Clinical trial NCT03874013
Conditions: Growth Hormone Deficiency
Sponsor: OPKO Health, Inc.
Start date: 2017-12-07; Completion date: 2020-03-06
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Treatment of children with growth failure due to growth hormone deficiency (GHD).

Primary • To evaluate the efficacy and safety of weekly MOD-4023 administration compared to daily Genotropin® administration in Japanese pre-pubertal children with GHD.

Secondary

• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of three different doses of MOD-4023 in Japanese pre-pubertal children with GHD.

Detailed description:
This is a 12-month, open-label, randomized, active controlled, parallel group study comparing the efficacy and safety of weekly MOD-4023 to daily recombinant human growth hormone (r-hGH), Genotropin ®. Both drugs will be injected subcutaneously (SC) using a pen device.

After a 4 week Screening period, patients meeting all the entry criteria and none of the exclusion criteria, will be eligible to participate in the study.

Eligible patients will be randomized in a 1:1 ratio, to receive either:

• MOD-4023 (investigational treatment): weekly MOD-4023 SC injections for 12 months; initially over the first 6 weeks, MOD-4023 will be administered in 3 stepwise escalating doses (0.25 mg/kg/week, 0.48 mg/kg/week and 0.66 mg/kg/week), each for two weeks sequentially. For the remaining 46 weeks, patients will continue to receive MOD-4023 at a dose of 0.66 mg/kg/week.

Or

• Genotropin® (reference treatment): daily Genotropin® (0.025 mg/kg/day which is equivalent to 0.175 mg/kg/week, divided equally into 7 daily injections over a week) SC injection for 12 months.

After the 6-week PK/PD sampling period, the dose of MOD-4023 and Genotropin® will be adjusted every 3 months based on a patient's body weight. Doses may be decreased for safety reasons according to the pre-defined dose-adjustment criteria (which will be based on the severity of adverse events (AEs) or repeated, elevated levels of IGF-1 Standard Deviation Score (SDS)).

The key safety data will be reviewed by an independent and external Data and Safety Monitoring Board (DSMB). DSMB review will also include a review of the number or percentage of patients requiring dose reductions due to AEs. Following the completion of the12-month treatment period, eligible patients will be consented to enroll into an open-label long term extension (LTE) period, and an amendment to this study protocol will be submitted prior to the first patient completes the 12 months treatment period. Eligible Genotropin®-treated patients will be switched to a MOD-4023 dose of 0.66 mg/kg/week in the LTE. The LTE is planned to continue until MOD-4023 marketing registration in Japan.

Arms: arm 1: MOD-4023 (investigational treatment): weekly MOD-4023 SC injections for 12 months; initially over the first 6 weeks, MOD-4023 will be administered in 3 stepwise escalating doses (0.25 mg/kg/week, 0.48 mg/kg/week and 0.66 mg/kg/week), each for two weeks sequentially. For the remaining 46 weeks, patients will continue to receive MOD-4023 at a dose of 0.66 mg/kg/week. arm 2: Genotropin® (reference treatment): daily Genotropin® (0.025 mg/kg/day).
Interventions: intervention 1: MOD-4023 intervention 2: Genotropin
Intervention descriptions: intervention 1: MOD-4023 is a long-acting modified recombinant human growth hormone (r-hGH) which utilizes C-terminal peptide (CTP) technology. It will be provided as a solution for injection containing 20 or 50 mg/mL MOD-4023 in a multi-dose disposable pre-filled PEN.

MOD-4023 will be administered as a SC injection once weekly, using a delivery device. intervention 2: Genotropin® is dispensed in a 2-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®) will be used for daily (evening/bedtime) SC administration of Genotropin® into the region of the upper arms, buttocks, thighs or abdomen (8 locations). Injection sites should be rotated.

Dose regimen for Genotropin®: 0.025 mg/kg/day (or 0.175 mg/kg/w divided equally to 7 injections over a week).

Protocol documents:
Prot_000.pdf: 
Signature Page for VV-TMF-35579 v9.0
Signature Page for
Reason for signing: Approved
Name:
Role: Quality Assurance
Date of signature: 14-Dec-2018 20:40:41
GMT+0000
Reason for signing: Approved
Name:
Role: 
Date o
Dec-2018 20:56:38
GMT+0000
Reason for signing: Approved
Name:
Role: Clinical Operations
Date of signature: 14-Dec-2018 20:58:13
GMT+0000
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CLINICAL STUDY PROTOCOL 
 
A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER, 12-MONTH, 
EFFICACY AND SAFETY STUDY OF WEEKLY MOD-4023 COMPARED TO 
DAILY GENOTROPIN® THERAPY IN JAPANESE PRE-PUBERTAL CHILDREN 
WITH GROWTH HORMONE DEFICIENCY 
 
 
Sponsor: 
OPKO Health Inc.  
4400 Biscayne Boulevard 
Miami, FL 33137, USA 
Tel: +1 305 575 4100  
Protocol Number: 
CP-4-009 Japan Country-Specific 
Investigational Product: 
MOD-4023 
Coordinating Investigator: 
, M.D. Ph.D. 
 Division of Endocrinology and Metabolism 
National Center for Child Health and Development 
Safety Medical Officer: 
, M.D. 
 Tanaka Growth Clinic, Tokyo, Japan 
 
Protocol Version: 
 
 
 
 
 
 
 
 
9.0 
 
Confidentiality Statement 
This protocol is a confidential communication document of OPKO Health Inc. (OPKO) The 
recipient of this document agrees not to disclose the information contained herein to others without 
prior written authorization of OPKO except that this document may be disclosed to appropriate 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) or duly authorized 
representatives of Regulatory authorities such as Pharmaceuticals and Medical Device Agency 
(PMDA). 
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Protocol Signature Page 
Protocol Title 
A Phase 3, Open-Label, Randomized, Multicenter, 12-Month, 
Efficacy and Safety Study of Weekly MOD-4023 Compared to Daily 
Genotropin® Therapy in Japanese Pre-Pubertal Children with Growth 
Hormone Deficiency 
Protocol Number 
CP-4-009; Japan Country-Specific 
Investigational Product: 
MOD-4023 
Study Phase 
3 
Sponsor 
OPKO Health Inc. 
4400 Biscayne Boulevard 
Miami, FL 33137, USA 
Tel: +1 305 575 4100 
Sponsor Representatives 
We, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the trial and that the protocol is in compliance with International Conference on 
Harmonisation (ICH) ,Good Clinical Practice (GCP) guidelines and Japanese GCP (J-GCP). 
 
 
Signature 
Date 
 
See Electronic Signature 
, OPKO 
 
 
See Electronic Signature  
, OPKO 
 
 
See Electronic Signature  
, Quality Assurance, OPKO 
 
 
Principal Investigator  
By signing below, I, the Investigator approve the protocol and agree to conduct the clinical trial 
according to all stipulations of the protocol as specified in both the clinical and administrative sections. 
I agree to comply with the ICH-GCP, local regulatory authority’s guidelines for the conduct of clinical 
trials, World Medical Association Declaration of Helsinki (and relevant updates) and applicable 
regulations. I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of OPKO.  
 
 
Investigator Signature 
Date 
 
 
Name 
Institution 
City, Country
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Protocol Synopsis 
Study Title 
A Phase 3, Open-Label, Randomized, Multicenter, 12-Month, Efficacy 
and Safety Study of Weekly MOD-4023 Compared to Daily Genotropin® 
Therapy in Japanese Pre-Pubertal Children with Growth Hormone 
Deficiency  
Protocol Number 
CP-4-009 
Investigational Product: 
MOD-4023 
Clinical Sites 
The study will be conducted in approximately 45-55 sites in Japan. 
Study Phase 
3 
Therapeutic Indication 
Treatment of children with growth failure due to growth hormone 
deficiency (GHD). 
Study Objectives  
Primary 
 
To evaluate the efficacy and safety of weekly MOD-4023 
administration compared to daily Genotropin® administration in 
Japanese pre-pubertal children with GHD. 
Secondary 
 
To evaluate the pharmacokinetics (PK) and pharmacodynamics 
(PD) profiles of three different doses of MOD-4023 in Japanese 
pre-pubertal children with GHD. 
Study Design 
This is a 12-month, open-label, randomized, active controlled, parallel 
group study comparing the efficacy and safety of weekly MOD-4023 to 
daily recombinant human growth hormone (r-hGH), Genotropin ®. Both 
drugs will be injected subcutaneously (SC) using a pen device. 
After a 4 week Screening period (with optional extension of 1 week if 
needed, for a total of up to 5 weeks) and approval of the study medical 
monitor, patients meeting all the inclusion criteria and none of the 
exclusion criteria, will be eligible to participate in the study. 
At Baseline, eligible patients will be randomized in a 1:1 ratio, to receive 
either: 
 
MOD-4023 (investigational treatment): weekly MOD-4023 SC 
injections for 12 months; initially over the first 6 weeks, MOD-
4023 will be administered in 3 stepwise escalating doses 
(0.25 mg/kg/week, 0.48 mg/kg/week and 0.66 mg/kg/week), each 
for two weeks sequentially. For the remaining 46 weeks, patients 
will continue to receive MOD-4023 at a dose of 0.66 mg/kg/week. 
Or  
 
Genotropin® (reference treatment): daily Genotropin® (0.025 
mg/kg/day which is equivalent to 0.175 mg/kg/week, divided 
equally into 7 daily injections over a week) SC injection for 12 
months. 
Patients allocated to the MOD-4023 treatment arm, will initially undergo a 
stepwise dose escalation over 6 weeks starting with low MOD-4023 dose 
of 0.25 mg/kg/week for 2 weeks, followed by an intermediate dose of 
0.48 mg/kg/week for 2 weeks and then a final dose of 0.66 mg/kg/week for 
2 weeks. These MOD-4023 patients will be assigned into one of 4 sampling 
sub-blocks (as shown in the table below) and undergo population-based PK 
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a If the patient’s screening process is delayed because of a benign illness or unforeseen benign condition (i.e. 
pharyngitis, viral GI problems, minor accident or trauma, etc.) or a technical issue that is related to screening 
procedures (for example, delays with lab results) extra time - equal to the time of patient’s unavailability - will be 
added to the duration of the Screening period, but not in excess of an additional weeks 1 (total of 5 weeks 
Screening period). 
b It is recommended that the parents' height will be measured at the site. If measured parental height is not 
available an estimate could be provided by the parent. 
c Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated stadiometer. 
Body weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy pocket 
items. 
d At Screening Visit, historical bone age assessment might be accepted if they were done no more than 6 months 
prior to the ICF signature date. If the patient will be eligible, the bone age should be repeated at Visit 2, before the 
dosing. The Visit 2 scan will be the baseline scan for these patients. 
e No time limitation for the historical GH stimulation tests.  
f Morning cortisol assessment will be subject to the investigator judgment.  
Screening Period (Visit 1; Week -4/ Day -28 to Week -1/Day -1) a 
Patients will complete screening procedures to determine eligibility. The 
Screening period will last up to 4 weeks (with optional extension of 1 
week, for a total of 5 weeks) and can be conducted over several visits 
prior to randomization. Prior to any study-specific investigations, written 
assent from pediatric patients (if needed, use appropriate 1 of 2 versions 
according to their education and their age) and consent from the parent(s) 
or legal guardian(s) will be obtained.  
The following assessments will be conducted at the screening visits:  
 
Inclusion/Exclusion criteria  
 
Estimated Parental heightb 
 
Auxology measurementsc, body mass index (BMI) and BMI SDS 
 
Patient’s Height SDS and Height Velocity (HV) SDS 
 
Demographics and Medical history, including a description of 
pituitary deficiencies, concomitant and previous medications 
 
Overall health status assessments – complete physical examination 
and vital signs 
 
Pubertal status (according to Tanner stages) 
 
Bone age determination with the method of TW2 using a central 
bone age readerd 
 
Assessment of biochemical markers and stimulation tests: 
- 
Two different GH stimulation (provocation) tests from the 
following list: insulin tolerance test (with serum cortisol 
response to hypoglycemia if insulin stimulation test is chosen); 
arginine test; clonidine test; glucagon test; L-dopa; and GHRP-
2. The minimal duration and number of samples for each test 
must conform to the specifications in Appendix D.e 
- 
Analysis of GH serum levels (and glucose and serum cortisol 
if Insulin tolerance test is performed) may be done by local 
laboratories and to be provided for study medical monitor 
review and approval prior to study entry 
- 
Assessment of morning cortisol (up to 8 am ±1 hour)f. 
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a Insulin tolerance test with serum cortisol response to hypoglycemia is adequate for assessment of adrenal 
insufficiency and no ACTH/CRH stimulation test is required if such results are available. 
b MRI to be performed upon physician judgment. In addition, MRI which was conducted within 6 months prior to 
ICF signature date will be acceptable.   
c Randomization must be performed prior to Baseline Visit and only after the medical monitor approval of the 
patient eligibility. Randomization must occur within the screening period. The Baseline Visit (Visit 2/Day 1) is 
to occur within 2 weeks (or 10 working days) after randomization.  
d Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated stadiometer. 
Body weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy pocket 
items. 
If morning cortisol is below 190 nmol/L (7 μg/dL), test for 
adrenal insufficiency will be required – Low dose ACTH or 
CRH stimulation test (only if the patient was not previously 
assessed for the hypothalamus-pituitary-adrenal axisa or has 
been diagnosed with adrenal insufficiency). The minimal 
duration and number of samples for each test must conform to 
the specifications in Appendix D. 
- 
Assessment of 
 IGF-1 SDS  
 
Assessment of anti-hGH antibody levels 
 
Assessments of routine safety laboratory tests: biochemistry, 
hematology, and urinalysis (see section 5.5.9) 
 
Assessment of thyroid: TSH, FT4 
 
Assessment of glucose metabolism: morning fasting insulin and 
glucose (will be tested as part of biochemistry panel) and HbA1c 
 
Parameters of lipid metabolism: morning fasting total cholesterol, 
triglycerides, HDL and LDL 
 
Head magnetic resonance imagingb (MRI) if possible with 
contrast – after two GH stimulation tests, based on physician 
recommendation 
Approximately 8-42 mL of blood will be drawn from the patients during 
the screening period. 
All lab assessments are done in a central laboratory unless stated 
otherwise.  
Key data and all test results obtained during screening will be reviewed 
by the study medical monitor and eligibility will be confirmed prior to 
randomization of each patient.  
 
Active Treatment Period (Baseline to Month 12)  
At Baseline (Visit 2/Day 1) or once eligible, eligible patients will be 
randomized in a 1:1 ratio to MOD-4023 (investigational treatment) or 
Genotropin® (reference therapy) and will undergo the following 
assessmentsc: 
 
Auxologyd measurements 
 
AE, local tolerability (injection site reactions assessment) and 
concomitant medications 
 
Overall health status assessment, including complete physical 
examination and vital sign assessments 
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a Bone age at Visit 2 will be performed in case bone age was not performed at screening. This test should be done 
prior to the first dose. 
 
Safety laboratory- biochemistry, hematology and urinalysis, (see 
section 5.5.9) 
 
Pubertal status (according to Tanner stages) 
 
Assessment of thyroid: TSH, FT4 
 
Assessment of biochemical markers: 
 IGF-
1 SDS (applicable for both arms), 
 
 
Assessment of MOD-4023 serum levels (applicable for MOD-
4023 treatment arm only) 
 
Parameters of glucose metabolism- morning fasting glucose (will 
be tested as part of biochemistry panel), morning fasting insulin 
and HbA1c 
 
Parameters of lipid metabolism- morning fasting total cholesterol, 
triglycerides, HDL and LDL 
 
Assessment of pre-dose anti-MOD 4023 and anti-hGH antibodies 
(depending on treatment arm allocation) 
 
Bone agea 
 
ECG pre-dosing  
 
Training for patients, parents or legal guardians on patient diary 
completion and drug administration including on site injection  
 
Administration of study drug at clinic 
 
Drug dispensing 
Approximately 9-12 mL of blood will be drawn from patients at baseline 
visit. 
During the Treatment period, patients will be scheduled to attend the 
following clinic visits according to their treatment allocation as shown in 
the table below. The Baseline Visit (Visit 2/first dose – described above) 
and Visits 6 to 9 (every three months) will be similar for both treatment 
arms (except where noted). Visits 3, 4 and 5 will differ between the 2 
treatment arms due to the 6-week dose escalation and PK/PD sampling in 
the MOD-4023 treatment arm. 
MOD-4023 Treatment Arm 
(Investigational) 
Genotropin® Treatment Arm 
(Reference) 
Visit 2 – Baseline – First dosing 
Visit 2 – Baseline – First dosing 
Visits 3 and 3.1 – Week 2 
First PK/PD sampling post 2nd dose 
for each dose level (according to 
sub-block PK/PD allocation) 
Visit 3 – Week 2  
Phone interview will be done. 
Per Appendix I.  
No clinic visit. 
Visits 4 and 4.1 – Month 1/Week 4 
Safety (only at Visit 4.1) and 
second PK/PD sampling post 2nd 
dose for each dose level (according 
to sub-block PK/PD allocation) 
Visit 4 – Month 1/Week 4 (±1 
week) 
Clinic visit 
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Visits 5 and 5.1 – Week 6 
Third PK/PD sampling post 2nd 
dose for each dose level (according 
to sub-block PK/PD allocation) 
Visit 5 – Week 6  
Phone interview will be done per 
Appendix I.  
No clinic visit. 
Visit 6 – Month 3/Week 13 (±1 
week) 
Clinic visit 
To be conducted 4 days (-1 day) 
post dose 
Visit 6 – Month 3/Week 13 (±1 
week) 
Clinic visit 
Visit 7 and 7.1 – Month 6/Week 26 
(±3 weeks) 
Two clinic visits: 
- Visit 7 Pre-dose immunogenicity 
assessments conducted same day as 
dosing 
- Visit 7.1 Post-dose assessments 
conducted 4 days (-1 day) after 
dose 
Visit 7 – Month 6/Week 26 (±1 
week) 
Clinic visit 
Visit 8 – Month 9/Week 39 (±1 
week) 
Clinic visit 
To be conducted 4 days (-1 day) 
post dose  
Visit 8 – Month 9/Week 39 (±1 
week) 
Clinic visit 
Visit 9 and 9.1 – EOT Visit – 
Month 12/Week 52 (±3 weeks) 
Two clinic visits: 
- Visit 9 Pre-dose immunogenicity 
assessments conducted same day as 
dosing 
- Visit 9.1 Post-dose assessments 
conducted 4 days (-1 day) after 
dose 
Visit 9 – EOT Visit – Month 
12/Week 52 (±1 week) 
Clinic visit 
Visit 10 – EOS visit – Month 
13/Week 56 (+1 week) 
Phone interview will be done. Per 
Appendix I.  
No clinic visit. 
Visit 10 – EOS visit – Month 
13/Week 56 (+1 week) 
Phone interview will be done. 
Per Appendix I.  
No clinic visit. 
Visit windows are relative to the visit, not to the dose, unless specified 
otherwise. 
 
Assessments for MOD-4023 treatment arm (Visits 3 to 9): 
The following assessments will be obtained at the visits 3 and 3.1, 4 
and 4.1, and 5 and 5.1. 
Visits 3, 4 and 5 will take place at Weeks 2, 4, and 6, respectively, for 
first PK/PD sampling post 2nd dose for each dose level (according to sub-
block PK/PD allocation).  Visits 3.1, 4.1, and 5.1 will take place at Weeks 
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a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated wall or equivalent 
mounted stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy 
pocket items. 
2, 4, and 6 respectively, for second PK/PD sampling post 2nd dose for 
each dose level (according to sub-block PK/PD allocation – refer to  
Table 2).  For each visit/sub-visit, the patient is expected to visit the clinic 
twice during the week to obtain two different post-dose PK/PD samples. 
 
Safety evaluation consisting of AE, local tolerability and 
Concomitant medications at all visits 
 
Complete physical examination and vital sign assessments at visits 
3.1, 4.1 and 5.1 only  
 
Safety laboratory: biochemistry, hematology and urinalysis (see 
section 5.5.9) at Visit 4.1 only 
 
Assessment of biochemical markers: 
, IGF-1 
SDS, 
 
(sampling time per sub-block allocation) 
 
MOD-4023 serum levels (sampling time per sub-block allocation) 
 
Assessment of anti-MOD-4023 antibodies at Visit 4.1 only 
 
Fundoscopy (if there are signs or symptoms indicative of benign 
intracranial hypertension) 
 
Weight measurement at Visit 4.1 only.  
 
Training on drug administration, injection site reactions, diary 
completion, and dosing review (Visits 3.1 and 4.1) 
 
Study drug return and accountability at Visit 4.1 only 
 
Individual dose adjustment and dispensing study drug at Visit 4.1 
only 
Approximately 6 mL of blood will be drawn from the patients at each visit, 
except for Visit 4.1. 
At Visit 4.1, approximately 12 mL of blood will be drawn from the patients.  
 
The following assessments will be obtained at Visit 6 (Month 3/Week 
13 ± 1week) and Visit 8 (Month 9/Week 39 ±1week):  
 
Auxology measurementsa  
 
AE, local tolerability, and concomitant medications  
 
Overall health status assessment, including complete physical 
examination and vital sign assessments  
 
Safety laboratory: biochemistry, hematology and urinalysis, (see 
section 5.5.9)  
 
Pubertal status (according to Tanner stages) 
 
Assessment of thyroid: TSH, FT4  
 
Assessment of biochemical markers: 
 IGF-
1 SDS 
 
 
 
Assessment of anti-MOD-4023 antibodies  
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a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated wall or equivalent 
mounted stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy 
pocket items. 
 
Fundoscopy (ONLY if there are signs or symptoms indicative of 
benign intracranial hypertension) 
 
Study drug return and accountability 
 
Individual dose adjustment and dispensing study drug 
Approximately 9 mL of blood will be drawn from the patients at those 
visits. 
 
Visit 7 and Visit 7.1 (Month 6/Week 26 ±3 weeks) 
Visit 7 will consist of two clinic visits, Visit 7 (pre-dose) and Visit 7.1 
(post-dose), at Week 26 ±3 weeks.  Visit 7 must be conducted prior to 
Visit 7.1. 
Visit 7 will take place at the clinic prior to dosing at any week during ±3 
weeks of Month 6/Week 26.  The following pre-dose immunogenicity 
assessments should be conducted on the same day of dosing: 
 
AE and concomitant medications 
 
Assessment of MOD-4023 serum levels 
 
Assessment of anti-MOD-4023 antibodies 
Approximately 6 mL of blood will be drawn from the patients at this visit. 
Visit 7.1 will take place at the clinic 4 days (-1 day) after dose at any week 
after Visit 7 during the ±3 weeks of Month 6/Week 26.  The following post-
dose assessments will be conducted 4 days (-1 day) after dose: 
 
Auxology measurementsa  
 
AE, local tolerability, and concomitant medications  
 
Overall health status assessment, including complete physical 
examination and vital sign assessments  
 
Safety laboratory: biochemistry, hematology and urinalysis, (see 
section 5.5.9)  
 
Pubertal status (according to Tanner stages) 
 
Assessment of thyroid: TSH, FT4  
 
Assessment of biochemical markers: 
 IGF-
1 SDS 
 
 
 
Parameters of glucose metabolism- morning fasting glucose (will 
be tested as part of biochemistry panel), morning fasting insulin 
and HbA1c  
 
Parameters of lipid metabolism- morning fasting total cholesterol, 
triglycerides, HDL and LDL  
 
ECG  
 
Fundoscopy (ONLY if there are signs or symptoms indicative of 
benign intracranial hypertension) 
 
Study drug return and accountability 
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a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated wall or equivalent 
mounted stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy 
pocket items. 
 
Individual dose adjustment and dispensing study drug 
Approximately 10 mL of blood will be drawn from the patients at this visit. 
 
Visit 9 and Visit 9.1 (Month 12/ Week 52 ±3 weeks) - End of 
Treatment (EOT) Visit Assessments   
Visit 9/EOT will consist of two clinic visits, Visit 9 (pre-dose) and Visit 
9.1 (post-dose), at Week 52 ±3 weeks.  Visit 9 must be conducted prior to 
Visit 9.1. 
Visit 9 will take place at the clinic prior to dosing at any week during ±3 
weeks of Month 12/Week 52.  The following pre-dose immunogenicity 
assessments should be conducted on the same day of dosing:  
 
AE and concomitant medications 
 
Assessment of MOD-4023 serum levels 
 
Assessment of anti-MOD-4023 
Approximately 6 mL of blood will be drawn from the patients at this visit. 
Visit 9.1 will take place at the clinic 4 days (-1 day) after dose at any week 
after Visit 9 during the ±3 weeks of Month 12/Week 52.  The following 
post-dose assessments will be conducted 4 days (-1 day) after dose:  
 
Auxology measurementsa   
 
AE, local tolerability and concomitant medications 
 
Overall health status assessment, including complete physical 
examination and vital sign assessments 
 
Safety laboratory biochemistry, hematology and urinalysis (see 
section 5.5.9) 
 
Pubertal status (according to Tanner stages) 
 
Assessment of thyroid: TSH, FT4 
 
Hormones and biochemical markers: 
 
IGF-1 SDS 
 
Parameters of glucose metabolism- morning fasting glucose (will 
be tested as part of biochemistry panel), morning fasting insulin 
and HbA1c 
 
Parameters of lipid metabolism- morning fasting total cholesterol, 
triglycerides, HDL and LDL 
 
Assessment of MOD-4023 serum levels  
 
Fundoscopy (ONLY if there are signs or symptoms indicative of 
increased intracranial hypertension( 
 
Bone age assessment 
 
Study drug return and accountability 
Approximately 10 mL of blood will be drawn from the patients at this 
visit. 
 
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a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated wall or equivalent 
mounted stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy 
pocket items. 
Assessments for Genotropin® Treatment Arm – Visits 3 to 9. 
At Visit 3 (Week 2) and Visit 5 (Week 6) a phone interview will be 
conducted according to Appendix I. No clinic visit. 
 
The following assessments will be conducted at Visit 4 (±1 week): 
 
AE, local tolerability and concomitant medications 
 
Overall health status assessment, including complete physical 
examination and vital signs assessments 
 
Safety laboratory: biochemistry, hematology and urinalysis (see 
section 5.5.9)  
 
Hormones and biochemical markers
 IGF-
1 SDS 
 
Fundoscopy (ONLY if there are signs or symptoms indicative of 
benign intracranial hypertension) 
 
Study drug return and accountability  
Approximately 7 mL of blood will be drawn from the patients at this visit 
(No blood samples will be collected at Visits 3 and 5. No clinic visit).  
 
The following assessments will be conducted at Visits 6 (±1 week), 7 
(±1 week) and 8 (±1 week): 
 
Auxology measurementsa  
 
AE, local tolerability and concomitant medications 
 
Overall health status assessment, including complete physical 
examination and vital signs assessments 
 
Safety laboratory: biochemistry, hematology and urinalysis (see 
section 5.5.9)   
 
Pubertal status (according to Tanner stages) 
 
Assessment of thyroid: TSH, FT4 
 
Hormones and biochemical markers: 
 IGF-
1 serum SDS 
 
Parameters of glucose metabolism: morning fasting glucose (will 
be tested as part of biochemistry panel), morning fasting insulin 
and HbA1c at Visit 7 only 
 
Parameters of lipid metabolism: morning fasting total cholesterol, 
triglycerides, HDL and LDL at Visit 7 only 
 
Fundoscopy (ONLY if there are signs or symptoms indicative of 
increased intracranial hypertension) 
 
Study drug return and accountability 
 
ECG at Visit 7 (Month 6/Week 26 ± 1day)  
 
Individual dose adjustment every 3 months  
 
Dispense study drug  
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a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated wall or equivalent 
mounted stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy 
pocket items. 
 
Anti-hGH antibodies  
Approximately 9 mL of blood will be drawn from the patients at those 
visits.   
 
Visit 9 (Month 12/Week 52 ±1 week) - End of Treatment (EOT) Visit: 
The following assessments will be conducted at visit 9, EOT visit:  
 
Auxology measurementsa  
 
AE, local tolerability and concomitant medications 
 
Overall health status assessment, including complete physical 
examination and vital signs assessments 
 
Safety laboratory: biochemistry, hematology and urinalysis (see 
section 5.5.9)  
 
Pubertal status (according to Tanner stages) 
 
Assessment of thyroid: TSH, FT4 
 
Hormones and biochemical markers: 
 IGF-
1 SDS 
 
Parameters of glucose metabolism: morning fasting glucose (will 
be tested as part of biochemistry panel), morning fasting insulin 
and HbA1c 
 
Parameters of lipid metabolism: morning fasting total cholesterol, 
triglycerides, HDL and LDL 
 
Fundoscopy (ONLY if there are signs or symptoms indicative of 
increased intracranial hypertension) 
 
Bone age assessment 
 
Study drug return and accountability 
 
Anti-hGH antibodies 
Approximately 9 mL of blood will be drawn from the patients at this visit.  
Patients in both arms will be requested to complete a patient diary at 
home to collect data on AEs, concomitant medications and local 
tolerability reactions on weekly basis (MOD-4023 after 1 weekly dosing; 
Genotropin® once a week post 1 dosing). 
 
For MOD-4023 and Genotropin®:  
Follow Up Period (Month 13) - Visit 10 - EOS Visit (Week 56 +1 
week)  
After 1 month following EOT visit (visit 9), phone interview should be 
conducted according to Appendix I. This phone interview will be 
considered as Visit 10 - End Of Study visit.  
Study Duration 
Study duration for each participating patient will be up to 13 months as 
follows in the main protocol: 
Screening period: Up to 1 month (4 weeks + 1 week extension)  
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a According to rounding policy IGF-1 results ≤-0.95 might be acceptable as well  
Active Treatment period: 12 months 
MOD-4023 Arm: 52 weeks (6 weeks dose escalation + 46 weeks) 
Genotropin® Arm: 52 weeks 
Follow Up period: 1 month 
Number of Patients 
Approximately 44 pre-pubertal children, boys not yet 11 (10 years and 
364 days) and girls not yet 10 (9 years and 364 days) years of age, 
respectively, will be included randomized in a 1:1 ratio to the weekly 
MOD-4023 arm and the daily Genotropin® comparator arm.  
Inclusion Criteria 
1. Pre-pubertal child aged ≥ 3 years old, and not yet 10 years for 
girls (9 years and 364 days) or not yet 11 years for boys (10 years 
and 364 days), on the date of ICF signature, with either isolated 
GHD, or GH insufficiency as part of multiple pituitary hormone 
deficiency. 
2. Confirmed diagnosis of GHD by 2 different types of GH 
provocation tests (standardized on growth foundation data): 
defined as a peak serum GH level of ≤ 6.0 ng/mL or ≤ 16 ng/mL 
when conducting GHRP-2 provocation test. 
Prior local laboratory results will be accepted subject to pre-
approval by the study medical monitor and if the tests were 
conducted as specified in the protocol.  
3. Bone age (BA) is not older than chronological age and should be 
less than 10 for girls and less than 11 for boys. 
4. Without prior exposure to any r-hGH therapy. 
5. Height SD score ≤ -2.0 at screening 
6. Impaired height velocity defined as: 
 
Annualized height velocity (HV) below the 25th percentile 
for CA (HV < -0.7 SDS) and gender according to the local 
primary care provider standard.  
 
