Conditions: Growth Hormone Deficiency
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 82
Healthy volunteers: no

Brief summary:
This is a Phase IV, multicenter, open-label, single-arm study of somatropin (rDNA origin) (Nutropin AQ v1.1) in pre-pubertal children with growth hormone deficiency (GHD) naïve to prior recombinant human growth hormone (rhGH) treatment. The study is designed to characterize the immunogenicity profile of somatropin (rDNA origin) injection when administered daily subcutaneously for 12 months. The clinical impact of immunogenicity will also be assessed.

Detailed description:

Arms:
arm 1: Children will receive daily SC injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.

Interventions: intervention 1: Somatropin
Intervention descriptions: intervention 1: Somatropin will be administered as SC injections at a dose of up to 0.043 mg/kg/day. The dose may be adjusted for a change in body weight of at least (plus \[+\]/minus \[-\]) 2 kilograms (kg) from baseline at the Month 6 study visit or for a change in insulin-growth factor-1 (IGF-1), as per investigator assessment.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Phase IV, Multicenter, Open-Label Study of the Immunogenicity of 
Nutropin AQ® V1.1 [Somatropin (rDNA Origin) Injection] 
Administered Daily to Naïve Growth Hormone-Deficient Children 
(iSTUDY) 
NCT Number: 
NCT02311894 
Document Date: 
Protocol Version 2: 22-Apr-15 
 
 


 
Title
22-Apr-2015 00:08:54
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
Nutropin AQ (Somatropin [rDNA origin])—Genentech, Inc. 
Protocol ML29543, Version 2 
PROTOCOL 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY 
OF THE IMMUNOGENICITY OF NUTROPIN AQ® 
V1.1 [SOMATROPIN (rDNA ORIGIN) INJECTION] 
ADMINISTERED DAILY TO NAÏVE GROWTH 
HORMONE-DEFICIENT CHILDREN (iSTUDY) 
PROTOCOL NUMBER: ML29543 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
BB IND 39,305 
TEST PRODUCT: 
Nutropin AQ® (Somatropin [rDNA origin] injection) 
(RO6823852) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
8 October 2014 
DATES AMENDED: 
Version 2:  See date stamp below 
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PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol ML29543 has been amended to include optional tests at screening, Month 6, 
and Month 12.  These tests include a serum sample to test CBC at screening (if results 
are not available within 12 months prior to informed consent) and serum samples for 
insulin growth factor-1 (IGF-1), which can be drawn at the discretion of the investigator 
at Month 6 and 12.  Optional tests also include X-ray to determine bone age eligibility at 
screening only if results are not available within 12 months prior to the enrollment date. 
Screening specifications were updated to allow patients who do not meet eligibility 
criteria to be re-screened once.  However, it was clarified that patients who have an 
abnormal CBC may have a repeat test done at the discretion of the investigator and may 
be enrolled if the investigator deems the results and clinical presentation of the patient 
are normal. 
In addition to change in body weight, change in IGF-1 was added as a reason for dose 
adjustment of study drug at Month 6 to be consistent with real-world standard clinical 
practice.  
Study assessments were updated to include clarification on CBC and bone age testing 
at screening.  Specifically, if a patient does not have on record a CBC and bone age 
result within 12 months prior to informed consent date (for CBC) and enrollment date (for 
bone age), they will be asked to undergo a blood draw and an X-ray for determination of 
bone age.   
Additional changes to the protocol included updates to the inclusion and exclusion 
criteria as follows: 
• 
The inclusion criterion regarding bone age for females ≤ 9 years and males 
≤ 11 years, as determined by X-ray of the left hand and wrist using Greulich and 
Pyle method, was changed to reflect that this can now be obtained up to 12 months 
prior to enrollment instead of up to 6 months prior to enrollment. 
• 
The inclusion criterion regarding normal CBC within 6 months was changed to within 
12 months prior to informed consent/assent. 
• 
The exclusion criterion stating that patients with multiple pituitary hormone 
deficiencies (secondary/tertiary hypothyroidism, central adrenal insufficiency, 
diabetes insipidus) not associated with an intracranial tumor or central nervous 
system irradiation must be controlled on replacement medications for ≥ 6 months 
prior to study entry was updated to specify that hormonal treatments, such as 
androgens and estrogens to initiate puberty, are not permitted during the study. 
 
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The protocol has also been updated to reflect the most current Genentech model 
document changes.  Reference to safety reporting requirements for events, such as 
drug-induced liver injury and neutropenia (Section 5) reflect new template language 
requirements for all Genentech protocols, and do not necessarily reflect events known to 
be related to treatment with growth hormone therapy.  
Additional minor changes have been made to improve clarity and consistency, and to 
adhere to protocol template standards.  Substantive new information appears in italics.  
This amendment represents cumulative changes to the original protocol. 
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PROTOCOL AMENDMENT, VERSION 2: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
1.1  
 
BACKGROUND ON GROWTH HORMONE DEFICIENCY 
Human growth hormone (hGH) is the most abundant and one of the most extensively 
studied pituitary hormones.  Because hGH, and later recombinant human growth 
hormones (rhGH) have been available for use in humans for more than 40 years decades, 
and therefore much is known about theits physiology and mechanism of action (Franklin 
and Geffner 2009).  …  
1.3  
 
STUDY RATIONALE 
Nutropin was approved by the FDA in 1994 for the treatment of GHD.  In the ensuing 
20 years, many technical advances have been made in large-scale manufacturing 
methods for recombinant DNA products. 
3.1  
 
DECRIPTION OF STUDY 
…   Approximately 80 patients will be enrolled at approximately 30 sites in the U.S. and 
will be treated with daily SC injections of Nutropin AQ v1.1 at a dose of up to 
0.043 mg/kg/day (0.3 mg/kg/week, which is the approved and indicated dosage for 
pediatric GHD; refer to the USPI for Nutropin AQ) for 12 months.  Dose adjustments for 
weight may be made at the Month 6 visit for changes in weight and insulin growth 
factor-1 (IGF-1) levels, if measured. 
Screening will be performed within 28 days prior to Day 1 unless otherwise specified, 
after which eligible patients will initiate study treatment.  Patients who do not meet 
eligibility criteria may be re-screened once for this study.  If during screening a subject 
is found to have an abnormal CBC, this test may be repeated within the same screening 
period at the discretion of the investigator and the subject may be enrolled if the second 
result is found to be normal per investigator assessment. 
…  Study assessments will be scheduled at 3-month intervals following the baseline visit 
with an additional visit for the Month 1 blood draw, which can be conducted at home with 
the help of a home health nurse.  … 
Patients who discontinue from the study early will be asked to return to the clinic within 
28 days (± 3 days) after the last dose of study drug for an early discontinuation visit, 
which will include the collection of serum samples for serum drug concentration and 
immunogenicity assessments. 
…  The annualized 6- and 12-month growth velocities for prepubertal patients who are 
anti GH antibody positive will be analyzed.  … 
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3.3.2 
 
Rationale for Patient Population 
The prepubertal GHD population was chosen for this study because healthy, prepubertal 
GHD children have well-characterized growth responses to rhGH.  Other pediatric 
populations for which Nutropin AQ is approved (Turner syndrome, chronic kidney 
disease, and idiopathic short stature) may show variant responses due to co-existing 
conditions and concomitant medications.  Since there is almost no difference in the 
responses between prepubertal girls and boys, stratification for gender was not 
considered.    
3.3.3 
 
Rationale for Antibody Assay Assessments 
As with all therapeutic proteins, there is potential for immunogenicity.  In the case of GH, 
antibodies with GH binding capacities below 2 mg/L have not been associated with 
growth attenuation (refer to the USPI for Nutropin AQ).  …  In clinical studies of 
pediatric patients who were treated with Nutropin or Nutropin AQ for the first time, 
antibodies with binding capacities ≥ 2 mg/L were not observed in any patients at 
6 months and or 15 months for Nutropin and Nutropin AQ, respectively (refer to the 
USPI for Nutropin AQ). 
…  Any samples positive for anti-GH antibody with a titer > 2.4 mg/L will also then be 
analyzed in an anti-GH neutralizing antibody assay and an anti-GH antibody binding 
capacity assay.  … 
3.4.1 
 
Primary Outcome Measure 
The primary outcome measure for this study is the occurrence of anti-GH antibodies in 
rhGH-naïve, prepubertal GHD children treated with Nutropin AQ v1.1. 
3.4.2 
 
Secondary Outcome Measures 
The occurrence of anti GH antibodies during this study will be compared to historical 
data from earlier studies (L0368g and L2762g).   
4.1.1 
 
Inclusion Criteria 
• 
Male or female patients age ≥ 3 years and < ≤ 14 years.  The patient may be 14 
years old exactly on the day of the first dose of study treatment.  
• 
Bone age ≤ 9 years (females) or ≤ 11 years (males) as determined by X-ray of the 
left hand and wrist using Greulich and Pyle method and obtained within the 
6 12 months prior to enrollment 
• 
Normal CBC within the 126 months prior to informed consent/assent 
 
4.1.2 
 
Exclusion Criteria 
• 
Short stature etiologies other than GHD (e.g., untreated hypothyroidism, short 
stature associated with GH encoding gene mutations, chromosomal defect 
associated with short stature) 
– 
Patients with multiple pituitary hormone deficiencies (secondary/tertiary 
hypothyroidism, central adrenal insufficiency, diabetes insipidus) not associated 
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with an intracranial tumor or CNS irradiation must be controlled on replacement 
medications for ≥ 6 months prior to study entry.  Hormonal treatments, such as 
androgens and estrogens to initiate puberty, are not permitted during the 
study. 
 
