Conditions: Pediatric Growth Hormone Deficiency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 224
Healthy volunteers: no

Brief summary:
This is an open-label, randomized, multicenter, efficacy and safety study of weekly MOD-4023 compared to daily Genotropin therapy in pre-pubertal children with growth hormone deficiency.

Detailed description:
The study consists of a 12 month, open-label, randomized, active controlled, parallel group study comparing the efficacy and safety of weekly MOD-4023 to daily growth hormone (GH), Genotropin. After 12 months, subjects will have the option to enter the long term open-label extension.

Arms:
arm 1: Once weekly subcutaneous injection of long acting r-hGH (MOD-4023) arm 2: Once daily subcutaneous injection of somatropin (r-hGH; Genotropin)

Interventions: intervention 1: MOD-4023 intervention 2: Somatropin
Intervention descriptions: intervention 1: Once weekly subcutaneous injection using pre-filled pen device. intervention 2: Once daily subcutaneous injection of Genotropin using pre-filled pen device.

Protocol document:
SAP_002.pdf: 
Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 1
T
Protocol for Clinical Study CP-4-006 (C
9) 
A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER, 12 MONTHS,
EFFICACY AND SAFETY STUDY OF WEEKLY SOMATROGON COMPARED TO
DAILY GENOTROPIN® THERAPY IN PRE-PUBERTAL CHILDREN WITH
GROWTH HORMONE DEFICIENCY
Open-label Extension (OLE)
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
3 Jan 2024
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................6
2.1.1. Estimand(s)...................................................................................................6
2.1.2. Additional Estimand(s).................................................................................7
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Efficacy Endpoints ....................................................................................................7
3.1.1. Annualized Height Velocity (cm/year).........................................................7
3.1.2. Change in Height SDS..................................................................................8
3.2. Biomarkers ................................................................................................................8
3.2.1. Change in Bone Maturation..........................................................................8
3.2.2. IGF-1 (ng/mL) and IGF-1-SDS....................................................................9
3.2.3. IGFBP-3 (ng/mL) and IGFBP-3-SDS ..........................................................9
3.3. Other Endpoint(s)......................................................................................................9
3.3.1. Additional Assessment .................................................................................9
3.4. Baseline Variables.....................................................................................................9
3.5. Safety Endpoints .......................................................................................................9
3.5.1. Adverse Events.............................................................................................9
3.5.2. Laboratory Data..........................................................................................10
3.5.3. Vital Signs ..................................................................................................10
3.5.4. Antibodies...................................................................................................10
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................11
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................11
5.1. Hypotheses and Decision Rules ..............................................................................11
5.2. General Methods .....................................................................................................11
5.2.1. Analyses for Continuous Endpoints ...........................................................11
5.2.2. Analyses for Categorical Endpoints ...........................................................12
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 3
5.2.3. Analyses for Time-to-Event Endpoints ......................................................12
5.3. Methods to Manage Missing Data ..........................................................................12
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Efficacy Endpoint....................................................................................................12
6.1.1. Main Analysis.............................................................................................12
6.1.2. Sensitivity/Supplementary Analyses ..........................................................12
6.2. Other Endpoint(s)....................................................................................................13
6.2.1. Immunogenicity (Antibodies).....................................................................13
6.3. Subset Analyses.......................................................................................................13
6.4. Baseline and Other Summaries and Analyses.........................................................13
6.4.1. Baseline Summaries....................................................................................13
6.4.2. Study Conduct and Participant Disposition................................................13
6.4.3. Study Treatment Exposure .........................................................................13
6.4.4. Concomitant Medications and Nondrug Treatments..................................13
6.5. Safety Summaries and Analyses .............................................................................13
6.5.1. Adverse Events ...........................................................................................14
6.5.2. Laboratory Data..........................................................................................14
6.5.3. Vital Signs ..................................................................................................14
6.5.4. Physical Examination .................................................................................14
7. INTERIM ANALYSES.......................................................................................................15
8. REFERENCES ....................................................................................................................15
9. APPENDICES .....................................................................................................................16
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 4
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................16
Appendix 2. Data Derivation Details.......................................................................................17
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................17
Appendix 2.2. Endpoint Derivations .......................................................................................18
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical 
Analyses/Populations................................................................................18
Appendix 3. Data Set Descriptions..........................................................................................18
Appendix 4. Statistical Methodology Details..........................................................................19
Appendix 5. List of Abbreviations...........................................................................................19
Appendix 6. List of Summary Tables......................................................................................21
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 5
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
V1
No separate CP-4-
006 (C0311009)
OLE protocol. 
Referring to 
Section 5.3 study 
procedure for LT-
OLE and sub-
section of OLE 
embedded in each 
section of the 
Amendment V5.0 
dated 2 May 2018
Original SAP
No
2. INTRODUCTION
Human growth hormone (hGH) is a 191-amino-acid pituitary protein that stimulates hepatic 
production and release of insulin-like growth factor-1(IGF-1) into the systemic circulation. 
IGF-1 is an important mediator in the promotion of linear growth in children and may play a 
role in the regulation of metabolism and body composition in adults. These factors are 
regulated through complex feedback mechanisms involving hGH, IGF-1 binding protein-3
(IGFBP-3) and their complexes.
The majority of currently available hGH products require daily or every other day 
subcutaneous (SC) or intramuscular (IM) 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 20082) and can limit the therapeutic utility of existing 
formulations.
Somatrogon is a long-acting r-hGH for SC administration. It consists of hGH fused to three 
copies of the C-terminal peptide (CTP) of the beta chain of human chorionic gonadotropin; 
one copy at the N-terminus and two copies (in tandem) at the C-terminus. Somatrogon is the 
International Nonproprietary Name (INN) of somatrogon and can be used interchangeably 
with MOD-4023.
The purpose of the current Phase 3 study is to demonstrate that weekly somatrogon
administration in pre-pubertal children with growth hormone deficiency (GHD) is clinically 
non-inferior to daily Genotropin® administration in terms of safety and efficacy after 12 
months treatment duration. The study will be conducted in a randomized, open-label, active-
controlled, parallel-group design. After completion of an initial 12-month treatment, patients 
will be eligible to continue treatment with weekly somatrogon in a single arm, long-term 
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 6
open-label extension (LT-OLE) study for the purpose of collecting additional long-term 
safety and efficacy information.
As the dose selection is driven by evaluating the annual increment in height velocity (HV), 
the annual HV data obtained for somatrogon was compared to Genotropin® results in the 
Phase 2 study for 52 patients (one patient was mis-diagnosed). Based on 12-month auxology 
data, it is most likely that a minimum somatrogon dose of 0.66 mg/kg/wk will provide an 
annualized HV comparable to daily hGH at a dose of 34 μg/kg/day.
This SAP provides the detailed methodology for summary and statistical analyses of the OLE 
data collected in Study CP-4-006 (
9). This document may modify the plans 
outlined in the protocol; however, any major modifications of the primary endpoint definition 
or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
LT-OLE Objective:
To assess the long-term efficacy, safety, and immunogenicity of somatrogon in the LT-OLE
period.
2.1.1. Estimand(s)
The estimand of this study uses the treatment policy strategy and estimates the effect for all 
participants treated regardless of whether an intercurrent event occurs. Each of them includes 
the following four attributes: 

Population: All patients who entered OLE period and had at least one dose of 
somatrogon;

Variable: 

Annualized height velocity (AHV) at each 12-month interval (cm/year)

Height standard deviation score (SDS) and change in height SDS;

Change in bone maturation (BM);

IGF-1 and IGF-1 SDS levels on day 4 (-1) after somatrogon dosing across study 
visits;

IGFBP-3 levels and IGFBP-3 SDS on day 4 (-1) after somatrogon dosing across 
study visits;

Pubertal status (according to Tanner stages);

For males that are 13 years and older: luteinizing hormone (LH), follicle-
stimulating hormone (FSH) and testosterone;
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 7

For females that are 12 years and older: LH, FSH and estradiol

Intercurrent event: All data after an intercurrent event (discontinuation of treatment, 
discontinuation of study, etc.), if collected, will be included;  

Population-level summary: descriptive summary for absolute values at each visit 
and/or change from previous interval. 
2.1.2. Additional Estimand(s)
Not Applicable. 
2.2. Study Design
The study will be divided into two parts: Main Study Period (main study) and OLE Period. 
The main study will consist of 12 months, open-label, multi-center, randomized, active 
controlled, parallel group study comparing efficacy and safety of weekly somatrogon to daily 
GH, Genotropin®. Both drugs will be injected using a PEN device.
Patients who received somatrogon during the main study will continue in the LT-OLE with 
the same dose (mg/kg/wk) of somatrogon. Patients who received Genotropin® during the 
main study will be switched to somatrogon and will begin treatment with a dose of 0.66 
mg/kg/wk beginning no less than one day after cessation of Genotropin® treatment.
The key safety data will be reviewed by an independent Data Safety Monitoring Board
(DSMB) approximately every 6 months. During the entire study (main study and LT-OLE), 
the dose of somatrogon 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 (which will be based on the severity of adverse events (AEs)
or repeated, elevated levels of IGF-1). The dose will be decreased based on two, repeated day 
4(-1) post-dose levels of IGF-1 SDS > +2.0. During the LT-OLE, dose reduction for IGF-1 
level >+2.0 SDS will be made following consultation with the Global Study Medical Monitor
on an individual patient basis. 
The LT-OLE will continue until marketing approval.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Efficacy Endpoints
3.1.1. Annualized Height Velocity (cm/year)
AHV at each 12 month is based on the difference between the height (HT) at each 12 month
and the height at the previous 12 month. 
    HT at Month 12 of current year – HT at Month 12 of prior year
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 8
AHV(cm/year) = --------------------------------------------------------------------------------------------
                        (Month 12 Visit Date of current year – Month 12 Visit Date of prior year) / 365.25   
The following algorithm will be used in case the reference visit (i.e., previous 12 month visit)
is missing:

If main period Month 12 (OLE Baseline), Visit 16 (OLE Month 12), Visit 20 (OLE 
Month 24), Visit 24 (OLE Month 36) are not missing, these will serve as reference
visits. 

If missing, create anchor visit which is the scheduled visit (non-missing) prior to the 
missed reference visit, or scheduled or unscheduled visit (non-missing) after the 
missed reference visit based on the anchor logic described below:
o A subject showed a missing reference visit at visit 16
o This subject completed Visit 15 (OLE Month 9; Anchor A) and Visit 17 (OLE 
Month 15; Anchor B) and did not complete an Unscheduled Visit. One of the 
scheduled visits (non-missing) will be determined as the Anchor Visit

Anchor logic:
o If Anchor B – Anchor A < 6 months (180 days) then Anchor A will be uses as the 
reference visit.
o If Anchor B – Anchor A  ≥ 6 months (180 days) then Anchor B will be uses as the 
reference visit.
o If a reference visit was performed out of window and reported as an unscheduled 
visit then unscheduled visit will be used as the reference visit, Anchor C.
3.1.2. Change in Height SDS 
Height SDS will be calculated as the Z-score using LMS method as:
Z = [ ((Height / M)^L) – 1] / (S * L), 
where L, M, S will be determined from the age and gender standards listed in 2000 CDC 
Growth Charts (www.cdc.gov/growthcharts) for age 2 to 20, or CDC reference datasets.
Change in height SDS will be calculated as the difference between the height SDS at each 
scheduled visit in OLE period and the height SDS at the main period baseline. 
3.2. Biomarkers
3.2.1. Change in Bone Maturation
Bone maturation will be calculated as bone age (BA) divided by chronological age (CA). BA 
will be determined by a central reader via X-ray according to the Greulich-Pyle method and 
reported in years and months. These results will be combined into a decimal value as: years + 
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 9
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 birthday + 1) / 365.25.
Change in BM at each visit in the OLE period will be calculated using the formula below: 
                                 BA at post-baseline visit – BA at baseline
Change in BM = -----------------------------------------------------
       CA at post-baseline visit – CA at baseline
3.2.2. IGF-1 (ng/mL) and IGF-1-SDS
IGF-1 levels and IGF-1 SDS will be measured and calculated on day 4 (-1) after somatrogon
dosing across study visits in OLE at every scheduled visit in OLE period. Change in IGF-1 
SDS at each visit will be calculated as the difference between the IGF-1 SDS values in the 
OLE period and the IGF-1 SDS at the main period baseline.
3.2.3. IGFBP-3 (ng/mL) and IGFBP-3-SDS 
IGFBP-3 levels and IGFBP-3-SDS will be measured and calculated on day 4 (-1) after 
somatrogon dosing across study visits in OLE at every scheduled visit in OLE period. 
Change in IGFBP-3 SDS at each visit will be calculated as the difference between the 
IGFBP-3 SDS values in the OLE period and the IGFBP-3 SDS at the main period baseline.
3.3. Other Endpoint(s)
3.3.1. Additional Assessment
The annual assessment will also be conducted according to the protocol schedule, including 
bone age, pubertal status (Tanner stage as stage I to V), LH, FSH, as well as testosterone for 
boys 13 years and older or estradiol for girls 12 years and older at every 12 months in the 
OLE period.
3.4. Baseline Variables
Baseline is defined as the main period baseline for efficacy and biomarker assessment.
Except the reference visit for AHV, is defined in Section 3.1 as the values at the previous 12
month in the OLE period.  
3.5. Safety Endpoints
3.5.1. Adverse Events
The AE including time of the onset, severity, action/treatment and outcome of the AE 
resolution, related to somatrogon treatment or not, will be collected at each scheduled visit 
with the visit window specified in the Schedule of Activities in the protocol.
An AE is considered as a treatment-emergent adverse event (TEAE) if the event started on or 
after the first dose of somatrogon in the OLE period of the study. The AE reporting period 
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 10
for this study will be defined as the duration from the first dose of somatrogon in the study 
until 28 calendar days following the final visit dose. AE 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.
3.5.2. Laboratory Data
Laboratory data will be collected according to the Schedule of Activities in the protocol, 
including hematology, chemistry, lipid profile, glucose metabolism, endocrinology and 
urinalysis lab tests.
3.5.3. Vital Signs
Vital sign data will be collected according to the Schedule of Activities in the protocol, 
including systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, 
temperature. Any clinically significant (CS) findings will be reported as an AE.
3.5.4. Antibodies
Blood samples for anti-drug antibodies (ADA) will be collected according to the Schedule of 
Activities in the protocol, including the ADA status (positive, negative, not done or not 
available) for the following items:

Anti-human GH (hGH) antibodies
o
neutralizing
o
non-neutralizing

Anti-somatrogon antibodies
o
neutralizing
o
non-neutralizing
ADA titer will be classified as 0 (i.e., ADA negative), 10, 50, 250, 1250, 6250. Titer values 
>6250 are reported as 6250.
ADA positivity will be defined as:

Tested positive after the receipt of drug during the study (either in main period or 
OLE), if main period baseline was tested negative or titer as 0; 

Post-baseline titer > 4x main period baseline titer, if main period baseline was tested 
positive.
Otherwise, it will be classified as ADA negative.
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 11
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
The term “full analysis subset” is used to describe the analysis set which is as complete as 
possible and as close as possible to the intention-to-treat ideal of including all enrolled 
patients entered the OLE period. The full analysis set will comprise all treated patients who 
have received at least one dose of active treatment during the main and OLE phase and who 
provide any follow-up data. The patients will be grouped by their original randomized 
treatment in the main period.
The analysis populations for reporting are defined in the following table. 
Population
Description
Enrolled
All participants who sign the informed consent document and 
continued in the OLE period.
Evaluable or Full 
Analysis Set (FAS)
All participants who continue to the OLE period of the study 
and take at least one complete dose of somatrogon (or partial 
dose if adverse events prevent completing dose). Participants 
will be analyzed overall and according to the randomized 
study drug that originally received in the main period.
Safety Analysis Set
All participants who continue to the OLE period of the study 
and take at least 1 complete dose of somatrogon (or partial 
dose if adverse events prevent completing dose). Participants 
will be analyzed overall and according to the randomized 
study drug that originally received in the main period.
Per Protocol Set (PP)
Not applicable.  
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There is no statistical hypothesis testing in the OLE period for this study.
5.2. General Methods
5.2.1. Analyses for Continuous Endpoints
Descriptive statistics will be provided for continuous variables using number of subjects (N), 
mean, standard deviation (SD), median, and range.
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 12
TMF Doc ID: 98.03
5.2.2. Analyses for Categorical Endpoints
Frequency and percentage for each category of the variable will be provided as a descriptive 
summary for each visit.
5.2.3. Analyses for Time-to-Event Endpoints
Not applicable.
5.3. Methods to Manage Missing Data
Missing reference value in calculating primary endpoint of AHV is specified in Section 3.1.  
The missing data for the post-baseline data of the primary endpoint and all secondary 
efficacy endpoints will not be imputed and be summarized as observed data.
Missing safety data will be handled according to the Pfizer Clinical Data Interchange 
Standards Consortium (CDISC) safety rulebook and data standard rules for imputation,
including missing dates (when the date is required for a calculation) and missing severity of 
adverse events.
6. ANALYSES AND SUMMARIES
There are two treatment groups in the OLE, defined as originally randomized to somatrogon 
and originally randomized to Genotropin® in the main study.
6.1. Efficacy Endpoint
6.1.1. Main Analysis

Estimand strategy: Treatment policy strategy for AHV every 12 months, as well as for 
absolute value and change from baseline for each of the efficacy endpoints, including 
height SDS, IGF-1 and IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS, BM, LH, FSH and 
testosterone or estradiol.

Analysis set: FAS (defined in Section 4).  

Analysis methodology: change from baseline to OLE Year 1, Year 2, Year 3, etc., will be
descriptively and graphically summarized.

Intercurrent events: Data after study drug discontinuation will be included.

Descriptive summary includes N, mean, SD, median, minimum, and maximum for
absolute value. It can be presented by treatment group (originally randomized to 
somatrogon, originally randomized to Genotropin®, and total), by ADA sub-groups 
including ADA status (positive or negative), ADA titers, and by visit.
6.1.2. Sensitivity/Supplementary Analyses
Not applicable. 
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 13
6.2. Other Endpoint(s)
6.2.1. Immunogenicity (Antibodies)
Frequency and percentage of anti-somatrogon antibodies in FAS will be reported by year and 
visit, if adequate data are collected.
6.3. Subset Analyses
There is no planned subset analysis for this study.
6.4. Baseline and Other Summaries and Analyses
Descriptive summary including N, mean, SD, median, minimum, and maximum will be 
presented for continuous baseline variables.  Frequency and percentage will be provided for 
categorical baseline variables. 
6.4.1. Baseline Summaries
The summaries will be provided for demographic data collected at the entry of the OLE 
period, if data permits.
6.4.2. Study Conduct and Participant Disposition
Frequency counts and percentage will be reported for participant discontinuation due to 
adverse events and reasons for discontinuation, completion of each OLE year, number of 
subjects assessed, and number of subjects achieved final height.  
Data will be reported in accordance with the Pfizer reporting standards.
6.4.3. Study Treatment Exposure
Frequency counts and percentage will be reported for 6-month intervals for treatment 
duration in main period and OLE phase. The patient year will be descriptively summarized 
(median, mean and SD) in main period and OLE.
6.4.4. Concomitant Medications and Nondrug Treatments
The concomitant medication(s) and non-drug treatment(s) in OLE period will be provided in 
the listings.
6.5. Safety Summaries and Analyses
All the safety data will be summarized descriptively through the appropriate data tabulations
in safety population (defined in Section 4) according to Pfizer Safety Rulebook and CDISC 
standards analyses, to evaluate any potential risk associated with the safety and toleration of 
administering somatrogon pediatric GHD patients.
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 14
6.5.1. Adverse Events
TEAE will be summarized with counts and percentage for safety population (defined in
Section 4). 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 system organ 
class (SOC) and preferred term (PT) will be summarized and sorted by descending order of 
overall incidence.  
All AEs will be reported in a data listing.
For analysis purposes, all AEs will be classified to the appropriate MedDRA PT and SOC. 
For each subject, multiple events that map to the same PT will only be counted once for the 
PT, and multiple PTs within an SOC will only be counted once for that SOC to assess patient 
incidence of events by PT and SOC. The count and percentage of patients with each PT and 
SOC will be summarized for each treatment group. Relationship and severity of AEs will be 
summarized (count and % of patients, incidence rate based on person-year) for each
treatment group. For these summaries, multiple occurrences of an event within a patient will 
be classified as a single observation with the strongest relationship and maximum severity 
ratings. In addition, frequency tables of all reported events with each associated relationship 
and severity will be presented. Serious adverse events (SAEs) will be classified by the 
investigator and will be summarized by treatment group, PT and SOC, as well as total 
patients exposed.
In addition to the SOC and PT defined in the live MedDRA version at the final reporting 
stage, the adverse event of special interest (AESI) will be also summarized using frequency 
and percentage.
6.5.2. Laboratory Data
Laboratory data will be descriptively summarized by each clinical laboratory panel of 
hematology, chemistry, lipid profile, glucose metabolism, endocrinology, urinalysis. Shift 
tables will also be provided for each panel to present the count and percentage shifts from 
baseline among the categories of low, normal, and high.
6.5.3. Vital Signs
All vital sign data will be listed by participant and visit.
Though vital signs will be collected during each site visit per standard of care, only vital sign 
collected at the baseline, Month 3, 6, 9 and 12 in each of the OLE year will be summarized 
descriptively. Absolute values, change from baseline, and percent change from baseline for 
vital sign data will be summarized using N, mean, SD, median and range.
6.5.4. Physical Examination
Physical examination and neurologic assessment data will be listed only by participant and 
visit.
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 15
7. INTERIM ANALYSES
There is no planned interim analysis in this study.
8. REFERENCES
1.
CDC reference standards for 2000 CDC growth charts and SAS programs at the CDC 
website (http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm).
2.
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
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 16
9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Not applicable.
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 17
3
Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
Annual ADA characterization will be performed based on the algorithm below using visit 
windows as applied to ADPC dataset. 
Period
om
o
Main
Day 2 (main dosing +1)
Day 410
OLE Year 1
Day 2/OLE Baseline (OLE dosing +1)
Day 410 (OLE Month 12)
OLE Year 2
Day 411
Day 774
OLE Year 3
Day 775
Day 1138
OLE Year 4
Day 1139
Day 1502
The following table will provide the adverse events reporting period to a given study period. 
Period
From
To
AE linking to 
study period
Main
On or post first Main 
dosing date/time (in 
exposure dataset)
Prior to the first OLE dosing 
date/time
If the new AE 
strictly starts 
between the 
start and end 
dates of a given 
period, it will 
be counted in 
that period.
OLE Year 1
(visit13 -16)
On or post first OLE dosing 
date/time (defined in 
exposure dataset)
Visit 16 end date; if Visit 16 is 
missing, then first OLE dosing 
date + 365
OLE Year 2
(visit 17-20)
“OLE Year 1 To” date + 1 
Visit 20 end date; if Visit 20 is 
missing, then “OLE Year 2 From” 
date + 365
OLE Year 3
(visit 21-24)
“OLE Year 2 To” date + 1
Visit 24 end date; if Visit 24 is 
missing, then “OLE Year 3 From” 
date + 365
OLE Year 4
(visit 25-28)
“OLE Year 3 To” date + 1
Visit 28 end date; if Visit 28 is 
missing, then “OLE Year 4 From” 
date + 365
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 18
3
Appendix 2.2. Endpoint Derivations
Not applicable.
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical 
Analyses/Populations
Not applicable.
Appendix 3. Data Set Descriptions
Not applicable.
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 19
Appendix 4. Statistical Methodology Details
Not applicable.
Appendix 5. List of Abbreviations
Abbreviation
Term
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
AHV
Annualized height velocity
BA
Bone age
BM
Bone maturation
CA
Chronological age
CDISC
Clinical Data Interchange Standards Consortium
CDC
Center of Disease Control and Prevention
CS
Clinical significance
CTP
C-terminal peptide
DSMB
Data Safety Monitoring Board
FAS
Full analysis set
FSH
Follicle-stimulating hormone
GHD
Growth hormone deficiency
hGH
Human growth hormone
HT
Height
HV
Height velocity
IGFBP3
Insulin-like growth factor-binding protein-3
IM
Intramuscular
INN
International Nonproprietary Name
LH
Luteinizing hormone
LT-OLE
Long-term open-label extension
MedDRA
Medical Dictionary for Regulatory Activities
OLE
Open-label extension
MedDRA
Medical Dictionary for Regulatory Activities
PP
Per protocol set
PT
Preferred term
r-hGH
Recombinant human growth hormone
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 20
Abbreviation
Term
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SDS
Standard deviation score
SOC
System organ class
TEAE
Treatment-emergent adverse event
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 21
Appendix 6. List of Summary Tables
“Total” indicates across ADA status in the summary tables below.
S
 
 
By treatment
 
By treatment
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 22
 
 
 
 
 
1 SDS and Change from Baseline vs. Time 
 
Somatrogon to 
Summary of Bone Maturation in 
OLE
 
 
 


Protocol CP-4-006 (C0311009) OLE (Somatrogon) Statistical Analysis Plan
Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 23
Type
Title 
Note
 
Summary of Treatment Emergent Serious Adverse Events by SOC 
 
 
 
 

Prot_000.pdf: 
 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 1 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER, 12 MONTHS, 
EFFICACY AND SAFETY STUDY OF WEEKLY MOD-4023 COMPARED TO 
DAILY GENOTROPIN® THERAPY IN PRE-PUBERTAL CHILDREN WITH 
GROWTH HORMONE DEFICIENCY 
 
 
Sponsor: 
OPKO Biologics Ltd.  
Ashlagan 16 Kiryat Gat, Israel 
Tel: +972-8-9300051  Fax: +972-8-9300091 
Protocol Number 
(No.): 
CP-4-006 Amendment 2, 27-APR-2018 
 
IND No.:  
 
EudraCT No.: 
2016-003874-42 
 
 
 
 
 
 
 
Safety Medical 
Officer: 
, MD 
Statistician: 
,  
 
 
 
 
 
Confidentiality Statement 
This protocol is a confidential communication document of OPKO Biologics Ltd. (OBL), an affiliate of OPKO 
Health, LLC. The recipient of this document agrees not to disclose the information contained herein to others 
without prior written authorization of OBL 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 Israeli Ministry of Health (MoH), European Medicinal Agency (EMA), or the 
United States of America (USA) Food and Drug Administration (FDA) under the condition that they maintain 
confidentiality. 
PPD
PPD
PPD
CCI




 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 3 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
 
 
Principal Investigator (PI) 
By signing below, I, the PI approve the protocol and agree to conduct the clinical study 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 OBL.  
 
