LT-OLE-PEN period:   
1. Screening period will last up to 6 weeks. 
2. Active treatment period – Main Study: 
a. Period I: 6-month repeated dosing including PK/PD sampling (see Section 5.1.2 for 
schedule).  
b. Period II: an additional 6-month continuous repeated dosing period (see Section 
5.1.2 for schedule).  
3. OLE period (Period III, 12 months) – 12 months continuous repeated dosing of MOD-4023. 
4. LT-OLE period (Period IV, from the second year OLE – long-term annual extension with 
repeated administration MOD-4023 at 0.66 mg/kg/week until transition to PEN. 
5. LT-OLE-PEN (Period V) - long-term, open-label extension using single patient use, multi-
dose, disposable pre-filled pen. Upon regulatory clearance and Sponsor's written 
approval, study patients should be switched to PEN. Patient will continue with their 
current dose.  Study duration will be until marketing approval; a yearly extension request 
will be submitted to local EC/IRB where it is required. An updated ICF for the LT-OLE-PEN 
period treatment should be signed during the first PEN transition visit, prior to using the 
PEN or any other assessments related to the transition to PEN. 
 
PERIOD I: SIX MONTH REPEATED DOSE (Main Study)  
Following screening, eligible patients will receive their weekly doses of MOD-4023 or daily 
dose of r-hGH for 6 months repeated dosing including PK/PD sampling. Safety will be assessed 
throughout this period.  
In order to introduce naïve patients to the allocated MOD-4023 dose in a gradual manner, a 
stepwise dose increase will be implemented. All patients randomized to receive one of the 
three MOD-4023 doses will start treatment for 2 weeks with the low MOD-4023 dose (0.25 
mg protein/kg). Based on the patient's dose allocation, this will be followed by a dose increase 
to the next dose level every two weeks until the final allocated dose is reached. 
 
 
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TABLE 5: DOSE INCREASE SCHEME FOR MOD-4023 COHORTS 
Cohort 
Dosing Scheme 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Cohort I 
0.25 
mg 
protein/kg/week 
 
 
PK/PD 
sampling 
Cohort II 
0.25 
mg 
protein/kg/week 
0.48 mg protein/kg/week 
 
 
PK/PD 
sampling 
Cohort III 
0.25 
mg 
protein/kg/week 
0.48 mg protein/kg/week 
0.66 
mg 
protein/kg/week 
 
PK/PD 
sampling 
Subsequent to the second dose administration of the targeted dose, limited (population-
based) PK and PD sampling will be performed as described in visit schedules in Section 5. The 
proposed sampling plan is based on the following: 
Selection of time points that will cover both the PK and PD absorption phase to the peak which 
was about 20 hours for PK and 40-60 hours for IGF-I (in the phase 2 study conducted in GHD 
adult patients) and having in addition time points to cover the PK elimination phase and PD 
return to baseline (remaining time points). 
This proposed sampling schedule was tested by simulating multiple data sets under these 
design conditions and all other conditions as the one of the upcoming and then fit those back 
using the same optimization procedures we will use after the trial. The results of that fitting 
procedure showed an average of only 15% in the percent error of the true simulating average 
PK/PD model parameters.  
Patients allocated to Genotropin cohort will undergo limited PK/PD sampling after the 8th 
Genotropin dose (start of week 2 of dosing), as described in visit schedules (section 5).  
Following the first 6 weeks of the study, all the patients will visit the hospital on a monthly 
basis. Patients allocated to the MOD-4023 dose cohorts (cohorts 1-3) will be monitored 
monthly for MOD-4023 serum levels, IGF-I and IGFBP-3 serum levels and routine safety 
assessments on day 4 after MOD-4023 dosing. In addition, after 5 months of dosing, patients 
allocated to MOD-4023 dosing will be asked to return to the medical center on the day of 
dosing in the morning hours prior to dosing in order to obtain a trough level MOD-4023 and 
PD (IGF-I and IGFBP-3) sample. Patients allocated to the Genotropin dose cohort (cohort 4) 
will be asked to return on any day during the relevant dosing week. 
During Period I, the dose of MOD-4023 and r-hGH will be adjusted to the patient’s body 
weight every three months. Doses may be decreased for safety reasons according to the pre-
defined dose-adjustment criteria (which will be based on the severity of AEs or on repeated 
consecutive elevated IGF-I levels, see section 5.8). For patients on MOD-4023, the dose may 
be decreased based on repeated consecutive day 4 levels of IGF-I above +2.0 SDS. For patients 
on Genotropin, the dose may be decreased based on repeated consecutive IGF-I levels above 
+2.0 SDS. 
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The study Medical Monitor will review all Adverse Events (AEs) from the entries on the e-CRF 
on a weekly basis and all SAE safety reports as received. The key safety data will be reviewed 
by an independent Data Safety Monitoring Board (DSMB) every 6 months approximately. 
After completion of this period each patient will be assessed separately, for the growth 
progress and overall safety. If the growth meets the pre-defined criteria (delta height SDS at 
least 0.2) and there are no safety concerns the patient will continue with the same dose, 
otherwise dose modifications will be performed, according to the pre-determined rules.   
PERIOD II: SIX MONTH CONTINUOUS DOSING (Main Study)  
During this six-month-continuous dosing period additional efficacy and safety data will be 
collected. During period II, patients will be kept on the originally allocated dose levels/dose 
regimens whenever possible. However, the dose may be adjusted due to safety reasons 
throughout the study and/or due to efficacy reasons after 6 months of dosing. Patients 
allocated to the r-hGH dose group will continue their doses as initiated earlier up to the end 
of the 12-month treatment period. Patients will visit the clinic every three months at which 
time safety and efficacy data will be collected. 
Derived height and growth parameters (HTSDS and HVSDS) will be calculated centrally, and 
the bone age will be determined by a central bone age reader from the provided copies of X-
ray films blinded for patient’s identity and chronological age. All laboratory samples, including 
samples collected during growth hormone stimulation tests, will be analyzed centrally. 
PERIOD III –12-Month OPEN LABEL EXTENSION (OLE) PERIOD 
Patients who completed 12 months of treatment in the Main Study will be eligible to continue 
to a 12-month OLE period. After completion of Period II each patient will be assessed 
individually for the growth progress and overall safety. If the growth meets the pre-defined 
criteria1, and there are no safety concerns, the patient will continue on the same dose, 
otherwise dose modifications will be performed according to the pre-determined rules. 
Patients who received MOD-4023 in the Main Study (initial 12 months of active treatment) 
will continue with the same dose (mg/kg) of MOD-4023 they received in the Main Study. For 
these patients, study visits will take place every 3 months (i.e. every 13±2 weeks, 4 days (or 3 
days, when necessary) after dosing). 
Patients who received active comparator, Genotropin, during the Main Study, will be 
switched to MOD-4023 (will be randomized to one of the three MOD-4023 cohorts). Their 
visit schedule during the first three months of the OLE will be as follows: Visit 1/OLE for first 
MOD-4023 injection (week 52 +1 day, which is on Month 12 visit of the Main Study), Visit 
2/OLE will be 28 days + 4 (-1) days after the first MOD-4023 injection and Visit 3/OLE will be 
3 months after first MOD-4023 injection (i.e. 13±2 weeks, on day 4 or 3 post dose, when 
necessary after the first MOD-4023 injection). All subsequent visits will be every three 
months, as for patients who were on MOD treatment in main study. 
Patients who are off treatment for over 
 between the last MOD-4023/Genotropin 
dose in the Main Study and the first OLE dose (2nd year) will be allowed to continue into the 
OLE period after informing the sponsor and attending an interim visit. 
                                                          
1 Delta Height SDS at least 0.2  
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During the OLE period, the DSMB will review the data at month 12 - or on an ad-hoc basis, if 
any safety concern arises. 
PERIOD IV – LT-OLE PERIOD  
LT-OLE starts from the 2nd year of OLE (i.e. the 3rd year of treatment in the study). Patients in 
Cohorts 1 and 2 who are entering the 2nd year of OLE (i.e. the 3rd year of treatment) will be 
switched to the highest dose 0.66 mg/kg/week after signing a separate informed consent. In 
selected group of patients from Cohorts 1 and 2 who have already entered the LT-OLE period, 
the switch to 0.66 mg/kg/week will be done at their next study visit after signing a separate 
informed consent. Patients in Cohort 3 will continue receiving 0.66 mg/kg/week.  
All patients switching to 0.66 mg/kg/week will be required to attend a site visit after 3 months. 
Patients on cohort 3 will continue with their routine visit schedule. 
Patients who are off treatment for over 
 between the last MOD-4023 in the OLE period 
and the first LT-OLE dose (3rd year) will be allowed to continue into the LT-OLE period after 
informing the sponsor and attending an interim visit. 
Patients will sign a separate informed consent to be eligible to enter OLE and LT-OLE. Patients 
who have already entered OLE will be re-consented for LT-OLE. Patients from Cohorts 1 and 
2 will be instructed by the investigator about the transition to the higher dose (0.66 
mg/kg/week) and will also be re-consented. 
Annual extension notification will be submitted to local EC/IRB. 
Treatment Period V (LT-OLE-PEN) – until marketing approval 
First year of LT-OLE-PEN period 
Upon regulatory clearance of protocol amendment 9 and after sponsor written approval, 
patients will be requested to come to the clinic for PEN visit 1 (PEN V1). PEN V1 will occur on 
a planned dosing day, sites should make any effort to schedule this visit according to the current 
visit schedule and consider to combine visits in order to minimize the burden on the patients. Patients 
should arrive to the clinic prior to dosing. This visit will serve as the ‘baseline’ for the LT-OLE-
PEN in which the consent/assent form for the LT-OLE-PEN period will be signed.  Patients 
should return used and unused vials that were dispensed during the study and kept at patient 
home. Site staff should remind the patients to bring all vials dispensed during the study (used 
and unused) before the visit.   
During PEN V1, the patients will be trained on the use of the PEN, the PEN will be dispensed 
and the first PEN dose will be administered at the clinic by the parents/legal guardians. Patient 
will continue his/her treatment with the same dose level as before the switch to PEN. In 
addition to the PEN, the patients will be provided with updated patient diary, instructions for 
use and dosing instructions.  
Four weeks (+1 week) after PEN Visit 1, the patients will be required to come for PEN Visit 2 
(PEN V2).  This visit should occur on Day 4 (-1) post dose. Completed patient diary and used 
PENs should be returned at this visit. If necessary, the patient will be re-trained on the PEN.  
 
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For the following visits, patients will come to the clinic 4 days (-1) post dose every 3 months 
(±2 weeks), counting from PEN V1.  
On month 12, in addition to 4 (-1) post dose visit, one more visit will be conducted on dosing 
day.  
All first year visits assessments are detailed in section 5.4.1. 
Second year of LT-OLE_PEN period until marketing approval 
From the second year of the LT-OLE-PEN period and until marketing approval visits will be 
conducted every 3 months (months 3, 6, 9 and 12) ±2 weeks, on day 4 (-1) post injection.  
All visits assessments are detailed in section 5.4.2. 
The investigator may conduct unscheduled visits, for safety reasons, or any other reason per 
investigator medical judgment. 
Throughout the LT-OLE-PEN period, patients will continue to complete a patient diary at 
home to collect dosing and safety data.  
Figure 1: Overall Study Design 
 
4. Study Population 
In order to enroll up to 56 patients (allocated to 4 cohorts) into the Main Study, a sufficient 
number of pre-pubertal males aged 3 – 11 and females aged 3 – 10, with either isolated 
growth hormone deficiency (GHD) or GH insufficiency as a part of multiple pituitary hormone 
deficiency, will be recruited from 10 to 12 countries and 20 to 40 different centers. All centers 
will be specialized in the treatment and management of pediatric GHD.  
The study population will consist of 2 subgroups:  
1. Patients with peak GH level of
 ng/ml (up to 40 patients). 
2. Patients with peak GH level of 
 ng/ml and 
 ng/ml (up to 16 patients).   
Patients must meet all of the inclusion and none of the exclusion criteria to be eligible. Patient 
eligibility will be verified by the study Medical Monitor before randomization.  
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Patients who complete 12 months of treatment in the Main Study will be eligible to continue 
the treatment with MOD-4023 in a 12-month OLE period, and subsequent LT-OLE period and 
LT-OLE-PEN period until marketing approval in their country. The LT-OLE-PEN period will be 
extended on an annual basis until marketing approval in each country, subject to submission 
of an annual extension notification to the local EC/IRB. 
4.1 INCLUSION CRITERIA 
1. Pre-pubertal child aged ≥ 3 years old and not above 10 years for girls or 11 years for 
boys, with either isolated GHD, or GH insufficiency as part of multiple pituitary 
hormone deficiency. 
2. Confirmed diagnosis of GHD by two different GH provocation tests defined as a peak 
plasma GH level of 
ng/ml1, determined by central laboratory using a validated 
assay2. If the patient has already been tested locally and reserve samples that were 
taken at appropriate time-points are available, these will be reanalyzed by the central 
laboratory3. Historical tests missing the -30 minutes time point will be accepted. If no 
reserve samples are kept (only for tests performed prior to site initiation), then the 
details of the locally performed tests will be reviewed by the Coordinating 
Investigator: if the results cannot be accepted, the patient will undergo both 
stimulation tests during the screening period and the samples will be analyzed by the 
central laboratory. At least one of the two stimulation tests (and preferably both) will 
be analyzed by the central laboratory. If the patient requires sex hormone priming 
(due to the age), and both stimulation tests must be performed during the Screening 
(no historical samples kept, or test was without priming), it is recommended to 
perform stimulation tests in consecutive setting in one day, or in two consecutive 
days, to avoid priming the patient twice. Local historical tests without sex-steroid 
priming will not be accepted for patients that require sex steroid priming according to 
the protocol. 
3. Bone age (BA) must be not older than chronological age, and should be no greater 
than 9 years for girls and 10 years for boys. 
4. Without prior exposure to any r-hGH therapy. 
5. Impaired height and height velocity defined as: 
a. Height (HT) of at least 2.0 standard deviations (SD) below the mean height for 
chronological age (CA) and gender according to the standards of Prader et al. 
(1989) (HT SDS ≤ -2.0);  
b. Annualized height velocity (HV) below the 25th percentile for CA (HV <-0.7 SDS) 
and gender according to the standards of Prader et al. (1989). The interval 
                                                          
1 Patients will be divided into two subgroups:  Patients with peak serum GH levels after stimulation test 
 ng/ml and 
patients with peak serum GH levels after stimulation test 
 and 
 ng/ml. 
2 Insulin tolerance test, with cortisol response to hypoglycemia if insulin stimulation test is chosen / Arginine test / 
Clonidine test / Glucagon test (plus or without propranolol) / L-dopa plus propranolol. 
3 Central laboratory results will be used for eligibility confirmation. 
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between two height measurements should be at least 6 months, but should 
not exceed 18 months prior to inclusion. 
6. BMI must be within ±2 SD of mean BMI for the chronological age and sex according to 
the 2000 CDC standards (www.cdc.gov/growthcharts). 
7. Baseline IGF-I level of at least 1 SD below the mean IGF-I level standardized for age 
and sex (IGF-I SDS ≤ -1.0) according to the central laboratory reference values. 
8. Children with normal fundoscopy (ophthalmoscopy) at screening (without 
signs/symptoms of intracranial hypertension as assessed by fundoscopy). 
9. Children with multiple hormonal deficiencies must be on stable replacement therapies 
for other hypothalamo-pituitary-organ axes for at least 3 months and 6 months for 
thyroid replacement therapy prior to the first study drug administration. 
10. Normal 46 XX karyotype for girls. 
11. Written informed consent of the parent or legal guardian of the patient and assent of 
the patient for the Main Study and for the OLE. 
Patients who completed the first year of treatment in the Main Study are allowed to 
enter the OLE. Patients who were off treatment for over 
 after completing the 
main study (or during the OLE) are allowed to participate/continue in the OLE after 
completing additional testing. 
Specific inclusion criteria for Period V (LT-OLE –PEN): 
12. Continuing participation in the LT-OLE-PEN period.  
13. Signed consent and assent (when applicable) form for the LT-OLE-PEN period. 
14. Investigator’s assessment and confirmation of the patient anticipated compliance to 
the protocol procedures. 
15. Agreement to refrain from sexual activity during the study i.e. observe complete 
sexual abstinence as the only acceptable contraceptive measure in this study. 
4.2 EXCLUSION CRITERIA  
1. Children with past or present intracranial tumor growth as confirmed by an MRI scan 
(with contrast). 
2. History of radiation therapy or chemotherapy. 
3. Malnourished children defined as:  
a. Serum albumin below the lower limit of normal (LLN) according to the 
reference ranges of central laboratory, AND 
b. Serum iron below the lower limit of normal (LLN) according to the reference 
ranges of central laboratory, AND 
c. BMI < -2 SD for age and sex. 
4. Children with psychosocial dwarfism. 
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5. Children born small for gestational age (SGA = birth weight and/or birth length < -2 SD 
for gestational age). 
6. Presence of anti-hGH antibodies at screening. 
7. Any clinically significant abnormality likely to affect growth or the ability to evaluate 
growth, such as, but not limited to, chronic diseases like renal insufficiency, spinal cord 
irradiation, etc. 
8. Patients with diabetes mellitus.  
9. Patients with impaired fasting sugar (based on WHO; fasting blood sugar >110 mg/dl 
or 6.1 mmol/l after repeated blood analysis). 
10. Chromosomal abnormalities and medical “syndromes” (Turner’s syndrome, Laron 
syndrome, Noonan syndrome, Prader-Willi Syndrome, Russell-Silver Syndrome, SHOX 
mutations/deletions and skeletal dysplasias), with the exception of septo-optic 
dysplasia. 
11. Closed epiphyses. 
12. Concomitant administration of other treatments that may have an effect on growth 
such as anabolic steroids and methylphenidate for attention deficit hyperactivity 
disorder (ADHD), with the exception of hormone replacement therapies (thyroxin, 
hydrocortisone, desmopressin (DDAVP)).  
13. Children requiring glucocorticoid therapy (e.g. asthma) that are taking a dose of 
greater than 400 µg/d of inhaled budesonide or equivalents1 for longer than 1 month 
during a calendar year. 
14. Major medical conditions and/or presence of contraindication to r-hGH treatment. 
15. Known or suspected HIV-positive patient, or patient with advanced diseases such as 
AIDS or tuberculosis. 
16. Drug, substance, or alcohol abuse. 
17. Known hypersensitivity to the components of study medication. 
18. Other causes of short stature such as coeliac disease, hypothyroidism and rickets. 
19. The patient and/or the parent/legal guardian are likely to be non-compliant in respect 
to study conduct. 
20. Participation in any other trial of an investigational agent within 30 days prior to 
Screening. 
 
 
 
                                                          
1 Approximately equivalent doses: Fluticasone: 264 µg/d; Beclomethasone: 504 µg/d; Flunisolide 1,000 µg/d; 
Triamcinolone: 1,000 µg/d. 
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Specific exclusion criteria for Treatment Period V (LT-OLE-PEN): 
21. Unresolved drug related SAE from previous treatment periods. 
22. Diagnosis of cancer.  
23. Patients who, based on the investigator’s judgment, have a clinically significant or 
unstable medical or surgical condition that may preclude safe and complete study 
participation. Conditions may include cardiovascular, peripheral vascular, pulmonary, 
hepatic, renal, neurological and metabolic disease.  
24. Concomitant administration of other treatments that may have an effect on growth 
such as anabolic steroids or replacement of sex hormones, with the exception of ADHD 
drugs or hormone replacement therapies (thyroxin, hydrocortisone, desmopressin 
[DDAVP]).  
25. Unsatisfactory treatment response defined as improvement of height SDS of less than 
0.2 SDS in a 6-month treatment interval if dose increase at this time point is not 
feasible.  
4.3 PATIENT IDENTIFICATION 
Parents or legal guardians (as well as patients when relevant) will sign an informed 
consent/assent form prior to any study activities. Upon signature of informed consent, the 
patient will be allocated a study number comprised of two digits to identify the site and three 
digits to identify the patient. This number will identify the patient throughout the study. In 
the case of re-screening, a new unique number will be allocated. 
Additional informed consent/assent forms will be signed by parents or legal guardians before 
the patient continues to the OLE, LT-OLE and LT-OLE-PEN periods. 
4.4 SCREENING FAILURES 
Patients who fail to meet the entrance criteria at any stage during the screening period are 
defined as screen failures. All screen failures will be documented on the screening log, which 
documents the screening number, patient’s initials and reason(s) for screen failure. The 
screening log will be kept in the Investigators Site File.  
Screen failure patients will be withdrawn from the study and receive common practice 
performed at the site. Screen failures will be replaced to achieve enrolment of up to 56 
patients. 
If a patient is not eligible, the Investigator will record the reason for screening failure in the 
screening eCRF. Patients who have completed the Screening visit and are assessed as not 
eligible (screening failures) may be considered for re-screening at a later time, subject to the 
Principal Investigator's approval. 
4.5 RANDOMIZATION 
In the Main Study, patients will be randomized in a 1:1:1:1 ratio to one of 3 different MOD-
4023 weekly dose cohorts, or the Genotropin cohort. 
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The randomization will ensure that the study population will consist of: up to 40 patients with 
peak GH level of 
 ng/ml (up to 10 patients per cohort) and up to 16 patients with peak GH 
level of 
 ng/ml and 
 ng/ml (up to 4 per cohort); 
Randomization will be stratified by: 
1. Stimulation tests peak plasma GH level: patients with peak GH level 
 ng/ml and 
patients with peak GH level 
 ng/ml and 
0 ng/ml. 
2. Patients with peak plasma GH level 
 ng/ml will additionally be stratified by age 
(patients ≤7 years and patients > 7 years), height SDS minus target height SDS (distance 
from target height SDS ≤ -3 and > -3) and by peak GH levels (
 Patients 
with peak GH levels 
 can be enrolled in the study. However, these patients have a 
separate randomization list.  
The randomization will be performed via a web-based electronic data capture (EDC) system 
once all screening data is available and reviewed by the Medical Monitor.  
In the OLE period all patients will receive MOD-4023. Patients who received MOD-4023 in the 
Main Study will continue on the same dose. Patients treated with Genotropin will be switched 
to MOD-4023 and will be randomized to one of the three MOD-4023 cohorts. 
4.6 REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT 
Patients are free to discontinue their participation in the study at any time and without 
prejudice to further treatment. The Investigator must withdraw any patient from the study if 
that patient requests to be withdrawn, or if it is determined that continuing in the study would 
result in a significant safety risk to the patient.   
Patients withdrawn from the study after starting treatment with MOD-4023 will not be 
replaced. 
The patient's participation in this study may be discontinued due to the following reasons: 
1. Request from regulatory agency, sponsor, primary care physician, or Investigator. 
2. Patient (or parent/legal guardian) withdraws consent. 
3. Adverse event (AE): 
o Occurrence of a malignancy during the course of study. 
o Evidence of growth of an intracranial tumor during the course of the study. 
o Development of benign intracranial hypertension, if the symptoms return 
following resumption of drug (after a temporary stop). 
o Occurrence of AE's following which the Investigator or the patient wishes to 
discontinue treatment (such as, but not limited to, slipped capital femoral 
epiphysis, scoliosis, avascular necrosis and development of lipoatrophy, etc.).  
o Development of a serious inter-current critical illness. 
o Abnormal laboratory values that affect the patient’s safety (if discontinuation 
is considered necessary by the Investigator or the Sponsor Medical Monitor).  
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4. A severe adverse drug reaction (if discontinuation of study medication is desired by 
the patient or considered necessary by the investigator or the Sponsor Medical 
Monitor).  If the Investigator decision is made because of a SAE or clinically significant 
laboratory value, the Medical Monitor is to be alerted immediately. 
5. Intake of prohibited concomitant medication.  
6. Unsatisfactory treatment response defined as improvement of height SDS of less than 
0.2 SDS in a 6-month treatment interval if dose increase at this time point is not 
feasible (Applicable for periods I-IV)  
7. Patient is unwilling or unable to continue the study or is lost-to-follow-up. 
8. Patient is non-compliant with study procedures/ study protocol. 
9. Investigator decides that withdrawal from the study is in the best interest of the 
patient: 
o Occurrence of neutralizing antibodies which, in the opinion of the Investigator, 
requires discontinuation of the patient.   
o Lack of patient compliance (if discontinuation is desired or considered 
necessary by the investigator or the Sponsor Medical Monitor).  
o A serious protocol deviation that affects the patient’s safety or the accuracy 
and/or validity of data. 
10. Patient meets one of the exclusion criteria during the study. 
11. Any clinically significant change in the patient’s medical condition. 
 
Discontinuation rules specific to the LT-OLE-PEN period: 
12. Positive urine pregnancy test or confirmed pregnancy. In case of confirmed 
pregnancy, the study drug should be discontinued and the Medical Monitor be 
alerted immediately. 
13. When the patient reaches a growth rate of 
12 months (the interval between 
two height measurements should be at least 6 months). 
 
4.6.1 Handling of Withdrawals 
If a patient is withdrawn from the study either at his or her request (or parent/legal guardian 
request) or at the Investigator’s discretion or fails to return, every effort should be made to 
determine the reason. This information will be recorded on the patient’s case report form 
(eCRF). All patients who withdraw from the study prematurely, regardless of cause, should 
undergo all early termination assessments (see Section 5.5.2). It is vital to obtain follow-up 
data for any patient withdrawn because of an AE or abnormal laboratory test finding. In any 
case, every effort must be made to undertake safety follow-up procedures. 
 
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If withdrawal is caused by an AE that the Investigator considers possibly related to the study 
drug, it will be reported to the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) and the Sponsor. 
Any serious adverse event must be reported to the Sponsor by telephone and in writing within 
24 working hours, and to the IRB/IEC according to site’s regulations (see Section 7.2). The 
study may also be terminated by the Principal Investigator (PI) following consultation with the 
Sponsor. 
All follow-up information will be recorded in the patient's eCRF until full patient recovery is 
achieved, and the PI has stated that the patient is dismissed from the medical care. 
Subsequent follow-up will be documented in the patient's personal file. 
5. Study Procedures and Assessments 
No protocol related procedures, including the cessation of prohibited concomitant 
medications, should be performed before the parent or legal guardian provides a written 
informed consent and the patients provide an assent (a signed assent for children who can 
read). Study related events and activities including specific instructions, procedures, 
concomitant medications, dispensing of study drugs and descriptions of AEs should be 
recorded in the appropriate source documents and eCRF.  
All visit windows will be on scheduled days or -1 day (except visit 9 main study) for MOD-
4023 dose cohorts unless it's specified otherwise. The study flow chart provides the summary 
of assessments scheduled for each visit during the Main Study (Appendix 1), 12 months OLE 
study (Appendix 2), Long Term OLE (LT-OLE) period (Appendix 3) and Long Term OLE PEN (LT-
OLE-PEN) period (Appendix 4 and Appendix 5). At each visit after start of treatment, patients 
will be given enough Investigational or Comparator Product for treatment until the next visit, 
as well as patient diary cards to record injection pain or other adverse events and other 
comments. 
5.1 MAIN STUDY  
5.1.1 Screening 
Patients’ eligibility will be determined during the screening period lasting for up to 6 weeks 
and the following key tests and assessments must be performed and data obtained:  
1. Informed consent of parent/legal guardian and patient assent. 
2. Data on growth history and current anthropometric measurements (auxology). 
3. Body weight. 
4. Medical history, including a description of pituitary deficiencies, concomitant and 
previous medications. 
5. Overall health status assessments – complete physical examination, vital signs, and 
ECG. 
6. Pubertal status (according to Tanner stages). 
7. Bone age determination – with the method of Greulich-Pyle using a central bone age 
reader. 
8. Assessment of biochemical markers and stimulation tests: 
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 Two different GH stimulation (provocation) tests: 
Insulin tolerance test (with cortisol response to hypoglycemia if insulin stimulation 
test is chosen) / arginine test / clonidine test / glucagon test (with or without 
propranolol) / L-dopa plus propranolol. Sex hormone priming will be performed 
prior to GH-stimulation tests for girls over the age of 8 and for boys over the age 
of 10 (for a description of the GH stimulation tests and sex hormone priming, refer 
to Appendix 7). If the patient has already been tested locally and reserve samples 
that were taken at appropriate time-points are available, these will be reanalyzed 
by the central laboratory1. Historical tests missing the -30 minutes time point will 
be accepted. If no reserve samples are kept (only for tests performed prior to site 
initiation), then the details of the locally performed tests will be reviewed by the 
Coordinating Investigator: if the results cannot be accepted, the patient will 
undergo both stimulation tests during the screening period and the samples will 
be analyzed by the central laboratory. At least one of the two stimulation tests 
(and preferably both) will be analyzed by the central laboratory. 
 Standard Dose Short ACTH test (only if the patient was not assessed previously for 
the hypothalamus-pituitary-adrenal axis, or if there are clinical or laboratory signs 
of adrenal insufficiency). 
 Assessment of insulin-like growth factor (IGF-I) and IGFBP-3 levels. 
 Assessment of anti-hGH antibody levels. 
 Assessments of routine safety biochemistry and hematology parameters. 
 Assessment of hormones (TSH, free T4, free T3 and cortisol). 
 Assessment of glucose metabolism (fasting insulin, glucose, and HbA1C). 
 Parameters of lipid metabolism (with Lp(a) lipoprotein).  
9. Head MRI performed in the 6 months prior to the trial.   
10. Fundoscopy. 
11. Assessment of karyotype in girls. 
12. SHOX evaluation in all patients. 
Key data and all test results obtained during the screening will be reviewed by the Sponsor 
Medical Monitor to verify eligibility prior to randomization of each patient. Following 
confirmation of eligibility by the Principal Investigator, the patients will be randomized to one 
of the dose groups.  
 