4.2  
 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is unblinded, open-label, single-arm study.  After written informed consent/assent 
has been obtained and eligibility has been established, the study site will obtain the 
patient’s unique identification number.  Approximately 80 patients will be enrolled in this 
unblinded, open label, single arm study. 
4.3.2 
 
Dosage, Administration, and Compliance 
Nutropin AQ v1.1 will be provided to the patient and administered at a dose of up to 
0.043 mg/kg/day (0.3 mg/kg/week).  and The dose may be adjusted at the Month 6 visit 
per investigator assessment for:  1) a change in body weight of at least ± 2 kg from 
baseline at the Month 6 study visit, if appropriate OR 2) a change in IGF-1 level (if 
tested and the investigator deems a change in dose is clinically indicated).   
Missed doses or drug holidays are discouraged.  Information on study treatment 
discontinuation and adverse events that may lead to discontinuation of treatment 
Guidelines for dosage modification and treatment interruption or discontinuation are is 
provided in Sections 4.6.2 and 5.1.1, respectively. 
…  The solution may be used for SC administration for 28 days after initial use when 
stored in the pen device at 2−8°C/236−46°F (under refrigeration).  …  Once study drug 
is assigned and dispensed to patients, they will be provided with containers for 
transport of the drug from the investigative sites to their homes for refrigerated storage.   
…  If the solution is cloudy, the contents must not be injectedadministered and the 
affected pens should be returned to the site. 
4.3.3 
 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(Nutropin AQ v1.1) will be provided by the Sponsor.  The investigational study site will 
acknowledge receipt of IMPs, using the Interactive Voice and Web Response System 
(IXWRS) to confirm the shipment condition and content.  Any damaged shipments will 
be replaced.  
4.4  
 
CONCOMITANT THERAPY 
Careful monitoring is advisable when Nutropin AQ v1.1 is administered in 
combination with insulin or other hypoglycemic agents, other drugs metabolized by 
CYP450 liver enzymes, or other hormone replacement therapy. 
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4.4.2 
 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements, medications to manage 
multiple pituitary hormone deficits as well as other chronic medications) used by a 
patient from 7 days prior to dosing to the study completion/early discontinuation visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  
Medications to manage multiple pituitary-hormone deficits or other chronic conditions 
should also be recorded as concomitant medications. 
Careful monitoring is advisable when Nutropin AQ v1.1 is administered in combination 
with insulin or other hypoglycemic agents, other drugs metabolized by CYP450 liver 
enzymes, or other hormone replacement therapy.    
4.5.1 
 
Informed Consent Forms and Screening Log 
If a patient does not have on record a CBC and bone age result within 12 months prior 
to informed consent (for CBC) or enrollment (for bone age), they will be asked to 
undergo a blood draw (to be analyzed at local laboratory for CBC) and an X-ray for 
determination of bone age to determine eligibility for the study. 
Patients who fail screening may be re-screened once for this study.  However, patients 
who are found to have an abnormal CBC may have a repeat test done within the same 
screening period at the discretion of the investigator and may be enrolled if the 
investigator deems the results and clinical presentation of the patient are normal. 
4.5.5 
 
Laboratory Assessments 
At screening, patients may be required to provide a blood sample to check for CBC, 
which will be analyzed at the local laboratory.  
At Month 6 and 12 study visits, optional samples may be drawn to check IGF-1 levels, 
which will also be analyzed at the local laboratory. 
For assessment of immunogenicity, samples will be drawn at each study visit The 
following laboratory tests are to be performed during the study, according to the 
schedule of assessments (see Appendix 1) and will be sent to the central laboratory to 
assess the following: 
• 
Samples for sSerum drug concentration.   and immunogenicity assessments will be 
collected at specified study visits.  GH concentration levels are necessary to 
interpret anti-GH antibody status and titers.  
• 
Immunogenicity, will be assessed utilizing the following assays, which will test for 
the presence of specific antibodies in patient serum: 
– 
anti-GH antibody screening assay 
– 
anti-GH neutralizing antibody assay 
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– 
anti-GH antibody binding capacity assay 
 
During the study treatment period, blood samples for immunogenicity should be drawn 
at least 12 hours after the last administration of Nutropin AQ v1.1 and prior to the next 
scheduled dose. 
The last blood sample for immunogenicity at Month 12 must be drawn at least 12 hours 
after the last dose of Nutropin AQ v1.1.  … 
4.6.3 
 
Study and Site Discontinuation 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7) 
 
5.3.1 
 
Adverse Event Reporting Period 
… After informed consent has been obtained but prior to initiation of study drug, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events). 
5.3.5.1  
Injection Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug injection should be captured as a diagnosis 
(e.g., "injection reaction") on the Adverse Event eCRF.  If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded 
on the dedicated Injection Reaction eCRF.   
If a patient experiences both a local and systemic reaction (e.g., generalized injection 
reaction and localized injection site reaction) to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Injection Reaction eCRF. 
5.3.5.3  
Adverse Events That Are Secondary to Other Events 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
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5.3.5.7  
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an 
elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.11 
Adverse Events in Individuals Not Enrolled in the Study 
If an adverse event inadvertently occurs in an individual not enrolled in the study 
(e.g., injury to the healthcare provider or caregiver during administration of study drug), 
the Adverse Event Form provided to investigators should be completed and submitted to 
Roche or its designee, either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators. 
5.4.4 
 
Reporting Requirements for NuSpin Device Complaints 
In this study, NuSpin is considered a medical device.  The investigator must report all 
NuSpin device complaints to the Sponsor.  The investigator should document as much 
information as possible on the Device Complaint eCRFIMP Deviation Form, including 
the product batch number, and forward the form to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event) (refer to the site pharmacy manual for 
further details).  and expiration date.  If the medical device complaint results in an 
adverse event to the study patient, the event must be reported on the Adverse Event 
eCRF and submitted through the EDC systemthe Complaint eCRF must be completed 
and submitted through the EDC immediately (i.e., no more than 24 hours after learning 
of the event).  The adverse event must be reported on the Adverse Event eCRF.  If the 
event is serious, the Adverse Event eCRF must be completed and submitted through the 
EDC immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 5.4.2.  If the medical device results in an adverse event to an individual other 
than the study patient, the event should be reported as described in Section 0. 
6.3  
 
OUTCOMES ANALYSES 
Descriptive statistics and graphic displays will be provided to summarize data from this 
study.  There are no formal statistical hypothesis tests to be performed.planned. 
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6.3.1 
 
Primary Endpoint 
The primary endpoint for this study is the proportion of patients who develop anti-GH 
antibodies after initiating treatment with Nutropin AQ v1.1.  
6.3.2 
 
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
• 
Proportion of patients with neutralizing antibody among those who had positive 
anti-GH antibody  
 
This analysis will be summarized by visit, as well as collectivelycumulatively, 
for patients who had at least one episode of  detectible anti-GH antibody at any 
post-baseline visit, as well as those who remained negative throughout the 
study never developed antibody.   
 