 
 
Investigator Signature 
Date 
 
Name 
Institution 
City, Country


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 4 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
PROTOCOL SYNOPSIS 
STUDY TITLE 
A phase 3, open-label, randomized, multicenter, 12 months, efficacy and safety 
study of weekly MOD-4023 compared to daily Genotropin® therapy in pre-
pubertal children with growth hormone deficiency. 
PROTOCOL NO. 
CP-4-006, Amendment 2, 27-APR-2018 
IND NO. 
 
EUDRACT NO. 
2016-003874-42 
CLINICAL 
SITES 
The study will be conducted in approximately 30-40 countries at approximately 
200 clinical sites.  
STUDY PHASE 
3 
THERAPEUTIC 
INDICATION 
Treatment of children with growth failure due to growth hormone deficiency 
(GHD). 
STUDY 
PRIMARY 
OBJECTIVE  
To demonstrate that weekly MOD-4023 administration is non-inferior to daily 
Genotropin administration. 
STUDY 
SECONDARY 
OBJECTIVES 
 
To evaluate the safety and tolerability of weekly MOD-4023 
administration. 
 
To demonstrate successful operation (single injection) of the MOD-
4023 single patient use, multi-dose, disposable pre-filled pen (PEN).  
 
Evaluation of participant and observer feedback on MOD-4023 device 
usability. 
 
To confirm the correct operation of devices returned for evaluation. 
LT-OLE 
OBJECTIVE 
To demonstrate long term (LT) safety and efficacy of MOD-4023 in an open-
label extension (OLE). 
OTHER 
OBJECTIVES 
To evaluate the effect of weekly MOD-4023 and daily Genotropin® 
administration on quality of life (QoL), as measured by the QoLISSY (Quality 
of Life in Short Stature Youth) in a specific number of countries (determined by 
availability of validated translated tools) during the first 12 months of treatment.  
STUDY DESIGN 
The study will initially consist of a 12 month, open-label, randomized, active 
controlled, parallel group study comparing the efficacy and safety of weekly 
MOD-4023 to daily growth hormone (GH), Genotropin®. Patients will enter a 
long term open-label extension to demonstrate continued safety and efficacy of 
MOD-4023 treatment (all patients) after successful completion of the first 12 
months of treatment.  
Initial Study Period (main study): After a screening period lasting up to 8 
weeks (wks), patients meeting the eligibility criteria, as approved by the Global 
Study Medical Monitor (MM), will be randomized in a 1:1 ratio to MOD-4023 
or Genotropin® for 12 months.  
If the patient’s screening process is delayed because of a benign illness or 
unforeseen benign condition (i.e. pharyngitis, viral gastrointestinal (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 will be 
added to the duration of the screening period, but not in excess of an additional 4 
wks (total of 12 wks). 
An independent and external Data and Safety Monitoring Board (DSMB) will 
review the key safety data approximately every 4 months or on ad hoc basis.  
CCI


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 5 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
LT-OLE Period (LT-OLE): Patients who received MOD-4023 during the main 
study will continue in the LT-OLE with the same dose (mg/kg/wk) of MOD-
4023. Patients who received Genotropin® during the main study will be switched 
to MOD-4023 and will begin treatment with a dose of 0.66 mg/kg/wk beginning 
no less than one day after cessation of Genotropin® treatment. The key safety 
data will be reviewed by an independent DSMB approximately every 6 months.    
During the entire study, doses will be adjusted based on the patients’ body 
weight every 3 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]). 
STUDY 
PROCEDURES 
Visit 1 - Screening Period (Day -56 to Day -1) 
The Screening period will last up to 8 wksa and can be conducted over several 
visits prior to eligibility approval and 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 (where applicable 
based on age and country) and consent from the parent(s) or legal guardian(s) 
will be obtained.  
The following assessments will be conducted at these screening visits:  
 
Inclusion/exclusion verification. 
 
Parental heightsb (Ht), and patients’ Ht, Ht SDS, Ht velocity (HV) and 
HV SDS. 
 
Body weight and body mass index (BMI) SDS. 
 
Medical history, including a description of pituitary deficiencies, 
concomitant and previous medications. 
 
Overall health status assessment, including complete physical 
examination and vital signs. 
 
Pubertal status (according to Tanner stages). 
 
Bone age (BA) determination according to the method of Greulich-Pyle 
using a central BA readerc. 
 
Assessment of biochemical markers and stimulation testsd: 
o Two different GH stimulation (provocation) tests: insulin 
tolerance test (ITT) (with serum cortisol response 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 laboratory results), extra time will be added to the duration of the 
screening period, but not in excess of an additional 4 wks (total of 12 wks screening period). 
b It's recommended that parents’ Ht be measured at the site. If measured parental Ht is not available an estimate 
should be provided by the parent. 
c Historical BA assessment might be accepted if it was done according to the method of Greulich-Pyle no more 
than 6 months prior to the informed consent form (ICF) signature date. If the patient is eligible, the BA must 
be repeated at Visit 2 prior to dosing. The Visit 2 scan will be the baseline scan for these patients.  
d Local, documented provocation tests that were performed prior to ICF signature, might be accepted by the 
global study MM according to his/her judgment. 
e ITT 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. Historical ACTH test is acceptable. 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 6 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
hypoglycemia if insulin stimulation test is chosen)/arginine 
test/clonidine test/glucagon test/L-dopa test. 
o Analysis of serum GH levels (and glucose and serum cortisol if 
ITT is performed) may be performed by local laboratories and 
must be provided for global MM review and approval. 
o Assessment of morning cortisol (at 8 am ± 1 hour) 
 
If morning cortisol is below 190 nmol/L (7 μg/dL), test 
for adrenal insufficiency will be required – low dose 
adrenocorticotropic hormone (ACTH)e or corticotropin 
releasing hormone (CRH) stimulation test (only if the 
patient 
was 
not 
previously 
assessed 
for 
the 
hypothalamus-pituitary-adrenal 
axis 
or 
has 
been 
diagnosed with adrenal insufficiency).  
o Assessment of IGF-1, IGF-1 SDS, IGF binding protein-3 
(IGFBP-3) and IGFBP-3 SDS levels.  
 
Assessment of anti-human GH (hGH) antibody (Ab) levels. 
 
Assessments of routine safety: chemistry, hematology and urinalysis.  
 
Assessment of thyroid function tests (thyroid stimulating hormone 
[TSH], free thyroxine [FT4]). 
 
Assessment of glucose metabolism (overnight fasting insulin, overnight 
fasting glucose and glycated hemoglobin [HbA1C]). 
 
Head magnetic resonance imaginga (MRI), if possible with contrast or 
computed tomography (CT) scan. 
 
Assessment of karyotype in girlsb. 
 
SHOX (short stature homeobox) gene evaluationc. Patients with 
confirmed multiple pituitary hormone deficiencies or confirmed 
structurally abnormal pituitary gland or other anatomical reasons for 
GHD do not require SHOX gene evaluation. SHOX gene evaluation is 
mandatory for isolated GHD with normal brain MRI. 
All laboratory assessments are performed by a central laboratory unless stated 
otherwise.  
Key data and all test results obtained during screening will be reviewed by the 
Global Study MM and eligibility will be confirmed prior to randomization of 
each patient.   It is recommended that the Investigator randomize the patient 
within 7 days of confirmed eligibility. 
Main Study Treatment Period (Day 1/Baseline to Month 12)  
Eligible patients will be randomized (centralized randomization within each 
region) in a 1:1 fashion to receive either weekly MOD-4023 or daily 
Genotropin® for 12 months.  
The following 3 stratification factors will be applied when randomizing patients 
to the treatment groups: 
                                                 
a Historical MRI or CT is permitted if within 12 months prior to ICF signature date.  For GHD associated with a 
congenital central nervous system (CNS) defect, the global study MM could allow for use of the historic MRI or 
CT > 12 months old.  
b. Historical karyotype data and chromosomal microarray data are acceptable. 
c Historical data is acceptable. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 7 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
Region: 
1. Western Europe, Israel, Australia, New Zealand, Canada and USA;  
2. Central and Eastern Europe, Greece, Turkey, Latin America and 
Asia, except for India and Vietnam;  
3. India and Vietnam. 
 
Peak GH levels (≤3 ng/mL; >3 to ≤7 ng/mL; and >7 to ≤10 ng/mL). The 
proportion of patients with peak GH levels >7 to ≤10 ng/mL, will be 
capped at 35-40% of total sample-size, in the randomization scheme. 
 
Chronological age (CA) (≥3 years to ≤7 years, 0 days; and >7 years, 0 
days) 
During main study, patients will be scheduled for clinic visits at Visit 2 
(Baseline/Day 1, first dose – no more than 2 wks post randomization), Visit 3 
(Day 10ab; 10+4 days post first dose), and at Wk 4 (1 month), 3 months and 
every 3 months thereafter (up to 12 months).  
Visit 2 (Day 1/Baseline) will be conducted on day of first dosing– no more than 
2 wks post randomization, Visit 4 (Month 1/Wk 4 [+1 wk]), Visit 5 Month 3/Wk 
13 [±1 wk]), Visit 6 (Month 6/Wk 26 [±1 wk]), Visit 7 (Month 9/Wk 39 [±1 
wk]), and Visit 8 (Month 12/Wk 52 [±1 wk]) will be conducted on day 4 (-1 
day) post dose to obtain IGF-1 measurements expected to reflect average levels 
of IGF-1 throughout the wk.  
The following assessments will be obtained at these visits:  
 
Auxology measurements (excluding Visit 3 and Visit 4): Actual Ht 
(average of three consecutive measurements) measured on a calibrated 
wall mounted stadiometer. 
 
AEs, local tolerability, and concomitant medications (on site or by 
phone) (all visits). 
 
Overall health status assessment, including complete physical 
examination and vital signs assessment (excluding Visit 3). 
 
Safety laboratory tests (excluding Visit 3): chemistry, hematology and 
urinalysis. 
 
Pubertal status (according to Tanner stages) (excluding Visits 3 and 4);  
 
Urine pregnancy test at every visit once a female patient reports first 
menstrual cycle (menarche) (excluding Visits 3 and 4). 
 
Assessment of thyroid function (excluding Visits 3 and 4): TSH, FT4.  
 
Assessment of biochemical markers (excluding Visit 3): IGF-1, IGF-1 
SDS, IGFBP-3 and IGFBP-3 SDS serum levels.  
 
Assessment of MOD-4023 serum levels (applicable for MOD-4023 arm 
only) (Visits 2, 3, 4, 5, 6a, 7 and 8a). 
 
Parameters of glucose metabolism (excluding Visits 3 and 4): overnight 
fasting glucose, overnight fasting insulin, HbA1c. 
 
Parameters of lipid metabolism (excluding Visits 3 and 4): overnight 
                                                 
a Applicable only for MOD-4023, Visit 3 assessments, if conducted on Day 14 (dosing day), should be 
performed prior to dosing. 
b Blood samples for MOD-4023 treatment group can be collected at site OR at patient's home, based on local 
regulations and nurse availability. If home visit, a questionnaire, as described in Appendix I, should be 
completed. If blood sample is collected on Day 14, it should be obtained prior to dosing. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 8 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
fasting cholesterol, triglycerides, high density lipoprotein (HDL), low 
density lipoprotein (LDL), lipoprotein a (Lp(a)), Free Fatty Acids 
(FFA). 
 
For males that are 13 years and older: Luteinizing Hormone (LH), 
Follicle-Stimulating Hormone (FSH) and testosterone. For females that 
are 12 years and older: LH, FSH and estradiol (Visit 8 only). 
 
Assessment of anti-MOD-4023 Ab (MOD-4023 arm) at Visits 2, 3, 4, 5, 
6a, 7, 8a. 
 
Assessment of anti-hGH Ab (Genotropin® arm) at Visits 2, 4, 5, 6, 7 and 
8 only. 
 
BA assessments at Visits 1, 2 (at Visit 2 only if historical data was 
provided for eligibility evaluation and not performed as part of Visit 1) 
and Visit 8 only. 
 
Fundoscopy (if there are signs or symptoms indicative of benign 
intracranial hypertension). 
 
ECG at Visit 2 for all patients, pre- dosing and ECG on Visit 6 for 
patients treated with daily Genotropin®. All MOD-4023 patients will 
undergo an ECG during Visit 6b, 7-12 hours post dosing.  
 
USA Only - The Participant Assessment Tool (PAT) completed at Wks 
1, 2, 3, 4, 5 and 6 for MOD-4023 treated patients. In any given wk a 
new PAT will be completed for each PEN used that wk (in some cases 
more than 1 PEN may be used for full dose administration, in which 
case a PAT will be completed for each PEN used that wk. In some 
cases, more than 1 injection from the same PEN may be needed, in 
which case only 1 PAT is completed for that PEN that wk). 
 
USA Only - The Observer Assessment Tool (OAT) completed at Wk 1 
for MOD-4023 treated patients. A new OAT will be completed for each 
PEN used (in some cases more than 1 PEN may be used for full dose 
administration, in which case an OAT will be completed for each PEN 
used. In some cases, more than 1 injection from the same PEN may be 
needed, in which case only 1 OAT is completed for that PEN). Wk 1 
corresponds to study Visit 2, which will be at the site. 
 
Individual dose adjustment every three months based on weight. 
 
Drug dispensing Visits 2, 4, 5, 6, 7 and 8 (for patients entering the LT-
OLE). 
 
QoL questionnaire (Visits 2 and 8 only); patients below the age of 7 and 
0 days will be completing the questionnaire with their parents/legal 
guardians using a parent questionnaire while patients above and 
including the age of 7 and 0 days will be encouraged to use the child 
questionnaire. The QoL questionnaire will be completed in specific 
countries (determined by availability of validated translated tools) as 
described in Appendix L. 
For MOD-4023 patients arm only, Visit 3 (Day 10 [+4 days] post first dose), 
Visits 6a (Month 6/Wk 26 [±3 wks]) and Visit 8a (Month 12/Wk 52 [±1 wk]) 
will be conducted on dosing day, blood samples will be taken pre-dose for 
assessment of MOD-4023 serum levels. These blood samples can be collected at 
site OR at patient's home, based on local regulations and nurse availability. If 
home visit, a questionnaire as described in Appendix I should be completed. 
For Genotropin® patients on Day 10 (+4 day) post first dose a phone interview 
will be conducted according to the questions as provided in Appendix I.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 9 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
For ECGs that will be conducted at Visit 6b, Month 6/Wk 26 (± 3 wk) at Time 
7-12 hours post-dose for MOD-4023 treated patients, patients will be requested 
to inject MOD-4023 during the day/night at their convenience and come to the 
study site at the requested time point for ECG.  
Visit 6a and 6b may be combined on the same day (only if 6a is done prior to 
dosing). 
Genotropin® patients will have an ECG assessment at Visit 6 (no time limitation, 
however date and time of the assessment will be recorded). 
Both MOD-4023 and Genotropin® treated patients will be required to complete a 
patient diary card at home or at site (if injection done on site). MOD-4023 
injected patients will complete the patient diary after every injection to collect 
data on AE, concomitant medications and local injection site reactions. 
Genotropin® injected patients will complete a patient diary once a wk 
(preferably on the same day of the wk, each wk) to collect data on AE, 
concomitant medications and local injection site reactions. 
 
LT-OLE (Visit 10 to Visit 16): 
After successful completion of 12 months treatment in the main study and 
continuing to meet the LT-OLE inclusion/exclusion criteria of this protocol, 
patients will be eligible to rollover into a single arm LT-OLE treatment period 
with MOD-4023. An informed consent/assent will be obtained from patients 
and/or parent or legal/authorized guardian. Patients who received MOD-4023 
during the main study will continue with the same dose (mg/kg/wk), adjusted for 
body weight, of MOD-4023 they received. For these patients, study visits will 
take place on Day 4 (-1) post-dose. These patients will consent to the LT-OLE 
preferably during Visit 7 of the main study to ensure availability of MOD-4023 
at their next visit. If necessary, informed consent can be obtained at Visit 8 main 
study/10 LT-OLE. These Patients will continue treatment at visit 8/10, skip 
Visits 9 and 11 and have a telephone visit at Visit 12 (one month post LT-OLE 
entry (Month 13 [±2wk])). 
Patients who received Genotropin®, during the main study will be switched to 
MOD-4023 starting no less than one day [+2wk] after cessation of Genotropin® 
treatment. Recommended injection days are indicated in Appendix E. These 
patients will consent to the LT-OLE preferably during Visit 7 of the main study 
to ensure availability of MOD-4023 at their next visit. If necessary, informed 
consent can be obtained at Visit 8/10. Patients will begin treatment with MOD-
4023 at Visit 8/10, skip Visit 9 and have additional onsite visits at Visit 11 
(Month 12, Day 10 post first MOD-4023 dose [10+4 days]) and Visit 12 (one 
month post first MOD-4023 dose (Month 13 [±2wk])).  All patients will be 
provided with a diary card. 
For all patients switching from Genotropin® to MOD-4023, the following will 
also be done: 
 
MOD-4023 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 device. 
 
Local tolerability after first dose administered at site.  
Patients who experience a delay for any reason between completion of the main 
study and entry into the LT-OLE may have to temporarily stop treatment. If 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 10 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
initiation/re-initiation of treatment occurs less than 90 days after Visit 8 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 LT-OLE after confirmation of availability of all required baseline LT-OLE 
assessments (Visit 8/10).  The following tests and assessments must be 
repeated: 
 
Safety laboratory tests: chemistry, hematology and urinalysis. 
 
Parameters of glucose metabolism: overnight fasting glucose, overnight 
fasting insulin, HbA1c. 
 
Assessment of anti-MOD-4023 Ab for all patients (Genotropin® group 
– baseline for future tests). 
 
Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGF-BP-3 and 
IGF binding protein-3 (IGFBP-3) SDS serum levels. 
 
Visit 11 (Month 12, Day 10 [+4 days] post first dose) will be performed for 
patients switching from Genotropin® to MOD-4023 only. The following 
assessments will be conducted at the study site or at the patient's home (if 
allowed according to local regulations): 
 
MOD-4023 serum levels.  
 
Anti-MOD-4023 Abs. 
 
AEs and local tolerability (aligned with Appendix H) assessment.  
 
Concomitant medication recording aligned with the questionnaire in 
Appendix I. 
 
Visit 12 (one month post first MOD-4023 dose (Month 13 [±2wk])) will be 
performed on site for patients switching from Genotropin® to MOD-4023. The 
following assessments will be conducted: 
 
AEs, local tolerability, and concomitant medications. 
 
Overall health status assessment, including complete physical 
examination and vital signs.  
 
Urine pregnancy test once a female patient reports first menstrual cycle 
(menarche). 
 
Safety laboratory tests: chemistry, hematology and urinalysis.  
 
Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGFBP-3 and 
IGFBP-3 SDS serum levels. 
 
MOD-4023 serum levels.  
 
Anti-MOD-4023 Abs. 
 
Fundoscopy (ONLY if there are signs or symptoms indicative of benign 
intracranial hypertension). 
 
Return of used and unused injection devices to the site and diary card. 
 
Drug dispensing and accountability. 
 
Existing MOD-4023 patients will have a telephone visit at Visit 12 (one month 
post LT-OLE entry [Month 13 ±2wk]) to ask about AEs, local tolerability and 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 11 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
concomitant medications. This visit will be completed using the questionnaire in 
Appendix I.   
All patients (existing MOD-4023 and Genotropin® to MOD-4023 switch): Visit 
13 (Month 15/Wk 65 [±2wk]), Visit 14 (Month 18/Wk 78 [±2wk]), Visit 15 
(Month 21/Wk 91 [±2wk]), Visit 16 (Month 24/Wk 104 [±4wk]): During the 
first year of LT-OLE, the following assessments will be conducted every three 
months (on day 4 (-1) post-dose for all patients:   
 
Auxology measurements: Actual height (average of three consecutive 
measurements) measured on a calibrated wall mounted stadiometer.  
 
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: IGF-1, IGF-1 SDS, IGFBP-3 and 
IGFBP-3 SDS serum levels.  
 
Assessment of MOD-4023 serum levels. 
 
Assessment of anti-MOD-4023 Ab. 
 
Fundoscopy (if there are signs or symptoms indicative of benign 
intracranial hypertension). 
 
Return of used and unused injection devices to the site and diary card. 
 
Drug dispensing and accountability. 
 