The interval between two height measurements should be at 
least 6 months, but should not exceed 18 months prior to 
inclusion.  
7. BMI must be within ±2 SDS of mean BMI for the chronological 
age and sex. 
8. Baseline IGF-1 level of at least 1 SDS below the mean IGF-1 
level standardized for age and sex (IGF-1 SDS ≤ -1)a according to 
the central laboratory reference values. A single re-test will be 
allowed (subject to approval from the study medical monitor) if 
all other criteria are met. 
9. Normal creatinine levels according to common practice reference 
ranges per age.  
10. Children with multiple hormonal deficiencies must be on stable 
replacement therapies (no change in dose) for other hypothalamo-
pituitary organ axes for at least 3 months prior to ICF signing. 
11. Clinical presentation of normal 46 XX karyotype for girls. 
12. Willing and able to provide written informed consent of the 
parent or legal guardian of the patient and written assent from 
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pediatric patients (when applicable based on age and Japan 
regulation). 
Exclusion Criteria 
1. Children with prior history of leukemia, lymphoma, sarcoma or 
any other forms of cancer. 
2. History of radiation therapy or chemotherapy.  
3. Malnourished children defined as BMI < -2 SDS for age and sex. 
4. Children with suspected psychosocial dwarfism by the discretion 
of the investigator. 
5. Children born small for gestational age (SGA – birth weight 
and/or birth length < -2 SDS 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. Children with diabetes mellitus. 
9. Known or suspected chromosomal abnormalities including 
Turner’s syndrome, Laron syndrome, Noonan syndrome, Prader-
Willi syndrome, Russell-Silver syndrome, SHOX (short stature 
homeobox) mutations/deletions and skeletal dysplasia’s, with the 
exception of septo-optic dysplasia. 
10. Concomitant administration of other treatments that may have an 
effect on growth such as anabolic steroids, sex steroids, with the 
exception of ADHD drugs or hormone replacement therapies 
(thyroxin, hydrocortisone, desmopressin [DDAVP])  
11. Children requiring glucocorticoid therapy (e.g. for asthma) that 
are taking chronically a dose greater than 400 µg/d of inhaled 
budesonide or equivalent as provided in Appendix J.  
12. Major medical conditions and/or presence of contraindication to 
r-hGH treatment. 
13. Known or suspected HIV-positive patient, or patient with 
advanced diseases such as AIDS or tuberculosis. 
14. Drug substance or alcohol abuse. 
15. Known hypersensitivity to the components of study medication. 
16. Other causes of short stature such as celiac disease, uncontrolled 
primary hypothyroidism and rickets. 
17. The patient and/or the parent/legal guardian are likely to be non-
compliant in respect to study conduct. 
18. Participation in any other clinical trial within 30 days prior to 
screening and throughout the entire study period (including 
administration of investigational agent). 
Investigational Product 
Route and Dosage Form 
MOD-4023 is a long-acting modified recombinant human growth 
hormone (r-hGH) which utilizes C-terminal peptide (CTP) technology. It 
will be provided as a solution for injection containing 20 or 50 mg/mL 
MOD-4023 in a multi-dose disposable pre-filled pen. 
MOD-4023 will be administered as a SC injection once weekly, using a 
delivery device, into the upper arms, buttocks, thighs or abdomen (8 
locations for injection as noted in Figure 1). 
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Injection sites should be rotated, it is recommended that all 8 injection 
sites should be used successively, using a different injection site at each 
subsequent injection.  
During the first 6 weeks of dose escalation phase, the starting dose for the 
weekly administration will be: 0.25 mg/kg/week for 2 weeks, followed by 
an intermediate dose of 0.48 mg/kg/week for 2 weeks and then a final 
dose of 0.66 mg/kg/week for 2 weeks. 
During the remaining 46 weeks, the starting dose for the weekly 
administration will be 0.66 mg/kg/week. 
Over the 6 weeks escalation period, patients will be instructed to inject at 
evening hours/bed time. Following the 6 weeks escalation period, during 
the treatment period, patients can choose to stay with evening injections 
or to switch to morning injections. The time of injection should be 
consistent until the end of the study.  
Reference Drug 
Genotropin® is dispensed in a 2-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 GoQuick pen) will be used for daily 
(evening/bedtime) SC administration of Genotropin® into the region of 
the upper arms, buttocks, thighs or abdomen (8 locations). Injection sites 
should be rotated.  
 Dose regimen for Genotropin®: 0.025 mg/kg/day (or 0.175 mg/kg/w 
divided equally to 7 injections over a week). 
Efficacy Endpoints 
Primary endpoint: 
 Annual HV in cm/year after 12 months of treatment.  
 
Secondary endpoints (Auxology/Clinical): 
 Annualized  HV after 6 months of treatment 
 Change in height SDS at 6 and 12 months, compared to Baseline  
 Change in bone maturation (BM) at the end of 12 months, compared to 
Baseline BA (calculated as BA/CA). 
PK / PD Endpoints 
Secondary endpoints (Biochemical): 
 IGF-1 SDS on day 4(-1) after MOD-4023 dosing across study visits 
(window only applies to visits 6 to 9) 
Safety Endpoints 
 Incidence of AEs and SAEs 
 Incidence of anti-MOD-4023 antibody formation (including 
characterization of the antibodies and neutralizing properties) 
 Local injection site assessment 
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 
 IGF-1 SDS 
 Parameters of glucose metabolism: morning fasting glucose, morning 
fasting insulin level and HbA1c 
 Thyroid status 
 Lipid metabolism parameters: morning fasting total cholesterol, LDL, 
HDL and triglycerides 
 All other safety hematology and biochemical laboratory parameters 
 Physical examination 
 Fundoscopy (normal/abnormal) 
 Vital signs 
 ECG 
Sample Size 
The primary efficacy endpoint is Annual HV in cm/year after 12 months of 
treatment.  
Assuming that the mean treatment difference in the HV is -0.8 cm/yr and 
the common SD is 2.5 cm/yr, a total 44 Patients (22 per treatment) will 
provide about 90% probability that the point estimate of the mean treatment 
difference of HV in the CP-4-009 study is greater than -1.8 cm/year (which 
is the non-inferiority margin in the global trial CP-4-006).  
Statistical Analysis 
Details on the statistical methods will be provided in a Statistical Analysis 
Plan (SAP) prior to database lock.  
The aim of this Phase 3 study is to demonstrate that Annual HV at 12 
months for weekly MOD-4023 is comparable to daily r-hGH within the 
range defined of 1.8 cm/year (non-inferiority margin in CP-4-006 study).  
Descriptive statistics and confidence intervals (CI) will be used to 
characterize the results. 
Primary Efficacy Analysis:   
The goal of the primary efficacy analysis is to estimate the mean treatment 
difference between weekly MOD-4023 and daily Genotropin® with respect 
to the primary efficacy endpoint (HV after 12 months of treatment).  Least 
square means and 95% CI for HV at 12 months will be derived from an 
Analysis of Covariance (ANCOVA) model, with treatment, gender, as 
factors (class variables); and peak hGH value during stimulation test, and 
baseline HV as covariates. The point estimate of the mean difference in HV 
between treatments will be used to assess comparability. Comparability 
will be concluded for the primary efficacy endpoint if the point estimate of 
the mean treatment difference (MOD-4023 – Genotropin®) is ≥ –
1.8 cm/year.  
Missing data will be handled by multiple imputation (using SAS PROC 
MI), assuming data missing at random.  Details will be provided in the 
SAP. 
Secondary Analysis: 
The continuous secondary efficacy endpoints measured at a single post-
baseline timepoint will be analyzed in the same manner as the primary 
endpoint, using the ANCOVA model which may include treatment group, 
age, and gender, peak hGH value during stimulation test, and the baseline 
value of the endpoint of interest to generate the least square treatment 
means. For the secondary endpoints that are measured over time, Mixed-
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effect Model Repeated Measure (MMRM) analysis with similar factors as 
the ANCOVA model (in the primary analysis) will be used to estimate the 
time-specific results. This MMRM approach is not intended to test for 
statistical significance of factors. These secondary analyses are considered 
to be supportive efficacy analyses.  
Safety Analysis:  
The assessment of safety will be based mainly on the frequency of 
treatment emergent AEs and on the number of laboratory values that fall 
outside of pre-determined ranges.  Data of all safety endpoints will be listed 
and tabulated. 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................19 
GLOSSARY............................................................................................................................23 
1.0 INTRODUCTION ..........................................................................................................26 
1.1 
Growth Hormone Deficiency ....................................................................................26 
1.2 
Current Therapy ........................................................................................................26 
1.3 
Investigational Therapy.............................................................................................27 
1.3.1 
Clinical Studies .....................................................................................................27 
1.3.2 
Study Rationale ....................................................................................................29 
1.3.3 
Rationale for Dose Selection ...............................................................................30 
2.0 STUDY OBJECTIVES ..................................................................................................32 
3.0 STUDY DESIGN ............................................................................................................33 
4.0 STUDY POPULATION .................................................................................................35 
4.1 
Inclusion Criteria .......................................................................................................35 
4.2 
Exclusion Criteria ......................................................................................................36 
4.3 
Patient Identification .................................................................................................36 
4.4 
Removal, Replacement or Early Withdrawal of Patients from Therapy or 
Assessment ..................................................................................................................37 
4.5 
Handling of Withdrawals ..........................................................................................37 
4.6 
Sponsor's Termination of Study ...............................................................................38 
5.0 INVESTIGATIONAL PLAN AND STUDY PROCEDURES ...................................39 
5.1 
Screening Period (Visit 1) – Week -4 /Day -28 to Week -1 /Day -1 .......................39 
5.2 
Active Treatment Period (Baseline to Month 12) ...................................................41 
5.2.1 
Visit 2 (Day 1/Baseline) – Both Treatment Arms ..............................................42 
5.2.2 
Treatment Period - MOD-4023 Treatment Arm – Visits 3 to 9 ......................43 
5.2.2.1 
Visits 3 and 3.1, 4 and 4.1, 5 and 5.1 (Weeks 2, 4 and 6) ............................43 
5.2.2.2 
Visit 6 (Month 3/Week 13 ±1 week) and Visit 8 (Month 9/Week 39 ±1 week)
..........................................................................................................................43 
5.2.2.3 
Visit 7 and Visit 7.1 (Month 6/Week 26 ±3 weeks)......................................44 
5.2.2.4 
Visit 9 and Visit 9.1 (Month 12/Week 52 ±3 weeks) – End of Treatment 
(EOT) Visit Assessments ...............................................................................45 
5.2.3 
Treatment Period - Genotropin® Treatment Arm – Visits 3 to 9 ....................46 
5.2.3.1 
Visit 4 (Month 1/Week 4 ±1week) .................................................................46 
5.2.3.2 
Visit 6 (Month 3/Week 13 ±1week), Visit 7 (Month 6/ Week 26 ±1week), 
and Visit 8 (Month 9/Week 39 ±1week) .......................................................46 
5.2.3.3 
Visit 9 (Month 12/Week 52 ±1week) - End of Treatment Visit ..................47 
5.2.4 
Follow up Period (Month 13) - Visit 10 - EOS Visit (Week 56 +1 week): Both 
Treatment Arms ...................................................................................................48 
5.3 
Efficacy Assessments and Endpoints .......................................................................48 
5.3.1 
Height and Annual HV ........................................................................................48 
5.3.2 
Bone Age ...............................................................................................................48 
5.4 
Assessments and Endpoints ......................................................................................49 
5.4.1 
PD and PK Evaluations .......................................................................................49 
5.4.1.1 
PK: Serum MOD-4023 levels ........................................................................49 
5.4.1.2 
PK/PD Sampling time - MOD-4023 Treatment Arm .................................49 
5.4.1.3 
 
5.5 
Safety Assessments and Endpoints ...........................................................................50 
5.5.1 
AEs ........................................................................................................................50 
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5.5.2 
Local injection site reactions ...............................................................................50 
5.5.3 
Concomitant Medication Use ..............................................................................51 
5.5.4 
Treatment Compliance ........................................................................................51 
5.5.5 
Vital Signs .............................................................................................................51 
5.5.6 
Physical Examination ..........................................................................................51 
5.5.7 
ECG .......................................................................................................................51 
5.5.8 
Fundoscopy ...........................................................................................................52 
5.5.9 
Laboratory Assessments ......................................................................................52 
6.0 INVESTIGATIONAL PRODUCT ...............................................................................54 
6.1 
Investigational Product .............................................................................................54 
6.1.1 
Identity of Investigational Product.....................................................................54 
6.1.2 
Reference Therapy ...............................................................................................54 
6.2 
Study Drug Administration ......................................................................................54 
6.3 
Dose Modification Plan..............................................................................................56 
6.3.1 
Dose Decrease .......................................................................................................56 
6.4 
Method of Assigning Patients to Treatment Groups ..............................................58 
6.5 
Shipment and Storage Condition of Investigational Product ................................59 
6.6 
Accountability and Compliance of Investigational Product ..................................59 
6.7 
Prior and Concomitant Therapy ..............................................................................59 
6.7.1 
General Guidelines...............................................................................................59 
6.7.2 
Disallowed Previous Medications/Therapies .....................................................60 
6.7.3 
Allowed Medications ............................................................................................60 
6.7.4 
Prohibited Concomitant Medication ..................................................................60 
7.0 SAFETY AND PHARMACOVIGILANCE .................................................................61 
7.1 
Adverse Event.............................................................................................................61 
7.2 
Serious Adverse Event ...............................................................................................62 
7.3 
Definition of an Unexpected AE ...............................................................................63 
7.4 
Definition of suspected unexpected serious adverse reaction (SUSAR) ...............63 
7.5 
Notification about Serious or Unexpected AEs .......................................................63 
7.6 
Independent DSMB ...................................................................................................65 
7.7 
Medication Errors ......................................................................................................66 
7.8 
Medical Device Complaint ........................................................................................66 
8.0 STATISTICAL ANALYSIS ..........................................................................................67 
8.1 
Sample Size Consideration ........................................................................................67 
8.2 
Analyzed Population Sets ..........................................................................................67 
8.2.1 
Full Analysis Set ...................................................................................................67 
8.2.2 
Per Protocol Set ....................................................................................................67 
8.2.3 
Safety Analysis Set ...............................................................................................67 
8.3 
Handling of Missing Data ..........................................................................................67 
8.4 
Endpoints ....................................................................................................................67 
8.4.1 
Primary Efficacy Endpoint .................................................................................67 
8.4.2 
Secondary Efficacy Endpoints ............................................................................67 
 
 
8.4.4 
Safety Outcomes ...................................................................................................68 
8.5 
Statistical Analysis .....................................................................................................68 
8.6 
Efficacy Analysis ........................................................................................................68 
8.6.1 
Safety Analysis .....................................................................................................69 
8.6.2 
PK/PD analysis .....................................................................................................69 
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9.0 ETHICS ...........................................................................................................................70 
9.1 
IRB ..............................................................................................................................70 
9.2 
Ethical Conduct of the Study ....................................................................................70 
9.3 
Protocol Revisions and/or Deviations.......................................................................70 
9.4 
Patient Information and Consent .............................................................................70 
9.5 
Patient Insurance .......................................................................................................71 
9.6 
Informing the General Practitioner .........................................................................71 
9.7 
Personal Data Protection ...........................................................................................71 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE ............................................72 
10.1 
Audits and Inspections ..............................................................................................72 
10.2 
Study Monitoring .......................................................................................................72 
10.2.1 
Source Documents ................................................................................................72 
10.2.2 
eCRF......................................................................................................................73 
10.3 
Quality Laboratory Standards .................................................................................73 
10.4 
Data Management ......................................................................................................73 
11.0 STUDY ADMINISTRATION .......................................................................................74 
11.1 
Participating Centers .................................................................................................74 
11.2 
Clinical Trial Supplies ...............................................................................................75 
11.3 
ISF ...............................................................................................................................75 
11.4 
Study Completion.......................................................................................................75 
11.5 
Final Report ................................................................................................................75 
11.6 
Retention of Study Records.......................................................................................75 
11.7 
Confidentiality and Publication ................................................................................76 
12.0 REFERENCES ...............................................................................................................77 
APPENDIX A: SCHEDULE OF ACTIVITIES – MOD-4023 TREATMENT ARM –
VISITS 1 – 5.1 .................................................................................................................79 
APPENDIX B: SCHEDULE OF ACTIVITIES – MOD-4023 TREATMENT ARM 
(VISITS 6 - 10) ................................................................................................................81 
APPENDIX C: SCHEDULE OF ACTIVITIES – GENOTROPIN® TREATMENT ARM
 ..........................................................................................................................................82 
APPENDIX D: STIMULATION TESTS ............................................................................84 
APPENDIX E: INSTRUCTIONS FOR OBTAINING HEIGHT MEASUREMENTS ..86 
APPENDIX F: INSTRUCTIONS FOR OBTAINING X-RAY FILMS ...........................87 
APPENDIX G: INJECTION SITE ASSESSMENT TABLE (LOCAL REACTIONS) 
AND PAIN ASSESSMENT ...........................................................................................88 
APPENDIX H: DECLARATION OF HELSINKI (2013) .................................................90 
APPENDIX I: PHONE INTERVIEW .................................................................................96 
APPENDIX J: CLINICALLY COMPARABLE DOSES OF INHALED 
CORTICOSTEROIDS ...................................................................................................97 
APPENDIX K: OPEN-LABEL EXTENSION PROTOCOL ............................................98 
  
 
 
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List of Tables 
Table 1: Overview of Visit Scheduling for both Treatment Arms ....................................41 
Table 2: Sampling Time during the 6-week dose escalation phase in MOD-4023 Arm ..49 
Table 3: AE Relationship Criteria........................................................................................62 
 
List of Figures 
Figure 1: Recommended rotation of injection sites for Genotropin® and MOD-4023 ....55 
Figure 2: Dose Adjustment Scheme .....................................................................................58 
 
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GLOSSARY 
Abbreviation 
Definition 
µg 
Microgram 
ACTH 
Adrenocorticotropic hormone  
ADHD 
Attention-deficit/hyperactivity disorder 
AE 
Adverse Event 
ALT 
Alanine Aminotransaminase (SGPT) 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase (SGOT) 
BA 
Bone Age 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CA 
Chronological Age 
CI 
Confidence Interval 
CPK 
Creatine Phosphokinase 
CRH 
Corticotropin Releasing Hormone 
CRO 
Contract Research Organization 
CTP 
C-terminal Peptide 
D 
Day 
Day 4 (-1) 
Day 3 or 4 post-injection 
DBPC 
Double-Blind Placebo-Controlled 
DDAVP 
Desmopressin acetate  
dL 
Deciliter 
DMP 
Data Management Plan 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End Of Study 
EOT 
End Of Treatment 
FDA 
Food and Drug Administration 
FT4 
Peripheral Thyroid Hormones 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
GH 
Growth Hormone 
GHD 
Growth Hormone Deficiency 
GHRP 
pure growth hormone secretagogue 
GRS 
Growth Hormone Research Society 
HbA1c 
Glycated hemoglobin (hemoglobin A1c) 
hCG 
Human Chorionic Gonadotropin 
HCT 
Hematocrit 
HDL 
High Density Cholesterol 
HGB 
Hemoglobin 
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Abbreviation 
Definition 
hGH 
Human Growth Hormone 
HV 
Height Velocity 
ICCC 
In Country Clinical Caretaker  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
 
 
IGF-1 
Insulin-like Growth Factor-I 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigator Site File 
J-GCP 
Japanese Good Clinical Practice 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Cholesterol 
LH 
Luteinizing Hormone 
nmol 
Nanomole 
M 
Meter 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mmol 
Millimole 
MRI 
Magnetic Resonance Imaging 
OLE 
Open-label extension  
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PMDA 
Pharmaceuticals and Medical Device Agency 
QA 
Quality Assurance 
RA 
Regulatory Assurance 
RBC 
Red Blood Cells 
r-hGH 
Recombinant Human Growth Hormone 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard deviation 
SDS 
Standard Deviation Score 
SGA 
Small for Gestational Age 
SHOX 
Short stature homeobox 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSH 
Thyroid Stimulating Hormone 
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Abbreviation 
Definition 
TW2 
Tanner-Whitehouse 2 
WBC 
White Blood Cells 
WHO 
World Health Organization 
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1 INTRODUCTION 
1.1 
Growth Hormone Deficiency  
Human growth hormone (hGH) is a 191-amino-acid pituitary protein that stimulates hepatic 
production and release of insulin-like growth factor-I (IGF-1) into the systemic circulation. 
IGF-1 is instrumental in the promotion of linear growth in children and in the control of 
metabolism and body composition in adults. These factors are regulated through complex 
feedback mechanisms involving hGH, insulin-like growth factor-1 binding protein 3 (IGF-
BP3) and their complexes (Shalet, Toogood et al. 1998; Bach 2004).  
A growth hormone deficiency (GHD) results in inadequate circulating IGF-1 levels and is 
manifested as abnormal linear growth in children (Krysiak, Gdula-Dymek et al. 2007; 
Thomas and Monson 2009).  
Childhood GHD can be congenital, acquired, or idiopathic. Underlying causes for congenital 
malformation include pituitary dysfunction due to abnormal neurodevelopment in utero of 
certain brain regions and genetic abnormalities. Etiology for acquired GHD includes brain 
tumors in the hypothalamic region, traumatic brain injury, infiltrative disease, cranial 
irradiation and surgical intervention. The idiopathic origin of GHD is poorly understood but it 
appears to be multifactorial (Rona and Tanner 1977).  
Data on incidence and prevalence rates of GHD are scarce. A nationwide study in Denmark 
reported average incidence rate of 2.58 males, and 1.7 females per 100,000 population for 
childhood onset of GHD (Stochholm, Gravholt et al. 2006). The prevalence and demographic 
features of childhood GHD in Belgium during the period 1986-2001 was estimated to be 
1/5600. The origin of GHD was idiopathic in 41% of the patients, congenital in 20% and 
acquired in 35%; there was male predominance in all three categories (Thomas, Massa et al. 
2004). The number of new cases has remained fairly constant over the last 2 decades. The 
Belgian data is comparable to other countries; the prevalence of GHD in the United States in 
the 1990’s was at least 1:3480, with male predominance (Lindsay, Feldkamp et al. 1994).  
Most morbidity in children with GHD relates to short stature. Average adult height for 
untreated patients with severe isolated GHD is 143 cm in men and 130 cm in women. The 
inability to achieve normal height can lead to early onset of severe psychosocial problems 
directly related to short stature. This is confounded 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 (Krysiak, Gdula-Dymek et al. 2007). 
1.2 
Current Therapy 
Recombinant hGH replacement therapy has been used for over 30 years in tens of thousands 
of patients (primarily children) and has proved to be safe and effective (Ho 2007;Cohen, 
Rogol et al. 2008). The main therapeutic goal of GH treatment in children with GHD is to 
enable short children to achieve normal height, with early improvement of the psychosocial 
problems related to short stature.  Treatment is by daily SC injection of r-hGH. The Growth 
Hormone Research Society (GRS) consensus guideline recommends a dose range of 0.025-
0.05 mg/kg/day. In Japan, daily GH treatment is approved at a dose of 0.025 mg/kg/day for 
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the treatment of GHD pediatric population. Treatment response is assessed by measurement 
of height and growth velocity and is usually continued until final height, epiphyseal closure, 
or both have been recorded. 
The majority of currently available hGH products require daily SC injections to maintain 
hGH blood levels within the effective therapeutic window. The burden of daily 
administration and its concomitant side effects (e.g., injection site discomfort, transient 
edema and arthralgia) cause a reduction in compliance (Rosenfeld and Bakker 2008) and can 
limit the therapeutic utility of existing formulations.  
Developments in drug delivery technology have allowed the use of slow-release preparations 
of GH in humans (Cook, Biller et al. 2002; Kemp, Fielder et al. 2004; Bidlingmaier, Kim et 
al. 2006)  The most successful technology so far has been the encapsulation of GH molecules 
in poly(D,L-lactic-co-glycolic acid) biodegradable microspheres (Makadia and Siegel 2011). 
A more recent formulation of GH called LB03002 is an injectable, sustained-release GH 
suspension of microparticles, consisting of GH incorporated into sodium hyaluronate, which 
are dispersed in an oil base of medium-chain triglycerides before injection.  Hyaluronate is a 
natural biomaterial found in connective tissues including skin and cartilage and is naturally 
degraded by hyaluronidase as part of the physiological turnover process.  This formulation 
has been demonstrated to have long acting properties with suitable PK and PD profiles 
(Bidlingmaier, Kim et al. 2006) and efficacy indistinguishable from daily GH treatment in 
childhood GHD when administered weekly (Peter, Bidlingmaier et al. 2012). 
1.3 
Investigational Therapy 
MOD-4023 is a long-acting r-hGH for SC administration. It consists of hGH fused to 3 
copies of the CTP of the beta chain of human chorionic gonadotropin (hCG); 1 copy at the N-
terminus and 2 copies (in tandem) at the C-terminus. 
The CTP 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). It 
is, therefore, suggested that the addition of CTP to a protein other than hCG may enable to 
increase the corresponding protein longevity. 
OPKO Biologics' (OPKO) proprietary CTP technology has enabled the production of a long-
acting hGH (MOD-4023), which may obviate the need for the numerous injections currently 
required in marketed hGH products. As demonstrated in animal models and clinical studies, 
MOD-4023 may be injected once per week resulting in similar clinical efficacy as compared 
to daily injections of r-hGH. 
1.3.1 
Clinical Studies 
MOD-4023 clinical development program includes, apart from the current study, 5 studies 
which have been completed and 1 which has been initiated. A Phase 1 study (CP-4-001) in 
healthy adult volunteers, and Phase 2 studies in GHD adults (CP-4-003) and pre-pubertal 
GHD children (CP-4-004), a Phase 1 study (CP-4-007) in adult Japanese and Caucasian 
subjects were completed. A Phase 3 pivotal study (CP-4-005) in adult subjects with GHD has 
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been completed as well and data analysis and an open-label extension (OLE) portion of the 
study is ongoing. 
The Phase 2, randomized, open-label, multicenter study (CP-4-003) in adults with GHD was 
designed to assess the safety, tolerability and PK/PD profile of 3 doses of MOD-4023 
administered on a weekly regimen and 1 exploratory dose on an every other week regimen. 
MOD-4023 was administered for a period of 4 weeks in adult GHD subjects who were 
previously on a stable, standard r-hGH treatment for at least 6 months. Fifty-four (54) 
subjects (48 men and 6 women) were enrolled and completed the study. The clinical adverse 
effects (such as headache) were consistent with those expected in a GHD population and 
were mostly of a mild nature. 
The Phase 2 study (CP-4-004) in pediatric population, which was recently completed, was 
designed to assess the safety, efficacy and tolerability of 3 MOD-4023 doses as compared to 
that of a commercially available standard daily r-hGH formulation in up to 56 pre-pubertal 
children with growth failure due to insufficient secretion of endogenous GH. Fifty-three (53) 
patients were enrolled into 1 of 3 MOD-4023 dose groups or daily r-hGH (Genotropin®) as a 
comparator. All 4 dose groups demonstrated promising growth response following 6 and 12 
months of treatment, as described in detail in the Investigator Brochure (IB). Majority of the 
patients (43 patients) enrolled in this study continued onto the third year open label extension 
phase of the trial and are all on MOD-4023 treatment. 
A Phase 3 pivotal study (CP-4-005) in adult subjects with GHD has been completed and 
analysis is ongoing. The study is a randomized, parallel-group, multi-center study consisting 
of a 26-week double-blind, placebo-controlled (DBPC) period, a 26-week long-term open-
label long term extension (OLE, all subjects receive MOD-4023), and a two-week washout 
perioda. The starting dose of study drug differed by gender, age and estrogen therapy; 
Individual dose titration was conducted according to a dose modification plan. Enrolment to 
this study has been completed. 
                                                 
a To obtain blood sample for MOD-4023 antibody assessment and MOD-4023 serum levels 
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A Phase 3 pivotal study (CP-4-006) in pediatric subjects with GHD has just been initiated 
and is expected to take 18 – 24 months to complete.  This is an open-label, randomized, 
multicenter, 12 months, efficacy and safety study of weekly MOD-4023 compared to daily 
Genotropin® therapy.   This study is being conducted in up to 30 countries and 191 clinical 
sites worldwide with a target of 220 patients enrolled and treated.   
For additional information on clinical studies please refer to the current version of the 
Investigator’s Brochure (IB). 
1.3.2 
Study Rationale 
In order to submit the product registration dossiers for pre-pubertal GHD in parallel to 
different global regulatory agencies, including Japan, the Sponsor planned to conduct two 
Phase III studies, CP-4-006 in global and CP-4-009 in Japan, and to provide integrated 
analysis to evaluate the consistency of the results between patients in CP-4-006 and Japanese 
patients in CP-4-009.  
A global phase 3 open-label, randomized, multicenter, 12 months, efficacy, and safety study 
(CP-4-006) of weekly MOD-4023 compared to daily Genotropin® treatment naïve pre-
pubertal GHD children has been started in early 2017. In this study, a MOD-4023 dose of 
0.66 mg/kg/week will be compared to daily Genotropin® at a dose of 0.025 mg/kg/day. The 
objectives of the phase 3 study are to demonstrate that weekly dose 0.66 mg/kg MOD-4023 is 
clinically comparable in terms of safety and efficacy and statistically non-inferior to daily 
administration Genotropin®. This study design has been agreed with the FDA and EMA. In 
addition, patients completing the 12 months treatment of the pivotal study will be offered to 
rollover to an open-label extension (OLE) study with weekly administration of MOD-4023 
which will be conducted until MOD-4023 marketing registration. 
As for Japan, at the formal consultation meeting held on 
 2016, PMDA stated 
 
. Accordingly, the Sponsor 
agreed to conduct a stand-alone Japan study (CP-4-009) and that the results of CP-4-006 and 
CP-4-009 will be part of the evaluation data for the complete clinical data package. Since the 
inclusion/exclusion criteria and the study design will be similar between CP-4-006 and CP-4-
009, it is expected that similar efficacy and safety outcomes will be obtained from both 
studies. 
After having the PMDA consultation meeting, the study design of CP-4-009 was confirmed 
as follows: 
- Comparable study design and treatment duration with CP-4-006 
 
PK/PD analysis during the first 6 weeks  
 
Inclusion /Exclusion criteria should be comparable 
- Genotropin® dosage is defined as 0.025 mg/kg/day, the approved dose in Japan 
- Following the completion of the12-month treatment period, eligible and accepting 
patients will be consented to enroll into an open-label extension (OLE) period, and an 
amendment to study protocol with be submitted prior to the first patient completes the 
12 months treatment period. Eligible Genotropin®-treated patients will be switched to 
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a MOD-4023 dose of 0.66 mg/kg/week in the OLE. The OLE is planned to continue 
until MOD-4023 marketing registration. 
- 40 patients (20 per arm) + 10 % dropout rate 
Since this target population is children with GHD, slow dose escalation and PK and PD 
sampling during the first 6 weeks on treatment are included. 
1.3.3 
Rationale for Dose Selection 
As previously pointed out, MOD-4023 is a new molecular entity with GH mechanism of 
action, demonstrating reduced receptor affinity and lower specific activity, although with an 
extended half-life.  
The in vitro activity and receptor binding affinity of MOD-4023 was established based on 
comprehensive characterization studies as part of the preclinical program. MOD-4023, which 
is comprised of 72.3% net hGH on a molar basis, demonstrated 10-20-fold reduction in 
affinity to GHR as compared to r-hGH (by Biacore analysis). This was further strengthened 
by 2 independent cell-based assays indicating that MOD-4023 had a significantly lower 
biological activity as compared to r-hGH. Based on the in vitro, in vivo and Phase 2 data, it 
was concluded that any dose comparisons between MOD-4023 and hGH on molecular basis 
are not reflective of the biological effect of the molecule. Therefore, the selection of MOD-
4023 dose for the future clinical study in Japan, or elsewhere, should be determined by safety 
parameters and the clinical effect, i.e. HV.  
This assumption was confirmed during the global multicenter Phase 2 pediatric study, when 
monitoring the IGF-1 response. Two (2) of the doses of MOD-4023 administered in the 
Phase 2 study, 0.48 and 0.66 mg/kg/week, resulted in comparable IGF-1 and IGF-BP3 
profiles to that of Genotropin® administered daily at a dose of 0.034 mg/kg/day. These 2 
doses of MOD-4023 were shown to maintain optimal IGF-1 serum levels, with values that 
were in the mid-range of the gender- and age-adjusted normal range (~0 SDS). The MOD-
4023 dose of 0.25 mg/kg/week failed to maintain normal IGF-1 serum levels mainly during 
the second part of the week, indicating that IGF-1 levels will be at the lower part of the 
normal range or even below it with the use of this dose on weekly basis.  
These observations were further confirmed by the population analysis based on the 
established PK/PD model in pediatric subjects, showing that with increasing doses IGF-1 
response is elevated. To examine the magnitude of differences between doses, the entire time 
course of IGF-1 was simulated for each subject in CP-4-004 (based on their dosing regimen 
and post hoc parameter estimates from the final population PK/PD model), then transformed 
into IGF-1 SDS units. Mean values for Cohort 3 and Cohort 2 (MOD-4023 dose of 0.66 and 
0.48 mg/kg/week) are around 0 SDS IGF-1, and consistently much lower than 0 for Cohort 1 
(0.25 mg/kg/week). In accordance with Consensus Guideline 2002 GRS, it is recommended 
that IGF-1 response should be kept within the mid-range of 0 SDS when treating children 
with GHD 
 
 
 
  
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As the population-based PK/PD model revealed no differences between healthy Caucasian 
and Japanese adults, it assumed that the data and the resulting model obtained from the Phase 
2 pediatric clinical trial (CP-4-004) applies to Japanese children and similar PK/PD and 
response is expected to be obtained and will be presumable confirmed when comparing the 
MOD-4023 PK-PD of Japanese children to non-Japanese.  
MOD-4023 at a dose of 0.66 mg/kg/week to daily Genotropin® at a dose of 0.025 mg/kg/day 
will likely to provide comparable auxology outcome at 12 months.  
 