8.2  
 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home NursingCaregiver's Informed 
Consent Form, if applicable) will be provided to each site.  … 
9.4  
 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech, a member of the Roche group, and will be 
managed by Genentech and a CRO.  The CRO will provide clinical operations 
management, project management, monitor study conduct, data management, patient 
enrollment and discontinuation, and medical monitoring for the duration of the study.  
An IXRS IWRS will be used to assign patient numbers, monitor enrollment and patient 
status, and to manage study treatment requests and shipments.   
APPENDIX 1:  Schedule of Assessments  
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
SAMPLE INFORMED CONSENT FORM AND SAMPLE INFORMED ASSENT 
FORM 
The sample Informed Consent Form and the sample Informed Assent Form have been 
revised to reflect the changes to the protocol. 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
PROTOCOL SYNOPSIS .................................................................................... 17 
1. 
BACKGROUND .......................................................................................... 23 
1.1 
Background on Growth Hormone Deficiency......................... 23 
1.2 
Background on Nutropin AQ® [somatropin 
(rDNA origin) injection]........................................................... 23 
1.3 
Study Rationale ..................................................................... 24 
2. 
OBJECTIVES.............................................................................................. 24 
3. 
STUDY DESIGN ......................................................................................... 25 
3.1 
Description of Study .............................................................. 25 
3.2 
End of Study.......................................................................... 26 
3.3 
Rationale for Study Design.................................................... 26 
3.3.1 
Rationale for Nutropin AQ v1.1 Dose and 
Schedule................................................................................ 26 
3.3.2 
Rationale for Patient Population ............................................ 26 
3.3.3 
Rationale for Antibody Assay Assessments .......................... 26 
3.4 
Outcome Measures ............................................................... 27 
3.4.1 
Primary Outcome Measure.................................................... 27 
3.4.2 
Secondary Outcome Measures ............................................. 27 
3.4.3 
Safety Outcome Measures .................................................... 27 
4. 
MATERIALS AND METHODS .................................................................... 27 
4.1 
Patients.................................................................................. 27 
4.1.1 
Inclusion Criteria.................................................................... 28 
4.1.2 
Exclusion Criteria................................................................... 28 
4.2 
Method of Treatment Assignment and Blinding..................... 29 
4.3 
Study Treatment .................................................................... 29 
4.3.1 
Formulation, Packaging, and Handling.................................. 29 
4.3.2 
Dosage, Administration, and Compliance.............................. 29 
4.3.3 
Investigational Medicinal Product Accountability ................... 30 
4.4 
Concomitant Therapy ............................................................ 31 
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4.4.1 
Permitted Therapy ................................................................. 31 
4.4.2 
Prohibited Therapy ................................................................ 31 
4.5 
Study Assessments ............................................................... 32 
4.5.1 
Informed Consent Forms and Screening Log........................ 32 
4.5.2 
Medical History and Demographic Data ................................ 32 
4.5.3 
Physical Examinations........................................................... 32 
4.5.4 
Height and Weight ................................................................. 33 
4.5.5 
Laboratory Assessments ....................................................... 33 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 33 
4.6.1 
Patient Discontinuation.......................................................... 33 
4.6.2 
Study Treatment Discontinuation........................................... 34 
4.6.3 
Study and Site Discontinuation.............................................. 34 
5. 
ASSESSMENT OF SAFETY....................................................................... 35 
5.1 
Safety Plan ............................................................................ 35 
5.1.1 
Adverse Events that May Lead to 
Discontinuation of Treatment with Nutropin AQ 
v1.1........................................................................................ 35 
5.2 
Safety Parameters and Definitions ........................................ 35 
5.2.1 
Adverse Events ..................................................................... 35 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 36 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 37 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 37 
5.3.1 
Adverse Event Reporting Period ........................................... 37 
5.3.2 
Eliciting Adverse Event Information ....................................... 38 
5.3.3 
Assessment of Severity of Adverse Events ........................... 38 
5.3.4 
Assessment of Causality of Adverse Events ......................... 38 
5.3.5 
Procedures for Recording Adverse Events............................ 39 
5.3.5.1 
Injection Reactions ................................................................ 39 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 39 
5.3.5.3 
Adverse Events that are Secondary to Other 
Events.................................................................................... 40 
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5.3.5.4 
Persistent or Recurrent Adverse Events................................ 40 
5.3.5.5 
Abnormal Laboratory Values ................................................. 41 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 41 
5.3.5.7 
Abnormal Liver Function Tests.............................................. 42 
5.3.5.8 
Deaths ................................................................................... 42 
5.3.5.9 
Preexisting Medical Conditions.............................................. 43 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 43 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 43 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 44 
5.4.1 
Emergency Medical Contacts................................................ 44 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 45 
5.4.3 
Reporting Requirements for Pregnancies.............................. 45 
5.4.3.1 
Pregnancies in Female Patients............................................ 45 
5.4.3.2 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 46 
5.4.4 
Reporting Requirements for NuSpin Device 
Complaints............................................................................. 46 
5.5 
Follow-Up of Patients after Adverse Events .......................... 46 
5.5.1 
Investigator Follow-Up........................................................... 46 
5.5.2 
Sponsor Follow-Up ................................................................ 46 
5.6 
Post-Study Adverse Events................................................... 47 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 47 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 47 
6.1 
Determination of Sample Size ............................................... 47 
6.2 
Summaries of Conduct of Study............................................ 48 
6.3 
Outcomes Analyses............................................................... 48 
6.3.1 
Primary Endpoint ................................................................... 48 
6.3.2 
Secondary Endpoints ............................................................ 48 
6.4 
Safety Analyses..................................................................... 49 
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6.5 
Handling of Missing Data....................................................... 49 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 49 
7.1 
Data Quality Assurance......................................................... 49 
7.2 
Electronic Case Report Forms............................................... 50 
7.3 
Source Data Documentation.................................................. 50 
7.4 
Use of Computerized Systems .............................................. 51 
7.5 
Retention of Records............................................................. 51 
8. 
ETHICAL CONSIDERATIONS.................................................................... 51 
8.1 
Compliance with Laws and Regulations ................................ 51 
8.2 
Informed Consent .................................................................. 52 
8.3 
Institutional Review Board or Ethics Committee.................... 53 
8.4 
Confidentiality........................................................................ 53 
8.5 
Financial Disclosure .............................................................. 53 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 54 
9.1 
Study Documentation ............................................................ 54 
9.2 
Protocol Deviations................................................................ 54 
9.3 
Site Inspections ..................................................................... 54 
9.4 
Administrative Structure......................................................... 54 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 55 
9.6 
Protocol Amendments ........................................................... 56 
10. REFERENCES ........................................................................................... 57 
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LIST OF TABLES 
Table 1 
Adverse Event Severity Grading Scale ....................................... 38 
Table 2 
Causal Attribution Guidance ....................................................... 39 
Table 3 
Clopper-Pearson 95% Confidence Intervals for the 
Proportion of Patients Who Are Anti-GH Antibody Positive 
Based on 50 and 60 Patients...................................................... 48 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments........................................................... 58 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY 
OF THE IMMUNOGENICITY OF NUTROPIN AQ® 
V1.1 [SOMATROPIN (rDNA ORIGIN) INJECTION] 
ADMINISTERED DAILY TO NAÏVE GROWTH 
HORMONE-DEFICIENT CHILDREN (iSTUDY) 
PROTOCOL NUMBER: ML29543 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
BB IND 39,305 
Nutropin AQ® (Somatropin [rDNA origin] injection) 
(RO6823852) 
TEST PRODUCT: 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
  