The following assessments will also be conducted at Visit 13 (Months 15), Visit 
14 (Month 18) and Visit 16 (Month 24) on day 4 (-1) post-dose visits: 
 
Safety laboratory tests: chemistry, hematology and urinalysis.  
 
Assessment of thyroid function: TSH, FT4. 
 
Parameters of glucose metabolism: overnight fasting glucose, overnight 
fasting insulin, HbA1c.  
 
Parameters of lipid metabolism: overnight fasting cholesterol, 
triglycerides, HDL, LDL, Lp(a), FFA.  
 
The following assessments will also be conducted at Visit 16 (Month 24) on day 
4 (-1) post-dose: 
 
ECG. 
 
Bone age. 
 
Pubertal status. 
 
For males that are 13 years and older: LH, FSH and testosterone. For 
females that are 12 years and older: LH, FSH and estradiol. 
Collection of samples for MOD-4023 serum levels and anti-MOD-4023 Ab 
levels must be performed on dosing day pre-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 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 12 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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.  
 
LT-OLE (Visits 17 to Study closure):   
Following completion of the first year of LT-OLE the following assessments 
will be conducted every three months on day 4 (-1) post-dose for all patients:   
 
Auxology measurements: Actual height (average of 3 consecutive 
measurements) measured on a calibrated wall mounted stadiometer.  
 
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). 
 
Return of used and unused injection devices to the site and diary card. 
 
Drug dispensing and accountability. 
 
The following assessments will also be conducted every six months on day 4 (-
1) post-dose visits: 
 
Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGFBP-3 and 
IGFBP-3 SDS serum levels.  
 
Safety laboratory tests: chemistry, hematology and urinalysis.  
 
Assessment of thyroid function: TSH, FT4. 
 
Parameters of glucose metabolism: overnight fasting glucose, overnight 
fasting insulin, HbA1c.  
 
Parameters of lipid metabolism: overnight fasting cholesterol, 
triglycerides, HDL, LDL, Lp(a), FFA.  
 
Assessment of MOD-4023 serum levels. 
 
Assessment of anti-MOD-4023 Ab. 
 
Additional assessments will be performed once a year, every 12 months on day 
4 (-1) post-dose visits: 
 
ECG.  
 
Bone age. 
 
Pubertal status (according to Tanner stages).  
 
For males that are 13 years and older: LH, FSH and testosterone. For 
females that are 12 years and older: LH, FSH and estradiol. 
After month 13 of LT-OLE, collection of samples for MOD-4023 serum levels, 
anti-MOD-4023 Ab levels and 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. If the visit is performed on dosing day, samples should be 
obtained pre-dose.  
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 13 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Patients will be contacted by telephone 30 days [± 5 days] after EOS/ET visit in 
order to obtain safety related information. 
STUDY 
DURATION 
Study duration for each participating patient in the main study will be up to 15 
months in total as follows: 
Screening period: up to 8 wks.  
If the patient’s screening process is delayed as described above, extra time will 
be added to the duration of the screening period, but not in excess of an 
additional 4 wks (total of 12 wks screening period). 
Treatment period: 12 months. 
The LT-OLE study will continue until marketing approval.  
Follow-up:   during the main study one month post dosing for those withdrawn 
or not continuing on in the LT-OLE, and one month post EOS/ET in the LT-
OLE. 
NUMBER OF 
PATIENTS 
Approximately 220 pre-pubertal boys and girls not yet 12 and 11 years of age, 
respectively, will be included and randomized 1:1 to the weekly MOD-4023 arm 
or the daily Genotropin® comparator arm. Eligible patients that complete the 
main study will be allowed to continue in the LT-OLE.  
INCLUSION 
CRITERIA 
Inclusion into the main study: 
1. Pre-pubertal children aged ≥3 years, and not yet 11 years for girls (10 years 
and 364 days) or not yet 12 years (11 years and 364 days) for boys, (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 two different GH provocation tests defined 
as a peak plasma GH level of ≤10 ng/mL, determined by local or central 
laboratory using a validated assaya.  Global study MM may accept prior 
local laboratory results; subject to pre-approval and if the tests were 
conducted as recommended in the protocol Appendix Bb.  
3. BA is not older than CA and should be <10 for girls and <11 for boys. 
4. Without prior exposure to any recombinant hGH (r-hGH) therapy (naïve 
patients). 
5. Impaired Ht velocity defined as: 
 
Annualized HV below the 25th percentile for CA (HV < -0.7 SDS) 
and gender according to the OPKO HV (Tanner, Prader and 
Hermanussen) calculator, provided.  
 
The interval between 2 Ht measurements should be at least 6 
months, but should not exceed, 18 months prior to inclusion.  
6. Baseline IGF-1 level of at least 1 standard deviation (SD) below the mean 
IGF-1 level standardized for age and sex (IGF-1 SDS ≤-1)c according to the 
central laboratory reference values. A single re-test will be allowed (subject 
to discussion with MM) if all other criteria are met. 
7. Normal calculated glomerular filtration rate (GFR) based on updated 
“bedside” Schwartz formula for pediatric patients (calculation is 
                                                 
a ITT, with serum cortisol response to hypoglycemia if insulin stimulation test is chosen / Arginine test / 
Clonidine test / Glucagon test / L-dopa test 
b Prior spontaneous nocturnal GH secretion should be  10 ng/mL. 
c According to rounding policy IGF-1 results ≤-0.95 might be acceptable as well  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 14 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
recommended below): 
 
Creatine Clearance Rate (CrCL) (mL/min/1.73 m2) =0.413*Ht/serum 
creatine (Scr)  
      
Ht:  in cm;  
 
Scr: in mg/dL. 
8. 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. 
9. Normal 46XX karyotype for girls.  
10. Willing and able to provide written informed consent of the parent or legal 
guardian of the patient and written assent from pediatric patients (where 
applicable based on age and country regulation). 
 
Inclusion into the LT-OLE: 
11. Completion of the main study (12 months of treatment) with adequate 
compliance.  
12. Willing and able to provide written informed consent of the parent or legal 
guardian of the patient and written assent from pediatric patients (where 
applicable based on age and country regulation).  
13. Agreement to refrain from sexual activity during the LT-OLE i.e. observe 
complete sexual abstinence as the only acceptable contraceptive measure 
during the LT-OLE (for pubertal and post-pubertal patients).  
EXCLUSION 
CRITERIA 
Exclusion during the main study 
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 psychosocial dwarfism. 
5. Children born small for gestational age (SGA – birth weight and/or birth 
length <-2 SDS for gestational age). 
6. Presence of anti-hGH Ab at screening. 
7. Any clinically significant (CS) 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. Types 1 and 2 diabetic patients who, in the opinion of the investigator, are 
not receiving standard of care treatment, or are non-compliant with their 
prescribed treatment or who are in poor metabolic control (Criteria for 
controlled diabetes are defined in Appendix F). 
9. Chromosomal abnormalities including Turner’s syndrome, Laron 
syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver 
syndrome, SHOX mutations/deletions and skeletal dysplasias.  
10. Concomitant administration of other treatments that may have an effect on 
growth such as anabolic steroids, or sex steroids, with the exception of 
Attention-Deficit/Hyperactivity Disorder (ADHD) drugs or hormone 
replacement therapies (thyroxin, hydrocortisone, desmopressin 
[DDAVP®]). 
11. Children requiring glucocorticoid therapy (e.g. for asthma) that are taking 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 15 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
chronically a dose greater than 400 µg/day of inhaled budesonide or 
equivalent as provided in Appendix J. 
12. Major medical conditions and/or presence of contraindication to r-hGH 
treatment. 
13. More than 1 closed epiphyses. 
14. Known or suspected Human Immunodeficiency Virus (HIV)-positive 
patient, or patient with advanced diseases such as Acquired 
Immunodeficiency Syndrome (AIDS) or tuberculosis. 
15. Drug, substance, or alcohol abuse. 
16. Known hypersensitivity to the components of study medication. 
17. Other causes of short stature such as celiac disease, uncontrolled primary 
hypothyroidism and rickets. 
18. The patient and/or the parent/legal guardian are likely to be non-compliant 
in respect to study conduct. 
19. Participation in any other study of an investigational agent within 30 days 
prior to ICF signature (including administration of investigational agent). 
20. Study enrollment requirements have been met or the study has been closed 
by the Sponsor prior to the completion of screening process.  
Exclusion during the LT-OLE: 
21. 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®]) 
22. Change in medical condition during the treatment period (such as, but not 
limited to, development of a serious inter-current critical illness, a severe 
adverse drug reaction, etc.) 
23. Positive pregnancy test. 
24. Unresolved drug related (MOD-4023 or Genotropin®) SAE from the 
treatment period as per MM judgement.  
INVESTIGATIONAL 
PRODUCT (IP) 
ROUTE AND 
DOSAGE FORM 
MOD-4023 is a long-acting modified 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 single patient use, multi-dose, disposable pre-filled 
pen (PEN).   
Somatrogon is the International Nonproprietary Name/United States Adopted 
Name (INN/USAN) of MOD-4023 and can be used interchangeably with MOD-
4023. 
MOD-4023 will be administered as a subcutaneous (SC) injection, preferably 
(but not required) in the morning hours once weekly, 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.  
The starting dose for the weekly administration will be 0.66 mg/kg/wk. All 
patients on Genotropin® that complete Visit 8/10 and continue into the LT-OLE 
will start treatment with MOD-4023 at 0.66 mg/kg/wk. 
IGF-1 SDS will be monitored throughout the study, and if a patient has an IGF-1 
level above +2.0 SDS, they will be requested to return for an unscheduled visit 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 16 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
within 4-6 wks after the > +2.0 SDS result, on day 4(-1) post dose (for MOD-
4023 treated patients).  If their IGF-1 level is still > +2.0 SDS, the most recent 
dose will be reduced by 15%.  They will continue to be monitored for any 
further dose reduction.  
REFERENCE 
THERAPY 
Genotropin® is a daily GH, and is used as the reference therapy in this study.  
A delivery device (Genotropin® 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.  
Starting dose regimen for Genotropin®: 0.034 mg/kg/day (which is equivalent to 
0.24 mg/kg/wk divided equally into 7 daily injections).  
IGF-1 SDS will be monitored throughout the study, and 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 wks after the > +2.0 SDS result, on any day post dose (for 
Genotropin® treated patients).  If their IGF-1 level is still above +2.0 SDS, the 
most recent dose will be reduced by 15%.  They will continue to be monitored 
for any further dose reduction. 
MAIN STUDY 
ENDPOINTS 
Primary efficacy endpoint: 
 Annual HV in cm/year after 12 months of treatment.  
Secondary efficacy endpoints (Auxology/Clinical): 
 Annualized HV after 6 months of treatment. 
 Change in Ht SDS at 6 and 12 months, compared to baseline.  
 Change in bone maturation (BM) at the end of 12 months, compared to 
Baseline BAa (calculated as BA/CA). 
Secondary endpoints (Biochemical): 
 Absolute IGF-1 and IGF-1 SDS levels on Day 4 (-1) after MOD-4023 dosing 
across study visits.  
 IGFBP-3 levels and IGFBP-3 SDS on Day 4 (-1) after MOD-4023 dosing 
across study visits. 
SAFETY 
ENDPOINTS 
 Incidence of AEs and serious adverse events (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: blood fasting glucose, fasting insulin 
level, HbA1c. 
 Thyroid (endrocrinology) status. 
 Lipid profile.  
 All other safety hematology, biochemical parameters and urinalysis. 
 Physical examination. 
 Vital signs. 
 Fundoscopy results- if performed (normal/abnormal). 
 ECG. 
OTHER 
ENDPOINT(S) 
 Proportion of successful single injections out of total number of single 
injections using the MOD-4023 PEN in USA patients at Wks 1, 2, 3, 4, 5, and 
                                                 
a Baseline BA can be taken at either Screening or Visit 2. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 17 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
6, based on the PAT. 
 Proportion of successful single injections out of total number of single 
injections using the MOD-4023 PEN in USA patients at Wk 1, based on the 
OAT. 
 Comments on the PAT related to successful or unsuccessful injection 
attempts. 
 Comments on the OAT related to successful or unsuccessful injection 
attempts. 
 Information gained by inspection of returned devices. 
 QoL core total score measured by the QoLISSY questionnaire at Baseline and 
month 12 in specific countries. 
LT-OLE 
ENDPOINT(S) 
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: blood fasting glucose, fasting 
insulin level, HbA1c; 
 Thyroid (endocrinology) status; 
 Lipid profile;  
 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 LT-OLE year 
1 and to previous values from LT-OLE year 2 onwards). 
 
Biochemical Endpoints 
 
IGF-1 and IGF-1 SDS levels on day 4 (-1) after MOD-4023 dosing 
across study visits.  
 
IGFBP-3 levels and IGFBP-3 SDS on day 4 (-1) after MOD-4023 
dosing across study visits. 
SAMPLE SIZE 
CALCULATION 
The aim of the study is to demonstrate that SC weekly MOD-4023 is non-
inferior to SC daily Genotropin® administration with respect to the primary 
efficacy endpoint of annual HV in cm/year after 12 months of treatment.  
Non-inferiority will be concluded if the lower bound of the 2-sided 95% 
confidence interval (CI) for the mean treatment difference (MOD-4023 – 
Genotropin®) in the primary efficacy endpoint is >–1.8 cm/year.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 18 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
The following assumptions were made in the sample size calculation: 
 
2-sided alpha of 0.05, 
 
80% power, 
 
between-patient standard deviation of annual growth rate of 2.5 cm/year in 
all treatment groups, 
 