5.1.2 Visit 1 – All Patients 
This visit will take place in the medical center for all patients on the day of the first dose. The 
following procedures will be performed (prior to dosing for MOD-4023 cohorts): 
1. Physical examination including height and weight;  
                                                          
1 Central laboratory results will be used for eligibility confirmation. 
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2. Vital signs (within one hour prior to dosing);  
3. AEs, local tolerability; 
4. Concomitant medications;  
5. Parameters of glucose metabolism (fasting glucose, insulin, and HbA1C);  
6. Other hormonal levels (TSH,  free T4,  free T3, cortisol);  
7. Baseline antigenicity (anti MOD-4023 antibodies for cohort 1-3 patients) and anti hGH 
for Genotropin patients   
8. Routine safety biochemistry and hematology;  
9. Parameters of lipid metabolism (with Lp(a) lipoprotein);  
10. IGF-I and IGFBP-3 serum levels, baseline MOD-4023 (cohorts 1-3) and Genotropin 
(cohort 4) levels; 
11. Training for parents or legal guardians on drug administration.  
Patients allocated to the MOD-4023 cohorts will be administered the first dose by the study 
staff in the morning hours, after completion of all of the above.  
The following procedures will be performed after dosing (for MOD-4023 cohorts): 
1. Vital signs: 30 min, 2 hours (±20 min) and 4 hours (±20 min) post dose; 
2. Injection site reaction: 30 min and 4h (±20 min) after injection. 
Patients allocated to the Genotropin cohort will be administered the first dose at home in 
the evening hours. 
 
5.1.3 PK/PD Visits (V2 - Week 2; V3 - Week 4; V4 -Week 6) 
All patients randomized to receive one of the three MOD-4023 doses will start treatment for 
2 weeks with the low MOD-4023 dose (0.25 mg protein/kg). Based on the patient's dose 
allocation, this will be followed by a dose increase to the next dose level every two weeks 
until the final allocated dose is reached (see Table 5). 
Subsequent to the second dose administration of the targeted dose, limited (population 
based) PK and PD sampling will be taken (according to Table 6 and Table 7).  
Patients allocated to a MOD-4023 dose cohort (cohorts 1-3) will be randomized within the 
cohort into one of three blocks and undergo limited PK/PD sampling (4 samples per patient 
over a period of one week), according to Table 6 below. 
 
 
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TABLE 6: MOD-4023 POPULATION PK AND PD SAMPLING SCHEME 
Visit (V2, V3, V4) 
a 
b 
c 
d 
e 
f 
g 
Time after dosing(h)/ 
Block number 
0h 
6h 
12h 
24h 
48h 
72h 
96h 
120h 
168h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
 
Patients allocated to the Genotropin dose cohort (cohort 4) will be randomized within the 
cohort into one of three blocks and undergo limited PK/PD sampling (4 samples per patient 
over a period of 24 hours), according to Table 7 below. 
TABLE 7: GENOTROPIN POPULATION PK AND PD SAMPLING SCHEME (VISIT 2) 
Time after dosing(h)/ 
Block number 
0h 
1h 
2h 
4h 
6h 
12h 
16h 
20h 
24h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
 
This blood sampling schedule may require hospitalization for some of the patients due to 
convenience reasons.  
During the first 6 weeks of the study, the visit schedule will be as follows (see scheme in 
Appendix 1: Schedule of Assessments – Main Study): 
5.1.3.1 Week 2: V2 (a-h) – MOD-4023 Dose Cohorts 
a. Dose Cohort 1: Patients allocated to dose cohort 1 will perform Visit 2 (PK/PD following 
the 2nd dose of MOD-4023 at target dose level) as follows: 
Visit  
a 
b 
c 
d 
e 
f 
g 
Time after dosing(h)/ 
Block number 
0h 
6h 
12h 
24h 
48h 
72h 
96h 
120h 
168h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
On day of dosing (V2a), all patients allocated to dose cohort 1 will arrive at the medical center 
in the morning hours (irrespective of the allocation to blood sampling blocks).  
The following procedures will be performed prior to dosing: 
1. Physical examination;  
2. Vital signs (within one hour prior to dosing);  
3. AEs, local tolerability;  
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4. Concomitant medications;  
5. Parameters of glucose metabolism (fasting glucose, insulin); 
6. IGF-I and IGFBP-3 serum levels (for patients in block 1);  
7. MOD-4023 serum levels (for patients in block 1). 
The following procedures will be performed after dosing: 
1. IGF-I and IGFBP-3 serum levels: (6h post-dose for patients in block 2 and 12h post-
dose for patients in block 3);  
2. MOD-4023 serum levels: (6h post-dose for patients in block 2 and 12h post-dose for 
patients in block 3); 
3. Vital signs: 30 min, 2 hours (±20 min), and 4 hours (±20 min) post-dose; 
4. Injection site reaction: 30 min and 4h (±20 min) after injection. 
In addition, the following procedures will be performed upon subsequent blood withdrawals 
throughout the week:  
1. Vital signs (prior to blood sampling);  
2. AEs and local tolerability (prior to blood sampling);  
3. Concomitant medications (prior to blood sampling); 
4. IGF-I and IGFBP-3 serum levels;  
5. MOD-4023 serum levels. 
 
b. Dose Cohorts 2+3: Patients allocated to dose cohorts 2 and 3 will perform visit 2h (4 days 
after dosing). The following procedures will be performed: 
1. Physical examination;  
2. Vital signs;  
3. AEs and local tolerability;  
4. Concomitant medications;  
5. Parameters of glucose metabolism (fasting glucose, insulin); 
6. IGF-I and IGFBP-3 serum levels;  
7. MOD-4023 serum levels. 
5.1.3.2 Week 4: V3 (a-h) – MOD-4023 Dose Cohorts 
a. Dose Cohort 2: Patients allocated to dose cohort 2 will perform Visit 3 - PK/PD following 
the 4th dose of MOD-4023 (2nd dose at target dose level) as follows: 
 
 
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Visit  
a 
b 
c 
d 
E 
f 
g 
Time after dosing(h)/ 
Block number 
0h 
6h 
12h 
24h 
48h 
72h 
96h 
120h 
168h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
 
On the day of dosing (V3a), all patients allocated to dose cohort 2 will arrive at the medical 
center in the morning hours (irrespective of the allocation to blood sampling blocks).  
The following procedures will be performed prior to dosing: 
1. Physical examination;  
2. Vital signs (within one hour prior to dosing);  
3. AEs, local tolerability;  
4. Concomitant medications;  
5. Parameters of glucose metabolism (fasting glucose, insulin); 
6. IGF-I and IGFBP-3 serum levels (for patients in block 1);  
7. MOD-4023 Serum levels (for patients in block 1). 
The following procedures will be performed after dosing: 
1. IGF-I and IGFBP-3 serum levels: (6h post-dose for patients in block 2 and 12h post-
dose for patients in block 3);  
2. MOD-4023 serum levels: (6h post-dose for patients in block 2 and 12h after dose for 
patients in block 3); 
3. Vital signs: 30 min, 2 hours (±20 min), and 4 hours (±20 min) post-dose; 
4. Injection site reaction: 30 min and 4h (±20 min) after injection. 
In addition, the following procedures will be performed upon subsequent blood withdrawals 
throughout the week:  
1. Vital signs (prior to blood sampling);  
2. AEs and local tolerability (prior to blood sampling);  
3. Concomitant medications (prior to blood sampling); 
4. IGF-I and IGFBP-3 serum levels;  
5. MOD-4023 serum levels. 
 
b. Dose Cohort 1 and Dose Cohort 3 (V3h): Patients allocated to dose cohort 1 will skip Visit 
3 and patients allocated to dose cohort 3 will perform visit 3h (4 days after dosing). 
The following procedures will be performed: 
1. Physical examination;  
2. Vital signs;  
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3. AEs and local tolerability;  
4. Concomitant medications;  
5. Parameters of glucose metabolism (fasting glucose, insulin); 
6. IGF-I and IGFBP-3 serum levels;  
7. MOD-4023 serum levels. 
 
5.1.3.3 Week 6: V4 (a-h) - MOD-4023 Dose Cohorts 
a. Dose Cohort 3: Patients allocated to dose cohort 3 will perform Visit 4 - PK/PD following 
the 6th dose of MOD-4023 (2nd dose at target dose level) as follows: 
 
Visit  
a 
b 
c 
d 
e 
f 
g 
Time after dosing(h)/ 
Block number 
0h 
6h 
12h 
24h 
48h 
72h 
96h 
120h 
168h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
 
On the day of dosing (V4a), all patients allocated to dose cohort 3 will arrive at the medical 
center in the morning hours (irrespective of the allocation to blood sampling blocks).  
The following procedures will be performed prior to dosing: 
1. Physical examination;  
2. Vital signs (within one hour prior to dosing);  
3. AEs, local tolerability;  
4. Concomitant medications;  
5. Parameters of glucose metabolism (fasting glucose, insulin, and HbA1C); 
6. Routine safety biochemistry, hematology, and urinalysis parameters;  
7. IGF-I and IGFBP-3 serum levels (for patients in block 1);  
8. MOD-4023 Serum levels (for patients in block 1). 
The following procedures will be performed after dosing: 
1. IGF-I and IGFBP-3 serum levels: (6h post-dose for patients in block 2 and 12h post-
dose for patients in block 3);  
2. MOD-4023 serum levels: (6h post-dose for patients in block 2 and 12h post-dose for 
patients in block 3); 
3. Vital signs: 30 min, 2 hours (±20 min), and 4 hours (±20 min) post-dose; 
4. Injection site reaction: 30 min and 4h (±20 min) after injection. 
In addition, the following procedures will be performed upon subsequent blood withdrawals 
throughout the week:  
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1. Vital signs (prior to blood sampling);  
2. AEs and local tolerability (prior to blood sampling);  
3. Concomitant medications (prior to blood sampling); 
4. IGF-I and IGFBP-3 serum levels;  
5. MOD-4023 serum levels. 
 
b. Dose Cohorts 1 and 2: Patients allocated to dose cohort 1 and 2 will perform visit 4h (4 
days after dosing) 
The following procedures will be performed: 
1. Physical examination;  
2. Vital signs;  
3. AEs and local tolerability;  
4. Concomitant medications;  
5. Parameters of glucose metabolism (fasting glucose, insulin, and HbA1C); 
6. Routine safety biochemistry, hematology, and urinalysis parameters;  
7. IGF-I and IGFBP-3 serum levels;  
8. MOD-4023 serum levels. 
 
5.1.3.4 Week 2 and 6: Visits 2 and 4 for Genotropin Cohort (Cohort 4) 
Patients allocated to Cohort 4 will perform Visits 2 and 4. Cohort 4 patients will skip Visit 3 
(week 4). 
Patients allocated to the Genotropin cohort (cohort 4) will return to the medical center for 
visits 2 and 4 during the 2nd and 6th week of treatment. The following procedures will be 
performed (prior to dosing if dosing is done at the medical center):  
1. Physical examination;  
2. Vital signs;  
3. AEs, local tolerability;  
4. Concomitant medications; 
5. Parameters of glucose metabolism - fasting glucose, insulin, and HbA1C (V4 only); 
6. Routine safety biochemistry, hematology, and urinalysis parameters (week 6 only – 
visit 4); 
7. IGF-I and IGFBP-3 serum levels;  
8. Genotropin serum levels. 
In addition, after the 8th Genotropin dose (at the beginning of week 2 of dosing) the patients 
allocated to the Genotropin cohort will undergo limited PK/PD sampling according to Table 7 
above. Patients allocated to the Genotropin dose cohort (cohort 4) will be randomized within 
the cohort into one of three blocks and undergo limited PK/PD sampling (4 samples per 
patient over a period of 24 hours), according to following scheme: 
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Time after dosing(h)/ 
Block number 
0h 
1h 
2h 
4h 
6h 
12h 
16h 
20h 
24h 
Block 1 
 
 
 
 
 
 
 
 
 
Block 2 
 
 
 
 
 
 
 
 
 
Block 3 
 
 
 
 
 
 
 
 
 
 
5.1.4 Monthly Follow Up Visits: Visit 5 (wk10), Visit 6 (wk14), Visit 7 (wk18), Visit 8 (wk22) 
- All Patients 
These visits will be performed on a monthly basis for all patients. For patients allocated to 
MOD-4023 dose cohorts, the visit will take place 4(-1) days after dosing. For patients allocated 
to Genotropin cohort, the visit will take place on any day during the dosing week.  
 
The following assessments will be performed: 
1. Physical examination and vital signs; 
2. AEs, local tolerability, and concomitant medications; 
3. Parameters of glucose metabolism: fasting glucose, insulin (every visit), HbA1c (only 
visit 6); 
4. Other hormonal levels: TSH,  free T4, free  T3, cortisol (only visit 6); 
5. Routine safety biochemistry, hematology, and urinalysis parameters; 
6. Patient’s height; 
7. Patient’s weight; 
8. Parameters of lipid metabolism (with Lp(a) lipoprotein at visit 6); 
9. PD: IGF-I and IGFBP-3 serum levels; 
10. MOD-4023 (cohort 1-3) and Genotropin (cohort 4) serum levels; 
11. Adjustment of dose to patient’s weight (only visit 6). 
 
5.1.5 Visit 9 (wk23) – Only MOD-4023 Dose Cohorts 
This visit will take place exactly one week (7 days) after MOD-4023 dosing, prior to 
administration of the next dose. If patient is unable to attend the visit, the entire visit can be 
postponed by one week in order to obtain pre-dose levels of MOD-4023 and IGF-I+IGFBP-3.  
 
The following assessments will be performed prior to MOD-4023 dosing: 
1. Physical examination and vital signs (prior to blood sampling); 
2. AEs, local tolerability, and concomitant medications (prior to blood sampling); 
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3. PD: IGF-I and IGFBP-3 serum levels (prior to dosing); 
4. MOD-4023 (cohort 1-3) serum levels (prior to dosing); 
5. MOD-4023 dosing. 
 
The following procedures will be performed after MOD-4023 dosing: 
1. Vital signs: 30 min, 2 hours (±20 min), and 4 hours (±20 min) post dose. 
2. Injection site reaction: 30 min and 4h (±20 min) after injection. 
 
5.1.6 Visit 10 (wk26) – All Cohorts 
The following assessments will be performed: 
1. Physical examination and vital signs; 
2. AEs, local tolerability, and concomitant medications; 
3. Parameters of glucose metabolism: fasting glucose, insulin, HbA1c;  
4. Other hormonal levels: TSH,  free T4,  free T3, cortisol;  
5. Antigenicity: anti MOD-4023 antibodies/anti-hGH antibodies;  
6. Routine safety biochemistry, hematology and urinalysis parameters; 
7. Patient’s height; 
8. Patient’s weight; 
9. Fundoscopy; 
10. Parameters of lipid metabolism (with Lp(a) lipoprotein); 
11. Pubertal status;  
12. PD: IGF-I and IGFBP-3 serum levels; 
13. MOD-4023 (cohort 1-3) and Genotropin (cohort 4) levels; 
14. Adjustment of dose to patient’s weight.  
 
After completion of visit 10, each patient will be assessed separately, for the growth progress 
and overall safety. If the growth meets pre-determined criteria1, and there are no safety 
concerns, the patient will continue with the same dose. 
 
5.1.7 V11 (month 9), V12 (month 12) – All Cohorts – PERIOD II 
This period will consist of 2 visits at Months 9 and 12. Month 9 visit will be conducted on day 
4(-1) after MOD-4023 dosing for MOD-4023 dose cohorts, and any day during the week for 
                                                          
1 Delta height SDS at least 0.2 
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Genotropin cohorts. Month 12 visit (final visit of the Main Study) will be conducted 4 days (-
1) after the last MOD-4023 dose for MOD-4023 cohorts and the day after the last Genotropin 
dose for Genotropin cohorts. Period II assessments will include the following at each visit: 
1. Physical examination and vital signs; 
2. AEs, local tolerability, and concomitant medications; 
3. Parameters of glucose metabolism: fasting glucose, insulin, and HbA1c; 
4. Other hormonal levels: TSH,  free T4,  free T3, cortisol; 
5. Antigenicity: anti MOD-4023 antibodies/anti-hGH antibodies (only month 12 visit); 
6. Routine safety biochemistry, hematology, and urinalysis parameters; 
7. Patient’s height; 
8. Patient’s weight; 
9. Parameters of lipid metabolism at both visits (with Lp(a) lipoprotein at month 12 only);  
10. Pubertal status (only month 12 visit); 
11. PD: IGF-I and IGFBP-3 serum levels; 
12. MOD-4023 (cohort 1-3) and Genotropin (cohort 4) serum levels;  
13. Fundoscopy (Month 12 only or earlier if there are signs or symptoms indicative of 
benign intracranial hypertension); 
14. ECG (Month 12 only); 
15. Bone age (Month 12 only). 
At the end of Period II, a formal data analysis of all endpoints will be performed. 
 
5.2 12-MONTH OPEN LABEL EXTENSION (OLE)   PERIOD III 
Visits (Visit 1 OLE/Day 1, Visit 2 OLE/Month 1, Visit 3 OLE/Month 3, Visit 4 OLE/Month 6, 
Visit 5 OLE/Month 9 and Visit 6 OLE/Month 12) 
Patients who completed 12 months of treatment in the Main Study will be eligible to continue 
to a 12-month OLE period. Patients who received MOD-4023 in the Main Study (initial 12 
months of active treatment) will continue to receive MOD-4023; dose will be same as in the 
Main Study. For these patients, study visits will take place every 3 months, starting at visit 3 
OLE.  
For these patients, V12 of the Main study will be considered as the first visit of the OLE phase 
in which the patient will receive the study drug for the next 3 months of the OLE.  
Patients who received active comparator, Genotropin, during the Main Study, will be 
switched to MOD-4023 (will be randomized to one of the three MOD-4023 cohorts). Their 
visit schedule during the first three months of the OLE will be as follows: Visit 1 OLE for the 
first MOD-4023 injection and training of MOD-4023 administration (week 52 +1 day, which is 
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on Month 12 visit of the Main Study), Visit 2 OLE will be 28 days + 4 (-1) days after the first 
MOD-4023 injection and Visit 3 OLE will be 3 months after first MOD-4023 injection (i.e. 13±2 
weeks + 4 (-1) days after the first MOD-4023 injection). All subsequent visits will be every 
three months (i.e. every 13±2 weeks, 4 days (or 3 days, when necessary) after dosing).  
Patients who are off treatment for over 
 between the last MOD-4023/Genotropin 
dose in the Main Study and the first OLE dose (2nd year) will be allowed to continue into the 
OLE period after the following tests will be conducted:  
 Parameters of glucose metabolism: fasting glucose, insulin, and HbA1c  
 Antigenicity: anti MOD-4023 antibodies (only Genotropin group – baseline for future 
tests) 
 Routine safety laboratory (biochemistry, hematology, and urinalysis)  
 PD: IGF-I and IGFBP-3 baseline serum levels  
 MOD-4023 baseline serum levels 
 
In the 12-month OLE visit (the second year of treatment) the following assessments will be 
included at each visit (unless otherwise specified): 
 Adjustment of dose for weight 
 local tolerability 
 Physical examination and vital signs; 
 AEs, and concomitant medications; 
 Parameters of glucose metabolism: fasting glucose, insulin, and HbA1c; 
 Other hormonal levels: TSH,  free T4,  free T3, cortisol; 
 Antigenicity: anti MOD-4023 antibodies (only once every 6 months); 
 Routine safety laboratory (biochemistry, hematology, and urinalysis);  
 Patient’s height; 
 Patient’s weight; 
 Parameters of lipid metabolism; 
 Lp(a) lipoprotein (only once at Month 12 OLE);  
 Pubertal status (only once at Month 12 OLE);  
 PD: IGF-I and IGFBP-3 serum levels; 
 MOD-4023 serum levels;  
 Fundoscopy (once at Month 12 OLE, or earlier if there are signs or symptoms indicative 
of benign intracranial hypertension); 
 ECG (only once at Month 12 OLE)  
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 Bone age (only once at Month 12 OLE);  
 Dispensing of drug and return of used drug  
 Patient diary dispensing and return of completed patient diaries  
5.3 LONG-TERM OPEN LABEL EXTENSION (LT-OLE) PERIOD IV 
LT-OLE starts from the 2nd year of OLE (i.e. the 3rd year of treatment in the study) and until 
transition to PEN (LT-OLE-PEN period). 
 
Patients in Cohorts 1 and 2 entering the LT-OLE will be switched to the highest MOD-4023 
dose 0.66 mg/kg/week after signing a separate informed consent (unless a different medical 
decision was made). In case patients from Cohorts 1 and 2 who have already entered the 2nd year 
of OLE, the switch to 0.66 mg/kg/week will be done at their next study visit after signing a 
separate informed consent. Patients in Cohort 3 will continue receiving 0.66 mg/kg/week.  
All patients switching to 0.66 mg/kg/week will be required to attend a site visit after 3 months 
(on day 3 or 4 post-dosing) for the following evaluations: physical examination and vital signs, 
patient’s height and weight, concomitant medications, glucose metabolism parameters 
(fasting glucose, insulin and HbA1c), antigenicity (anti MOD-4023 antibodies), routine safety 
laboratory (biochemistry, hematology and urinalysis), IGF-I and IGFBP-3 serum levels.   
In case the switch to the 0.66 mg/kg/week dose is on month 9 visit, the 3 months follow up 
visit will take place on dosing day. Additional visit will take place 3-4 post dosing in which only 
IGF-I, IGFBP-3 and MOD-4023 serum levels will be measured.  
In general, if the IGF-I value will be above +2.0 SDS, please refer to section 5.8.3.  
Patients who are off treatment for over 
 between the last MOD-4023 in the OLE period 
and the first LT-OLE dose (3rd year) will be allowed to continue into the LT-OLE period after 
the following tests and assessments will be conducted:  
 Parameters of glucose metabolism: fasting glucose, insulin, and HbA1c  
 Antigenicity: anti MOD-4023 antibodies  
 Routine safety laboratory (biochemistry, hematology, and urinalysis)  
 PD: IGF-I and IGFBP-3 baseline serum levels  
 MOD-4023 baseline serum levels 
 
The following assessments will be conducted once every 3 months (13 ±2 weeks) during LT-
OLE (on day 4 (-1) post dose): 
 Auxology measurements: Actual height measured on a calibrated stadiometer and 
body weight measurement; 
 Adjustment of dose for weight; 
 AEs; 
 Local tolerability; 
 Concomitant medication; 
 Dispensing of drug and return of used drug  
 Patient diary dispensing and return of completed diaries   
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The following assessments will be conducted every 6 months (±2 weeks) on day 4 (-1) post 
dose on top of the 3 month assessments: 
 
 IGF-I, IGFBP-3 and MOD-4023 serum levels. 
 Once a year, patients will be required to attend another visit on dosing day (in addition 
to the semi-annual visit on day 3 or 4 post dosing) where the following additional 
assessments will be conducted (on top of the three and six months assessments):Anti-
MOD-4023 antibodies; 
 MOD- 4023 serum levels  
 Physical examination; 
 Vital signs; 
 Parameters of glucose metabolism (fasting glucose, fasting insulin and HbA1c); 
 Other hormonal levels (TSH,  free T4,  free T3, cortisol); 
 Parameters of lipid metabolism; 
 Routine safety laboratory (biochemistry, hematology and urinalysis); 
 Pubertal status;  
 ECG; 
 Bone age; 
 For males above the age of 13 - LH, FSH and testosterone. For females above the age 
of 12 - LH, FSH and estradiol; 
 Fundoscopy (if indicated). 
  
5.4 LONG-TERM OPEN LABEL EXTENSION PEN (LT-OLE-PEN) PERIOD V- UNTIL MARKETING APPROVAL 
5.4.1 First year of LT-OLE-PEN period 
5.4.1.1 PEN Visit 1 (PEN V1) – Dosing Day 
Upon regulatory clearance of protocol Amendment 9 and sponsor's written approval, patients 
will be requested to come to the clinic for a visit named PEN Visit 1 (PEN V1). PEN V1 will 
occur on a planned dosing day, sites should make any effort to schedule this visit according 
to the current visit schedule and consider to combine visits in order to minimize the burden 
on the patients. Patients should arrive at the clinic prior to dosing. The visit will serve as 
‘baseline’ to the LT-OLE-PEN period, in which the consent/assent form for the LT-OLE-PEN 
period will be signed. Patients should return used and unused vials that were dispensed 
during the study and kept at patient home. Site staff should remind the patients to bring all 
vials dispensed during the study (used and unused) before the visit.   
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Prior to rolling over into the LT-OLE-PEN period, specific period inclusion/exclusion criteria 
should be assessed (as specified in section 4.1). In addition changes in status of ongoing AEs 
or concomitant medications since completion of the LT-OLE period IV.  
During PEN V1, the patients will be trained on the use of the PEN, the PEN will be dispensed, 
and the first PEN dose will be administered at the clinic by the parents/legal guardians. Patient 
will continue his/her treatment with the same dose level as before the switch to PEN. Patients 
will be provided with updated patient diary, instructions for use and dosing instructions. 
The following will be done during PEN V1, pre dose: 
 Auxology measurements (actual height measured on calibrated stadiometer); 
 Body weight measurement; 
 Adjustment of dose for weight; 
 AEs; 
 Urine pregnancy test for females of child bearing potential (In case of positive result 
please refer to section 7.4); 
 Local tolerability; 
 Concomitant medication;  
 Dispensing of drug;  
 Return of all used and unused vials; 
 IGF-I, IGFBP-3 and MOD-4023 serum levels (PK); 
 Anti MOD-4023 antibodies (ADA); 
 Physical examination; 
 Vital signs; 
 Parameters of glucose metabolism (fasting glucose, fasting insulin and HbA1c);  
 Routine safety laboratory (biochemistry, hematology and urinalysis);   
 Other hormonal levels (TSH,  free T4 and cortisol);  
 Lipid metabolism parameters; 
 Pubertal status; 
 For males above the age of 13 - LH, FSH and testosterone. For females above the age 
of 12 - LH, FSH and estradiol; 
 Training on PEN; 
 Fundoscopy- if required; 
 Bone age assessment - Will be performed in case the previous assessment was done 
more than 6 months prior to this visit.  
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 Provide patient diary and return of completed diaries; 
 
5.4.1.2 PEN Visit 2 (PEN V2) - Week 4 (+1 weeks) counting from PEN V1   
Patients will come for PEN Visit 2 (PEN V2) 4 weeks (+1 week) following PEN V1, day 4 (-1) 
post dose.  Patients will bring back the used PEN and the completed patient diary at this 
visit. In addition, if necessary, the patient will be re-trained on the PEN until the site and the 
patient are confident.  
During PEN V2 the following will be conducted: 
 Body weight measurement; 
 Adjustment of dose for weight; 
 AEs; 
 Urine pregnancy test for females of child bearing potential (In case of positive result 
please refer to section 7.4); 
 Local tolerability; 
 Concomitant medication;  
 Dispensing and return of drug;  
 IGF-I, IGFBP-3 and MOD-4023 serum levels (PK); 
 Anti MOD-4023 antibodies (ADA); 
 Physical examination; 
 Vital signs; 
 Fundoscopy (if required);  
 Provide patient diary and return of completed diaries; 
 Training on PEN (if required). 
 
Following routine visits schedule per patient is described in Appendix 4 and Appendix 5. The 
patients should follow the study specific visit assessments.  
Following the completion of PEN V1 and PEN V2 patients will come to the clinic 4 days (-1 day) 
post dose every 3 months, (±2 weeks), counting from PEN V1. 
  
5.4.1.3 Months 3 and 6 (±2 week) visits counting from PEN V1  
The following will be conducted on these visits:  
 Auxology measurements (actual height measured on calibrated stadiometer);  
 Body weight measurement;  
 Adjustment of dose for weight; 
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 AEs; 
 Urine pregnancy test for females of child bearing potential (in case of positive result 
please refer to section 7.4); 
 Local tolerability; 
 Concomitant medication; 
 Dispensing of drug and return of used drug  
 IGF-I and IGFBP-3; 
 MOD-4023 serum levels;Anti-MOD-4023 antibodies; 
 Fundoscopy (if required); 
 Physical examination and vital signs; 
 Parameters of glucose metabolism (fasting glucose, fasting insulin and HbA1c);  
 Routine safety laboratory (biochemistry, hematology and urinalysis);   
 Other hormonal levels (TSH,  free T4 and cortisol);  
 Lipid metabolism parameters; 
 Pubertal status; 
 Provide patient diary and return of completed diaries; 
 
5.4.1.4 Month 9 (±2 week) visit counting from PEN V1  
The following will be conducted at this visit:  
 Auxology measurements (actual height measured on calibrated stadiometer); 
 Body weight measurement; 
 Adjustment of dose for weight; 
 AEs; 
 Urine pregnancy test for females of child bearing potential (in case of positive result 
please refer to section 7.4); 
 Local tolerability; 
 Concomitant medication; 
 Dispensing of drug and return of used drug;  
 Provide patient diary and return of completed diaries; 
 IGF-I and IGFBP-3; 
 MOD-4023 serum levels; 
 Anti-MOD-4023 antibodies; 
 Fundoscopy (if required); 
 Physical examination and vital signs; 
 Pubertal status; 
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5.4.1.5 Months 12 (±2 week) visit counting from PEN V1  
On month 12 (±2 weeks) post PEN V1 two visit will be conducted, one on day 4 (-1) post 
injection and one on dosing day. 
 