 
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2 STUDY OBJECTIVES 
The purpose of the current Phase 3 study is to demonstrate that weekly MOD-4023 
administration in pre-pubertal children with GHD is clinically comparable to daily 
Genotropin® administration in terms of safety and efficacy in the Japanese population. 
Primary Objective: 
To evaluate the efficacy and safety of weekly MOD-4023 administration and daily 
Genotropin® administration in pre-pubertal GHD Japanese children. 
Secondary Objective: 
To evaluate the PK and PD profiles of 3 different doses of MOD-4023 in pre-pubertal GHD 
Japanese children. 
 
 
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3 STUDY DESIGN 
The study will consist of 12 months, open-label, multi-center, randomized, active controlled, 
parallel group study comparing efficacy and safety of weekly MOD-4023 to daily r-hGH, 
Genotropin®. 
Both drugs will be injected SC using a pen device. 
To introduce naïve Japanese pediatric GHD patients to the allocated MOD-4023 dose in a 
gradual manner, a stepwise dose escalation and PK/PD blood sampling will be implemented 
during first 6-weeks. 
After a Screening period lasting for 4 weeks (+ additional 1 week if needed)a and approval of 
the study medical monitor, patients meeting all the inclusion criteria and none of the 
exclusion criteria, will be eligible to participate in the study. At Baseline, eligible patients 
will be randomized in a 1:1 ratiob to receive: 
 MOD-4023 (investigational treatment): weekly MOD-4023 SC injections for 12 
months; initially over the first 6 weeks, MOD-4023 will be administered in 3 
escalating doses (0.25 mg/kg/week, 0.48 mg/kg/week and 0.66 mg/kg/week), each for 
2 weeks. Then for the remaining 46 weeks, patients will continue to receive MOD-
4023 at a dose of 0.66 mg/kg/week. 
 Genotropin® (reference treatment): daily SC Genotropin® (0.025 mg/kg/day which is 
equivalent to 0.175 mg/kg/week, divided equally into 7 daily injections over a week) 
for 12 months. 
Patients allocated to the MOD-4023 treatment arm, will initially undergo a stepwise dose 
escalation over 6 weeks starting with low MOD-4023 dose of 0.25 mg/kg/week for 2 weeks, 
followed by an intermediate dose of 0.48 mg/kg/week for 2 weeks and then a final dose of 
0.66 mg/kg/week for 2 weeks. These patients will be assigned into one of 4 sampling sub-
blocks (as shown in Table 2) 
 
 In each sub-block, for each dose level, 
there will be different sampling time collection relative to the second injection of each dose 
(from pre-dose (-12), 12 (±3), 18 (±3), 36 (±6), 48 (±12), 72 (±12), 96 (±12) and 120 (±12) 
hours post dose). Six (6) blood samples for PK/PD will be obtained from each patient; 2 
samples for 0.25 mg/kg/week dose, 2 for 0.48 mg/kg/week dose and 2 for 0.66 mg/kg/week 
dose. At the end of the 6-week dose escalation phase, patients will continue the study for 
another 46 weeks at dose of 0.66 mg/kg/week. Over this 6 weeks escalation period, patients 
will be instructed to inject at evening/bed time hours. Following the 6 weeks escalation 
period, during the treatment period, patients can choose to stay with evening injection or to 
                                                 
a If the patient’s screening process is delayed because of a benign illness or unforeseen benign condition (i.e. 
pharyngitis, viral GI problems, minor accident or trauma, etc.) or a technical issue that is related to screening 
procedures (for example, delays with lab results) extra time - equal to the time of patient’s unavailability - will 
be added to the duration of the Screening period, but not in excess of an additional weeks 1 (total of 5 weeks 
Screening period). 
b Randomization must be performed prior to Baseline Visit and only after the medical monitor approval of the 
patient eligibility. Randomization must occur within the screening period. The Baseline Visit (Visit 2/Day 1) is 
to occur within 2 weeks (or 10 working days) after randomization.  
 
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switch to morning injection. The time of injection should be consistent until the end of the 
study.  
Following the period above, the dose of MOD-4023 and Genotropin® will be adjusted every 
3 months based on the patient’s body weight. Doses may be decreased for safety reasons 
according to the pre-defined dose-adjustment criteria (section 6.3); dose adjustment will be 
based on the severity of AEs or repeated and elevated levels of IGF-1 SDS.  
The key safety data will be reviewed by an independent DSMB at a minimum once every 6 
months. 
The total duration of patients' participation in the study will be up to 14 months (up to 5 
weeks of Screening, 12 months of active treatment and 1 month of follow up). The study will 
be conducted at approximately in 45-55 sites in Japan. 
Following the completion of the 12-month treatment period, eligible and accepting patients 
will be consented to enroll into an open-label extension (OLE) period, and an amendment to 
this study protocol will be submitted prior to the first patient completes the 12 months 
treatment period. Eligible Genotropin®-treated patients will be switched to a MOD-4023 
dose of 0.66 mg/kg/week in the OLE. The OLE is planned to continue until MOD-4023 
marketing registration in Japan.  
 
 
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4 STUDY POPULATION 
Pre-pubertal children (boys 3-10 (10 years and 364 days) years, girls 3-9 (9 years and 364 
days) years), diagnosed with GHD. 
4.1 
Inclusion Criteria 
Patients must meet all inclusion criteria to be eligible for the study: 
1. Pre-pubertal child aged ≥ 3 years old, and not yet 10 years for girls (9 years and 364 
days) or not yet 11 years for boys (10 years and 364 days), on the date of ICF 
signature, with either isolated GHD, or GH insufficiency as part of multiple pituitary 
hormone deficiency. 
2. Confirmed diagnosis of GHD by 2 different types of GH provocation tests 
(standardized on growth foundation data): defined as a peak serum GH level of ≤ 6.0 
ng/mL or ≤ 16 ng/mL when conducting GHRP-2 provocation test. 
Prior local laboratory results will be accepted subject to pre-approval by the study 
medical monitor and if the tests were conducted according to 1 of the protocols in 
Appendix D. 
3. BA is not older than chronological age and should be less than 10 for girls and less 
than 11 for boys. 
4. Without prior exposure to any r-hGH therapy. 
5. Height SD score ≤ -2.0 at screening. 
6. Impaired height velocity defined as: 
 Annualized HV below the 25th percentile for CA (HV < -0.7 SDS) and gender 
according to the local primary care provider standard.  
 The interval between 2 height measurements should be at least 6 months, but 
should not exceed 18 months prior to inclusion. 
7. BMI must be within ±2 SDS of mean BMI for the chronological age and sex. 
8. Baseline IGF-1 level of at least 1 SD below the mean IGF-1 level standardized for age 
and sex (IGF-1 SDS ≤ -1)a according to the central laboratory reference values. A 
single re-test will be allowed (subject to approval from the study medical monitor) if 
all other criteria are met. 
9. Normal creatinine levels according to common practice reference ranges per age. 
10. Children with multiple hormonal deficiencies must be on stable replacement therapies 
(no change in dose) for other hypothalamo-pituitary-organ axes for at least 3 months 
prior ICF signing.  
11. Clinical presentation of normal 46 XX karyotype for girls. 
12. Willing and able to provide written informed consent of the parent or legal guardian 
of the patient and written assent from pediatric patients (when applicable based on age 
and Japan regulation). 
                                                 
a According to rounding policy IGF-1 results ≤-0.95 might be acceptable as well  
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4.2 
Exclusion Criteria 
Patients must NOT meet any exclusion criteria to be eligible for the study: 
1. Children with prior history of leukemia, lymphoma, sarcoma or any other cancer. 
2. History of radiation therapy or chemotherapy.  
3. Malnourished children defined as BMI < -2 SDS for age and sex. 
4. Children with psychosocial dwarfism by the discretion of the investigator. 
5. Children born small for gestational age (SGA – birth weight and/or birth length < -2 
SDS 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. Children with diabetes mellitus.  
9. Known or suspected chromosomal abnormalities including Turner’s syndrome, Laron 
syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, 
SHOX mutations/deletions and skeletal dysplasia’s, with the exception of septo-optic 
dysplasia. 
10. Concomitant administration of other treatments that may have an effect on growth 
such as anabolic steroids, or sex steroids, with the exception of ADHD drugs or 
hormone replacement therapies (thyroxin, hydrocortisone, desmopressin (DDAVP)).  
11. Children requiring glucocorticoid therapy (e.g. for asthma) that are taking chronically 
a dose greater than 400 µg/d of inhaled budesonide or equivalent as described in 
Appendix J.  
12. Major medical conditions and/or presence of contraindication to r-hGH treatment. 
13. Known or suspected HIV-positive patient, or patient with advanced diseases such as 
AIDS or tuberculosis. 
14. Drug, substance, or alcohol abuse. 
15. Known hypersensitivity to the components of study medication. 
16. Other causes of short stature such as celiac disease, uncontrolled primary 
hypothyroidism and rickets. 
17. The patient and/or the parent/legal guardian are likely to be non-compliant in respect 
to study conduct. 
18. Participation in any other trial of an investigational agent within 30 days prior to 
screening and throughout the entire study period (including administration of 
investigational agent). 
4.3 
Patient Identification  
A unique identification number will be assigned by the Electronic Data Capture (EDC) 
system when an individual patient (if feasible) and parent/legal guardian signs the informed 
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consent form and starts the screening process. Following eligibility confirmation, the patient 
will be randomizeda through the IRT system in a 1:1 ratio to receive either MOD-4023 or 
Genotropin®.  
4.4 
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 or parent/legal guardian requests to be withdrawn. Patients withdrawn from the 
study prior to completing 12 months of treatment will not be replaced.  
The patient’s participation in this study may be discontinued due to the following reasons: 
 Withdrawal of the patient’s/parent’s consent (with specific withdrawal reason collected, 
as possible) 
 Occurrence of a malignancy during the course of study (reported as an AE) 
 Development of serious inter-current critical illness (reported as an AE) 
 Lack of patient compliance (if discontinuation is desired or considered necessary by the 
investigator or the study medical monitor) 
 Severe adverse drug reaction (if discontinuation of study medication is desired by the 
patient or considered necessary by the investigator or the study medical monitor) 
(reported as an AE) 
 Serious protocol deviation that affects patient safety, and accuracy, and/or validity of 
data 
 Lost to follow-up 
 Study enrollment closed prior to full qualification to study or study closure for any 
other reason by the Sponsor. 
4.5 
Handling of Withdrawals 
If a patient is withdrawn from the study or fails to return either at his or her request or at the 
investigator’s discretion after randomization, every effort should be made to determine the 
reason. This information will be recorded on the patient’s electronic case report form (eCRF). 
All patients who withdraw from the study prematurely, regardless of cause, should undergo 
all EOT Visit (Visit 9) and EOS Visit (Visit 10) procedures. Patients should be invited to the 
site for the EOT Visit (visit 9) within 3-7 days and should be phone interviewed (EOS Visit, 
Visit 10) one month after the last drug administration. It is vital to obtain follow-up data for 
any patient withdrawn due to an AE or abnormal laboratory test finding. In any case, every 
effort must be made to undertake safety follow-up procedures. If a patient wishes to 
withdraw, the difference between treatment discontinuation (i.e. patient will cease to receive 
medication but will continue to come for the follow-up visits) and study withdrawal should 
                                                 
aRandomization must be performed prior to Baseline Visit and only after the medical monitor approval of the 
patient eligibility. Randomization must occur within the screening period. The Baseline Visit (Visit 2/Day 1) is 
to occur within 2 weeks (or 10 working days) after randomization.  
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be explained. Patients should be encouraged to continue the follow-up visits and at minimum 
provide a height measurement at 12 months even if they discontinue the study treatment 
early.  
4.6 
Sponsor's Termination of Study  
The Sponsor reserves the right to discontinue the study at any time for any reason. 
Regulatory Authorities also have the right to terminate the study. 
 
 
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5 INVESTIGATIONAL PLAN AND STUDY PROCEDURES 
Schedule of Assessments for this study are shown in Appendix A, Appendix B and Appendix 
C. No protocol related procedures, including the stopping of prohibited concomitant 
medications should be performed before the patient (if feasible) and parent/legal guardian 
provides written informed consent. 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.  
5.1 
Screening Period (Visit 1) – Week -4 /Day -28 to Week -1 /Day -1 
The Screening period will last up to 4 weeksa and can be conducted over several visits prior 
to randomization. Screening visits are intended to collect current clinical data and to perform 
all required investigations needed to establish a patient’s eligibility for the study. Prior to any 
study specific investigations, written assent from pediatric patients (if needed, use appropriate 
1 of 2 versions according to their education and age) and consent from the parent(s) or legal 
guardian(s) will be obtained. Upon completion of the Informed Consent process and 
obtaining written consent from the parent(s) or legal guardians(s) a patient is deemed to be 
'enrolled’ into the study. 
The following assessments will be conducted at the screening visits:  
 Inclusion/Exclusion criteria  
 Estimated Parental heights b 
 Patient’s Height SDS and HV SDS 
 Auxology measurementsc,  BMI and BMI SDS 
 Demographic and Medical history, including a description of pituitary deficiencies, 
concomitant and previous medications 
 Overall health status assessments – complete physical examination, vital signs. 
 Pubertal status (according to Tanner stages) 
 Bone age determination with the method of TW2 using a central bone age reader.d 
                                                 
a If the patient’s screening process is delayed because of a benign illness or unforeseen benign condition (i.e. 
pharyngitis, viral GI problems, minor accident or trauma, etc.) or other technical issue that is related screening 
procedures (for example- delays with lab results) extra time - equal to the time of patient’s unavailability - will 
be added to the duration of the Screening period, but not in excess of an additional weeks 1 (total of 5 weeks 
screening period). 
b It is recommended that parent’s height will be measured at the site. If measured parental height is not available 
an estimate 
  could be provided by the parent. 
c Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated 
stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and 
heavy pocket items. 
d At Screening Visit, historical bone age assessment might be accepted if they were done no more than 6 
months prior to the ICF signature   date. If the patient will be eligible, the bone age should be repeated at Visit 2, 
before the dosing. The Visit 2 scan will be the baseline scan for these patients. 
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 Assessment of biochemical markers and stimulation tests: 
- 
Two (2) different types GH stimulation (provocation) tests from the following 
list: insulin tolerance test (with serum cortisol response to hypoglycemia if 
insulin stimulation test is chosen); arginine test; clonidine test; glucagon test; 
L-dopa; and GHRP-2. The minimal duration and number of samples for each 
test must conform to the specifications in Appendix D.  
- 
Analysis of GH serum levels (and glucose and serum cortisol if Insulin 
tolerance test is performed) may be done by local laboratories and to be 
provided for the study medical monitor review and approval prior to study 
entrya. 
- 
Assessment of morning cortisol (up to 8am ±1 hour)b 
If morning cortisol is below 190 nmol/L (7 μg/dL), test for adrenal 
insufficiency will be required – Low dose ACTH or CRH stimulation test 
(only if the patient was not previously assessed for the hypothalamus-pituitary-
adrenal axisc or has been diagnosed with adrenal insufficiency). The minimal 
duration and number of samples for each test must conform to the 
specifications in Appendix D.  
- 
Assessment of 
 IGF-1 SDS 
 
Assessment of anti-hGH antibody levels 
 Assessments of Routine safety laboratory tests: biochemistry, hematology and 
urinalysis (see section 5.5.9) 
 Assessment of thyroid: TSH, FT4 
 Assessment of glucose metabolism: morning fasting insulin and glucose (will be 
tested as part of biochemistry panel) and HbA1c 
 Parameters of lipid metabolism: morning fasting total cholesterol, triglycerides, HDL 
and LDL 
 Head MRId if possible with contrast – to be done only after the two GH stimulation 
tests based on physician recommendation 
Approximately 8-42 mL of blood will be drawn from the patients during the screening 
period. The total blood volume to be collected during screening period (maximum 5 weeks) 
is shown. The maximum blood volume per day differs according to the selection of 
assessments. Based on the pediatric clinical guidance, appropriate blood sampling has to be 
performed so that the required minimum blood volume is obtained, such as GH stimulation 
tests and other assessments are taken on different days. All laboratory assessments are done 
in a central laboratory unless stated otherwise.  
                                                 
a No time limitation for the historical GH stimulation tests. 
b Morning cortisol assessment will be subject to the investigator judgment. 
c Insulin tolerance test with serum cortisol response to hypoglycemia is adequate for assessment of adrenal 
insufficiency and no ACTH stimulation test is required if such results are available. 
d MRI to be performed upon investigator judgment. In addition,  MRI which was conducted within 6 month 
prior to ICF signature date  will be acceptable 
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Key data and all test results obtained during screening will be reviewed by the Study medical 
monitor and eligibility will be confirmed by the study medical monitor prior to randomization 
of each patient.  
5.2 
Active Treatment Period (Baseline to Month 12)  
During Treatment period, patients will be scheduled to attend the following clinic visits 
according to their treatment allocation as shown in the Table 1. The Baseline visit (first dose) 
and Visits 6 to 9 (every 3 months) will be similar for both treatment arms (except where 
noted). Visits 3, 4 and 5 will differ between the 2 treatment arms due to the 6-week dose 
escalation and PK/PD sampling in the MOD-4023 treatment arm. 
Table 1: Overview of Visit Scheduling for both Treatment Arms 
MOD-4023 Treatment Arm (Investigational) 
Genotropin® Treatment Arm (Reference) 
Visit 2 – Baseline – First dosing 
Visit 2 – Baseline – First dosing 
Visits 3 and 3.1 – Week 2 
First PK/PD sampling post 2nd dose for each dose level 
(according to sub-block PK/PD allocation) 
Visit 3 – Week 2  
Phone interview will be done. Per Appendix I. 
No clinic visit. 
Visits 4 and 4.1 – Month 1/ Week 4 
Safety (only at Visit 4.1) and second PK/PD sampling 
post 2nd dose for each dose level (according to sub-
block PK/PD allocation) 
Visit 4 – Month 1/ Week 4 (±1 week). 
Clinic visit 
Visits 5 and 5.1 – Week 6 
Third PK/PD sampling post 2nd dose for each dose 
level (according to sub-block PK/PD allocation) 
Visit 5 – Week 6.  
Phone interview will be done per Appendix I.  
No clinic visit. 
Visit 6 – Month 3/Week 13 (±1 week) 
Clinic visit 
To be conducted 4 days (-1 day) post dose  
Visit 6 – Month 3/Week 13 (±1 week) 
Clinic visit 
Visit 7 and 7.1 – Month 6/Week 26 (±3 weeks)  
Two clinic visits: 
- Visit 7 Pre-dose immunogenicity Assessments 
conducted same day as dosing 
- Visit 7.1 Post-dose assessments conducted 4 days (-1 
day) after dose 
Visit 7 – Month 6/Week 26 (±1 week) 
Clinic visit 
Visit 8 – Month 9/Week 39 (±1 week) 
Clinic visit 
To be conducted 4 days (-1 day) post dose 
Visit 8 – Month 9/Week 39 (±1 week) 
Clinic visit 
Visit 9 and 9.1 – EOT visit – Month 12/Week 52 (±3 
weeks) 
Two clinic visits: 
- Visit 9 Pre-Dose Immunogenicity Assessments 
conducted same day as dosing 
- Visit 9.1 Post-dose assessments conducted 4 days (-1 
day) after dose 
Visit 9 – EOT visit- Month 12/Week 52 (±1 week) 
Clinic visit 
Visit 10 – EOS visit – Month 13/Week 56 (+1 week) 
Phone interview will be done per Appendix I.  
No clinic visit. 
Visit 10 – EOS visit – Month 13/Week 56 (+1 
week) 
Phone interview will be done per Appendix I.  
No clinic visit. 
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Visit windows are relative to the visit, not to the dose, unless specified otherwise. 
5.2.1 
Visit 2 (Day 1/Baseline) – Both Treatment Arms 
At Baseline (Visit 2) or once eligible, eligible patients will be randomized in a 1:1 ratio to 
MOD-4023 (investigational treatment) or Genotropin® (reference therapy)a. 
The following assessments will be conducted on Day 1/Baseline: 
 Auxology measurementsb 
 AE, local tolerability and concomitant medications 
 Overall health status assessment, including complete physical examination and vital 
signs assessments 
 Safety laboratory: biochemistry, hematology and urinalysis (see section 5.5.9) 
 Pubertal status (according to Tanner stages) 
 Assessment of thyroid: TSH, FT4 
 Assessment of biochemical markers: 
 IGF-1 SDS (applicable 
for both arms), 
 
 
 Assessment of MOD-4023 serum levels (applicable for MOD-4023 treatment arm 
only) 
 Parameters of glucose metabolism: morning fasting glucose (will be tested as part of 
biochemistry panel), morning fasting insulin and HbA1c 
 Parameters of lipid metabolism: morning fasting total cholesterol, triglycerides, HDL 
and LDL 
 Assessment of pre-dose anti-MOD 4023 and anti-hGH antibodies (depending on 
treatment arm allocation) 
 Bone agec 
 ECG pre-dosing  
 Training for patients, parents or legal guardians on drug administration  
 Administration of study drug at clinic 
 Dispense study drug and patient diary 
Approximately 9-12 mL of blood will be drawn from patients at baseline visit. 
                                                 
a Randomization must be performed prior to Baseline Visit and only after the medical monitor approval of the 
patient eligibility. Randomization must occur within the screening period. The Baseline Visit (Visit 2/Day 1) is 
to occur within 2 weeks (or 10 working days) after randomization. 
b Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated 
stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and 
heavy pocket items. 
c Bone age at Visit 2 will be performed in case bone age was not performed at screening. This test should be 
done prior the first dose. 
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5.2.2 
Treatment Period - MOD-4023 Treatment Arm – Visits 3 to 9 
5.2.2.1 
Visits 3 and 3.1, 4 and 4.1, 5 and 5.1 (Weeks 2, 4 and 6) 
Visits 3, 4 and 5 will take place at Weeks 2, 4, and 6, respectively, for first PK/PD sampling 
post 2nd dose for each dose level (according to sub-block PK/PD allocation). Visits 3.1, 4.1 
and 5.1 will take place at Weeks 2, 4, and 6, respectively, for second PK/PD sampling post 
2nd dose for each dose level (according to sub-block PK/PD allocation – refer to Table 2).  
For each visit/sub-visit, the patient is expected to visit the clinic twice during the week to 
obtain two different post-dose PK/PD samples. 
The following assessments will be conducted at these visits: 
 Safety evaluation consisting of AE, local tolerability and concomitant medication at 
all visits 
 Complete physical examination and vital signs assessments at visits 3.1, 4.1 and 5.1 
only 
 Safety evaluation consisting of safety laboratory: biochemistry, hematology and 
urinalysis (see section 5.5.9) at Visit 4.1 only 
 Assessment of biochemical markers: 
, IGF-1 SDS, 
 
 
 MOD-4023 serum levels (sampling time per sub-block allocation) 
 Fundoscopy (if there are signs or symptoms indicative of benign intracranial 
hypertension) 
 
Weight measurement at Visit 4.1 only.  
 Study drug return and accountability (Visit 4.1 only) 
 Training on drug administration, injection site reactions, diary completion, and dosing 
review (Visits 3.1 and 4.1) 
 Assessment of Anti-MOD-4023 at Visit 4.1 only 
 Dispense study drug and patient diary at Visit 4.1 only 
Approximately 6 mL of blood will be drawn from the patients at each visit, except for Visit 
4.1. 
At Visit 4.1, approximately 12 mL of blood will be drawn from the patients.  
5.2.2.2 
Visit 6 (Month 3/Week 13 ±1 week) and Visit 8 (Month 9/Week 39 ±1 week)  
The following assessments will be conducted at Visits 6 and 8 on day 4 (-1 day) post dose: 
 Auxology measurementsa 
 AE, local tolerability and concomitant medications 
                                                 
a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated 
stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and 
heavy pocket items. 
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 Overall health status assessment, including complete physical examination and vital 
signs assessments 
 Safety laboratory- biochemistry, hematology and urinalysis (see section 5.5.9)  
 Pubertal status (according to Tanner stages) 
 Assessment of thyroid: TSH, FT4 
 Assessment of biochemical markers: 
, IGF-1 SDS 
 Assessment of MOD-4023 serum levels 
 Assessment of anti-MOD-4023 antibodies. 
 Fundoscopy (ONLY if there are signs or symptoms indicative of increased 
intracranial hypertension) 
 Study drug return and accountability 
 Individual dose adjustment and dispensing study drug and patient diary 
Approximately 9 mL of blood will be drawn from the patients at those visits.  
5.2.2.3 
Visit 7 and Visit 7.1 (Month 6/Week 26 ±3 weeks)  
Visit 7 will consist of two clinic visits, Visit 7 (pre-dose) and Visit 7.1 (post-dose), at Week 
26 ±3weeks.  Visit 7 must be conducted prior to Visit 7.1.  
Visit 7 will take place at the clinic prior to dosing at any week during ±3 weeks of Month 
6/Week 26.  The following pre-dose immunogenicity assessments should be conducted on the 
same day of dosing: 
 AE and concomitant medications 
 Assessment of MOD-4023 serum levels 
 Assessment of anti-MOD-4023 
Approximately 6 mL of blood will be drawn from the patients at this visit. 
Visit 7.1 will take place at the clinic 4 days (-1 day) after dose at any week after Visit 7 
during the ±3 weeks of Month 6/Week 26. The following post-dose assessments will be 
conducted 4 days (-1 day) after dose: 
 Auxology measurementsa  
 AE, local tolerability, and concomitant medications  
 Overall health status assessment, including complete physical examination and vital 
sign assessments  
 Safety laboratory: biochemistry, hematology and urinalysis, (see section 5.5.9)  
                                                 
a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated 
stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and 
heavy pocket items. 
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 Pubertal status (according to Tanner stages) 
 Assessment of thyroid: TSH, FT4  
 Assessment of biochemical markers: 
 IGF-1 SDS 
 
Assessment of MOD-4023 serum levels 
 Parameters of glucose metabolism- morning fasting glucose (will be tested as part of 
biochemistry panel), morning fasting insulin and HbA1c  
 Parameters of lipid metabolism- morning fasting total cholesterol, triglycerides, HDL 
and LDL  
 ECG  
 Fundoscopy (ONLY if there are signs or symptoms indicative of benign intracranial 
hypertension) 
 Study drug return and accountability 
 Individual dose adjustment and dispensing study drug and patient diary 
Approximately 10 mL of blood will be drawn from the patients at this visit. 
5.2.2.4 
Visit 9 and Visit 9.1 (Month 12/Week 52 ±3 weeks) – End of Treatment (EOT) 
Visit Assessments  
Visit 9/EOT will consist of two clinic visits, Visit 9 (pre-dose) and Visit 9.1 (post-dose), at 
Week 52 ±3 weeks.  Visit 9 must be conducted prior to Visit 9.1. 
Visit 9 will take place at the clinic prior to dosing at any week during ±3 weeks of Month 
12/Week 52.  The following pre-dose immunogenicity assessments should be conducted on 
the same day of dosing: 
 AE and concomitant medications 
 Assessment of MOD-4023 serum levels 
 Assessment of anti-MOD-4023 
Approximately 6 mL of blood will be drawn from the patients at this visit. 
Visit 9.1 will take place at the clinic 4 days (-1 day) after dose at any week after Visit 9 
during the ±3 weeks of Month 12/Week 52. The following post-dose assessments will be 
conducted 4 days (-1 day) after dose: 
 Auxology measurementsa 
 AE, local tolerability and concomitant medications 
 Overall health status assessment, including complete physical examination and vital 
signs assessments 
 Safety laboratory: biochemistry, hematology and urinalysis (see section 5.5.9) 
                                                 
a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated stadiometer. Body 
weight, ideally fasted in the morning, without shoes and having removed all outwear and heavy pocket items. 
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 Pubertal status (according to Tanner stages) 
 Assessment of thyroid: TSH, FT4 
 