non-inferiority margin of –1.8 cm/year, 
 
true mean treatment difference (MOD-4023 – Genotropin®) in the primary 
efficacy endpoint of –0.8 cm/year. 
With these assumptions, 100 treated patients per group will provide 80% power 
for the non-inferiority test. To allow for an approximate 10% dropout rate, 110 
patients will be randomized to each treatment group, for a total of 220 patients.  
STATISTICAL 
ANALYSIS: 
Details on the statistical methods will be provided in a Statistical Analysis Plan 
(SAP) prior to database lock.  
The aim of the present study is to demonstrate that in terms of annual HV at 12 
months (primary efficacy endpoint), weekly MOD-4023 is non-inferior to daily 
Genotropin® administration by a non-inferiority margin of 1.8 cm/year.  
With 
µM 
and 
µC 
representing 
the 
mean 
annual 
HV  
at 12 months for the MOD-4023 and the Genotropin® (Control) group, 
respectively, the following hypotheses will be tested:  
Null hypothesis H0: µM < µC – 1.8 cm/year;   
Versus (vs.) 
Alternate hypothesis H1: µM ≥ µC – 1.8 cm/year 
Non-inferiority will be concluded for the primary efficacy endpoint if the lower 
bound of the 2-sided 95% CI for the mean treatment difference (MOD-4023 – 
Genotropin®) is ≥–1.8 cm/year.  
Primary Efficacy Analysis: The CI for the difference of means between the 2 
treatments will be derived from an analysis using Analysis of Covariance 
(ANCOVA).   The ANCOVA model will include the stratification classes for 
treatment, age group, peak hGH value during stimulation test, region and 
gender, and Baseline Ht SDS as a covariate.  The determination of non-
inferiority will be based on least squares means for the 2 treatments from the 
ANCOVA and the 95% CI of the differences between the treatments.  
Summary statistics for HV at end of treatment and for absolute change in HV 
from Baseline to end of treatment, will be presented by treatment group (and 
further stratified by factors used in the ANCOVA model). 
Secondary Analyses: Annualized HV after 6 months of treatment, and change 
(from Baseline) in Ht SDS at 6 and 12 months will be summarized with 
descriptive statistics.  These 3 endpoints will each be analyzed using a similar 
ANCOVA model as used for the primary endpoint, with terms for treatment and 
the randomization strata (age, peak hGH value during stimulation test, region), 
gender and baseline value for each endpoint of interest. The model-derived least 
square means and standard error (SE) will be used to construct 95% CI for the 
difference between treatment groups.  These analyses are considered as 
supportive efficacy analyses. 
Change in BM, calculated as BA/CA at the end of 12 months, compared to 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 19 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Baseline will be characterized with descriptive statistics (mean, SD, and 95% 
CI) for each treatment group. 
Primary Efficacy Sensitivity Analysis: The ANCOVA-based primary efficacy 
analysis will be repeated using the modified intent-to-treat (mITT) set and the 
per protocol (PP) set.  
The ANCOVA-based primary efficacy analysis will be repeated on the full 
analysis set using last observation carried forward (LOCF) in place of multiple 
imputation for the handling of missing data. 
OAT and PAT (USA Only) 
OAT and PAT results will be summarized by using descriptive statistics.  
Proportion and counts of successful single injections out of total number of 
single injections using the MOD-4023 PEN in USA patients at Wks 1, 2, 3, 4, 5, 
and 6, based on the PAT will be reported. Similarly, counts and proportion of 
successful single injections out of total number of single injections using the 
MOD-4023 PEN in USA patients at Wk 1, based on the OAT will be reported. 
Details on the criteria constituting a successful single injection based on OAT 
and PAT, along with statistical methods to be used for descriptive summaries 
will be included in the SAP.  
Comments on the PAT and OAT related to successful or unsuccessful injection 
attempts 
The written comments provided on the PAT and OAT for successful or 
unsuccessful injection attempts will be listed. Any other written comments will 
also be listed. 
Information gained by inspection of returned devices 
Summary of the information gathered by inspecting the returned devices will be 
reported. 
The QoLISSY core total score at Baseline, 12 months and change from Baseline 
to month 12, for each group will be summarized using descriptive statistics. This 
will be done for specific countries as listed in the Appendix L.  
Biochemical Endpoints 
IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS will be summarized 
descriptively by visit.  Statistical comparisons between treatment groups are not 
planned.   Incidence of IGF-1 SDS >2.0 will summarized at each visit and in 
total as percentage of total samples. 
Safety data will be reported mainly using descriptive summaries for treatment 
emergent AEs and laboratory values that fall outside of pre-determined ranges. 
Both listings and tabular summaries will be reported for all safety endpoints. 
LT-OLE: 
The assessment of safety and efficacy (auxology/clinical and biochemical 
endpoints) during the LT-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 LT-OLE will be provided.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 20 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
TABLE OF CONTENTS 
Protocol Signature Page ...................................................................................................................... 2 
Protocol Synopsis................................................................................................................................ 4 
Table of Contents .............................................................................................................................. 20 
List of Tables .................................................................................................................................... 23 
List of Figures ................................................................................................................................... 23 
Glossary ............................................................................................................................................ 24 
1. Introduction ................................................................................................................................... 28 
1.1 Growth Hormone Deficiency ............................................................................................ 28 
1.2 Current Therapy ................................................................................................................ 28 
1.3 Investigational Therapy ..................................................................................................... 29 
1.3.1 Clinical Studies .............................................................................................................. 29 
1.3.2 Study Rationale .............................................................................................................. 30 
1.3.3 Rationale for Dose Selection .......................................................................................... 31 
2. Study Objectives ........................................................................................................................... 31 
3. Study Design ................................................................................................................................. 32 
4. Study Population ........................................................................................................................... 33 
4.1 Inclusion Criteria ............................................................................................................... 33 
4.2 Exclusion Criteria .............................................................................................................. 34 
4.3 Patient Identification ......................................................................................................... 35 
4.4 Removal, Replacement, or Early Withdrawal of Patients from Therapy or Assessment .. 35 
4.5 Handling of Withdrawals .................................................................................................. 36 
4.6 Sponsor's Termination of Study ........................................................................................ 37 
5. Investigational Plan and Study Procedures ................................................................................... 37 
5.1 Visit 1 - Screening Period (Day – 56 to Day -1) ............................................................... 37 
5.2 Main Study Treatment Period (Day 1/Baseline to Month 12) .......................................... 39 
5.2.1 Visit 2 (Day 1/Baseline) – recommended injection days as indicated in Appendix E ... 39 
5.2.2 Visit 3 , (Day 10 [+4days] post first dose) for MOD-4023 arm only ............................. 40 
5.2.3 Visit 3 (Day 10 [+4 days] post first dose) for Genotropin arm only .............................. 41 
5.2.4 Visit 4 (Month 1/Wk 4 [+1wk]) ..................................................................................... 41 
5.2.5 Visit 5 (Month 3/Wk 13 [±1wk]), Visit 6 (Month 6/Wk 26 [±1wk]), Visit 7 (Month 9/Wk 
39 [±1wk]), Visit 8 (Month 12/Wk 52 [±1wk]) ............................................................ 41 
5.2.6 Visit 6a (Month 6/Wk 26 [±3 wk]) and Visit 8a (Month 12/Wk 52 [±1 wk]) – MOD-4023 
Arm Only ....................................................................................................................... 42 
5.2.7 Visit 6b (Month 6/Wk 26 [±3 wk]) – MOD-4023 Arm Only ........................................ 42 
5.2.8 Visit 9 (Month 13/Wk 56 (±5 days)) – Only for patients not continuing on into the OLE 
study .............................................................................................................................. 42 
5.3 LT-OLE Period (Visits 10 to 16) ...................................................................................... 43 
5.3.1 Visit 11 (Month 12, Day 10 [+4days] post first MOD-4023 dose) for patients switching 
from Genotropin® to MOD-4023 only .......................................................................... 44 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 21 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.3.2 Visit 12 (one month post first MOD-4023 dose(Month 13 [±2wk])) will be performed on 
site for patients switching from Genotropin® to MOD-4023 ....................................... 44 
5.3.3 Visit 13 (Month 15/Wk 65 [±2wk]), Visit 14 (Month 18/Wk 78 [±2wk]), Visit 15 (Month 
21/Wk 91 [±2wk]), Visit 16 (Month 24/Wk 104 [±4wk]) ............................................ 44 
5.4 LT-OLE (Visits 17 to Study closure) ................................................................................ 45 
5.5 Early Discontinuation Study Visit ..................................................................................... 47 
5.6 Unscheduled Visit ............................................................................................................. 47 
5.7 Efficacy Assessments and Endpoints ................................................................................ 48 
5.7.1 Ht and Annual HV ......................................................................................................... 48 
5.7.2 BA .................................................................................................................................. 48 
5.7.3 Biochemical Markers: IGF-1 and IGFBP-3 ................................................................... 48 
5.8 Safety Assessments and Endpoints ................................................................................... 48 
5.8.1 AEs ................................................................................................................................. 49 
5.8.2 Local Tolerability (Injection Site Reactions) ................................................................. 49 
5.8.3 Concomitant Medication Use ......................................................................................... 50 
5.8.4 Treatment Compliance ................................................................................................... 50 
5.8.5 Vital Signs ...................................................................................................................... 50 
5.8.6 Physical Examination ..................................................................................................... 50 
5.8.7 ECG ................................................................................................................................ 50 
5.8.8 Fundoscopy .................................................................................................................... 50 
5.8.9 Laboratory Assessments ................................................................................................. 51 
5.9 MOD-4023 Device Usability ............................................................................................ 51 
5.9.1 PAT as provided in Appendix M (USA Only). .............................................................. 51 
5.9.2 OAT as provided in Appendix N (USA Only). .............................................................. 52 
5.9.3 Assessment of Successful Operation of the MOD-4023 PEN ....................................... 52 
5.10 PUBERTAL ASSESSMENT .......................................................................................... 52 
5.11 QoL Questionnaire .......................................................................................................... 53 
6. IP .  ................................................................................................................................................. 54 
6.1 Identity of IP ..................................................................................................................... 54 
6.2 Reference Therapy ............................................................................................................ 54 
6.3 Study Drug Administration ............................................................................................... 54 
6.4 Dose Modification Plan ..................................................................................................... 56 
6.4.1 Dose Decrease ................................................................................................................ 56 
6.5 Method of Assigning Patients to Treatment Groups ......................................................... 58 
6.6 Blinding ............................................................................................................................. 58 
6.7 Accountability and Compliance of IP ............................................................................... 58 
6.8 Destruction of IP and Other Supplies ................................................................................ 59 
6.9 Prior and Concomitant Therapy ........................................................................................ 59 
6.9.1 General Guidelines ......................................................................................................... 59 
6.9.2 Disallowed Previous Medications/Therapies ................................................................. 59 
6.9.3 Allowed Medications ..................................................................................................... 59 
6.9.4 Prohibited Concomitant Medication .............................................................................. 60 
7. Safety and Pharmacovigilance ...................................................................................................... 60 
7.1 Adverse Event ................................................................................................................... 60 
7.2 Serious Adverse Event ...................................................................................................... 61 
7.3 Definition of an Unexpected Adverse Event ..................................................................... 62 
7.4 Definition of suspected unexpected serious adverse reaction (SUSAR)........................... 62 
7.5 Notification about Serious or Unexpected Adverse Events .............................................. 62 
7.5.1 Initial Notification .......................................................................................................... 62 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 22 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
7.5.2 Contact Persons and Numbers: ...................................................................................... 62 
7.6 Reporting of Pregnancies Occurring During the Study..................................................... 64 
7.7 Independent Data and Safety Monitoring Board (DSMB) ................................................ 65 
7.8 Medication Errors .............................................................................................................. 65 
7.9 Medical Device Complaint Reporting Requirements ....................................................... 65 
8. Statistical Analysis Method .......................................................................................................... 66 
8.1 Sample Size Consideration................................................................................................ 66 
8.2 Analyzed Population Sets ................................................................................................. 66 
8.2.1 Safety Analysis Set ........................................................................................................ 66 
8.2.2 Full Analysis Set ............................................................................................................ 66 
8.2.3 Modified Intent-to-Treat Set .......................................................................................... 66 
8.2.4 Per Protocol Set .............................................................................................................. 66 
8.2.5 Full Analysis Subset ....................................................................................................... 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 (Auxology/Clinical) ...................................................... 67 
8.4.3 Biochemical Endpoints .................................................................................................. 67 
8.4.4 Safety Endpoints ............................................................................................................ 67 
8.4.5 Additional Endpoints ..................................................................................................... 68 
8.4.6 Safety Endpoints ............................................................................................................ 68 
8.4.7 Auxology/Clinical Endpoints ......................................................................................... 68 
8.4.8 Biochemical Endpoints .................................................................................................. 69 
8.5 Statistical Analysis ............................................................................................................ 69 
8.6 Efficacy Analysis .............................................................................................................. 69 
8.6.1 Secondary Endpoint Analyses ........................................................................................ 70 
8.6.2 Primary Efficacy Sensitivity Analysis ........................................................................... 70 
8.6.3 Biochemical Markers Analysis ...................................................................................... 70 
8.6.4 Additional Endpoints Analysis....................................................................................... 70 
8.6.5 LT-OLE Analysis ........................................................................................................... 71 
8.6.6 Safety Analysis ............................................................................................................... 72 
8.6.7 Adverse Events ............................................................................................................... 72 
8.6.8 Clinical Laboratory Findings ......................................................................................... 72 
8.6.9 Vital Signs, Fundoscopy and ECG ................................................................................. 72 
9. Ethics ............................................................................................................................................ 73 
9.1 Institutional Review Board or Independent Ethics Committee ......................................... 73 
9.2 Ethical Conduct of the Study ............................................................................................ 73 
9.3 Protocol Revisions and/or Deviations ............................................................................... 73 
9.4 Patient Information and Consent ....................................................................................... 73 
9.5 Patient Insurance ............................................................................................................... 74 
9.6 Informing the General Practitioner ................................................................................... 74 
9.7 Personal Data Protection ................................................................................................... 74 
10. Quality Control and Quality Assurance ...................................................................................... 74 
10.1 Audits and Inspections .................................................................................................... 75 
10.2 Study Monitoring ............................................................................................................ 75 
10.2.1 Source Document ......................................................................................................... 75 
10.2.2 Electronic Case Report Form (eCRF) .......................................................................... 76 
10.3 Quality Laboratory Standards ......................................................................................... 76 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 23 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
10.4 Data Management ........................................................................................................... 76 
11. Study Administration .................................................................................................................. 76 
11.1 Participating Centers ....................................................................................................... 76 
11.2 Required Documents Prior to Study Initiation ................................................................ 76 
11.3 Clinical Study Supplies ................................................................................................... 77 
11.4 Investigator Site File (ISF) .............................................................................................. 77 
11.5 Study Completion ............................................................................................................ 78 
11.6 Final Report ..................................................................................................................... 78 
11.7 Retention of Study Records ............................................................................................ 78 
11.8 Confidentiality and Publication ....................................................................................... 78 
12. References ................................................................................................................................... 80 
LIST OF TABLES 
Table 1: AE Relationship Criteria ..................................................................................................... 61 
LIST OF FIGURES 
Figure 1: Recommended rotation of injection sites for Genotropin® and MOD-4023 ..................... 55 
Figure 2: Dose Decrease Adjustment Scheme .................................................................................. 57 
LIST OF APPENDICES 
Appendix A: STUDY FLOW CHART / SCHEDULE OF EVENTS ........................................................ 82 
Appendix B: GROWTH HORMONE STIMULATION TESTS .............................................................. 91 
Appendix C: INSTRUCTIONS FOR OBTAINING HEIGHT MEASUREMENTS...................................... 93 
Appendix D: INSTRUCTIONS FOR OBTAINING X-RAY FILMS ....................................................... 94 
Appendix E: RECOMMENDED INJECTION DAYS ............................................................................ 95 
Appendix F: GLYCEMIC TARGETS FOR CHILDREN AND ADOLESCENTS WITH TYPE 1 
DIABETES ..............  .......................................................................................................................... 96 
Appendix G: DECLARATION OF HELSINKI (2013) ......................................................................... 97 
Appendix H: EXAMPLE INJECTION SITE ASSESSMENT TABLE (LOCAL REACTIONS) AND 
PAIN ASSESSMENT  ........................................................................................................................ 103 
Appendix I: EXAMPLE PHONE INTERVIEW FOR VISITS DONE AT HOME. .................................. 106 
Appendix J: CLINICALLY COMPARABLE DOSES OF INHALED CORTICOSTEROIDS ................... 107 
Appendix K: LIST OF CENTRAL TECHNICAL FACILITIES ........................................................... 108 
Appendix L: QOL QUESTIONNAIRE .............................................................................................. 110 
Appendix M: PARTICIPANT ASSESSMENT TOOL (PAT) .............................................................. 124 
Appendix N: OBSERVER ASSESSMENT TOOL (OAT) .................................................................. 126 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 24 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
GLOSSARY 
Abbreviation 
Definition 
µg 
Microgram 
Ab 
Antibody  
ACTH 
Adrenocorticotropic Hormone  
ADHD 
Attention-Deficit/Hyperactivity Disorder 
AE 
Adverse Event 
AIDS 
Aquired Immmunodeficiency Syndrome 
ALT 
Alanine Aminotransaminase (SGPT) 
ANCOVA 
Analysis of Covariance 
AST 
Asparate Transaminase (SGOT) 
BA 
Bone Age 
BM 
Bone Maturation 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CA 
Chronological Age 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
cm 
Centimeter  
CNS 
Central Nervous System 
CPK 
Creatinine Phosphokinase 
CrCL 
Creatinine Clearance 
CRH 
Corticotropin Releasing Hormone 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CT 
Computed Tomography 
CTP 
C-terminal Peptide 
day 4(-1) 
Day 3 or 4 Post-injection 
DBPC 
Double-Blind Placebo-Controlled 
DDAVP 
Desmopressin 
dL 
Deciliter 
DMP 
Data Management Plan 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
EMA 
European Medicinal Agency  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 25 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Abbreviation 
Definition 
EOS 
ET 
End of Study 
Early Termination 
EU 
European Union 
FAS 
Full Analysis Subset 
FDA 
Food and Drug Administration 
FFA 
Free Fatty Acids 
FSH  
Follicle-Stimulating Hormone  
FT4 
Free Thyroxine 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
GH 
Growth Hormone 
GHD 
Growth Hormone Deficiency 
GHR 
Growth Hormone Receptor 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GRS 
Growth Hormone Research Society 
H0 
Null Hypothesis 
H1 
Alternative Hypothesis 
HbA1C 
Glycated Hemoglobin (Hemoglobin A1c) 
hCG 
Human Chorionic Gonadotropin 
HCT 
Hematocrit 
HDL 
High Density Lipoproteins 
HGB 
Hemoglobin 
hGH 
Human Growth Hormone 
HIV 
Human Immunodeficiency Virus 
HV 
Height Velocity 
HV SDS 
Height Velocity Standard Deviation Score 
Ht 
Height 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGFBP-3 
IGF-1 Binding Protein 3 
IGF-1 
Insulin-like Growth Factor-1 
IM 
Intramuscular 
IND 
INN 
Investigational New Drug 
International Nonproprietary Name  
INR 
International Normalized Ratio (for blood clotting time) 
IP 
Investigational Product 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 26 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigator’s Site File 
ITT 
Insulin Tolerance Test 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Cholesterol 
LFT 
Liver Function Test 
LH 
Luteinizing Hormone 
LOCF 
Last Observation Carried Forward 
LP(a) 
LT 
Lipoprotein (a) 
Long term 
m 
Meter 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min. 
Minute 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
MM 
Medical Monitor 
MoH 
Ministry of Health 
mmol 
Millimole 
MRI 
Magnetic Resonance Imaging 
mSV 
Millisievert 
N 
Number 
ng 
Nanogram 
nmol 
Nanomole 
No. 
Number 
NOAEL 
No Observed Adverse Effect Level 
OAT 
Observer Assessment Tool 
OBL 
OPKO Biologics Ltd. 
OLE 
Open Label Extension 
PA 
Posterior to Anterior 
PAT 
Participant Assessment Tool 
PD 
Pharmacodynamics 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 27 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Abbreviation 
Definition 
PEN 
Single patient use, multi-dose, disposable pre-filled pen containing 20 or 
50 mg/mL MOD-4023 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Prothrombin Time 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
QA 
Quality Assurance 
QoL 
Quality of Life 
QoLISSY 
Quality of Life in Short Stature Youth 
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 
SD 
Standard Deviation 
SDS 
Standard Deviation Score 
SE 
Standard Error 
SGA 
Small for Gestational Age 
SHOX 
Short stature homeobox 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t 
Time 
t1/2 
Half-life 
Tmax 
Time Of Maximum Concentration 
TSH 
Thyroid Stimulating Hormone 
UK 
United Kingdom 
USA 
USAN 
United States of America 
United States Adopted Name 
vs 
Versus 
WBC 
White Blood Cells 
WHO 
World Health Organization 
wk 
Week 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 28 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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 IGF-1 into the systemic circulation. IGF-1 is an important mediator in the 
promotion of linear growth in children and may play a role in the regulation of metabolism and 
body composition in adults. These factors are regulated through complex feedback mechanisms 
involving hGH, IGFBP-3 and their complexes (Shalet, Toogood et al. 1998; Bach 2004).  
A 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 demographics 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 7%; there was male 
predominance in all 3 categories (Thomas, Massa et al. 2004).  The number of new cases has 
remained fairly constant over the last 2 decades. The Belgian data are comparable to other 
countries; the prevalence of GHD in the USA 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. The inability to achieve normal Ht 
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). Persistency of GHD into adulthood is associated with 
increased risk of cardiovascular morbidity and mortality. 
1.2 CURRENT THERAPY 
Recombinant hGH (r-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 Ht, 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, although 
in Europe generally a dose of 0.025-0.035 mg/kg/day or 0.7-1.0 mg/m² body surface area/day is 
recommended (according to the Summary of Product Characteristics (SmPC) of Somatropin 
products).  Treatment response is assessed by measurement of Ht and growth velocity and is 
usually continued until final Ht, epiphyseal closure, or both have been recorded. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 29 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
The majority of currently available hGH products require daily or every other day SC or 
intramuscular (IM) 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 pharmacokinetic (PK) and pharmacodynamic (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 three copies 
of the CTP of the beta chain of human chorionic gonadotropin (hCG); one copy at the N-terminus 
and two copies (in tandem) at the C-terminus. 
The CTP provides hCG with the required longevity to maintain pregnancy (initial half-life (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 (Hershkovitz et al. 2015). 
Somatrogon is the INN/USAN of MOD-4023 and can be used interchangeably with MOD-4023. 
1.3.1 Clinical Studies 
MOD-4023 clinical development program includes, apart from the current study, five studies 
which have been completed. Two (2) Phase 1 studies (CP-4-001, CP-4-007) in healthy adult male 
volunteers, and Phase 2 studies in GHD adults (CP-4-003) and pre-pubertal GHD children (CP-
4-004) were completed. A Phase 3 pivotal study (CP-4-005) in adult patients with GHD is 
completed and pending final clinical study report. Currently, both CP-4-004 and CP-4-005 are 
continuing as an OLE until marketing approval. 
The Phase 1 study (CP-4-001) was conducted in 24 healthy adult male volunteers 
 
 
 
 
 
 
CCI


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 30 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
 
Another Phase 1 study (CP-4-007) was conducted in healthy male Caucasian and Japanese 
volunteers.  A total of 42 subjects were enrolled and randomized, 
 
 
 
 
  
 
  
 
 
 
 
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 three doses of MOD-4023 
administered on a weekly regimen and one exploratory dose on an every other wk regimen. MOD-
4023 was administered for a period of four wks in adult GHD patients who were previously on a 
stable, standard r-hGH treatment for at least six months. Fifty-four (54) patients (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 completed Phase 2 study (CP-4-004) in a pediatric population was designed to assess the 
safety, efficacy and tolerability of three 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 and treated 
with 52 of them finishing the 12-month portion of the study. All three MOD-4023 dose groups 
demonstrated a growth response comparable to daily r-hGH after 12 months of treatment, as 
described in detail in the Investigator Brochure (IB), with a safety profile consistent with 
commercially available r-hGH products.  
A Phase 3 pivotal study (CP-4-005) in adult patients with GHD was recently completed. The study 
is a randomized, parallel-group, multi-center study consisting of a 26-wk double-blind, placebo-
controlled (DBPC) period, a 26-wk long-term OLE, in which all patients receive MOD-4023, and a 
two-wk 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. The main 
study, first 12 months, has been completed and is currently being analyzed and reported.  
For additional information on clinical studies, please refer to the current version of the IB. 
1.3.2 Study Rationale 
OBL’s 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 wk resulting in similar clinical efficacy as compared to daily injections of r-hGH. 
                                                 
a To obtain blood samples for MOD-4023 Ab assessment and MOD-4023 serum levels. 
CCI
CCI


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 31 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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 (non-inferior) to daily Genotropin® 
administration in terms of safety and efficacy after 12 months treatment duration. The study will be 
conducted in a randomized, open-label, active-controlled, parallel-group design. After completion 
of an initial 12 months treatment patients will be eligible to continue treatment with weekly MOD-
4023 in a single arm, long term open-label extension (LT-OLE) study for the purpose of collecting 
additional long term safety and efficacy information. 
1.3.3 Rationale for Dose Selection 
MOD-4023 is a new molecular entity with GH mechanism of action demonstrating reduced 
receptor affinity, lower specific activity, but with an extended, optimized t1/2.  
The in vitro activity and receptor binding affinity of MOD-4023 were established based on 
comprehensive characterization studies as part of the non-clinical program. MOD-4023, which is 
comprised of 72.3% net hGH on a molar basis, demonstrated 10 to 20-fold reduction in affinity to 
GH receptors (GHR) as compared to r-hGH (Biacore analysis). This was further strengthened by 
two independent cell-based assays analysis indicating that MOD-4023 had a significantly lower 
biological activity as compared to daily hGH. 
Based on the in vitro non-clinical pharmacological findings and Phase 2 data it was concluded that 
any dose comparisons between MOD-4023 and hGH that were initially done on molar basis were 
not reflective of the biological effect of the molecule. Therefore, the selection of MOD-4023 dose 
for the Phase 3 studies was determined by safety parameters and in particular by the clinical effect, 
i.e. HV. 
This assumption was confirmed during the 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/wk, resulted in comparable IGF-1 and IGFBP-3 profiles to that of Genotropin® 
administered daily at a dose of 34 µg/kg/day.  These two doses of MOD-4023 were shown to 
maintain IGF-1 serum levels, with values that were in the middle part of the gender and age-
adjusted normal range (~0 SDS).  MOD-4023 dose of 0.25 mg/kg/wk failed to maintain normal 
IGF-1 serum levels mainly during the second part of the wk, 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-based model. Mean IGF-1 SDS 
values for Cohort 3 and Cohort 2 (MOD-4023 dose of 0.66 and 0.48 mg/kg/wk, respectively) were 
around 0 SDS IGF-1, and consistently much lower than 0 for Cohort 1 (0.25 mg/kg/wk). Therefore, 
it is proposed that MOD-4023 doses of 0.48 and 0.66 mg/kg/wk are more likely to result in IGF-1 
and IGFBP-3 levels that are comparable to daily Genotropin® injections within the well-established 
suitable safety range with no direct correlation to GH molar content. 
As the dose selection is driven by evaluating the annual increment in HV, the annual HV data 
obtained for MOD-4023 was compared to Genotropin® results in the Phase 2 study for 52 patients 
(one patient was mis-diagnosed). Based on 12-month auxology data, it is most likely that a 
minimum MOD-4023 dose of 0.66 mg/kg/wk will provide an annualized HV comparable to daily 
hGH at a dose of 34 µg/kg/day.   
2. STUDY OBJECTIVES 
Primary Objective: 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 32 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
To demonstrate that weekly MOD-4023 administration is non-inferior to daily Genotropin® 
administration. 
Secondary Objective: 
 To evaluate the safety and tolerability of weekly MOD-4023 administration. 
 To demonstrate successful operation (single injection) of the MOD-4023 single patient use, 
multi-dose, disposable pre-filled pen (PEN).  
 Evaluation of participant and observer feedback on MOD-4023 device usability. 
 To confirm the correct operation of devices returned for evaluation. 
 
LT-OLE Objective: 
 To demonstrate LT safety and efficacy of MOD-4023 in an OLE.  
 
Other Objectives: 
To evaluate the effect of weekly MOD-4023 and daily Genotropin® administration on QoL, as 
measured by the QoLISSY in a specific number of countries (determined by availability of 
validated translated tools) during the first 12 months of treatment.  
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 GH, 
Genotropin®. 
Both drugs will be injected using a PEN device. 
The study will be divided into two parts: 
Main Study Period (main study): After an 8 wk screening perioda, patients meeting the eligibility 
criteria, as approved by global study MM, will be randomized in a 1:1 ratio to weekly SC doses of 
MOD-4023 (investigational treatment) or daily SC administration of Genotropin® (reference 
therapy) for 12 months. The key safety data will be reviewed by an independent DSMB every 4 
months or on an ad hoc basis.   
LT-OLE Period (LT-OLE): Patients who received MOD-4023 during the main study will 
continue in the LT-OLE with the same dose (mg/kg/wk) of MOD-4023. Patients who received 
Genotropin® during the main study will be switched to MOD-4023 and will begin treatment with a 
dose of 0.66 mg/kg/wk beginning no less than one day after cessation of Genotropin® treatment. 
The key safety data will be reviewed by an independent DSMB approximately every 6 months.    
During the entire study (main study and LT-OLE), 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 (which will be based on the severity 
                                                 
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 laboratory results) extra time will be added to the duration of the screening 
period, but not in excess of an additional four wks (total of 12 wks screening period). 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 33 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
of AEs or repeated, elevated levels of IGF-1). The dose will be decreased based on two, repeated 
day 4(-1) post-dose levels of IGF-1 SDS ≥ +2.0 (Section 6.4). During the LT-OLE, dose reduction 
for IGF-1 level >+2.0 SDS will be made following consultation with the Global Study MM on an 
individual patient basis 
The total duration of patient participation in the main study will be up to 15 months (12 months of 
treatment, up to eighta (+4) wks of screening and one month post dosing EOS follow up for patients 
not continuing in the LT-OLE, discontinued early or following study closure).  
The LT-OLE will continue until marketing approval.  
The study will be conducted at approximately 200 sites in 30-40 countries worldwide.  
4. STUDY POPULATION 
Pre-pubertal children (boys 3-11 years, girls 3-10 years), diagnosed with GHD. 
4.1 INCLUSION CRITERIA 
Patients must meet all inclusion criteria to be eligible for the main study: 
1. Pre-pubertal children aged ≥3 yrs old and not yet 11 years for girls (10 years and 364 days) 
or not yet 12 years (11 years and 364 days) for boys (on the date of ICF signature) with 
either isolated GHD, or GH insufficiency as part of multiple pituitary hormone deficiencies. 
2. Confirmed diagnosis of GHD by 2 different GH provocation tests defined as a peak plasma 
GH level of ≤10 ng/ml, determined by local (if done prior to signing the ICF) or central 
laboratory using a validated assaya. Prior local laboratory results will be accepted subject to 
pre-approval by global study MM and if the tests were conducted according to one of the 
protocols in Appendix Bb.  
3. BA is not older than CA and should be < 10 for females and < 11 for males. 
4. No prior exposure to any r-hGH therapy. 
5. Impaired Ht and HV defined as: 
 Annualized HV below the 25th percentile for CA (HV < -0.7 SDS) and gender 
according to the OPKO HV (Tanner, Prader and Hermanussen) calculator, provided.  
 The interval between 2 Ht measurements should be at least 6 months, but should not 
exceed 18 months prior to inclusion.  
6. Baseline IGF-1 level of at least 1 SD below the mean IGF-1 level standardized for age and 
sex (IGF-1 SDS ≤ -1)c according to the central laboratory reference values. A single re-test 
will be allowed (subject to discussion with MM) if all other criteria are met. 
7. Normal calculated GFR based on updated “bedside” Schwartz formula for pediatric patients 
(recommended calculation is provided below): 
CrCL (mL/min/1.73 m2) =0.413 * Ht / Scr;  
Ht: in cm;  
Scr: mg/dL; 
                                                 
a ITT, with serum cortisol response to hypoglycemia if insulin stimulation test is chosen / Arginine test / Clonidine test 
/ Glucagon test / L-dopa test. 
b Prior spontaneous nocturnal GH secretion should be  10 ng/mL. 
c According to rounding policy IGF-1 results -≤-0.95 might be acceptable as well.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 34 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
8. 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.  
9. Normal 46XX karyotype for girls. 
10. Willing and able to provide written informed consent of the parent or legal guardian of the 
patient and written assent from pediatric patients (where applicable based on age and 
country regulation). 
 