On month 12 (±2 weeks) on day 4 (-1) post injection IGF-I and IGFBP-3 will be assessed.  
On month 12 (±2 weeks) on dosing day, the following will take place (pre dose): 
 Auxology measurements (actual height measured on calibrated stadiometer); 
 Body weight measurement; 
 Adjustment of dose for weight; 
 AEs; 
 Urine pregnancy test for females of child bearing potential (in case of positive result 
please refer to section 7.4); 
 Local tolerability; 
 Dispensing of drug and return of used drug;  
 Concomitant medication; 
 Anti-MOD-4023 antibodies; 
 MOD- 4023 serum levels;  
 Physical examination; 
 Vital signs; 
 Parameters of glucose metabolism (fasting glucose, fasting insulin and HbA1c); 
 Other hormonal levels (TSH, free T4, cortisol); 
 Parameters of lipid metabolism; 
 Routine safety laboratory (biochemistry, hematology and urinalysis); 
 Pubertal status;  
 ECG around Tmax (7-12 hours post dosing). In case not possible to conduct the ECG 
around Tmax at this 12 month visit, it can be performed on month 12 ± 3 weeks (7-12 
hours post dose) 
 Bone age; 
 For males above the age of 13 - LH, FSH and testosterone. For females above the age 
of 12 - LH, FSH and estradiol; 
 Fundoscopy (if required); 
 Provide patient diary and return of completed diaries 
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5.4.2 Second year of LT-OLE-PEN until marketing approval  
From the second year of the LT-OLE-PEN period and until marketing approval, visits will be 
conducted every 3 months, ±2 weeks (months 3, 6, 9 and 12) on day 4 (-1) post injection.  
The following will be conducted at each visit:  
 Auxology measurement (actual height measured on calibrated stadiometer); 
 Body weight measurement; 
 Adjustment of dose for weight; 
 AEs; 
 Local tolerability; 
 Concomitant medications; 
 Dispensing of drug and return of used drug;  
 Fundoscopy (if required); 
 IGF-I and IGFBP-3; 
 Physical examination and vital signs; 
 Urine pregnancy test for females of child bearing potential (in case of positive result 
please refer to section 7.4); 
 Pubertal status; 
 Provide patient diary and return of completed diaries; 
 
In addition, the following will be conducted every 6 months, on month 6 and month 12 
visits: 
 MOD-4023 serum levels; 
 Anti MOD-4023 antibodies; 
 Parameters of glucose metabolism (fasting glucose, fasting insulin and HbA1c); 
 other hormonal levels (TSH, free T4, cortisol); 
 Parameters of lipid metabolism; 
 Routine safety laboratory (biochemistry, hematology and urinalysis); 
 
In addition, the following will be conducted once a year, on 12 month visit:  
 ECG; 
 Bone age; 
 For males above the age of 13 - LH, FSH and testosterone. For females above the age 
of 12 - LH, FSH and estradiol 
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Throughout the LT-OLE-PEN period, patients will continue to complete a patient diary at 
home to collect dosing and safety data.  
 
If splitting the dose between 2 different injections, the Patient should complete new diary 
page for each PEN or injection: 
 
Weekly dose 
Number of patient 
Diary pages 
1 injection 
1 
2 injections from the 
same pen 
2 
2 injections from 2 
different pens 
2 
 
The investigator may conduct unscheduled visits, for safety reasons, or any other reason per 
investigator medical judgment. 
 
5.5 UNSCHEDULED AND EARLY TERMINATION VISITS 
5.5.1 Unscheduled Visits  
Unscheduled visits are those visits that will occur between regularly scheduled visits and will 
be performed in order to assess a previously noted adverse event, abnormal/alarming 
laboratory values, and or clinical findings. In such cases, the patient’s parent or legal guardian 
will be contacted via telephone to arrange an unscheduled visit to assess the noticed 
abnormalities. Only focused assessments are foreseen for these visits and there will be no 
need to collect very extensive additional laboratory or other safety and efficacy data. If blood 
collection is required, this should in principle not exceed the volume foreseen for the 
assessment of questionable/targeted parameter(s) and/or should not be over 50% of volume 
foreseen for the routine safety panel at regularly scheduled visits. If urgent or more 
convenient for the patient, a local laboratory can be used.  
According to point 4.5.4 of GCP-ICH, the investigator may implement a deviation form, or a 
change in the protocol, to eliminate an immediate hazard to a trial patient without prior 
IRB/IEC approval/favorable opinion. In this case the IRB/IEC will be notified retrospectively. 
5.5.2 Early Termination and End of Study Visits – Main Study, OLE, LT-OLE and LT-OLE-PEN 
Periods 
Early termination visits are appointed for the early termination/withdrawal of a patient from 
this clinical study. These visits may be performed on the same day as originally scheduled 
visits, or appointed separately. Data collection from these visits should primarily be guided 
according to GCP principles, protecting patient’s safety and wellbeing. The schedule of 
assessments for early termination and end of study visits (both for patients in the Main Study 
and for those in other study periods) should follow those requested for the last Study visit 
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(i.e. month 12) of each period.  The structure of early termination visit should be as much as 
possible similar to the last study visit.  
5.6 EFFICACY ASSESSMENTS 
Efficacy assessments will be done according to the schedule provided in Appendix 1: Schedule 
of Assessments – Main Study. 
Height measurements must be performed according to Appendix 9. with a calibrated wall-
mounted (e.g. Harpenden or similar) stadiometer and should ideally be conducted at the 
same time of the day for each visit, preferably in the morning. To ensure consistency of 
results, ideally the same auxologist will perform these measurements for each patient at each 
visit to minimize the variability of measurements. The time of measurement and the 
observer’s name is to be recorded in the CRF. The arithmetic mean of three independent 
readings will be recorded for each visit in the CRF. 
The means and the standard deviations (SD) of height for age and gender for normal children 
will be derived from the standards of Prader et al (Prader A, 1989). 
The HV standardized for chronological age (CA) and gender (HVSDS) will be determined 
according to the standards of Prader et al (Prader A, 1989). 
Predicted adult height (PAHT) will be calculated for children above 7 years of chronological 
age using Bayley-Pinneau tables for children with bone age greater than 6 years and a 
modified Bayley-Pinneau table for children with a bone age of 4-6 years (Bayley N, 1952). SD 
scores for PAHT will be based on normative data for adults. 
Bone age (BA) will be determined by X-ray according to the method of Greulich and Pyle 
(Greulich & Pyle, 1959) at the Screening visit and 12 months and every 12 months in the OLE 
periods. X-ray films of the left hand and wrist will be taken as outlined in Appendix 10 and will 
be sent to a qualified central reader. The central reader will be blinded to the CA 
(chronological age), drug allocation, and name of the patients. X-ray films will hold only an 
identification number and gender. Details of the central bone age reader and the procedure 
for blinding and shipping of X-rays will be provided to the Investigator. 
5.7 SAFETY ASSESSMENTS 
Safety assessments will consist of: monitoring and recording of all adverse events including 
serious adverse events, monitoring of glucose and lipid metabolism, thyroid status, cortisol 
levels, local injection site reactions, antibody formation, regular monitoring of hematology 
and blood biochemistry and urinalysis, regular monitoring of vital signs and physical 
condition. 
5.7.1 Laboratory Safety Assessments 
Analyses of routine hematology, serum biochemistry parameters and urinalysis, glucose and 
lipid parameters, antibody evaluation, IGF-I, as well as hormonal (thyroid and adrenal) status 
will be performed at a central laboratory. 
Additional information regarding the collection, shipment of samples, reporting of results and 
alerting of extreme values will be provided in the Laboratory Manual. 
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Special attention will be paid to the monitoring of the following laboratory parameters:  
 Indicators of glucose metabolism; 
 Indicators of lipid metabolism; 
 Assessment of IGF-I levels as safety parameters;  
 Hormonal status with special attention to the thyroid and adrenal status;  
 Assessment of liver enzymes; 
 Assessment of MOD-4023 and r-hGH antigenicity. 
5.7.1.1 IGF-I  
IGF-I will be measured using the IDS-iSYS assay. The assay is based on chemiluminescence 
technology. Samples are incubated with an acidic solution to dissociate IGF-I from the binding 
proteins. A portion of this, along with neutralisation buffer, a biotinylated anti-IGF-I 
monoclonal antibody and an acridinium labelled anti-IGF-I monoclonal antibody is incubated 
for a further period of time. Streptavidin labelled magnetic particles are then added and 
following a further incubation step, the magnetic particles are “captured” using a magnet. 
After a washing step and addition of trigger reagents, the light emitted by the acridinium label 
is directly proportional to the concentration of IGF-I in the original sample. 
IGF-I will be assessed according to the schedule provided in Appendix 1: Schedule of 
Assessments – Main Study to Appendix 5. 
5.7.1.2 Assessment of glucose metabolism 
Impaired glucose metabolism may lead to the discontinuation of study treatment. Glucose 
metabolism will be assessed through fasting insulin, fasting glucose levels and HbA1C levels. 
Fasting glucose, insulin, and HbA1C will be assessed according to the schedule provided in 
Appendix 1: Schedule of Assessments – Main Study to Appendix 5. 
Safety monitoring of potentially impaired glucose metabolism will also include parameters 
that have been associated with insulin resistance (e.g., fasting lipid profiles, changes in blood 
pressure, weight and BMI). 
5.7.1.3 Indicators of lipid metabolism 
In GHD patients, administration of GH has resulted in lipid mobilization, reduction in body fat 
stores, and increase in plasma fatty acids. However there still exists a slight controversy about 
potential atherogenic effects of chronic GH replacement therapy. Parameters that will be 
assessed in this protocol are: total cholesterol, HDL-cholesterol, LDL-cholesterol triglycerides 
and Lp(a) lipoprotein (Lp(a) lipoprotein will not be measured in the LT-OLE-PEN period). 
Monitoring of changes in lipid metabolism may be meaningful from two aspects, as an 
indicator of atherogenesis and as an indicator of insulin resistance. Lp(a) lipoprotein has been 
selected as a potentially challenging parameter. Previously there were reports indicating that 
Lp(a) lipoprotein, as well as the risk of atherogenesis increase under the treatment of r-hGH 
(Mooser V, 1997) (Olivecrona H, 1993), however there were several publications confirming 
that Lp(a) doesn’t change during the GH treatment (Hassan HMS, 1995 ) (Hassan HMS, 1996). 
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One explanation for these contradictory findings could be the high variability of the assays 
used (Wieringa G, 2000), however the effects of sustained release and long-acting growth 
hormones have not been sufficiently investigated.  
Indicators of lipid metabolism will be assessed according to the schedule in Appendix 1: 
Schedule of Assessments – Main Study to Appendix 5. 
5.7.1.4 Hormonal status with special attention on thyroid and adrenal status 
Cortisol: Blood cortisol should be monitored throughout the study since GH treatment may 
unmask previously undiagnosed or sub-clinical central hypoadrenalism.  
Supra-physiological glucocorticoid treatment may attenuate the growth promoting effect of 
somatropin (as for asthma). Therefore, children requiring a glucocorticoid dose of greater 
than 400 µg/d of inhaled budesonide or equivalents (approximately equivalent doses: 
Fluticasone: 264 µg/d; Beclomethasone: 504 µg/d; Flunisolide 1,000 µg/d; Triamcinolone: 
1,000 µg/d) for longer than 1 month during a calendar year will not be included in the study 
or may be discontinued if additional dosing is required. 
Thyroid hormones: Blood TSH and T4 should be monitored throughout the study since GH 
treatment may unmask previously undiagnosed or sub-clinical central hypothyroidism. 
Undiagnosed/untreated hypothyroidism attenuates growth and metabolism. Upon diagnosis 
of hypothyroidism, thyroid hormone replacement therapy should be initiated following 
approval by Coordinating Investigator. Thyroid dose should be adjusted throughout the study 
so that T4 levels will be close to the median range. 
 
Gonadotrophic hormones - (applicable only for the LT-OLE and LT-OLE-PEN periods) - FSH, 
LH and Estradiol for females that are 12 years old and above and LH, FSH and testosterone 
for males that are 13 years old and above. 
5.7.1.5 Assessment of antigenicity 
Immunogenicity of MOD-4023 and of r-hGH will be assessed.   
Baseline data for anti-hGH will be collected at Screening, and no patients with positive anti-
hGH antibodies will be included in the study. Baseline anti-MOD levels will be measured at 
Visit 1. During the treatment period, samples will be taken according to the schedule in 
Appendix 1: Schedule of Assessments – Main Study to Appendix 5. 
5.7.1.6 MOD-4023 hGH Concentrations 
Samples for MOD-4023 concentrations will be collected according the schedule specified in 
Appendix 1: Schedule of Assessments – Main Study to Appendix 5.  
Full blood (and blood smears) will be collected for hematology assessments.  
The following parameters will be evaluated: hemoglobin, erythrocyte count, hematocrit, 
mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular 
hemoglobin concentration (MCHC), leukocytes, differential blood count of leukocytes, 
platelet count. 
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Hematology will be assessed according to the schedule in Appendix 1: Schedule of 
Assessments – Main Study to Appendix 5. 
5.7.1.7 Blood biochemistry  
The following parameters will be evaluated: sodium, potassium, calcium, phosphate, chloride, 
total bilirubin, alkaline phosphatase, lactate dehydrogenase (LDH), serum glutamic 
oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-
glutamyl transferase (GGT), albumin, total proteins, creatinine, urea-nitrogen, uric acid, 
serum iron and transferrin, albumin. 
Blood chemistry will be assessed according to the schedule in Appendix 1: Schedule of 
Assessments – Main Study to Appendix 5. 
5.7.2 Vital signs and Physical Examination 
Body temperature, sitting blood pressure, respiratory rate and pulse rate (after at least 5 min 
rest) will be assessed according to the schedule in Appendix 1: Schedule of Assessments – 
Main Study to Appendix 5, as per standard practice at each investigational site.  
Physical examination, that includes assessment of head (external), eyes, ears, nose and 
throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, 
central nervous system and, where appropriate, other body systems will be performed.  
Physical examinations will be performed according to the schedule in Appendix 1: Schedule 
of Assessments – Main Study to Appendix 5. 
5.7.3 Local Injection Site Reactions  
Assessment of local tolerability will be performed by examining the injection sites (by the 
Investigator if a reaction is present at the time of a visit) and on the basis of anamnestic data 
and records in the patient diary.  
The abnormal injection site reaction is defined as: 
 Injection site reaction which is observed at the time of visit and moderate to severe in 
intensity. 
 Injection site reaction between the last and present visit, or remaining at the time of 
visit which require medical attention, or injection site reaction resulting from a 
previous injection, other than the last injection. 
 Any other injection site reaction deemed abnormal to the investigator’s judgment, 
other than those ordinarily observed in subcutaneous injections. 
Observations will be recorded on appropriate eCRF pages. If an injection site reaction meets 
the criteria defined for an “abnormal result’” it will be considered an AE. 
 Pain and Tenderness: For patients in all Cohorts, injection site pain will be evaluated 
by the investigator or designated personnel if the injection is given at the medical 
center, and by the parent/legal guardian if the injection is given at home. The pain will 
be evaluated using the 
 Pain Rating Scale (Appendix 8). In addition, 
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each patient and parent/guardian will be queried during study visits regarding possible 
injection site pain.  
 Site status: For patients in all Cohorts, injection site status will be evaluated by the 
Investigator, or designated using the Injection Site Assessment Visual Analogue Scale 
(Appendix 8) at each of the PK/PD sampling time points. In addition, each patient and 
parent/guardian will be queried during study visits regarding possible site reactions. 
The Investigator’s Local Assessment of Tolerability eCRF page will be designed to capture the 
following information. 
 Description of the reaction; 
 Location: left arm/right arm/left thigh/right thigh/left buttock/right buttock/left part 
of abdomen/right part of abdomen; 
 Duration: Onset, end date; 
 Intensity: grading according to the scales provided in appendices; 
 Action taken: action(s) taken by patients, medical intervention or concomitant 
medication; 
 Comments. 
Patient-reported local site reactions and diary records will be captured on the “Local 
Tolerability assessment” CRF page. Only data about reaction type (e.g. pain, erythema, etc.), 
frequency, and intensity will be captured. 
5.7.4 Fundoscopy and MRI 
Fundoscopy (opthalmoscopy) will be performed by the Investigator or an ophthalmologist 
consultant in order to assess signs of increased intracranial pressure prior to initiating or as a 
result of GH replacement. At screening (or within 6 months prior to screening), to confirm the 
diagnosis of GH deficiency and to confirm that there is no evidence of pituitary adenoma or 
any other intracranial tumor, a magnetic resonance imaging scan (MRI) with contrast will be 
done. It will be performed by the relevant department of the hospital according to the routine 
practice. During the study, MRIs may be performed per the investigator’s discretion, (i.e. 
when there is suspicion of either growth of pituitary adenoma or any other intracranial 
tumor). 
Fundoscopy will be performed according to the schedule in Appendix 1: Schedule of 
Assessments – Main Study to Appendix 5. 
5.7.5 ECG 
ECG will be performed according to the schedule in Appendix 1: Schedule of Assessments – 
Main Study to Appendix 5. 
In the first year of the LT-OLE-PEN period ECG will be performed once a year on 12 months 
visit around Tmax (7 to 12 hours post injection). In case not possible to conduct the ECG 
around Tmax at this 12 month visit, it can be performed on month 12 ± 3 weeks (7-12 hours 
post dose). Adverse Events 
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Adverse events (AEs) will be assessed immediately following the written informed consent 
and assent (if applicable) and at all study visits throughout the study. Any AEs that occur 
throughout the study will be recorded. Any new systemic AE that occurs between scheduled 
visits should be brought to the attention of the Investigator and recorded in the patient’s 
medical file and on the appropriate eCRF page.  
For a list of common AEs associated with human GH, please refer to the Investigator’s 
brochure. 
 
5.8 DOSE MODIFICATION AND DISCONTINUATION 
The following symptoms and laboratory abnormalities measured at a single occasion or 
repeatedly, are considered to be the main guide for the decision about dose modification or 
treatment interruption: 
 Growth factors plasma levels: 
o Repeated consecutive IGF-I > +2.0 SDS  
 Glucose tolerance 
o HbA1c level > 6.2 %  
o Fasting glucose level is > 5.5 mmol/L 
 Increase of liver enzymes (≥ 2x of ULN) 
 Immune response 
o Development of high anti-growth hormone antibody titre with strong 
neutralizing effect 
 Any other CTC grade 3 or 4 laboratory abnormality  
 Development of intracranial hypertension or pseudotumor cerebri - If a patient has 
persistent severe headaches for more than 1 day not relieved by aspirin or other 
analgesics or visual disturbances, then examine the patient for papilledema (to be 
confirmed by an ophthalmologist).  If there is papilledema, perform an MRI of the 
head with contrast; if there are signs of intracranial hypertension, perform a lumbar 
puncture (LP) and record the opening pressure. Only positive MRI findings and 
increased opening pressure on LP confirm the diagnosis of pseudotumor. 
In the Main Study, dose efficacy will be analysed first after 6 months of treatment on an 
individual patient level. Patients who do not achieve the minimally satisfactory growth rate 
(i.e. delta height SDS of at least 0.2) at this time point will be moved to the next highest dose 
group for the remaining 6 months of treatment. Dose efficacy will be analysed again after 12 
months of treatment on an individual patient level. Patients who do not achieve the minimally 
satisfactory growth rate at this time point will be moved to the next highest dose group. If the 
patient is in the highest dose group, the Coordinating Investigator of the study will be 
informed. 
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Cohort 1-3 patients transitioning to the OLE will continue with the same dose (mg/kg) in which 
they completed the main study. 
In the OLE period, the patients who were in cohort 4, in the main study (e.g. treated with 
Genotropin) will be randomized to one of the MOD-4023 treatment groups. 
In the LT-OLE period, all patients will be switched to the highest MOD-4023 dose 0.66 
mg/kg/week. 
In the LT-OLE-PEN period, patients should continue with the same dose.  
 The dose modifications will be performed according to the same rules as in the main study, 
including adjustment for weight every 3 months. 
5.8.1 Dose Modifications Based on Adverse Effects (main study) 
If a patient develops a severe GH-related adverse event at any time during the course of the 
study (Main and OLE), the Sponsor, the Coordinating Investigator, the investigator or the Data 
Safety Monitoring Board (DSMB) may propose one of three options: 
1. If the patient is allocated to Cohort 1 (0.25 mg protein/kg/week) the following dose 
will not be given. If the symptoms disappear, the patient will continue on the same 
dose level as initially allocated. In case the symptoms reoccur, the patient may be 
withdrawn from the study. 
2. If the patient is allocated to Cohort 2 (0.48 mg protein/kg/week) the dose will be 
lowered to the lower dose level (0.25 mg/kg/week) for a 2-4 week period. The patient 
may be re-challenged, once the symptoms disappear, with the same dose level as 
initially allocated. In case symptoms reoccur, the patient may be kept on the reduced 
dose level.  
3.  If the patient is allocated to Cohort 3 dose (0.66 mg protein/kg/week) the dose will 
be reduced by 15% to 0.56 mg/kg/week.  If the symptoms are resolved, the patient 
will continue on the same dose level. 
In case the AE is persist or the symptoms reoccur the dose will be reduced again by 
15% to 0.48 mg/kg/week.  Patients, who had their dose reduced twice and who still 
have symptoms or they reoccur will be required to have individual medical 
consultation, depends on AE and /or symptoms assessment. 
It is recommended to consult with study Medical Monitor prior to dose changes (the 
Medical Monitor must be informed of such a change after the event if prior 
consultation is not possible). 
4. Patient will be withdrawn from the study either:  
 Without attempt of dose reduction if such a severe AE(s) develops that may affect 
patient safety and wellbeing. 
 If symptoms do not disappear after the transient dose interruptions or dose 
reductions (Please see case 1-3 above). 
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5.8.2 Overdose with the Study Medication  
An accidental overdose is not an AE if there are no signs or symptoms. Any undesirable 
medical occurrence resulting from an accidental overdose is an AE, and should be recorded 
and reported on the appropriate AE case report form. Since accidental overdoses with the 
study drug could have serious clinical consequences and/or represent a compliance issue, 
they should be reported immediately to 
 Safety Team 
 and 
evaluated by the Sponsor. The investigator should document any case of overdose and 
monitor the patient. Parent, or legal guardian training on adverse event reporting will be 
conducted at the screening visit and re-reviewed prior to patient randomization and 
additional retraining will be done before entering the OLE. 
5.8.3 Dose adjustment paradigm  
Doses may be decreased for safety reasons according to the pre-defined dose-adjustment 
criteria (which will be based on the severity of AEs or repeated, elevated levels of IGF-I SDS).  
The dose will be decreased based on two repeated day 4(-1) levels of IGF-I > +2.0 Standard 
Deviation Score (SDS).  
If a patient has an IGF-I level above +2.0 SDS, they will be requested to return for an 
unscheduled visit within 4-6 weeks after the >+2.0 SDS result, on day 4(-1) post dose.  If their 
IGF-I level is still above +2.0 SDS, the most recent dose will be reduced by 15% (i.e. in case the 
starting dose is 0.66 mg/kg/week, reduction to 0.56 mg/kg/week). The patient will be treated 
with the new dose for at least 4 weeks before a subsequent IGF-I determination can result in 
a further dose modification.  If the next scheduled visit is less than 4 weeks after the dose 
reduction was effectuated, the IGF-I result at that visit must NOT be used for additional dose 
recalculation. At the time of the next visit (or at an extra, unscheduled visit which complies 
with the 4 week minimum time period), IGF-I will be resampled. If the IGF-I is still above +2.0 
SDS, the dose will be reduced an additional 15% (i.e. in case the starting dose is 0.66 
mg/kg/week, reduction to 0.48 mg/kg/week). If the IGF-I is still above +2.0 SDS following 2 
dose reductions (at least 4 weeks after second dose reduction), the sponsor Medical Monitor 
(with the assistance of the DSMB if necessary) will decide on course of treatment on an 
individual basis.  
If AEs are defined as “severe” and drug-related, dose reduction will be introduced upon 
discussion with Sponsor Medical Monitor and DSMB - dose should be reduced at a similar 
manner as above in two step approach.  
 
 
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Figure 2: Overall Dose Adjustment Scheme 
This figure is an example for a dose of 0.66 mg/kg/week. The rules also applies for patients who 
receive lower doses.  
 
 
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NO 
Reassess IGF-1 at 4-6 weeks after 
result on day 4 (-1) post dose 
IGF-1 > 2.0 
SDS? 
YES 
Reduce dose by 15% 
to 0.56 mg/kg/week 
NO 
Assess IGF-1 al next day 4 (-1) visit 
and at least 4 weeks after 1st dose 
reduction 
Reduce dose by 15% 
to 0.48 mg/kg/week 
NO 
Assess IGF-1 at next day 4 (-1) visit 
and at least 4 weeks after 2nd dose 
reduction 
Seek 
individual 
medical 
consultation 
NO 
Keep at current 
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6. Investigational Product 
6.1 INVESTIGATIONAL THERAPY AND REFERENCE THERAPY 
6.1.1 MOD-4023 
The active component of MOD-4023 is a recombinant human growth hormone modified by 
adding carboxyl terminal peptides (CTP) to the protein molecule, thereby extending its life 
span in the human body.  
MOD-4023 will be provided in single use vials as a solution for injection containing 
 or 
 
mg protein1/ml (having a net r-hGH content of 
%) in 
 
  
In the LT-OLE-PEN period, MOD-4023 will be provided as a solution for injection containing 
 or 
 mg/mL MOD-4023 for a single patient use, multi-dose disposable pre-filled PEN.  The 
formulation will include 
 
6.1.2 MOD-4023 Administration (all study periods) 
In the main study, patients will be administered a weekly dose of one of the three different 
dose strengths of MOD-4023 based on equal molar conversion of the weekly cumulative r-
hGH dose.  The weekly dose regimens will be as follows. 
TABLE 8: MAIN STUDY WEEKLY DOSE REGIMENS 
COHORT 
Weeks 1-2 
Weeks 3-4 
Subsequent doses 
1: MOD-4023 
0.25 mg 
protein/kg/week* 
0.25 mg protein/kg/week 
0.25 mg 
protein/kg/week 
2: MOD-4023 
0.25 mg 
protein/kg/week 
0.48 mg 
protein/kg/week** 
0.48 mg 
protein/kg/week 
3: MOD-4023 
0.25 mg 
protein/kg/week 
0.48 mg protein/kg/week 
0.66 mg 
protein/kg/week*** 
* Equivalent to 0.18 mg hGH/kg weekly injection 
** Equivalent to 0.35 mg hGH/kg weekly injection 
*** Equivalent to 0.48 mg hGH/kg weekly injection 
In the 12 months-OLE the patients will continue with the same dose (mg/kg) of MOD-4023 
they received in the Main Study. 
Patients who received active comparator, Genotropin, during the Main Study, will be 
switched to MOD-4023 (will be randomized to one of the three MOD-4023 cohorts).  
In the LT-OLE all patients will receive 0.66 protein mg/kg/week. 
In LT-OLE-PEN patients will continue his/her treatment with the same dose.  
                                                          
1 MOD-4023 concentration (mg protein/ml) refers to the protein backbone 
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In all study periods, MOD-4023 will be administered as a SC injection preferably in the 
morning hours once weekly, using the PEN into the upper arms, buttocks, thighs, or abdomen 
(8 locations). It is recommended that all 8 injection sites are used successively, using a 
different injection site at each subsequent injection. The same injection site should be used 
only after all other injection sites have been rotated (see recommended rotation scheme in 
Figure 3 below).   
 