Assessment of MOD-4023 serum levels 
 Hormones and biochemical markers: 
 IGF-1 SDS 
 Parameters of glucose metabolism: morning fasting glucose (will be tested as part of 
biochemistry panel), morning fasting insulin and HbA1c  
 Parameters of lipid metabolism: morning fasting total cholesterol, triglycerides, HDL 
and LDL 
 Fundoscopy (ONLY if there are signs or symptoms indicative of increased 
intracranial hypertension), 
 Bone age assessment 
 Study drug return and accountability 
Approximately 10 mL of blood will be drawn from the patients at this visit.  
5.2.3 
Treatment Period - Genotropin® Treatment Arm – Visits 3 to 9 
At Visit 3 (Week 2) and Visit 5 (Week 6) a phone interview will be conducted according to 
Appendix I. No clinic visit. 
5.2.3.1 
Visit 4 (Month 1/Week 4 ±1week)  
The following assessments will be conducted at Visit 4: 
 AE, local tolerability, and concomitant medications 
 Overall health status assessment, including complete physical examination and vital 
sign assessments 
 Safety laboratory: biochemistry, hematology and urinalysis (see section 5.5.9) 
 Biochemical markers: 
 IGF-1 SDS 
 Fundoscopy (ONLY if there are signs or symptoms indicative of benign intracranial 
hypertension) 
 Study drug return and accountability  
 Dispense study drug and patient diary 
Approximately 7 mL of blood will be drawn from the patients at this visit (No blood samples 
will be collected at Visits 3 and 5. No clinic visit).  
5.2.3.2 
Visit 6 (Month 3/Week 13 ±1week), Visit 7 (Month 6/ Week 26 ±1week), and 
Visit 8 (Month 9/Week 39 ±1week)  
The following assessments will be conducted at Visits 6, 7 and 8: 
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 Auxology measurementsa  
 AE, local tolerability and concomitant medications 
 Overall health status assessment, including complete physical examination and vital 
signs assessments 
 Safety laboratory: biochemistry, hematology and urinalysis (see section 5.5.9) 
 Pubertal status (according to Tanner stages)  
 Assessment of thyroid: TSH, FT4 
 Hormones and biochemical markers: 
 IGF-1 SDS 
 Parameters of glucose metabolism: morning fasting glucose (will be tested as part of 
biochemistry panel), morning fasting insulin and HbA1c at visit 7 only 
 Parameters of lipid metabolism:- morning fasting total cholesterol, triglycerides, HDL 
and LDL at visit 7 only  
 Fundoscopy (ONLY if there are signs or symptoms indicative of benign intracranial 
hypertension) 
 Study drug return and accountability 
 ECG at Visit 7 (Month 6/Week 26 ± 1day)  
 Individual dose adjustment every three months  
 Dispense study drug and patient diary 
 Anti-hGH antibodies 
Approximately 9 mL of blood will be drawn from the patients at those visits. 
5.2.3.3 
Visit 9 (Month 12/Week 52 ±1week) - End of Treatment Visit 
The following assessments will be conducted at Visit 9, EOT visit:  
 Auxology measurementsb  
 AE, local tolerability and concomitant medications 
 Overall health status assessment, including complete physical examination and vital 
signs assessments 
 Safety laboratory: biochemistry, hematology and urinalysis (see section 5.5.9) 
 Pubertal status (according to Tanner stages) 
 Assessment of thyroid: TSH, FT4 
                                                 
a Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated wall or equivalent 
mounted stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and 
heavy pocket items. 
b Actual height (mean of 3 consecutive measurements per patient per visit) measured on a calibrated wall or equivalent 
mounted stadiometer. Body weight, ideally fasted in the morning, without shoes and having removed all outwear and 
heavy pocket items. 
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 Hormones and biochemical markers: 
 IGF-1 SDS 
 Parameters of glucose metabolism: morning fasting glucose (will be tested as part of 
biochemistry panel), morning fasting insulin and HbA1c 
 Parameters of lipid metabolism: morning fasting total cholesterol, triglycerides, HDL 
and LDL  
 Fundoscopy (ONLY if there are signs or symptoms indicative of increased 
intracranial hypertension) 
 Bone age assessment  
 Study drug return and accountability 
 Anti-hGH antibodies  
Approximately 9 mL of blood will be drawn from the patients at this visit.  
5.2.4 
Follow up Period (Month 13) - Visit 10 - EOS Visit (Week 56 +1 week): Both 
Treatment Arms 
After 1 month following EOT Visit, phone interview should be conducted according to 
Appendix I. This phone interview will be considered as Visit 10- End of Study Visit.  
5.3 
Efficacy Assessments and Endpoints 
5.3.1 
Height and Annual HV 
Height measurements must be performed according to Appendix E with a calibrated 
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 initials is to be recorded in the 
eCRF. Three independent readings will be recorded for each visit in the eCRF. 
Height will be measured in centimeters. 
The Height SDS will be derived from the age and gender according to the local primary care 
provider standard. 
Annualized HV will be calculated in centimeters as the change in height from Visits 2 to 9 
(after 12 months of treatment), using the actual elapsed days. 
5.3.2 
Bone Age 
Bone age will be determined by X-ray according to TW2 using central bone age reader at 
Screening (Visit 1), and/or Visit 2a (Baseline) and Visit 9 (Month 12). X-ray films of the left 
hand and wrist will be taken as outlined in Appendix F and will be sent to a qualified central 
reader. The central reader will be blinded to the chronological age, drug allocation and name 
of the patients. X-ray films will hold only an identification number and gender. Details of the 
                                                 
a Bone age assessment should be performed at Visit 2 only if not performed at screening 
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For patients allocated to MOD-4023 treatment arm, 
will be evaluated during the 
first 6 weeks of dose escalation phase as described in section 5.4.1.2. 
5.5 
Safety Assessments and Endpoints  
Safety assessments will be based on changes from baseline of clinical AEs (including 
injection site reaction) reported by the patient or observed by the investigator, concomitant 
medication use, treatment compliance, vital signs, ECG, physical examination and laboratory 
assessments (hematology, biochemistry, glucose metabolism, lipid metabolism, 
endocrinology, IGF-1 levels, immunogenicity and urinalysis).  
5.5.1 
AEs 
AEs, including injection site reactions, will be assessed at all study visits throughout the 
study (except at pre-dose Visits 7 and 9 for injection site reaction). In addition, patients will 
be requested to complete a patient diary at home to collect data on AE, concomitant 
medications and local site reactions. 
Any AEs that occur throughout the study will be recorded. Any new AE that occur 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. AEs should be followed until 
resolution or stabilization. 
5.5.2 
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 every visit) and on the basis of anamnestic 
data and records in the patient diary. Observations of local injection site reactions will be 
recorded on the appropriate eCRF pages. 
The patients will be trained to record, at least once weekly, any injection site reaction in their 
diaries.  
An abnormal injection site reaction is defined as: 
 Injection site reaction which is observed at the time of visit or reported during phone 
call and moderate to severe in intensity. 
 Injection site reaction between the last and present visit, and/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. 
 Pain score ≥ 4 (As reported in the patient diary)  
If an injection site reaction meets the criteria for “abnormal” defined above, it will be 
considered and assessed as an AE. 
 Pain: For patients, injection site pain will be evaluated by the investigator or 
designated personnel if the injection is given at the medical center, and by the 
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parent/legal guardian if the injection is given at home. The pain will be evaluated at 
least once weekly using the Pain Assessment Scale (Appendix G). In addition, each 
patient and parent/guardian will be queried during study visits regarding possible 
injection site pain.  
 Pain score ≥4 should be reported as an AE  
Photographs of Injection Site Reactions 
If possible with any case of an abnormal local site reaction assessed and recorded as an AE, 
the investigator will document the local site reaction by photo that will be kept signed and 
dated in the patient medical record.  
5.5.3 
Concomitant Medication Use 
Use of concomitant medication will be recorded at all study visits. 
5.5.4 
Treatment Compliance 
Study drug return accountability will be performed at Visits 4 (for the Genotropin® arm), 
Visit 4.1 (for MOD-4023 arm) and Visits 6, 7, 8 and 9 (for both arms). 
5.5.5 
Vital Signs 
Vital signs measurements will include body temperature, respiration, blood pressure and 
heart rate after the patient has sat quietly for at least 5 minutes and using the same arm 
throughout the study where possible. 
5.5.6 
Physical Examination 
A complete physical examination will be performed and will include appearance, eyes, ears, 
nose, head, throat, neck, chest, lungs, heart, abdomen, extremities, skin and musculoskeletal 
system. Clinically significant findings at screening will be reported as medical history and as 
AEs after the Screening Visit. Weight will be measured, ideally fasted in the morning, 
without shoes and having removed all outwear such as jackets, sweaters or sweatshirts and 
heavy pocket items.  
5.5.7 
ECG 
ECG (preferably 12-lead) will be performed on Visit 2 (pre-dose) and Visit 7 for both 
Genotropin® and MOD-4023 arms (no time limitation). 
Initially ECG output will be evaluated by the investigator at time of performance (signed and 
dated) and the printout (including photocopy) should be kept in the patient’s medical file. 
When potentially clinically significant findings are detected by the investigator, a local 
cardiologist should be consulted for a definitive interpretation. All communications and 
diagnoses should be filed in the patient’s medical file. 
The final determination of whether the ECG findings are of clinical significance to the patient 
rests with the investigator and reported as normal /abnormal in the eCRF. 
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5.5.8 
Fundoscopy  
Fundoscopic evaluations will be conducted only if there are symptoms of increased 
intracranial pressure (persisting headache different from typical headache patterns or 
headache accompanied by nausea/vomiting that is not self-limited and/or associated with 
other symptoms suggestive of infectious illness such as fever or myalgia’s). 
Fundoscopy will be performed according to standard of care and confirmed by an 
ophthalmology evaluation if necessary. 
5.5.9 
Laboratory Assessments 
All routine clinical laboratory assessments will be performed by local central laboratory (LSI 
Medience Corporation) according to the schedule in Appendix A, Appendix B and Appendix 
C. The laboratory evaluations will include: 
1. GH stimulation (provocation) tests: insulin tolerance test (with serum cortisol 
response to hypoglycemia if insulin stimulation test is chosen)/arginine 
test/clonidine test/glucagon test /L-dopa/ GHRP-2. Will be performed at 
Screening Visit.  
2. Morning cortisol at Screening Visit, if applicable. 
3. ACTH or CRH stimulation test at Screening Visit (If morning cortisol is 
below 190 nmol/L (7 μg/dL). 
4. Hematology: Red Blood Cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), 
Mean Cell Hemoglobin (MCH), Mean Cell Hemoglobin Concentration (MCHC), 
Mean Corpuscular Volume (MCV), White Blood Cell (WBC) count and differential, 
platelet count, at all study visits except for Visits 3, 3.1, 4 (MOD-4023 arm), 5, 5.1, 7 
(MOD-4023 arm) and Visit 9 (MOD-4023 arm). 
5. Serum biochemistry: glucose,  total protein, albumin, total bilirubin, ALT (SGPT), 
AST (SGOT), GGT, LDH, CPK, alkaline phosphatase, sodium, potassium, calcium, 
phosphate, BUN, creatinine, at all study visits except for Visits 3, 3.1, 4 (MOD-4023 
arm), 5, 5.1, 7 (MOD-4023 arm) and Visit 9 (MOD-4023 arm). 
6. Urinalysis: pH, glucose, ketones, erythrocytes, leukocytes, protein at all study visits 
except for Visits 3, 3.1, 4 (MOD-4023 arm) 5, 5.1, 7 (MOD-4023 arm) and Visit 9 
(MOD-4023 arm). 
7. Lipid metabolism: morning fasting total cholesterol, LDL, HDL and triglycerides at 
Screening, Baseline, Visit 7 and Visit 9 (Genotropin® arm) and Visit 7.1 and Visit 9.1 
(MOD-4023 arm). 
8. Glucose metabolism: morning fasting glucose (will be tested as part of biochemistry 
panel), fasting insulin and HbA1C at Screening, Baseline, Visit 7 and Visit 9 
(Genotropin® arm) and Visit 7.1 and Visit 9.1 (MOD-4023 arm).  
9. Assessment of thyroid: TSH, FT4 at all study Visits except for Visits 3, 3.1, 4, 4.1, 5, 
5.1, Visit 7 (MOD-4023 arm) and Visit 9 (MOD-4023 arm). 
10. Immunogenicity (will be performed by Intertek, San Diego): antibodies to MOD-4023 
at Visits 2 (Baseline, pre-dose), 4.1, 6, 7 (pre-dose), 8 and Visit 9 (pre-dose) (MOD-
4023 arm only).  
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Antibodies to hGH at Visit 2 (Baseline, pre-dose) and Visits 6, 7, 8 and Visit 9 
(Genotropin® arm only). 
11. Immunogenicity: antibodies to hGH (will be performed by University Hospital 
Leipzig, Leipzig, Germany) at Screening Visit (both arms).  
For further details on blood sample collection and shipment to the central laboratory, 
please refer to the Central Laboratory Manual. 
If a patient discontinues prematurely from the study for the reasons specified in section 4.4, 
the same procedures planned for EOT Visit (Visit 9- 12 months / Week 52) and EOS Visit 
(Visit 10 - 13 months / Week 56) will be conducted (Patients should be invited to EOT Visit 
(visit 9) within 3-7 days and should be phone interviewed (EOS Visit, Visit 10) one month 
after the last drug administration). Other procedures and evaluations will be completed as 
deemed necessary by the investigator.  
 
 
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6 INVESTIGATIONAL PRODUCT  
6.1 
Investigational Product  
6.1.1 
Identity of Investigational Product 
MOD-4023 is a long-acting modified r-hGH which utilizes CTP technology.  
MOD-4023 will be provided as a solution for injection containing 20 or 50 mg/mL MOD-
4023 in a multi-dose disposable pre-filled pen.  
The device used in this study has not been approved or certified in Japan.  
The formulation includes 
 
6.1.2 
Reference Therapy 
Genotropin® is a daily GH, which will be used as the reference therapy in this study.  
A Genotropin® GoQuick pen delivery device will be used for daily (evening/bedtime) SC 
administration of Genotropin® into the region of the upper arms, buttocks, thighs or abdomen 
(8 locations). Injection sites should be rotated.  
The pen device is intended to assist self-injecting adult and pediatric patients, healthcare 
professionals and caregivers with the daily SC injection of the r-hGH, primarily self-
administered at home or in a healthcare environment. 
Dose regimen for Genotropin®: 0.025 mg/kg/day (or 0.175 mg/kg/w divided equally to 7 
injections over a week). 
6.2 
Study Drug Administration 
MOD-4023 will be administered as a SC injection once weekly. Over the 6 weeks of the 
escalation period, patients will be instructed to inject at evening hours/bed time. At the 
treatment period, patients can choose to stay with evening injection or to switch to morning 
injection. The time of injection should be consistent until the end of the study. MOD-4023 
will be administered using the pen into the upper arms, buttocks, thighs or abdomen (8 
locations for injection). It is recommended that all 8 injection sites are used successively, 
using a different injection site at each subsequent injection. It is recommended that the same 
injection site should be used only after all other injection sites have been rotated (see 
recommended rotation scheme below). 
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Figure 1: Recommended rotation of injection sites for Genotropin® and 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 
whole week and will continue taking the study medication on the regular day the following 
week. 
If a patient on Genotropin® misses a dose he/she should resume the medication with the next 
scheduled dose and should not double any doses. 
The patient should notify site staff about the delayed injection or the missed dose and be 
instructed by the site when the next visit is scheduled. 
In case the delayed injection is in the week when an onsite 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-1 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 for a single injection on a pen, the patient 
should be instructed how to split the dose into 2 injections. The partial dosing can occur in 2 
cases:    
1. Split dose from the same pen:  This may occur when the prescribed dose exceeds the 
maximum dose which can be selected according to the pen amount.  The maximum 
dose per injection for the MOD-4023 24 mg pen is 12 mg and the maximum dose 
injection for the MOD-4023 60 mg pen is 30 mg.  The patient’s first injection would 
be the maximum dose and the second injection would be the remaining dose of the 
full prescribed dose. 
For example, if the full prescribed dose is 33.5 mg and the pen only allows the dose 
selector to be set to 30.0 mg, the patient should inject another 3.5 mg using the same 
pen. 
2. Split dose from 2 pens (the current pen and a new pen):  This may occur when the 
amount of medication remaining in the pen is not sufficient for the full prescribed 
dose. 
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For example, if the full prescribed dose is 25.0 mg and the volume left in the current 
pen is 20.5 mg, the patient should inject another 4.5 mg from the new pen. 
It is recommended to encourage the patients to use a calculator to plan the doses and to 
calculate the dose that should be adjusted for the second injection. 
It is very important that for the second injection, whether from the same pen or from a new 
pen, the patient replaces the needle and rotates the injection site and completes the patient 
diary for each of the 2 injections administered.  When the second injection is from a new pen, 
the new pen must be primed accordingly to the Instructions for Use provided. 
Further details are provided in the Patient Diary. 
Missed, delayed, or split doses should be reported in the Patient Diary and the appropriate 
eCRF. 
6.3 
Dose Modification Plan 
During study conduct, the dose of MOD-4023 and Genotropin® will be assessed every 3 
months based on patient’s body weight. Doses will be determined by the EDC system and 
will include an automatic rounding – either up or down – to the closest pen increment (0.2 
increments in 20 mg/mL pens and 0.5 increments in 50 mg/mL pens). 
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-1 
SDS).  
6.3.1 
Dose Decrease  
For patients on MOD-4023, the dose will be decreased based on 2, repeated day 4(-1) levels 
of IGF-1 > +2.0 SDS. For patients on Genotropin®, the dose may be decreased based on 
repeated IGF-1 levels > +2 SDS.  
If a patient has an IGF-1 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, for 
MOD-4023 treated patients, or any day for Genotropin®. If their IGF-1 level is still above 
+2.0 SDS, the most recent dose will be reduced by 15% (i.e. to 0.56 mg/kg for MOD-4023; 
21µg/kg/day for Genotropin®). The patient will be treated with the new dose for at least 4 
weeks before a subsequent IGF-1 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-1 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-1 will be resampled. If the IGF-1 is still above +2.0 SDS, the dose will be 
reduced an additional 15% to 0.48 mg/kg for MOD-4023 and to 18 µg/kg/day for 
Genotropin® arm. If the IGF-1 is still above +2.0 SDS following 2 dose reductions (at least 4 
weeks after second dose reduction), the medical monitor (with the assistance of the DSMB if 
necessary) will decide on course of treatment on an individual basis. This information is 
summarized in Figure 2 below.  
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If AEs are defined as “severe” AND drug related, dose reduction will be introduced upon 
discussion with the medical monitor and DSMB - dose should be reduced at a similar manner 
as above in 2 steps approach.  
Every attempt should be made to maintain the patient on the originally allocated dose if 
possible. In case the investigator does not plan to decrease the dose as described in the 
protocol, the medical monitor should be notified. 
The key safety data will be reviewed by an independent and external DSMB at least once 
every 6 months. The DSMB will also include review of number or percentage of patients 
requiring dose reductions due to IGF-1 above +2.0 SDS, and number or percentage of 
patients whose IGF-1 remains above +2.0 SDS, despite dose reductions (in both MOD-4023 
and Genotropin® arms). DSMB review will also include review of number or percentage of 
patients requiring dose reductions due to AEs. 
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Figure 2: Dose Adjustment Scheme (example is for MOD-4023) 
 
Scheme and percent reduction is applicable for the MOD-4023 and Genotropin® arm as well 
and in case AEs are defined as “severe” and drug related. 
6.4 
Method of Assigning Patients to Treatment Groups 
Eligible patients will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups, MOD-
4023 or GH Genotropin® (reference therapy) for 12 months. 
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Randomization will be performed through the IRT system. The treatment codes for each 
patient will be held according to EDC.  
6.5 
Shipment and Storage Condition of Investigational Product 
Shipment, Storage, Dispensing and Return of the Investigational Product and the reference 
drug will be managed through the IRT system.  
The investigational drug will be packed and shipped at 2-8°C in appropriate boxes with 
temperature loggers.  
The investigator or study pharmacist should refer to the pharmacy manual for instructions on 
how to acknowledge receipt of all shipments of study drug and ancillary supplies and how to 
keep record of how much study drug was returned, used and unused by each patient.  
All investigational products must be kept refrigerated (2-8°C) 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 investigator trained and certified team member or the local 
pharmacist are authorized to dispense and administer study drug.  
6.6 
Accountability and Compliance of Investigational Product 
The investigator must maintain complete and adequate records documenting the receipt, use, 
loss, or other disposition of the investigational product supplies. All investigational products 
(MOD-4023 and Genotropin®) will be accounted for using a drug accountability form/record. 
The investigator is responsible that all investigational products accountability records are 
accurate and available for review by the study monitor, Sponsor or designee or the relevant 
regulatory authority.  
At the last study visit, all used and unused MOD-4023/Genotropin® study drugs (pen) 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 approval. 
Destruction of Investigational Product Supplies 
The Sponsor or designee will provide guidance on the destruction of used and unused 
investigational product and expired laboratory kits (e.g., at the site). If destruction is 
authorized to take place at the investigator site, the investigator must ensure that the materials 
are destroyed in compliance with applicable environmental regulations, institutional policy, 
and any special instructions provided by Sponsor. All destruction must be adequately 
documented. 
6.7 
Prior and Concomitant Therapy 
6.7.1 
General Guidelines 
All prior treatments received by the patient within 30 days of the initial Screening Visit will 
be recorded on the patient’s eCRF including the treatment's name, indication and the start and 
stop dates.  
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Any medications (including prescription, over-the-counter, herbal and food 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 must be recorded on the eCRF, 
along with the indication, start and stop dates, and the dose.  
6.7.2 
Disallowed Previous Medications/Therapies 
The following medications are not permitted prior to the Screening Visit: 
 Any r-hGH therapy 
 Systemic corticosteroids other than in replacement doses within the 3 months 
before ICF signing (temporary adjustment of glucocorticoids, as appropriate, is 
acceptable) 
 Anabolic steroids other than gonadal steroid replacement therapy within 2 months 
before study entry 
 Use of investigational products (within 30 days prior to ICF signing) 
6.7.3 
Allowed Medications 
The only concomitant medications allowed to be used in this study are those used at baseline 
to control existing medical condition and/or those taken during the study to treat adverse 
events. All concomitant medications used to treat AEs will be recorded in the patient’s 
medical file and on the appropriate eCRF page.  
Careful monitoring is advisable when MOD-4023 is administered in combination with other 
drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction 
studies have not been conducted. 
6.7.4 
Prohibited Concomitant Medication 
The following medications are not permitted during the study and may lead to withdrawal of 
the patient from the study: 
 Any hormonally active medication other than replacement therapy for pituitary 
failure. Glucocorticoid replacement dosing should be carefully adjusted in 
children receiving MOD-4023 and Genotropin® and glucocorticoid treatments to 
avoid both hypoadrenalism and an inhibitory effect on growth. 
 Any new long-term glucocorticoid treatment should be noted on the concomitant 
medication form and the patient should be retained in the safety population, but 
not the per-protocol population. Short term glucocorticoid treatment is allowed.  
 Anabolic steroids (Including testosterone replacement therapy) should not be 
taken. 
 Weight loss drugs. 
 Psychiatric medications typically associated with weight changes and/or diabetes 
excluding medications used to treat ADHD. 
 
 
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7 SAFETY AND PHARMACOVIGILANCE 
7.1 
Adverse Event 
An AE is any adverse change from the patient baseline condition, whether or not considered 
investigational product related. This includes any subjective signs, symptoms or diagnosis, 
clinical significant deviation from baseline laboratory values or vital signs, or worsening 
(more severe, more frequent or increased in duration during the investigational product 
treatment) of the concomitant disease present at Baseline visit (after initiation of 
investigational product treatment). Stable chronic conditions that are present prior to study 
entry and do not worsen during the study will not be considered AEs. Disease-related AEs 
will be considered AEs only if they worsen beyond what would be expected in the normal 
progression of the disease. In all cases, the etiology should, as much as possible, be identified 
and the Sponsor notified.  
An abnormal result of diagnostic procedures including abnormal laboratory or vital signs 
findings will be considered an AE if it: 
 Results in patient’s withdrawal by the investigator 
 Is associated with clinical signs or symptoms 
 Is considered by the physician to be of clinical significance 
AEs reported by the patient or observed by the investigator will be individually listed on an 
AE form in the eCRF as follows: the specific event or condition, whether the event was 
present pre-study, the dates and times of occurrence, duration, severity, relationship to study 
medication, specific countermeasures and outcome.  
The intensity or severity of the AE will be characterized as: 
 Mild: Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
 Moderate: Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
 Severe:  Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required; hospitalization possible. 
The investigator will document in his/her opinion the relationship of the AE to study 
treatment using the criteria outlined in Table 3. 
 
 
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Hospitalization for elective treatment of a pre-study condition that did not worsen while on 
study and hospitalizations for treatment of non-AE (e.g. cosmetic surgery) are not considered 
SAEs. 
Significant medical events are those which may not be immediately life-threatening, but 
may jeopardize the patient and may require intervention to prevent one of the other serious 
outcomes listed above. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization; resulting in an AE will normally be considered serious by this criterion. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, or 
that they occurred as a consequence of the event.  
Any new SAE that occurs following 30 days of last study drug administration and is 
considered to be related (possibly) to the investigational product or study participation should 
be recorded and reported immediately. 
A life-threatening AE is any AE that places the patient, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction 
that, had it occurred in a more severe form, might have caused death. 
7.3 
Definition of an Unexpected AE 
An unexpected adverse drug experience (event) is any AE, the specificity or severity of 
which is not consistent with information in the current IB for an unapproved investigational 
product or package insert/summary of product characteristics for an approved product 
(package inserts are available separately at the participating center). 
7.4 
Definition of suspected unexpected serious adverse reaction (SUSAR) 
A SUSAR is a Suspected Unexpected Serious Adverse Reaction. An Adverse Reaction is 
defined as any AE caused by a drug. A suspected adverse reaction is defined as an adverse 
event for which there is reasonable possibility that the drug caused the AE. The "reasonable 
possibility" means that there is evidence to suggest a causal relationship between the drug 
and the AE, any unexpected SAE that may be related to study drug is a SUSAR. Because 
knowledge of treatment assignment is needed to complete the determination, the Sponsor's 
designee will provide the final determination as to whether an SAE is a SUSAR. 
7.5 
Notification about Serious or Unexpected AEs 
Initial notification  
Each SAE must be reported by the investigator to the Sponsor or designee (OPKO Miami 
pharmacovigilance), to the study medical monitor and to Japan Safety Group (ICCC) 
immediately (within 24 hours) upon 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 considered unexpected 
by the Sponsor or designee and is thought to be possibly related to the study drug, a Safety 
Associate shall urgently request further information from the investigator through the project 
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leader. This is essential for collecting information to report to the competent regulatory 
authority (RA). 
SAE Reporting and Contact Information 
All SAEs will be entered initially on the AE eCRF in EDC and an email notification should 
be sent to: the study medical monitor, OPKO Miami Pharmacovigilance Group and Japan 
Safety Group. In addition, the investigator will complete the CP-4-009 SAE Report Form that 
will be outside the EDC system. This form will be available for completion electronically as a 
pdf or may be printed for completion. The completed SAE Report Form will then be scanned 
and a copy sent to the study medical monitor, Japan Safety Group mailbox and to OPKO 
Miami Pharmacovigilance Group mailbox per the below specified contact information.  
1. Medical Monitor: 
 
 Tanaka Growth Clinic 
2-36-7, Yohga, Setagaya-ku 
Tokyo, Japan 158-0097 
TEL：
  FAX：
 
E-mail： CP4009_medical_monitor@opko.com 
2. OPKO Miami Pharmacovigilance Unit: 
  
4400 Biscayne Blvd 
Miami, FL 33137 
Email: 
 
Phone: 
 
3. Japan Safety Group (ICCC: EPS International Holdings Co., Ltd.) 
 
 
1-8 Tsukudo-cho, Shinjuku-ku 
Tokyo, Japan, 160-0821 
Email: 
 
Phone: 
 