Inclusion into the LT-OLE: 
11. Completion of the main study (12 months of treatment) with adequate compliance.  
12. Willing and able to provide written informed consent of the parent or legal guardian of the 
patient and written assent from pediatric patients (where applicable based on age and 
country regulation).  
13. Agreement to refrain from sexual activity during the LT-OLE i.e. observe complete sexual 
abstinence as the only acceptable contraceptive measure during the LT-OLE (for pubertal 
and post-pubertal patients).  
4.2 EXCLUSION CRITERIA 
1. Children with prior history of leukemia, lymphoma, sarcoma or any other form of 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. 
5. Children born small for gestational age (SGA – birth weight and/or birth length <-2 SDS 
for gestational age).  
6. Presence of anti-hGH Ab at screening. 
7. Any CS 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. T2 and T1 diabetic patients, who in the opinion of the investigator are not receiving 
standard of care treatment or are non-compliant with their prescribed treatment or who are 
in poor metabolic control. Criteria for controlled diabetes are defined in Appendix F. 
9. Chromosomal abnormalities including Turner’s syndrome, Laron syndrome, Noonan 
syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX mutations/deletions 
and skeletal dysplasias. 
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/day of inhaled budesonide or equivalent as described in Appendix 
J. 
12. Major medical conditions and/or presence of contraindication to r-hGH treatment. 
13. More than 1 closed epiphyses.  
14. Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS 
or tuberculosis. 
15. Drug, substance, or alcohol abuse. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 35 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
16. Known hypersensitivity to the components of study medication. 
17. Other causes of short stature such as celiac disease, uncontrolled primary hypothyroidism 
and rickets. 
18. The patient and/or the parent/legal guardian are likely to be non-compliant in respect to 
study conduct. 
19. Participation in any other study of an investigational agent within 30 days prior to ICF 
signature (including administration of investigational agent). 
20. Study enrollment requirements have been met or the study has been closed by the Sponsor 
prior to the completion of screening process. 
 
Exclusion during the LT-OLE: 
21. 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®]) 
22. Change in medical condition during the treatment period (such as, but not limited to, 
development of a serious inter-current critical illness, a severe adverse drug reaction, etc.) 
23. Positive pregnancy test. 
24. Unresolved drug related (MOD-4023 or Genotropin®) SAE from the treatment period as 
per MM judgement.  
4.3 PATIENT IDENTIFICATION  
A unique identification number will be assigned by the Electronic Data Capture (EDC) system 
when an individual patient or their legal guardian or parent signs the ICF and starts the screening 
process. Following eligibility confirmation by global study MM, the patient will be randomized 
through the Interactive Web Response Technology system (IRT). The randomization will be 
stratified based on: 
1. Geographical region (1. Western Europe, Israel, Australia, New Zealand, Canada and USA; 
2. Central and Eastern Europe, Greece, Turkey, Latin America, Asia except for India and 
Vietnam; 3. India and Vietnam); 
2. GH peak levels at Screening ≤3 ng/mL; >3 to ≤7 ng/mL; and >7 to ≤10 ng/mL; and 
3. CA (3-7 and 0 days, above 7). 
The unique identification number assigned during the main study will continue to be used in the 
LT-OLE.  
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 during the 12 
months of treatment post first dose will not be replaced. Those patients withdrawn who have 
successfully completed screening, but prior to first dose, will be replaced. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 36 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
The patient's participation in this study may be discontinued due to the following reasons: 
 Request from regulatory agency, sponsor, primary care physician, or Investigator.  
 Withdrawal of the patient’s/parent’s/legal guardian's consent for any additional study 
participation or procedure, including lost to follow up (with specific withdrawal reason 
collected, as possible). 
 AE: 
o Occurrence of a malignancy during the course of the study. 
o Development of serious intercurrent critical illness. 
o Development of benign intracranial hypertension, if the symptoms return 
following resumption of drug (after a temporary stop). 
o Occurrence of AEs following which the Investigator, or the patient wishes to 
discontinue treatment (such as, but not limited to, slipped capital femoral 
epiphysis, scoliosis, avascular necrosis and development of lipoatrophy, etc.). 
 Intake of prohibited concomitant medication (in consultation with the MM).  
 Investigator decides that withdrawal from the study is in the best interest of the patient e.g. 
patient non-compliance, occurrence of neutralizing Ab, protocol deviation(s) (including 
protocol deviation(s) that affect patient safety and accuracy, and/or validity of data) etc. 
 Any clinically significant change in the patient’s medical condition.  
 
During the LT-OLE: 
 Girls with a BA of ≥13.5 years and boys with a BA of ≥16 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 LT-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.  
 When the patient's annualized growth rate is ≤ 2 cm/12 months (the interval between two 
height measurements should be at least six months).  
Patients can be re-screened for inclusion in the main study one time.  Any data collected during 
the original screening period will be acceptable as historical data, EXCEPT safety laboratory 
data and IGF-1 and IGFBP-3 levels, which must be repeated and evaluated for eligibility.  In 
this case, the patient will be assigned a new screening number.  
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 early 
termination assessments (see Section 5.5). 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 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 37 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
made to undertake safety follow-up procedures. If a patient wishes to withdraw, the difference 
between treatment discontinuation and study withdrawal will be explained. Patients should be 
encouraged to continue the follow up visits and at minimum provide a Ht measurement at 
12 months of the initial treatment period 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. 
5. INVESTIGATIONAL PLAN AND STUDY PROCEDURES 
A schedule of events for this study is shown in Appendix A. No 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 VISIT 1 - SCREENING PERIOD (DAY – 56 TO DAY -1)  
The screening period will last up to 8 wksb and can be conducted over several visits prior to 
randomization, to minimize blood volume withdrawals per visit. 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 assessments, written assent from 
pediatric patients (where applicable based on age and country) 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 these screening visits:  
 Inclusion/exclusion verification. 
 Parental Htc, and patients’ Ht, Ht SDS, HV and HV SDS. 
 Body weight and BMI SDS. 
 Medical history, including a description of pituitary deficiencies, concomitant and previous 
medications. 
 Overall health status assessment, including complete physical examination and vital signs. 
 Pubertal status (according to Tanner stages).  
                                                 
a Illiterate patients should provide their consent in a method that is accepted according to local regulations.   
b 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 laboratory results) extra time will be added to the duration of the screening 
period, but not in excess of an additional four wks (total of 12 wks screening period). 
c It's recommended that parents will be measured at the site. If measured parental Ht is not available an estimate should 
be provided by the parent.  It should also be noted that the patient’s birth date is required for accurately reporting of Ht 
SDS. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 38 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
  BAa determination with the method of Greulich-Pyle using a central BA reader. 
 Assessment of biochemical markers and stimulation tests: 
 Two (2) different GH stimulation (provocation) tests from the following list: ITT 
(with serum cortisol response to hypoglycemia if insulin stimulation test is chosen); 
arginine test; clonidine test; glucagon test; L-dopa test.  The minimal duration and 
number of samples must conform to the specifications in Appendix B for each test. 
 
The use of a local laboratory for assessment of GH serum levels (and glucose and serum cortisol if 
the insulin tolerance test is performed) might be acceptable, if done prior to ICF signature, and if 
the results are reviewed and approved by the global study MM prior to study entry.  
 Assessment of morning cortisol (at 8 am ± 1 hour). 
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 axisb or has been diagnosed with adrenal 
insufficiency).    
 Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS 
serum levels.  
 
Assessment of anti-hGH Ab. 
 Safety laboratory tests: chemistry, hematology, urinalysis. 
 Assessment of thyroid function: TSH, FT4.  
 Parameters of glucose metabolism: overnight fasting insulin, overnight fasting glucose and 
HbA1C. 
 Head MRIc, if possible with contrast or CT scan – recommended to be performed only after 
the two GH stimulation tests. 
 Assessment of karyotype in girlsd. 
 SHOX gene evaluatione. 
The Global Study MM will review key data and all test results obtained during Screening; the 
eligibility will be confirmed by the Global Study MM prior to randomization of each patient.  
It is recommended that the Investigator randomize the patient within 7 days of Global Study MM 
confirmation of eligibility and to bring the patient back in for the Baseline visit (Visit 2) within 2 
wks of randomization. 
                                                 
a Historical BA assessment might be accepted if they were done with the method of Greulich-Pyle no more than 6 
months prior to the ICF signature date. If the patient is eligible, the BA should be repeated at Visit 2 prior to dosing. 
The Visit 2 scan will be the Baseline scan for these patients. 
b ITT 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. 
c Historical MRI or CT is permitted if within 12 months; MRI or CT which was conducted no more than 12 months 
prior to ICF signature data will be acceptable.  For GHD associated with a congenital CNS defect, the medical monitor 
could allow for use of the historic MRI or CT > 12 months old. 
d Historical karyotype data and chromosomal microarray data are acceptable.   
e Historical data is acceptable. SHOX gene evaluation is only necessary for isolated GHD with a normal brain MRI. 
Patients with clear multiple pituitary hormone deficiencies or structurally abnormal pituitary gland do not require 
SHOX gene evaluation. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 39 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.2 MAIN STUDY TREATMENT PERIOD (DAY 1/BASELINE TO MONTH 12)  
Eligible patients will be randomized (central randomization within each regiona) in a 1:1 fashion 
within each stratum to receive either weekly MOD-4023 (0.66 mg/kg/wk) or daily Genotropin® 
(0.034 mg/kg/day or 0.24 mg/kg/wk) for 12 months.  
Visit 2 (Day 1/Baseline) will be conducted on day of first dosing. Subsequent visits, Visit 4 (Month 
1/Wk 4 [+1 wk]), Visit 5 (Month 3/Wk 13 [±1 wk]), Visit 6 (Month 6/Wk 26 [±1 wk]), Visit 7 
(Month 9/Wk 39 [±1 wk]), and Visit 8 (Month 12/Wk 52 [±1wk]) will be conducted on day 4 (-1 
day) post doseb to obtain IGF-1 measurements expected to reflect average levels throughout the 
wk. 
Visit 3 (Day 10 [+4 days]c post first dose) for the collection of immunogenicity and PK sample will 
be conducted for MOD-4023 arm only. This visit can be done at the patient’s home or at the study 
site, based on local regulations and nurse availability. If home visit is conducted, a questionnaire, 
as described in Appendix I should be completed, collecting information on AE, local tolerability 
and concomitant medications. 
Visits 6a (Month 6/Wk 26 [±3wk]) and Visit 8a (Month 12/Wk 52 [±1wk]) will be conducted on 
dosing day for the MOD-4023 arm only for the collection of immunogenicity and PK sample. This 
visit can be done at the patient’s home or at the study site, based on local regulations and nurse 
availability. If home visit is conducted, a questionnaire as described in Appendix I should be 
completed as well. Samples must be collected prior to dosing of MOD-4023. 
In parallel to MOD-4023 patients Visit 3 (Day 10 [+4 days]), a phone interview will be conducted 
to Genotropin® arm patients and/or parents/guardians according to the questionnaire provided in 
Appendix I in which AE, local tolerability and concomitant medication information will be 
collected.  
For the ECG that will be conducted at Visit 6b (Month 6/Wk 26 [± 3wks]) at 7-12 hours post-dose 
for MOD-4023 treated patients, patients will be requested to inject MOD-4023 during the 
day/night at their convenience and come to the study site at the requested time point for ECG.  
Visits 6a and 6b might be combined on the same day (only if 6a is done prior to dosing). 
The patient will come to the study site in the morning, perform the blood tests, afterwards will 
inject on site and will come back 7-12 hours post dosing for ECG assessment. 
Genotropin® patients will have an ECG assessment at Visit 6 (no time limitation).  
5.2.1 Visit 2 (Day 1/Baseline) – recommended injection days as indicated in Appendix E 
Visit 2 must be conducted within 2 wks of randomization.   
The following assessments will be conducted on Day 1/Baseline: 
                                                 
a 1. Western Europe, Israel, Australia, New Zealand, Canada and USA; 2. Central and Eastern Europe, Greece, Turkey, 
Latin America and Asia except for India and Vietnam 3. India and Vietnam. 
b All visits, except Visit 3, can be conducted within the specified window to accommodate patient availability, but must 
be conducted on day 4 (-1) post dose. 
c Applicable only for MOD-4023, Visit 3 assessments, if conducted on Day 14 (dosing day), should be done prior to 
dosing. 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 40 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 Auxology measurements: Actual Ht (mean of three consecutive measurements) measured 
on a calibrated wall mounted stadiometer.  
 AEs, local tolerability (aligned with Appendix H), and concomitant medications. 
 Overall health status assessment, including complete physical examination and vital signs. 
 Safety laboratory tests: chemistry, hematology and urinalysis. 
 Pubertal status (according to Tanner stages). 
 Assessment of thyroid function and biochemical markers: TSH, FT4, IGF-1, IGF-1 SDS, 
IGFBP-3 and IGFBP-3 SDS serum levels. 
 Assessment of MOD-4023 serum levels (applicable for MOD-4023 arm only). 
 Parameters of glucose metabolism: overnight fasting glucose, overnight fasting insulin, 
HbA1c. 
 Parameters of lipid metabolism: overnight fasting cholesterol, triglycerides, HDL, LDL, 
Lp(a), FFA. 
 Assessment of anti-MOD 4023 and anti-hGH Ab (depending on arm of study). 
 BAa. 
 ECG pre-dosing. 
 Training for patients, parents or legal guardians on drug administration.  
 Fundoscopy (if there are signs or symptoms indicative of benign intracranial hypertension). 
 Training for patients, parents or caregiver for completing the PAT assessment. 
 Administration of study drug at the study site by patient or parent/caregiver. 
 MOD-4023 on-site OAT assessment (USA only). 
 MOD-4023 on-site PAT assessment (USA only). 
 QoL Questionnaire completion (in specific countries as indicated in Appendix L). 
 Drug dispensing and accountability. 
5.2.2 Visit 3 b,c (Day 10 [+4days] post first dose) for MOD-4023 arm only 
The following assessments will be conducted at the study site or at the patient's home (if allowed 
according to local regulations): 
 MOD-4023 serum levels.  
 Anti-MOD-4023 Abs. 
 AEs and local tolerability (aligned with Appendix H) assessment.  
 Concomitant medication recording aligned with the questionnaire in Appendix I. 
                                                 
a BA will be done at Visit 2 only in cases where historical bone scans (<6 months prior to Screening) were used to 
fulfill entry criteria.  When performed, BA scans will be completed prior to dosing. 
b Applicable only for MOD-4023, Visit 3 assessments, if conducted on Day 14 (dosing day), should be done prior to 
dosing. 
c Blood samples for MOD 4023 treatment group can be collected at site OR at patient's home, based on local 
regulations and nurse availability. If home visit, a questionnaire, as described in Appendix I, should be completed. If 
blood sample is collected on Day 14, it should be done prior to dosing. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 41 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.2.3 Visit 3 (Day 10 [+4 days] post first dose) for Genotropin arm onlya 
 Phone interview and questionnaire completion as provided in Appendix I.  
 AEs and local tolerability (aligned with Appendix H) assessment.  
 Concomitant medication recording aligned with the questionnaire in Appendix I. 
5.2.4 Visit 4 (Month 1/Wk 4 [+1wk]) 
The following assessments will be conducted at Visit 4 on Day 4 (-1) post dose: 
 AEs, local tolerability, and concomitant medications. 
 Overall health status assessment, including complete physical examination and vital signs. 
 Safety laboratory tests: chemistry, hematology and urinalysis.  
 Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS 
serum levels. 
 MOD-4023 serum levels (applicable for MOD-4023 arm only). 
 Fundoscopy (ONLY if there are signs or symptoms indicative of benign intracranial  
hypertension). 
 Anti-MOD-4023 Abs (MOD-4023 arm only). 
 Anti-hGH Abs (Gentropin® arm). 
 Return of used and unused injection devices to the site, diary card and PAT forms (USA 
patients only).  
 Drug dispensing and accountability.  
5.2.5 Visit 5 (Month 3/Wk 13 [±1wk]), Visit 6 (Month 6/Wk 26 [±1wk]), Visit 7 (Month 9/Wk 39 
[±1wk]), Visit 8 (Month 12/Wk 52 [±1wk]) 
The following assessments will be conducted at Visits 5, 6, 7 and 8 on Day 4 (-1) post dose: 
 Auxology measurements: Actual Ht (mean of three consecutive measurements) measured 
on a calibrated wall mounted stadiometer.  
 AEs, local tolerability, and concomitant medications. 
 Overall health status assessment, including complete physical examination and vital signs. 
 Safety laboratory tests: chemistry, hematology and urinalysis.  
 Pubertal status (according to Tanner stages);  
  Urine pregnancy test at every visit once a female patient reports first menstrual cycle 
(menarche). 
 Assessment of thyroid function and biochemical markers: TSH, FT4, IGF-1, IGF-1 SDS, 
IGFBP-3 and IGFBP-3 SDS serum levels.  
 Parameters of glucose metabolism: overnight fasting glucose, overnight fasting insulin, 
HbA1c.  
 Parameters of lipid metabolism: overnight fasting cholesterol, triglycerides, HDL, LDL, 
Lp(a), FFA. 
                                                 
a For the Genotropin® arm a visit by phone interview will be conducted as described in Appendix I. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 42 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 Fundoscopy (ONLY if there are signs or symptoms indicative of increased intracranial 
hypertension). 
 BA at Visit 8 only. 
 Individual dose adjustment every three months. 
 Drug dispensing and accountability. 
 MOD-4023 serum levels (MOD 4023 patients only). 
 Anti-hGH Ab (Genotropin® patients only).  
 ECG (Visit 6 only for Genotropin® patients). Patients in the Genotropin® arm will be 
requested to inject the study drug preferably at night and come to the clinic the following 
day for ECG assessment. 
 Return of used and unused injection devices and diary cards.   
 Return of completed PAT forms (USA only) (Visit 5 only) (applicable for MOD-4023 arm 
only). 
 Anti-MOD-4023 Ab (Visits 5 and 7, MOD-4023 arm only, Visit 8 both arms). 
 Informed consent for the LT-OLE (Visit 7 (preferred) or 8). 
 QoL questionnaire (QoLISSY) at Visit 8 only. 
 For males that are 13 years and older: LH, FSH and testosterone. For females that are 12 
years and older: LH, FSH and estradiol (Visit 8 only). 
5.2.6 Visit 6a (Month 6/Wk 26 [±3 wk]) and Visit 8a (Month 12/Wk 52 [±1 wk]) – MOD-4023 
Arm Only 
Visit 6a and 8a will be conducted on dosing day before dosinga, for MOD-4023 arm patients only.  
The following assessments will be conducted at the study site or at the patient home (if allowed 
according to local regulations): 
 MOD-4023 serum levels.  
 Anti-MOD-4023 Ab.  
 AEs and local tolerability (aligned with Appendix H) assessment.  
 Concomitant medication recording aligned with the questionnaire in Appendix I. 
5.2.7 Visit 6b (Month 6/Wk 26 [±3 wk]) – MOD-4023 Arm Only 
Patients in the MOD-4023 arm will be requested to inject the study drug during the day/night at 
their convenience and come to the study site at 7-12 hours post-dose for ECG assessment. 
Visit 6a and 6b may be combined and conducted on the same date; in such case, the patient will 
inject the study drug at the study site following blood samples collection and will come back for 
ECG measurements (Visit 6b) 7-12 hours post dosing. 
5.2.8 Visit 9 (Month 13/Wk 56 (±5 days)) – Only for patients not continuing on into the OLE study 
Patients not continuing in the OLE study will be contacted 30 days (± 5 days) after Visit 8 
(inclusive of 8a) in order to obtain safety related information (see questionnaire in Appendix I). 
                                                 
a These visits can be done on any dosing day within the visit window. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 43 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.3 LT-OLE PERIOD (VISITS 10 TO 16) 
After completion of 12 months treatment in the main study and continuing to meet the LT-OLE 
inclusion/exclusion criteria of this protocol, patients will be eligible to rollover into a single arm 
LT-OLE treatment period with MOD-4023. An informed consent/assent will be obtained from 
patients and/or parent/s or legal/authorized guardian as required per local regulation.  
Patients who received MOD-4023 during the main study will continue with the same dose of 
MOD-4023 (mg/kg/wk), adjusted for body weight. For these patients, study visits will take place 
every three months on Day 4 (-1) post-dose. These patients will consent to the LT-OLE preferably 
during Visit 7 of the main study to ensure availability of MOD-4023 at their next visit. If 
necessary, informed consent can be obtained at Visit 8 main study/10 LT-OLE. These Patients will 
continue treatment at Visit 8/10, skip Visits 9 and 11 and have a telephone visit at Visit 12 (one 
month post LT-OLE entry (Month 13 [±2wk]). 
Patients who received Genotropin®, during the main study will be switched to MOD-4023 starting 
no less than one day [+2wk] after cessation of Genotropin® treatment.  Recommended injection 
days are indicated in Appendix E.  These patients will consent to the LT-OLE preferably during 
Visit 7 of the main study to ensure availability of MOD-4023 at their next visit. If necessary, 
informed consent can be obtained at Visit 8/10. Patients will begin treatment with MOD-4023 at 
Visit 8/10, skip Visit 9 and have additional onsite visits at Visit 11 (Month 12, Day 10 post first 
MOD-4023 dose [10+4 days]) and Visit 12 (one month (Month 13 post first MOD-4023 dose 
[±2wk]).  All Patients will be provided with a diary card. 
For all patients switching from Genotropin® to MOD-4023, the following will also be done: 
 
MOD-4023 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 device. 
 
Local tolerability after first dose administered at site.  
Patients who experience a delay for any reason between completion of the main study and entry 
into the LT-OLE may have to temporarily stop treatment. If initiation/re-initiation of treatment 
occurs less than 90 days after Visit 8 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 LT-OLE after confirmation 
of availability of all required baseline LT-OLE assessments (Visit 8/10). The following tests and 
assessments must be repeated: 
 Safety laboratory tests: chemistry, hematology and urinalysis. 
 Parameters of glucose metabolism: overnight fasting glucose, overnight fasting insulin, 
HbA1c. 
 Assessment of anti-MOD-4023 Ab for all patients (Genotropin® group – baseline for future 
tests). 
 Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGF-BP-3 and IGF binding 
protein-3 (IGFBP-3) SDS serum levels. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 44 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.3.1 Visit 11 (Month 12, Day 10 [+4days] post first MOD-4023 dose) for patients switching from 
Genotropin® to MOD-4023 only 
The following assessments will be conducted at the study site or at the patient's home (if allowed 
according to local regulations): 
 MOD-4023 serum levels.  
 Anti-MOD-4023 Abs. 
 AEs and local tolerability (aligned with Appendix H) assessment.  
 Concomitant medication recording aligned with the questionnaire in Appendix I. 
5.3.2 Visit 12 (one month post first MOD-4023 dose(Month 13 [±2wk])) will be performed on site 
for patients switching from Genotropin® to MOD-4023 
The following assessments will be conducted at Visit 12 on Day 4 (-1) post dose:  
 AEs, local tolerability, and concomitant medications. 
 Overall health status assessment, including complete physical examination and vital signs.  
 Urine pregnancy test once a female patient reports first menstrual cycle (menarche). 
 Safety laboratory tests: chemistry, hematology and urinalysis.  
 Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS 
serum levels. 
 Fundoscopy (ONLY if there are signs or symptoms indicative of benign intracranial  
 
hypertension). 
 MOD-4023 serum levels.  
 Anti-MOD-4023 Abs. 
 Fundoscopy (ONLY if there are signs or symptoms indicative of benign intracranial 
hypertension). 
 Return of used and unused injection devices to the site and diary card. 
 Drug dispensing and accountability. 
 