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by the CRO. 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY OF THE 
IMMUNOGENICITY OF NUTROPIN AQ® V1.1 [SOMATROPIN 
(rDNA ORIGIN) INJECTION] ADMINISTERED DAILY TO NAÏVE 
GROWTH HORMONE-DEFICIENT CHILDREN (iSTUDY) 
PROTOCOL NUMBER: 
ML29543 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
BB IND 39,305 
Nutropin AQ® (Somatropin [rDNA origin] injection) (RO6823852) 
TEST PRODUCT: 
PHASE: 
IV 
INDICATION: 
Somatropin-naïve prepubertal growth hormone-deficient children 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
The primary objective for this study is to characterize the immunogenicity profile of 
Nutropin AQ v1.1 when administered as a daily subcutaneous (SC) injection for 12 months 
(per the U.S. Prescribing Information [USPI] for Nutropin AQ). 
The clinical impact of immunogenicity will also be assessed during the course of the study by 
evaluating patients for functional growth attenuation in association with the development of 
anti-growth hormone (GH) antibodies.  
Study Design 
Description of Study 
This is a Phase IV, multicenter, open-label, single-arm study of somatropin (rDNA origin) 
(Nutropin AQ v1.1) in naïve prepubertal children with growth hormone deficiency (GHD).   
Approximately 80 patients will be enrolled at approximately 30 sites in the U.S. and will be 
treated with daily SC injections of Nutropin AQ v1.1 at a dose of up to 0.043 mg/kg/day (0.3 
mg/kg/week, which is the approved and indicated dosage for pediatric GHD; refer to the USPI 
for Nutropin AQ) for 12 months.  Dose adjustments may be made at the Month 6 visit for 
changes in weight and insulin growth factor-1 (IGF-1) levels, if measured. 
Screening will be performed within 28 days prior to Day 1 unless otherwise specified, after 
which eligible patients will initiate study treatment.  Patients who do not meet eligibility criteria 
may be re-screened once for this study.  If during screening a subject is found to have an 
abnormal CBC, this test may be repeated within the same screening period at the discretion of 
the investigator and the subject may be enrolled if the second result is found to be normal per 
investigator assessment. 
Historical laboratory and radiographic tests will be reviewed prior to obtaining informed consent 
and initiation of study drug.  Study assessments will be scheduled at 3-month intervals following 
the baseline visit with an additional visit for the Month 1 blood draw, which can be conducted at 
home with the help of a home health nurse.  Study assessments will include physical 
examinations, height and weight measurements, assessment of pubertal status, and collection 
of serum samples for study-specific laboratory assessments (serum drug concentration and 
immunogenicity assessments).  Patients will otherwise be treated and followed as determined 
by their health care provider.  
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Patients who complete the Month 12 visit will be considered to have completed the study. 
Patients will be contacted by phone 28 (± 3) days after the Month 12 visit to collect adverse 
events.  
Patients who discontinue from the study early will be asked to return to the clinic within 28 (± 3 
days) days after the last dose of study drug for an early discontinuation visit, which will include 
the collection of serum samples for serum drug concentration and immunogenicity assessments. 
Growth response will be monitored throughout the study.  The annualized 6- and 12-month 
growth velocities for prepubertal patients will be analyzed.  Growth velocities of patients who 
enter puberty during the study will not be included in the 6- and 12-month velocity analyses.  
However, these patients will remain in the study and their antibody data will be assessed.   
Safety assessments will consist of monitoring and recording of all serious and non-serious 
adverse events as outlined in Section 5.2. 
Please see Appendix 1 for the schedule of assessments performed during the study. 
Number of Patients 
Approximately 80 patients will be enrolled at approximately 30 sites in the study in the U.S. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent/Assent Form 
– The parent(s)/guardian(s) must be willing to give written informed consent; and 
– The child may be required to give written informed assent (if able, and dependent on 
state/Institutional Review Board requirements). 
• 
Willing to adhere to the visit schedules and meet study requirements 
– For patients below the legal age of consent, both child and parent must be able to 
adhere to dose and visit schedules and meet study requirements.   
• 
Ability to comply with study assessments for the full duration of the study (1 year)  
• 
Male or female patients age ≥ 3 years and <  14 years.  The patient may be 14 years old 
exactly on the day of the first dose of study treatment. 
• 
Bone age ≤ 9 years (females) or ≤ 11 years (males) as determined by X-ray of the left hand 
and wrist using Greulich and Pyle method and obtained within the 12 months prior to 
enrollment 
• 
Prepubertal (Tanner I) males and females by physical exam 
• 
Diagnosis of GHD (stimulated GH < 10 ng/mL) by two standard pharmacologic tests 
obtained up to 12 months prior to informed consent/assent  
– Acceptable GH stimulation tests include:  insulin tolerance test (considered two tests if 
done sequentially with arginine); arginine stimulation test (considered two tests if done 
sequentially with insulin); glucagon stimulation test; clonidine stimulation test; L-dopa 
stimulation test; L-dopa + inderal stimulation test (considered one test if done together). 
• 
Normal thyroid function test within the 12 months prior to informed consent/assent 
• 
Normal CBC within the 12 months prior to informed consent/assent 
• 
Documentation of prior height and weight measurements, with height standard deviation 
score (SDS) ≤ −1.5 (≤ 5th percentile) for idiopathic isolated GHD patients 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any previous rhGH treatment 
• 
Short stature etiologies other than GHD (e.g., untreated hypothyroidism, short stature 
associated with GH encoding gene mutations, chromosomal defect associated with short 
stature) 
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– Patients with multiple pituitary hormone deficiencies (secondary/tertiary hypothyroidism, 
central adrenal insufficiency, diabetes insipidus) not associated with an intracranial 
tumor or central nervous system irradiation must be controlled on replacement 
medications for ≥ 6 months prior to study entry.  Hormonal treatments, such as 
androgens and estrogens to initiate puberty, are not permitted during the study. 
• 
Acute critical illness or uncontrolled chronic illness, which in the opinion of the investigator 
and Medical Monitor, would interfere with participation in this study, interpretation of the 
data, or pose a risk to patient safety 
• 
Chronic illnesses such as inflammatory bowel disease, celiac disease, heart disease, and 
diabetes 
• 
Bone diseases such as achondroplasia or hypochondroplasia, intracranial tumor, irradiation, 
and traumatic brain injury 
• 
Patients receiving oral or inhaled chronic corticosteroid therapy (> 3 months) for other 
medical conditions other than central adrenal insufficiency 
• 
Patients who require higher (2 × or greater than maintenance) doses of corticosteroids for 
more than 5 days in the 6 months prior to enrollment in the study 
• 
Patients with active malignancy or any other condition that the investigator believes would 
pose a significant hazard to the patient if recombinant human growth hormone (rhGH) were 
initiated   
• 
Females with Turner syndrome (documented with a karyotype or short stature homeobox 
[SHOX] analysis at any time prior to informed consent/assent), regardless of their GH status 
• 
Prader-Willi syndrome regardless of GH status 
• 
Born small for gestational age regardless of GH status 
• 
Presence of scoliosis requiring monitoring 
• 
Previous participation in another clinical trial or investigation of GH, treatment for growth 
failure, or treatment with a biologic agent 
• 
Patients with closed epiphyses 
• 
Patients with a known hypersensitivity to somatropin, excipients, or diluent 
Length of Study/End of Study 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  LPLV 
is expected to occur approximately 12 months after the last patient is enrolled and receives the 
first Nutropin AQ v1.1 injection. 
Outcome Measures 
Primary Outcome Measure 
The primary outcome measure for this study is the occurrence of anti-GH antibodies in 
rhGH-naïve, prepubertal GHD children treated with Nutropin AQ v1.1. 
Secondary Outcome Measures 
The secondary outcome measures for this study are to assess: 
• 
The occurrence of functional growth impairment in association with positive antibody 
formation in patients treated with Nutropin AQ v1.1  
This will be considered in any patient who demonstrates an initial growth response greater 
than pretreatment velocity after treatment with Nutropin AQ v1.1, but then slows to below 
pretreatment velocity in the ensuing 6- to 12-month period (or reaches ≤ 2 cm per year) 
• 
The difference between the annualized 6- and 12-month growth velocities for patients who 
were anti-GH antibody-positive at any post-baseline visit and those who were anti-GH 
antibody-negative at all visits (including baseline)  
• 
The formation of neutralizing antibodies, and the association between the presence of 
neutralizing anti-GH antibodies and growth attenuation 
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Safety Outcome Measures 
No specific safety assessments are planned for this study.  However, analysis of all safety 
events will be performed (see Section 6.4).  
Investigational Medicinal Product 
Test Product 
Nutropin AQ v1.1 will be supplied by the Sponsor as labeled study drug using the 
Nutropin AQ v1.1 NuSpin™ 10 device for the 1-year duration of this study.  For information on 
the formulation, packaging, and handling of Nutropin AQ v1.1, see the pharmacy manual and 
the USPI for Nutropin AQ. 
Nutropin AQ v1.1 will be provided to the patient and administered at a dose of up to 
0.043 mg/kg/day (0.3 mg/kg/week).  The dose may be adjusted at the Month 6 visit per 
investigator assessment for:  1) a change in body weight of at least ± 2 kg from baseline OR 
2) a change in IGF-1 level (if tested and the investigator deems a change in dose is clinically 
indicated).  The dose of Nutropin AQ v1.1 will be administered via SC injections by the patient 
or caregiver. 
Statistical Methods 
Outcomes Analysis 
Primary Endpoint 
The primary endpoint for this study is the proportion of patients who develop anti-GH antibodies 
after initiating treatment with Nutropin AQ v1.1.  
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
• 
Proportion of patients who exhibit growth attenuation (defined as initial growth response 
greater than pretreatment velocity followed by reduction in growth response to below the 
pretreatment velocity in the subsequent 6- to 12-month treatment period or reaching ≤ 2 cm 
per year) 
– Cross tabulation between growth attenuation status (i.e., with or without) and anti-GH 
antibody status (i.e., positive or negative) will be provided for any antibody and for 
neutralizing anti-GH antibody, respectively, at each visit.  Similar tables will also be 
provided for patients who had at least one positive anti-GH antibody (anti-GH antibody 
and neutralizing antibody, respectively) at any follow-up visit against those who never 
developed antibody after treatment.  
• 
Proportion of patients with neutralizing antibody among those who had positive anti-GH 
antibody  
– This analysis will be summarized by visit, as well as cumulatively, for patients who had 
detectible anti-GH antibody at any post-baseline visit, as well as those who remained 
negative throughout the study.   
• 
Annualized 6- and 12-month growth velocities and height SDS will be summarized 
separately for patients who were anti-GH antibody-positive at any post-baseline follow-up 
visit and those who were anti-GH antibody-negative at all visits (including baseline).  
Graphic displays of the individual patient growth patterns along with the longitudinal 
antibody profile over the course of the study will be prepared.  Patients who enter puberty 
during the study period will be included up to the last visit at which they were determined to 
be prepubertal. 
Additional analyses deemed appropriate for assessing immunogenicity will be described in the 
Statistical Analysis Plan.  
Safety Analysis 
Safety analyses will include all patients who received at least one dose of study drug.  
Adverse events will be summarized by mapped term, appropriate thesaurus level, and toxicity 
grade.  Summaries (or listings, if appropriate), including investigator assessments of 
relationship to study drug, will also be produced for each of the following: 
• 
Serious adverse events 
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• 
All events leading to the withdrawal of treatment 
• 
All events by severity 
• 
All events possibly indicative of hypersensitivity  
Determination of Sample Size   
A target enrollment of 80 patients was chosen to allow for a projected 10−15% dropout rate and 
exclusion of growth data for an estimated 10% of patients who might enter puberty during the 
study period and leave sufficient patient numbers to compare to previous studies of 
immunogenicity.  This target enrollment was based on enrollment in a previous study (L0368) 
which planned to enroll 60 patients for the assessment of growth rate and change in height SDS.  
An initial sample size was chosen to ensure that at least 50 patients would complete the study 
(L0368 FR 30SEP97; Sec 4.8.4). 
This study is expected to yield a minimum of 50 evaluable patients.  Given a sample size of 50, 
and an assumed 50% of patients developing anti-GH antibodies, the 95% confidence interval 
around this proportion will be (35.53%, 64.47%).  This interval was calculated using 
Clopper-Pearson methodology.  Fluctuations in the proportion of patients developing anti-GH 
antibodies and the increase of evaluable patients will result in more precise confidence intervals.  
The exact confidence intervals for the scenarios for sample size of 50 and 60 in combination 
with the proportion of patients who are anti-GH antibody positive of 50% and 20% are listed in 
the table below. 
 