Figure 3: Injection Sites and Recommended Rotation for MOD-4023 
 
 
 
 
Sterile, disposable syringes and needles (provided by OPKO Biologics) will be used for the 
administration of the MOD-4023 for the first four administration periods (excluding the LT-
OLE-PEN period). In the LT-OLE-PEN period the patients will use single patient use, multi-dose 
disposable pre-filled PEN containing 20 or 50 mg/mL MOD-4023.  
If a patient on MOD-4023 treatment misses a dose for not more than 72 hours (i.e. the dose 
is ≤72 h late), then he/she will take a full dose as soon as he/she remembers that an injection 
was missed. Then the patient will go back to taking the study medication on the regular day 
of the week. If the dose is more than 72 hours late, the patient will not take a dose for the 
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Left arm 
0 Left buttocks 
@ Left abdomen 
0 
Leftthigh 
Rightarm (D 
Right buttocks (D 
Right abdomen G) 
Right thigh 0 
Arms: 
Back upper area 
(Healthcare provider 
or caregiver only) 
Abdomen: 
Buttocks: 
Thighs: 
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whole week and will continue taking the study medication on the regular day the following 
week.   
The patient should notify site staff about the delayed injection or the missed dose and be 
instructed by the site as for the next visit schedule. 
In case the delayed injection is in the week when an on-site visit is planned, the site should 
confirm that the visit date follows the proper post injection interval (for example: 3-4 days 
post dosing, in case IGF-I samples should be collected). If not, the visit date should be 
rescheduled to meet protocol visit dates requirements. In case the injection was missed, the 
on-site visit in that week should be rescheduled, to meet the required post dosing interval. 
In case the prescribed dose cannot be fully set, the patient should be instructed how to split 
the dose into two injections. The partial dosing can occur in two cases: 
1. Two injections using one PEN. In case the prescribed dose is higher than the 
maximum dose which can be delivered by a single injection according to the PEN 
concentration, the patient should be instructed to subtract the dose already 
received from the prescribed dose and set the PEN accordingly. 
For example, in the 
mg/ml pen, if the full prescribed dose is  13.6 mg and the 
PEN allows only to set the dose selector to  12.0mg, the patient should inject 
another  1.6 mg using the same PEN. 
2. Split dose between two PENs, the current PEN and a new PEN.  This may happen 
when the complete dose cannot be fully administered from the used PEN, the 
patient should be instructed to subtract the dose already received from the 
prescribed dose and set the new PEN accordingly. 
For example, in the 
mg/ml pen, if the full prescribed dose is 25.0 mg and the 
volume left in the current PEN allows only to set the dose selector to 20.5 mg, the 
patient should inject another 4.5 mg from the new PEN. 
It is recommend to encourage the patients to use a calculator to plan the doses and to 
calculate the dose which should be adjusted for the second injection. 
Patient should be reminded that the injection site should be rotated for each injection. That 
is, for the second injection, whether from the same PEN or a new PEN, the patient should 
rotate the injection site and complete the patient diary page for each of the two injections 
administered. 
Further details are provided in the Patient Dosing Instructions document. 
Patients and parents/legal guardians will be instructed to call the investigator in the event a 
dose was missed and record this information in the patient diary.  During the  
PK/PD period (first 2, 4 or 6 weeks of treatment depending on the dose cohort), any deviations 
from weekly dosing will be considered a protocol deviation. 
Missing/Delayed dose should be reported in the patient diary and eCRF. 
 
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6.1.3  Reference Non-Investigational Medicinal Product (Non-IMP): Genotropin (Period I) 
Genotropin (used only in the main study) lyophilized powder contains somatropin [rDNA 
origin], which is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid 
residues and a molecular weight of 22,124 daltons. The amino acid sequence of the product 
is identical to that of human growth hormone of pituitary origin (somatotropin). 
Genotropin is synthesized in a strain of Escherichia coli that has been modified by the addition 
of the gene for human growth hormone. Genotropin is a sterile white lyophilized powder 
intended for subcutaneous injection. 
Genotropin 5.3 mg is dispensed in a two-chamber cartridge. The front compartment contains 
recombinant 
 
. The rear compartment contains m-Cresol and mannitol in 
water for injection. 
6.1.4 Genotropin Administration (Period I) 
Genotropin (used only in the main study) will be administered to patients in Cohort 4 during 
the Main Study only at a dose of 0.24 mg/kg/week (0.034 mg/kg/day), divided and 
administered as a daily subcutaneous dose (7 times a week) at bedtime. 
Genotropin will be administered with a delivery device (Genotropin Pen) for subcutaneous 
injection into the region of the upper arms, buttocks, thighs, or abdomen. It is recommended 
that all injection sites (left upper arm, right upper arm, left buttock, right buttock, left thigh, 
right thigh, left abdomen, and right abdomen) are used successively, using a different 
injection site at each subsequent injection. The same injection site should be used only after 
all other injection sites have been rotated.   
6.2 PACKAGING AND LABELING OF STUDY MEDICATION 
6.2.1 MOD-4023 vials (Periods I to IV) 
The study drug will be provided as glass vials for use until the LT-OLE-PEN period. The bottles 
will be packed and labeled in compliance with the GMP, Annex 13 of drugs used in clinical 
trials. 
Patients will be provided with dosing and storage instructions, and study drug vials in special 
cool bags.   
Medication labels will comply with the legal requirements of each country and will be printed 
in the local language. The storage conditions for the study drug will be described on the 
medication label. 
 
MOD-4023 will be labelled with:  
 Product name; 
 Patient’s code; 
 Protein concentration; 
 Lot number; 
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 Expiry date; 
 Protocol number; 
 Sponsor’s name;  
 Storage instructions.  
6.2.2 MOD-4023 PEN (Period V) 
During the LT-OLE-PEN period, study drug will be provided as single patient use, multi-dose 
disposable pre-filled PEN and will be supplied to the site in cartons of 1 PEN/box.   
Storage and dosing instruction are provided in the patient dosing instruction document. 
Patients will be provided with study drug Pens in special cool bags.   
6.2.3 The PENs will be packed and labelled in compliance with the FDA, EU and ICH 
guidelines. Genotropin (Periods I) 
Genotropin will be supplied from a central source packed in cartons with 1 cartridge each. In 
addition to the manufacture’s label, Genotropin will be labelled according to GMP, ANNEX 13 
requirements. 
6.3 DISTRIBUTION AND SHIPMENT OF STUDY MEDICATION 
The study investigational drug will be packed and shipped in appropriate boxes. If upon arrival 
at the clinical investigation site, the study drug supplies appear to be damaged, the study 
monitor should be contacted immediately.  
Each shipment of study drug supplies for the study will be accompanied by a shipment form 
describing the contents of the shipment, product certificate of analysis, acknowledgement of 
receipt and other appropriate documentation. The shipment form will assist in maintaining 
current and accurate inventory records. The study staff will confirm the receipt of clinical 
supply and will return signed drug accountability logs to the study monitor. 
All study supplies should arrive at the Pharmacy/Investigational site in sufficient quantity and 
in time to enable dosing as scheduled. The Sponsor or its representative must notify the PI 
prior to dispatch of drug supplies, with the anticipated date of their arrival.   
If upon arrival at the clinical investigational site, the study drug supplies appear to be 
damaged, site staff should follow pharmacy manual instructions. 
6.4 STORAGE, DISPENSING AND RETURN OF THE INVESTIGATIONAL PRODUCT 
Records should be kept by the Investigator or pharmacist as to how much study drug was 
used by each patient. The study monitors must periodically check the study drug supplies to 
ensure expiry date and sufficient quantity of study drug.  
All investigational products must be kept in a locked area with access to the study drug limited 
to designated study personnel. Only personnel under the supervision of either the 
Investigator or the local pharmacist are authorized to dispense study drug.  
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During storage at the pharmacy, the temperature of the refrigerators and freezers will be 
monitored continuously and recorded by a pharmacist on a temperature log. The Sponsor will 
be notified of any deviation from the storage conditions. 
Further details and instructions will be provided in the Pharmacy Manual. 
In the LT-OLE-PEN period, drug dispensing and clinical supplies inventory will be managed 
through IRT system. The Investigator will be responsible for inventory and accountability of all 
clinical trial supplies at his/her site, exercising accepted medical and pharmaceutical practices. 
The supplies and inventory record must be made available for inspection upon request.  
Upon completion or termination of the study, the Investigator will keep the remaining clinical 
supplies along with a copy of the inventory record and a record of the clinical supplies returned. 
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by this protocol.  
6.4.1 MOD-4023 (all study periods) 
MOD-4023 vials (main, OLE and LT-OLE periods) will be shipped on dry ice, after which it 
should be stored in a freezer (-20oC). Patients will receive the frozen vials and will keep them 
refrigerated until used. Before administration it should be kept at ambient room temperature 
for 30 min to 1h. If injection is performed at the site, the frozen vial should be thawed in a 
refrigerator (+2 to +8oC) for 24 h. 
In the LT-OLE-PEN period, the investigational drug (PEN) will be shipped in +2oC to +8oC in 
appropriate shippers with temperature loggers. At the sites and patients home the PEN 
should be stored in +2oC to +8oC (refrigerator temperature).The Investigator or study 
pharmacist will acknowledge receipt of all shipments of study drug to the clinical 
investigational site through the IRT system.   
The assigned study team member(s) will hand-out the study medication and instruct the 
patient and parent, or legal guardian on its usage. The amount needed for the period between 
two visits will be handed out at each visit.  
The packaging and storage instructions and further details are described in the Instructions 
for Use and IP labels. 
6.4.2 Genotropin (Period I) 
Genotropin cartridges must be stored at 4°C (2°-8°C/36°-46°F); do not freeze. Protect from 
light. The cartridges of Genotropin contain a diluent with a preservative. Thus, after 
reconstitution, they may be stored under refrigeration for up to 28 days. 
The assigned study team member(s) will dispense Genotropin cartridges to the patients 
according to their weight and dosing schedule and instruct the patients and parents or legal 
guardians on its usage. The amount needed for the period between two visits will be handed 
out at every visit. The study site pharmacist will be responsible for the dispensation. The 
cartridges, as well as the boxes, will be re-labeled according to GMP, ANNEX 13 requirements.  
 
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6.5 ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL PRODUCT 
Each delivery must be acknowledged by the hospital pharmacist (or authorized study team 
member responsible for the investigational medicinal product) by filling in the receipt record 
form. The study staff will confirm the receipt of clinical supply and will return signed drug 
accountability logs to the study monitor.  
The medical center pharmacist (or authorized study team member responsible for the 
investigational medicinal product) is responsible for ensuring the supervision of the storage 
and allocation of these supplies, which will be forwarded to the Investigator at the 
appropriate time before administration. The Investigator may dispense investigational drug 
only to patients enrolled in the study. 
Compliance to protocol procedures will be assessed according to the schedule in Appendix 1: 
Schedule of Assessments – Main Study to Appendix 5, and will be based on drug 
accountability and patient’s diary review. Patients and parents, or legal guardians will be 
instructed to bring their diaries to each visit.  Study drug compliance may be enhanced with 
regular telephone reminders.  
Drug accountability records must be maintained by the clinical investigational site at all times. 
At the last study periods visits, all used and unused investigational drug will be assessed for 
accountability by the study monitor, as detailed in the study monitoring plan. Interim 
accountability and destruction may also be performed during the study, following Sponsor’s 
written approval. 
The patient number, the date, batch number/pack number, and quantity of study drug used 
by the patient will be checked for correctness and recorded on the appropriate accountability 
forms. Unused drug supplies will be returned to the Sponsor or destroyed at the site only 
after approval of drug accountability forms by Sponsor QA. At the end of the study, all the 
clinical supply and the corresponding accountability forms must be returned by the study 
monitor for reconciliation and destruction. A photocopy of these records must be kept at the 
clinical investigation site. 
The inventory will be made available to the study monitor who will verify accountability and 
dose during the course of the study. 
Study drug orders, records of study drug receipts, dispensing records, and inventory forms 
located at the site will be examined and reconciled by the study monitor periodically during 
and at the end of the study.  Detailed instructions will be provided in the Pharmacy Manual.  
All medication supplies are to be used only for this protocol and not for any other purpose.  
The investigator must not destroy any medication labels, or any partly-used or unused 
medication supply. At the conclusion of the study and, as appropriate, during the course of 
the study, the investigator will return all used and unused medication containers, medication 
labels and a copy of the completed medication disposition form to CRO monitor or to the 
Sponsor address provided in the investigator folder at each site. 
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6.6 BLINDING  
This is an open-label study. Due to different dose frequencies and dosing techniques, it is not 
practical to employ any blinding methods. A double-blind double-dummy design in this 
particular indication is deemed to be unethical.  
6.7 PRIOR AND CONCOMITANT THERAPY  
6.7.1 General Guidelines 
All prior treatments received by the patient within 30 days before the initial Screening visit 
will be recorded on the patient’s eCRF including the treatment's name, indication and the 
start and stop dates. 
Any medications (including prescription, over-the-counter, herbal supplements and health 
store products) to be taken during the study must be approved by the Investigator.  
All approved concomitant medications taken by the patient during all study periods must be 
recorded on the eCRF, along with the indication, and start and stop dates as well as daily dose.   
If the administration of a non-permitted concomitant medication becomes necessary, 
participation in the study may be discontinued. 
Prior medications will be defined as any medication with start of administration from 30 days 
prior to screening up to the first dose of study drug, regardless of continuation status. 
Concomitant medications will be defined as any medication administered during the period 
starting at or after the first dose of study drug (MOD-4023 or Genotropin) until 
discontinuation of study drug (in all study periods), regardless of the start date for the 
concomitant medication. 
 
6.7.2 Allowed Medications 
The following medications are allowed: 
1. Dose replacement therapy for pituitary insufficiencies of other axes is permitted, but 
doses of all agents must be stable for at least 3 months prior to study entry; however, 
thyroid replacement should be stable for 6 months prior to randomization. As growth 
hormone may enhance the transformation of hydrocortisone to cortisone, the 
investigator may increase the dose of hydrocortisone replacement therapy, as 
needed. Also in case of development of hypothyroidism after the start of GH 
replacement treatment, the investigator may prescribe and adjust a dose of thyroid 
replacement therapy, as needed (after consultation with the Sponsor Medical 
Monitor). 
2. Excessive glucocorticoid therapy may prevent optimal response to somatropin. If 
Glucocorticoid replacement therapy is required, patients may receive hydrocortisone 
in replacement doses. These doses of glucocorticoids (<12 mg/m2/d) will not interfere 
with the growth promoting effects of somatropin and are permitted in this protocol. 
If required, the glucocorticoids may be increased periodically for stress coverage.  
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3. Glucocorticoid therapy for indications other than adrenal replacement (e.g. asthma) 
may be administered in a dose equivalent to inhaled budesonide of not more than 400 
µg/d for no longer than 1 month during any one calendar year (approximately 
equivalent doses: Fluticasone: 264 µg/d; Beclomethasone: 504 µg/d; Flunisolide 1,000 
µg/d; Triamcinolone: 1,000 µg/d).  
4. Over-the-counter vitamins, mineral preparations, calcium supplements or 
corresponding dietary supplements may only be taken if their use and dose is agreed 
by the study Investigator beforehand.  
All medications must be documented appropriately in the CRF. 
 
6.7.3 Prohibited Concomitant Medication  
The following medications are prohibited: 
1. Estrogen is not permitted as concomitant therapy. 
2. Weight-reducing drugs or appetite suppressants, anabolic steroids, gonadal steroid 
replacement therapy and systemic corticosteroids other than in replacement doses 
are not permitted as concomitant therapy in the main study, OLE and LT-OLE periods 
3. In LT-OLE-PEN period, Psychiatric medications typically associated with weight 
changes and/or diabetes are not allowed, with the exception of ADHD drugs or 
hormone replacement therapies (thyroxin, hydrocortisone, desmopressin [DDAVP]).  
4. The use of any drugs for recreational use (e.g., barbiturates, marijuana, ecstasy, etc.) 
is forbidden.  
During all study periods , the coordinating investigator should be informed as soon as possible 
about any new medications (including prescription, over-the-counter, herbal supplements 
and health store products) taken by the patient. 
7. Safety and Pharmacovigilance  
7.1 ADVERSE EVENTS 
Information about all adverse events, whether volunteered by the patient, recorded in the 
patient’s diary, discovered by investigator questioning, or detected through physical 
examination, laboratory test or other means, will be collected and recorded on the Adverse 
Event Case Report Form and followed-up as appropriate. An adverse event is defined as any 
undesirable sign, symptom or medical condition occurring after starting the study drug (or 
therapy) even if the event is not considered to be related to the study drug (or therapy). Study 
drug (or therapy) includes the drug (or therapy) under evaluation. 
Medical conditions/diseases present before starting the study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in the 
protocol). The period for collecting adverse events begins after signing the informed consent 
form and continues until 4 weeks after the patient has received the last dose of study 
treatment. 
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Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant or require therapy.  Such 
adverse events are recorded on the Adverse Events Case Report Form under the signs, 
symptoms or diagnosis associated with them.  
Any AE that occurs in the course of a clinical study must be monitored and followed-up until: 
 It has receded 
 Pathological laboratory findings have returned to normal 
 Steady state has been achieved 
It is the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
Whenever possible, the Investigator(s) should always group signs and symptoms into a single 
term that constitutes a single unifying diagnosis. The Investigator’s opinion of the association 
of each AE to study drug, the duration, frequency, intensity, countermeasures and the 
outcome of each AE will be documented. 
The event’s relationship to the study drug should be indicated according to the following 
definitions: 
Relationship to study drug definitions: 
 
1. Not related 
 
This category applies to those adverse events which, after careful 
consideration, are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc.) 
2. Unlikely to be related 
(at least two conditions 
fulfilled) 
In general, this category can be considered applicable to those adverse 
events which, after careful medical consideration at the time of evaluation, 
are judged to be unrelated to the test drug. An adverse event may be 
considered unlikely related if or when: 
1) It does not follow a reasonable temporal sequence from administration 
of the study drug 
2) It could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered 
to the patient 
3) It does not follow a known pattern of response to the study drug 
4) It does not reappear or worsen when the drug is re-administered 
3. Possibly related 
(at least two conditions 
fulfilled) 
This category applies to those adverse events for which, after careful 
medical consideration at the time of evaluation, a connection with the 
study drug administration appears unlikely, but cannot be ruled out with 
certainty. An adverse event may be considered possibly related if or when: 
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1) It follows a reasonable temporal sequence from administration of the 
drug 
2) It could not readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered 
to the patient 
3) It follows a known pattern of response to the study drug 
4. Probably related 
(at least three 
conditions fulfilled) 
This category applies to those adverse events which, after careful medical 
consideration at the time of evaluation, are felt with a high degree of 
certainty to be related to the study drug. An adverse experience may be 
considered related if or when: 
1) It follows a reasonable temporal sequence from administration of the 
drug 
2) It could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other models 
of therapy administered to the patient 
3) It disappears or decreases on cessation or reduction in dose. There are 
important exceptions when an adverse event does not disappear upon 
discontinuation of the drug, yet drug-relatedness clearly exists (e.g. 
bone marrow depression, fixed drug eruptions, tardive dyskinesia) 
4) It follows a known pattern of response to the test drug 
5. Definitely related 
(all four conditions 
fulfilled) 
This category applies to those adverse events which the investigator feels 
are inconvertibly related to the study drug. An adverse event may be 
assigned as definitely related if or when: 
1) It follows a reasonable temporal sequence from administration of the 
drug 
2) It could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the patient 
3) It disappears or decreases on cessation or reduction in dose and recurs 
with re-exposure to drug 
4) It follows a known pattern of response to the study drug 
 
 
 
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The intensity and frequency of the AE will be classified using the definitions below. 
The following intensity grades should be used: 
Mild 
The event is easily tolerated by the patient and does not affect the patient’s 
usual daily activities. (Grade I) 
Moderate 
The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities. (Grade II) 
Severe 
The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities. (Grade III) 
Life Threatening 
The event is incapacitating, and results in the inability to perform daily 
activities; events which are unacceptable, intolerable, or which are 
irreversible or life threatening. (Grade IV) 
 
The frequency of the event should be indicated according to the following definitions: 
Single Episode  
This is the first and only experience/episode of the event in the patient. 
Recurrent 
The patient has experienced the event more than once. 
Continuous 
The event is continuing. 
Action Taken with Study Drug should be indicated according to the following definitions (all 
applicable options should be checked): 
None 
No treatment was required and no changes were made to study drug 
administration and dose. 
Study drug permanently 
discontinued 
Study drug was discontinued. 
Study drug dose 
reduced 
Due to the adverse event, the study drug dose was reduced. 
Study drug delayed 
Due to the adverse event, the study drug dosing was delayed. 
 
Treatment Given for AEs should be indicated according to the following options: 
Concomitant 
medications 
Medications given to specifically treat the AE. 
Concomitant procedures 
Procedures performed specifically to treat the AE. 
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Other 
The patient was provided other treatment. 
None 
No treatment or medication was required for the AE. 
 
AE Outcome should be indicated according to the following definitions: 
Ongoing 
AE continues at the end of the patient’s participation in the 
study (or at the time of reporting of a SAE). 
Resolved 
Patient has returned to baseline state of health, or in the 
Investigator’s opinion no further improvement or worsening of 
the adverse event is expected. 
Resolved with sequelae 
Patient has recovered from the AE with residual incapacity. 
Death 
AE was the primary cause of death 
Patient lost to follow-up 
Outcome is unknown 
 
In the event of any abnormalities considered to be clinically significant by the investigating 
physician, patients will be followed up with appropriate medical management until the 
outcome is determined or stabilized, according to the Investigator’s clinical judgment.  
 
7.2 SERIOUS ADVERSE EVENTS  
Information about all serious adverse events (SAEs) will be collected and recorded on the 
Serious Adverse Event Report Form. To ensure patients’ safety each SAE must also be 
reported to 
 within 24 hours of learning of its occurrence.  
An SAE is an undesirable sign, symptom or medical condition which: 
1. Is fatal or life-threatening. 
2. Requires or prolongs hospitalization. 
3. Results in persistent or significant disability/incapacity.  
4. Constitutes a congenital anomaly or a birth defect. 
5. Is medically significant, in that it may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed above. 
Events not to be reported as SAEs are hospitalizations for the following:  
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, like training for the study drug administration, 
hospitalization for the period of pharmacokinetic sampling. 
 Treatment, which was elective or pre-planned for a pre-existing condition that is 
unrelated to the indication under study and did not worsen. 
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 Admission to a hospital or other institution for general care not associated with any 
deterioration in condition. 
 Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
aforementioned definitions of “serious” and not resulting in hospital admission.  
The period for collecting and reporting SAEs for this study starts after the patient has provided 
assent (where applicable) and the parent(s)/guardian(s) has provided written informed 
consent, and continues until the formal end of study-notification. 
7.2.1 Notification of Serious Adverse Events 
7.2.1.1 Reporting responsibility 
Each serious adverse event (SAE) must be reported by the investigator to the 
 Safety 
group within 24 hours of learning of its occurrence, even if it is not felt to be treatment-
related. Follow-up information about a previously reported SAE must also be reported within 
24 hours of the investigator receiving it. If the SAE is unexpected and is thought to be possibly 
related to the study drug, a Clinical Safety Associate shall urgently request further information 
from the investigator. This is essential for collecting information to report to the competent 
regulatory authority (RA). All safety information obtained will be provided to the DSMB for 
review and assessment. The DSMB in collaboration with the sponsor will assess any suspected 
unexpected serious adverse reaction (SUSAR) occurring during the study to determine 
whether additional risks are imposed on patients and make a decision as to suspending 
further enrollment until a final decision has been made. The Sponsor may need to issue an 
investigator notification, to inform all investigators involved in any study with the same drug 
(or therapy) that this SUSAR has occurred. 
7.2.1.2 Reporting procedures 
The investigator must complete the Serious Adverse Event Report Form in English, assess the 
relationship to study treatment, and submit it electronically via eCRF within 24 hours to 
 CRO.  
Follow-up information is to be submitted on a new SAE Form. The new form should clearly 
state that it is a follow-up to the previously reported SAE and give the date of the original 
report. The follow-up SAE report should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or discontinued study 
participation.  
 
 
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7.2.1.3 Contact persons and numbers 
All SAE forms should be notified to the following address: 
  
 
 
 
 
 
 
 
 
  
 
 
 
7.2.1.4 Information to include on SAE form 
The following information should be provided in the SAE form to accurately and completely 
record the event: 
1. 
Investigator name and site address. 
2. 
Patient study identification number. 
3. 
Patient’s initials. 
4. 
Patient demographics (gender, date of birth or age, weight, height). 
5. 
Clinical Event: 
 Description 
 Date and time of onset, stop date, or duration  
 Severity 
 Treatment (including hospitalization) 
 Relationship to study drug (causality) 
 Action taken regarding study drug 
 Information on recovery and any sequelae 
 If the SAE resulted in death 
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o Cause of death (whether or not the death was related to study drug) 
o Autopsy findings (if available) 
 Medical History case report form (copy) 
 Concomitant Medication case report form (copy) 
 Any relevant reports (laboratory, discharge, etc.) 
Accompanying documentation, such as copies of hospital case reports, autopsy reports, and 
other documents when applicable, should be summarized on the SAE form and a copy of the 
source document may be sent if required. The patient’s personal details will be removed and 
replaced with study identifiers i.e. study number and initials, if applicable. 
Reporting of SAEs and other relevant safety information to the Health Authorities, Ethics 
Committees, Principal and Coordinating Investigators and Trial Investigators required by the 
above-mentioned functionaries and institutions will be fulfilled according to the current local 
laws and guidance. The detailed reporting duties and division of responsibilities between the 
sponsor and 
 CRO will be detailed in a separate document (Medical Management 
Manual). Once an event has been assessed as a SUSAR, then information must meet the 
expedited reporting requirements to the local regulatory authorities. The investigator is 
obliged to familiarize herself/himself with the reporting requirements for investigators in 
her/his country. The monitor can help with this.  
 
7.3 ANTICIPATED ADVERSE EVENTS 
Frequent AE in children are related to viral infections and bacterial infections:  
Upper respiratory infection, lower respiratory infection, tonsillitis, ear infection, 
gastroenteritis, skin infection, allergic disease, asthma, arthritis, trauma secondary to physical 
activity, fracture, scoliosis. 
Frequent symptoms in children are: weakness, fever, headache, hoarseness, cough, 
headache, dizziness, earache, abdominal pain, diarrhea, constipation, leg pains, musculo-
skeletal pain, arthralgia, pruritus, skin rash, injection site pain, injection site swelling. 
Frequent operations in children are: Tonsillectomy, adenoidectomy, acute appendicitis 
 
7.4 PREGNANCY REPORTING AND FOLLOW-UP 
For female child, it is possible that she may enter puberty during the course of the study and 
could theoretically become pregnant. As she cannot continue in the study if she were to 
become pregnant, the study physician is obligated to discuss this issue ahead of time with the 
patient and her parents. Study participants are requested to refrain from sexual activity 
during the study i.e. observe complete sexual abstinence as the only acceptable contraceptive 
measure in this study. 
Furthermore, pubertal female child should undergo urine pregnancy test at each upcoming 
visit including EOS visit. 
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If a patient were to become pregnant or thinks she may have become pregnant during the 
study, study physician should be informed immediately, such information will be recorded in 
study documentation and the patient will be asked to stop taking the study medication as it 
may cause unforeseen risks to the unborn baby. Serum pregnancy test will be scheduled 
immediately in such cases, and in the case of the negative result the test should be repeated 
in 2 weeks to confirm or exclude the pregnancy. In case of negative test results the patient 
will be offered to remain in the study and complete the remaining study procedures as 
scheduled. The pregnancy will be reported to the Medical Monitor, pharmacovigilance and 
sponsor and follow up period on mother and child will be defined based on individual basis 
and per discussion with DSMB. 
For male participant, the study physician is obligated to discuss this issue of possible 
conception ahead of time with the male patients and his parents. Study participants are 
requested to refrain from sexual activity during the study i.e. observe complete sexual 
abstinence as the only acceptable contraceptive measure in this study.  
If partner of the male patient becomes pregnant, study physician should be informed 
immediately. The patient mustn’t stop taking the study medication. The pregnancy will be 
reported to the Medical Monitor, pharmacovigilance and sponsor and follow up period on 
mother and child will be defined based on individual basis and per discussion with DSMB. 
7.5 PEN DEVICE COMPLAINT REPORTING REQUIREMENTS 
Any devices which are perceived to malfunction (either before or during use) will be returned 
through a formal complaint system and evaluated to understand the root cause of the failure.  
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be recorded on a complaint form either at the site or using the 
24/7 Helpline.  This includes potential incidents or malfunctions associated with the use of a 
medical device product.  An incident or malfunction of the PEN is an event that might have 
led to death or serious deterioration in health, or if it occurred again might lead to death or 
serious deterioration in health. Sponsor is to be notified immediately of all medical device 
complaints of the investigator’s awareness of the event.  
8. Statistical Analysis 
8.1 STATISTICAL METHODS 
Details of applicable statistical methods will be provided in a Statistical Analysis Plan.  
Data from all clinical assessments will be listed and, where appropriate, summarized by cohort 
using descriptive statistics. Endpoints will be summarized by cohorts and stratifying variables 
as well.  
Summary statistics (arithmetic mean, standard deviation, minimum value, lower quartile, 
median, upper quartile, maximum value, number of non-missing values) will be presented for 
continuous variables (absolute values at each time point and changes from baseline if 
applicable). Frequency statistics (counts and percentages) will be presented for categorical 
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variables. Where appropriate, the presentation of results will include shift tables, plots or 
confidence intervals.  
All statistical evaluations, including efficacy analysis, will be purely exploratory; no hypothesis 
tests will be conducted, hence this pilot study is not powered. 
The assessment of safety will be based mainly on the frequency of AEs, frequency of patients 
developed anti-MOD-4023 antibody and on the number of laboratory values that fall outside 
of pre-determined ranges. Data of all safety endpoints will be listed and tabulated. 
When all patients complete the Main Study a full analysis (CSR) will be performed based on 
the SAP. 
When all patients will complete the second year of treatment an additional analysis will be 
performed. 
8.2 SAMPLE SIZE  
There are no previous pediatric GHD patients for MOD-4023 available to support a formal 
sample size calculation. 
A sample size of 12 patients per cohort has been chosen in this pilot investigation (14 patients 
will be enrolled to get 12 per protocol evaluable patient in each cohort). Each cohort is 
stratified according to peak GH levels with up to 10 patients having peak stimulation test GH 
levels ≤7 ng/ml and up to 4 patients with peak GH levels 
 and 
 ng/ml. The justifications 
for this sample size are based on rationale about feasibility; precision about the mean and 
variance; and regulatory considerations as described by (Julious, 2005). 
 