Existing MOD-4023 patients will have a telephone visit at Visit 12 (one month post LT-OLE entry 
[Month 13 ±2wk]) to ask about AEs, local tolerability and concomitant medications. This visit will 
be completed using the questionnaire in Appendix I.  
5.3.3 Visit 13 (Month 15/Wk 65 [±2wk]), Visit 14 (Month 18/Wk 78 [±2wk]), Visit 15 (Month 
21/Wk 91 [±2wk]), Visit 16 (Month 24/Wk 104 [±4wk])  
During the first year of LT-OLE, the following assessments will be conducted every three months 
on day 4 (-1) post-dose for all patients:   
 Auxology measurements: Actual height (average of three consecutive measurements) 
measured on a calibrated wall mounted stadiometer.  
 Overall health status assessment, including complete physical examination and vital signs 
assessment. 
 Individual dose adjustment based on weight. 
 AEs, local tolerability, and concomitant medications. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 45 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
  Urine pregnancy test at every visit once a female patient reports first menstrual cycle 
(menarche).  
 Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS 
serum levels.  
 Assessment of MOD-4023 serum levels. 
 Assessment of anti-MOD-4023 Ab. 
 Fundoscopy (if there are signs or symptoms indicative of benign intracranial hypertension). 
 Return of used and unused injection devices to the site and diary card. 
 Drug dispensing and accountability. 
 
The following assessments will also be conducted at Visit 13 (Month 15), Visit 14 (Month 18) and 
Visit 16 (Month 24) on day 4 (-1) post-dose visits: 
 Safety laboratory tests: chemistry, hematology and urinalysis.  
 Assessment of thyroid function: TSH, FT4. 
 Parameters of glucose metabolism: overnight fasting glucose, overnight fasting insulin, 
HbA1c.  
 Parameters of lipid metabolism: overnight fasting cholesterol, triglycerides, HDL, LDL, 
Lp(a), FFA.  
 
The following assessments will also be conducted at Visit 16 (Month 24) on day 4(-1) post-dose: 
 ECG. 
 Bone age. 
 Pubertal status. 
 For males that are 13 years and older: LH, FSH and testosterone. For females that are 12 
years and older: LH, FSH and estradiol.  
Collection of samples for MOD-4023 serum levels and anti-MOD-4023 Ab levels must be 
obtained on dosing day pre- 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.  
5.4 LT-OLE (VISITS 17 TO STUDY CLOSURE) 
Following completion of the first year of LT-OLE the following assessments will be conducted 
every three months on day 4 (-1) post-dose for all patients:   
 Auxology measurements: Actual height (average of 3 consecutive measurements) measured 
on a calibrated wall mounted stadiometer.  
 Overall health status assessment, including complete physical examination and vital signs 
assessment. 
 Individual dose adjustment based on weight. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 46 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 AEs, local tolerability, and concomitant medications. 
 Urine pregnancy test at every visit once a female reports first menstrual cycle (menarche). 
 Fundoscopy (if there are signs or symptoms indicative of benign intracranial hypertension). 
 Return of used and unused injection devices to the site and diary card. 
 Drug dispensing and accountability. 
 
The following assessments will also be conducted every six months on day 4 (-1) post-dose visits: 
 Assessment of biochemical markers: IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS 
serum levels.  
 Safety laboratory tests: chemistry, hematology and urinalysis.  
 Assessment of thyroid function: TSH, FT4. 
 Parameters of glucose metabolism: overnight fasting glucose, overnight fasting insulin, 
HbA1c.  
 Parameters of lipid metabolism: overnight fasting cholesterol, triglycerides, HDL, LDL, 
Lp(a), FFA.  
 Assessment of MOD-4023 serum levels. 
 Assessment of anti-MOD-4023 Ab. 
 
Additional assessments will be performed once a year, every 12 months on dosing day or Day 4(-
1): 
 ECG. 
 Bone age.  
 Pubertal status (according to Tanner stages). 
 For males that are 13 years and older: LH, FSH and testosterone. For females that are 12 
years and older: LH, FSH and estradiol.  
The following assessments will be conducted during the EOS/ET visit: 
 Auxology measurements- Actual Ht (mean of 3 consecutive measurements) measured on a 
calibrated wall mounted stadiometer.  
 AEs, local tolerability, and concomitant medications. 
 Overall health status assessment, including complete physical examination and vital sign 
assessments. 
 Safety laboratory (chemistry, hematology and urinalysis).  
 Pubertal status. 
 Urine pregnancy test for female patients who have reported menarche. 
 Thyroid function and biochemical markers: TSH, FT4, IGF-1, IGF-1 SDS, IGFBP-3 and 
IGFBP-3 SDS serum levels.  
 Parameters of glucose metabolism (overnight fasting glucose, overnight fasting insulin, 
HbA1c).  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 47 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 Parameters of lipid metabolism (overnight fasting cholesterol, triglycerides, HDL, LDL, 
Lp(a), FFA). 
 For males that are 13 years and older: LH, FSH and testosterone. For females that are 12 
years and older: LH, FSH and estradiol. 
 Fundoscopy (ONLY if there are signs or symptoms indicative of increased intracranial 
hypertension). 
 Bone age. 
 MOD-4023 serum levels. 
 ECG. 
 Return of used and unused injection devices and diary cards.   
 Anti-MOD-4023 Abs.  
 
Patients will be required to visit the study site for assessment of biochemical markers on day 4 (-1) 
post-dose. If a visit is performed on a dosing day, collection of MOD-4023 serum levels and anti-
Mod-4023 Ab levels must be obtained pre-dose. For End of Treatment during LT-OLE Year 1, the 
ECG will be conducted at 7-12 hours post-dose and 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. An ECG must still be obtained even if patients do not take the final dose. 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. For ET from LT-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 30 days [± 5 days] after EOS/ET visit in order to obtain safety 
related information. 
5.5 EARLY DISCONTINUATION STUDY VISIT 
If, during the main study, a patient discontinues prematurely from the study for the reasons 
specified in Section 4.4, the same procedures planned for Visit 8 (12 months/Wk 52 [±1 wk]) will 
be conducted. Other procedures and evaluations will be completed as deemed necessary by the 
Investigator.  
If, during the LT-OLE, a patient discontinues prematurely from the study for the reasons specified 
in Section 4.4, the same procedures for LT-OLE EOS/ET will be conducted.  
5.6 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. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 48 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.7 EFFICACY ASSESSMENTS AND ENDPOINTS 
5.7.1 Ht and Annual HV 
Ht measurements must be performed according to Appendix C with a calibrated wall-mounted (e.g. 
Harpenden or similar) stadiometer and should ideally be conducted at the same time of the day for 
each visit, preferably in the morning. To ensure consistency of results, ideally the same auxologist 
will perform these measurements for each patient at each visit to minimize the variability of 
measurements. The time of measurement and the observer’s initials is to be recorded in the eCRF. 
Three (3) independent readings will be recorded for each visit in the eCRF. 
The Ht Standard Deviation Score (Ht SDS) will be derived from the age and gender standards from 
2000 Center for Disease Control Growth Charts (www.cdc.gov/growthcharts) by the Sponsor 
during the study. 
Annualized HV will be calculated in cm as the change in Ht from Visit 2 to Visit 8 (after 12 
months of treatment) during the main study and again every 12 months thereafter compared to the 
measurement taken 12 months prior during the LT-OLE. 
5.7.2 BA 
BA will be determined by X-ray according to Greulich-Pyle method (Greulich 1959) using central 
BA reader during the main study at Screening (Visit 1), Visit 2a, and Visit 8 (Month 12). X-ray 
films of the left hand and wrist will be taken as outlined in Appendix D and will be sent to a 
qualified central reader. The central reader will be blinded to the CA, drug allocation, and name of 
the patients. X-ray films will hold only an identification number and gender. Details of the central 
BA reader and the procedure for blinding and shipping of X-rays will be provided to the 
investigator. 
During the LT-OLE, BA will be determined by X-ray every 12 months. The central reader will be 
blinded to the CA and name of the patient.  
5.7.3 Biochemical Markers: IGF-1 and IGFBP-3 
hGH stimulates hepatic production and release of IGF-1 into the systemic circulation. IGF actions 
are modulated by a family of 6 structurally-related binding proteins (IGFBPs 1-6), which bind 
IGFs, but not insulin with high affinity. More than 99% of IGFs bind to IGFBPs. In particular, 
IGFBP-3 is the predominant circulating IGFBP. 
Clinical evaluations of IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS will be performed at every 
study visit during the main study except Visits 3, 6a, 6b, 8a, and 9. During the LT-OLE, these 
evaluations will be performed as per the schedule of events in Appendix A.   
5.8 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 
                                                 
a If not done with the central reader during the Screening visit. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 49 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
metabolism, thyroid function, IGF-1 levels, immunogenicity and urinalysis). AEs and concomitant 
medication use will be assessed at every visit. Physical examination and safety laboratory 
assessments will be performed according to the schedule of events in Appendix A.   
5.8.1 AEs 
AEs, including local tolerability (i.e. injection site reactions), will be assessed at all study visits 
(excluding Visits 1 and 6b) throughout the study. In addition, patients will be requested to 
complete a patient diary at home to collect data on AE, concomitant medications and local 
tolerability. 
Any AEs that occur throughout the study will be recorded. Any new AE that occurs between 
scheduled visits should be brought to the attention of the investigator and recorded in the patient’s 
medical file and on the appropriate eCRF page. AEs should be followed until resolution or 
stabilization. 
5.8.2 Local Tolerability (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, excluding Visit 1) 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 and parents/legal guardians 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 reported or observed at the time of visit or during a phone 
call and is of moderate to severe in intensity. 
 Injection site reaction between the last and present visit or remaining at the time of visit 
which require medical attention, or injection site reaction resulting from a previous 
injection, other than the last injection. 
 Any other injection site reaction deemed abnormal to the investigator’s judgment, other 
than those ordinarily observed in subcutaneous injections. 
 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 parent/legal guardian if 
the injection is given at home. The pain will be evaluated at least once weekly using a Pain 
Rating Scale and recorded in the patient diary. 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 
An optional photograph of an abnormal local injection site reaction may be taken. Photographs 
may be taken by site staff during a visit or by a patient or parent/caregiver between study visits in 
which case a copy should be given to study staff at the next study visit.  The photograph, if 
available will be kept signed and dated in the patient medical record. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 50 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.8.3 Concomitant Medication Use 
Use of concomitant medication will be recorded at all study visits (excluding visit 6b). 
5.8.4 Treatment Compliance 
Diary cards will be reviewed at each visit for treatment compliance from previous visits. 
5.8.5 Vital Signs 
Vital signs measurements will be recorded at all study visits during the main study except Visits 3, 
6a, 6b, 8a and 9 and as per the schedule of events in Appendix A during the LT-OLE.  Vital Signs 
will include body temperature, respiration, blood pressure (BP) and heart rate after the patient has 
sat quietly for at least 5 minutes. 
5.8.6 Physical Examination 
A complete physical examination will be performed at all study visits during the main study except 
Visits 3, 6a, 6b, 8a and 9 and as per the schedule of events in Appendix A during the LT-OLE. The 
physical examination will include appearance, eyes, ears, nose, head, throat, neck, chest, lungs, 
heart, abdomen, extremities, skin and musculoskeletal system. Weight will be measured as part of 
the physical examination at relevant visits, ideally fasted in the morning, without shoes and having 
removed all outwear such as jackets, sweaters or sweatshirts and heavy pocket items. CS findings 
at screening will be reported as medical history and as AEs after the Screening visit. 
5.8.7 ECG 
During the main study, ECG (preferably 12-lead) will be performed at Visit 2 (pre-dose), Visit 6b 
at 7-12 hours post dosing (MOD-4023 arm) and at Visit 6 for Genotropin® arm (no time 
limitation). During the LT-OLE, ECG (preferably 12-lead) will be performed annually every 12 
months until study closure. 
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. 
5.8.8 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 myalgias). 
Fundoscopy will be performed according to standard of care and confirmed by an ophthalmology 
evaluation if necessary. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 51 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
5.8.9 Laboratory Assessments  
All routine clinical laboratory assessments will be performed by central laboratory as provided in 
Appendix K according to the schedule in Appendix A, other than urine pregnancy testing, when 
required, which will be conducted at the local laboratory. 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, prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin 
time (PTT) (if indicated only). 
2. Serum chemistry: total protein, albumin, total bilirubin, alanine aminotransaminase (ALT), 
asparate transaminase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase 
(LDH), creatinine phosphokinase (CPK), alkaline phosphatase, sodium, potassium, 
calcium, phosphate, blood urea nitrogen (BUN), liver function test (LFT), creatinine. 
3. Lipid metabolism: overnight fasting cholesterol, triclycerides, high density lipoprotein 
(HDL), low density lipoprotein (LDL), lipoprotein a (Lp(a)), Free Fatty Acids (FFA).  
4. Glucose metabolism: overnight fasting glucose and insulin, HbA1C. 
5. Thyroid function: TSH, FT4. 
6. Immunogenicity: anti-MOD-4023 Ab (MOD-4023 arm only during the main study and all 
patients during the LT-OLE) and Abs to r-hGH (all patients). It is recommended that if the 
Genotropin patients normally administer their drug in the morning, that they wait on those visit 
days to administer the Genotropin® until after the blood sampling.    
7. IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS levels. 
8. MOD-4023 serum levels (MOD-4023 arm only during the main study and all patients 
during the LT-OLE).  
9. Urinalysis: pH, glucose, ketones, erythrocytes, leukocytes, protein. 
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. 
5.9 MOD-4023 DEVICE USABILITY  
5.9.1 PAT as provided in Appendix M (USA Only). 
The PAT will be used to record all the patient’s or caregiver’s injections using MOD-4023 PEN at 
Wks 1, 2, 3, 4, 5 and 6.  It will be completed on site at Wk 1 and at home at Wks 2, 3, 4, 5, and 6 
by the actual user of the PEN or parent/legal guardian. The PAT will be completed for all injection 
attempts at Wks 1, 2, 3, 4, 5, and 6 whether the patient was able to complete the injection or not. 
At Visit 2, prior to MOD-4023 on site injection, patients and caregivers will be trained to use the 
device as outlined in the Patient Dosing Instructions Booklet. In addition, patients and caregivers 
will be trained on the completion of the PAT and instructed the following:  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 52 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 In any given wk a new PAT will be completed for each PEN used that wk (in some cases more 
than 1 PEN may be used for full dose administration; in some cases, more than 1 injection 
from the same PEN may be needed, in which case only 1 PAT is completed for that PEN that 
wk). 
 On Visit 4 (Month 1/Wk 4 [+1 wk]), to bring the completed PATs and confirming proper 
recording by the study staff. 
 To complete the PAT forms (including the first injection) post MOD-4023 weekly injections.  
The PAT forms completed after Visit 4 will be collected on Visit 5 (3 months). 
 To return all used injection devices and PAT forms as defined in the schedule of activities. If 
the PAT forms are not completely and correctly filled in as determined by the PI, up to 4 
additional wks will be added to the PAT assessment time, not to exceed a total of 6 dose 
administrations.  
5.9.2 OAT as provided in Appendix N (USA Only). 
The OAT will be used to record the observer’s assessment of an administration with the device on 
site during Visit 2 after patient or caregiver injected MOD-4023.  
 A new OAT will be completed for each PEN used (in some cases more than 1 PEN may be 
used for full dose administration, in which case an OAT will be completed for each PEN used; 
in some cases, more than 1 injection from the same PEN may be needed, in which case only 1 
OAT is completed for that PEN). 
5.9.3 Assessment of Successful Operation of the MOD-4023 PEN 
All USA MOD-4023 injection devices used during the main study will be collected and returned to 
the study site. A subset of returned devices will be examined to provide evidence of appropriate 
device function and robustness.  In addition, any devices which are perceived to malfunction 
(either before or during use) will be returned through a formal complaint system and evaluated to 
understand the root cause of the failure.  
5.10 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 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 53 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
cases, and in the case of the negative result the test should be repeated in two wks 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).  
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 LT-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.  
The pregnancy must be reported to the Global Study MM, pharmacovigilance (see section 7.6) 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. 
5.11 QOL QUESTIONNAIRE 
QoL will be measured using the QoLISSY questionnaire which was developed to provide 
clinicians and researchers a validated tool to assess the impact of short stature on children. The 
QoLISSY core questionnaire consists of 22 like-scaled items assigned to the core dimensions: 
Physical, Social, and Emotional. 
For patients below the age of 7 and 0 days a parental QoLISSY core questionnaire will be 
completed guided by the parent or caregiver. Patients above and including the age of 7 and 0 days 
will be encouraged to complete the child QoLISSY core questionnaire on its own. Both 
questionnaires are provided in Appendix L as well as a designated list of countries in which it will 
be completed.  
The QoLISSY core total score is calculated by the sum of the means of these 3 dimensions and 
divided by 3. All scores will be transformed from raw scores to 0 to 100 scores, consistent with the 
QoLISSY scoring manual.  Higher values represent a higher QoL.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 54 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
The QoLISSY will be administered at Visit 2 and at the end of the study Visit 8, i.e., after 
12 months of treatment at designated countries (determined by availability of translated tools) per 
the list in Appendix L. 
6. 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 citrate, histidine, sodium chloride, m-cresol, Poloxamer 188, pH = 
6.6.   
6.2 REFERENCE THERAPY 
Genotropin® is a daily GH, which will be used as the reference therapy during the main study.  
A delivery device (Genotropin® 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.  
The device is intended to assist self-injecting adult and paediatric patients, healthcare professionals 
and caregivers with the daily SC injection of the r-hGH, primarily self-administered at home or in a 
healthcare environment 
Starting dose regimen for Genotropin®: 0.034 mg/kg/day (or 0.24 mg/kg/wk divided equally to 7 
injections over a wk).  Genotropin® will be used and monitored according to the approved product 
labeling and dose adjusted based on weight every 3 months during the main study. 
6.3 STUDY DRUG ADMINISTRATION 
MOD-4023 will be administered as a SC injection preferably (but not required) in the morning 
hours once weekly, using the PEN into the upper arms, buttocks, thighs, or abdomen (8 locations). 
It is recommended that all 8 injection sites are used successively, using a different injection site at 
each subsequent injection. The same injection site should be used only after all other injection sites 
have been rotated (see recommended rotation scheme below).   
The starting dose for the administration will be 0.66 mg/kg/wk. All patients on Genotropin® that 
complete Visit 8/10 and continue into the LT-OLE will start treatment with MOD-4023 at 0.66 
mg/kg/wk.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 55 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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 
hours 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 wk. 
If the dose is more than 72 hours late, the patient will not take a dose for the whole wk and will 
continue taking the study medication on the regular day the following wk.   
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 wk 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 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 wk 
should be rescheduled, to meet the required post dosing interval. 
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. 
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. Two (2) injections using 1 PEN. In case the prescribed dose is higher than the 
maximum dose which can be selected according to the PEN amount, the patient should 
be instructed to subtract the dose already received from the prescribed dose and set the 
PEN accordingly. 
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 between 2 PENs, the current PEN and a new PEN.  This may happen when 
the complete dose cannot be fully administered from the PEN in use, the patient should 
be instructed to subtract the dose already delivered from the prescribed dose and set the 
new PEN accordingly. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 56 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
For example, if the full prescribed dose is 25.0 mg and the volume left on the current 
PEN only allows the dose selector to be set to 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 complete the patient diary for each 
of the 2 injections administered. 
Further details are provided in the Patient Dosing Instructions Booklet. 
Missing/Delayed dose should be reported in the patient diary and eCRF. 
6.4 DOSE MODIFICATION PLAN 
The dose of MOD-4023 and Genotropin® (main study) will be assessed every 3 months based on 
patient’s body weight. Doses will be determined by the IRT 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).  
6.4.1 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. For patients on Genotropin®, the dose may be decreased based on repeated 
IGF-1 levels > +2.0 SDS. 
If a patient has an IGF-1 level > +2.0 SDS, they will be requested to return for an unscheduled visit 
within 4-6 wks 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 > +2.0 SDS, the most recent 
dose will be reduced by 15% (i.e. to 0.56 mg/kg/wk for MOD-4023; 29 µg/kg/day for 
Genotropin®). The patient will be treated with the new dose for at least 4 wks before a subsequent 
IGF-1 determination can result in a further dose modification.  If the next scheduled visit is less 
than 4 wks 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 wk minimum time period), IGF-1 will be retested. If the IGF-1 is still > 
+2.0 SDS, the dose will be reduced an additional 15% to 0.48 mg/kg/wk for MOD-4023 and to 
24.7 µg/kg/day for Genotropin® arm. If the IGF-1 is still > +2.0 SDS following 2 dose reductions 
(at least 4 wks after second dose reduction), the Global Study MM (with the assistance of the 
DSMB if necessary) will decide on course of treatment on an individual basis. During the LT-OLE 
dose reduction for IGF-1 level >+2.0 SDS will be made following consultation with the Global 
Study MM on an individual patient basis.  
If AEs are defined as “severe” AND drug-related, dose reduction will be introduced upon 
discussion with the Global Study MM and DSMB - dose should be reduced at a similar manner as 
above in a 2-step approach.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 57 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Every attempt should be made to maintain the patient on the originally allocated dose if possible. 
In case that the investigator does not plan to decrease the dose as described in the protocol, the 
Global Study MM should be notified. 
The key safety data will be reviewed by an independent and external DSMB at least once every 4 
months during the main study and approximately every 6 months during the LT-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, despite dose 
reductions (in both MOD-4023 and Genotropin® cohorts). DSMB review will also include review 
of number or percentage of patients requiring dose reductions due to AEs. 
Figure 2: Dose Decrease Adjustment Scheme 
The scheme and percent reduction is applicable for the Genotropin® arm as well, and in case that 
AEs are defined as “severe” AND drug-related. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 58 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
6.5 METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
During the main study, eligible patients will be randomly assigned in a 1:1 ratio (centralized 
randomization for each region as defined in the stratification factors) to one of two treatment 
groups, MOD-4023 or Genotropin® (reference therapy) for 12 months. 
The following stratification factors will be considered when adding patients to one of the treatment 
groups: 
1. Peak GH levelsa (≤3 ng/mL; >3 to ≤7 ng/mL; and >7 to ≤10a ng/mL). 
2. CA (≥3 years to ≤ 7 years, 0 days; and > 7 years, 0 days.). 
3. Region (1. Western Europe, Israel, Australia, New Zealand, Canada and USA; 2. Central and 
Eastern Europe, Greece, Turkey, Latin America and Asia except for India and Vietnam; 3. 
India and Vietnam). 
Randomization will be performed through an IRT. The treatment codes for each patient will be 
held according to EDC. Shipment, Storage, Dispensing and Return of the IP will be managed 
through the IRT. 
6.6 BLINDING 
In order to minimize any potential sources of bias in this open-label study, certain identified roles 
will remain blinded to the treatment assignments (and to any other treatment-identifying 
information), during the main study.  Details on the blinding procedures used will be provided in 
the Data Management Plan (DMP).   
6.7 ACCOUNTABILITY AND COMPLIANCE OF IP 
The IP will be packed and shipped at 2-8°C in appropriate boxes with temperature loggers. If, upon 
arrival at the study site, study drug supplies appear to be damaged or temperature control does not 
appear to have been maintained, the study monitor and drug supplier should be contacted 
immediately.  
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, how to keep record of 
how much study drug was returned used and unused by each patient.  
All IP 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.  
The investigator must maintain complete and adequate records documenting the receipt, use, loss, 
or other disposition of the IP supplies.  All IP will be accounted for using a drug accountability 
form/record either on paper or electronically. The investigator is responsible that all IP 
accountability records are accurate and available for review by the study monitor, Sponsor or 
designee or the relevant regulatory authority.  
                                                 
a Proportion of patients with peak GH levels >7 to ≤10 ng/mL, will be capped at 35-40% of total sample-size, in the 
randomization scheme. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 59 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
All used and unused study drugs (PENs) will be assessed for accountability by the study monitor as 
detailed in the study monitoring plan. Interim accountability and destruction may also be 
performed during the study, following Sponsor’s written approval. 
6.8 DESTRUCTION OF IP AND OTHER SUPPLIES 
The Sponsor or designee will provide guidance on the destruction of used and unused IP, used and 
unused ancillaries and expired laboratory kits. If destruction is authorized to take place at the 
Investigator’s site, the Investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions provided by 
the Sponsor. All destruction must be approved in advance in writing by the Sponsor and adequately 
documented. 
6.9 PRIOR AND CONCOMITANT THERAPY 
6.9.1 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.  
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 and start and stop dates, dose and dose frequency.  
6.9.2 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 IP (within 30 days of ICF signing). 
6.9.3 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 AEs. 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. In patients with diabetes mellitus requiring drug therapy, the dose of 
insulin and/or oral/injectable agent may require adjustment when MOD-4023 treatment is initiated. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 60 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
6.9.4 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. 
7. SAFETY AND PHARMACOVIGILANCE 
7.1 ADVERSE EVENT 
An AE is any adverse change from the patient baseline condition, whether or not considered IP 
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 IP treatment) of the concomitant disease present at baseline visit 
(after initiation of IP 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 sign 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 CS. 
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 counter measures 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. 