N 
Proportion of Patients 
Who Are Anti-GH 
Antibody Positive 
95% Confidence 
Interval 
(Lower Limit) 
95% Confidence 
Interval 
(Upper Limit) 
50 
0.5 
0.3553 
0.6447 
60 
0.5 
0.3681 
0.6319 
50 
0.2 
0.1003 
0.3372 
60 
0.2 
0.1078 
0.3230 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AVN 
avascular necrosis 
CNS 
central nervous system 
CRO 
contract research organization 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FDA 
U.S. Food and Drug Administration 
GH 
growth hormone 
GHD 
growth hormone deficiency 
GHRH 
growth hormone-releasing hormone 
HIPAA 
Health Insurance Portability and Accountability Act 
hGH 
human growth hormone 
ICH 
International Conference on Harmonisation 
IGF-1 
insulin growth factor-1 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LPLV 
last patient, last visit 
rhGH 
recombinant human growth hormone 
SC 
subcutaneous 
SCFE 
slipped capital femoral epiphysis 
SDS 
standard deviation score 
SHOX 
short stature homeobox 
ULN 
upper limit of normal 
USPI 
U.S. Prescribing Information 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON GROWTH HORMONE DEFICIENCY  
Human growth hormone (hGH) is the most abundant and one of the most extensively 
studied pituitary hormones.  hGH and recombinant human growth hormones (rhGH) 
have been available for use in humans for decades, and therefore much is known about 
the physiology and mechanism of action (Franklin and Geffner 2009).  This knowledge 
base has been further enhanced by the study of the naturally occurring clinical 
syndromes of growth hormone deficiency (GHD) and excess.   
GHD, as defined by inadequate endogenous secretion of hGH, results in proportionate 
dwarfism in children, who are usually more than two standard deviations below average 
height.  The etiologies can be genetic or developmental and present from birth or 
manifested during growth; organic from central nervous system (CNS) tumors, head 
trauma, radiation, and infection; or idiopathic (Procter et al. 1998).  The development of 
sensitive immunoassays to measure hGH in blood has enabled physicians to diagnose 
this syndrome in children whose serum hGH level does not increase substantially after 
administration of arginine, L-dopa, clonidine, glucagon, or the induction of hypoglycemia.  
When given a growth hormone-releasing hormone (GHRH), many patients with 
idiopathic GHD release hGH.  This indicates that in some patients the fundamental 
abnormality lies not in the pituitary itself, but rather in the inability of the hypothalamus 
and higher centers to induce normal hGH release (Procter et al. 1998). 
Treatment with exogenous GH began in the 1960s and 1970s with human pituitary 
extracted GH injected intramuscularly three times a week, and progressed to rhGH in 
the mid-1980s, first with subcutaneous (SC) injections three times a week, and then with 
daily SC injections.  
1.2 
BACKGROUND ON NUTROPIN AQ® [SOMATROPIN 
(rDNA ORIGIN) INJECTION] 
Nutropin [somatropin (rDNA origin) for injection] is a lyophilized form of hGH produced 
by recombinant DNA technology.  Nutropin has 191 amino acid residues and a 
molecular weight of 22,125 Daltons.  The amino acid sequence of the product is identical 
to that of pituitary-derived 22kD hGH.  Nutropin AQ [somatropin (rDNA origin) injection] 
is a liquid formulation with the chemical structure of somatropin identical to lyophilized 
Nutropin. 
In vitro and in vivo nonclinical and clinical testing has demonstrated that Nutropin is 
therapeutically equivalent to pituitary-derived hGH.   
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Nutropin AQ is approved by the U.S. Food and Drug Administration (FDA) and is 
indicated for: 
• 
Pediatric patients:  Treatment of children with growth failure due to GHD, idiopathic 
short stature, Turner syndrome, and chronic kidney disease up to the time of renal 
transplantation 
• 
Adult patients:  Treatment of adults with either childhood-onset or adult-onset GHD 
 