The investigator must complete the CP-4-009 SAE Report Form in English; assess the 
relationship to study treatment and submit to the above contacts via the email address 
specified within 24 hours to OPKO Miami Pharmacovigilance as well as to the study medical 
monitor and Japan Safety Group as above specified. 
Follow-Up of SAEs / SUSARs 
Follow-up information is to be submitted on a new SAE Report Form. The new form should 
clearly state that it is a follow-up to the previously reported SAE and include 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 
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participation.  The follow up report may also include copies of site’s case reports, autopsy 
reports and other documents, when requested and applicable. 
Accompanying documentation, such as copies of study site’s case reports, autopsy reports 
and other documents when applicable, should be summarized on the SAE form and a copy of 
the source document should be emailed to Japan Safety Group and to the study medical 
monitor. The above mentioned Japanese documentations should be translated by the Japan 
Safety Group to English, if required, and provided to OPKO Pharmacovigilance Group. The 
patient’s personal details will be removed and replaced with study identifiers i.e. study 
number and initials, if applicable. 
In addition, all AEs / SAEs / SUSARs will be reported to the head of the study sites and to 
the PMDA as required by local regulations and ICH-GCP guidelines.  
Minimal information should include: 
 An identifiable patient (e.g. Patient study code number) 
 An identifiable reporting source 
 All related AEs 
 The suspect medicinal product 
The contact information for follow up SAE reporting is the same as for initial SAE reports 
(see above section).  
Once emailed, the SAE form and accompanying documentation should be placed in the SAE 
section of the investigator’s file. If supplementary information on a SAE has to be sent, the 
SAE form to be used must be marked as “follow-up report”. 
SAEs and Non-SAE Reporting Period 
SAEs / SUSARs that occur during the study will continue to be followed until their 
satisfactory resolution or stabilization. 
All AEs (including SAEs) must be followed until resolution or stabilization and until 30 days 
after the patient last drug administration. In exceptional cases, it may be defined as “ongoing 
without further follow-up” by the investigator and Sponsor’s decision. 
7.6 
Independent DSMB 
An independent and external DSMB will be established for the study, to periodically review 
the safety information generated during the conduct of the study and is allowed to request 
efficacy data if considered necessary for benefit/risk assessment. The primary responsibility 
of the DSMB is to provide guidance to regarding the safe conduct of the study based on their 
periodic review of safety data. The DSMB will review study safety summaries reported.  
The DSMB’s membership, full scope of responsibilities, operating procedures, data 
availability and reporting and record keeping requirements will be established by Sponsor 
and/or its representative. DSMB working procedures will be described in a DSMB charter 
prior to enrolling the first patient.  
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The key safety data will be reviewed by an independent DSMB approximately once every 6 
months. DSMB will also include review of number or percentage of patients requiring dose 
reductions due to IGF-1 above +2.0 SDS, and number or percentage of patients whose IGF-1 
remains above +2.0 SDS, despite dose reductions (in both MOD-4023 and Genotropin® 
cohorts). DSMB will also include review of number or percentage of patients requiring dose 
reductions due to AEs. 
7.7 
Medication Errors 
Medication errors may result from the administration of the investigational product by the 
wrong patient, or at the wrong time, or at the wrong dosage strength.  
Medication errors include: 
 Medication errors involving patient exposure to the investigational product 
 Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient 
Such medication errors occurring to a study participant are to be captured in the EDC system. 
7.8 
Medical Device Complaint 
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, must be reported by the investigator to the Sponsor, and the device 
must not be used. 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. 
If the device complaint is considered unexpected by the Sponsor, Sponsor or its designated 
ICCC shall urgently request further information from the investigator through the project 
leader. In addition, all potential incidents or malfunctions will be reported to the head of the 
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8 STATISTICAL ANALYSIS 
8.1 
Sample Size Consideration 
The primary efficacy endpoint is Annual HV in cm/year after 12 months of treatment.  
Assuming that the mean treatment difference is -0.8 cm/yr and the common SD is 2.5 cm/yr, 
a total 40 patients (20 per treatment) will provide about 90% probability that the point 
estimate of the mean treatment difference of HV in CP-4-009 is greater than -1.8 cm/year 
(which is the non-inferiority margin in the global trial CP-4-006).  
8.2 
Analyzed Population Sets 
8.2.1 
Full Analysis Set 
The Full Analysis Set will include all randomized patients. 
8.2.2 
Per Protocol Set 
The Per Protocol Set will be all randomized patients who completed the study per protocol 
and who did not have any major protocol deviations. 
8.2.3 
Safety Analysis Set 
The safety analysis set will include all patients who have received at least one dose of study 
treatment. 
8.3 
Handling of Missing Data 
Multiple Imputation (using SAS PROC MI) assuming data missing at random will be used to 
impute missing observations in the primary efficacy analysis. Sensitivity analyses will be 
performed to evaluate the effect of missing data. Details on the method used to handle 
missing data and all sensitivity analyses for missing data will be provided in the SAP. 
8.4 
Endpoints 
8.4.1 
Primary Efficacy Endpoint 
 HV in cm/year after 12 months of treatment.  
8.4.2 
Secondary Efficacy Endpoints 
Auxology/Clinical endpoints: 
 Annualized height velocity after 6 months of treatment 
 Change in height SDS at 6 and 12 months, compared to Baseline  
 Change in bone maturation (BM) at the end of 12 months, compared to Baseline 
(BM calculated as BA/CA)  
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8.4.3 
Secondary PK/PD Endpoints 
Biochemical endpoints: 
 IGF-1 SDS on day 4(-1) after MOD-4023 dosing across study visits (window only 
applies to Visits 6 to 9) 
8.4.4 
Safety Outcomes 
 Incidence of AEs and SAEs 
 Incidence of anti-MOD-4023 antibody formation (including characterization of 
the antibodies and neutralizing properties) 
 Local injection site assessment 
 IGF-1 serum levels and SDS 
 Parameters of glucose metabolism: morning fasting glucose, morning fasting 
insulin level, HbA1c 
 Thyroid status  
 Lipid metabolism parameters: morning fasting total cholesterol, LDL cholesterol, 
HDL cholesterol and triglycerides  
 All other safety hematology and biochemical laboratory parameters 
 Physical examination 
 Fundoscopy (normal/abnormal) 
 Vital signs 
 ECG 
8.5 
Statistical Analysis 
The planned final analysis will be done after all patients complete 12 months treatment. 
Details of applicable statistical methods will be provided in a SAP prior to database lock. The 
primary analysis set for all the efficacy analyses will be the Full Analysis Set.  
8.6 
Efficacy Analysis 
The aim of the Phase 3 study is to demonstrate that in terms of the primary efficacy endpoint, 
Annual HV at 12 months, weekly MOD-4023 is comparable to daily r-hGH within the range 
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defined of 1.8 cm/year (non-inferiority margin in CP-4-006 study). Descriptive statistics and 
confidence intervals will be used to characterize the results. 
Primary Efficacy Analysis:  
The goal of the primary efficacy analysis is to estimate the mean treatment difference 
between weekly MOD-4023 and daily Genotropin® with respect to the primary efficacy 
endpoint (HV after 12 months of treatment). Least square means and 95% CI for HV at 12 
months will be calculated from an ANCOVA model, with treatment, gender, as factors (class 
variables); and peak hGH value during stimulation test, and baseline HV as covariates. The 
point estimate of the mean difference in HV between treatments will be used to assess 
comparability. Comparability will be concluded for the primary efficacy endpoint if the point 
estimate of the mean treatment difference (MOD-4023 – Genotropin®) is ≥ –1.8 cm/year.  
Missing data will be handled by multiple imputation (by using SAS PROC MI), assuming 
data missing at random. Details will be provided in the SAP. 
Secondary Analysis:  
The continuous secondary efficacy endpoints measured at a single post-baseline timepoint 
will be analyzed in the same manner as the primary endpoint, using the ANCOVA model 
which may include treatment group, age, and gender, peak hGH value during stimulation test, 
and the baseline value of the endpoint of interest to generate the least square treatment means. 
For the secondary endpoints that are measured over time, MMRM analysis with similar 
factors as the ANCOVA model (in the primary endpoint) will be used to estimate the time 
specific results. This MMRM approach is not intended to test for statistical significance of 
factors. These analyses are considered to be supportive efficacy analyses.  
8.6.1 
Safety Analysis 
All safety analyses will be conducted using the Safety Analysis Set. The assessment of safety 
will be based mainly on the frequency of treatment emergent AEs and on the number of 
laboratory values that fall outside of pre-determined ranges. Data of all safety endpoints will 
be listed and tabulated. 
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9 ETHICS 
9.1 
IRB 
Prior to initiation of the study, the sponsor or its designated ICCC will submit the study 
protocol and amendments, sample ICF and any other documents that may be requested to the 
IRB for review and approval. The Head of the study site will request that the IRB to provide 
written approval of the study and will keep on file records of approval of all documents 
pertaining to this study. The investigator will not begin the study until the protocol and ICF 
have been approved by the IRB. The investigator must agree to make any required progress 
reports to the Head of the study site, as well as reports of SAEs, serious medical device (pen) 
complaint, life-threatening conditions, or death. The sponsor or its designated ICCC must 
report those information to the IRB as required by local regulations. 
9.2 
Ethical Conduct of the Study 
All clinical work conducted under this protocol is subject to ICH-GCP and J-GCP guidelines. 
This includes an inspection by Sponsor or its designee, health authority or IRB 
representatives at any time. The investigator must agree to the inspection of study-related 
records by health authority representatives and/or Sponsor or its designee.  
The study will be conducted in accordance with Sponsor’s or designee’s SOPs and the 
following guidelines: 
 ICH-GCP: Consolidated Guideline (ICH of Technical Requirements for the 
Registration of Pharmaceuticals for Human Use, May 1996). 
 Declaration of Helsinki: Brazil, 2013 (Appendix H). 
 Local country guidelines for conducting clinical trials 
9.3 
Protocol Revisions and/or Deviations 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the investigator). The Sponsor will make reasonable efforts to have the investigators 
agreement in regards to these changes. All protocol modifications must be submitted to the 
IRB in accordance with local requirements and, if required, to RAs, 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 
will be required for notifications. 
9.4 
Patient Information and Consent 
Prior to screening for the study each patient and parents/legal guardians will be informed in 
detail about the study drugs to be administered and the nature of the clinical investigation 
with its risks and discomforts to be expected. The basic elements of informed consent as 
specified by J-GCP, the FDA (21 CFR 50.25) and ICH-GCP will be followed. Written 
consent will be obtained from parents/legal guardian of each patient to be involved in the 
clinical trial by using the IRB approved ICF prior to the conduct of any study-related activity. 
In addition to this, the investigators will try to obtain assents from patients. Parents/legal 
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guardian of each patient will be given a copy of the written ICF. The parents/legal guardian 
of patients will also be instructed that they are free to withdraw their consent and discontinue 
their children’s participation in the study at any time without prejudice. Each patient’s chart 
will include the signed ICF for study participation obtained from their parents/legal guardian 
as well as assents if obtained. When the study treatment is completed and the eCRF has been 
monitored, the ICF will be kept in the investigator’s central study file for the required period 
of time. Regulatory authorities may check the existence of the signed ICF in this central study 
folder if not having done so during the study.  
9.5 
Patient Insurance 
The Sponsor has an insurance policy for the total duration of the study covering the patients 
and investigators in respect to the risks involved in conducting this study according to this 
protocol. The insurance policy will be filed in the investigator's file or can be made available 
to the investigator and to the IRB upon request. 
9.6 
Informing the General Practitioner 
The investigator will inform the patient's primary care physician of his/her participation in the 
study, by sending a letter to the physician if required by the local authorities. 
9.7 
Personal Data Protection 
The Sponsor complies with the principle of the patient’s right to protection against invasion 
of privacy. Throughout this trial, all data will be identified only by an identification number 
and/or date of birth. 
The data will be blinded in all data analyses. The patient must be informed and consent is 
required that authorized personnel of the Sponsor and/or designee (Study Monitor, Auditor 
etc.) and relevant health RA will have direct access to personal medical data to assure a high 
quality standard of the study.  
 
 
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10  QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and designated ICCC maintain a quality assurance (QA) system with written 
SOPs to ensure that clinical trials are conducted and data are generated, documented and 
reported in compliance with the protocol, GCP, J-GCP and applicable regulatory 
requirements.  
10.1 
Audits and Inspections 
The investigator/the Head of the study site should understand that source documents for this 
trial should be made available to appropriately qualified personnel from the Sponsor QA or 
its designees or to RA inspectors after appropriate notification. The verification of the eCRF 
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. 
The study monitor will advise the investigator regarding the practical conduct of the study 
and maintaining compliance with the protocol, GCP, J-GCP and all applicable regulatory 
requirements. 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 eCRF will be reviewed for 
completeness with corresponding source documents and patient medical records. 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’s study file to ensure completeness of documentation in all respects 
of clinical study conduct.  
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. The investigator 
or appointed delegate will meet with the study monitor during these on-site visits, cooperate 
in providing the documents for inspection and respond to inquiries.  
10.2.1 
Source Documents 
The Head of the study site will permit study-related monitoring, audits by or on behalf of the 
Sponsor, IRB 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 site’s records, charts, diaries, x-rays and laboratory results, printouts, pharmacy 
records, care records, completed scales for each study participant. Source documents should 
be kept in a secure and limited access area. 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.  
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Source data for patients registered to the study should indicate date informed consent was 
signed, participation in clinical protocol number and title, treatment number, evidence that 
inclusion/exclusion criteria have been met. 
10.2.2 
eCRF 
An eCRF will be used to store and transmit patient information. The file structure and format 
for the eCRF will be provided by the Sponsor or their representative and should be handled in 
accordance with the instructions provided. 
The eCRF must be reviewed and electronically signed and dated by the investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by treating 
personnel or the study coordinator. The eCRF must be completed as soon as possible after 
any patient evaluation or communication. If data is to be changed due to erroneous input or 
other reason, an electronic audit trail will track these changes. The eCRFs and computers that 
store them must be accessible to study monitors and other regulatory auditors. 
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 central laboratory. 
10.4 
Data Management 
An eCRF will be used for the current study and a data management plan (DMP) will be 
prepared by the Sponsor and/or it designated representative. 
Various edit checks will be performed for the purpose of ensuring the accuracy, integrity and 
validity of the database. These edit checks may include: 
 Missing value checks 
 Range checks 
 Consistency checks 
 Sequence checks 
 Probabilistic checks 
 Protocol adherence checks 
Queries generated from these checks will be sent to the investigational site for resolution and 
the database will be updated to reflect query resolutions as appropriate. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, 18.1 or 
higher). Prior and concomitant medications will be coded according to the World Health 
Organization (WHO) Drug Dictionary.  
 
 
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11   STUDY ADMINISTRATION 
11.1 
Participating Centers 
Approximately 45 - 55 sites will participate in this study.  
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: 
 Appropriate IRB documentation properly signed and dated by the required Head 
of the study site (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-investigatorsa 
 IRB name and address; and membership list 
 Letter of approval from the IRB for both protocol (identified by protocol title and 
number) and informed consent form (identified by protocol title and number) 
 Copy of the IRB -approved written ICF to be used in the study (that has also been 
approved by the Sponsor) 
 Provisions for direct access to source/data documents if necessary for trial-related 
monitoring, audits, IRB review and regulatory inspection 
 If applicable, medical license of participating investigator and / or sub-investigator 
Upon satisfactory receipt of all required regulatory documents, Sponsor will arrange that 
study drugs be delivered to the study site. Supply of all other study materials will be the 
responsibility of OPKO 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 to include review of study protocol, instructions 
for eCRF completion, AE reporting and overall responsibilities including those for drug 
accountability and study file maintenance. 
The investigator and/or designee will prepare an Investigator's Study File (ISF). This file 
should 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. 
                                                 
a Can be collected at Site Initiation Visit 
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11.2 
Clinical Trial Supplies 
The Sponsor and/or designated representative will be responsible for supplying IP clinical 
trial supplies through the IRT system. IP clinical supplies inventory will be managed through 
the IRT system. Other clinical trial supplies (i.e. ancillaries, lab supplies, etc.) will be 
managed outside of the 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. 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, are not limited to: laboratory supplies, study drugs 
and ancillary items. 
11.3 
ISF 
The ISF will be prepared by the investigator and/or designee by the time of the initiation 
visit. All documents required for the conduct of the study as specified in the ICH-GCP 
guidelines and J-GCP guidelines will be maintained by the investigator in an orderly manner 
in the ISF and made available for monitoring and/or auditing by the Sponsor and RAs. 
11.4 
Study Completion 
This study is expected to end when the last enrolled patient completes Visit 10- EOS visit. 
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 
 eCRF properly completed by appropriate study personnel and signed by the 
investigator 
 Completed Drug Accountability Records 
 Statement of outcome for each serious adverse event reported 
 Copies of protocol amendments and IRB as well as relevant health authority 
approval/notification (if applicable) 
11.5 
Final Report 
A final study report will be developed at completion of data analysis. This report will be a 
clinical and statistical integrated report, according to the ICH E3 guidelines. 
11.6 
Retention of Study Records 
Per the J-GCP the investigator and the head of the study site/or designee will retain copies of 
the approved protocol, completed eCRF, informed consent documents, relevant source 
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documents and all other supporting documentation related to the project for 15 years. If the 
investigator and the head of the study site/or designee 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. 
These files must be made available for inspection upon reasonable request by authorized 
representatives of Sponsor and/or the relevant regulatory agencies. 
11.7 
Confidentiality and Publication 
Patient medical information obtained by the study is confidential and disclosure to third 
parties other than those noted below is prohibited. Throughout the study, all data will be 
identified only by the patient identification number and where applicable, the patient’s initials 
and birthdates. 
At the patient's request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. Personal physician 
will be notified by site personnel of patient participation in the study. 
All information supplied by OPKO in association with this study and not previously 
published, is considered confidential information. This information includes, but is not 
limited to, the IB, the protocol, eCRFs and other scientific data. Any data collected during the 
study are also considered confidential. This confidential information shall remain sole 
property of OPKO, shall not be disclosed to others without the written consent of OPKO and 
shall not be used except in the performance of this study. 
The information developed during the conduct of this study is also considered confidential 
and will used by OPKO. This information may be disclosed as deemed necessary by OPKO. 
To allow the use of this information derived from this study, the investigator is obliged to 
provide OPKO with complete test results and all data developed in this study.  
 
 
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Krysiak, R., A. Gdula-Dymek, et al. (2007). "Growth hormone therapy in children and 
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Lindsay, R., M. Feldkamp, et al. (1994). "Utah Growth Study: growth standards and the 
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Peter, F., M. Bidlingmaier, et al. (2012). "Three-year efficacy and safety of LB03002, a once-
weekly sustained-release growth hormone (GH) preparation, in prepubertal children with GH 
deficiency (GHD)." The Journal of clinical endocrinology and metabolism 97(2): 400-407. 
Prader A, L. R., Molinari L, Issler C (1989). "Physical growth of Swiss children from birth to 
20 years of age. First Zurich longitudinal study of growth and development." Helvetica 
Paediatrica Acta: 52: 51-125. 
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Rona, R. J. and J. M. Tanner (1977). "Aetiology of idiopathic growth hormone deficiency in 
England and Wales." Archives of disease in childhood 52(3): 197-208. 
Rosenfeld, R. G. and B. Bakker (2008). "Compliance and persistence in pediatric and adult 
patients receiving growth hormone therapy." Endocrine practice : official journal of the 
American College of Endocrinology and the American Association of Clinical 
Endocrinologists 14(2): 143-154. 
Shalet, S. M., A. Toogood, et al. (1998). "The diagnosis of growth hormone deficiency in 
children and adults." Endocrine reviews 19(2): 203-223. 
Stochholm, K., C. H. Gravholt, et al. (2006). "Incidence of GH deficiency - a nationwide 
study." European journal of endocrinology / European Federation of Endocrine Societies 
155(1): 61-71. 
Thomas, J. D. and J. P. Monson (2009). "Adult GH deficiency throughout lifetime." Eur J 
Endocrinol 161 Suppl 1: S97-S106. 
Thomas, M., G. Massa, et al. (2004). "Prevalence and demographic features of childhood 
growth hormone deficiency in Belgium during the period 1986-2001." European journal of 
endocrinology / European Federation of Endocrine Societies 151(1): 67-72. 
 
 
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APPENDIX D: STIMULATION TESTS 
GH Stimulation Tests  
After the nationwide standardization of GH measurement kits in 2005, a peak GH 
concentration equal to or less than 6ng/mL (16 ng/mL in GHRP-2 test) is the diagnostic 
criteria for GHD in Japan when the kits use recombinant hGH as standards (Tanaka, T. Horm 
Res 2005;64(suppl 2):6-11). However, the considerable variations were observed again by 
the annual nationwide control survey, GH value by Beckman should be judged after 
calculation by the correction formula (Katsumata N. Endocr J 2016;63:933-936). 
The following GH stimulation tests are recommended, but the final decision regarding 
which test will be performed will be made by the investigator. 
Insulin Tolerance Test 
Regular human insulin (0.1 IU/kg) will be administered intravenously (iv) at time point 0. 
The test will be interpretable if the blood glucose level decreases below 40 mg/dL. 
Administration of oral dextrose, sugar containing juice, or iv 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 = 0, 15, 30, 60, and 90 min (5 sampling points ± 5 min) for glucose, hGH (except 
15 min) and cortisol determination (except 15 min).  
At the 15 min time point glucose levels should be measured at bedside by a simple glucose 
meter. Additional samples may be obtained during hypoglycemia at the discretion of the 
investigator. 
A normal ACTH reserve is defined as a baseline cortisol level above (5 μg/dL) or an increase 
in peak cortisol level above (18 μg/dL). 
Clonidine test 
After fasting overnight, clonidine ( 0.1 mg/m2 body surface, given orally, 0.15 mg maximum) 
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 or with saline 
flush, Heparin Lock if necessary. Blood will be collected at the following intervals: t = 0, 30, 
60, 90 and 120 (5 sampling points ± 5 min) 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. If BP drops to 20% below baseline, start a normal saline 
bolus over 1 hour and monitor BPs every 15 minutes. 
Arginine test 
Soluble 10% arginine hydrochloride (0.5 g/kg) will be given iv 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 = 0, 30, 60 and 90, 120 min (5 sampling points ± 5 min) for hGH 
measurement 
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Glucagon test 
After fasting overnight, glucagon (0.03 mg/kg with a maximal total dose of 1 mg) will be 
given intramuscularly (im) 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 0, 60, 90, 120, 150 and 180 min (± 5 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 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.  
L-Dopa test 
After fasting overnight L-Dopa will be given orally at time-point t=0 at a dose of 10 mg/kg 
(maximum 500 mg). Blood samples will be obtained by an indwelling catheter. Blood will be 
collected at the following intervals: 0, 30, 60, 90 and 120 min (5 sampling points ± 5 min). 
GHRP-2 test 
After fasting overnight, GHRP-2 (2 μg/kg, maximum 100 μg) will be administered iv at t=0. 
Blood will be collected for hGH measurement at 0, 15, 30, 45 and 60 min (± 5 min) relative 
to the time of GHRP-2 administration.  
CRH and ACTH Stimulation Tests 
CRH Stimulation Test  
CRH at a dose of 1.5 μg/kg (maximum 100 μg) will be given iv at time point 0. Blood will be 
collected at the following intervals: t=0, 30, 60, 90 and 120 min (5 sampling points ± 5 min) 
for ACTH and cortisol determination. 
ACTH Stimulation Test  
After fasting overnight, ACTH (Cortrosyn, Daiichi-Sankyo Company, Ltd, Japan) at dose of 
1 μg/1.73 m2 body surface will be given iv at time point 0. Blood will be collected at the 
following intervals: 0, 30 and 60 min (3 sampling points ± 5 min) post injection for cortisol 
level determination. 
 
 
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APPENDIX E: INSTRUCTIONS FOR OBTAINING HEIGHT 
MEASUREMENTS 
Height will be measured in cm. 
Verify the stadiometer is calibrated prior to height measurement.  
Use the following instructions when obtaining height measurements. 
Please repeat the following instructions for 3 consecutive measurement per patient per visit. 
It's recommended that the height measurement will be conducted by the same trained person. 
1. Use a wall or equivalent 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 0.2 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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APPENDIX F: INSTRUCTIONS FOR OBTAINING X-RAY FILMS 
BA Assessment using the Tanner-Whitehouse 2 Method:  
BA assessment is a procedure frequently employed in pediatric radiology and is a reliable 
indicator of the skeletal maturity of an individual. The pattern of ossification in the bones of 
the hand and wrist occurs in a fairly predictable manner and is age specific until the cessation 
of adolescence when bone elongation is complete.  BA assessments and their comparison 
with chronological age are important in pediatric endocrinology for diagnosing diseases 
which result in abnormalities of stature (tall or short) in children. Serial measurements of 
bone age are also critical in determining the effectiveness of established treatments of these 
diseases as well as use in clinical trials in pediatric populations with new drug candidates for 
assessment eligibility as well as efficacy and/or safety.  
The most common imaging modality for assessment of BA is X-ray of bones of the hand and 
wrist in a PA view. Assessments are usually done in the left hand and wrist bones to 
determine the developmental status of individual bones or epiphysis, and a “skeletal age” is 
ascribed based on the particular indicator or indicators visible on X-ray. The hand 
radiographs are quite safe and do not expose the patient to any significant radiation exposure 
with an effective dose of radiation received during a single exposure being below 0.0001-
0.001 mSV which is below the exposure one would receive through natural background 
radiation in 20 minutes or in two minutes on a transatlantic flight. 
For this study, the bone age will be assessed by central review using a read model agreed 
upon with the Sponsor for eligibility and efficacy. The central reviewers will ascribe a BA 
which corresponds to the appropriate structural features that represent a comparable 
developmental stage based on the gender of the patient based on the Tanner-Whitehouse 2 
Method (Murata M. Japanese specific BA standard on the TW2. Clin Pediatr Endocrinol 
1993; (Suppl 3):35-41).   
The imaging vendor will provide image acquisition parameters and guidelines to the study 
sites in order to ensure appropriate acquisition and positioning to facilitate robust reads.  
Radiographs will be received by the imaging vendor either as DICOM files from digital 
instruments or as a hard copy film from conventional X-ray instruments.  The imaging 
vendor will digitize the films and blind and mask as needed to ensure that all radiographs will 
be provided to reviewers in a standardized, de-identified digital format  
 
 
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APPENDIX G: INJECTION SITE ASSESSMENT TABLE (LOCAL 
REACTIONS) AND PAIN ASSESSMENT 
Assessment by the PI and Medical Staff 
Assessment of local tolerability will be performed by examining the injection sites by the 
investigator or designated personnel to evaluate if a reaction is present at the time of every 
visit according to the below.  
Observations of local injection site reactions will be recorded on the appropriate eCRF pages. 
If an injection site reaction meets the criteria for “abnormal” defined above, it will be 
considered and assessed as an AE. 
The investigator is encouraged to properly photo the local injection site if the reaction is 
considered as abnormal and was assessed as an AE and to properly record it in the patient’s 
medical file. Photographs of injection site reactions will be taken and used to document any 
clearly observed clinical effect of MOD-4023 or Genotropin® but will not be formally 
evaluated.  
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. 
 
 
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Pain  
For patients, 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 Assessment Scale (below). In 
addition, each patient and parent/guardian will be queried during study visits regarding 
possible injection site pain.  
The patients should be trained to record any injection site reaction in their diaries.  
Pain score above or equal 4 is considered as an AE.  
 
Pain Assessment 
 
 
 
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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APPENDIX H: DECLARATION OF HELSINKI (2013) 
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 DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
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 be applied with consideration of all other relevant paragraphs. 
2.  
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.  
General Principles 
3.  
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.” 
4.  
It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this duty. 
5.  
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. 
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 and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7.  
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8.  
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
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personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 
10.  Physicians must 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. 
11.  Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12.  Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13.  Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14.  Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this 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. 
15.  Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16.  In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17.  All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research 
in comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18.  Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study.  
Vulnerable Groups and Individuals 
19.  
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
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All vulnerable groups and individuals should receive specifically considered 
protection. 
20.  
Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in 
a non-vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research. 
Scientific Requirements and Research Protocols  
21.  
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. 
22.  
The design and performance of each research study involving human subjects must be 
clearly described and justified 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, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions. 
Research Ethics Committees 
23.  
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the 
researcher, the Sponsor and any other undue influence and must be duly qualified. 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 amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions. 
Privacy and Confidentiality  
24.  
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
25.  
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent 
may be enrolled in a research study unless he or she freely agrees. 
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26.  
In medical research involving human subjects capable of giving informed consent, 
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, post-study provisions 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.  
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27.  
When seeking informed consent for participation in a research study the physician 
must 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 must be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
28.  
For a potential research subject who is incapable of giving informed consent, 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 group represented by 
the potential subject, the research cannot instead be performed with persons capable 
of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29.  
When a potential research subject who is deemed incapable of giving informed 
consent 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. 
30.  
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary characteristic of 
the research group. In such circumstances the physician must 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 must be obtained as soon as possible from the subject or a legally authorized 
representative. 
31.  
The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision 
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to withdraw from the study must never adversely affect the patient-physician 
relationship. 
32.  
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations, the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33.  
The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following 
circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention and the 
patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irreversible harm 
as a result of not receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.  
In advance of a clinical trial, Sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be 
disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36.  
Researchers, authors, Sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. 
Researchers 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. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.  
In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions 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 judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. This intervention should 
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subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made 
publicly available. 
© World Medical Association, Inc. – All Rights reserved. 
 
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APPENDIX I: PHONE INTERVIEW  
Phone Interview for Genotropin® arm will be conducted on Visit 3 and Visit 5.  
Phone Interview will be conducted on Visit 10 (EOS Visit) for both arms. 
During the OLE, Phone Interviews will be conducted at the following visits: 
- 
Visit 11 and Visit 12 for existing MOD-4023 patients only 
- 
Visit 13 for all patients 
- 
Follow Up Visit for all patients  
 
Phone interview wil be done by the investigator or designated personnel and 
the following questions will be addressed by the patient and his legal 
guardian/parents  
Please explain the necessity of the call.  
We are calling you today to check how you feel ; we would like to ask you a few questions if 
this is OK with you. 
In case the patient/parents/legal guardiuan refuse to answer- Please mark "not intersted" and 
complete a protocol deviation. 
1. From your last visit, do you feel any different? Y/N 
If yes, please specify. 
2. Are you taking any new medications? Y/N 
If yes, please specify. 
3. Have any changes in injection sites occurred in the past week/since the last injection drug 
administration? 
If yes, please specify. 
 