 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 62 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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 after the study period and is considered to be related (possibly/probably) 
to the IP or study participation should be recorded and reported immediately. 
A life-threatening adverse drug experience 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 ADVERSE EVENT 
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 IP 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 AE 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; however, unexpected SAEs that occur following 
treatment with a placebo solution usually does not qualify as a SUSAR. Because knowledge of 
treatment assignment during the main study is needed to complete the determination, the Sponsor's 
designee will provide the final determination as to whether an SAE is a SUSAR. During the LT-
OLE the Sponsor will provide the final determination as to whether an SAE is a SUSAR.  
7.5 NOTIFICATION ABOUT SERIOUS OR UNEXPECTED ADVERSE EVENTS 
7.5.1 Initial Notification  
Each SAE must be reported by the Investigator to the Safety group 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 unexpected and is thought to be possibly related to the study drug, a 
Clinical Safety Associate shall urgently request further information from the investigator. This is 
essential for collecting information to report to the competent regulatory authority (RA). 
7.5.2 Contact Persons and Numbers: 
All SAE forms should be electronically sent via EDC both to the Global Study MM and to the 
global pharmacovigilance group. An appropriate distribution list is maintained within the EDC for 
reporting purposes.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 63 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
, MD 
 
 
 
 
Phone: 
 
Fax: 
 
Email: 
  
 
Pharmacovigilance Unit: 
inVentiv Health Clinical / Syneos Health 
"Commerzone", Bldg # 4, 6th Floor, Yerwada Jail Road, 
Yerwada, Pune 411006, India 
 
These preliminary reports will be followed within 24 hours by detailed descriptions that will 
include a completed SAE form, copies of hospital case reports, autopsy reports and other 
documents, when requested and applicable and available. 
The Investigator must complete the SAE Report Form (in the EDC system) in English, assess the 
relationship to study treatment and submit it electronically via eCRF within 24 hours to the global 
pharmacovigilance group.  
Follow-up information is to be submitted on a new SAE Form (in the EDC system). The new form 
should clearly state that it is a follow-up to the previously reported SAE and give the date of the 
original report. The follow-up SAE report should describe whether the event has resolved or 
continues, if and how it was treated and whether the patient continued or discontinued study 
participation. 
The following information should be provided in the SAE form to accurately and completely 
record the event (some of the data is automatically populated by the EDC which still maintains data 
privacy requirements): 
1. Investigator name and site address. 
2. Patient study identification number. 
3. Patient demographics (gender, date of birth or age (in accordance with local regulations), 
weight, Ht). 
4. Clinical Event: 
 Description - Description of event, referral to experts, additional tests done and results 
of these tests. 
 Date and time of onset, stop date, or duration.  
 Severity. 
 Treatment (including hospitalization). 
 Relationship to study drug (causality). 
 Action taken regarding study drug. 
 Information on recovery and any sequelae. 
PPD
PPD
PPD
PPD
PPD
PPD


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 64 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 If the SAE resulted in death: 
o Cause of death (whether or not the death was related to study drug). 
o Autopsy findings (if available). 
 Medical History CRF (copy). 
 Concomitant Medication CRF (copy). 
 Any relevant reports (laboratory, discharge, etc.). 
Accompanying documentation, such as copies of hospital case reports, autopsy reports and other 
documents when applicable, should be summarized on the SAE form and a copy of the source 
document may be sent if required. The patient’s personal details will be removed and replaced with 
study identifiers i.e. study number and initials, if applicable. 
In addition, all AEs / SAEs / SUSARs will be reported to the local Ethics Committees (EC) and 
RAs 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. 
Follow-Up of SAEs / SUSARs 
Follow-up of SAEs / SUSARs that occur during the study will continue until their satisfactory 
resolution or stabilization. 
If supplementary information becomes available, a follow-up SAE Report Form must be completed 
by the site based on EDC system and emailed within 24 hours to Safety group. 
The contact information for follow up SAE reporting is the same as for initial SAE reports (see 
above section).  
The SAE form and accompanying documentation should be placed in the SAE section of the 
Investigator’s file and/or patient medical file. If supplementary information on a SAE has to be 
sent, the SAE form to be used must be marked as “follow-up report”. 
Follow-Up Reports on Non-Serious AE 
All AEs must be followed until resolution or stabilization. In exceptional cases, it may be defined 
as “ongoing without further follow-up” by the Investigator and Sponsor’s decision. 
7.6 REPORTING OF PREGNANCIES OCCURRING DURING THE STUDY 
Following administration of IP, pregnancy cases in any female patient (as well as in female 
partners of male patients) will be reported, if known, until the patient completes or withdraws from 
the study. The pregnancy will be reported immediately by phone and by faxing/emailing a 
completed Pregnancy Report to the Sponsor (or designee) within 24 hours of knowledge of the 
event. The pregnancy will not be processed as an SAE; however, the Investigator will follow the 
patient until completion of the pregnancy and must assess the outcome in the shortest possible 
time, but not more than, 30 days after completion of the pregnancy. The Investigator should notify 
the Sponsor (or designee) of the pregnancy outcome by submitting a follow-up Pregnancy Report.  
Dosing in the study should be stopped upon immediate notification of the pregnancy. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 65 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
If the outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted foetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the Investigator will report the 
event by phone and by faxing/emailing a completed SAE Form to the Sponsor (or designee) within 
24 hours of knowledge of the event, as outlined above. 
7.7  INDEPENDENT DATA AND SAFETY MONITORING BOARD (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 the Sponsor 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.  
The key safety data will be reviewed by an independent DSMB in approximately once every 4 
months during the main study and approximately every 6 months during the LT-OLE. 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 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. 
7.8 MEDICATION ERRORS 
Medication errors may result from the administration or consumption of the IP 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 IP; 
 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 patient is to be captured in the EDC system. 
7.9 MEDICAL DEVICE COMPLAINT REPORTING REQUIREMENTS 
All medical device complaints, regardless of whether the medical device complaint is associated 
with an AE, will be reported to the Sponsor on a designated form through a formal complaint 
system.  Complaints may include incidents, potential incidents, and/or queries by clinical study 
patients and or clinical study site personnel on the function or use of the PEN or the drug product 
within the PEN.  An incident or malfunction of the PEN is an event that might have led to death or 
serious deterioration in health, or if it occurred again might lead to death or serious deterioration in 
health. 
Sponsor is to be notified of all medical device complaints within 24 hours of the Investigator’s 
awareness of the event.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 66 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
8. STATISTICAL ANALYSIS METHOD 
8.1 SAMPLE SIZE CONSIDERATION 
The aim of the main study is to demonstrate that weekly MOD-4023 is not inferior to daily r-hGH 
administration. Non-inferiority will be claimed if the 2-sided 95% CI for mean treatment difference 
(MOD-4023 ─ Genotropin®) in the primary efficacy endpoint will lie entirely above “non-
inferiority margin” of -1.8 cm/year.  
The following assumptions were made in the sample size calculation: 
 2-sided alpha of 0.05. 
 80 % power. 
 Between-patient SD of annual growth rate is 2.5 cm/year in all treatment groups. 
 Non-inferiority margin is -1.8 cm/year.  
 The true mean treatment difference (MOD-4023 – Genotropin®) is -0.8 cm/year. 
With these assumptions, 100 patients per group will provide 80 % power for the non-inferiority 
test. To allow for an approximate 10 % dropout rate, 110 patients will be randomized to each 
treatment group (Total N=220 patients). 
8.2 ANALYZED POPULATION SETS 
Five (5) analysis sets will be used for this study: Safety Analysis Set, Full Analysis Set, Full 
Analysis Subset (FAS), modified intent-to-treat (mITT )Set, and the per Protocol (PP) Set. 
8.2.1 Safety Analysis Set 
The safety analysis set will include all patients who have received at least one dose of study 
treatment.  Patients will be analyzed according to actual treatment received. 
8.2.2 Full Analysis Set 
The full analysis set will include all patients randomized and will be the primary efficacy analysis 
set. Patients will be analyzed according to randomized treatment group. 
If study enrollment is closed prior to subject full qualification and/or study closure for any other 
reason by the Sponsor and/or patients lost to follow up between Visit 1 and Visit 2, the patient will 
be excluded from the study. 
8.2.3 Modified Intent-to-Treat Set 
The mITT set will include all patients who received at least one dose of study drug and had at least 
one post-baseline assessment of Ht. Patients will be analyzed according to randomized treatment 
group. 
8.2.4 Per Protocol Set 
The PP set will consist of all randomized patients who did not have any major protocol deviations.  
The patients who have any major protocol deviations will be identified before database lock by the 
clinical team in a blinded review.   
LT-OLE: 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 67 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
8.2.5 Full Analysis Subset 
The term “full analysis subset” is used to describe the analysis set which is as complete as possible 
and as close as possible to the intention-to-treat (ITT) ideal of including all enrolled patients.  
The full analysis set will comprise all treated patients who have received at least one dose of active 
treatment and who provide any follow-up data. The patients will be grouped by their original 
treatment in the treatment period.   
8.3 HANDLING OF MISSING DATA 
The method for handling missing data will be described in the SAP. The primary method of 
imputation will be with multiple imputation assuming missing at random, using SAS PROC MI.  
Details on all sensitivity analyses related to the handling of missing data will also be provided in 
the SAP.     
LT-OLE: 
No imputation will be made for missing measurements.  Patients who discontinued early will have 
their last available data summarized.    
8.4 ENDPOINTS 
8.4.1 Primary Efficacy Endpoint 
The primary efficacy endpoint during the main study is the Annual HV in cm/year after 12 months 
of treatment.   
HV (cm/year) at Visit 8 (12 months) 
 = (Ht at Visit 8 ─ Ht at Visit 2)/((Date of Visit 8 ─ Date of Visit 2)/365.25); 
where Visit 2 is the Baseline visit. 
(Note: HV at any other post-baseline Visit xx is also computed using formula above by replacing 
Visit 8 with Visit xx). 
8.4.2 Secondary Efficacy Endpoints (Auxology/Clinical) 
 Annualized HV after 6 months of treatment;  
 Change in Ht 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 (BM calculated as BA/CA). 
8.4.3 Biochemical Endpoints 
 Absolute IGF-1 and IGF-1 SDS levels on day 4(-1) after MOD-4023 dosing across 
study visits; 
 IGFBP-3 and IGFBP-3 SDS levels at on day 4(-1) after MOD-4023 dosing across study 
visits. 
8.4.4 Safety Endpoints 
 Incidence of AEs and SAEs; 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 68 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 Incidence of anti-MOD-4023 Ab formation (including characterization of the Ab and 
neutralizing properties); 
 Local injection site reaction assessment; 
 Parameters of glucose metabolism: blood fasting glucose, fasting insulin level, HbA1c; 
 Thyroid (endocrinology) status; 
 Lipid profile;  
 All other safety hematology, biochemical parameters and urinalysis; 
 Physical examination; 
 Fundoscopy results - if performed (normal/abnormal); 
 Vital signs; 
 ECG. 
8.4.5 Additional Endpoints 
 Proportion of successful single injections out of total number of single injections using 
the MOD-4023 PEN in US patients at Wks 1, 2, 3, 4, 5, and 6, based on the PAT. 
 Proportion of successful single injections out of total number of single injections using 
the MOD-4023 PEN in US patients at Wk 1, based on the OAT. 
 Comments on the PAT related to successful or unsuccessful injection attempts. 
 Comments on the OAT related to successful or unsuccessful injection attempts. 
 Information gained by inspection of returned devices. 
 QoL endpoint measured by the QoLISSY core questionnaire at Baseline and month 12 
at specific countries per Appendix L. 
 
LT-OLE: 
8.4.6 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: blood fasting glucose, fasting insulin level, HbA1c; 
 Thyroid (endocrinology) status; 
 Lipid profile;  
 All other safety hematology, biochemical parameters and urinalysis; 
 Physical examination; 
 Fundoscopy results - if performed (normal/abnormal); 
 Vital signs; 
 ECG. 
8.4.7 Auxology/Clinical Endpoints 
 
Annual HV in cm/year at each 12-month interval. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 69 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 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 LT-OLE year 1 and to previous values from 
LT-OLE year 2 onwards). 
8.4.8 Biochemical Endpoints 
 IGF-1 and IGF-1 SDS levels on day 4 (-1) after MOD-4023 dosing across study visits.  
 IGFBP-3 levels and IGFBP-3 SDS on day 4 (-1) after MOD-4023 dosing across study 
visits. 
8.5 STATISTICAL ANALYSIS 
The main study database will be cleaned and locked for analysis after the last patient completes 12 
months treatment.  
The assessment of safety during the LT-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/auxological and biochemical endpoints.  
The Sponsor reserves the right to stop enrollment when the targeted number of randomized patients 
is reached.  If this situation arises, non-randomized patients that are undergoing Screening will be 
considered a Screen Failure. 
Details of applicable statistical methods for the main study and LT-OLE will be provided in two 
separate SAPs prior to database lock of the main study and final study closure of the LT-OLE.  
8.6 EFFICACY ANALYSIS 
The aim of the present study is to demonstrate that in terms of the primary efficacy endpoint, 
Annualized HV at 12 months, weekly MOD-4023 is non-inferior to daily Genotropin® by a 
non-inferiority margin of 1.8 cm/year.  
With µM and µC representing the mean annual HV for the MOD-4023 and the Genotropin® 
(Control) group, respectively, the following hypotheses will be tested:  
Null hypothesis H0: µM < µC -1.8 cm/year;  
vs. 
Alternate hypothesis H1: µM ≥ µC -1.8 cm/year 
Non-inferiority will be concluded if the lower bound of the 2-sided 95 % CI for the mean treatment 
difference “MOD-4023 – Genotropin®”, in the primary efficacy endpoint is ≥ -1.8 cm/year.  
The CI for the difference of means between the 2 treatments will be derived from an analysis using 
ANCOVA.  The ANCOVA model will include classification terms for treatment, age group, 
gender, peak hGH levels, and region.  The model will also include Baseline Ht SDS as a covariate.  
The determination of non-inferiority will be based on least squares means for the 2 treatments from 
the ANOCVA and the 95 % CI of the differences between the treatments.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 70 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Descriptive statistics will be reported for observed and change from Baseline to annual HV values 
at 12 months during the main study and every 12 months thereafter.  
ANCOVA-based statistics will be reported by the categorical terms used in the ANCOVA model: 
age group, gender, peak GH levels, and region. 
8.6.1 Secondary Endpoint Analyses 
A similar ANCOVA model as used for the primary endpoint will be used to analyze: 
 annualized HV at 6 months;  
 change in Ht SDS at 6 months; 
 change in Ht SDS at 12 months. 
Least square mean estimates for the 2 treatments and the 95 % CI of 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 to 12 months.  
Descriptive statistics will be reported for HV and Ht SDS at each visit. 
Series plots of mean values +/- SE will be reported for HV and Ht SDS by visit and treatment. 
ANCOVA-based statistics will be reported by the categorical terms used in the ANCOVA model: 
age group, gender, peak GH levels, and region. 
8.6.2 Primary Efficacy Sensitivity Analysis 
The ANCOVA-based primary efficacy analysis will be repeated using the mITT set and the PP 
set.  
The ANCOVA-based primary efficacy analysis will be repeated on the full analysis set using last 
observation carried forward (LOCF) in place of multiple imputations for the handling of missing 
data. 
8.6.3 Biochemical Markers Analysis 
Descriptive statistics will be reported for observed and change from Baseline for all biochemical 
endpoints at each visit.  
The number and percent of patients who achieved IGF-1 normalization (defined as IGF-1 SDS 
between -0.5 and 1.5, inclusive) will be summarized. The number and percent of patients who had 
IGF-1 SDS > 2.0 will be summarized at each visit. 
8.6.4 Additional Endpoints Analysis 
OAT and PAT (USA Patients Only) 
OAT and PAT results will be summarized by using descriptive statistics.  
The number and percentage of successful single injections for PAT will be summarized overall. A 
successful single injection for PAT will be based on the questions “Did the dose window show ‘0’ 
when you finished your injection?” and “Do you believe that a full dose was injected?” The single 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 71 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
injection is considered successful if the subject answers “Yes” to both questions for all attempts on 
the form. A subject can have multiple successful single injections at one visit. 
Intermittent missing observations for the PAT will be imputed as a failure if both the prior and 
subsequent observations are a failure. Otherwise, intermittent missing observations will be imputed 
as a success. 
The number and percentage of successful single injections for OAT will be summarized overall. A 
successful single injection for OAT will be based on the question “…did the user successfully 
inject into an acceptable injection site without physical assistance?” The single injection is 
considered successful if the observer answers “Yes” to the question for all attempts on the form. A 
subject can have multiple successful single injections at 1 visit. 
The number and percentage of successful single injections for PAT and OAT will also be 
summarized by age group, sex, and race.  
The number and percentage of the number of attempts required to achieve a success will be 
summarized for PAT and OAT. 
Comments on the PAT and OAT related to successful or unsuccessful injection attempts will be 
listed.  
Information gained by inspection of returned devices will be listed.   
Quality of Life Questionnaire 
The 3 dimensions (physical, social, and emotional) of the QoLISSY questionnaire will be 
calculated individually and as a combined core total score based on the QoLISSY scoring manual. 
This core score is calculated as the sum of the means of these 3 dimensions and divided by 3. All 
scores will be transformed from raw scores to 0 to 100 scores. 
8.6.5 LT-OLE Analysis 
During the LT-OLE the primary goal of this safety and efficacy analysis is to report on the effect of 
long-term treatment on Annual HV and other auxological/clinical and biochemical measures.  
 Annual HV will be summarized with descriptive statistics each year of LT-OLE treatment. 
For patients who discontinue without annual measurement, their HV will be calculated 
based on their last available measure.  
 Change in Ht SDS every 12 months (the last value within each year compare to the value 
12 months earlier) will be summarized with descriptive statistics.  
 Change in bone maturation (BM) every 12 months, (compared to Week 52 BA (calculated 
as BA/CA) at completion of LT-OLE year 1 and to previous values from LT-OLE year 2 
onwards). 
 IGF-1, IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS will be summarized with descriptive 
statistics at each visit.  A summary of the incidence of IGF-1 SDS >2.0 at each visit will be 
provided.   


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 72 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
8.6.6 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. 
LT-OLE: 
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. Each of the listed safety 
endpoints will be summarized with descriptive statistics for each year and overall.  Data of all 
safety endpoints will be listed.  
8.6.7 Adverse Events 
AEs will be coded with Medical Dictionary for Regulatory Activities (MedDRA). 
For analysis purposes, all AEs will be classified to the appropriate MedDRA preferred term (PT) 
and system organ class (SOC). For each patient, multiple events that map to the same PT will only 
be counted once for the PT, and multiple PTs within an SOC will only be counted as 1 occurrence 
for that SOC to assess patient incidence of events by PT and SOC. The count and percentage of 
patients with each PT and SOC will be summarized for each treatment group. 
Relationship and severity of AEs will be summarized (patient count, % of patients) for each 
treatment group. For these summaries, multiple occurrences of an event within a patient will be 
classified as a single observation with the strongest relationship and maximum severity ratings. In 
addition, frequency tables of all reported events with each associated relationship and severity will 
be presented.  
SAEs will be classified as SAEs by the investigator and will be summarized by treatment group, 
PT and SOC, as well as total patients exposed.  
8.6.8 Clinical Laboratory Findings 
Any CS laboratory data will be reported as an AE. Laboratory data will be reported by analyte for 
each treatment group. There will not be any hypothesis testing. The laboratory results will be 
presented at each visit along with the raw change from Baseline for quantitative data. 
Presence/absence or normal/abnormal results will be summarized as count and percentage. In 
addition, shift tables summarizing changes from normal to out-of-normal range will be provided. 
Descriptive statistics (the number and percentage of patients) of patients with the presence of anti-
r-hGH and anti-MOD-4023 Abs will be summarized. 
8.6.9 Vital Signs, Fundoscopy and ECG  
Any CS findings will be reported as an AE. The summary of abnormal findings at each visit will be 
displayed by treatment group.  Descriptive statistics of vital signs will be calculated at each 
scheduled visit and will include the raw change from Baseline.   