See the Nutropin AQ Investigator’s Brochure and the U.S. Prescribing Information (USPI) 
for Nutropin AQ for details on nonclinical and clinical studies, dosage, and safety profile. 
1.3 
STUDY RATIONALE 
Nutropin was approved by the FDA in 1994 for the treatment of GHD.  In the ensuing 
years, many technical advances have been made in large-scale manufacturing methods 
for recombinant DNA products. 
To use the most advanced methodology and equipment to ensure a continued supply of 
Nutropin AQ, Genentech has updated its manufacturing process while continuing to use 
the same Escherichia coli GH production system.  Chemical and biological 
characterization (including potency) has demonstrated comparability of drug substance 
produced by the original and updated manufacturing processes and, based on this, the 
new manufacturing process that is used to produce Nutropin AQ v1.1 has been 
approved by FDA. 
This study, performed in children with GHD, will assess the immunogenicity profile of 
Nutropin AQ produced by the new manufacturing process. 
2. 
OBJECTIVES 
The primary objective for this study is to characterize the immunogenicity profile of 
Nutropin AQ v1.1 when administered as a daily SC injection for 12 months (per the USPI 
for Nutropin AQ). 
The clinical impact of immunogenicity will also be assessed during the course of the 
study by evaluating patients for functional growth attenuation in association with the 
development of anti-GH antibodies.  
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a Phase IV, multicenter, open-label, single-arm study of somatropin (rDNA origin) 
(Nutropin AQ v1.1) in naïve prepubertal children with GHD.   Approximately 80 patients 
will be enrolled at approximately 30 sites in the U.S. and will be treated with daily SC 
injections of Nutropin AQ v1.1 at a dose of up to 0.043 mg/kg/day (0.3 mg/kg/week, 
which is the approved and indicated dosage for pediatric GHD; refer to the USPI for 
Nutropin AQ) for 12 months.  Dose adjustments may be made at the Month 6 visit for 
changes in weight and insulin growth factor-1 (IGF-1) levels, if measured. 
Screening will be performed within 28 days prior to Day 1 unless otherwise specified, 
after which eligible patients will initiate study treatment.  Patients who do not meet 
eligibility criteria may be re-screened once for this study.  If during screening a subject 
is found to have an abnormal CBC, this test may be repeated within the same screening 
period at the discretion of the investigator and the subject may be enrolled if the second 
result is found to be normal per investigator assessment. 
Historical laboratory and radiographic tests will be reviewed prior to obtaining informed 
consent and initiation of study drug.  Study assessments will be scheduled at 3-month 
intervals following the baseline visit with an additional visit for the Month 1 blood draw, 
which can be conducted at home with the help of a home health nurse.  Study 
assessments will include physical examinations, height and weight measurements, 
assessment of pubertal status, and collection of serum samples for study-specific 
laboratory assessments (serum drug concentration and immunogenicity assessments).  
Patients will otherwise be treated and followed as determined by their health care 
provider.  
Patients who complete the Month 12 visit will be considered to have completed the study.  
Patients will be contacted by phone 28 ± 3 days after the Month 12 visit to collect 
adverse events. 
Patients who discontinue from the study early will be asked to return to the clinic within 
28 days (± 3 days) after the last dose of study drug for an early discontinuation visit, 
which will include the collection of serum samples for serum drug concentration and 
immunogenicity assessments. 
Growth response will be monitored throughout the study.  The annualized 6- and 
12-month growth velocities for prepubertal patients will be analyzed.  Growth velocities 
of patients who enter puberty during the study will not be included in the 6- and 
12-month velocity analyses.  However, these patients will remain in the study and their 
antibody data will be assessed.   
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Safety assessments will consist of monitoring and recording of all serious and 
non-serious adverse events as outlined in Section 5.2. 
Please see Appendix 1 for the schedule of assessments performed during the study. 
3.2 
END OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur approximately 12 months after the last patient is enrolled and 
receives the first Nutropin AQ v1.1 injection. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Nutropin AQ v1.1 Dose and Schedule 
The Nutropin AQ v1.1 treatment route, dose, and dosing regimen used in this study are 
consistent with what is approved for treatment of children with GHD (refer to the 
USPI for Nutropin AQ). 
3.3.2 
Rationale for Patient Population 
The prepubertal GHD population was chosen for this study because healthy, prepubertal 
GHD children have well-characterized growth responses to rhGH.  Other pediatric 
populations for which Nutropin AQ is approved (Turner syndrome, chronic kidney 
disease, and idiopathic short stature) may show variant responses due to co-existing 
conditions and concomitant medications.   
3.3.3 
Rationale for Antibody Assay Assessments 
As with all therapeutic proteins, there is potential for immunogenicity.  In the case of GH, 
antibodies with GH binding capacities below 2 mg/L have not been associated with 
growth attenuation (refer to the USPI for Nutropin AQ).  In a very small number of 
patients treated with Nutropin AQ, where binding capacity was above 2 mg/L, 
interference with growth response was observed.  In clinical studies of pediatric patients 
who were treated with Nutropin or Nutropin AQ for the first time, antibodies with binding 
capacities ≥ 2 mg/L were not observed in any patients at 6 months or 15 months for 
Nutropin and Nutropin AQ, respectively (refer to the USPI for Nutropin AQ). 
In this study, all serum samples taken for immunogenicity assessments will be analyzed 
in an anti-GH antibody screening assay.  Any samples positive for anti-GH antibody with 
a titer > 2.4 mg/L will then be analyzed in an anti-GH neutralizing antibody assay and an 
anti-GH antibody binding capacity assay.  Neutralizing antibody assays are an additional 
method for assessing anti-therapeutic antibodies that can result in changes in the 
toxicology, pharmacokinetics, and efficacy of biotechnology-derived pharmaceuticals.  
Growth attenuation due to the development of neutralizing anti-GH antibodies is rare and, 
when reported, usually occurs in patients with mutations in the GH encoding gene 
(Schwarz et al. 1987; Cogan and Phillips 2006).  When this rare event occurs, the 
growth response in the first 3−6 months is followed by a rapid decline in annualized 
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growth velocity to below pretreatment rates.  Conversely, in those patients without a 
genetic mutation who develop antibodies, the binding capacity is usually low, and a 
functional effect on growth has very rarely been detected (Buzi et al. 1989;             
Pirazzoli et al. 1995).  GH-1 mutation testing may be performed at the discretion of the 
investigator and will not be conducted as part of the protocol.  Data from this study will 
be used to determine if the immunogenicity profile of Nutropin AQ v1.1 produced by the 
new manufacturing process is different from the original product.  This study will also 
include outcome measures to evaluate the growth of GHD children being treated with 
Nutropin AQ v1.1 to determine if any variations in growth are associated with antibody 
development. 
3.4 
OUTCOME MEASURES  
3.4.1 
Primary Outcome Measure 
The primary outcome measure for this study is the occurrence of anti-GH antibodies in 
rhGH-naïve, prepubertal GHD children treated with Nutropin AQ v1.1. 
3.4.2 
Secondary Outcome Measures 
The secondary outcome measures for this study are to assess: 
• 
The occurrence of functional growth attenuation in association with positive antibody 
formation in patients treated with Nutropin AQ v1.1  
This will be considered in any patient who demonstrates an initial growth response 
greater than pretreatment velocity after treatment with Nutropin AQ v1.1, but then 
slows to below pretreatment velocity in the ensuing 6- to 12-month period (or 
reaches ≤ 2 cm per year). 
• 
The difference between the annualized 6- and 12-month growth velocities for 
patients who were anti-GH antibody-positive at any post-baseline visit and those 
who were anti-GH antibody-negative at all visits (including baseline)  
• 
The formation of neutralizing antibodies, and the association between the presence 
of neutralizing anti-GH antibodies and growth attenuation 
 