 
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APPENDIX J: CLINICALLY COMPARABLE DOSES OF INHALED 
CORTICOSTEROIDS 
 
Kelly et al., Annals of Pharmacotherapy 2009 March, Volume 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX K: OPEN-LABEL EXTENSION PROTOCOL  
 
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Reason for signing: Approved
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CLINICAL SUB-STUDY PROTOCOL 
 
EXTENSION STUDY OF THE PHASE 3, OPEN-LABEL, RANDOMIZED, 
MULTICENTER, 12-MONTH, EFFICACY AND SAFETY STUDY OF WEEKLY 
MOD-4023 COMPARED TO DAILY GENOTROPIN® THERAPY IN JAPANESE 
PRE-PUBERTAL CHILDREN WITH GROWTH HORMONE DEFICIENCY  
 
 
 
Sponsor: 
OPKO Health, Inc.  
4400 Biscayne Blvd 
Miami, FL 33137 
USA 
Protocol Number:  
CP-4-009  
 
CTN Number: 
29-0329 
 
 
 
 
 
 
 
 
 
Safety Medical 
Officer: 
, MD 
Statistician: 
 Ph.D.  
Research Global Point 
 
 
 
 
Confidentiality Statement 
This protocol is a confidential communication document of OPKO Health, Inc. The recipient of this document 
agrees not to disclose the information contained herein to others without prior written authorization of OPKO 
except that this document may be disclosed to appropriate Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC) or duly authorized representatives of Regulatory Authorities of Pharmaceuticals and Medical 
Devices Agency, Japan, European Medicinal Agency (EMA), or the United States of America (USA) Food and 
Drug Administration (FDA) under the condition that they maintain confidentiality. 
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PROTOCOL SYNOPSIS 
SUB-STUDY TITLE 
Extension Study of the Phase 3, Open-Label, Randomized, 
Multicenter, 12-month,Efficacy and Safety Study of Weekly 
MOD-4023 Compared to Daily Genotropin® Therapy in Japanese 
Pre-Pubertal Children with Growth Hormone Deficiency  
PROTOCOL NO. 
CP-4-009  
CTN NUMBER 
29-0329 
CLINICAL SITES 
The study will be conducted at CP-4-009 active clinical sites with 
qualified and interested patients.  
STUDY PHASE 
3 
THERAPEUTIC 
INDICATION 
Treatment of children with growth failure due to growth hormone 
deficiency (GHD). 
STUDY OBJECTIVE  To demonstrate the safe switch of patients who have completed 
12 months treatment with daily Genotropin ® to weekly MOD-
4023, and to document long term safety and efficacy of weekly 
MOD-4023 treatment in an open-label extension (OLE). 
STUDY DESIGN 
The study will consist of a single-arm, open-label extension 
(OLE) study with weekly MOD-4023 injections.  
Patients who have successfully completed 12 months of treatment 
in study CP-4-009 and meet the OLE inclusion/exclusion criteria 
of this protocol will be eligible to rollover into this OLE study. 
Patients who received Genotropin® for 12 months during the 
main study CP-4-009, will be switched to receive a dose of 0.66 
mg/kg per week of MOD-4023 (no less than one day after 
cessation of Genotropin® treatment).  Patients who have received 
MOD-4023 for 12 months during the main study will continue in 
the OLE with the same dose (mg/kg/wk) of MOD-4023.  
During the OLE study, the MOD-4023 dose will be adjusted 
based on the patients’ body weight every three months. The dose 
may be decreased for safety reasons according to the pre-defined 
dose-adjustment criteria (based on the severity of adverse events 
(AEs) or repeated, elevated levels of insulin-like growth factor-1 
(IGF-1) standard deviation score (SDS). During the OLE dose 
reduction for IGF-1 level >+2.0 SDS will be made following 
consultation with the Study MM on an individual patient basis. 
The key safety data will be reviewed by an independent Data 
Safety Monitoring Board (DSMB) once every 6 months. 
The study will be conducted, subject to Sponsor, Regulatory 
Authority and IRB approvals. 
STUDY 
PROCEDURES 
After successful completion of 12 months of treatment in the CP-
4-009 main study and meeting the OLE inclusion/exclusion 
criteria of this protocol, and upon receipt of necessary Regulatory 
and IRB approvals, patients will be eligible to rollover into the 
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OLE study with MOD-4023. An informed consent/assent will be 
obtained from patients and/or parents or legal/authorized 
guardian for this extension study.  
Patients who do not qualify to continue in the trial or who are not 
interested in continuing into the OLE should complete the End of 
Treatment (EOT) Visit, which is equivalent to visit 9/9.1, and 
should complete a phone interview for visit 10 within 4 weeks 
(+1 week) to complete End of Study Assessments according to 
the CP-4-009 main study protocol schedule of activities.  
Patients who received MOD-4023 during the main CP-4-009 
study will continue in the OLE with the same dose (mg/kg/week) 
of MOD-4023, adjusted for body weight. For these patients, 
study visits will take place every three months on day 4 (-1 day) 
post-dose. Pre-dose assessments will be taken at month 6 and 
month 12 during the first year. These patients will consent to the 
OLE preferably during Visit 8 (week 39) of the main study to 
ensure availability of MOD-4023 at their first visit of the OLE 
study.  Informed consent can also be obtained at main study Visit 
9/9.1/OLE Baseline Visit 9.2 (week 52). MOD-4023 patients will 
continue treatment and receive study drug at OLE Visit 9.2, skip 
Visit 10 (close out or end of main study), and have phone 
interviews at OLE Visits 11, 12, and 13 as described in the 
schedule of activities. Visits will occur every 3 months thereafter 
beginning at Visit 14. All patients will be provided with a patient 
diary throughout the trial as described in the Schedule of 
Activities (Appendix A). 
Patients who received Genotropin® during the CP-4-009 main 
study will complete the main study assessments and will be 
switched to MOD-4023 at Visit 9. Dosing of MOD-4023 
treatment at 0.66 mg/kg/wk will begin 1 day and no more than 2 
weeks after cessation of Genotropin® treatment (at Visit 9/OLE 
Visit 9.2). These patients will consent to the OLE preferably 
during Visit 8 of the main study to ensure availability of MOD-
4023 at their first visit of OLE study (main study Visit 9/OLE 
Visit 9.2). Patients will skip Visit 10 (close out or end of main 
study) and have additional onsite subsequent visits at Visit 11 
(Month 12.5, Day 10 post first MOD-4023 dose [10+4 days]), 
Visit 12 (1 month post first MOD-4023 dose (Month 1 [±1wk]), 
and Visit 14 (Month 3 [±1wk]). A phone interview will occur at 
OLE Visit 13 (Month 2 [±1wk]). Visits will occur every three 
months thereafter, until study closure.  All patients will be 
provided with a patient diary throughout the trial as described in 
the Schedule of Activities (Appendix A of the OLE Sub-
Protocol). 
For all patients switching from Genotropin® to MOD-4023, the 
following assessments will be performed at OLE Visit 9.2: 
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 MOD-4023 and associated diaries will be dispensed based 
on patient weight at a starting dose of 0.66 mg/kg/wk. 
 Training on and administration of MOD-4023, using the 
pen device, and diary completion. 
 Local tolerability assessment after first dose administered 
at site.  
 Urine pregnancy test at every visit once a female patient 
reports first menstrual cycle (menarche).  
Patients who experience a delay for any reason between 
completion of the main study and entry into the OLE may have to 
temporarily stop treatment. If initiation/re-initiation of treatment 
occurs less than 90 days after Visit 9 only training on and 
administration of MOD-4023 and local tolerability after first dose 
administered at site is required.     
Patients who are off treatment for more than 90 days due to 
technical reasons (e.g. delay in approval of Protocol Amendment) 
may be allowed to continue into the OLE after confirmation of 
availability of all required baseline OLE assessments (Visit 9).  In 
addition to the onsite training, dose administration of MOD-4023, 
and local tolerability assessment, the following tests and 
assessments below must be repeated at the time of the 
unscheduled visit at the site: 
 Overall health status assessment, including complete 
physical examination and vital sign assessments. 
 Safety laboratory tests: chemistry, hematology and 
urinalysis. 
 Parameters of glucose metabolism: morning fasting 
glucose, morning fasting insulin, HbA1c. 
 Assessment of thyroid: TSH, FT4. 
 Parameters of lipid metabolism: morning fasting total 
cholesterol, LDL, triglycerides, and HDL.  
 Assessment of anti-MOD-4023 Ab for all patients. 
 Assessment of biochemical markers: 
 IGF-1 
SDS. 
 Urine pregnancy test at every visit once a female patient 
reports first menstrual cycle (menarche).  
OLE Treatment – Year 1 
During the first year of OLE treatment, the following assessments 
will be conducted on Day 4 (-1 day) post dose during onsite visits 
for patients making the switch from Genotropin® to MOD-4023 
(Visits 11 – 12):  
 Safety laboratory tests: chemistry, hematology, and 
urinalysis (only Visit 12). 
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 Overall health status assessment, including complete 
physical examination and vital signs assessment.  
 AEs, local tolerability, and concomitant medications. 
 Urine pregnancy test at every visit once a female patient 
reports first menstrual cycle (menarche).  
 Assessment of biochemical markers: 
 
 calculate the related IGF-1 SDS (only Visit 12). 
 
. 
 Assessment of anti-MOD-4023 Ab. 
 Fundoscopy (if there are signs or symptoms indicative of 
benign intracranial hypertension). 
 Dispense study drug and patient diary (only Visit 12).a 
 Patient diary review, study drug return & accountability 
(only Visit 12). 
For patients making the switch from Genotropin® to MOD-4023, 
a phone interview will be conducted at Visit 13. 
Existing MOD-4023 patients will have a phone interview at 
Visits 11, 12, and 13 as indicated in the schedule of activities to 
ask about AEs and concomitant medications. These visits will be 
completed using the questionnaire in Appendix I of the main 
study protocol.  
The following assessments will be conducted on day 4 (-1 day) 
post-dose for all patients during the first year of OLE treatment at 
months three (Visit 14), six (Visit 15), nine (Visit 16), and twelve 
(Visit 17): 
 Pre-dose assessment of MOD-4023 serum levels and anti-
MOD-4023 Ab (Visit 15 and Visit 17 only). 
 Safety laboratory tests: chemistry, hematology, and 
urinalysis 
 Auxology measurements: Height (average of 3 
consecutive measurements) and body weight 
measurements (see Appendix E in the main study protocol 
for height instructions) 
 Overall health status assessment, including complete 
physical examination and vital signs assessment  
 Individual dose adjustment based on weight  
 AEs, local tolerability, and concomitant medications. 
 Urine pregnancy test at every visit once a female patient 
reports first menstrual cycle (menarche).  
 Assessment of biochemical markers: 
 
calculate the related IGF-1 SDS  
                                                 
a Patient Diary will be re-issued for further completion.  
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 
. 
 Post-dose assessment of anti-MOD-4023 Ab (Visit 14 and 
Visit 16 only). 
 Fundoscopy (if there are signs or symptoms indicative of 
benign intracranial hypertension). 
 Dispense study drug and patient diary. 
 Patient diary review, study drug return & accountability. 
 Assessment of thyroid function: TSH, FT4 (except Visit 
16). 
 Parameters of glucose metabolism: morning fasting 
glucose, morning fasting insulin, HbA1c (except Visit 
16). 
 Parameters of lipid metabolism: morning fasting 
cholesterol, triglycerides, high density lipoprotein (HDL), 
and low density lipoprotein (LDL) (except Visit 16).  
OLE Treatment – Year 2 until study closure 
Following completion of the first year of OLE treatment the 
following assessments will be conducted for all patients on day 4 
(-1 day) post-dose every three months :   
 Auxology measurements: Height and body weight 
measurements. 
 Overall health status assessment, including complete 
physical examination and vital signs assessment. 
 Individual dose adjustment based on weight. 
 AEs, local tolerability, and concomitant medications. 
 Urine pregnancy test at every visit once a female patient 
reports first menstrual cycle (menarche).  
 Fundoscopy (if there are signs or symptoms indicative of 
benign intracranial hypertension). 
 Dispense study drug and patient diary. 
 Patient diary review, study drug return & accountability. 
The following assessments will be conducted for all patients on 
day 4 (-1 day) post-dose every six months: 
 Assessment of biochemical markers: I
 
 related  IGF-1 SDS calculation  
 Safety laboratory tests: chemistry, hematology and 
urinalysis.  
 Assessment of thyroid function: TSH, FT4. 
 Parameters of glucose metabolism: morning fasting 
glucose, morning fasting insulin, HbA1c.  
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 Parameters of lipid metabolism: morning fasting 
cholesterol, triglycerides, HDL, and LDL.  
 Assessment of MOD-4023 serum levels. 
 Assessment of anti-MOD-4023 Ab. 
OLE Treatment – Annually from Year 1 until study completion 
Additional assessments will be performed once a year, on day 4 
(or -1 day) post-dose at month 12 (OLE Visit 17) and Year 2 
onward: 
 ECG 
 Bone age 
 Pubertal status (according to Tanner stages) 
 For males that are 13 years and older: LH, FSH and 
testosterone will be analyzed. For females that are 12 
years and older: LH, FSH and estradiol will be analyzed 
(from OLE treatment year 2 until study closure). 
 Pre-dose and post-dose assessment of MOD-4023 serum 
levels annually 
 Pre-dose assessment of Abs to MOD-4023 annually  
Year 1 (including end of study (EOS) during year 1): ECG should 
be conducted around the time of maximum concentration (Tmax) 
(7-12 hours post-dose). For the ECG that will be conducted at 7-
12 hours post-dose patients will be requested to inject MOD-4023 
during the day/night at their convenience and come to the study 
site at the requested timepoint for the ECG. Visits may be split to 
allow for pre-dose blood collection for serum levels and antibody 
tests and post-dose ECG or the patient will be asked to come to 
the study site for blood collection, administer the required dose, 
and return to the study site 7-12 hours post-dose. An ECG must 
still be obtained even if patients do not take the final dose. 
For EOS from OLE Year 2 onwards ECG can be conducted 
without a timeframe requirement i.e. at any time, although the 
date and time that each is performed will be recorded.   
Patients will be contacted by telephone 4 weeks [± 1 week] after 
ET visit in order to obtain safety related information (local 
tolerability, AEs, prior and concomitant medications). 
STUDY DURATION 
Patients will continue with weekly MOD-4023 treatment until 
study closure or discontinuation rules have been met. 
The OLE study will continue until marketing approval.  
NUMBER OF 
PATIENTS 
Up to 44 boys and girls who have been randomized and treated in 
the main study CP-4-009 and have completed 12 months of 
treatment will be eligible to continue in the OLE study of MOD-
4023 therapy.  
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INCLUSION 
CRITERIA 
1. Completion of the main study (12 months of treatment) with 
adequate compliance and adherence to the visit schedule and 
without major protocol deviation according to the main study 
protocol.    
2. Willing and able to provide written informed consent of the 
parent or legal guardian of the patient and written assent from 
pediatric patients.  
EXCLUSION 
CRITERIA 
1. Concomitant administration of other treatments that may 
have an effect on growth such as anabolic steroids, or sex 
steroids (other than for hormonal replacement), with the 
exception of ADHD drugs or hormone replacement therapies 
(thyroxin, hydrocortisone, testosterone, 
estrogen/progesterone, desmopressin [DDAVP®]). 
2. Change in medical condition during the treatment period 
(such as, but not limited to, occurrence of a malignancy 
during the course of study, development of a serious inter-
current critical illness, a severe adverse drug reaction, etc.) 
3. 
Unresolved drug related (MOD-4023 or Genotropin®) SAE 
from the treatment period as per MM judgement. 
STATISTICAL 
ANALYSIS 
STATISTICS: 
Safety Endpoints 
 Incidence of AEs and SAEs; 
 Incidence of anti-MOD-4023 Ab formation (including 
characterization of the Ab and neutralizing 
properties); 
 Local injection site reaction assessment; 
 Parameters of glucose metabolism: morning blood 
fasting glucose, fasting insulin level, HbA1c; 
 Thyroid (endocrinology) status; 
 Parameters of Lipid metabolism/profile; morning 
fasting total cholesterol, triglycerides, HDL and LDL; 
 All other safety hematology, biochemical parameters 
and urinalysis; 
 Physical examination; 
 Fundoscopy results - if performed (normal/abnormal); 
 Vital signs; 
 ECG. 
Auxology/Clinical Endpoints 
 Annual HV in cm/year at each 12-month interval. 
 Change in height SDS every 12 months (compared to 
the previous values).  
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 Change in bone maturation (BM) every 12 months, 
(compared to Week 52 BA (calculated as BA/CA) at 
completion of OLE year 1 and to previous values from 
OLE year 2 onwards). 
Biochemical Endpoints 
 
 IGF-1 SDS levels on day 4 (-1) after 
MOD-4023 dosing across study visits.  
The assessment of safety and efficacy (auxology/clinical and 
biochemical endpoints) during the OLE will be based on 
descriptive statistics and summarized by patient’s treatment in the 
treatment period and overall. No hypothesis testing will be 
performed. The descriptive statistics will include means, standard 
deviations, quartiles/ranges for continuous variables, and counts 
with percentages for categorical data. 95% CI will be used to 
further describe the clinical endpoints. A separate SAP for the 
OLE will be provided. 
PATIENT DIS-
CONTINUATION 
RULES 
Specific discontinuation criteria during the OLE: 
 When the patient's annualized growth rate is ≤ 2 cm/12 
months, and Girls with a BA of ≥15 years and boys with a 
BA of ≥17 years.  
 Positive urine pregnancy test or confirmed pregnancy. In 
case of pregnancy, the study drug should be discontinued, 
and the Study MM be alerted immediately. All pregnancy 
tests used in this study, either urine or serum, must have a 
sensitivity of at least 25 mIU/mL and must be performed 
by a certified laboratory.  Pregnancy tests will also be 
done whenever one menstrual cycle is missed during 
treatment (main study and OLE) and when potential 
pregnancy is otherwise suspected and may be repeated if 
requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.  In 
the case of a positive confirmed pregnancy, the patient 
will be withdrawn from administration of investigational 
product but may remain in the study for follow up.  
 
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TABLE OF CONTENTS 
CLINICAL SUB-STUDY PROTOCOL ................................................................................1 
PROTOCOL SYNOPSIS ........................................................................................................2 
TABLE OF CONTENTS ......................................................................................................10 
GLOSSARY............................................................................................................................11 
1 
INTRODUCTION ..........................................................................................................14 
1.1 
Overview .....................................................................................................................14 
1.2 
Study Rationale ..........................................................................................................14 
1.3 
Rationale for Study Dose ...........................................................................................14 
2 
STUDY OBJECTIVE .....................................................................................................15 
3 
STUDY DESIGN ............................................................................................................16 
4 
STUDY POPULATION .................................................................................................17 
4.1 
Inclusion Criteria for the OLE Study ......................................................................17 
4.2 
Exclusion Criteria for the OLE Study .....................................................................17 
4.3 
Patient Identification .................................................................................................17 
4.4 
Removal, Replacement or Early Withdrawal of Patients from Therapy or 
Assessment ..................................................................................................................17 
4.5 
Sponsor's Termination of Study ...............................................................................18 
5 
INVESTIGATIONAL PLAN AND STUDY PROCEDURES ...................................19 
5.1 
OLE Study Procedures ..............................................................................................19 
5.1.1 OLE Rollover Period .................................................................................................19 
5.1.2 OLE Treatment – Year 1 ..........................................................................................21 
5.1.3 OLE Treatment – Year 2 until study closure ..........................................................22 
5.1.4 OLE Treatment – Annually from Year 1 until study closure/completion ............23 
5.2 
Early Discontinuation Study Visit ............................................................................23 
5.3 
Unscheduled Visit.......................................................................................................23 
5.4 
Safety Assessments and Endpoints ...........................................................................24 
5.4.1 Treatment Compliance ..............................................................................................24 
5.4.2 ECG .............................................................................................................................24 
5.4.3 Laboratory Assessments ............................................................................................24 
5.5 
PUBERTAL ASSESSMENT ....................................................................................25 
6 
INVESTIGATIONAL PRODUCT (IP) ........................................................................27 
6.1 
Identity of IP ...............................................................................................................27 
6.2 
Reference Therapy .....................................................................................................27 
6.3 
Study Drug Administration ......................................................................................27 
6.4 
Dose Modification Plan..............................................................................................28 
6.4.1 Dose Decrease .............................................................................................................29 
7 
STATISTICS ...................................................................................................................30 
7.1 
Data Analysis ..............................................................................................................30 
8 
STUDY ADMINISTRATION .......................................................................................31 
8.1 
Participating Centers .................................................................................................31 
8.2 
Study Completion.......................................................................................................31 
9 
OLE SECTIONS PERTAINING TO MAIN STUDY PROTOCOL .........................32 
APPENDIX A: STUDY FLOW CHART / SCHEDULE OF ACTIVITIES ....................34 
 
 
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GLOSSARY 
Abbreviation 
Definition 
Ab 
Antibody  
ADHD 
Attention-Deficit/Hyperactivity Disorder 
AE 
Adverse Event 
ALT 
Alanine Aminotransaminase (SGPT) 
AST 
Aspartate Transaminase (SGOT) 
BA 
Bone Age 
BM 
Bone Maturation 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CA 
Chronological Age 
CI 
Confidence Interval  
cm 
Centimeter  
CPK 
Creatinine Phosphokinase 
CS 
Clinically Significant 
day 4(-1) 
Day 3 or 4 Post-injection 
DDAVP 
Desmopressin 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
EOS 
ET 
End of Study 
Early Termination 
FDA 
Food and Drug Administration 
FSH  
Follicle-Stimulating Hormone  
FT4 
Free Thyroxine 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GH 
Growth Hormone 
GHD 
Growth Hormone Deficiency 
HbA1C 
Glycated Hemoglobin (Hemoglobin A1C) 
HCT 
Hematocrit 
HDL 
High Density Lipoproteins 
HGB 
Hemoglobin 
hGH 
Human Growth Hormone 
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Abbreviation 
Definition 
HV 
Height Velocity 
HV SDS 
Height Velocity Standard Deviation Score 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like Growth Factor-1 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISF 
Investigator’s Site File 
kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Cholesterol 
LH 
Luteinizing Hormone 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
mg 
Milligram 
mL 
Milliliter 
MM 
Medical Monitor 
ng 
Nanogram 
No. 
Number 
OLE 
Open Label Extension 
PEN 
Single patient use, multi-dose, disposable pre-filled pen containing 20 
or 50 mg/mL MOD-4023 
PI 
Principal Investigator 
QA 
Quality Assurance 
RA 
Regulatory Authority 
RBC 
Red Blood Cells 
r-hGH 
Recombinant Human Growth Hormone 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SCr 
Serum Creatinine 
SDS 
Standard Deviation Score 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t 
Time 
Tmax 
Time Of Maximum Concentration 
TSH 
Thyroid Stimulating Hormone 
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Abbreviation 
Definition 
UK 
United Kingdom 
USA 
United States of America 
WBC 
White Blood Cells 
WHO 
World Health Organization 
wk 
Week 
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1 INTRODUCTION 
1.1 
Overview 
Long term safety and efficacy of MOD-4023 has been demonstrated in an ongoing phase 2 
study in which 48 pediatric GHD patients have been treated long term since the study 
intiation in 2013. Patients who have completed 12 months treatment in the main study of CP-
4-009 will be offered to switch to once a week adminstration of MOD-4023 (from the daily 
Genotropin® group) or continue with the weekly MOD-4023.  
1.2 
Study Rationale 
Over 80% of the patients that started in the phase 2 CP-4-004 study for the treatment of 
pediatric growth hormone deficiency are in the fourth and fifth years of dosing with the 
weekly MOD-4023. Robust efficacy of MOD-4023 continues year after year and safety 
profile of MOD-4023 in the treatment of pediatric GHD patients has been unremarkable. 
Patients who enroll in the CP-4-009 study are of the similar exclusion/inclusion criteria as 
those patients who have been treated in the CP-4-004 clinical trial with MOD-4023. There is 
adequate evidence of long term efficacy and safety of weekly MOD-4023 treatment to 
support the continuation of treating pediatric GHD patients who are and would be enrolled in 
the CP-4-009 study. The proposed extension of CP-4-009 clinical trial will enable the 
collection of continuous efficacy and long term safety data of weekly treatment with MOD-
4023 in Japanese pediatric growth hormone deficiency patients.  
The second objective of this extension study is to evaluate the safety switch of daily growth 
hormone treatment to weekly MOD-4023 treatment in Japanese pediatric GHD patients. In 
the CP-4-009 study, half of the patients (estimated to be 22) are treated with daily 
Genotropin®. Data collected from patients who would be switched in this study, will provide 
information to assist endocrinologists in assessing the risk and benefit of patients who 
consider switching from current daily rhGH treatment to weekly MOD-4023.    
1.3 
Rationale for Study Dose 
In part, the extension study is to allow patients who have been treated with MOD-4023 at the 
weekly dose of 0.66 mg/kg, to continue the same treatment until the product becomes 
available in the market and to collect long term safety data.  The other objective is to offer 
patients who have been randomized to daily rhGH to be treated with weekly MOD-4023. The 
dose of 0.66 mg/kg has been demonstrated to be safe and effective in the CP-4-004 clinical 
trial in pediatric GHD patients for over four years, including switches from daily Genotropin® 
injection to 0.66 mg/kg/week in 11 patients. As well this dose is being used in a multi-
national pediatric study CP-4-006 which was initiated in April 2017. 
 
 
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2 STUDY OBJECTIVE 
To demonstrate the safe switch of patients who have completed 12 months treatment with 
daily Genotropin® to weekly MOD-4023, and to document long term safety and efficacy of 
weekly MOD-4023 treatment in an open-label extension (OLE). 
 
 
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3 STUDY DESIGN 
The study will consist of a single-arm, open-label extension (OLE) study with weekly MOD-
4023 injections.  
Patients who have successfully completed 12 months of treatment in study CP-4-009 and 
meet the OLE inclusion/exclusion criteria of this protocol will be eligible to rollover into this 
OLE study. Patients who received Genotropin® for 12 months during the main study CP-4-
009, will be switched to receive a dose of 0.66 mg/kg/week of MOD-4023 (no less than one 
day after cessation of Genotropin® treatment).  Patients who received MOD-4023 for 12 
months during the main study will continue in the OLE with the same dose (mg/kg/wk) of 
MOD-4023.  
During the OLE study, MOD-4023 dose will be adjusted based on the patients’ body weight 
every three months. The dose may be decreased or maintained for safety reasons according to 
the pre-defined dose-adjustment criteria (based on the severity of adverse events (AEs) or 
repeated, elevated levels of insulin-like growth factor-1 (IGF-1) standard deviation score 
(SDS). During the OLE dose reduction for IGF-1 level >+2.0 SDS will be made following 
consultation with the Study MM on an individual patient basis  
The key safety data will be reviewed by an independent Data Safety Monitoring Board 
(DSMB) once every 6 months. 
The study will be conducted, subject to Sponsor, Regulatory Authority and IRB approvals. 
Study drug will be available until study discontinuation or marketing approval.  
 
 
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4 STUDY POPULATION 
Pediatric GHD patients who completed the 12 months of treatment in accordance with the 
CP-4-009 main study are eligible to enter into this open label extension study.  
4.1 
Inclusion Criteria for the OLE Study 
Patients must meet all inclusion criteria to be eligible for this study: 
1. Completion of the main study (12 months of treatment) with adequate compliance and 
adherence to the visit schedule and without major protocol deviation according to the 
main study protocol.  
2. Willing and able to provide written informed consent of the parent or legal guardian 
of the patient and written assent from pediatric patients.  
4.2 
Exclusion Criteria for the OLE Study 
1. Concomitant administration of other treatments that may have an effect on growth 
such as anabolic steroids, or sex steroids (other than for hormonal replacement), with 
the exception of Attention-Deficit/Hyperactivity Disorder (ADHD) drugs or hormone 
replacement therapies (thyroxin, hydrocortisone, testosterone, estrogen/progesterone, 
desmopressin [DDAVP®]). 
2. Change in medical condition during the treatment period (such as, but not limited to, 
occurrence of a malignancy during the course of study, development of a serious 
inter-current critical illness, a severe adverse drug reaction, etc.). 
3. Unresolved drug related (MOD-4023 or Genotropin®) SAE from the study CP-4-009 
as per Global Study MM judgement. 
4.3 
Patient Identification  
The unique identification number assigned during the main study will continue to be used in 
the OLE.  
4.4 Removal, Replacement or Early Withdrawal of Patients from Therapy or 
Assessment   
The patient’s participation in this OLE study may be discontinued due to the reasons 
indicated in the main study protocol Section 4.4.  Additional specific discontinuation criteria 
during the OLE are listed below: 
 When the patient's annualized growth rate is ≤ 2 cm/12 months, and Girls with a BA 
of ≥15 years and boys with a BA of ≥17 years.   
 Positive urine pregnancy test or confirmed pregnancy. In case of pregnancy, the study 
drug should be discontinued, and the Global Study MM be alerted immediately. All 
pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory.  Pregnancy tests 
will also be done whenever one menstrual cycle is missed during treatment (main 
study and OLE) and when potential pregnancy is otherwise suspected and may be 
repeated if requested by institutional review boards (IRBs)/ethics committees (ECs) or 
if required by local regulations.  In the case of a positive confirmed pregnancy, the 
patient will be withdrawn from administration of investigational product but may 
remain in the study for follow up.  
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4.5 
Sponsor's Termination of Study  
The Sponsor reserves the right to discontinue the study at any time for any reason. 
Regulatory Authorities also have the right to recommend to terminate the study. 
 
 
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5 INVESTIGATIONAL PLAN AND STUDY PROCEDURES 
A schedule of activities for this study is shown in Appendix A of this OLE protocol. No OLE 
protocol related procedures, including the cessation of prohibited concomitant medications 
should be performed before patients provide writtena assent (where applicable) and consent 
from the parent(s) or legal guardian(s) is obtained. 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/or 
eCRF.  
5.1 
OLE Study Procedures  
Visit 10 – EOS Visit (Month 13/Wk 56 (+1 week)) – Only for patients not continuing on into 
the OLE study. 
Patients not continuing in the OLE study will be contacted 4 weeks (+ 1 week) after Visit 9 
(inclusive of 9.1) in order to obtain safety related information (see questionnaire in Appendix 
I of the main study protocol). 
OLE ROLLOVER PERIOD 
After successful completion of 12 months of treatment in the CP-4-009 main study and 
meeting the OLE inclusion/exclusion criteria of this protocol, and upon receipt of necessary 
Regulatory and IRB approvals, patients will be eligible to rollover into the OLE study with 
MOD-4023 treatment. An informed consent/assent will be obtained from patients and/or 
parents or legal/authorized guardian for this extension study.  
Patients who do not qualify to continue in the trial or who are not interested in continuing 
into the OLE should complete the End of Treatment Visit, which is equivalent to visit 9/9.1, 
and should complete a phone interview for visit 10 within 4 weeks (+1 week) to complete 
End of Study Assessments according to the CP-4-009 main study protocol schedule of 
activities.  
Patients who received MOD-4023 during the main CP-4-009 study will continue in the OLE 
with the same dose (mg/kg/week) of MOD-4023, adjusted for body weight. For these 
patients, study visits will take place every three months on day 4 (-1 day) post-dose.  Pre-dose 
assessments will be taken at month 6 and month 12 during the first year. These patients will 
consent to the OLE preferably during Visit 8 (week 39) of the main study to ensure 
availability of MOD-4023 at their first visit of the OLE study.  If necessary, informed consent 
can be obtained at main study Visit 9/9.1/OLE Visit 9.2 (week 52/OLE Baseline). MOD-
4023 patients will continue treatment and receive study drug at OLE Visit 9.2, skip Visit 10 
(close out or end of trial) main study, and have a phone interview at OLE Visits 11, 12, and 
13 as described in the schedule of activities. Visits will occur every 3 months thereafter 
beginning at Visit 14. All patients will be provided with a patient diary throughout the trial as 
described in the Schedule of Activities. 
Patients who received Genotropin® during the CP-4-009 main study will complete the main 
study assessments and will be switched to MOD-4023 at Visit 9. Dosing of MOD-4023 
treatment at 0.66 mg/kg/week will begin 1 day after cessation of Genotropin® treatment (at 
Visit 9/OLE Visit 9.2). Patients should start MOD-4023 one day after cessation and no more 
than 2 weeks after cessation of Genotropin®. These patients will consent to the OLE 
preferably during Visit 8 of the main study to ensure availability of MOD-4023 at their first 
                                                 
a Illiterate patients should provide their consent in a method that is accepted according to local regulations.   
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visit of OLE study (Visit 9/OLE Visit 9.2). Patients will skip visit 10 (close out or end of trial 
of the main study) and have additional onsite subsequent visits at Visit 11 (Month 12.5, Day 
10 post first MOD-4023 dose [10+4 days]), Visit 12 (1 month post first MOD-4023 dose 
(Month 1 [±1wk]), and Visit 14 (Month 3 [±1wk]). A phone interview will occur at OLE 
Visit 13 (Month 2 [±1wk]). Visits will occur every three months thereafter, until study 
closure.  All patients will be provided with a patient diary throughout the trial as described in 
the Schedule of Activities. 
For all patients switching from Genotropin® to MOD-4023, drug will be dispensed and the 
following assessments will be performed at OLE Visit 9.2: 
 MOD-4023 and associated diaries will be dispensed based on patient weight at a 
starting dose of 0.66 mg/kg/wk. 
 Training on and administration of MOD-4023 using the pen device and diary 
completion. 
 Local tolerability after first dose administered at site.  
 Urine pregnancy test at every visit once a female patient reports first menstrual cycle 
(menarche).  
Patients who experience a delay for any reason between completion of the main study and 
entry into the OLE may have to temporarily stop treatment. If initiation/re-initiation of 
treatment occurs less than 90 days after Visit 9, only training on and administration of MOD-
4023 and local tolerability after first dose administered at site is required.   
Patients who are off treatment for more than 90 days due to technical reasons e.g. delay in 
approval of Protocol Amendment may be allowed to continue into the OLE after 
confirmation of availability of all required baseline OLE assessments (Visit 9). In addition to 
the onsite training, dose administration of MOD-4023, and local tolerability assessment, the 
following tests and assessments below must be repeated at the time of the unscheduled visit 
at the site: 
 
Overall health status assessment, including complete physical examination and 
vital sign assessments. 
 