The selected sample size is large enough that there is about a 50% chance of identifying at 
least 1 patient in the cohort who experiences a treatment emergent adverse event where the 
nature of the event is such that the true chance that a patient has this type of an event during 
the treatment period is 5%.  
 
If the true chance that a patient has event 
during the treatment period is: 
then the chance of identifying at least 1 patient 
who experiences the event during the treatment 
period is: 
5 % 
50% 
10 % 
78% 
15 % 
90% 
20 % 
96% 
 
When combining all MOD-4023 patients (n=42) there is about a 94 percent chance of 
identifying at least 1 patient in the entire group of patients treated with MOD-4023 who 
experiences a treatment emergent event where the nature of the event is such that the true 
chance that a patient has this type of an event during the treatment period is 5%.  
In fact,  
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If the true chance that a patient has event 
during the treatment period is 
then the chance of identifying at least 1 patient 
who experiences the event during the treatment 
period in a sample of size 42 is 
5 % 
94% 
10 % 
99.7% 
15 % 
100% 
8.3 POPULATION ANALYSIS 
The data from randomized patients who did not receive any study medication will be excluded 
from the statistical analysis and will only be listed individually in the Appendix of the final 
study report. 
The following data subsets will be analyzed: 
Safety analysis subset (SAS) 
The safety analysis set will include all randomized patients who have received at least one 
dose of active treatment. 
Full analysis subset (FAS) 
The term “full analysis subset” is used to describe the analysis set which is as complete as 
possible and as close as possible to the intention-to-treat (ITT) ideal of including all 
randomized patients.  
The full analysis set will comprise all randomized patients who have received at least one dose 
of active treatment and who provide any follow-up data for the primary target variables.  
Per protocol subset (PP) 
The basis of PP subset is the full analysis set. 
Handling of drop-outs and missing values will be performed as for the full analysis dataset. 
Protocol deviations excluding patients from the Per Protocol analysis set will be defined in the 
statistical analysis plan and will include failure to satisfy inclusion or exclusion criteria, taking 
any not permitted concomitant medication during the study, serious non-compliance. 
8.3.1 Background and Demographic Characteristics 
Assessments made at the screening and baseline visits will be summarized by treatment 
group. These assessments will include demographic characteristics and other relevant 
parameters and prognostic factors. By-treatment summaries will serve to identify any 
imbalances between the treatment groups at baseline. Summary tables will be provided for 
the full analysis set, for the per-protocol analysis set and for the safety analysis set by means 
of descriptive statistics and frequency tables, where appropriate. In accordance with Altman, 
no significance tests will be performed to assess baseline comparability. 
8.3.2 Study Medication 
For each patient, the individual extent of exposure will be calculated in terms of:  
 Total duration of treatment  
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 Total dose  
These variables will be listed by patient, sorted by treatment group and patient number. 
Summary statistics per treatment group will be tabulated. 
Study drug compliance will be calculated as specified in the Statistical Analysis Plan. It will be 
listed by patient and presented for the FAS and the PP set by means of summary statistics by 
treatment group.  
8.3.3 Concomitant Therapy 
Previous and current medication will be summarized by counts and percentages, overall (any 
pervious or current medication) and per WHO-DRL category. This table will include those 
medications reported on the “Previous and current medication (all visits)” CRF, which have a 
stop date prior to the date of first administration of study medication. All other medication 
entered on these CRF pages will be considered as concomitant medication. 
Previous and current non-medicinal therapy will be handled and tabulated in the same way 
as specified above for previous and current medication. 
8.4 EFFICACY EVALUATION 
The secondary and 
 efficacy endpoints related to IGF-I and IGFBP-3 assessments 
will be subsumed under biochemical endpoints and may serve as pharmacodynamic 
endpoints. 
EFFICACY ENDPOINTS: 
Primary endpoints (Main study): 
 Annual Height Velocity in cm/year at 12 months (Baseline Visit – Visit 1). 
Secondary endpoints (Auxology/Clinical) (Main study): 
 Height velocity at 6 months (Baseline Visit – Visit 1); 
 Delta height SDS at 6 and 12 months (compared to visit 1/Baseline  value). 
Secondary endpoints (Biochemical) (All study periods): 
 Absolute IGF-I levels on day 4 after MOD-4023 dosing; 
 IGF-I SDS on day 4 after MOD-4023 dosing. 
 
 
 
 
 
OLE endpoints (including LT-OLE and LT-OLE-PEN) 
 Annual Height Velocity in cm/year at  each 12 months interval; 
 Delta height SDS every 12 months (compared to the previous value); 
 
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8.4.1 Methods of Efficacy Analysis 
The efficacy analysis will be exploratory, and based upon descriptive summary statistics, 
confidence intervals, exploratory nature statistical tests and graphical data presentations. For 
those parameters (IGF-I or other pharmacodynamic parameters subsumed under secondary 
biochemical endpoints) in which the analysis reveals that a consideration of extent of 
availability – similar to PK parameters – seems to be a meaningful supplement to the usual 
descriptive statistics, additionally, appropriate areas under the time-concentration curves 
may be defined and determined. 
The effect of dose or dose group on the primary and secondary efficacy criteria subsumed 
under biochemical endpoints may be analyzed using ANOVA (analysis of variance) methods. 
Primary and secondary clinical endpoints will be calculated using SAS or other validated 
software and these endpoints may be analyzed using ANOVA methods in order to compare 
the treatment arms. 
The efficacy analysis will be performed based upon the FAS and PP subsets and subgroups 
based on peak hGH level following stimulation tests. 
SAFETY ENDPOINTS: (All study periods) 
 Incidence of adverse events; 
 Incidence of anti-MOD-4023 antibody formation (including characterization of the 
antibodies and neutralizing properties); 
 Local injection site assessment; 
 IGF-I levels; 
 Parameters of glucose metabolism: blood glucose, fasting insulin level, HbA1c; 
 Thyroid status; 
 Lipid parameters;  
 Cortisol levels; 
 All other hematology and biochemical parameters; 
 Physical examination; 
 Vital signs. 
8.5 SAFETY EVALUATION 
The assessment of safety will be based mainly on the frequency of AEs, frequency of anti-
MOD-4023 antibody development and on the number of laboratory values that fall outside 
of laboratory normal ranges. Other safety data (e.g. vital signs, special tests, etc.) will be 
considered as appropriate. 
AEs will be listed by treatment group and patient for the treatment phase. AEs will be 
summarized by presenting, for each treatment group, the number and percentage of patients 
having any AE, having an AE in each body system and having each individual AE. Any other 
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information collected (e.g. severity or relatedness to study medication) will be listed as 
appropriate. 
Summaries and analyses will be based on treatment-emergent adverse events (TEAE), which 
are defined as AEs occurring after the first administration of study medication (as recorded 
on the study discontinuation / end of study CRF) or AEs present before the first dose and 
ongoing after administration with increased severity. Other AEs (pre-treatment AEs) will only 
be listed. 
If appropriate, laboratory and/or ECG data will be summarized by presenting shift tables using 
extended normal ranges (baseline to most extreme post-baseline value), by presenting 
summary statistics of raw data (means, medians, standard deviations, ranges) and change 
from baseline values and by the flagging of notable values in data listings. 
Blood glucose, HbA1c, cortisol, thyroid panel tests and lipid panel tests (with special attention 
on LpA) will be evaluated using standard descriptive statistics, the number of patients who 
had values outside normal values, and by listing values considered clinically relevant by the 
investigator.  
Data from other tests (e.g. blood pressure or vital signs) will be listed, notable values will be 
flagged, and any other information collected will be listed as appropriate. Summary statistics 
will be given where appropriate.  
In addition the number and percentage of patients developing antibodies, including 
neutralizing antibodies, will be summarized by cohort.  
Local tolerability will be summarized based on the investigator’s assessments of pain, 
tenderness, erythema, warmth and swelling which will be done by a scale and predetermined 
schedule during intensive PK/PD sampling. 
The safety analysis will be performed based upon the safety analysis subset.  
8.6 PK/PD EVALUATION  
PK/PD parameters will be calculated utilizing a population PK modeling approach, based on 
limited sampling in each patient.  
The proposed analysis strategy will include the following steps: 
1. Estimate the Population PK/PD means and variances using the Population PK/PD 
analysis.  
2. Perform an Empirical Bayesian estimation to retrieve the individual PK/PD model 
Parameters.  
3. Use these individual PK/PD estimates to generate individual concentration time profile 
using rich sampling to cover the entire desired time range for Non compartmental 
Analysis calculation. 
4. Perform Non compartmental Analysis for estimation of AUC and Cmax. 
 
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9. Ethics 
9.1 ETHICS AND GOOD CLINICAL PRACTICE (GCP) 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Sponsor/CRO standard operating procedures and:  
1. ICH 
Harmonized 
Tripartite 
Guidelines 
for 
Good 
Clinical 
Practice 
1996. 
Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
3. Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human Patients). 
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 ICH-Good Clinical 
Practice that it conforms to. 
9.2 INSTITUTIONAL REVIEW BOARD (IRB) /INDEPENDENT ETHICS COMMITTEE (IEC) 
Before initiating a trial, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the trial protocol/amendment(s), written 
informed consent form, consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients and parents, 
or legal guardians. A signed and dated statement that the protocol and informed consent 
have been approved by the IRB/IEC must be given to the Sponsor before the study initiation. 
The name and occupation of the chairman and the members of the IRB/IEC must be supplied 
to the Sponsor. Any amendments to the protocol, other than administrative ones, produced 
during the course of the study must be approved by these committees. 
9.3 INFORMED CONSENT 
Informed consent for the patient to participate in the clinical study must be given in writing 
prior to participation in the study. 
 It must be signed and personally dated by the parent and/or legal guardian and by the 
investigator and/or the study team member designated by the investigator to conduct the 
informed consent procedure.  Children who can read well are expected to sign an assent form 
prior to the commencement of any study-related procedures. Children who cannot read well 
will be assessed for maturity by the investigator to determine whether an assent can be 
obtained.   
The investigator must explain to each patient and parent (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 
patient must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
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The informed consent (for parents/legal guardian) and assent form (for patients) should be 
given by means of a standard written statement, written in non-technical language. The 
parent/legal guardian (and where appropriate, the patient) should read and consider the 
statement before signing and dating it, and should be given a copy of the signed document. 
If the patient cannot read or sign the documents, oral presentation may be made or signature 
given by the patient’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. 
Additional informed consent form should be signed (re-consent process) by the patient or by 
parents/legal guardian before entering OLE, LT-OLE and LT-OLE-PEN study.  
The informed consent form and assent form is considered to be the part of the protocol, and 
must be submitted by the investigator with it for IRB/IEC approval. The Sponsor will supply a 
proposed informed consent form and assent form, which complies with regulatory 
requirements and is considered appropriate for the study. Any changes to the proposed 
consent form suggested by the investigator must be agreed to by the Sponsor before 
submission to the IRB/IEC and a copy of the approved version must be provided to the 
Sponsor monitor after IRB/IEC approval. 
9.4 DECLARATION OF HELSINKI 
The investigator must conduct the trial in accordance with the principles of the Declaration 
of Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon 
request or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/b3.htm 
9.5 INSURANCE 
The Sponsor will obtain liability insurance, which covers health impairments resulting from 
the medications and/or substances/investigational products administered in the course of the 
study for which the patient has given his/her written informed consent to participate.  The 
liability insurance also covers health impairments resulting from measures carried out on the 
body of the person in connection with this study of a medication and/or 
substance/investigational product carried out in accordance with the study protocol 
procedures. 
9.6 DATA SAFETY MONITORING BOARD (DSMB) 
An independent DSMB will be convened for this study. Its duty is to regularly review the 
progress of the study and assess the accumulating safety data from the study. It will, after 
each meeting, advise the Sponsor on the continuing safety of current participants in the study 
and on the continuing validity and scientific merit of the study. All decisions about the conduct 
of the study will rest solely with the Sponsor.  
Membership of the DSMB will comprise at least one adult endocrinologist, two pediatric 
endocrinologists, and one biostatistician. All of them will have expertise in their field, 
extensive experience in clinical studies and experience of serving on other drug safety 
monitoring committees.  
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DSMB procedures will be described in the DSMB Charter, which will be approved by the 
Sponsor and by each Board member. 
9.7 PROTOCOL AMENDMENTS, OTHER CHANGES IN STUDY CONDUCT 
9.7.1 Protocol Exceptions and Deviations 
No protocol deviations are anticipated as it is expected that patients will meet all eligibility 
criteria.  Departures from the protocol should be avoided, unless required for the safety of 
the patient.  Protocol deviations, and if possible the reason for occurrence, will be 
documented by the study monitor and will be included in the final clinical study report.  
Should any protocol deviation occur, the Investigator must report the deviations to the 
Sponsor and if required, to the IRB/IEC in accordance with local regulations, within reasonable 
time. 
9.7.2 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/IEC in 
accordance with local requirements and, if required, to the Regulatory Authority, either as an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
patients, or when the changes involve only logistical or administrative aspects of the trial. No 
approval is required for notifications. 
9.7.3 Other Changes in Study Conduct 
Changes in study conduct are not permitted. Any unforeseen changes in study conduct will 
be recorded in the clinical study report. 
All clinical work conducted under this protocol is subject to GCP requirements. This includes 
an inspection by the sponsor and/or health authority representatives at any time. The 
investigator will agree to the inspection of study-related records by health authority 
representatives and/or the sponsor or its delegates. 
10. Quality Control and Quality Assurance 
The study will be conducted according to GCP as outlined by ICH Topic E6 step 5 guidelines. 
The CRO maintains a quality assurance system with written SOPs to ensure that clinical trials 
are conducted and data are generated, documented and reported in compliance with the 
protocol, GCP and applicable regulatory requirements. 
10.1 AUDITS AND INSPECTIONS 
The study may be audited according to the Sponsor's QA inspection program. The purpose of 
an audit is to determine whether or not the study is being conducted and monitored in 
compliance with study protocol and ICH GCP guideline. Audit visit(s) will be arranged in 
advance with site personnel at a mutually acceptable time. 
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Sponsor quality assurance or its 
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designees or to regulatory authority inspectors after appropriate notification. The verification 
of the CRF data must be by direct inspection of source documents. These audits or inspections 
may take place at any time, during or after the study, and are based on the national 
regulations, as well as ICH guidelines.  
10.2 STUDY MONITORING 
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a CRO 
or a contract monitor. The study monitor will advise the Investigator regarding the practical 
conduct of the study and maintaining compliance with the protocol, GCP and all applicable 
regulatory requirements.   
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a CRO 
representative will review the protocol and CRFs with the Investigator and his staff. 
Throughout the course of the study, the study monitor will oversee the conduct and the 
progress of the study by frequent contacts with the Investigator. This will include telephone 
calls and on-site visits.  During the on-site visits, the CRF will be reviewed for completeness 
with corresponding source documents.  As part of the data audit, source documents will be 
made available for review by the study monitor. The study monitor will also perform drug 
accountability checks and may periodically request review of the Investigator study file to 
ensure completeness of documentation in all respects of clinical study conduct.  
Periodically, some or all of the facilities used in the study (e.g. local laboratory, pharmacy) 
may be reviewed. Monitoring visits will be arranged in advance with site personnel at a 
mutually acceptable time. Sufficient time must be allowed by the site personnel for the 
monitor to review CRFs and relevant source documents. The Investigator should be available 
to answer questions or resolve data clarifications. The Investigator or appointed delegate will 
receive the study monitor during these on-site visits, cooperate in providing the documents 
for inspection, and respond to inquiries.   
The Investigator will ensure that the study participants are aware of and consent that 
personal information may be scrutinized during the data verification process as part of study-
related monitoring and auditing by properly authorized persons associated with OPKO 
Biologics or inspection by domestic and/or foreign regulatory authority(ies). However, 
participation and personal information should be treated as strictly confidential to the extent 
that the applicable law permits, and not be publicly available.  
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period.   
10.3 QUALITY LABORATORY STANDARDS 
Laboratory tests or evaluations described in this protocol will be conducted in accordance 
with quality laboratory standards as described in the SOPs of the local institution laboratory 
and central laboratories. 
Before the study begins, the laboratories to be used in the study will provide a list of the 
reference ranges for all laboratory tests to be undertaken and details of the method used for 
quality control. These will be held in the Investigator file and the trial master file. The 
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methods employed for each assay should be available on request. Any change in the 
laboratory, procedures, references, values, etc. during the study must be notified promptly 
to the Sponsor. The laboratories may also be audited by the Sponsor or by Regulatory 
Authorities.  
10.4 STUDY DOCUMENTATION 
Study documents will include the following: 
 Signed ICFs (for Main and OLE, LT-OLE and LT-OLE-PEN periods); 
 Source documents (e.g. patient files, medical notes); 
 Investigator copies of the CRFs and SAE reports; 
 Investigator site file + contents; 
 Study manual (Including laboratory manual); 
 Study Pharmacy manual; 
 Investigator meeting binder and or other training materials. 
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period.  
10.5 SOURCE DOCUMENTS 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents.  
Source documents are original records in which raw data are first recorded. These may be 
office/clinic/hospital records, charts, diaries, x-rays, laboratory results, printouts, pharmacy 
records, care records, and completed scales for each study participant.  Source documents 
should be kept in a secure area with limited access.  All source documents must be accurate, 
clear, unambiguous, permanent and capable of being audited. They should be made using a 
permanent form of recording (ink, typing, printing, optical disc etc.). They should not be 
obscured by correcting fluid or have temporary attachments (such as removable self-stick 
notes). Source documents that are computer generated and stored electronically must be 
printed, signed and dated by the Investigator.  
Source data for patients registered to the study should indicate the date the ICF was signed, 
clinical protocol number and title, treatment number, and evidence that inclusion/exclusion 
criteria have been met. 
10.6 RECORDING OF DATA ON ELECTRONIC CASE REPORT FORMS (ECRFS) 
The eCRF is an integral part of the study and subsequent reports. The eCRF provided by OPKO 
Biologics must be used to capture all study data recorded in the patient’s medical record. The 
eCRF must be kept current to reflect patient status during the course of the study. Only a 
patient identification number and patient initials will be used to identify the patient. The 
investigator must keep a separate log of patient names and medical record numbers (or other 
personal identifiers). 
 
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The study will use an Internet-Based Remote Data Entry System, primarily to collect clinical 
trial data at the investigational sites. The system complies with 21 CFR Part 11 and ICH E6 
Good Clinical Practice. The system will be used to enter, modify, maintain, archive, retrieve, 
and transmit data. The system used for this study is Target e*CRF™ (Target Health, Inc., New 
York, NY, USA). The system was configured based on requirements from the Sponsor.  Paper 
source documents are to be retained to enable a reconstruction and evaluation of the trial. 
No original observations will be entered directly into the computerized system. Source 
documents include the hospital patient files and study worksheets provided by the Sponsor. 
Data will be recorded in the study worksheets as appropriate in order to complete and/or 
clarify source data. 
The design of the computerized system complies with all applicable regulatory requirements 
for record keeping and record retention in clinical trials (21 CFR Part 11 and ICH E6 Good 
Clinical Practice) to the same degree of confidence as is provided with paper systems.  Clinical 
investigators must retain either the original or a certified copy of all source documents sent 
to a sponsor or contract research organization, including query resolution correspondence. 
The system is designed so that changes to any record do not obscure the original information. 
The audit record clearly indicates that a change was made and clearly provides a means to 
locate and read the prior information. All changes to the data have an electronic audit trail, 
in accordance with 21 CFR 11.10(e). Electronic signatures will be used in conformance with 
21 CFR Part 11. 
No data will be directly entered into the e-CRF without source documentation. Corrections 
are made in source documents by crossing out the error with a single line, making the correct 
entry in close proximity to the data field, then initialing and dating the strike-through and the 
new entry. 
10.7 INVESTIGATOR SITE FILE 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for monitoring 
and/or auditing by the Sponsor and regulatory agencies. 
10.8 CLINICAL TRIAL SUPPLIES 
The Sponsor will be responsible for the supplying, administrating, inventory, and 
accountability of all clinical trial supplies, exercising accepted medical and pharmaceutical 
practices. An accurate and timely record of the disposition of all clinical supplies must be 
maintained. The supplies and inventory record must be made available for inspection upon 
request. Upon completion or termination of the study, the Investigator will keep the 
remaining clinical supplies along with a copy of the inventory record and a record of the 
clinical supplies returned. Under no circumstances will the Investigator allow the study 
drugs to be used other than as directed by this protocol. 
Clinical trial supplies include, however, not limited to: lab supplies and study drugs. 
 
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10.9 DATA MANAGEMENT 
Data items are entered indirectly from source data documents by designated Accelsiors‐
trained investigator staff using single data entry with electronic verification. 
 staff 
reviews the data for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are generally sent to the investigational site using 
an electronic data query system which provides an automatic audit trail of the corrections 
made by designated investigator staff. Laboratory data will be recorded by Data Management 
to Clinical Data Management system based on the received source documentation. 
After the data have been entered and saved, various edit checks will be performed for the 
purpose of ensuring the accuracy, integrity, and validity of the collected data. These should 
include: 
 Missing value checks; 
 Range checks; 
 Consistency checks; 
 Sequence checks; 
 Probabilistic checks; and 
 Protocol adherence checks. 
It is the responsibility of the study site and investigator to resolve all data queries that arise 
during data validation in a timely manner. 
When all study data is collected, and the database is complete and accurate, a database 
quality control (QC) check is performed on 100% of key safety and efficacy (critical) variables 
and portion of randomly selected non‐critical variables. If all critical and selected non‐critical 
data is quality checked and the error rate is acceptable the database can be locked. Any 
changes to the database after that time can only be made by joint written agreement 
between the Sponsor, the Statistician and the Clinical Data Manager.  
Ongoing QC can additionally be performed at any time‐point during the conduct of a clinical 
study. 
10.9.1 Coding Dictionaries 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List which employs the Anatomical Therapeutic Chemical classification system. 
Coexistent diseases and adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary (version 10.0 or higher). 
11. Study Administration 
11.1  REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION 
Prior to the start of this study, all pre-investigational requirements must be met by the 
Investigator and study site. These may include: 
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 Appropriate local health authority documentation properly signed and dated by the 
required Investigator (i.e. the submission package); 
 Signed copy (original) of the approved protocol; 
 Completed and signed statement of Investigator; 
 A signed Clinical Trial Agreement; 
 Curriculum vitae for the Investigator and sub-Investigator (can be collected at site 
initiation visit); 
 IRB/IEC name and address; and membership list (can be collected at site initiation visit); 
 Letter of approval from the IRB/IEC for both protocol (identified by protocol title and 
number) and ICF (identified by protocol title and number); 
 Copy of the Sponsor and IRB/IEC-approved written ICF to be used in the study; 
 Provisions for direct access to source/data documents if necessary for trial-related 
monitoring, audits, IRB/IEC review, and regulatory inspection. 
Upon satisfactory receipt of all required regulatory documents, the Sponsor will arrange that 
study drugs be delivered to the study site. Supply of all other study materials will be the 
responsibility of OPKO Biologics and/or designee. Patient entry should not begin until after 
the required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred. All personnel expected to be involved in the 
conduct of the study will undergo orientation which will include review of study protocol, 
instructions for CRF completion, AE reporting, and overall responsibilities including those for 
drug accountability and study file maintenance. 
The Investigator and/or designee (study monitor) will prepare an Investigator's File. This file 
which will be used for all trial related documents. The Investigator will be responsible for 
keeping the Investigator's file updated and ensuring that all required documents are filed. The 
file will be inspected during monitoring visits. 
11.2 STUDY COMPLETION 
The Main study is expected to end when all required patients have been enrolled and the last 
patient has completed the Main study (first 12 months of treatment) and the query resolution 
has been completed and clinical study report (CSR) has been compiled  
The LT-OLE-PEN is expected to end when marketing approval is received in countries where 
the study was conducted. 
Data and materials that are required before the study can be considered complete and/or 
terminated are: 
 Laboratory findings, clinical data, and all special test results from screening 
through the end of the follow-up period; 
 CRF (including correction forms) properly completed by appropriate study 
personnel and signed by the Investigator; 
 Completed Drug Accountability Records; 
 Statement of outcome for each SAE reported; 
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Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable). 
11.3 SPONSOR'S TERMINATION OF STUDY  
OPKO Biologics reserves the right to discontinue the study at any time for medical or 
administrative reasons. 
Such reasons may be any of, but not limited to, the following:  
 Inefficacy of the study medication,  
 Occurrence of AEs unknown to date in respect of their nature, severity, and 
duration or the unexpected incidence of known AEs,  
 Medical or ethical reasons affecting the continued performance of the 
study. 
Regulatory Authorities also have the right to terminate the study for any reason. 
11.4 CLINICAL STUDY REPORT 
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines. 
11.5 RETENTION OF DOCUMENTS 
The investigator must maintain source documents for each patient in the study, consisting of 
all demographic and medical information, including laboratory data, electrocardiograms, etc., 
and keep a copy of the signed informed consent form. All information on eCRFs must be 
traceable to these source documents in the patient's file. Data without a written or electronic 
record will be defined before trial start and will be recorded directly on the case report forms, 
which will be documented as being the source data.  
The Investigator will retain copies of the approved protocol, completed CRF, ICFs, relevant 
source documents, and all other supporting documentation related to the project for 15 years 
in a secure and safe facility with limited access. If the Investigator is unable to retain the study 
documents for the required amount of time, Sponsor or designee must be informed of the 
individual who will be assuming this responsibility. 
Further retention, if required, will be negotiated at the end of this 15-year period. In that case, 
OPKO Biologics will notify, in writing, the Investigator when the clinical study data may be 
discarded. The Investigator will take measures to prevent accidental or premature destruction 
of these documents.  
These files must be made available for inspection upon reasonable request by authorized 
representatives of Sponsor and/or the relevant regulatory agencies. 
11.6 PUBLICATION OF RESULTS  
The results of this study will not be published or communicated to any scientific meeting 
without the express agreement of the Sponsor. When permission is given, the Sponsor 
reserves the opportunity to discuss the content and conclusions of any abstract, presentation 
or paper before the material is submitted for publication. Any formal presentation or 
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publication of data from this trial will be considered as a joint publication by the 
investigator(s) and the appropriate Sponsor personnel. Authorship will be determined by the 
mutual agreement. For multicenter studies it is mandatory that the first publication is based 
on data from all centers, analyzed as stipulated in the protocol by the Sponsor statisticians, 
and not by the investigators. Investigators participating in multicenter studies agree not to 
present data gathered from one center or a small group of centers before the full publication, 
unless formally agreed to by all other investigators and the Sponsor. 
The Sponsor must receive copies of any intended communication in advance of publication 
(at least 15 working days for an abstract or oral presentation and 45 working days for a journal 
submission). The Sponsor will review the communications for accuracy (in order to avoid 
potential discrepancies with submissions to health authorities), verify that confidential 
information is not being inadvertently divulged and provide any relevant supplementary 
information.  
The principal investigator will be required to sign the final integrated study report.  
11.7 DISCLOSURE AND CONFIDENTIALITY 
By signing the protocol, the investigator agrees to keep all information provided by the 
Sponsor in strict confidence and to require similar confidentiality from his/her staff and the 
IRB/IEC. Confidential Information includes, without limitation, the protocol or the protocol 
synopsis, and all other study-related information; any trade secrets, inventions or research 
and development information; information related to technology, know-how, engineering or 
other data, processes or techniques; manufacturing, planning or marketing information. 
Study documents provided by the Sponsor (protocols, investigators' brochures, CRFs and 
other material) will be stored appropriately to ensure confidentiality. The information 
provided by the Sponsor to the investigator may not be disclosed to others without direct 
written authorization from the Sponsor, except to the extent necessary to obtain the 
informed consent from patients who wish to participate in the trial.  
 
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12. Investigator's Statement of Responsibility 
By my signature, I confirm that my staff and I have carefully read and understood this 
protocol and agree to comply with the conduct and terms of the study specified therein. In 
particular, I/we have agreed to:  
1. Abide by all obligations stated on Form FDA 1572; 
2. Conduct the study according to the protocol, its amendments, and study guides; 
3. Obtain Ethics Committee approval of the study, any amendments to the study, and 
periodic re-approval, as required; 
4. Obtain witnessed, written informed consent from each study participant or their legal 
representative; 
5. Report all serious adverse events to the Sponsor or its agents and to the Ethics 
Committee, as required by the protocol and Ethics Committee regulations; 
6. Assure access by study monitors to original source documents;  
7. Cooperate fully with any study-related GCP audit as performed by the Sponsor and/or 
Regulatory Agencies; 
8. Maintain confidentiality and assure security of confidential documents such as the 
protocol, consent form, case report form, investigator’s brochure, final study reports, 
manuscript, and/or unpublished data and correspondence.   
 