3.4.3 
Safety Outcome Measures 
No specific safety assessments are planned for this study.  However, analysis of all 
safety events will be performed (see Section 6.4).  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Only prepubertal rhGH-naïve patients who meet the inclusion/exclusion criteria specified 
below will be enrolled.  Approximately 80 patients will be enrolled in the study in the U.S.  
Investigators must keep a record of all patients who are screened.   
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent/Assent Form 
– 
The parent(s)/guardian(s) must be willing to give written informed consent; and 
– 
The child may be required to give written informed assent (if able, and 
dependent on state/Institutional Review Board [IRB] requirements) 
• 
Willing to adhere to the visit schedules and meet study requirements 
– 
For patients below the legal age of consent, both child and parent must be able 
to adhere to dose and visit schedules and meet study requirements.   
• 
Ability to comply with study assessments for the full duration of the study (1 year)  
• 
Male or female patients age ≥ 3 years and < 14 years.  The patient may be 14 years 
old exactly on the day of the first dose of study treatment.  
• 
Bone age ≤ 9 years (females) or ≤ 11 years (males) as determined by X-ray of the 
left hand and wrist using Greulich and Pyle method and obtained within the 
12 months prior to enrollment 
• 
Prepubertal (Tanner I) males and females by physical exam 
• 
Diagnosis of GHD (stimulated GH < 10 ng/mL) by two standard pharmacologic tests 
obtained up to 12 months prior to informed consent/assent.   
– 
Acceptable GH stimulation tests include:  insulin tolerance test (considered two 
tests if done sequentially with arginine); arginine stimulation test (considered 
two tests if done sequentially with insulin); glucagon stimulation test; clonidine 
stimulation test; L-dopa stimulation test; L-dopa + inderal stimulation test 
(considered one test if done together). 
• 
Normal thyroid function test within the 12 months prior to informed consent/assent 
• 
Normal CBC within the 12 months prior to informed consent/assent 
• 
Documentation of prior height and weight measurements, with height standard 
deviation score (SDS) ≤  −1.5 (≤ 5th percentile) for idiopathic isolated GHD patients 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any previous rhGH treatment 
• 
Short stature etiologies other than GHD (e.g., untreated hypothyroidism, short 
stature associated with GH encoding gene mutations, chromosomal defect 
associated with short stature) 
– 
Patients with multiple pituitary hormone deficiencies (secondary/tertiary 
hypothyroidism, central adrenal insufficiency, diabetes insipidus) not associated 
with an intracranial tumor or CNS irradiation must be controlled on replacement 
medications for ≥ 6 months prior to study entry.  Hormonal treatments, such as 
androgens and estrogens to initiate puberty, are not permitted during the 
study. 
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• 
Acute critical illness or uncontrolled chronic illness, which in the opinion of the 
investigator and Medical Monitor, would interfere with participation in this study, 
interpretation of the data, or pose a risk to patient safety 
• 
Chronic illnesses such as inflammatory bowel disease, celiac disease, heart disease, 
and diabetes 
• 
Bone diseases such as achondroplasia or hypochondroplasia, intracranial tumor, 
irradiation, and traumatic brain injury 
• 
Patients receiving oral or inhaled chronic corticosteroid therapy (> 3 months) for 
other medical conditions other than central adrenal insufficiency 
• 
Patients who require higher (2 × or greater than maintenance) doses of 
corticosteroids for more than 5 days in the 6 months prior to enrollment in the study 
• 
Patients with active malignancy or any other condition that the investigator believes 
would pose a significant hazard to the patient if rhGH were initiated   
• 
Females with Turner syndrome (documented with a karyotype or short stature 
homeobox [SHOX] analysis at any time prior to informed consent/assent), 
regardless of their GH status 
• 
Prader-Willi syndrome regardless of GH status 
• 
Born small for gestational age regardless of GH status 
• 
Presence of scoliosis requiring monitoring 
• 
Previous participation in another clinical trial or investigation of GH, treatment for 
growth failure, or treatment with a biologic agent 
• 
Patients with closed epiphyses 
• 
Patients with a known hypersensitivity to somatropin, excipients, or diluent 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is unblinded, open-label, single-arm study.  After written informed consent/assent 
has been obtained and eligibility has been established, the study site will obtain the 
patient’s unique identification number.   
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
Nutropin AQ v1.1 will be supplied by the Sponsor as labeled study drug using the 
Nutropin AQ v1.1 NuSpin™ 10 device for the 1-year duration of this study.  For 
information on the formulation, packaging, and handling of Nutropin AQ v1.1, see the 
pharmacy manual and the USPI for Nutropin AQ. 
4.3.2 
Dosage, Administration, and Compliance 
Nutropin AQ v1.1 will be provided to the patient and administered at a dose of up to 
0.043 mg/kg/day (0.3 mg/kg/week).  The dose may be adjusted at the Month 6 visit per 
investigator assessment for:  1) a change in body weight of at least ± 2 kg from baseline 
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OR 2) a change in IGF-1 level (if tested and the investigator deems a change in dose is 
clinically indicated).   
The dose of Nutropin AQ v1.1 will be administered via SC injections by the patient or 
caregiver.  Instructions and training on Nutropin AQ v1.1 administration with the NuSpin 
device will be provided by a trained study nurse coordinator.   
Administration of the first dose of Nutropin AQ v1.1 (Day 1, baseline visit) should occur 
after the patient receives dosing administration instruction in the clinic and after the initial 
blood sample is drawn. 
Blood samples scheduled after baseline (Months 1, 3, 6, 9, and Month 12 or early 
discontinuation) should be taken at least 12 hours after the last dose of 
Nutropin AQ v1.1 and prior to the next dose.      
Missed doses or drug holidays are discouraged.  Information on study treatment 
discontinuation and adverse events that may lead to discontinuation of treatment is 
provided in Sections 4.6.2 and 5.1.1, respectively. 
The Nutropin AQ v1.1 solution contained within the NuSpin device contains a phenol 
preservative.  The solution may be used for SC administration for 28 days after initial 
use when stored in the pen device at 2−8°C/36−46°F (under refrigeration).  Avoid 
freezing the contents of the NuSpin device.  The Nutropin AQ v1.1 contained within the 
device is light sensitive and should be protected from light.  Store the NuSpin device 
refrigerated in a dark place when it is not in use.  Once study drug is assigned and 
dispensed to patients, they will be provided with containers for transport of the drug 
from the investigative sites to their homes for refrigerated storage.   
The solution in the device should be clear immediately after removal from the refrigerator.  
Allow the pen cartridge to come to room temperature and gently swirl.  If the solution is 
cloudy, the contents must not be administered and the affected pens should be returned 
to the site. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  Section 5.3.5.11 summarizes available safety 
data related to overdosing of Nutropin AQ. 
4.3.3 
Investigational Medicinal Product Accountability 
Study drug will be shipped to the investigator site, logged into the appropriate forms, and 
dispensed at the baseline visit and at each 3-month visit. 
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All investigational medicinal products (IMPs) required for completion of this study 
(Nutropin AQ v1.1) will be provided by the Sponsor.  The study site will acknowledge 
receipt of IMPs, using the Interactive Web Response System (IWRS) to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.  
Unused, returned, or expired IMPs will either be disposed of at the study site according 
to the study site’s institutional standard operating procedure or returned to the Sponsor 
with the appropriate documentation.  The site's method of IMP destruction must be 
agreed upon by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.4 
CONCOMITANT THERAPY 
Careful monitoring is advisable when Nutropin AQ v1.1 is administered in 
combination with insulin or other hypoglycemic agents, other drugs metabolized by 
CYP450 liver enzymes, or other hormone replacement therapy. 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to dosing to the study completion/early discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
Medications to manage multiple pituitary-hormone deficits or other chronic conditions 
should also be recorded as concomitant medications. 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
• 
Any type of investigational therapy 
• 
Other rhGH therapy 
• 
Estrogen or androgens 
• 
Immunosuppressive drugs other than maintenance corticosteroids as described 
above 
 
Notify the Medical Monitor immediately if high dose (> 2 times replacement therapy) oral 
or systemic corticosteroids are prescribed.  Patients who require high dose oral or 
systemic corticosteroids for more than 5 days in any 6-month period will be terminated 
from the study. 
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The above list of medications is not necessarily comprehensive.  The investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent from the parent(s) or a legally authorized representative of the 
child, and patient assent, if applicable, for participation in the study must be obtained 
before performing any study-specific screening tests or evaluations.  Informed Consent 
Forms and Assent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before the first dose of study drug.  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
If a patient does not have on record a CBC and bone age result within 12 months prior 
to informed consent (for CBC) or enrollment (for bone age), they will be asked to 
undergo a blood draw (to be analyzed at local laboratory for CBC) and an X-ray for 
determination of bone age to determine eligibility for the study. 
Patients who fail screening may be re-screened once for this study.  However, patients 
who are found to have an abnormal CBC may have a repeat test done within the same 
screening period at the discretion of the investigator and may be enrolled if the 
investigator deems the results and clinical presentation of the patient are normal. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, prior height and weight 
measurements, and all prescription medications used by the patient in the 30 days prior 
to the screening visit. 
Demographic data will include date of birth, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
Limited physical examinations should be performed as per the standard of care 
guidelines for a child with GHD undergoing GH therapy.  Pubertal status and 
confirmation of prepubertal status, presence of hip or knee pain, appearance of spine 
(i.e., appearance of significant scoliosis), and routine fundoscopic examination for 
absence of signs of intracranial pressure must be recorded.  New or worsened clinically 
significant abnormalities after baseline should be recorded as adverse events, if 
applicable.  
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4.5.4 
Height and Weight 
Height (three measurements at the same visit with a stadiometer or equivalently fixed 
measuring device) and weight will be recorded.   
4.5.5 
Laboratory Assessments 
At screening, patients may be required to provide a blood sample to check for CBC, 
which will be analyzed at the local laboratory.  
At Month 6 and 12 study visits, optional samples may be drawn to check IGF-1 levels, 
which will also be analyzed at the local laboratory. 
For assessment of immunogenicity, samples will be drawn at each study visit (see 
Appendix 1) and will be sent to the central laboratory to assess the following: 
• 
Serum drug concentration.  GH concentration levels are necessary to interpret 
anti-GH antibody status and titers.  
• 
Immunogenicity, utilizing the following assays: 
– 
anti-GH antibody screening assay 
– 
anti-GH neutralizing antibody assay 
– 
anti-GH antibody binding capacity assay 
 