Safety laboratory tests: chemistry, hematology and urinalysis. 
 
Parameters of glucose metabolism: morning fasting glucose, morning fasting 
insulin, HbA1c. 
 
Assessment of thyroid: TSH, FT4. 
 
Parameters of lipid metabolism: morning fasting total cholesterol, LDL, 
triglycerides, and HDL. 
 
Assessment of anti-MOD-4023 Ab for all patients . 
 
Assessment of biochemical markers: 
 IGF-1 SDS. 
 
Urine pregnancy test at every visit once a female patient reports first menstrual 
cycle (menarche).  
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OLE TREATMENT – YEAR 1 
During the first year of OLE treatment, the following assessments will be conducted on Day 
4 (-1 day) post dose during onsite visits for patients making the switch from Genotropin® to 
MOD-4023 (Visits 11 – 12):  
 
Safety laboratory tests: chemistry, hematology, and urinalysis (only Visit 12) 
 
Overall health status assessment, including complete physical examination and 
vital signs assessment  
 
AEs, local tolerability, and concomitant medications. 
 
Urine pregnancy test at every visit once a female patient reports first menstrual 
cycle (menarche).  
 
Assessment of biochemical markers: 
 calculate the related  
IGF-1 SDS (only Visit 12) 
 
 
 
Assessment of anti-MOD-4023 Ab. 
 
Fundoscopy (if there are signs or symptoms indicative of benign intracranial 
hypertension). 
 
Dispense study drug and patient diary (only Visit 12).a 
 
Patient diary review, study drug return & accountability (only Visit 12). 
For patients making the switch from Genotropin® to MOD-4023, a phone interview will be 
conducted at Visit 13. 
Existing MOD-4023 patients will have a phone interview at Visits 11, 12, and 13 as indicated 
in the schedule of activities to ask about AEs and concomitant medications. These visits will 
be completed using the questionnaire in Appendix I of the main study protocol.  
The following assessments will be conducted on day 4 (-1 day) post-dose for all patients 
during the first year of OLE treatment at months three (Visit 14), six (Visit 15), nine (Visit 
16), and twelve (Visit 17): 
 
Pre-dose assessment of MOD-4023 serum levels and anti-MOD-4023 Ab (Visit 15 and 
Visit 17 only). 
 
Safety laboratory tests: chemistry, hematology, and urinalysis 
 
Auxology measurements: Height (average of 3 consecutive measurements) and 
body weight measurements (see Appendix E in the main protocol for height 
instructions) 
 
Overall health status assessment, including complete physical examination and 
vital signs assessment  
 
Individual dose adjustment based on weight  
 
AEs, local tolerability, and concomitant medications. 
                                                 
a Patient Diary will be re-issued for further completion. 
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 
Urine pregnancy test at every visit once a female patient reports first menstrual 
cycle (menarche).  
 
Assessment of biochemical markers: 
 calculate the related  
IGF-1 SDS  
 
 
 
Post-dose assessment of anti-MOD-4023 Ab (Visit 14 and Visit 16 only). 
 
Fundoscopy (if there are signs or symptoms indicative of benign intracranial 
hypertension). 
 
Dispense study drug and patient diary. 
 
Patient diary review, study drug return & accountability. 
 
Assessment of thyroid function: TSH, FT4 (except Visit 16). 
 
Parameters of glucose metabolism: morning fasting glucose, morning fasting 
insulin, HbA1c (except Visit 16). 
 
Parameters of lipid metabolism: morning fasting cholesterol, triglycerides, high 
density lipoprotein (HDL), and low density lipoprotein (LDL) (except Visit 16).  
OLE TREATMENT – YEAR 2 UNTIL STUDY CLOSURE 
Following completion of the first year of OLE treatment the following assessments will be 
conducted for all patients on day 4 (-1 day) post-dose every three months:   
 
Auxology measurements: Height and body weight measurements. 
 
Overall health status assessment, including complete physical examination and 
vital signs assessment. 
 
Individual dose adjustment based on weight. 
 
AEs, local tolerability, and concomitant medications. 
 
Urine pregnancy test at every visit once a female patient reports first menstrual 
cycle (menarche).  
 
Fundoscopy (if there are signs or symptoms indicative of benign intracranial 
hypertension). 
 
Dispense study drug and patient diary. 
 
Patient diary review, study drug return & accountability. 
The following assessments will be conducted for all patients on day 4 (-1 day) post-dose 
every six months: 
 
Assessment of biochemical markers: 
 related  IGF-1 SDS 
calculation  
 
Safety laboratory tests: chemistry, hematology and urinalysis.  
 
Assessment of thyroid function: TSH, FT4. 
 
Parameters of glucose metabolism: morning fasting glucose, morning fasting 
insulin, HbA1c.  
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 
Parameters of lipid metabolism: morning fasting cholesterol, triglycerides, HDL, 
and LDL.  
 
Assessment of MOD-4023 serum levels. 
 
Assessment of anti-MOD-4023 Ab. 
OLE TREATMENT – ANNUALLY FROM YEAR 1 UNTIL STUDY CLOSURE/COMPLETION  
Additional assessments will be performed once a year, on day 4 (or -1 day) post-dose at 
month 12 (OLE Visit 17) and Year 2 onward: 
 
ECG 
 
Bone age 
 
Pubertal status (according to Tanner stages)  
 
For males that are 13 years and older: LH, FSH and testosterone will be analyzed. 
For females that are 12 years and older: LH, FSH and estradiol will be analyzed 
(from OLE treatment year 2 until study closure). 
 
Pre-dose and post-dose assessment of MOD-4023 serum levels annually 
 
Pre-dose assessment  of Abs to MOD-4023 annually 
Year 1 (including end of study (EOS) during year 1): ECG should be conducted around the 
time of maximum concentration (Tmax) (7-12 hours post-dose). For the ECG that will be 
conducted at 7-12 hours post-dose patients will be requested to inject MOD-4023 during the 
day/night at their convenience and come to the study site at the requested timepoint for the 
ECG. Visits may be split to allow for pre-dose blood collection for serum levels and antibody 
tests and post-dose ECG or the patient will be asked to come to the study site for blood 
collection, administer the required dose, and return to the study site 7-12 hours post-dose. An 
ECG must still be obtained even if patients do not take the final dose. 
For EOS from OLE Year 2 onwards ECG can be conducted without a timeframe requirement 
i.e. at any time, although the date and time that each is performed will be recorded.   
Patients will be contacted by telephone 4 weeks [± 1 week] after EOS/ET visit in order to obtain 
safety related information (local tolerability, AEs, prior and concomitant medications). 
5.2 
Early Discontinuation Study Visit 
If, during the OLE, a patient discontinues prematurely from the study for the reasons 
specified in Section 4.4, the same procedures for OLE End of Study (EOS)/ET will be 
conducted.  
5.3 
Unscheduled Visit 
An unscheduled visit may be performed at any time during the study at the patient's request 
or as deemed necessary by the Investigator or requested by the Global Study MM. The date 
and reason for the unscheduled visit will be recorded. AE monitoring and concomitant 
medication recording will be performed by the Investigator. Other procedures and evaluations 
will be completed as deemed necessary by the Investigator and may include (but not limited 
to) laboratory tests, ECG, vital signs and physical examination. 
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5.4 
Safety Assessments and Endpoints  
Safety assessments will be based on changes from baseline of clinical AEs (including local 
tolerability, i.e. injection site reaction) reported by the patient or observed by the investigator, 
concomitant medication use, treatment compliance, vital signs, ECG, physical examination, 
fundoscopy and laboratory assessments (hematology, blood chemistry, glucose metabolism, 
lipid metabolism, thyroid function, 
, immunogenicity and urinalysis). AEs and 
concomitant medication use will be assessed at every visit. Adverse events that meet the 
definition of a serious adverse event (SAE) must be reported within 24 hours of awareness to 
the sponsor and designee.  SAE evaluation and reporting is detailed in the main study 
protocol (section 7.2). Physical examination and safety laboratory assessments will be 
performed according to the schedule of activities in Appendix A.   
TREATMENT COMPLIANCE 
OLE Study drug return accountability and patient diary will be reviewed at each visit for 
treatment compliance from previous visits (except scheduled telephone visits). 
ECG 
During the OLE, ECG (preferably 12-lead) will be performed annually every 12 months until 
study closure. 
Year 1 (including end of study (EOS) during year 1): ECG should be conducted around the 
time of maximum concentration (Tmax) (7-12 hours post-dose). For the ECG that will be 
conducted at 7-12 hours post-dose patients will be requested to inject MOD-4023 during the 
day/night at their convenience and come to the study site at the requested timepoint for the 
ECG. Visits may be split to allow for pre-dose blood collection for serum levels and antibody 
tests and post-dose ECG or the patient will be asked to come to the study site for blood 
collection, administer the required dose, and return to the study site 7-12 hours post-dose. An 
ECG must still be obtained even if patients do not take the final dose. 
For EOS from OLE Year 2 onwards ECG can be conducted without a timeframe requirement 
i.e. at any time, although the date and time that each is performed will be recorded.   
Initially ECG output will be evaluated by the Investigator at time of performance (signed and 
dated) and the printout (including photocopy) should be kept in the patient’s medical file. 
When potentially CS findings are detected by the investigator, a cardiologist should be 
consulted for a definitive interpretation. All communications and diagnoses should be filed in 
the patient’s medical file. 
The final determination of whether the ECG findings are of CS to the patient rests with the PI 
and reported as normal /abnormal in the eCRF. 
LABORATORY ASSESSMENTS  
All routine clinical laboratory assessments will be performed by local central laboratory (LSI 
Medience Corporation) according to the schedule in Appendix A of this OLE protocol. The 
laboratory evaluations will include: 
1. Hematology: Red Blood Cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), 
Mean Cell Hemoglobin (MCH), Mean Cell Hemoglobin Concentration (MCHC), 
Mean Corpuscular Volume (MCV), White Blood Cell (WBC) count and differential, 
platelet count. 
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2. Serum biochemistry: glucose,  total protein, albumin, total bilirubin, ALT (SGPT), 
AST (SGOT), GGT, LDH, CPK, alkaline phosphatase, sodium, potassium, calcium, 
phosphate, BUN, creatinine. 
3. Urinalysis: pH, glucose, ketones, erythrocytes, leukocytes, protein. 
4. Lipid metabolism: morning fasting cholesterol, LDL, triglycerides, and HDL. 
5. Glucose metabolism: morning fasting glucose (will be tested as part of biochemistry 
panel), fasting insulin and HbA1C. 
6. Assessment of thyroid: TSH, FT4. 
7. Immunogenicity (will be performed by Intertek, San Diego): antibodies to MOD-4023 
for all patients during the OLE.  
8. 
 for all patients during the OLE. 
9. 
 for all patients during the OLE (will be performed by 
Intertek, San Diego). 
10. Urine pregnancy test.  
11. Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) and testosterone (for 
males that are 13 years and older). 
12. LH, FSH and estradiol (for females that are 12 years and older). 
For further details on blood sample collection and shipment to the central laboratory, please 
refer to the Central Laboratory Manual. 
5.5 
PUBERTAL ASSESSMENT  
Patients may enter puberty during the course of the study and contraception might become 
relevant. The puberty state is evaluated on routine basis as described above.  Once a female 
patient reports first menstrual cycle (menarche) study sites should perform urine pregnancy 
test at every visit. 
For a female child, even though she is pre-pubertal at enrollment, 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 investigator or delegated 
study staff is obligated to discuss this issue ahead of time with the patient and her 
parents/legal guardian.  Patients must refrain from sexual activity during the study i.e. 
observe complete sexual abstinence as the only acceptable contraceptive measure in this 
study. 
If a patient were to become pregnant or thinks she may have become pregnant during the 
study, the Investigator 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 
two weeks to confirm or exclude the pregnancy.  
In case of negative test results confirmed by the second negative test result, based on the 
Investigator’s recommendation, the Sponsor may allow the patient to return to the full study 
schedule with guidance from Sponsor, if applicable, or the patient will be offered to remain in 
the study without study medication, but to complete the remaining study procedures as 
scheduled (missed visits are recommended to be realized).  
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All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at least 
25 mIU/mL and must be performed by a certified laboratory.  Pregnancy tests will also be 
done whenever one menstrual cycle is missed during treatment and when potential pregnancy 
is otherwise suspected and may be repeated if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations.  In the case of a positive 
confirmed pregnancy, the patient will be withdrawn from administration of investigational 
product but may remain in the study for follow up.  
The pregnancy must be reported to the Global Study MM, pharmacovigilance and Sponsor.  
A follow-up period on mother and child will be defined based on individual basis and per 
discussion with DSMB.  
Male patients  
The effect of MOD-4023 on sperm is not known.  
The Investigator is obligated to discuss this issue of possible conception ahead of time with 
male patients and his parents/legal guardian. Patients 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, the Investigator should be informed 
immediately. The patient doesn’t need stop taking the study medication. The pregnancy will 
be reported to the Global Study MM, pharmacovigilance and Sponsor and follow-up period 
on mother and child will be defined based on individual basis and per discussion with DSMB. 
 
 
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6 INVESTIGATIONAL PRODUCT (IP)  
6.1 
Identity of IP 
MOD-4023 is a long-acting modified r-hGH which utilizes CTP technology. MOD-4023 will 
be provided as a solution for injection containing 20 or 50 mg/mL MOD-4023 in a multi-dose 
disposable pre-filled PEN.  
The formulation will include 
 
   
6.2 
Reference Therapy 
Genotropin® is a daily GH, which will be used as the reference therapy during the main 
study, but not used in the OLE study. No additional dosing with Genotropin® is allowed after 
the patient completes the main study Visit 9 and should be switched to MOD-4023 according 
to this protocol. If the patient wishes to continue on Genotropin® after the main study is 
completed, they will not be allowed to participate in the OLE study.  
6.3 
Study Drug Administration 
MOD-4023 will be administered as a SC injection 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 1).   
Figure 1 
Recommended rotation of injection sites for MOD-4023 
 
 
The starting MOD-4023 dose for the administration will be 0.66 mg/kg/wk. All patients on 
Genotropin® that complete the main study and continue into the OLE will start treatment with 
MOD-4023 at 0.66 mg/kg/wk.  
If a patient misses the weekly scheduled dose of MOD-4023, the patient should inject the 
dose as soon as possible as long as it is less than or equal to 72 hours from the time of the 
patient’s usual injection. If more than 72 hours have passed, then the patient should skip the 
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injection. In either case, the patient should return to the regular injection 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: three to 
four days post dosing, in case 
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 for a single injection on a PEN, the patient 
should be instructed how to split the dose into 2 injections. The partial dosing can occur in 2 
cases: 
1. Split dose from the same PEN:  This may occur when the prescribed dose exceeds 
the maximum dose which can be selected according to the PEN amount.  The 
maximum dose per injection for the MOD-4023 24 mg pen is 12 mg and the 
maximum dose injection for the MOD-4023 60 mg pen is 30 mg.  The patient’s 
first injection would be the maximum dose and the second injection would be the 
remaining dose of the full prescribed dose. 
For example, if the full prescribed dose is 33.5 mg and the PEN only allows the 
dose selector to be set to 30.0 mg, the patient should inject another 3.5 mg using 
the same PEN. 
2. Split dose from 2 PENS (the current PEN and a new PEN):  This may occur when 
the amount of medication remaining in the pen is not sufficient for the full 
prescribed dose. 
For example, if the full prescribed dose is 25.0 mg and the volume left in the 
current PEN is 20.5 mg, the patient should inject another 4.5 mg from the new 
PEN. 
It is recommended to encourage the patients to use a calculator to plan the doses and to 
calculate the dose that should be adjusted for the second injection. 
It is very important that for the second injection, whether from the same PEN or from a new 
PEN, the patient replaces the needle and rotates the injection site and completes the patient 
diary for each of the 2 injections administered.  When the second injection is from a new 
PEN the new pen must be primed accordingly to the Instructions for Use provided. 
Further details are provided in the Patient Diary. 
Missed, delayed, or split doses should be reported in the Patient Diary and the appropriate 
eCRF. 
6.4 
Dose Modification Plan 
The dose of MOD-4023 will be assessed every 3 months and adjusted based on patient’s 
body weight. Doses will be calculated by the Electronic Data Capture (EDC) system and will 
be rounded – either up or down – to the closest PEN increment (0.2 mg increments in 
20 mg/mL pens and 0.5 mg increments in 50 mg/mL pens). 
Doses may be decreased for safety reasons (which will be based on the severity of AEs or 
repeated, elevated levels of IGF-1 SDS).  
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DOSE DECREASE 
For patients on MOD-4023, the dose will be decreased based on two, repeated day 4 (-1) 
levels of IGF-1 > +2.0 SDS.  
During the OLE dose reduction for IGF-1 level >+2.0 SDS will be made following 
consultation with the Study MM on an individual patient basis.  
If AEs are defined as “severe” AND drug-related, dose reduction will be initiated upon 
discussion with the Study MM and DSMB. 
Every attempt should be made to maintain the patient on the originally allocated dose if 
possible. In case the investigator does not plan to decrease the dose as described in the 
protocol, the Study MM should be consulted. 
The key safety data will be reviewed by an independent and external DSMB approximately 
every 6 months during the OLE. The DSMB will also include review of number or 
percentage of patients requiring dose reductions due to IGF-1 > +2.0 SDS and number or 
percentage of patients whose IGF-1 remains > +2.0 SDS. DSMB review will also include 
review of number or percentage of patients requiring dose reductions due to AEs. 
 
 
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7 STATISTICS 
7.1 
Data Analysis 
Safety Endpoints 
 Incidence of AEs and SAEs; 
 Incidence of anti-MOD-4023 Ab formation (including characterization of the Ab 
and neutralizing properties); 
 Local injection site reaction assessment; 
 Parameters of glucose metabolism: morning blood fasting glucose, fasting insulin 
level, HbA1c; 
 Thyroid (endocrinology) status; 
 Parameters of lipid metabolism/profile; morning fasting total cholesterol, 
triglycerides, HDL and LDL; 
 All other safety hematology, biochemical parameters and urinalysis; 
 Physical examination; 
 Fundoscopy results - if performed (normal/abnormal); 
 Vital signs; 
 ECG. 
Auxology/Clinical Endpoints 
 Annual HV in cm/year at each 12-month interval. 
 Change in height SDS every 12 months (compared to the previous values).  
 Change in bone maturation (BM) every 12 months, (compared to Week 52 BA 
(calculated as BA/CA) at completion of OLE year 1 and to previous values from 
OLE year 2 onwards). 
Biochemical Endpoints 
 
 IGF-1 SDS levels on day 4 (-1) after MOD-4023 dosing across study 
visits.  
The assessment of safety and efficacy (auxology/clinical and biochemical endpoints) during 
the OLE will be based on descriptive statistics and summarized by patient’s treatment in the 
treatment period and overall. No hypothesis testing will be performed. The descriptive 
statistics will include means, standard deviations, quartiles/ranges for continuous variables, 
and counts with percentages for categorical data. 95% CI will be used to further describe the 
clinical endpoints. A separate SAP for the OLE will be provided. 
 
 
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8 STUDY ADMINISTRATION 
8.1 
Participating Centers 
Approximately 25-35 sites will participate in the OLE study. A list of all participating sites 
will be kept in the electronic study master file.   
8.2 
Study Completion 
The goal for the OLE study is for every patient to complete the first year of the OLE (a 
completion of 24 months on IP).  The OLE study will continue until product approval, to 
collect additional safety and efficacy information.  Study completion will be defined when 
regulatory approval and post-marketing data collection is defined or if the sponsor decides to 
terminate the study early.  
 
 
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9 OLE SECTIONS PERTAINING TO MAIN STUDY PROTOCOL  
The OLE phase of the study is a continuation of the main study with patients rolling into the 
OLE with no or minimum interruption of treatment. This protocol serves to describe the 
purpose, treatment criteria, and procedures specifically for the OLE phase of the clinical trial. 
The below sections and Appendix of the main study continue to be relevant to the OLE as 
they are considered to have the same information for both the main study and the OLE study.  
Please reference the main study protocol for more information on the sections below.   
 Section 1.1 Growth Hormone Deficiency 
 Section 1.2 Current Therapy  
 Section 1.3 – Investigational Therapy 
o 1.3.1 – Clinical Studies (only) 
 Section 5.3 Efficacy Assessments and Endpoints 
 Section 5.5 Safety Assessments and Endpoints 
o 5.5.1 – AEs 
o 5.5.2 – Local Injection Site Reactions 
o 5.5.3 – Concomitant Medication Use 
o 5.5.5 – Vital Signs 
o 5.5.6 – Physical Examination 
o 5.5.8 – Fundoscopy 
 Section 6.5 Shipment and Storage Condition of Investigational Product 
 Section 6.6 Accountability and Compliance of Investigational Product 
 Section 6.7 Prior and Concomitant Therapy 
 Section 7.0 Safety and Pharmacovigilance  
 Section 7.1 Adverse Event 
 Section 7.2 Serious Adverse Event 
 Section 7.3 Definition of an Unexpected AE 
 Section 7.4 Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 Section 7.5 Notification about Serious or Unexpected AEs 
 Section 7.6 Independent DSMB 
 Section 7.7 Medication Errors 
 Section 7.8 Medical Device Complaint  
 Section 8.6 Efficacy Analysis  
 Section 9.0 Ethics 
 Section 9.1 IRB 
 Section 9.2 Ethical Conduct of the Study 
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 Section 9.3 Protocol Revisions and/or Deviations 
 Section 9.4 Patient Information and Consent 
 Section 9.5 Patient Insurance 
 Section 9.6 Informing the General Practitioner 
 Section 9.7 Personal Data Protection  
 Section 10.0 Quality Control and Quality Assurance 
 Section 10.1 Audits and Inspections 
 Section 10.2 Study Monitoring  
 Section 10.3 Quality Laboratory Standards  
 Section 10.4 Data Management 
 Section 11.0 Study Administration 
 Section 11.2 Clinical Study Supplies 
 Section 11.3 ISF 
 Section 11.5 Final Report 
 Section 11.6 Retention of Study Records 
 Section 11.7 Confidentiality and Publication  
 Section 12.0 References  
 Appendix E: Instructions for Obtaining Height Measurements  
 Appendix F: Instructions for Obtaining X-Ray Films 
 Appendix G: Injection Site Assessment Table (Local Reactions) and Pain Assessment 
 Appendix H: Declaration of Helsinki (2013) 
 Appendix I: Phone Interview 
 Appendix J: Clinically Comparable Doses of Inhaled Corticosteroids  
 
 
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SAP_001.pdf: 
Version: OPKO-CP-4-009-SAP-v3.0.docx 
 
STATISTICAL ANALYSIS PLAN 
Version 3.0 
19 May 2020 
 
 
 
Protocol: CP-4-009 
 
A Phase 3, Open-Label, Randomized, Multicenter, 12 Months, Efficacy 
and Safety Study of Weekly MOD-4023 Compared to Daily 
Genotropin® Therapy in Japanese Pre-Pubertal Children with Growth 
Hormone Deficiency 
 
 
OPKO Health Inc. 
4400 Biscayne Boulevard 
Miami, FL 33137, USA 
 
 
PREPARED BY 
 
Pfizer R&D Japan 
Shinjuku Bunak Quint Bldg. 
3-22-7, Yoyogi, Shibuya-ku Tokyo 151-8589 Japan 
 
 
 
 
 
 
This document is confidential and proprietary to OPKO Health Inc. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be reproduced, published, 
or otherwise disclosed without the prior written approval of OPKO Health Inc.  


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Statistical Analysis Plan 
Protocol No. CP-4-009 
 
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Version: OPKO-CP-4-009-SAP-v3.0.docx 
 
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DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
1.0 
2018-03-27 
Initial version 
2.0 
2020-04-08 
4.2 
Full Analysis Set 
Full Analysis Set definition was updated. 
 
5.1 
Disposition of Subjects 
Summary of the number of subjects prematurely discontinuing 
treatment was removed. 
 
6.1 
Demographics and Baseline Characteristics 
Bone maturation was added. 
Height Velocity was changed to Height SDS. 
 
8.1.1 
Handling of Dropouts or Missing Data 
Handling of missing data for the primary analysis was changed to 
multiple imputation (MI) from carrying the last non-missing 
height value forward (LHCF) on the assumption of missing not at 
random (MNAR). 
 
8.1.3 
Assessment Time Windows 
Unscheduled assessments within the visit window were not 
selected for analysis. 
 
8.3 
Analysis Methods 
95% CIs were added in Table 8-1. 
 
8.3.1 
Primary Efficacy Analyses 
Descriptive statistics of observed annual HV values at 12 months 
by ADA status was added. 
 
8.3.2 
Secondary Efficacy Analyses 
Univariate 95% CI was included in descriptive statistics for BM 
observed and change from baseline at 12 months. 
 
8.3.3 
Primary Efficacy Sensitivity Analysis 
The tipping point approach was removed. 


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The similar analysis to the ANCOVA-based primary efficacy 
analysis, but using the different missing imputation method,  
were added. 
The similar analysis to the ANCOVA-based primary efficacy 
analysis, but including different covariates, were added. 
 
8.3.4 
Biochemical Markers Analysis 
Descriptive statistics of 
 by ADA status was added. 
 
9.2 
Adverse Events 
Summary of TEAEs by SOC and PT and by ADA status was 
added. 
 
9.3 
Serious Adverse Events and Other Significant Adverse 
Events 
Summary of TEAEs by subject was added. 
Summary of severe TEAEs was added. 
Summary of TEAEs resulting in death was removed. 
Summaries of TEAEs of special interests were added. 
 
9.4 
Injection Site Reactions and Pain 
Summary of ISR by ADA status was added. 
Summaries of pain scores, ISR erythema/redness, bruising, and 
induration/swelling with number of injections as the 
denominator, where every injection are counted and summarized 
were removed. 
Summaries of pain scores, ISR erythema/redness, bruising, and 
induration/swelling with number of subjects with ISR as the 
denominator were added. 
 
9.6.3.5 Hypersensitivity 
Summary of Hypersensitivity by ADA status was added. 
 
 
12. 
CHANGES TO THE ANALYSES PLANNED IN THE 
PROTOCOL 
Changes described in the Protocol CP-4-009 Administrative 
Change Letter #2 to Version 9.0 of the Protocol were shown. 
 
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Discrepancies eliminated and typographical errors corrected. 
3.0 
2020-05-19 
6.1 
Demographics and Baseline Characteristics 
Handlings of peak GH was specified for continuous variable. 
8.3.3 
Primary Efficacy Sensitivity Analysis 
Condition was added for the 3rd sensitivity analysis. 






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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 8 
1. 
PURPOSE OF THE ANALYSES ............................................................................ 10 
2. 
PROTOCOL SUMMARY ........................................................................................ 11 
2.1 
Study Objectives ......................................................................................... 11 
2.1.1 
Primary Objective .............................................................................. 11 
2.1.2 
Secondary Objectives ........................................................................ 11 
2.2 
Study Endpoints .......................................................................................... 11 
2.2.1 
Primary Endpoint ............................................................................... 11 
2.2.2 
Secondary Endpoints ......................................................................... 11 
2.2.3 
Safety Endpoints ................................................................................ 11 
2.3 
Study Design .............................................................................................. 12 
2.4 
Study Population ......................................................................................... 13 
2.5 
Treatment Regimens................................................................................... 13 
2.5.1 
Reference Therapy Dosing Regimen ................................................. 13 
2.5.2 
Investigational Product Dosing Regimen:........................................... 13 
2.6 
Treatment Group Assignments ................................................................... 14 
2.7 
Sample Size Determination ......................................................................... 14 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 15 
4. 
ANALYSIS SETS ................................................................................................... 17 
4.1 
Safety Analysis Set ..................................................................................... 17 
4.2 
Full Analysis Set ......................................................................................... 17 
4.3 
Per Protocol Set .......................................................................................... 17 
5. 
STUDY SUBJECTS ............................................................................................... 18 
5.1 
Disposition of Subjects ................................................................................ 18 
5.2 
Protocol Deviations ..................................................................................... 18 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 19 
6.1 
Demographics and Baseline Characteristics ............................................... 19 
6.2 
Medical History ........................................................................................... 19 
6.3 
Prior and Concomitant Medications ............................................................. 19 
6.3.1 
Prior Medications ............................................................................... 20 
6.3.2 
Concomitant Medications ................................................................... 20 
6.3.3 
Prohibited Concomitant Medications .................................................. 20 
7. 
EXTENT OF INVESTIGATIONAL PRODUCT EXPOSURE ................................... 21 
8. 
EFFICACY EVALUATION ..................................................................................... 22 
8.1 
Overview of Efficacy Analysis Issues .......................................................... 22 
8.1.1 
Handling of Dropouts or Missing Data ................................................ 22 
8.1.2 
Multicenter Studies ............................................................................ 22 
8.1.3 
Assessment Time Windows ............................................................... 22 
8.2 
Efficacy Variables ....................................................................................... 22 
8.2.1 
Primary Efficay Endpoint .................................................................... 22 
8.2.2 
Secondary Efficacy Endpoints ........................................................... 23 
8.2.3 
Biochemical Markers ......................................................................... 23 
8.3 
Analysis Methods ........................................................................................ 23 
8.3.1 
Primary Efficacy Analyses ................................................................. 24 


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8.3.2 
Secondary Efficacy Analyses ............................................................. 24 
8.3.3 
Primary Efficacy Sensitivity Analysis .................................................. 25 
8.3.4 
Biochemical Markers Analysis ........................................................... 25 
9. 
SAFETY EVALUATION ......................................................................................... 26 
9.1 
Overview of Safety Analysis Methods ......................................................... 26 
9.2 
Adverse Events ........................................................................................... 26 
9.3 
Serious Adverse Events and Other Significant Adverse Events .................. 26 
9.4 
Injection Site Reactions and Pain ................................................................ 27 
9.5 
Clinical Laboratory Evaluation ..................................................................... 27 
9.6 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 28 
9.6.1 
Vital Signs .......................................................................................... 28 
9.6.2 
Physical Examinations ....................................................................... 28 
9 6 3 
Other Safety Measures 
 28 
11. INTERIM ANALYSES AND DATA MONITORING ................................................. 31 
11.1 
Data Monitoring ........................................................................................... 31 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 32 
13. APPENDICES ........................................................................................................ 33 
13.1 
Schedule of Events ..................................................................................... 33 
 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BA 
Bone Age 
BLQ 
Below the Limit of Quantification 
BM 
Bone Maturation 
CA 
Chronological Age 
CI 
Confidence Interval 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eDISH 
Evaluation of Drug Induced Serious Hepatotoxicity 
GH 
Growth Hormone 
GHD 
Growth Hormone Deficiency 
hGH 
Human Growth Hormone 
HV 
Height Velocity 
 
 
IGF-1 
Insulin-like Growth Factor-1  
ISR 
Injection Site Reaction 
NCS 
Not Clinically Significant 
MedDRA 
Medical Dictionary for Regulatory Activities 
PEN 
Single subject use, multi-dose, disposable pre-filled pen 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
QTcF 
Fredericia’s Corrected QT Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
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LIST OF ABBREVIATIONS (continued) 
SD 
Standard Deviation 
SDS 
Standard Deviation Score 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
WHO DD 
World Health Organization Drug Dictionary 
 


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1. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) details the analyses planned for data collected in 
study CP-4-009, a phase III study sponsored by OPKO Health Inc., including the 
definition of the analysis populations, derivation of variables, convention of analysis 
scope, and statistical methodology for the analyses of efficacy, safety and tolerability of 
Somatrogon (MOD-4023) compared to Genotropin®.  
This plan follows the methods described in the protocol and provides more specific 
details. Any changes to the analysis as described in the protocol will be documented in 
detail in this plan. Any deviations from this SAP during the actual data analysis will be 
documented in the clinical study report (CSR). 