 
Name and address of the site  
 
Principal Investigator of the site 
 
 
 
Printed Name____________________________ 
 
Signature_________________________ 
 
 
Date_______________________ 
 
 
 
 
 
 
 
 
 
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Appendix 1: Schedule of Assessments – Main Study 
Main Study 
 
Treatment Period 
X – Done in all Cohorts 
M – Done in (MOD-4023) Cohorts 1-3 
G – Done in (Genotropin) Cohort 4 
Screening 
Period I 
Period II 
Months 1-6 
Months 7-12 
≤6 weeks 
W1 
(V1) 
W2* 
(V2) 
W3 
 
W4* 
(V3)/ [M] 
W5 
 
W6* 
(V4) 
W10 
(V5) 
W14  
(V6) 
W 
18 
(V7) 
W22  
(V8) 
W23 
(V9)/ 
[M] 
W26 
(V10) 
Month 
9 
(V11) 
Month 
12 
(V12) 
Informed consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Previous and concomitant medication 
X 
Throughout the study 
Demography 
X 
 
 
Dose escalation for Cohorts 2 and 3 
 
Dose escalation for Cohort 3 
 
 
 
 
 
 
 
 
 
Growth history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Actual height 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
Body weight 
X 
X 
 
 
 
X 
X1 
X 
X 
 
X1 
X 
X 
Physical examination  
X 
X 
X 
M 
X 
X 
X 
X 
X 
M 
X 
X 
X 
Vital signs2 
X 
X5 
X5 
M5 
X5 
X 
X 
X 
X 
M5 
X 
X 
X 
Injection Site Reaction (local 
tolerability) 
 
M6 
X6 
M6 
X6 
X 
X 
X 
X 
X6 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Pubertal status (Tanner) 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Bone age (Greulich-Pyle) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Karyotype in girls 
X 
 
 
 
  
 
 
 
 
 
 
 
 
SHOX evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
GH stimulation tests7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Routine safety 
biochemistry/hematology and 
urinalysis 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
IGF-I and IGFBP-3 
X 
X 
According to sampling tables at the end of 
this appendix 
X 
X 
X 
X 
M 
X 
X 
X 
MOD-4023 levels 
 
M 
According to sampling tables at the end of 
this appendix 
M 
M 
M 
M 
M 
M 
M 
M 
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Main Study 
 
Treatment Period 
X – Done in all Cohorts 
M – Done in (MOD-4023) Cohorts 1-3 
G – Done in (Genotropin) Cohort 4 
Screening 
Period I 
Period II 
Months 1-6 
Months 7-12 
≤6 weeks 
W1 
(V1) 
W2* 
(V2) 
W3 
 
W4* 
(V3)/ [M] 
W5 
 
W6* 
(V4) 
W10 
(V5) 
W14  
(V6) 
W 
18 
(V7) 
W22  
(V8) 
W23 
(V9)/ 
[M] 
W26 
(V10) 
Month 
9 
(V11) 
Month 
12 
(V12) 
Genotropin levels 
 
G 
According to sampling tables at the end of 
this appendix 
G 
G 
G 
G 
 
G 
G 
G 
Anti-MOD- 4023 antibodies 
 
M 
 
 
 
 
 
 
 
 
 
 
M 
 
M 
Anti-hGH antibodies 
X 
G 
 
 
 
 
 
 
 
 
G 
 
G 
Thyroid status ( free T4,  free T3, TSH) 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Cortisol levels 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Standard dose short ACTH test3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting glucose, fasting insulin 
X 
X 
X 
M 
X 
X 
X 
X 
X 
 
X 
X 
X 
HbA1C 
X 
X 
 
 
X 
 
X 
 
 
 
X 
X 
X 
Lipid panel  
X8 
X8 
 
 
 
X 
X8 
X 
X 
 
X8 
X 
X8 
AE assessment 
 
Throughout the study 
Fundoscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
 
X4 
MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MOD-4023 administration 
 
M 
M 
M 
M 
 
 
 
 
M 
 
 
M9 
Genotropin administration 
 
 
G 
 
 
 
 
 
 
 
 
 
G10 
Training for study medication 
administration 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Hand-out of study medication 
 
X 
X 
M 
X 
X 
X 
X 
X 
 
X 
X 
 
Hand-out of patient diary 
 
X 
X 
M 
X 
X 
X 
X 
X 
 
X 
X 
 
Return and accountability of study 
medication 
 
 
 
M 
X 
X 
X 
X 
X 
 
X 
X 
X 
Return and review of patient diary 
 
 
 
M 
X 
X 
X 
X 
X 
 
X 
X 
X 
1 Dose adjustment will be made according to weight measured on three monthly bases. 
2 Heart rate, blood pressure, body temperature, respiratory rate. 
3 Only for patients for which the insulin-stimulation test has not been used or glucagon test has shown peak cortisol level below 500 nmol/l. Will be done at any point during 
the study if there is suspicion of de novo hypoadrenalism. 
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4 Earlier if there are clinical signs of intracranial hypertension. 
5 Vital signs: for all patients allocated to cohorts 1- 3 (MOD) - Pre-dose and at 30 mins, 2h (±20 mins) and 4h (±20mins); for patients in cohorts 4 (Genotropin) at any time 
during the visit.  
6 Injection site reaction: 30 min and 4h (±20 min) post dosing for MOD-4023 cohorts and at any time during the visit for patients in cohort 4 (Genotropin). 
7 Insulin tolerance test, with cortisol response to hypoglycemia if insulin stimulation test is chosen / Arginine test / Clonidine test / Glucagon test (plus or without 
propranolol) / L-dopa plus propranolol. At least one of the two stimulation tests must be analyzed by the central lab. 
8 with Lp(a) lipoprotein. 
9 Last MOD-4023 dosing 4 (-1) days before V12.  
10 Last Genotropin dosing 1 day before V12.  
 
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MOD-4023 Dose Cohorts (Cohorts 1-3) PK/PD Sampling Scheme 
 
Visit  
a 
b 
c 
d 
e 
f 
g 
Time after dosing(h)/ 
Block number 
0h 
6h 
12h 
24h 
48h 
72h 
96h 
120h 
168h 
Block 1 
3.5 ml 
 
 
3.5 ml 
3.5 ml 
 
3.5 ml 
 
 
Block 2 
 
3.5 ml 
 
 
3.5 ml 
3.5 ml 
 
3.5 ml 
 
Block 3 
 
 
3.5 ml 
3.5 ml 
 
3.5 ml 
 
 
3.5 ml 
 
 
 
Genotropin Dose Cohort (Cohort 4) PK/PD Sampling Scheme 
 
Time after dosing(h)/ 
Block number 
0h 
1h 
2h 
4h 
6h 
12h 
16h 
20h 
24h 
Block 1 
3.5 ml 
 
3.5 ml 
3.5 ml 
 
 
3.5 ml 
 
 
Block 2 
 
3.5 ml 
 
3.5 ml 
3.5 ml 
 
 
3.5 ml 
 
Block 3 
 
 
3.5 ml 
 
3.5 ml 
3.5 ml 
 
 
3.5 ml 
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Appendix 2: Schedule of Assessments – 12-Month Open Label Extension (Ole) – Period III 
 
Assessments 
OLE visit # 
FIRST YEAR OLE STUDY MONTH 
follow 
up  Visit1 
Day 1 & 
Month 12  
Month 3  
Month 6  
Month 9  
Month 12 
Visit 0 
Visits 1-2   
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Previous and concomitant medication 
 
X 
X 
X 
X 
X 
Actual height 
 
X 
X 
X 
X 
X 
Body weight 
 
X 
X 
X 
X 
X 
Physical examination  
 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
Injection Site Reaction (local tolerability) 
 
X 
X 
X 
X 
X 
ECG 
 
 
 
 
 
X 
Pubertal status (Tanner) 
 
 
 
 
 
X 
Bone age (Greulich-Pyle) 
 
 
 
 
 
X 
Routine safety biochemistry/hematology 
and urinalysis 
X 
X 
X 
X 
X 
X 
IGF-I and IGFBP-3 
X 
X 
X 
X 
X 
X 
MOD-4023 serum levels 
X 
X 
X 
X 
X 
X 
Anti-MOD- 4023 antibodies 
X3 
 
 
X 
 
X 
Thyroid status ( free T4,  free T3, TSH) 
 
X 
X 
X 
X 
X 
Cortisol levels 
 
X 
X 
X 
X 
X 
Fasting glucose, fasting insulin 
X 
X 
X 
X 
X 
X 
HbA1C 
X 
X 
X 
X 
X 
X 
Lipid panel  
 
X 
X 
X 
X 
X 
Lipoprotein  
 
 
 
 
 
X 
AE assessment 
 
X 
X 
X 
X 
X 
Fundoscopy 
 
 
 
 
 
X4 
MOD-4023 administration 
 
X 
 
 
 
 
Training for study medication 
administration 
 
X 
 
 
 
 
Dispense study medication 
X 
X 
X 
X 
X 
X 
Dispense patient diary 
X 
X 
X 
X 
X 
X 
Return and accountability of study 
medication 
 
X 
X 
X 
X 
X 
Return and review of patient diary 
 
X 
X 
X 
X 
X 
 
                                                          
1 Applicable only to patients who were off-treatment for over 
 between Main Study Month 12 and Visit 1 OLE. 
2 Applicable only patients who received Genotropin in the Main Study and switched to MOD-4023 will attend the following 
visits: 
Day 1 is Month 12 visit of the Main Study in which the patient will be trained on medication administration and Visit 2/OLE 
will be 28 days + 4 (-1) days after the first MOD-4023 injection. 
3 Applicable for Genotropin patients  
4 Earlier if there are clinical signs of intracranial hypertension. 
 
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Appendix 3: Schedule of Assessments – Long-Term OLE (LT-OLE) Period IV from Second Year of OLE/Third Year of Treatment until switch to 
LT-OLE-PEN period 
 
follow 
up  
Visit1 
First 
Month 
3 visit2  
(on day 
3 or 4 
post-
dosing) 
Early termination 
visit3 
LT OLE visits by Month over each year until switch to LT-
OLE-PEN period 
 
Month 3 
visit  
 
Month 6 
visit 
 
Month 9 
visit 
 
Month 12  each 
year and End of 
Study Visit 
Assessments 
Visit 0 
Visit 1a 
On 
Dosing 
Day 
day 4 (-1) 
post dose 
day 4 (-1) 
post 
dose 
day 4 (-1) 
post dose 
day 4 (-1) 
post dose 
On 
Dosing 
Day  
day 4 (-
1) post 
dose 
Auxology measurements: Actual height measured on a 
calibrated stadiometer and body weight measurement 
 
X 
X 
 
X 
X 
X 
X 
 
Adjustment of dose for weight 
 
 
X 
 
X 
X 
X 
X 
 
AEs 
 
 
X 
 
X 
X 
X 
X 
 
Local tolerability 
 
 
X 
 
X 
X 
X 
X 
 
Concomitant medication 
 
X 
X 
 
X 
X 
X 
X 
 
Dispensing of drug 
 
 
 
 
X 
X 
X 
X 
 
IGF-I, IGFBP-3 and MOD-4023 serum levels 
X 
X 
 
X 
 
X 
 
 
X 
MOD-4023 serum levels 
 
 
X 
 
 
 
 
X 
 
Anti-MOD-4023 antibodies 
X 
X 
X 
 
 
 
 
X 
 
Physical examination 
 
X 
X 
 
 
 
 
X 
 
Vital signs 
 
X 
X 
 
 
 
 
X 
 
Glucose metabolism (fasting glucose & insulin, HbA1c) 
X 
X 
X 
 
 
 
 
X 
 
Other hormonal levels (TSH,  free T4, free  T3, cortisol) 
 
 
X 
 
 
 
 
X 
 
                                                          
1 Applicable only to patients who were off-treatment for over 60 days between OLE Month 12 and Visit 1 LT-OLE. 
2 This visit applies only to patients in Cohorts 1 and 2 who switch to MOD-4023 0.66 mg/kg/week; this will be their first visit after the switch. Selected group of patients may be switched 
during the 2nd year and will be required to undergo this visit three months after their switch. 
3 This visit applies to patients who discontinue the study prematurely for any reason (including not switching to higher dose). 
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follow 
up  
Visit1 
First 
Month 
3 visit2  
(on day 
3 or 4 
post-
dosing) 
Early termination 
visit3 
LT OLE visits by Month over each year until switch to LT-
OLE-PEN period 
 
Month 3 
visit  
 
Month 6 
visit 
 
Month 9 
visit 
 
Month 12  each 
year and End of 
Study Visit 
Parameters of lipid metabolism 
 
 
X 
 
 
 
 
X 
 
Routine safety laboratory (biochemistry, hematology and 
urinalysis) 
X 
X 
X 
 
 
 
 
X 
 
Pubertal status 
 
 
X 
 
 
 
 
X 
 
ECG 
 
 
X 
 
 
 
 
X 
 
Bone age 
 
 
X 
 
 
 
 
X 
 
LH, FSH and Testosterone4 
 
 
X 
 
 
 
 
X 
 
LH, FSH and Estradiol5 
 
 
X 
 
 
 
 
X 
 
Patient diary dispensing and return of completed diaries 
 
 
 
 
X 
X 
X 
X 
X 
                                                          
4 For male patients that are at the age of 13 years and above. 
5 For female patients that are at the age of 12 years and above. 
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Appendix 4: Schedule of Assessments – Long-Term OLE PEN (LT-OLE-PEN) Period V first 
year 
 
PEN Visit 1 
(PEN V1) 
 
 PEN Visit 
2 (PEN 
V2) 
4 weeks 
(+1) after 
PEN visit 
V1 
LT OLE PEN visits by Month over the first 
year 
 
Month 
3 visit 
(±2 
week)  
Month 
6 visit 
(±2 
week) 
Month 
9 visit  
(±2 
week) 
 
Month 12  
(±2 week)1 
Assessments 
On Dosing 
Day (pre-
dose) 
day 4 (-1) 
post dose 
day 4 (-
1) post 
dose 
day 4 
(-1) 
post 
dose 
day 4 
(-1) 
post 
dose 
On 
Dosing 
Day 
day 4 
(-1) 
post 
dose 
Informed consent/ assent 
X 
 
 
 
 
 
 
Auxology measurements (actual 
height measured on calibrated 
stadiometer)  
X 
 
X 
X 
X 
X 
 
Body Weight measurement 
X 
X 
X 
X 
X 
X 
 
Adjustment of dose for weight 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
 
Local tolerability 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
 
 
 
X 
X 
X 
X 
X 
 
Dispensing of drug 
X 
X 
X 
X 
X 
X 
 
Return of used drugs  
X2 
X 
X 
X 
X 
X 
 
Training on PEN  
X 
X3 
 
 
 
 
 
Fundoscopy- If required 
X 
X 
X 
X 
X 
X 
 
IGF-I, IGFBP-3  
X 
X 
X 
X 
X 
 
X 
MOD- 4023 serum levels  
X 
X 
X 
X 
X 
X 
 
Anti-MOD-4023 antibodies 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
Glucose metabolism (fasting glucose & 
insulin, HbA1c) 
X 
 
X 
X 
 
X 
 
Other hormonal levels (TSH,  free T4, 
cortisol) 
X 
 
X 
X 
 
X 
 
Parameters of lipid metabolism 
X 
 
X 
X 
 
X 
 
Routine safety laboratory 
(biochemistry, hematology and 
urinalysis) 
X 
 
X 
X 
 
X 
 
Urine pregnancy test4 
X 
X 
X 
X 
X 
X 
 
                                                          
1 In case ET/EOS visit is conducted all assessment should be done at one visit with no split.  
2 Return of used and unused MOD-4023 vials.  
3 If required. 
4 For females of child bearing potential. In case urine pregnancy test is positive, please refer to section 7.4 in the protocol. 
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PEN Visit 1 
(PEN V1) 
 
 PEN Visit 
2 (PEN 
V2) 
4 weeks 
(+1) after 
PEN visit 
V1 
LT OLE PEN visits by Month over the first 
year 
 
Month 
3 visit 
(±2 
week)  
Month 
6 visit 
(±2 
week) 
Month 
9 visit  
(±2 
week) 
 
Month 12  
(±2 week)1 
Pubertal status 1 
X 
 
X 
X 
X 
X 
 
ECG around Tmax (7-12 hours post 
dose)2 
 
 
 
 
 
X 
 
Bone age 
X3 
 
 
 
 
X 
 
LH, FSH and Testosterone4 
X 
 
 
 
 
X 
 
LH, FSH and Estradiol5 
X 
 
 
 
 
X 
 
Provide patient diary and return of 
completed diaries 
 
 X 
X 
X 
X 
X 
X 
 
 
 
 
                                                          
1 In case the patient becomes pubertal, childbearing potential and refraining from sexual activity will be discussed with the 
patient. 
2 In case not possible to conduct the ECG around Tmax at the 12 months visit, it can be performed on month 12± 3 weeks 
(7-12 hours post dose). 
3 Bone age measurement will be performed in case the previous assessment was done more than 6 months prior to this 
visit.  
4 For male patients that are at the age of 13 years and above. 
5 For female patients that are at the age of 12 years and above. 
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Appendix 5: Schedule of Assessments – Long-Term OLE PEN (LT-OLE-PEN) Period V from 
2nd year until marketing approval 
 
LT OLE PEN visits by Month over each year the study is running 
 
Month 3 visit 
(±2 week) 
Month 6 visit 
(±2 week) 
Month 9 visit 
(±2 week) 
 
Month 12 
(±2 week)1 
Assessments 
day 4 (-1) post 
dose 
day 4 (-1) post 
dose 
day 4 (-1) post 
dose 
day 4 (-1) post 
dose 
Auxology measurements: actual 
height measured on calibrated 
stadiometer 
X 
X 
X 
X 
Body weight measurement  
X 
X 
X 
X 
Adjustment of dose for weight 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
Local tolerability 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
Dispensing of drug 
X 
X 
X 
X 
Return of used drugs  
X 
X 
X 
X 
Fundoscopy - If required 
X 
X 
X 
X 
IGF-I, IGFBP-3  
X 
X 
X 
X 
MOD- 4023 serum levels  
 
X 
 
X 
Anti-MOD-4023 antibodies 
 
X 
 
X 
Physical examination 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Glucose metabolism (fasting glucose 
& insulin, HbA1c) 
 
X 
 
X 
Other hormonal levels (TSH,  free T4, 
cortisol) 
 
X 
 
X 
Parameters of lipid metabolism 
 
X 
 
X 
Routine safety laboratory 
(biochemistry, hematology and 
urinalysis) 
 
X 
 
X 
Urine pregnancy test2 
X 
X 
X 
X 
Pubertal status3 
X 
X 
X 
X 
ECG 
 
 
 
X 
Bone age 
 
 
 
X 
LH, FSH and Testosterone4 
 
 
 
X 
LH, FSH and Estradiol5 
 
 
 
X 
Provide patient diary and return of 
completed diaries 
X 
X 
X 
X6 
 
 
                                                          
1 In case ET/EOS visit is conducted all assessment should be done as one with no split.  
2 For females of child bearing potential. In case urine pregnancy test is positive, please refer to section 7.4 in the protocol. 
3 In case the patient becomes pubertal, childbearing potential and refraining from sexual activity will be discussed with the 
patient. 
4 For male patients that are at the age of 13 years and above. 
5 For female patients that are at the age of 12 years and above. 
6 Dispensing patient diary is not applicable for termination visit, only return of completed diaries. 
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Appendix 6: World Medical Association Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI - Ethical Principles for Medical 
Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant 
paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA 
encourages other participants in medical research involving human subjects to 
adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, 
including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, 
"The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act in the patient's best 
interest when providing medical care." 
5. Medical progress is based on research that ultimately must include studies 
involving human subjects. Populations that are underrepresented in medical 
research should be provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual 
research subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures 
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and treatments). Even the best current interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, 
accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks 
and burdens. 
9. Medical research is subject to ethical standards that promote respect for all 
human subjects and protect their health and rights. Some research 
populations are particularly vulnerable and need special protection. These 
include those who cannot give or refuse consent for themselves and those who 
may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and 
standards for research involving human subjects in their own countries as well 
as applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. 
12. Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that 
may harm the environment. 
14. The design and performance of each research study involving human subjects 
must be clearly described in a research protocol. The protocol should contain 
a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest, incentives for subjects and provisions for 
treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions 
identified as beneficial in the study or access to other appropriate care or 
benefits. 
15. The research protocol must be submitted for consideration, comment, 
guidance and approval to a research ethics committee before the study begins. 
This committee must be independent of the researcher, the sponsor and any 
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other undue influence. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed 
to reduce or eliminate any of the protections for research subjects set forth in 
this Declaration. The committee must have the right to monitor ongoing 
studies. The researcher must provide monitoring information to the 
committee, especially information about any serious adverse events. No 
change to the protocol may be made without consideration and approval by 
the committee. 
16. Medical research involving human subjects must be conducted only by 
individuals with the appropriate scientific training and qualifications. Research 
on patients or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the 
physician or other health care professional and never the research subjects, 
even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or 
community is only justified if the research is responsive to the health needs 
and priorities of this population or community and if there is a reasonable 
likelihood that this population or community stands to benefit from the results 
of the research. 
18. Every medical research study involving human subjects must be preceded by 
careful assessment of predictable risks and burdens to the individuals and 
communities involved in the research in comparison with foreseeable benefits 
to them and to other individuals or communities affected by the condition 
under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject. 
20. Physicians may not participate in a research study involving human subjects 
unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians must immediately stop 
a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
research subjects. 
22. Participation by competent individuals as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or 
community leaders, no competent individual may be enrolled in a research 
study unless he or she freely agrees. 
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23. Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information and to minimize the impact of 
the study on their physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential 
subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of 
individual potential subjects as well as to the methods used to deliver the 
information. After ensuring that the potential subject has understood the 
information, the physician or another appropriately qualified individual must 
then seek the potential subject's freely-given informed consent, preferably in 
writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians 
must normally seek consent for the collection, analysis, storage and/or reuse. 
There may be situations where consent would be impossible or impractical to 
obtain for such research or would pose a threat to the validity of the research. 
In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the 
physician should be particularly cautious if the potential subject is in a 
dependent relationship with the physician or may consent under duress. In 
such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek 
informed consent from the legally authorized representative. These individuals 
must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the population represented 
by the potential subject, the research cannot instead be performed with 
competent persons, and the research entails only minimal risk and minimal 
burden. 
28. When a potential research subject who is deemed incompetent is able to give 
assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorized representative. 
The potential subject's dissent should be respected. 
29. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical 
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or mental condition that prevents giving informed consent is a necessary 
characteristic of the research population. In such circumstances the physician 
should seek informed consent from the legally authorized representative. If no 
such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to 
give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee. Consent to remain in the 
research should be obtained as soon as possible from the subject or a legally 
authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors have a duty to make publicly 
available the results of their research on human subjects and are accountable 
for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results should be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication.  
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE  
31. The physician may combine medical research with medical care only to the 
extent that the research is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the 
patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best current proven intervention, except in the 
following circumstances:  
 
The use of placebo, or no treatment, is acceptable in studies where no 
current proven intervention exists; or 
 
Where for compelling and scientifically sound methodological reasons 
the use of placebo is necessary to determine the efficacy or safety of 
an intervention and the patients who receive placebo or no treatment 
will not be subject to any risk of serious or irreversible harm. Extreme 
care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to 
be informed about the outcome of the study and to share any benefits that 
result from it, for example, access to interventions identified as beneficial in 
the study or to other appropriate care or benefits. 
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34. The physician must fully inform the patient which aspects of the care are 
related to the research. The refusal of a patient to participate in a study or the 
patient's decision to withdraw from the study must never interfere with the 
patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have 
been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgment it offers hope of saving 
life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its 
safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made publicly available. 
 
 
 
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Appendix 7: Growth Hormone Stimulation Tests and Other Assessments 
Growth Hormone Stimulation Tests 
As stated in the 2000 Growth Hormone Research Society Consensus Guideline: “In a child with 
clinical criteria for GHD, a peak GH concentration less than 
 ng/ml has traditionally been 
used to support the diagnosis. At the present time, a new GH reference standard is being 
introduced that may require a downward adjustment of the lower limit of normal” (Growth 
Hormone Research Society Consensus Guidelines for the Diagnosis and Treatment of Growth 
Hormone (GH) Deficiency in Childhood and Adolescence (2000))1. 
The new standard is currently used in the USA and EU. However, the common clinical practice 
remains to treat patients with GH below 
ng/ml. The cutoff for this study is in line with this 
common clinical practice. 
Two different GH-stimulation tests will be done to confirm the diagnosis and eligibility of 
patients. At least one of the two stimulation tests (and preferably both) will be analyzed by 
the central laboratory. 
Sex Hormone Priming 
Prior to the stimulation tests performed during the screening period, sex hormone priming 
will be performed as follows:  
Boys - A single dose of 100 mg intramuscular depo-testosterone will be administered 5 days 
before the stimulation test. 
Girls - Ethinylestradiol will be given as 25 µg p.o. twice a day over 5 days before the stimulation 
test (a total of 10 doses) or Beta estradiol will be given as 2 mg p.o. once a day for 3 days 
before the stimulation test (a total of 3 doses). 
If the patient requires sex hormone priming (due to the age) and both stimulation tests must 
be performed during the Screening (no historical samples were kept, or the test was without 
priming), it is recommended to perform stimulation tests in one of the following two settings, 
so as to avoid priming the patient twice. Local historical tests without sex-steroid priming will 
not be accepted for patients that require sex steroid priming according to the protocol.  
It is possible to perform combined growth hormone stimulation tests, in the two following 
ways, so as to avoid priming the patient twice:  
a) Perform two GH stimulation tests in a consecutive setting, in one day: immediately after 
drawing the last sample of the first test the stimulating agent of the second test will be 
given (there is no need for the -30 sample for the second test). After most of the tests, 
patients need some time to rest (ITT, glucagon), and are even sleepy (clonidine), so the 
second test performed immediately after the first one brings no additional discomfort. In 
this setting, one priming is to be performed, before the first test only. 
b) Perform two GH stimulation tests in two consecutive days, with the sex hormone priming 
before the first test only; female patients should then have one additional day of receiving 
                                                          
1 JCEM 2000. Vol. 85 (11): 3990-3993. 
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■ 


 
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Ethinylestradiol (2 additional doses) or Beta estradiol (1 additional dose), before the 
second stimulation test. 
The investigator, together with parents/legal guardians, will make the decision which one 
is more convenient for the patient. 
Insulin Tolerance Test 
Regular human insulin (0.10-0.15 IU/kg) will be administered intravenously (i.v.) at time point 
0. The test will be interpretable if the blood glucose level decreases below 40 mg/dL. 
Administration of i.v. dextrose will be allowed if the patient develops severe signs of 
hypoglycemia. ITT is contraindicated in patients with a history of seizures or coronary artery 
disease. 
Blood will be collected at the following intervals: t = – 30, 0, 15, 30, 45, 60, 90, and 120 min 
(8 sampling points) for glucose, hGH and cortisol determination.  
A normal ACTH reserve is defined as a baseline cortisol level above 190 nmol/l (7 μg/dL) or an 
increase in peak cortisol level above 500 nmol/l (18 μg/dL). 
Clonidine test 
After fasting overnight, clonidine (0.15 mg/m2 body surface, given orally) will be given at time 
t = 0, and venous blood will be obtained by an indwelling catheter inserted in a cubital vein 
and kept patent by slow infusion of isotonic saline. Blood will be collected at 30 min intervals, 
between t = - 30 to +150 min (7 sampling points) for hGH measurement. Caution should be 
exercised when performing this test however, as clonidine causes side effects such as 
tiredness and decreased blood pressure. Thus, blood pressure must be monitored prior to, 
and up to 30 min after normalization. 
Arginine test 
Soluble arginine hydrochloride (0.5 g/kg) will be given i.v. from time t = 0 to t = 30 min after 
an overnight fast. Blood samples will be obtained by an indwelling catheter inserted in a 
cubital vein and kept patent by slow infusion of isotonic saline. Blood will be collected at the 
following intervals: t = –30, 0, 15, 30, 45, 60, 90, and 120 min (8 sampling points) for hGH 
measurement.  
Glucagon test 
After fasting overnight, glucagon (0.03 mg/kg with a maximal total dose of 1 mg) will be given 
i.m. or s.c. at time t = 0, and venous blood will be obtained by an indwelling catheter inserted 
in a cubital vein and kept patent by slow infusion of isotonic saline. Blood will be collected for 
hGH measurement at -30, 0, 60, 90, 120, 150 and 180 min relative to the time of glucagon 
administration.  
Glucagon test is not recommended for assessing the cortisol status. However, a normal ACTH 
reserve can be defined as a peak cortisol level above 500 nmol/l (18 μg/dl). If the peak cortisol 
level reached during the glucagon test (referring to a historical test only) is lower, then an 
ACTH stimulation test is needed to confirm the diagnosis of hypoadrenalism.  
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L-Dopa test 
After fasting overnight L-Dopa will be given orally at time-point t=0 in dose of 125 mg if body 
weight is less than 15 kg, else 250 mg if body weight is less than 35 kg, else 500 mg if body 
weight is greater than 35 kg. Blood samples will be obtained by an indwelling catheter 
inserted in a cubital vein and kept patent by slow infusion of isotonic saline. Blood will be 
collected at the following intervals: –30, 0, 30, 60, 90 and 120 minutes. 
Cortisol levels  
Screening serum cortisol (in conjunction with a screening ITT for GH reserve; or glucagon test) 
and routine follow-up serum cortisol will be determined in ALL screened patients 
with/without pre-existing central hypoadrenalism, and additional serum cortisol will be 
determined when there is suspicion of either de novo central hypoadrenalism or exacerbation 
of pre-existing central hypoadrenalism. Screening ACTH stimulation (Standard Dose Short 
ACTH test) will be performed only in patients without pre-existing central hypoadrenalism, 
and additional ACTH stimulation tests will be performed when there is suspicion of de novo 
central hypoadrenalism. 
The Standard Dose Short ACTH test will be performed after overnight fasting. An i.v. catheter 
will be inserted into the cubital vein; a baseline sample for serum cortisol will be taken and 
then the set will be heparinized. Subsequently, 250 µg of alpha 1-24 ACTH will be injected 
intravenously as a bolus and blood samples for serum cortisol will be taken at 30 and 60 min 
post dose.  
If the cortisol level remains below 18 μg/dL (500 nmol/L) at both post-dose time-points, the 
child should be investigated outside of this protocol for primary or secondary adrenal 
insufficiency. Associated clinical symptoms like lethargy, weight loss, anorexia, nausea, 
vomiting, hyperpigmentation, shock, hypoglycaemia, eosinophylia and electrolyte imbalance 
will further emerge the need for the investigation of adrenal insufficiency.  
Assessment of pubertal status 
Pubertal status will be documented by physical examination according to the schedule in 
Appendix 1. Boys will be assessed for descent of the testes and testis volumes, girls for the 
breast development according to Tanner stages (Tanner JM, 1976). Pubic hair rating will also 
be recorded according to Tanner stages. 
 