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 73 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
9. ETHICS 
9.1 INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE 
Prior to initiation of the study, the PI will submit the study protocol and amendments, sample ICF 
and any other documents that may be requested to the IRB/IEC for review and approval. The 
Investigator will request that the IRB/IEC 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/IEC. The Investigator must 
agree to make any required progress reports to the IRB, as well as reports of SAEs, life-threatening 
conditions, or death. 
9.2 ETHICAL CONDUCT OF THE STUDY 
All clinical work conducted under this protocol is subject to GCP guidelines. This includes an 
inspection by Sponsor or its designee, health authority or IRB/IEC 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 standards operating procedures (SOPs) 
and the following guidelines: 
 GCP: International Council for Harmonization (ICH): Integrated Addendum to ICH E6 
(R1): Guideline for Good Clinical Practice E6 (R2), 09 November 2016. 
 Declaration of Helsinki: Brazil, 2013 (Appendix G). 
 Local country guidelines for conducting clinical studies. 
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). All protocol modifications must be submitted to the IRB/IEC 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 study patients, or when the changes involve only 
logistical or administrative aspects of the study. No approval will be required for notifications. 
9.4 PATIENT INFORMATION AND CONSENT 
Prior to screening for the study each patient and parent(s)/legal guardian 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 the FDA 
(21 CFR 50.25) and ICH-GCP will be followed.a Written consent will be obtained from each 
patient to be involved in the clinical study by using the IRB/IEC-approved ICF prior to the conduct 
of any study-related activity. Each patient will be given a copy of the written ICF. The patients will 
also be instructed that they are free to withdraw their consent and discontinue their participation in 
the study at any time without prejudice. Each patient’s chart will include the signed ICF for study 
                                                 
a Illiterate patients should provide their consent in a method that is accepted according to local regulations.   
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 74 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
participation. When the study treatment is completed and the eCRF has been monitored, the ICF 
will be kept in the Investigator’s Site File for the required period of time. RAs may check the 
existence of the signed ICF in this central study folder if not having done so during the study.  
Children and adolescents are legally unable to provide informed consent to participate in clinical 
studies. Informed consent must be obtained instead from the legally acceptable representative of 
the child or adolescent, usually their parent(s) or legal guardian. However, children and adolescents 
should be involved in health-care decisions affecting them. To that end, ICH guidelines, EMA 
Guideline on the Ethics of Clinical Trials in Children and FDA regulations require that the assent 
from the child or adolescent be obtained when this is appropriate and when the potential patient is 
capable of providing assent. The determination of appropriateness and capacity of children in the 
study to provide assent is made by the relevant IRB/EC, though it may be left to the investigator to 
assess whether assent is actually obtainable from children of a young age, such as preschool-aged 
children.   
Assent may not be required if, consistent with local law and regulatory requirements, the IRB/EC 
determines that the intervention or procedure involved in the research holds out a prospect of direct 
benefit that is important to the health or well-being of the potential patients and is available only in 
the context of the research.  Even where the IRB/EC determines that patients are capable of 
assenting, the IRB/EC may still waive the assent requirement under special circumstances.  Where 
parental permission is to be obtained, the IRB/EC may find that permission of 1 parent is sufficient 
if consistent with local law and regulatory requirements.  For clinical investigations involving 
greater than minimal risk, permission is generally required from both parents unless only 1 parent 
has legal custody, or one parent is deceased, unknown, incompetent, or not reasonably available. 
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 Site File and can be made available to the 
Investigator and to the IRB/IEC 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 annually, by sending a letter or email to the physician if required by the local authorities. 
9.7 PERSONAL DATA PROTECTION 
The Sponsor complies with a patient's right to protection against invasion of privacy. Throughout 
this study, all data will be identified only by an identification number, date of birth and patient 
initials (where/if applicable). 
The personal 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, 
strategic partners etc.) and relevant health RA will have direct access to personal medical data to 
assure a high-quality standard of the study.  
10. QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and designated clinical research organizations (CRO) maintain a quality assurance 
system with written SOPs to ensure that clinical studies are conducted, and data are generated, 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 75 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
documented and reported in compliance with the protocol, GCP and applicable regulatory 
requirements.  
10.1 AUDITS AND INSPECTIONS 
The Investigator should understand that source documents for this study should be made available 
to appropriately qualified personnel from the Sponsor Quality Assurance 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 or a 
contract monitor. The study monitor will advise the Investigator regarding the practical conduct of 
the study and maintaining compliance with the protocol, GCP and all applicable regulatory 
requirements. Prior to Screening, the study monitor will evaluate the site’s source documents to 
ensure thorough, accurate and compliant source worksheets/systems are available for study 
reporting. 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, 
remote monitoring via the EDC and on-site visits. During the on-site visits, the eCRF will be 
reviewed for completeness with corresponding source documents. As part of the data audit, source 
documents will be made available for review by the study monitor. The study monitor will also 
perform drug accountability checks and may periodically request review of the Investigator’s Site 
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 receive the study monitor during these on-site visits, cooperate in providing 
the documents for inspection and respond to inquiries.  
10.2.1 Source Document 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents. 
Source documents are original records in which raw data are first recorded. These may be 
office/clinic/hospital records, charts, diaries, x-rays 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.  
Source data for patients registered to the study should indicate date informed consent/assent was 
signed, participation in clinical protocol number and title, treatment number, evidence that 
inclusion/exclusion criteria have been met. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 76 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
10.2.2 Electronic Case Report Form (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 laboratories. 
10.4 DATA MANAGEMENT 
An eCRF will be used for the current study and a data management plan will be prepared by the 
Sponsor and/or 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 MedDRA, version 18.1 or higher. Prior and concomitant medications 
will be coded according to the World Health Organization (WHO) Drug Dictionary.  
11. STUDY ADMINISTRATION 
11.1 PARTICIPATING CENTERS 
Approximately 200 sites in 30-40 countries worldwide will participate in this study. A list of all 
participating sites will kept in the electronic study master file. 
11.2 REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION 
Prior to the start of the study, Investigator's and study site compliance with all pre-investigational 
requirements will be evaluated and confirmed based on the site essential documents. The list may 
include: 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 77 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 Appropriate local health authority documentation properly signed and dated by the 
required Investigators (i.e., the submission package); 
 Signed copy (original) of the approved protocol and Investigator’s Brochure; 
 Completed and signed statement of Investigator; 
 Signed Clinical Trial Agreement; 
 Curriculum vitae for the Investigator and sub-Investigatorsa; 
 IRB/IEC name and address; and membership list; 
 Letter of approval from the IRB/IEC for both protocol (identified by protocol title and 
number), informed consent form (identified by protocol title and number) and other 
study related patient materials; 
 Provisions for direct access to source/data documents if necessary for study-related 
monitoring, audits, IRB/IEC review and regulatory inspection. 
Upon satisfactory receipt of all required regulatory documents, Sponsor will arrange that IP be 
delivered to the study site. Supply of all other study materials will be the responsibility of OBL 
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 or CRO/study monitor will prepare an investigator's study file 
(ISF). This file should be used for all study related documents. The investigator will be responsible 
for keeping the ISF updated and ensuring that all required documents are filed. The file will be 
inspected during monitoring visits. 
11.3 CLINICAL STUDY SUPPLIES 
The Sponsor and/or designated representative will be responsible for supplying clinical study 
supplies. The Investigator will be responsible for inventory and accountability of all clinical study 
supplies at his/her study 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. 
11.4 INVESTIGATOR SITE FILE (ISF) 
The ISF partitions may be provided by the designated CRO at the initiation visit. All documents 
required for the conduct of the study as specified in the ICH-GCP guidelines will be maintained by 
the Investigator in an orderly manner in the ISF and made available for monitoring and/or auditing 
by the Sponsor or designee, strategic partners and/or RAs. 
                                                 
a Can be collected at the Site Initiation Visit. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 78 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
11.5 STUDY COMPLETION 
This study is expected to end at drug approval. An annual extension request will be submitted to 
local EC/IRB, where applicable. 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 SAE reported; 
 Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable). 
11.6 FINAL REPORT 
A study report will be developed at completion of data analysis following completion of the main 
study. A final study report will be developed at study closure. These reports will comprise clinical 
and statistical integrated reports, according to the ICH E3 guidelines. 
11.7 RETENTION OF STUDY RECORDS 
The Investigator will retain copies of the approved protocol, completed eCRF, informed consent 
documents, relevant source documents and all other supporting documentation related to the 
project for 15 years. If the Investigator is unable to retain the study documents for the required 
amount of time, Sponsor or designee must be informed in writing 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 RA. 
11.8 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 (where 
applicable/available) and birth dates. 
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. The personal physician will be 
notified by site personnel of patient participation in the study if required by the local authorities. 
All information supplied by OBL 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 OBL, shall not be 
disclosed to others without the written consent of OBL 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 OBL. This information may be disclosed as deemed necessary by OBL. To allow the use 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 79 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
of this information derived from this study, the investigator is obliged to provide OBL with 
complete test results and all data developed in this study.  
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 80 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
12. REFERENCES 
Bach, L. A. (2004). "The insulin-like growth factor system: towards clinical applications." The 
Clinical biochemist. Reviews / Australian Association of Clinical Biochemists 25(3): 155-
164. 
Bidlingmaier, M., J. Kim, et al. (2006). "Comparative pharmacokinetics and pharmacodynamics of 
a new sustained-release growth hormone (GH), LB03002, versus daily GH in adults with 
GH deficiency." J Clin Endocrinol Metab 91(8): 2926-2930. 
Cohen, P., A. D. Rogol, et al. (2008). "Consensus statement on the diagnosis and treatment of 
children with idiopathic short stature: a summary of the Growth Hormone Research 
Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for 
Paediatric Endocrinology Workshop." The Journal of clinical endocrinology and 
metabolism 93(11): 4210-4217. 
Cook, D. M., B. M. Biller, et al. (2002). "The pharmacokinetic and pharmacodynamic 
characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-
deficient adults." The Journal of clinical endocrinology and metabolism 87(10): 4508-4514. 
Greulich, W., & Pyle, S. (1959). "  Radiographic Atlas of Skeletal Development of the Hand and 
Wrist. Stanford University Press, 2nd edition.". 
Hershkovitz O., Bar-Ilan A., et al (2015) "In Vitro and in Vivo Characterization of MOD-4023, a 
Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone." Mol 
Pharmaceutics 13(2): 631-639. 
Ho, K. K. (2007). "Consensus guidelines for the diagnosis and treatment of adults with GH 
deficiency II: a statement of the GH Research Society in association with the European 
Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of 
Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia." European 
journal of endocrinology / European Federation of Endocrine Societies 157(6): 695-700. 
Kemp, S. F., P. J. Fielder, et al. (2004). "Pharmacokinetic and pharmacodynamic characteristics of 
a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient children." 
The Journal of clinical endocrinology and metabolism 89(7): 3234-3240. 
Krysiak, R., A. Gdula-Dymek, et al. (2007). "Growth hormone therapy in children and adults." 
Pharmacol Rep 59(5): 500-516. 
Lindsay, R., M. Feldkamp, et al. (1994). "Utah Growth Study: growth standards and the prevalence 
of growth hormone deficiency." The Journal of pediatrics 125(1): 29-35. 
Makadia, H. K. and S. J. Siegel (2011). "Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable 
Controlled Drug Delivery Carrier." Polymers 3(3): 1377-1397. 
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. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 81 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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. 
 




















 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 91 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX B: GROWTH HORMONE STIMULATION TESTS 
As stated in the 2000 Growth Hormone Research Society Consensus Guideline: “In a child 
with clinical criteria for GHD, a peak GH concentration less than 10 ng/mL has 
traditionally been used to support the diagnosis. At the present time, a new GH reference 
standard is being introduced that may require a downward adjustment of the lower limit of 
normal” (Growth Hormone Research Society Consensus Guidelines for the Diagnosis and 
Treatment of Growth Hormone (GH) Deficiency in Childhood and Adolescence (2000))a. 
The new standard is currently used in the USA and European Union (EU). However, the 
common clinical practice remains to treat patients with GH ≤ 10 ng/mL. The cutoff for this 
study is in line with this common clinical practice. 
The following GH stimulation tests are recommended, but the final decision regarding 
which test will be performed will be made by the investigator. 
ITT 
Regular human insulin (0.075-0.15 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, 45, 60, and 90 min (6 
sampling points) for glucose, hGH and cortisol determination. 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 190 nmol/L (7 μg/dL) or 
an increase in peak cortisol level above 500 nmol/L (18 μg/dL). 
Clonidine test 
After fasting overnight, clonidine (up to 0.15 mg/m2 body surface, given orally) will be given 
at time (t) = 0, and venous blood will be obtained by an indwelling catheter inserted in a 
cubital vein and kept patent by slow infusion of isotonic saline or with saline flush, heparin 
lock if necessary. Blood will be collected at the following intervals: t = 0, 30, 60, 90, 120 and 
150 min (6 sampling points) for hGH measurement. Caution should be exercised when 
performing this test, however, as clonidine causes side effects such as tiredness and decreased 
BP. Thus, BP 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 BP every 15 
minutes. 
Arginine test 
Soluble 10% arginine hydrochloride (0.5 g/kg) will be given iv from 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 
                                                 
a JCEM 2000. Vol. 85 (11): 3990-3993. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 92 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
following intervals: t = 0, 30, 45, 60 and 90, 120 min (6 sampling points) for hGH 
measurement.  
Glucagon test 
After fasting overnight, glucagon (0.03 mg/kg with a maximal total dose of 1 mg) will be 
given i.m. or s.c. at time t = 0, and venous blood will be obtained by an indwelling catheter 
inserted in a cubital vein and kept patent by slow infusion of isotonic saline. Blood will be 
collected for hGH measurement at 0, 60, 90, 120, 150 and 180 min relative to the time of 
glucagon administration.  
Glucagon test is not recommended for assessing the cortisol status. However, a normal 
ACTH reserve can be defined as a peak cortisol level above 500 nmol/L (18 μg/dL). If the 
peak cortisol level reached during the glucagon test (referring to a historical test only) is 
lower, then an ACTH stimulation test is needed to confirm the diagnosis of hypoadrenalism.  
L-Dopa test 
After fasting overnight L-Dopa will be given orally at time-point t=0 at a dose of 125 mg if 
body weight is less than 15 kg, else 250 mg if body weight is less than 35 kg, else 500 mg if 
body weight is greater than 35 kg. Since L-Dopa alone is not available in the USA, the 
combination of Carbidopa/Levodopa can be used which is given as 25/250 mg (if > 15 kg) or 
10/100 mg (if <15 kg). Blood samples will be obtained by an indwelling catheter inserted in a 
cubital vein and kept patent by slow infusion of isotonic saline. Blood will be collected at the 
following intervals: 0, 30, 60, 90 min. 
 Propranolol priming of L-dopa test is NOT required 
If any of the above tests are administered in tandem, the last sample of the first test will 
be the baseline of the second test, decreasing the sample number by 1.  
Any of the tests listed in Appendix B are acceptable. 
 The tests SHOULD be performed sequentially, they may NOT be simultaneous 
o  In case the historical GH stimulation tests were done simultaneously, the data will 
be evaluated on individual basis and borderline stimulation test results may lead 
the global study MM to request 1 additional test, as outlined above. In such cases, 
both global study MM will review the historical and enrollment data before such a 
request is made. 
 IF the tests are performed sequentially, the 0 min sample for Agent 2 MAY be the final 
sample timepoint for Agent 1 
 As all of the tests outlined in Appendix B have a minimum of 90 min, the final sample for 
a 2-agent sequential test should be NO LESS THAN 180 min 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 93 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX C: INSTRUCTIONS FOR OBTAINING HEIGHT MEASUREMENTS 
Use the following instructions when obtaining Ht measurements. 
Please repeat the following instructions for 3 consecutive measurement per patient per visit. It 
is recommended that the Ht measurement will be conducted by the same trained person.  
1. Use a wall-mounted calibrated stadiometer, ensure foot plate is in place. 
2. Patients should not stretch prior to Ht 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 2 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.  
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 94 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX D: INSTRUCTIONS FOR OBTAINING X-RAY FILMS 
BA Assessment using the Greulich and Pyle 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 CA are important in pediatric endocrinology for diagnosing diseases which result in 
abnormalities of stature (tall or short) in children. Serial measurements of BA are also critical 
in determining the effectiveness of established treatments of these diseases as well as use in 
clinical studies 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 posterior to anterior (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 min or in 2 min on a transatlantic flight. 
The Greulich and Pyle Method is a holistic method based on “The radiographic atlas of 
skeletal development of the hand and wrist” (second edition, 1959). The atlas contains many 
standard plates which represent normal bone growth and development of the hand from 
infancy through adolescence separately for males and females.   
For this study, the BA 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 Greulich and Pyle Atlas.   
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. 
 
 




 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 96 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX F: GLYCEMIC TARGETS FOR CHILDREN AND ADOLESCENTS 
WITH TYPE 1 DIABETES 
 
HbA1C  
<7.5%  
Plasma glucose before meals  
90-130 mg/dL (5.0-7.2 mmol/L) 
Plasma glucose at bedtime and overnight  
90-150 mg/dL (5.0-8.3 mmol/L) 
Source: American Diabetes Association, Standards of Medical Care in Diabetes, January 2015, Volume 38 
(Supplement 1), S70–S76. 
 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 97 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX G: 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. 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 98 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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 
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 patients 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.  


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 99 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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. 
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 patients 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 patients 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 patients and information 
regarding provisions for treating and/or compensating patients 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 patients 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.  
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 100 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Privacy and Confidentiality  
24.  
Every precaution must be taken to protect the privacy of research patients and the 
confidentiality of their personal information. 
Informed Consent  
25.  
Participation by individuals capable of giving informed consent as patients 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. 
26.  
In medical research involving human patients 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 patients 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 patients 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 patients who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 101 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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 patients 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 
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. 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 102 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human patients 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 patients 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 
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. 
 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 103 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX H: EXAMPLE 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 may 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. 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 104 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
Swelling 
Grade Description 
 
0 
NONE  
No swelling detected 
 
1 
MILD  
Palpable “firmness” only 
 
2 
MODERATE < 4 cm swelling 
 
3 
SEVERE 
> 4 cm swelling 
Swelling will be assessed by a member of the study staff. An additional assessment by a 
physician will be made in case a local reaction has been evaluated as moderate or severe. 
 
Itching 
Grade Description 
 
0 
NONE  
 
 
1 
MILD  
 
 
2 
MODERATE  
 
3 
SEVERE 
 
The patients will be asked the degree of itching they are experiencing. An additional 
assessment by a physician will be made in case a local reaction has been evaluated as 
moderate or severe. 
 
 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 105 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
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 Rating 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 to 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. 
 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 106 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
APPENDIX I: EXAMPLE PHONE INTERVIEW FOR VISITS DONE AT HOME.  
Please note that this questionnaire is subject to change.  Please refer to the Ethics approved 
patient documents for use at each specific clinical site.   
Phone interview will be done by the investigator or designated personnel and the 
following questions will be addressed by the patient and his legal guardian/parents  
Name of person conducting phone interview: 
________________________________________________ 
Role (per Delegation of Responsibilities 
Log):_______________________________________________ 
 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. 
If the patient/parents/legal guardiuan refuses to answer complete the following steps: 
 Not interested 
 Complete a protocol deviation in the EDC. 
If the patient/parents/legal guardian are willing to speak, please ask the following questions: 
1. From your last visit, do you feel any different? 
 Yes 
 No 
If yes, please specify and record appropriate AEs (if required) in the patient records and EDC: 
 
__________________________________________________________________________________ 
2. From your last visit, have you taken any new medications or have any existing medications 
changed? 
 Yes 
 No 
If yes, please specify and record appropriate con. meds. or changes to existing con. meds. in the 
patient records and EDC:  
__________________________________________________________________________________ 
3. Have any changes in injection sites occurred in the past weeks? 
 Yes 
 No 
If yes, please specify and record appropriate AEs (if required) in the patient records and EDC: 
 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 107 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX J: CLINICALLY COMPARABLE DOSES OF INHALED 
CORTICOSTEROIDS 
Kelly et al., Annals of Pharmacotherapy 2009 March, Volume 43. 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 108 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX K: LIST OF CENTRAL TECHNICAL FACILITIES 
General Safety Europe:  
1. Covance – Central Lab 
7, rue Moïse Marcinhes  
1217 Meyrin  
Switzerland  
Tel: (+41) 58.822.7000  
Fax: (+41) 58.822.6999 
 
2. Endocrine Research Laboratory 
Medizinische Klinik – Innenstadt Klinikum der Universität (Dr. Bidlingmaier) 
Ziemssenstraße 1, 80336 Munich, Germany 
Tel.: (+49) 89.5160.2277 
 
3. Institute of Laboratory Medicine 
Clinical Chemistry and Molecular Diagnostics 
University Hospital Leipzig 
Liebigstr. 27 (postal address) 
Paul-List-Str. 13-15 (delivery address) 
D-04103 Leipzig 
Germany 
Tel.: (+49) 341.9722241 
(+49) 341.9722450 
Fax: (+49) 341.9722249 
(+49) 341.9722414 
 
4. Labo Medische Genetica 
Department of Medical Genetics 
University and University Hospital of Antwerp 
Prins Boudewijnlaan 43/6 
2650 Edegem 
Belgium 
Phone: (+32) 3.275.9706 
Phone: (+32) 3.275.9719 
Fax: (+32) 3.275.9723 
 
 
General Safety US: 
1. Covance USA 
8211 SciCor Drive  
Indianapolis, IN 46214-2985 
USA  
Tel: (+1) 317.271.1200  
Fax: (+1) 317.273.403 
 
2. LabCorp Center for Esoteric Testing 
1447 York Court 
Burlington, NC 27215 
USA 
Tel.: (+1) 336.584.9525 
Fax: (+1) 336.436.0568 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 109 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
3. Intertek Pharmaceutical Services 
10420 Wateridge Circle 
San Diego, CA 92121 
USA 
Tel.: (+1) 858.558.2599 
(+1) 858.210.3413 
Fax: (+1) 858.558.2600 
 
General Safety APAC: 
1. Covance – Singapore 
1, International Business Park  
#05-12A/B The Synergy  
Singapore 609917  
Tel.: (+65) 6560.8793  
Fax: (+65) 6565.5901 
 
2. PPD Central Lab (Singapore) 
61, The Galen, #02-11/14 
Science Park 2 
Singapore 117525 
Tel.: (+65) 6594.6200 
 
 
 
 
 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 110 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX L: QOL QUESTIONNAIRE 
The QoLISSY questionnaire will be completed at Visits 2 and 8 by patients with the support 
of their parents/caregiver. 
For patients between the age of 3-7 and 0 days, a Parent Questionnaire will be used. 
For patients above and including the age of 7 and 0 days, a Child Questionnaire will be 
encouraged to be used. 
The questionnaires are provided in the following order.  
The QoLISSY questionnaire will only be filled in the following countries using a validated 
translated tool: 
USA, Australia, New Zealand, Belarus, Russia, Ukraine, France, United Kingdom (UK), 
Germany, Spain, Italy, Argentina, Chile, Brazil. 
 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 111 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
IDENTIFIER/ SUBJECT NUMBER:___________ 
 
 
Parent Questionnaire (for patients below the age of 7 and 0 days) 
 
QoLISSY
 P 
 
Date: ________________ Name: ___________________________________  
 
 
 
 
 
 
 
Full name of your child:  
 
 
 
Dear Parent, 
We would like to invite you to help us find out more about how your child feels related to 
his/her height. 
 Please answer the following questions. There are no right or wrong answers. It is important 
that you answer ALL the questions and also that we can see your answers clearly. 
 When you think of your answer please think about the last week. If a question is difficult to 
answer please try it nevertheless by choosing the closest answer – you can also write a 
note on the last page. 
 If you have any difficulties or concerns please write them down on the last page.  
 
This is how it works: 
Please read every question carefully. What answer comes to your mind first? Choose the box 
that fits your answer best and mark the box as in the example below. 
 










 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 116 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 
 
IDENTIFIER/ SUBJECT NUMBER: ________________ 
 
 
Child Questionnaire (for patients above and including the age of 7 
and 0 days) 
 
QoLISSY
 C 
 
Date: ________________ Name: __________________________________  
 
 
 
Date of birth: _________ First name: _______________________ ID: ___  
 
Hi! 
We are interested in how you feel about yourself and we would like to invite you to help 
us find out. The questions relate to your life in general, your height and your strengths 
and difficulties. 
 Please answer the following questions. There are no right or wrong answers: the most 
important thing is that you tell us HOW YOU FEEL. It is important that you answer 
ALL the questions and also that we can see your marks clearly. 
 When you think of your answer please think about the past week. If a question is 
difficult to answer please try it nevertheless by choosing the closest answer – you can 
also write a note on the last page.  
 If you have any difficulties or concerns please write them down on the last page.  
 
















 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 124 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX M: PARTICIPANT ASSESSMENT TOOL (PAT) 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 125 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 126 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
APPENDIX N: OBSERVER ASSESSMENT TOOL (OAT) 
 


 
 
Protocol for Clinical Study CP-4-006 - USA 
 
Page 127 of 127 
Effective Date: Date of final electronic approval 
 
 
Confidential Document 
 


Signature Page for CP-4-006 Protocol US v5.0
Signature Page for RIM-CLIN-000053 v5.0
Approval
Regulatory
30-Apr-2018 18:49:13 GMT+0000
Approval
Medical
30-Apr-2018 19:07:49 GMT+0000
Approval
Clinical
01-May-2018 11:14:20 GMT+0000
Approval
QA & Regulatory
02-May-2018 08:55:19 GMT+0000
PPD
PPD
PPD
PPD