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2. 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to demonstrate that annual (12 month) height 
velocity (HV) from weekly Somatrogon administration is comparable to daily 
Genotropin administration in children with growth hormone deficiency (GHD). 
2.1.2 Secondary Objectives 
The secondary objectives of the study are to evaluate the safety and tolerability of 
Somatrogon in subjects with GHD, and to characterize other growth parameters 
(change in height standard deviation score (SDS) and bone age (BA)/maturation), and 
biochemical markers (insulin-like growth factor-1 (IGF-1) 
 
, associated with growth hormone (GH) therapy. 
2.2 
Study Endpoints 
2.2.1 Primary Endpoint 
The primary efficacy endpoint is the annual HV in cm/year after 12 months of 
treatment. 
2.2.2 Secondary Endpoints 
Secondary auxology efficacy endpoints include: 
 Annualized HV after 6 months of treatment 
 Change in height SDS at 6 and 12 months, compared to baseline 
 Change in bone maturation (BM) at the end of 12 months, compared to Screening 
bone age (calculated as BA/chronological age (CA)) 
Secondary biochemical marker endpoints include: 
 IGF-1 SDS on day 4(-1) after Somatrogon dosing across study visits 
2.2.3 Safety Endpoints 
The safety endpoints include: 
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 Incidence of adverse events (AE)  
 Serious adverse events (SAE) and adverse events leading to discontinuation of 
treatment 
 Incidence of anti-Somatrogon antibody formation (including characterization of 
the antibodies and neutralizing properties) 
 Local injection site assessment 
 IGF-1 serum levels and SDS 
 Parameters of glucose metabolism: blood fasting glucose, fasting insulin level, 
HbA1c 
 Thyroid status 
 Lipid parameters 
 All other safety hematology and biochemical parameters  
 Physical examination 
 Fundoscopy (normal/abnormal) 
 Vital signs 
 Electrocardiogram (ECG) 
2.3 
Study Design 
The study will consist of a 12 month, open-label, randomized, active controlled, parallel 
group study comparing the efficacy and safety of weekly Somatrogon to daily GH, 
Genotropin.  
Both drugs will be injected using a single subject use, multi-dose, disposable pre-filled 
pen (PEN) device. 
After a screening period lasting up to 4 weeks, subjects meeting the eligibility criteria, as 
approved by global study medical monitor, will be randomized in a 1:1 ratio to: 
 Somatrogon (investigational treatment): weekly subcutaneous (SC) injections for 
12 months; initially over the first 6 weeks, Somatrogon will be administered in 3 
stepwise escalating doses (0.25 mg/kg/week, 0.48 mg/kg/week, and 0.66 
mg/kg/week) each for 2 weeks sequentially. For the remaining 46 weeks, patients 
will continue to receive Somatrogon at a dose of 0.66 mg/kg/week 
 Genotropin (reference therapy): daily SC injections for 12 months; 0.025 
mg/kg/daily which is equivalent to 0.175 mg/kg/week divided equally to 7 
injections over a week  
If the subject’s screening process is delayed because of a benign illness or unforeseen 
benign condition (i.e. pharyngitis, viral gastrointestinal problems, minor accident or 


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trauma, etc.) or a technical issue that is related to screening procedures (for example, 
delays with lab results), extra time – equal to the time of subject’s unavailability – will be 
added to the duration of the screening period, but not in excess of one additional week 
(total of 5 weeks screening period).  
During the study, Somatrogon and Genotropin dose will be adjusted based on the 
subjects’ body weight every three months. The dose may be decreased or maintained for 
safety reasons according to the pre-defined dose-adjustment criteria (based on the 
severity of AEs or repeated, elevated levels of IGF-1 SDS).  
2.4 
Study Population 
Pre-pubertal boys and girls not yet 11 and 10 years of age, respectively, and diagnosed 
with GHD. 
2.5 
Treatment Regimens 
2.5.1 Reference Therapy Dosing Regimen 
Genotropin is a daily GH, which will be used as the reference therapy in this study.  
A PEN (5.3 mg or 12 mg) will be used for daily (evening/bedtime) SC administration 
of Genotropin into the region of the upper arms, buttocks, thighs or abdomen (8 
locations). Injection sites should be rotated.  
Dose regimen for Genotropin: 0.025 mg/kg/daily (which is equivalent to 0.175 
mg/kg/week divided equally into 7 daily injections).  
2.5.2 Investigational Product Dosing Regimen: 
Somatrogon is a long-acting modified recombinant human GH which utilizes C-
terminal peptide technology. It will be provided as a solution for injection containing 
20 or 50 mg/mL Somatrogon in a PEN.  
Somatrogon will be administered as a SC injection using the PEN into the upper 
arms, buttocks, thighs, or abdomen (8 locations).  
Injection sites should be rotated, it is recommended that all 8 injection sites should be 
used successively, using a different injection site at each subsequent injection.  
Initially over the first 6 weeks, Somatrogon will be administered in 3 stepwise 
escalating doses (0.25 mg/kg/week, 0.48 mg/kg/week, and 0.66 mg/kg/week) each for 
2 weeks sequentially. For the remaining 46 weeks, patients will continue to receive 
Somatrogon at a dose of 0.66 mg/kg/week.  


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2.6 
Treatment Group Assignments 
Subjects will be randomized in a 1:1 ratio to Somatrogon (investigational treatment) or 
daily Genotropin (reference therapy) for 12 months. The randomization will not be 
stratified.  
2.7 
Sample Size Determination 
The aim of the study is to demonstrate that weekly Somatrogon is comparable to daily 
Genotropin administration with respect to the primary efficacy endpoint of annual HV in 
cm/year after 12 months of treatment.  
Comparability will be concluded if the mean treatment difference (Somatrogon – 
Genotropin) for the primary efficacy endpoint is ≥ –1.8 cm/year.  
The following assumptions were made in the sample size calculation:  
 between-subject standard deviation (SD) of annual growth rate of 2.5 cm/year in 
all treatment groups  
 comparability margin of –1.8 cm/year  
 true mean treatment difference (Somatrogon – Genotropin) in the primary 
efficacy endpoint of –0.8 cm/year.  
With these assumptions, 20 subjects per group will provide approximately 88% 
probability that the observed difference between Somatrogon and Genotropin will be 
greater than -1.8 cm/year. 


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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following general analysis and reporting conventions will be followed for this study, 
unless otherwise specified. 
All data displays:  
 All tables, listings, and figures will have a header showing the protocol number, 
page number (X of Y), as well as a footer indicating SDTM creation date, source 
data, output file name with path, and generation date/time. 
Summary tables and data listings:  
 Unless otherwise specified, data will be summarized by treatment and overall. 
 Descriptive statistics for categorical variables will be count and percentage and 
will be presented in the format ‘n (%)’. Unless otherwise specified, the percentage 
in summary tables will be calculated using number of subjects in the population 
(header n) for each treatment as denominator.  
 Descriptive statistics for continuous variables will be number of observations (n), 
mean, SD, median, minimum, and maximum. 
 Minimum and maximum will be reported to the same level of precision as the 
original data. Mean and median will be reported to 1 more decimal than the 
original data. SD will be reported to 2 more decimals than the original data.  
 Analysis of covariance (ANCOVA) estimates and confidence intervals (CI) will 
be reported to 1 more decimal than the original data. Standard errors will be 
reported to 2 more decimal places than the original data. P-values will be reported 
to 4 decimal places. 
 No preliminary rounding will be performed; rounding will only occur after 
analysis.  
 All data collected will be presented in the data listings. Unscheduled assessments 
or early discontinuation measurements will be presented in the data listings but 
will not be included in the calculation of summary statistics presented by visit. 
 Data from subjects excluded from an analysis population will be presented in the 
data listings but will not be included in the calculation of summary statistics, 
where applicable. 
 Data from each subject will be separated by a blank line. Within a data listing, if a 
descriptive item appears line after line (e.g., repetition of a subject number, date, 
visit, etc.), only the first occurrence will be displayed (e.g., in Listing of Vital 
Signs, subject number, date and visit will only be displayed on first row when 
presenting all parameters collected at same visit). Repetition of actual results or 
outcomes (e.g., AEs, lab results, vital sign values, etc.) will not be collapsed.  


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 Data listings will be sorted in the order of treatment, subject, and time of 
assessment, as applicable. 
 When change from baseline is calculated, baseline is the last assessment before 
receiving the first dose of treatment. 
Minor changes to the mocks after formal SAP approval will not necessitate re-approval 
unless changes to the text of the SAP are required. 
SAP amendment will be made in accordance with OPKO Health Inc. standard operating 
procedure (DM.003). 
All analyses will be performed using SAS® version 9.4 or higher. 


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4. 
ANALYSIS SETS 
Three analysis sets will be used for this study: Safety Analysis Set, Full Analysis Set, and 
Per Protocol Set. 
4.1 
Safety Analysis Set 
The safety analysis set will include all subjects who have received at least one dose of 
study treatment. Subjects will be analyzed according to actual treatment received. 
4.2 
Full Analysis Set 
The full analysis set will include all subjects who were randomized and have received at 
least one dose of study treatment, and will be the primary efficacy analysis set. Subjects 
will be analyzed according to randomized treatment group. 
4.3 
Per Protocol Set 
The per protocol (PP) set will consists of all randomized subjects who did not have any 
major protocol deviations.  
The subjects who have any major protocol deviations will be identified before database 
lock by the clinical team in a blinded review.  


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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number of subjects screened and randomized will be summarized.  
The number and percentage of subjects in each analysis set, completing the study, 
prematurely discontinuing the study, and the reason for study discontinuation, will be 
summarized.  
The number and percentage of subjects in the full analysis set at each visit (i.e., subjects 
who have data for each visit) will be summarized.  
5.2 
Protocol Deviations 
Protocol deviations will be summarized by deviation classification and category for all 
randomized subjects. 


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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics analyses will be performed using the Safety 
Analysis Set. 
6.1 
Demographics and Baseline Characteristics 
Descriptive statistics will be used to summarize the following variables:  
 age 
 sex 
 race 
 father’s height 
 mother’s height 
 target height 
 bone age 
 bone maturation 
 height SDS 
 weight 
 body mass index 
 peak GH* 
For continuous variable, the peak GH is calculated based on GH test. GHRP-2 if 
performed will be ignored. If there are two GH tests performed, higher value in the 2 
different tests was used as baseline peak GH value. 
6.2 
Medical History 
Medical history will be summarized by System Organ Class (SOC) and Preferred Term 
(PT) based on the coded data by the Medical Dictionary for Regulatory Activities 
(MedDRA®), version 19.1 or higher. The count and percentage of medical condition 
SOC and PT will be provided for past events and for ongoing conditions.  
6.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO 
DD) Dec 2016 or higher.  
If the start date of medication is completely missing in which the day, month, and year 
are all unknown or only the day is known, then the start date will not be imputed.  
For the partial start date of medication,  


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 If the year is present and the month and day are missing or the year and day are 
present and the month is missing, set month and day to January 1. 
 If the year and month are present and the day is missing, set day to 1st day of 
month. 
 If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
If the end date of medication is completely missing which the day, month, and year are 
all unknown or only the day is known, then the end date will not be imputed. 
For the partial end date of medication, 
 If the year is present and the month and day are missing or the year and day are 
present and the month is missing, set month and day to December 31. 
 If the year and month are present and the day is missing, set day to last day of the 
month. 
6.3.1 Prior Medications 
Prior medications will be defined as medications that are utilized prior to first dose of 
study drug. Medications with missing start date are considered prior.  
Prior medications will be summarized by anatomical therapeutic chemical (ATC) 
level 2 class and PT.  
6.3.2 Concomitant Medications 
Concomitant medications will be defined as medications that are utilized on or after 
first dose of study drug. Medications with missing end dates are considered 
concomitant. Medications with missing start dates and non-missing end dates will be 
considered concomitant if the end date is on or after first dose.  
Concomitant medications will be summarized by ATC level 2 class and PT.  
6.3.3 Prohibited Concomitant Medications 
Prohibited concomitant medications will be summarized by ATC level 2 class and 
PT.  


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7. 
EXTENT OF INVESTIGATIONAL PRODUCT EXPOSURE 
Extent of exposure will be summarized using the Safety Analysis Set. 
Descriptive statistics will be reported for duration of treatment. Duration of treatment is 
defined as: 
 Genotropin: last dose date – first dose date + 1 
 Somatrogon: last dose date – first dose date + 7 
The number and percentage of subjects experiencing dose reduction due to IGF-1 SDS > 
2 will be summarized.  


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8. 
EFFICACY EVALUATION 
8.1 
Overview of Efficacy Analysis Issues 
8.1.1 Handling of Dropouts or Missing Data 
For the Somatrogon assay, values below the limit of quantification (BLQ) at the 
baseline visit will be treated as 0 in statistical analysis of the results.  
For the height-related primary and secondary endpoints of HV and height SDS, 
multiple imputation assuming missing not at random using SAS PROC MI will be 
used to impute missing results. The imputation will be by treatment group. The 
imputation model will be the same as the primary analysis model. For the primary 
endpoint, annual HV, the imputed value in the Somatrogon group will be reduced by 
1.8 cm/yr, the non-inferiority margin to avoid imputing to the common mean (Koch1). 
A total of 100 imputed datasets will be created, and the seed will be set using the 
database lock date in YYYYMMDD format, and stored in order to be able to 
replicate the results. An ANCOVA model as described for the primary analysis will 
be used to calculate the least square means and 95% confidence interval of the 
treatment difference for each imputed set. These results will then be combined for 
evaluation with SAS PROC MIANALYZE. The number of imputed datasets may be 
increased if necessary to achieve adequate numerical precision. 
8.1.2 Multicenter Studies 
Study center will not be utilized during analysis. 
8.1.3 Assessment Time Windows 
Scheduled assessments are the preferred source for visit-level data.  
8.2 
Efficacy Variables 
8.2.1 Primary Efficacy Endpoint 
8.2.1.1 
Annual HV at 12 Months 
Annual HV at 12 months is based on the difference between the heights at 12 
months and baseline.  
 
1 Koch GC, Comments on ‘Current issues in non-inferiority trials’ by Thomas R Fleming. 2008. Statistics in 
Medicine 27(3):333-42. 


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ܪ݁݅݃ℎݐ ܸ݈݁݋ܿ݅ݐݕ ൬ܿ݉
ݕ݁ܽݎ൰
= ቈ ܯ݋݊ݐℎ 12 ܪ݁݅݃ℎݐ ሺܿ݉ሻ− ܤܽݏ݈݁݅݊݁ ܪ݁݅݃ℎݐ ሺܿ݉ሻ
ܯ݋݊ݐℎ 12 ݀ܽݐ݁−ܤܽݏ݈݁݅݊݁ ݀ܽݐ݁
 ቉
∗365.25 
8.2.2 Secondary Efficacy Endpoints 
8.2.2.1 
Annualized HV at 6 Months 
Annualized HV after 6 months will be calculated based on the difference between 
the heights at 6 months and baseline. 
8.2.2.2 
Change in Height SDS at 6 and 12 Months 
Height SDS will be determined from the age and gender standards listed in the 
national survey in year 2000 (Ministry of Health, Labor and Welfare's Infant and 
Children's Growth Survey Report (0 to 6 years old) and the Ministry of 
Education, Culture, Sports, Science and Health Statistics Report (6 to 17 years 
old) in 2000 (http://jspe.umin.jp/medical/taikaku.html).  
8.2.2.3 
Change in BM at 12 Months 
BM is calculated as BA divided by CA. BA will be determined by a central reader 
via X-ray according to Tanner-Whitehouse 2 Method2 and reported in years and 
months. These results will be combined into a decimal value as:  
years + months/12  
CA will be determined based on the assessment date. A decimal value will be 
calculated as: 
 
age in years + (assessment date – date of most recent birthday)/365.25 
8.2.3 Biochemical Markers 
Biochemical markers of interest are 
IGF-1 SDS, 
 IGF-1 SDS 
will be determined from the age and gender standards listed in the article by Isojima 
T. et al.3. 
8.3 
Analysis Methods 
Analyses will be based on the full analysis set. 
 
2 Murata M. Japanese specific BA standard on the TW2. Clin Pediatr Endocrinol 1993; (Suppl 3):35-41 
3 Standardized central curves and reference intervals of serum insulin-like growth factor-I (IGF-I) levels in a 
normal Japanese population using the LMS method. Endocrine Journal 2012, 59 (9), 771-780 
CCI
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Table 8-1 gives an overview of the analysis methods that will be used for each of the 
efficacy variables. 
Table 8-1 
Efficacy Variables and Analysis Methods 
Efficacy Variables 
Method 1 
Method 2 
Method 3 
 
 
 
 
Annual HV at 12 Months 
ANCOVA, 95% CI
Descriptive stats 
 
Annualized HV at 6 Months 
ANCOVA, 95% CI
Descriptive stats 
 
Change in Height SDS at 6 and 12 Months
ANCOVA, 95% CI
Descriptive stats 
 
Change in BM at 12 Months 
 
Descriptive stats 
Univariate 95% CI
Biochemical Markers 
 
Descriptive stats 
 
 
 
 
 
8.3.1 Primary Efficacy Analyses 
The aim of the present study is to demonstrate that in terms of the primary efficacy 
endpoint, Annual HV at 12 months, weekly Somatrogon is comparable to daily 
Genotropin.  
Comparability will be concluded if the mean treatment difference "Somatrogon – 
Genotropin" in the primary efficacy endpoint is ≥ -1.8 cm/year.  
The difference of means between the two treatments will be derived from an 
ANCOVA. The ANCOVA model will include classification terms for treatment and 
gender. The model will also include baseline peak GH value and height SDS as 
covariates. The determination of comparability will be based on least squares means 
for the two treatments from the ANCOVA and the difference between the treatments. 
Descriptive statistics will be reported for observed annual HV values at 12 months. In 
addition, descriptive statistics will be reported for observed annual HV values at 12 
months by ADA status. 
Annual HV values at 12 months will be presented in a scatter plot by treatment. 
ANCOVA-based statistics will be reported by the categorical term used in the 
ANCOVA model: gender. 
8.3.2 Secondary Efficacy Analyses 
A similar ANCOVA model as used for the primary endpoint will be used to 
summarize: 
 annualized HV at 6 months  
 change in height SDS at 6 months 
 change in height SDS at 12 months 


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Least square mean estimates for the two treatments and the difference between the 
treatments will be presented. 
Descriptive statistics will also be reported for each of these endpoints. 
Descriptive statistics (including univariate 95% CI) will be reported for BM observed 
and change from baseline at 12 months.  
Scatter plots by treatment will be reported for each of these endpoints. 
Descriptive statistics will be reported for HV and height SDS at each visit. 
Box plots will be reported for HV and height SDS by visit and treatment. 
ANCOVA-based statistics will be reported by the categorical term used in the 
ANCOVA model: gender. 
8.3.3 Primary Efficacy Sensitivity Analysis 
The ANCOVA-based primary efficacy analysis will be repeated using the PP set.  
The similar analysis to the ANCOVA-based primary efficacy analysis, but using the 
different missing imputation method, will be repeated using the FAS. The method 
will be carrying the last non-missing height value forward and using this value to 
derive HV. Unscheduled and early discontinuation measurements will be carried 
forward. 
The similar analysis to the ANCOVA-based primary efficacy analysis, but including 
different covariates, will be repeated using the FAS. The model will include 
classification terms for treatment, Peak GH level (low vs high, based on: ≤3 ng/mL or 
>3 to ≤6 ng/mL; or if GHRP-2 provocation test is used, ≤10 ng/mL or >10 to ≤16 
ng/mL, if there are adequate number of subjects in each of the classification levels) 
and chronological age (3-7 years old or above 7 years old). The model will also 
include height SDS as continuous variable. 
8.3.4 Biochemical Markers Analysis 
Descriptive statistics will be reported for observed and change from baseline for all 
biochemical endpoints at each visit. In addition, descriptive statistics will be reported 
for 
 by ADA status. 
The number and percent of subjects who had IGF-1 SDS > 2 will be summarized at 
each visit. The number and percent of subjects who had consecutive IGF-1 SDS > 2 
assessments anytime post-baseline will be summarized.  
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9. 
SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
All summaries of safety are to be performed on the Safety Analysis Set unless stated 
otherwise. 
9.2 
Adverse Events 
All AEs that occurred during this clinical trial will be coded using MedDRA version 19.1 
or higher.  
A treatment-emergent adverse event (TEAE) is defined as an AE that is starting or 
worsening at the time of or after study drug administration. AEs with partial dates will be 
assessed using the available date information to determine treatment-emergent status; 
AEs with missing onset date/time will be considered as TEAE. AEs with missing resolve 
date/time will be considered as ongoing. 
All AEs captured in the database will be listed; however, only TEAEs will be 
summarized.  
The number and percentage of subjects who experienced at least one TEAE as well as the 
number and percentage of subjects who experienced each specific SOC and PT will be 
summarized and sorted by descending order of overall incidence. In addition, the number 
and percentage of subjects who experienced each specific SOC and PT will be 
summarized by ADA status. 
Within each SOC or PT, subjects experiencing multiple occurrences of the same event 
will be counted only once.  
TEAEs will be summarized by relationships (all causalities and treatment related). 
TEAEs are considered related to study drug if the relationship is one of: "possibly 
related", "related", or missing. 
9.3 
Serious Adverse Events and Other Significant Adverse Events 
The following subsets of TEAEs will be summarized by subject and by SOC and PT: 
 SAE 
 severe AE 
 leading to study drug withdrawal 
 leading to study drug reduction or interruption 
 leading to study discontinuation 
Separate data listings will be provided for each of the above categories of TEAEs. 


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TEAEs will also be summarized by maximum severity (mild < moderate < severe) within 
SOC and PT. Missing AE severity will be considered severe.  
TEAEs will also be summarized by maximum severity (mild < moderate < severe) and 
strongest relationship (not related < related) within SOC and PT.  
TEAEs of special interest will also be summarized by event type and PT. The event type 
will be described in the safety narrative plan.  
Deaths will be presented in a data listing. 
9.4 
Injection Site Reactions and Pain 
Injection site reactions (ISR) will be summarized by SOC and PT. In addition, ISR will 
be summarized by SOC and PT by ADA status. 
Pain scores will be summarized with number of overall subjects and subjects with ISR as 
the denominator. For each subject, ISR pain score will be summarized by maximum 
severity. In both summaries, missing values will be considered "hurts worse". 
ISR erythema/redness, bruising, and induration/swelling will be summarized with 
number of overall subjects and subjects with ISR as the denominator. For each subject 
and reaction type, symptoms will be summarized by maximum severity. In both 
summaries, missing values will be considered "severe".  
9.5 
Clinical Laboratory Evaluation 
Descriptive statistics will be reported for observed and change from baseline clinical 
laboratory measurements at each visit. Lab tests will be presented alphabetically within 
each of the following categories: 
 hematology 
 chemistry 
 lipid profile 
 glucose metabolism 
 endocrinology 
 urinalysis 
For each laboratory test, a shift from baseline will be presented at each visit. Categories 
will be ‘Low’, ‘Normal’, and ‘High’.  
For each laboratory test, box plots will be created by visit and treatment group. 
The number and percentage of subjects with increases in either of the following will be 
summarized at each visit and anytime post-baseline: 


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 ALT >2xULN, >3xULN, >5xULN 
 AST >2xULN, >3xULN, >5xULN 
 Bilirubin >3xULN and (ALT > 2xULN or AST > 2xULN) 
Two evaluation of Drug Induced Serious Hepatotoxicity (eDISH) scatter plots will be 
produced: maximum bilirubin vs. maximum ALT and maximum bilirubin vs. maximum 
AST.  
9.6 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.6.1 Vital Signs 
Descriptive statistics will be reported for observed and change from baseline vital 
sign measurements at each visit. The vital signs data will include: 
 systolic blood pressure (mmHg) 
 diastolic blood pressure (mmHg) 
 heart rate (beats/min) 
 respiratory rate (breaths/min) 
 temperature (degree C)  
9.6.2 Physical Examinations 
Physical examination findings will be reported as medical history at screening and as 
AEs after screening. As such, there will be no physical examination summaries. 
9.6.3 Other Safety Measures 
9.6.3.1 
Electrocardiograms (ECG, 12-lead) 
Descriptive statistics will be reported for observed and change from baseline ECG 
measurements at each visit. The ECG data will include: 
 heart rate (beats/min) 
 PR interval (msec) 
 QRS interval (msec) 
 QT interval (msec) 
 RR interval (msec) 
 QTc interval (msec) 
 Fredericia’s corrected QT interval (QTcF)  
o calculated as QT interval/Cubic root of (60/heart rate) 


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The interpretation for each ECG will be categorized as normal, abnormal not 
clinically significant (NCS), or abnormal clinically significant (CS). The number 
and percentage of subjects in each category will be presented by visit.  
A shift from baseline table will be presented by visit.  
9.6.3.2 
Fundoscopy 
The number and percentage of subjects who had fundoscopy done will be 
summarized. The number and percentage of subjects experiencing intracranial 
hypertension will be summarized. 
9.6.3.3 
Immunogenicity 
The number and percentage of subjects with the presence of each of the following 
will be summarized at each visit: 
 anti-recombinant human Growth Hormone (r-hGH) antibodies  
o neutralizing 
o non-neutralizing 
 anti-Somatrogon antibodies  
o neutralizing 
o non-neutralizing 
Descriptive statistics will be reported for anti-r-hGH and anti-Somatrogon 
antibody titers at each visit. 
9.6.3.4 
Pregnancy 
The population under study consists of pre-pubertal children. As such, no 
pregnancy assessments will be performed. In case of pregnancy, study treatment 
will be terminated, and study procedures will be performed as scheduled. 
9.6.3.5 
Hypersensitivity 
Hypersensitivity will be summarized by ADA status. 


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10. 
 
 
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11. 
INTERIM ANALYSES AND DATA MONITORING 
11.1 
Data Monitoring 
An independent and external data safety monitoring board (DSMB) will be established. 
The primary responsibility of the DSMB will be to provide guidance to the Sponsor 
regarding the safe conduct of the study based on their periodic review of safety data. The 
DSMB will review study safety summaries. Efficacy data on individual subjects will be 
available to assist safety reviews. The DSMB’s membership, full scope of 
responsibilities, operating procedures, access to data, and reporting and record keeping 
requirements will be established by Sponsor and/or its representative, and will be 
described in a DSMB charter.  


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12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
According to the Protocol CP-4-009 Administrative Change Letter #2 to Version 9.0 of 
the Protocol, the following analyses were not conducted. 
8.4.3 Secondary PK/PD Endpoints 
Biochemical endpoints: 
IGF-BP3 SDS 
 
8.6 EFFICACY ANALYSIS 
Secondary Analysis: 
For the secondary endpoints that are measured over time, MMRM analysis with 
similar factors as the ANCOVA model (in the primary endpoint) will be used to 
estimate the time specific results. This MMRM approach is not intended to test for 
statistical significance of factors. These analyses are considered to be supportive 
efficacy analyses. 
 
In addition, the following strikethrough and underlined parts were changed. 
 
8.2.1 Full Analysis Set 
The Full Analysis Set will include all randomized patients who were randomized and 
have received at least one dose of study treatment. 
 
8.3 HANDLING OF MISSING DATA 
Multiple Imputation (using SAS PROC MI) assuming data missing not at random will 
be used to impute missing observations in the primary efficacy analysis. Sensitivity 
analyses will be performed to evaluate the effect of missing data. 
 
8.6 EFFICACY ANALYSIS 
Primary Efficacy Analysis: 
The goal of the primary efficacy analysis is to estimate the mean treatment difference 
between weekly MOD-4023 and daily Genotropin® with respect to the primary 
efficacy endpoint (HV after 12 months of treatment). Least square means and 95% CI 
for HV at 12 months will be calculated from an ANCOVA model, with treatment, 
gender, as factors (class variables); and peak hGH value during stimulation test, and 
baseline HVHeight SDS as covariates. 
 


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13. 
APPENDICES 
13.1 
Schedule of Events 
The screening period, Visit 1, can take place over a 4 to 5 week period. Randomization 
will take place prior to or on Visit 2 (Day 1/Baseline), which is on day of first dosing. 
Visits 3, 4, and 5 will differ between the 2 treatment arms due to the 6-week dose 
escalation and PK/PD sampling in the MOD-4023 treatment arm. Visits 6 to 9 (every 3 
months) will be similar for both treatment arms (except where noted).  


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    Statistical Analysis Plan 
Protocol No. CP-4-009 
 
 
 
 
     
       19 May 2020 
Version: OPKO-CP-4-009-SAP-v3.0.docx 
 
 
 
 
 
      Page 34 of 38 
 
Figure 13-1: Schedule of Events - Part 1 of 5 
 




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                                                                CONFIDENTIAL 
 
 
 
    Statistical Analysis Plan 
Protocol No. CP-4-009 
 
 
 
 
     
       19 May 2020 
 
Version: OPKO-CP-4-009-SAP-v3.0.docx 
 
 
 
 
 
      Page 36 of 38 
 
Figure 13-3: Schedule of Events - Part 3 of 5 
 


OPKO Health Inc. 
                                                                CONFIDENTIAL 
 
 
 
    Statistical Analysis Plan 
Protocol No. CP-4-009 
 
 
 
 
     
       19 May 2020 
 
Version: OPKO-CP-4-009-SAP-v3.0.docx 
 
 
 
 
 
      Page 37 of 38 
 
Figure 13-4: Schedule of Events - Part 4 of 5 
 


OPKO Health Inc. 
                                                                CONFIDENTIAL 
 
 
 
    Statistical Analysis Plan 
Protocol No. CP-4-009 
 
 
 
 
     
       19 May 2020 
 
Version: OPKO-CP-4-009-SAP-v3.0.docx 
 
 
 
 
 
      Page 38 of 38 
 
Figure 13-5: Schedule of Events - Part 5 of 5