 
 
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Appendix 8: Injection Site Assessment Table (Local Reactions) 
 
Redness 
 
Grade Description 
 
0 
NONE  
No visible redness 
 
1 
MILD 
 
0 to 2 cm redness 
 
2 
MODERATE 
2 to 5 cm redness 
 
3 
SEVERE 
Greater than 5 cm redness 
Redness will be assessed by a member of the study staff. An additional assessment by a physician will be made 
in case a local reaction has been evaluated as moderate or severe. 
 
Bruising 
 
Grade Description 
 
0 
NONE  
No visible bruising 
 
1 
MILD 
 
0 to 2 cm bruising 
 
2 
MODERATE 
2 to 5 cm bruising 
 
3 
SEVERE Greater than 5 cm bruising 
Bruising will be assessed by a member of the study staff. An additional assessment by a physician will be made 
in case a local reaction has been evaluated as moderate or severe. 
 
Swelling 
 
Grade Description 
 
0 
NONE  
No swelling detected 
 
1 
MILD 
 
Palpable “firmness” only 
 
2 
MODERATE 
< 4 cm swelling 
 
3 
SEVERE > 4 cm swelling 
Swelling will be assessed by a member of the study staff. An additional assessment by a physician will be made 
in case a local reaction has been evaluated as moderate or severe. 
 
Itching 
Grade Description 
 
0 
NONE  
 
 
1 
MILD 
 
 
 
2 
MODERATE 
 
 
3 
SEVERE  
The patients will be asked the degree of itching they are experiencing. An additional assessment by a physician 
will be made in case a local reaction has been evaluated as moderate or severe. 
 
 
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Pain 
 
 
 
The patients will be asked to point to the face that best describes the pain they are experiencing (in 
the patient diary) and circle the corresponding number. 
 
 
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Pain Assessment 
Wong-Baker Faces scale 
®®®®®® 
0 
1 
2 
3 
4 
5 
No 
Hurt 
Hurts 
Hurts 
a little 
a little 
bit 
more 
Hurts 
Hurts 
Hurts 
even 
a whole worse 
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Appendix 9: Instructions for Obtaining Height Measurements 
Use the following instructions when obtaining height measurements: 
1. Use a wall-mounted calibrated stadiometer. 
2. Patients should not stretch prior to height determination. 
3. The patient must be standing without shoes. 
4. The patient should be wearing only light clothing so that the patient's pose can be 
observed. 
5. The patient's gaze must be forward and horizontal. (Frankfurt position) 
6. Heels must be placed together. -If the patient has genu valgum (knock-knee), the 
knees must be in contact with each other and the heels as close to each other as 
possible. 
7. Heels, buttocks, shoulders, and occiput of the cranium must be in contact with the 
stadiometer. 
8. Upward pressure must be applied to the mandibular rami (jaw). 
9. Shoulders should be relaxed and pressure applied to the abdomen to reduce lordosis 
(spine curvature). 
10. The counterweight head rest is lowered until it is in contact with the highest part of 
the patient's head. 
11. Measurement is read at the horizontal level with the counter. 
12. Have the patient step away from the stadiometer and repeat the previous steps two 
more times. Repeated determinations must be within 0.5 cm of each other, otherwise 
the complete measurement needs to be repeated and recorded. 
13. Record all measurement, the time of measurement and the observer’s Name in the 
CRF.  
 
 
 
 
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Protocol for Clinical Study CP-4-004 
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Confidential Document 
Appendix 10: Instructions for Obtaining X-Ray Films 
It is necessary to have a good assessment of the skeletal age from an X-ray of the hand. The 
X-ray should be taken of the left hand, which is placed palm down, wrist and hand flat on the 
film holder, fingers should be slightly separate and the axis of the hand, wrist and forearm 
should be a straight line. Center the tube half way between the tips of the fingers at least 3 
cm of the radius, in order to obtain a picture of the hand epiphyses and the distal radius, the 
longitudinal axis should meet the 3rd finger ray and the horizontal axis should cross the head 
of the 3rd metacarpal. A 24/30 cm no-screen card board holder should be used. A small focus 
should be used with a film-focus distance of 1.00 m. 
Films should only be identified by center number, patient number and the gender of the 
patient. 
Historical films (if not older than 6 months at Screening), should mask the patient’s 
identification details, and contain only the center number, patient number and the gender of 
the patient. 
Either originals or high quality copies should be sent to central bone age reader. 
Detailed study specific instructions will describe the handling and circulation of X-ray films. 
 
 
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Appendix 11: List of Central Technical Facilities 
 
 
 
Testing USA 
 
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13. References 
Bayley N, P. S. (1952). Tables for predicting adult height form skeletal age revised for Greulich and 
Pyle standards. Journal of Pediatrics, 40: 423-441. 
Greulich , W., & Pyle, S. (1959). Radiographic Atlas of Skeletal Development of the Hand and Wrist. 
Stanford University Press, 2nd edition. 
Hassan HMS, K. H. (1995 ). Lipoprotein(a) changes during growth hromone treatment. Clinical 
Endocrinology , 43 655. 
Hassan HMS, K. H. (1996). Body composition, atherogenic risk factors and apolipoproteins following 
growth hormone treatment . Acta Paediatrica , 85 899-901. 
Julious, S. (2005). Sample size of 12 per group rule of thumb for a pilot study. Phamaceutical 
Statistics, 4: 287-291. 
Mooser V, H. H. (1997). Lipoprotein(a) and growth hormone: is the puzzle solved? European Journal 
of Endocrinology, 137: 450-2. 
Olivecrona H, E. S. (1993). Increased concentrations of serum lipoprotein(a) in response to growth 
hormone treatment. British Medical Journal, 306: 1726-1727. 
Prader A, L. R. (1989). Physical growth of Swiss children from birth to 20 years of age. First Zurich 
longitudinal study of growth and development. Helvetica Paediatrica Acta, 52: 1-125. 
Tanner JM, W. R. (1976). Clinical longitudinal standards for height, weight, height velocity, weight 
velocity, and stages of pubery. Archives of Disease in Childhood, 3: 170-179. 
Wieringa G, T. A. (2000, August). Changes in lipoprotein(a) levels measured by six kit methods during 
growth hormone treatment of growth hormone-deficient adults. Growth Hormone & IGF 
Research, pp. 10(4):230-1. 
 
 
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SAP_001.pdf: 
Open Label Extension Statistical Analysis Plan
OPKO Biologics Ltd.
Protocol No. CP-4-004
Page 1 of 30
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STATISTICAL ANALYSIS PLAN
Version 3.0
Date: 24 June 2024
For the Open Label Extension (OLE) of
Protocol: CP-4-004
Safety and dose finding study of different MOD-4023 dose levels
compared to daily r-hGH therapy in pre-pubertal growth hormone
deficient children
OPKO Biologics Ltd.
16 Ashlagan St.
Kiryat Gat, Israel
Date of the Protocol: CP-4-004 Version 10, 03 October 2017 (Global Amendment 9)
Prepared by:
OPKO Health, Inc
4400 Biscayne Blvd.
Miami, FL 33137, USA


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Protocol No. CP-4-004
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DOCUMENT VERSION CONTROL
Version Number
Date
Comments/Change
1.0
31 May 2019
Original final.
2.0
03 Oct 2019
Added baseline summaries for Height (HT) standard 
deviation score (SDS), insulin like growth factor-1
(IGF-1) SDS, Bone Age (BA), and Height Velocity
(HV).
Added the calculation of cumulative change in HT 
SDS from year 1 baseline, based on original dosing 
group.
Added the classification of antibody status as 
determined from year 1 results, in addition to the 
classification based only on OLE results.
HV and HT SDS will be presented at each year based 
on original dosing group, in addition to the summary 
across dosing groups. 
Pubertal status will be summarized for each year.
3.0
24 June 2024
Updated to include data from all visits to end of study 
(EOS) closure.
Updated relevant table and listing titles to reflect all 
additional years of data to EOS closure.
Prepared by, on the title page, update to OPKO 
Health, Inc.




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Protocol No. CP-4-004
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN .............................................................................................1 
TABLE OF CONTENTS ..............................................................................................................3 
1 
LIST OF ABBREVIATIONS................................................................................................6 
2 
INTRODUCTION ..................................................................................................................8 
3 
OBJECTIVES AND ENDPOINTS.......................................................................................9 
3.1 
Objectives............................................................................................................................9 
3.1.1 
Primary Objectives ......................................................................................................9 
3.1.2 
Secondary Objectives...................................................................................................9 
3.2 
Endpoints............................................................................................................................9 
3.2.1 
Safety Endpoints ..........................................................................................................9 
3.2.2 
Growth Outcomes........................................................................................................9 
4 
STUDY DESIGN ..................................................................................................................10 
4.1 
Sample Size and Statistical Power Consideration.........................................................10 
4.2 
Treatment Assignment and Randomization..................................................................10 
4.3 
Study Flow Chart OLE (Periods III, IV, V)..................................................................11 
5 
ANALYSIS POPULATIONS (ANALYSIS SETS) ...........................................................16 
6 
CONVENTION FOR REPORTING TREATMENT PERIODS.....................................16 
7 
STATISTICAL ANALYSIS METHODS...........................................................................16 
7.1 
Statistical Methods...........................................................................................................16 
7.2 
Interim Analysis...............................................................................................................16 
7.3 
Adjustment for Clinical Center ......................................................................................16 
7.4 
Data Handling and Missing Data ...................................................................................16 
7.5 
Issues of Laboratory Data ...............................................................................................17 
8 
DEMOGRAPHICS, BASELINE CHARACTERISTICS AND STUDY SUMMARY ..17 
8.1 
Patient Disposition ...........................................................................................................17 
8.2 
Demographics...................................................................................................................17 
8.3 
Weight, Height and BMI.................................................................................................17 
8.4 
Medical History................................................................................................................17 
9 
ANALYSIS OF SAFETY ENDPOINTS ............................................................................18 
9.1 
Adverse Events.................................................................................................................18 
9.2 
Antibodies.........................................................................................................................19 
9.3 
Injection Site Reactions and Pain...................................................................................19 
9.4 
IGF-1 and IGF-1 SDS......................................................................................................20 
9.5 
IGFBP-3............................................................................................................................20 
9.6 
Laboratory Test Results..................................................................................................20 
9.7 
Physical Examinations.....................................................................................................21 
9.8 
Vital Signs.........................................................................................................................21 
9.9 
ECG...................................................................................................................................22 
9.10 
Magnetic Resonance Imaging (MRI) .............................................................................22 
9.11 
Fundoscopy.......................................................................................................................22 
9.12 
Concomitant Medications ...............................................................................................22 
9.13 
Extent of Exposure...........................................................................................................22 
10 GROWTH OUTCOMES.....................................................................................................23 
10.1 
Annualized HV.................................................................................................................23 
10.2 
Achievement of Final Adult Height................................................................................23 


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10.3 
Change in Height SDS .....................................................................................................24 
10.4 
Bone Maturation..............................................................................................................24 
10.5 
Pubertal Status.................................................................................................................24 
11 LIST OF TABLES AND DATA LISTINGS......................................................................24 
11.1 
Tables ................................................................................................................................24 
11.2 
Listings..............................................................................................................................28 
11.3 
Figures...............................................................................................................................29 


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Protocol No. CP-4-004
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1
LIST OF ABBREVIATIONS
ADA:
Anti-somatrogon antibodies
AE:
Adverse Event
ALT:
Alanine Aminotransferase
AST:
Aspartate Aminotransferase 
ATC:
Anatomical Therapeutic Chemical code
BA:
Bone Age
BM:
Bone Maturation
BMI:
Body Mass Index
CA:
Chronologic Age
ECG:
Electrocardiogram
EOS:
End of Study
FSH:
Follicle Stimulating Hormone
FT4:
Free Thyroxin
GGT:
Gamma-GlutamylTransferase
HDL:
High Density Lipoprotein
hGH:
Human Growth Hormone
HLT:
Highest Level Term
HT:
Height
HV:
Height Velocity
IGF-1:
Insulin-like Growth Factor – 1
IMP: 
Investigational Medicinal Product
ISR:
Injection Site Reaction
kg:
kilograms
LDH:
Lactate Dehydrogenase
LDL:
Low Density Lipoprotein
LH:
Lutinizing Hormone
ml:
Millilitre
MCH:
Mean Corpuscular Hemoglobin
MCHC:
Mean Corpuscular Hemoglobin Concentration
MCV:
Mean Corpuscular Volume
MedDRA:
Medical Dictionary for Drug Regulatory Activities


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Protocol No. CP-4-004
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mg:
milligram
MRI:
Magnetic Resonance Imaging
ng:
nanogram
No:
Number
OLE:
Open Label Extension
PEN:
Single patient multidose pen delivery device
PT:
Preferred Term
rhGH:
Recombinant Human Growth Hormone
SAE:
Serious Adverse Event
SAP:
Statistical Analysis Plan
SD:
Standard Deviation
SDS:
Standard Deviation Score
SGOT:
Serum Glutamic Oxaloacetic Transaminase
SGPT:
Serum Glutamic Pyruvic Transaminase
SMQ:
Standardized MedDRA Queries
SOC:
System Organ Class
T3:
Triiodothyronine
T4:
Free Thyroxine
TEAE:
Treatment Emergent Adverse Event
TSH:
Thyroid Stimulating Hormone
UA:
Urinalysis
ULN:
Upper Limit of Normal
WHO:
World Health Organisation
wk:
Week


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Protocol No. CP-4-004
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2
INTRODUCTION
This statistical analysis plan (SAP) details data analysis of the OLE periods of protocol CP-4-
004, version 10, 3 Oct 2017 (
).  The first 12 months of 
this study consisted of two periods, Periods I and II, with the primary objective of evaluating 
three doses of somatrogon to a commercially available standard daily recombinant human 
growth hormone (rhGH) formulation. The ongoing long-term open-label treatment covered by 
this plan starts with Period III (after the completion of Period II), through Period V (treatment 
with PEN formulation) to the end of study for all patients. This plan provides more specific 
details for the analysis than in the protocol, and any differences from the analysis as outlined in 
the protocol will be documented in this plan.  Any difference from this plan that arise during the 
actual analysis of the data will be documented in the study report. 
The International Nomenclature Name for MOD-4023 is somatrogon, which will be used 
subsequently throughout this document.  The somatrogon designation was assigned after the 
commencement of CP-4-004.


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Protocol No. CP-4-004
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3
OBJECTIVES AND ENDPOINTS
3.1
Objectives
3.1.1
Primary Objectives
The primary objective of this analysis is to evaluate the safety of somatrogon in extended 
treatment after the Periods I and II, including the transition to PEN to the EOS.
3.1.2
Secondary Objectives
The secondary objective is to evaluate the growth outcome of somatrogon in long term treatment 
beyond the initial 12 months of the primary study, including the transition to PEN to the EOS.
3.2
Endpoints
3.2.1
Safety Endpoints
1.
Incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs)
and adverse events (AEs) leading to discontinuation
2.
Incidence of anti-somatrogon antibody formation (including characterization of the
antibodies and neutralizing properties)
3.
Local injection site assessment
4.
IGF-1 levels and IGF-1 SDS
5.
IGF binding protein-3 (IGFBP-3) levels
6.
Parameters of glucose metabolism: blood glucose, fasting insulin level, glycosylated
hemoglobin A1c (HbA1c).
7.
Thyroid status (free thyroxine [FT4], triiodothyronine [T3], and thyroid stimulating
hormone [TSH])
8.
Lipid parameters
9.
Cortisol levels
10.
All other hematology and biochemical parameters
11.
Physical examination
12.
Vital signs
13.
Electrocardiogram (ECG) parameters
3.2.2
Growth Outcomes
1.
Annualized HV (cm/year)
2.
Change in HT SDS
3.
Annual bone maturation (BM)


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Protocol No. CP-4-004
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4
STUDY DESIGN
CP-4-004 is an open label, randomized, multi-center study with yearly extension until marketing 
approval. The main study (Periods I and II) consisted of three dose levels (0.25 mg/kg, 0.48
mg/kg, and 0.66 mg/kg) of the investigational drug somatrogon administered weekly, and one 
active control, daily rhGH therapy (Genotropin®). 
After the 12 months study (main study, including Period I and II), all patients continued with 
open label treatment, to be continued until marketing approval. There are three defined extension 
periods:
x
Period III:  OLE of 12 months duration with continuous dosing with the original three
assigned dose levels of somatrogon (0.25, 0.48 and 0.66 mg/kg/week).  Patients who were
originally assigned to daily Genotropin were randomly re-assigned to one of the three dose
levels.
x
Period IV:  Long-term OLE, where all patients were transitioned to 0.66 mg/kg/week.  This
was originally planned to follow the 12 months in Period III.   However, due to timing of
regulatory approval in different regions, the transition to 0.66 mg/kg/week varied, and did not
start at the beginning of 3rd year for all patients.
x
Period V:  Long-term OLE with PEN device and formulation.  The transition to PEN takes
placed based on regulatory approval and patient scheduling, so the study month of transition
will vary and not be at a specific study month.
Some patients may have an interval of 
without treatment between periods. Patients
may also have dose adjustment per the dose adjustment paradigm as specified in the protocol.  
Patients with adjusted doses will be kept in the main treatment dose groups as defined, and not 
be analyzed as additional dose groups.
4.1
Sample Size and Statistical Power Consideration
All patients who completed 12 months of treatment in the main study (Periods I and II) were 
eligible to enroll into the OLE (Periods III, IV, etc.).  Fifty-three (53) patients completed Period
II and started the OLE. There are no formal power considerations nor hypothesis tests for the 
OLE data.
4.2
Treatment Assignment and Randomization
Patients who were randomized to somatrogon in the main study (Periods I and II) continued with 
the same dose (mg/kg) of somatrogon they received in the main study. Patients who received the 
active control during the main study (Periods I and II) were randomized to one of the three 
somatrogon doses (0.25 mg/kg, 0.48 mg/kg, and 0.66 mg/kg) at the start of Period III. Patients
were then transitioned to 0.66 mg/kg in Period IV, and finally to PEN for Period V.   In addition, 
individual dose modification may be made based on the assessment of the growth progress and 
overall safety per pre-determined rules within the protocol.


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Protocol No. CP-4-004
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4.3
Study Flow Chart OLE (Periods III, IV, V)
Period III (starting 2nd year of treatment, i.e. first year OLE)
OLE
Day 1 and Month 1 
OLE 1
Visits 1-2 
Every 3 
months OLE
visit 
Every 6 
months OLE
visit 
Every  12 
months  
Previous and concomitant medication
X
X
Actual HT
X
X
Body weight
X
X
Physical examination 
X
X
Vital signs
X
X
Injection site reaction (local 
tolerability)
X
X
ECG
X
Pubertal status (Tanner)
X
BA (Greulich-Pyle)
X
Routine safety biochemistry/
hematology and urinalysis
X
X
IGF-I and IGFBP-3
X
X
Somatrogon serum levels
X
X
Anti-somatrogon antibodies
X
Thyroid status (FT4, T3, TSH)
X
X
Cortisol levels
X
X
Fasting glucose, fasting insulin
X
X
HbA1c
X
X
Lipid panel 
X
X2
Lipoprotein 
X
AE assessment
X
X
Fundoscopy2
X2
Somatrogon administration
X
Training for study medication 
administration
X
Dispense study medication
X
X
Dispense patient diary
X
X
Return and accountability of study 
medication
X
X
Return and review of patient diary
X
X
1 Only patients who received Genotropin in the main study and switched to somatorogon will attend these 2 visits-
applicable only for first year of extension 
2 Earlier if there are clinical signs of intracranial hypertension 


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Periods IV (Treatment with 0.66 mg/kg)
OLE
Every 3 months 
OLE visit  - day 
4 (-1) post dose
Every 6 months 
OLE visit – day 
4 (-1) post dose
Every 12 months OLE and 
EOS when marketing 
approval received - on 
dosing day
Auxology measurements: Actual HT
measured on a calibrated stadiometer 
and body weight measurement
X
Adjustment of dose for weight
X
AEs
X
Local tolerability
X
Concomitant medication
X
Dispensing of drug
X
IGF-1, IGFBP-3 and somatrogon serum 
levels
X
Anti-somatrogon antibodies
X
Physical examination
X
Vital signs
X
Parameters of glucose metabolism 
(fasting glucose, fasting insulin and 
HbA1c)
X
Other hormonal levels (TSH, FT4, T3, 
cortisol)
X
Parameters of lipid metabolism
X
Routine safety laboratory 
(biochemistry, hematology and 
urinalysis)
X
Pubertal status 
X
ECG
X
BA
X
Lutinizing hormone (LH), follicle 
stimulating hormone (FSH) and 
testosterone.3
X
LH, FSH and estradiol4
X
3 For male patients that are on the age 13 years old and above
4 For female patients that are at the age of 12 years old and above


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Period V LT-OLE PEN – First 12 Months
OLE PEN
Every 3 months 
OLE visit  - day 
4 (-1) post dose
Every 6 months 
OLE visit – day 
4 (-1) post dose
Every 12 months OLE and 
EOS when marketing 
approval received - on 
dosing day/ from second 
year, visits are done on day 4 
(-1) post dose
Auxology measurements: Actual HT
measured on a calibrated stadiometer 
and body weight measurement
X
Adjustment of dose for weight
X
AEs
X
Local tolerability
X
Concomitant medication
X
Dispensing of drug
X
Return of used drugs
X
IGF-1, IGFBP-3
X
Somatrogon serum levels
X
X - from second 
year
X
Anti-somatrogon antibodies
X
X - from second 
year 
Physical examination
X
Vital signs
X
Glucose metabolism (fasting glucose, 
fasting insulin and HbA1c)
X5
X – from second 
year 
Other hormonal levels (TSH, FT4, T3, 
cortisol)
X5
X – from second 
year
Parameters of lipid metabolism
X5
X – from second 
year
Routine safety laboratory 
(biochemistry, hematology and 
urinalysis)
X5
X – from second 
year
Urine pregnancy test
X
Pubertal status 
X
ECG around Tmax (7-12 hours post 
dose)7
X
BA
X
LH, FSH and testosterone.3
X
LH, FSH and estradiol4
X
5 Data collected every 3 months with the exception of month 9.
3 For male patients that are on the age 13 years old and above
4 For female patients that are at the age of 12 years old and above


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Long-Term OLE PEN (LT-OLE-PEN) Period V From 2nd Year Until Marketing Approval
LT OLE PEN visits by Month over each year the study is running
Month 3 visit
(±2 week)
Month 6 visit
(±2 week)
Month 9 visit
(±2 week)
Month 12
(±2 week)5
Assessments
day 4 (-1) post 
dose
day 4 (-1) post 
dose
day 4 (-1) post 
dose
day 4 (-1) post 
dose
Auxology measurements: actual height 
measured on calibrated stadiometer
X
X
X
X
Body weight measurement 
X
X
X
X
Adjustment of dose for weight
X
X
X
X
AEs
X
X
X
X
Local tolerability
X
X
X
X
Concomitant medication
X
X
X
X
Dispensing of drug
X
X
X
X
Return of used drugs 
X
X
X
X
Fundoscopy - If required
X
X
X
X
IGF-I, IGFBP-3
X
X
X
X
MOD- 4023 serum levels 
X
X
Anti-MOD-4023 antibodies
X
X
Physical examination
X
X
X
X
Vital signs 
X
X
X
X
Glucose metabolism (fasting glucose & 
insulin, HbA1c)
X
X
Other hormonal levels (TSH,  free T4, 
cortisol)
X
X
Parameters of lipid metabolism
X
X
Routine safety laboratory (biochemistry, 
hematology and urinalysis)
X
X
Urine pregnancy test6
X
X
X
X
Pubertal status7
X
X
X
X
ECG
X
Bone age
X
LH, FSH and Testosterone8
X
5 In case ET/EOS visit is conducted all assessment should be done as one with no split.  
6 For females of child bearing potential. In case urine pregnancy test is positive, please refer to section Error! Reference source 
not found. in the protocol. 
7 In case the patient becomes pubertal, childbearing potential and refraining from sexual activity will be discussed with the 
patient. 
8 For male patients that are at the age of 13 years and above. 


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LT OLE PEN visits by Month over each year the study is running
Month 3 visit
(±2 week)
Month 6 visit
(±2 week)
Month 9 visit
(±2 week)
Month 12
(±2 week)5
LH, FSH and Estradiol9
X
Provide patient diary and return of 
completed diaries
X
X
X
X10
9 For female patients that are at the age of 12 years and above.
10 Dispensing patient diary is not applicable for termination visit, only return of completed diaries.


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5
ANALYSIS POPULATIONS (ANALYSIS SETS)
Since this is an OLE with patients from the primary study, all patients will be included in a 
single Full Analysis Set for reporting.
6
CONVENTION FOR REPORTING TREATMENT PERIODS
Periods III and IV:  The protocol defines Period III as a 12 month period when patients are in 
three specific dose groups, and Period IV as starting on 0.66 mg/kg/week after 12 months in 
Period III.  Because of the differences in timing of transition to the 0.66 mg/kg/week dose, all 
data from Periods III and IV will be presented in 12 month intervals, starting with the first dose 
of treatment at the start of Period III.   The dose at the beginning of each 12 month period will be 
used to classify the patient to a dose group for disposition purposes.   For the first 12 months, the 
results will be reported by the assigned dose group.   After the initial year on OLE, all patient
results will be summarized in a single treatment group, regardless of assigned dose level, or any 
individual patient dose adjustments.  
For patients with gaps of 
 in treatment, the re-start of treatment will be the start of the 
new 12 month interval, regardless of the elapsed days.  Safety data collected during the period 
without treatment will be included in the previous 12 month interval.  
Period V:   This period will contain data from patients on PEN treatment.  Baseline data for this 
period will be the data collected at the visit for the first PEN dose, prior to the first PEN dose.
The cumulative change in HT SDS from the start of treatment in Period I will also be 
summarized.  For these summaries, the original dosing assignment will be used, and the 
reporting periods will be at each of the scheduled Month 12 visit of the period.   Gaps in 
treatment will be included, so that the elapsed time may be longer than 12 months.   
7
STATISTICAL ANALYSIS METHODS
7.1
Statistical Methods
This is an open label long-term extension study.  No formal hypothesis testing will be performed. 
Descriptive statistics will include mean, median, standard deviation, minimum, maximum, range,
count and confidence intervals to present the results.   All output will be created with SAS 
version 9.4 or higher.
7.2
Interim Analysis
Not applicable.
7.3
Adjustment for Clinical Center
The analysis will not be stratified by study site.
7.4
Data Handling and Missing Data
Because of the observational nature of this study, missing data in general will not be imputed, 
except for:
1. specific items associated with AEs as specified in Section 9.1;


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2. missing day or month will be imputed to the 1st of each if needed for calculations, unless this
imputation contradicts a previous date (such as between start and stop dates).  In this case,
the imputed date will be last day or month, or be missing and presented as “ongoing.”
Unscheduled assessments or multiple results within a specified visit window will be listed, but
not used in the visit summary.  The assessment closest to the scheduled visit date will be used.   
Early termination assessments will be assigned to the appropriate annual interval based on 
treatment month within a period.
7.5
Issues of Laboratory Data
If there were two or more evaluable results in a given visit, the latest test result will be used for 
analysis. If the evaluable result was indicated by <nn, half of the value (= nn/2) will be used for
the summary. If the evaluable result was >nn, the value (= nn) will be used for the summary.
8
DEMOGRAPHICS, BASELINE CHARACTERISTICS AND STUDY 
SUMMARY
8.1
Patient Disposition
The number and percentage of patients entering and completing each 12 month period will be 
summarized by the dose level at the beginning of each period.  A listing will be provided to show 
the reason for discontinuation and time of discontinuation for each patient.
Protocol deviations will be listed and summarized within each period, but will not be used to 
define patient groups.  
8.2
Demographics
The demographics (age, gender, race) will be summarized using descriptive statistics at the start 
of Period III, and for each 12 month reporting period.
Age will be the age at the start of each reporting period, calculated from the date of day 1 of each 
period and the date of birth. If the date of birth is not available, then the age will be calculated 
from the elapsed months added to the age reported at the beginning of Period 1 of the study.  
8.3
Weight, Height and BMI
Patient weight, HT, body mass index (BMI), HT SDS, IGF-1 SDS, BA, and HV will summarized 
at the start of OLE.   Patient weight, HT and BMI will be summarized for each 12 month period.
The patient’s reported HT for each visit is the average of the three consecutive measurements
made by study personnel.  See Section 10.1 for details on HT outcomes.
8.4
Medical History
The medical history data collected in the main study will be summarized for the patients in the 
OLE by System Organ Class (SOC) and preferred terms based on the coded data by the Medical 
Dictionary for Drug Regulatory Activities (MedDRA). The count and percentage of ongoing 
medical condition per preferred terms will also be provided.


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9
ANALYSIS OF SAFETY ENDPOINTS
9.1
Adverse Events
AEs will be coded using MedDRA v20.1. TEAEs for each 12 month period will be defined as 
those that start in each 12 month period and separately for Period V on PEN, which will be 
cumulative.  The denominator used for calculation of AE rates will be the number of patients at 
the beginning of each period or year.  For patients who have gaps in treatment, the events that 
start in the gap will be included in the prior treatment period.   In addition, a summary of AEs for 
the entire extension period will be provided.  
The results will be presented:
x
by order of the frequency of AEs by the MedDRA preferred term (PT)
x
by severity of AEs
x
by the relationship of AEs to the study drug
x
and all SAEs
Patient incidence of AEs of special interest will also be summarized overall and by SOC through
the entire extension period.   The AEs of special interest are:
Adverse Event of Special Interest
MedDRA v20.1 Definition Criteria
Glucose metabolism impairment
Hyperglycaemia/new onset diabetes mellitus (standardized 
medDRA queries [SMQ]) Full Scope
Thyroid function impairment
Thyroid dysfunction (SMQ) Full Scope
Intracranial hypertension
Increased intracranial pressure disorders (high level term 
[HLT] - All Paths)
Neoplasias
Malignancy (SMQ) Full Scope
Intracranial aneurysm
Central nervous system aneurysms and dissections (HLT -
All Paths)
Immunogenicity (including positive 
anti-drug antibody and allergic 
reactions) and Hypersensitivity
Laboratory result parameter: Anti somatrogon antibody or 
Neutralizing Antibody present, Anaphylactic reaction (SMQ) 
Narrow Scope, Angioedema (SMQ) Narrow Scope, 
Hypersensitivity (SMQ) Narrow Scope
Injection site reactions (including 
lipoatrophy/skin dystrophy)
Injection site reactions (HLT - All Paths) and select PTs 
(Lack of injection site rotation, Lipoatrophy, Skin 
hypertrophy, and Skin dystrophy) and PTs containing 
'Administration site'
Epiphysiolysis
PT Epiphysiolysis
Haemangioma of skin
PT Haemangioma of skin
Oedema
Oedema NEC (HLT - All paths) and Total fluid volume 
increased (HLT - All Paths)
Scoliosis
PT Scoliosis
Acute and chronic pancreatitis
Acute and chronic pancreatitis (HLT - All Paths)
Increased Protein kinase
PT Blood creatine phosphokinase increased


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Adverse Event of Special Interest
MedDRA v20.1 Definition Criteria
Adrenal cortical hypofunctions
Adrenal cortical hypofunctions (HLT - All Paths)
Myalgia
PT of Myalgia
Myositis
PT of Myositis
Arthralgia
PT of Arthralgia
A listing of TEAEs that lead to withdrawal from the study will also be provided.
Missing values will be treated as missing except for causality, intensity, and outcome of an AE, at
which occurrence a “worst case” approach will be taken in the analysis. Thus, if causality is
missing the AE will be regarded as related to the investigational medicinal product (IMP), if the
intensity is missing the intensity of the AE will be regarded as severe, and if the outcome is
missing and the stop date is not provided the outcome is regarded as “ongoing.” If the
classification of SAE ( seriousness) is missing, all efforts should be made prior to database lock to 
make sure that this information is available.
9.2
Antibodies
Anti-somatrogon antibody (ADA), anti-somatrogon neutralizing antibody, and anti-hGH 
neutralizing antibody will be tested at month six and month 12 in Period III and then every six
months thereafter.  The results of the antibody testing will be summarized for each test at each of
the OLE and PEN time points tested.  The titer and specificity (anti-hGH and CTP) of confirmed 
ADA will be summarized.  The anti-somatrogon and anti-hGH neutralizing antibody status 
(positive or negative) are only assessed when a patient is confirmed positive for ADA, so any 
sample that has not shown somatrogon specificity will be considered negative for NAb. The 
numeric values for titer will be summarized by median, min and max.  
Overall incidence of TEAEs and injection site reactions will also be summarized by ADA status.
HV, HT SDS, and peak IGF-1 SDS will be summarized for each reporting period by ADA
status.
ADA status will be assigned on a rolling or dynamic basis.  A patient is only considered ADA 
positive at the beginning of the year in which they test positive and for the remainder of the 
study.
9.3
Injection Site Reactions and Pain
Incidence of injection site reaction (ISR) AEs will be summarized by SOC and PT, including 
pain, redness, bruising, swelling, or itching at the injection site.  Summaries will be provided for 
each 12 month period, and during Period V on PEN.  
The 
 pain scores will be summarized with number of overall patients at 
the beginning of each year as the denominator.  For each patient, ISR pain score will be 
summarized by maximum severity for each period. Missing values will be considered "hurts 
worse." 
ISR erythema/redness, bruising, induration/swelling, itching, and tenderness scores will be 
summarized with number of overall patients at the beginning of each year as the denominator.  


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For each patient and reaction type, symptoms will be summarized by maximum severity.
Missing values will be considered "severe.”
9.4
IGF-1 and IGF-1 SDS
IGF-1 will be listed for each patient, but not summarized.  IGF-1 SDS will be listed, and 
summarized at each visit.  In addition, the number and proportion of patients with IGF-1 SDS >
2 will be summarized.  The denominator will be the number of patients with results at each visit.  
For the summaries of each 12 month period with multiple visits, each patient will be counted 
once, and will be counted as having IGF-1 SDS >2 if any results within that summarized interval 
is >2. IGF-1 SDS will also be summarized by ADA status.  
9.5
IGFBP-3
IGFBP-3 levels will be provided in a listing.
9.6
Laboratory Test Results
Clinical laboratory measurements will be summarized with descriptive statistics at each visit.  
Changes within each 12 month period will use the first visit of the 12 month period as the 
baseline.  For Period V the baseline will be the first visit with PEN injection.  If data from the 
first visit of each period are not available, the last previous visit data will be used.   Summary of 
abnormal results (reported as low, high, clinically significant) will be provided for each 12
month period, with the number of patients at the beginning of each period for the denominator.  
The following laboratory results will be presented: 
x
Glucose Metabolism, Endocrinology, and Lipid Metabolism:
Glucose Metabolism
Endocrinology
Lipid Metabolism
Fasting blood Glucose
FT4
Cholesterol
Fasting Insulin
T3
High density lipoprotein (HDL)
HbA1c
Thyrotropin (= TSH)
Low density lipoprotein (LDL)
Cholesterol
Cortisol, Free
Lipoprotein-A
Females >=12 y.o.: FSH, LH and 
estradiol 
Triglycerides
Male >=13 y.o.:  FSH, LH and 
testosterone


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x
Chemistry, Hematology, and Urinalysis:
Clinical Chemistry
Hematology
Urinalysis
Albumin
Differential Blood Count of
Leukocytes
Bilirubin
Alkaline phosphatase
Erythrocyte Count
Glucose
Calcium
Hematocrit
Ketones
Chloride
Hemoglobin
Leukocyte Esterase
Creatinine
Leukocytes
Nitrite
Gamma-glutamyl Transferase
(GGT)
Mean Corpuscular Hemoglobin
(MCH)
pH
Lactate Dehydrogenase (LDH)
Mean Corpuscular Hemoglobin
Concentration (MCHC)
Protein
Phosphate
Mean Corpuscular Volume
(MCV)
Specific Gravity
Potassium
Platelet Count
Urinalysis Blood
Serum Glutamic Oxaloacetic
Transaminase (SGOT)
Urobilinogen
Serum Glutamic Pyruvic
Transaminase (SGPT)
Serum Iron and Transferrin
Sodium
Total Bilirubin
Total Proteins
Urea (blood urea nitrogen)
Uric Acid
The increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total 
bilirubin will be examined for liver function. The count and percentage of the increases will be 
tabulated for each visit including baseline. The increases of ALT and AST will be examined in 
three categories, i.e. >2 × upper limit of normal (ULN), >3 × ULN, and >5 × ULN, and that of 
total bilirubin combined with ALT or AST increases will be examined in 1 category, total 
bilirubin >3 × ULN and ALT or AST >2 × ULN.
9.7
Physical Examinations
Physical examination data (every three months in Period III and every 12 months in the later 
period) will be tabulated by frequency count and percentage for each organ system category by 
visit.
9.8
Vital Signs
The vital signs (systolic / diastolic blood pressure in seated position, respiratory rate, pulse rate, 
and body temperature) will be summarized at each visit. The change from the beginning of OLE, 
and the change within each year for continuous parameters will be presented.


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9.9
ECG
The ECG parameters (heart rate, PR interval, QRS interval, QT interval, RR intervals, QTc-Bazett
interval) will be listed.   The clinical assessments: Normal / Abnormal – same as screening /
Abnormal – new, clinically not significant / Abnormal – new, clinically significant or aggravated,
collected at the end of each OLE and PEN year will be summarized as proportion of patients with 
each assessment, with the number of patients at the beginning of the period as the denominator.
9.10
Magnetic Resonance Imaging (MRI)
MRI results will be listed for each visit. 
9.11
Fundoscopy
The fundoscopy examination is done at the end of the first year of the OLE period and performed 
if there is any clinical sign of intracranial hypertension. The number and percentage of patients
who have fundoscopy done in each 12 month period, and the number and percentage of patients
who have signs of intracranial hypertension in each period will be presented.
9.12
Concomitant Medications
Medications will be coded and presented using World Health Organization (WHO) Drug 
Dictionary version September 2017, Anatomical Therapeutic Chemical Code (ATC) level 2, as 
well as, the primary term.  The medications used within each 12 month period will be 
summarized by ATC level 2.  For PEN treatment in Period V, the medications will be separately 
summarized.  
9.13
Extent of Exposure
The total duration of treatment (in months) for each patient will be calculated as:
1. The total duration since first treatment in this study (since the first dose of Period I)
a.
For patients initially randomized to Genotropin, the total duration of exposure to
somatrogon will be calculated from the date for first treatment with somatrogon.
2. The total duration in each assigned dose level and on PEN.
3. The overall exposure will be calculated as Last dose – First dose + 7 days (to account for the
once weekly dose exposure).  To convert to months, the total daily exposure will be divided
by 30.147.
Because of potential gaps in treatment between periods, the total duration may not represent 
continuous exposure.  A listing of the patients with gaps in treatment will be provided showing 
the time period without treatment. 
The number and proportion of patients who have the dose adjusted due to IGF-1 SDS >2 or other 
reasons will be summarized by reason for each 12 month period, with the denominator as the 
number of patients who started each period.   The listings will show the dose at which the IGF-1
SDS excursion occurred.  


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10
GROWTH OUTCOMES
10.1
Annualized HV
Descriptive statistics or HT will be presented.  Annualized HV between two time intervals X and 
Y will be calculated as:
ܪ݄݁݅݃ݐܸ݈݁݋ܿ݅ݐݕ ൬ܿ݉
ݕ݁ܽݎ൰
ൌቈܯ݋݊ݐ݄ܺܪ݄݁݅݃ݐሺܿ݉ሻെܴ݂݁݁ݎ݁݊ܿ݁ܯ݋݊ݐ݄ܻܪ݄݁݅݃ݐሺܿ݉ሻ
ܯ݋݊ݐ݄ܺ݀ܽݐ݁െܴ݂݁݁ݎ݁݊ܿ݁ܯ݋݊ݐ݄ܻ݀ܽݐ݁
቉כ ͵͸ͷǤʹͷ
HV will be calculated for the following intervals:
1. Periods III and IV
a.
12 month intervals, with the first 12 months starting with the first injection of Period III.
Gaps in treatment will not alter that calculation of these 12 month intervals.
b. Last 6 and 12 month interval, using the last measure in Period IV with the measures at 6
and 12 months prior to the last measure as the reference.
2. Period V (PEN)
a.
Intervals of 6 and 12 months from the start of the PEN injection as the reference for the
first year.
b. After the first year of PEN, HV at the end of each year uses the measure at the Month 12
visit in each year with the measure at the Month 12 visit of the prior year as the reference.
In cases where there is a gap in treatment between years, the measure at the restart of
treatment (if available) will be used as the reference.
HV will also be presented for each treatment year, including Periods I and II, by the original 
treatment group assignment. 
For patients who discontinue from the study between these specific defined visits for the 
calculations, their last HT measurement and date will be used for the annualized HV in the 
interval of interest.
Annualized HV by year, annualized HV on PEN treatment, change in HT SDS by year and 
change in HT SDS on PEN treatment will be summarized by ADA status.
10.2
Achievement of Final Adult Height
The number (and proportion) of patients who achieve adult height will be summarized by age.  
The denominator for proportion for this summary will be the total of patients in the study, so that 
patients who discontinue from the study are simply considered not to have achieved adult height.   
A Kaplan-Meier curve will be used to display the proportion of patients achieving adult height 
by age. For the Kaplan-Meier curve, discontinued patients will be censored, and removed from 
the denominator. Achievement of final adult height is defined as the HT when annualized HV < 
1 cm/year over at least six-month period.


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10.3
Change in Height SDS
HT SDS will be summarized with descriptive statistics at the end of OLE years 1 - 4 and for each 
year on PEN. HT SDS will also be presented for each treatment year, including Period I and II, 
by the original treatment group assignment and total. In addition, HT SDS will be summarized 
by ADA status. Descriptive statistics will be used to characterize the change in HT SDS.  The 
change in HT SDS will be calculated from baseline of Period I, as well as each 12 month period.
In addition, the cumulative change in HT SDS from the baseline at Period I will be calculated for 
each of the scheduled Month 12 visit of each year, using the original treatment groups 
assignment and total.
10.4
Bone Maturation
BM will be evaluated as the BA divided by the chronological age (CA). 
BM = BA/CA
BA is reported as year and months, and will be converted to a decimal value as years + 
months/12.  
CA will be calculated as (date of BA assessment – Birth date)/365.25.
BM will be calculated at 12 month intervals.  The change in BM will be calculated as the change 
in BA/change in CA for each of the intervals defined for the calculation of HV, when the BA 
assessment is available. Descriptive statistics will be used to characterize the change in BM.
10.5
Pubertal Status
The pubertal status will be reported at the end of each year of the OLE and PEN periods.
11
LIST OF TABLES AND DATA LISTINGS
11.1
Tables
Table No.
Description
2.1
Overall Summary of patients with treatment-emergent adverse events (Safety Analysis Set)
3.1
Summary of treatment emergent adverse event (All causality) in >= 2% of patients (Safety 
Analysis Set)
3.1b
Summary of treatment emergent adverse event (All causality) in >= 5% of patients (Safety 
Analysis Set)
4
Summary of Somatrogon Patient Disposition - CP-4-004 OLE
4.1
Summary of AESI - CP-4-004 OLE (Safety Analysis Set)
5.1
Summary of treatment-emergent serious adverse events (All Causalities) (Safety Analysis 
Set)
6
Summary of Antibody Titers Overall and by Year: Full Analysis Set
10
Annualized Height Velocity at End of each OLE and PEN Year by ADA Status: Full 
Analysis Set
11
Highest IGF-1 SDS During OLE and PEN Years by ADA Status: Full Analysis Set


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Table No.
Description
20
Adverse Events of Special Interest in PEN Years: Full Analysis Set
1.2.2
Height SDS at Baseline and End of Main Study, End of OLE and PEN Years by Initial 
Cohort Assignment: Full Analysis Set
1.2.2.1
Cumulative Change in Height SDS at End of Main Study, End of OLE and PEN Years by
Initial Cohort Assignment: Full Analysis Set
1.2.3
Highest IGF-1 SDS During OLE and PEN Years: Full Analysis Set
14.1.1.1
Disposition of Patients – Year 1 OLE
14.1.1.2
Disposition of Patients – OLE Years 2-4 and PEN
14.1.2.1
Demographics at Start of OLE (Year 1): Full Analysis Set
14.1.2.2
Demographics at Start of Years 2-4 and PEN: Full Analysis Set
14.1.3
Medical History at Start of Main Study: Full Analysis Set
14.1.4.1
Characteristics at Start of OLE (Year 1): Full Analysis Set
14.1.4.2
Weight, Height, and BMI at Start of OLE Years 2-4 and PEN Years: Full Analysis Set
14.2.1.1
Annualized Height Velocity at End of OLE Years: Full Analysis Set
14.2.1.2
Annualized Height Velocity on PEN: Full Analysis Set
14.2.1.3
Annualized Height Velocity (cm/yr) at End of Main Study, End of each OLE and PEN Year
by Initial Cohort Assignment: Full Analysis Set
14.2.2.1
Height SDS at End of OLE and PEN Years: Full Analysis Set
14.2.2.2
Height SDS at Baseline and End of Main Study, End of each OLE and PEN Year by Initial 
Cohort Assignment: Full Analysis Set
14.2.3.1
Annual Change in Height SDS at End of each OLE Year: Full Analysis Set
14.2.3.2
Annual Change in Height SDS at End of each PEN Year: Full Analysis Set
14.2.3.3
Cumulative Change in Height SDS at End of Main Study, End of each OLE and PEN Year 
by Initial Cohort Assignment: Full Analysis Set
14.2.4.1
Bone Age at End of each OLE and PEN Year: Full Analysis Set
14.2.4.2
Bone Maturation Change at End of each OLE Year: Full Analysis Set
14.2.4.3
Bone Maturation Change at End of each PEN Year: Full Analysis Set
14.3.1.1
Overall Summary of Patients with Treatment-Emergent Adverse Events: Full Analysis Set
14.3.1.2
Overall Incidence of Treatment-Emergent Adverse Events by SOC and Preferred Term: Full 
Analysis Set
14.3.1.3
Overall Incidence of Serious Treatment-Emergent Adverse Events by SOC and Preferred 
Term: Full Analysis Set
14.3.1.4
Overall Incidence and Severity of Treatment-Emergent Adverse Events by SOC and 
Preferred Term: Full Analysis Set
14.3.1.5
Overall Incidence and Relationship of Treatment-Emergent Adverse Events by SOC and 
Preferred Term: Full Analysis Set
14.3.1.6
Overall Incidence of Treatment-Emergent Adverse Events that Lead to Withdrawal from the 
Study by SOC and Preferred Term: Full Analysis Set


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Table No.
Description
14.3.2.1
Annual Incidence of Treatment-Emergent Adverse Events by SOC and Preferred Term: Full 
Analysis Set
14.3.2.2
Annual Incidence of Serious Treatment-Emergent Adverse Events by SOC and Preferred 
Term: Full Analysis Set
14.3.2.3
Annual Incidence and Severity of Treatment-Emergent Adverse Events by SOC and 
Preferred Term: Full Analysis Set
14.3.2.4
Annual Incidence and Relationship of Treatment-Emergent Adverse Events by SOC and 
Preferred Term: Full Analysis Set
14.3.2.5
Annual Incidence of Treatment-Emergent Adverse Events of Special Interest by Preferred 
Term: Full Analysis Set
14.3.4.1
Overall Incidence of Injection Site Reactions by SOC and Preferred Term: Full Analysis Set
14.3.4.2
Annual Incidence of Injection Site Reactions by SOC and Preferred Term: Full Analysis Set
14.3.4.3
Overall Summary of Injection Site Pain, Redness, Bruising, Swelling, and Itching Score: Full 
Analysis Set
14.3.4.4
Annual Summary of Injection Site Pain, Redness, Bruising, Swelling, and Itching Score: Full 
Analysis Set
14.3.5.1
Summary of IGF-1 SDS at End of each OLE and PEN Year: Full Analysis Set
14.3.5.2
Summary of IGF-1 SDS >2 by Year: Full Analysis Set
14.4.1
Summary of Antibody Titers Overall and by Year: Full Analysis Set
14.4.2.1
Annualized Height Velocity at End of OLE and PEN Years by ADA Status: Full Analysis Set
14.4.2.2
Annualized Height Velocity on PEN by ADA Status: Full Analysis Set
14.4.2.3
Annualized Height Velocity (cm/yr) at End of Main Study, End of each OLE and PEN Year 
by ADA Status and Initial Cohort Assignment: Full Analysis Set
14.4.2.4
Height SDS at End of each OLE and PEN Year by ADA Status: Full Analysis Set
14.4.2.5
Height SDS at Baseline and End of Main Study, End of each OLE and PEN Year by ADA 
Status and Initial Cohort Assignment: Full Analysis Set
14.4.2.6
Annual Change in Height SDS at End of each OLE Year By ADA Status: Full Analysis Set
14.4.2.7
Annual Change in Height SDS at End of each PEN Year by ADA Status: Full Analysis Set
14.4.2.8
Cumulative Change in Height SDS at End of Main Study, End of each OLE and PEN Year 
by ADA Status and Initial Cohort Assignment: Full Analysis Set
14.4.2.9
Highest IGF-1 SDS During OLE and PEN Years by ADA Status: Full Analysis Set
14.4.3.1
Annual Incidence of Treatment-Emergent Adverse Events by SOC and Preferred Term by 
ADA Status: Full Analysis Set
14.4.3.2
Annual Incidence of Serious Treatment-Emergent Adverse Events by SOC and Preferred 
Term by ADA Status: Full Analysis Set
14.4.3.3
Annual Incidence and Severity of Treatment-Emergent Adverse Events by SOC and 
Preferred Term by ADA Status: Full Analysis Set
14.4.3.4
Annual Incidence and Relationship of Treatment-Emergent Adverse Events by SOC and 
Preferred Term by ADA Status: Full Analysis Set


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Table No.
Description
14.4.3.5
Annual Incidence of Treatment-Emergent Adverse Events of Special Interest by Type and 
Preferred Term by ADA Status: Full Analysis Set
14.4.3.6
Overall Incidence of Injection Site Reactions by SOC and Preferred Term by ADA Status: 
Full Analysis Set
14.4.3.7
Annual Incidence of Injection Site Reactions by SOC and Preferred Term by ADA Status: 
Full Analysis Set
14.5.1.1
Laboratory Test Results – Glucose Metabolism: Full Analysis Set
14.5.1.2
Laboratory Test Abnormal Results – Glucose Metabolism: Full Analysis Set
14.5.2.1
Laboratory Test Results – Endocrinology: Full Analysis Set
14.5.2.2
Laboratory Test Abnormal Results – Endocrinology: Full Analysis Set
14.5.3.1
Laboratory Test Results – Lipid Metabolism: Full Analysis Set
14.5.3.2
Laboratory Test Abnormal Results – Lipid Metabolism: Full Analysis Set
14.5.4.1
Laboratory Test Results – Clinical Chemistry: Full Analysis Set
14.5.4.2
Laboratory Test Abnormal Results – Clinical Chemistry: Full Analysis Set
14.5.5.1
Laboratory Test Results – Hematology: Full Analysis Set
14.5.5.2
Laboratory Test Abnormal Results – Hematology: Full Analysis Set
14.5.6.1
Laboratory Test Results – Urinalysis: Full Analysis Set
14.5.6.2
Laboratory Test Abnormal Results – Urinalysis: Full Analysis Set
14.5.7
Laboratory Test Results – Increases in ALT, AST, and Total Bilirubin: Full Analysis Set
14.6.1
Vital Signs by Visit and Change from Start of OLE: Full Analysis Set
14.6.2
Physical Examination Abnormalities by Visit: Full Analysis Set
14.6.3.1
ECG Results by Visit and Change Within Each Year: Full Analysis Set
14.6.3.2
Electrocardiogram (ECG) Abnormal Shifts by Year: Full Analysis Set
14.6.4
Concomitant Medications Within Each Year by ATC2 and Preferred Term: Full Analysis Set
14.7.1
Total Duration of Treatment: Full Analysis Set
3.1.1
Summary of treatment emergent adverse event (All causality) by SOC and PT (Safety 
Analysis Set)
6.1.1
Summary of treatment-emergent adverse events leading to study drug withdrawn (All 
Causalities) (Safety Analysis Set)
6.1.2
Summary of treatment-emergent adverse events leading to study drug reduction or 
interruption (All Causalities) (Safety Analysis Set)
6.1.3
Summary of treatment-emergent adverse events leading to study discontinuation (All 
Causalities) (Safety Analysis Set)
OC15.4
Annual Incidence and Severity of Treatment-Emergent Adverse Events by SOC and 
Preferred Term: Full Analysis Set
OC15.6
Annual Incidence and Relationship of Treatment-Emergent Adverse Events by SOC and 
Preferred Term: Full Analysis Set


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11.2
Listings
Listing No.
Description
16.1.7
Randomization
16.2.1.1
Patient Disposition
16.2.1.1b
Patient Disposition - CP-4-004 OLE
16.2.1.1c
Listing of Patients final height as of last known visit in Study CP-4-004
16.2.1.2
Trial Inclusion/Exclusion Criteria
16.2.1.3
Inclusion/Exclusion Criteria Not Met
16.2.10
Comments
16.2.2
Protocol Deviations
16.2.4.1
Patient Demographics
16.2.4.2
Medical History at Start of Main Study
16.2.4.3
ACTH Test Results
16.2.4.4
MRI Results
16.2.4.5
Pubertal Status at Start of OLE (Year 1)
16.2.5.1
Patient Visits
16.2.5.2
Drug Accountability
16.2.6.1
Height, Height SDS, Change in Height SDS, and Height Velocity at Each Visit
16.2.6.1.b
Listing of antibodies and efficacy data in all patients in Study CP-4-004 OLE
16.2.6.2
Bone Age by Visit
16.2.6.3
Bone Maturation by Visit
16.2.7.1
All Adverse Events
16.2.7.2
All Serious Adverse Events
16.2.7.3
All Adverse Events Leading to Withdrawal from the Study
16.2.7.4
All Adverse Events of Special Interest
16.2.7.5
All Injection Site Reactions
16.2.8.1
IGF-1 and IGF-1 SDS Results at Each Visit
16.2.8.2
IGF-1 SDS > 2
16.2.8.3
IGFBP-3 Results at Each Visit
16.2.8.4
Glucose Metabolism Results
16.2.8.5
Endocrinology Results
16.2.8.6
Lipid Metabolism Results
16.2.8.7
Chemistry Results
16.2.8.8
Hematology Results
16.2.8.9
Urinalysis Results


Open Label Extension Statistical Analysis Plan
OPKO Biologics Ltd.
Protocol No. CP-4-004
Page 29 of 30
Confidential
Listing No.
Description
16.2.8.10
Pregnancy Test Results
16.2.8.11
Gonadotropic Hormone Results
16.2.8.12
MOD-4023 Serum Levels
16.2.9.1
Vital Sign Results by Visit
16.2.9.2
Physical Examination Results
16.2.9.3
Electrocardiogram Results
16.2.9.4
Concomitant Medications
16.2.9.5
Exposure and Duration of Treatment
16.2.9.6
Antibody Titers
16.2.9.6b
Antibody Titers (Anti-hGH Nab)
16.2.9.7
Injection Site Pain, Redness, Bruising, Swelling, and Itching Scores by Visit
16.2.9.8
Fundoscopy
16.2.9.9
Weight and Height at Each Visit
16.2.9.10
Pubertal Status by Visit
16.2.9.11
Summary of Dose Adjustments
16.2.9.12
Listing of antibodies to somatrogon and individual efficacy data in patients with CTP+ in 
Study CP-4-004 (Main and OLE)
11.3
Figures
Figure No.
Description
7
Height SDS and Cumulative Change in Height SDS by Year and by ADA Status in Study 
(All Cohorts Combined)
8
IGF-1 SDS by Year by ADA Status in Study
14.2.1.1&2
Annualized Height Velocity
14.2.1.3
Summary of Annualized Height Velocity for All Cohorts Combined at Each Year of Study
14.2.2.2A
Summary of Height SDS by Initial Cohort Assignment at Each Year of Study
14.2.2.2B
Summary of Height SDS by Year of Study and Initial Cohort Assignment
14.2.2.2C
Summary of Height SDS for All Cohorts Combined at Each Year of Study
14.3.5.1
IGF-1 SDS
14.4.2.1&2
Annualized Height Velocity by ADA Status
14.4.2.3
Summary of Annualized Height Velocity for All Cohorts Combined at Each Year of Study 
by ADA Status
14.4.2.5&8
Summary of Height SDS for All Cohorts Combined at Each Year of Study by ADA Status
14.4.2.9
Peak IGF-1 SDS by ADA Status
14.5.1.1
Clinical Laboratory Summary: Glucose Metabolism
14.5.2.1
Clinical Laboratory Summary: Endocrinology


Open Label Extension Statistical Analysis Plan
OPKO Biologics Ltd.
Protocol No. CP-4-004
Page 30 of 30
Confidential
Figure No.
Description
14.5.3.1
Clinical Laboratory Summary: Lipid Profile
14.5.4.1
Clinical Laboratory Summary: Chemistry
14.5.5.1
Clinical Laboratory Summary: Hematology
14.5.6.1
Clinical Laboratory Summary: Urinalysis
16.2.8.7
Maximum Bilirubin Versus Maximum ALT and AST


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