During the study treatment period, blood samples for immunogenicity should be drawn 
at least 12 hours after the last administration of Nutropin AQ v1.1 and prior to the next 
scheduled dose. 
The last blood sample for immunogenicity at Month 12 must be drawn at least 12 hours 
after the last dose of Nutropin AQ v1.1.  In the event of early discontinuation, an early 
discontinuation visit should be scheduled within 28 days after the last dose of 
Nutropin AQ v1.1 and a blood sample will be collected for a final assessment of serum 
drug concentration and immunogenicity. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance, specifically defined as:  refusal to allow for serum draws for 
antibodies; failure to adhere to study visit schedule; failure to comply with GH 
administration by giving less than 85% of daily injections over each 3-month interval 
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• 
Development of growth failure with velocity decrease to below pretreatment velocity 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed as part of the study for any 
reason after consent has been withdrawn.  Patients who withdraw from the study 
prematurely will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients who experience a protocol-defined adverse event may be discontinued from 
treatment (see Section 5.1.1).  Patients who discontinue study treatment prematurely will 
be asked to return to the clinic for an early discontinuation visit and may undergo final 
study assessments.  The primary reason for premature study treatment discontinuation 
should be documented on the appropriate eCRF.  Patients who discontinue study 
treatment prematurely may remain in the study and continue to be followed per the 
schedule of assessments for sample collection, reporting of adverse events, and height 
and weight measurements. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• 
Patient enrollment is unsatisfactory 
• 
Recall or other unforeseen problems with the drug and/or device 
• 
FDA or other government health and regulatory agencies request termination  
 
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
Sites that are closed may be replaced at the Sponsor’s discretion. 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Patient safety will be monitored through physical exams and incidence or severity of 
adverse events and serious adverse events.  
5.1.1 
Adverse Events That May Lead to Discontinuation of Treatment 
with Nutropin AQ v1.1 
Management of specific adverse events should follow the information provided in the 
USPI for Nutropin AQ, published guidelines, and standard of care practices in the 
monitoring of patients receiving rhGH therapy. 
Events that may lead to discontinuation of Nutropin AQ v1.1 include, but are not limited 
to, the following: 
• 
Papilledema by fundoscopy  
• 
Somatropin-induced intracranial hypertension   
• 
Evidence of recurrent or new malignancy 
• 
New or recurrent event of slipped capital femoral epiphysis (SCFE) or avascular 
necrosis (AVN) 
• 
Diabetes mellitus 
• 
Pancreatitis 
• 
New scoliosis or significant scoliosis progression 
• 
Anaphylactic reactions/severe hypersensitivity 
• 
Acute critical illness requiring intensive care hospitalization  
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events.   
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
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• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
– 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, severe, or life-threatening; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
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5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions).  Those adverse events of special 
interest for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
– 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4, 5.5, and 5.6.  
The investigator is also responsible for reporting medical device complaints 
(see Section 5.4.4). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all serious adverse events and non-serious adverse 
events, regardless of relationship to study drug, will be reported until 28 days after the 
last dose of study drug as provided in this study.   After this period, the investigator 
should report any serious adverse events that are believed to be related to prior study 
drug treatment (see Section 5.6). 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  A consistent methodology 
of non-directive questioning should be adopted for eliciting adverse event information at 
all patient evaluation timepoints.  Examples of non-directive questions include the 
following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 1 provides guidance for assessing adverse event severity. 
Table 1 
Adverse Event Severity Grading Scale  
Grade 
Severity 
1 
Mild; transient or mild discomfort (< 48 hours); no medical intervention or 
therapy required 
2 
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required 
3 
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible 
4 
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable 
Notes:  Developed by the Division of Microbiology and Infectious Diseases, National Institute of 
Allergy and Infectious Diseases. 
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2). 
  
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 2): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
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• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 2 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Injection Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug injection should be captured as a diagnosis on the 
Adverse Event eCRF.   
If a patient experiences both a local and systemic reaction (e.g., generalized injection 
reaction and localized injection site reaction) to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
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based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult 
patient, only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.  
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory 
abnormality observed during physician’s caring for the patient should be reported as an 
adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × the upper limit of normal [ULN] associated 
with cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the 
Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an 
elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2 ). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).     
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
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5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").   
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
– 
The patient has not experienced an adverse event 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.   
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
Short-term overdose could lead initially to hypoglycemia and subsequently to 
hyperglycemia.  Furthermore, overdose with somatropin is likely to cause fluid retention. 
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Long-term overdose could result in signs and symptoms of gigantism and/or acromegaly 
consistent with the known effects of excess GH. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Sections 5.2.2 and 5.4.2 for further details) 
• 
Non-serious adverse events of special interest (see Sections 5.2.3 and  5.4.2 for 
further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/Ethics Committee (EC). 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
Genentech Medical Monitor contact information: 
Medical Monitor: 
, M.D. 
Telephone No: 
 (South San Francisco)  
Alternate Telephone No: 
 (South San Francisco)  
  
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events (see Section 5.2.2) and non-serious 
adverse events of special interest (see Section 5.2.3) will be reported until 28 days after 
the last dose of study drug.  Investigators should record all case details that can be 
gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  
A report will be generated and sent to Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee (Genentech) immediately (i.e., no more than 
24 hours after learning of the event), either by faxing or by scanning and emailing the 
form using the fax number or email address provided below.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Genentech Drug Safety Fax No.:  (650) 225-4682  
Alternate Fax No:  
 
Genentech Drug Safety email:  us_drug.safety@gene.com 
 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
Should patients enter puberty during the study and become pregnant, the following 
information will apply. 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche or its 
designee (Genentech) immediately (i.e., no more than 24 hours after learning of the 
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pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided in Section 5.4.2.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
5.4.3.2 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).  Any abortion should be reported in the same 
fashion (as the Sponsor considers abortions to be medically significant). 
5.4.4 
Reporting Requirements for NuSpin Device Complaints 
In this study, NuSpin is considered a medical device.  The investigator must report all 
NuSpin device complaints to the Sponsor.  The investigator should document as much 
information as possible on the IMP Deviation Form, including the product batch number, 
and forward the form to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event) (refer to the site pharmacy manual for further details).  If the 
medical device results in an adverse event to the study patient, the event must be 
reported on the Adverse Event eCRF and submitted through the EDC system.  If the 
event is serious, the Adverse Event eCRF must be completed immediately (i.e., no more 
than 24 hours after learning of the event), as outlined in Section 5.4.2. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.    
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
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5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  
The investigator should report these events directly to Roche or its designee 
(Genentech), either by faxing or by scanning and emailing the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided in Section 5.4.2. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the USPI for Nutropin AQ. 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
A target enrollment of 80 patients was chosen to allow for a projected 10−15% dropout 
rate and exclusion of growth data for an estimated 10% of patients who might enter 
puberty during the study period and leave sufficient patient numbers to compare to 
previous studies of immunogenicity.  This target enrollment was based on enrollment in 
a previous study (L0368) which planned to enroll 60 patients for the assessment of 
growth rate and change in height SDS.  An initial sample size was chosen to ensure that 
at least 50 patients would complete the study (L0368 FR 30SEP97; Sec 4.8.4). 
This study is expected to yield a minimum of 50 evaluable patients.  Given a sample size 
of 50, and an assumed 50% of patients developing anti-GH antibodies, the 95% 
confidence interval around this proportion will be (35.53%, 64.47%).  This interval was 
calculated using Clopper-Pearson methodology.  Fluctuations in the proportion of 
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patients developing anti-GH antibodies and the increase of evaluable patients will result 
in more precise confidence intervals.  The exact confidence intervals for the scenarios 
for sample size of 50 and 60 in combination with the proportion of patients who are anti-
GH antibody positive of 50% and 20% are listed in Table 3. 
Table 3 
Clopper-Pearson 95% Confidence Intervals for the Proportion of 
Patients Who Are Anti-GH Antibody Positive Based on 50 and 
60 Patients 
N 
Proportion of Patients 
Who Are Anti-GH 
Antibody Positive 
95% Confidence 
Interval 
(Lower Limit) 
95% Confidence 
Interval 
(Upper Limit) 
50 
0.5 
0.3553 
0.6447 
60 
0.5 
0.3681 
0.6319 
50 
0.2 
0.1003 
0.3372 
60 
0.2 
0.1078 
0.3230 
  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Patients enrolled, visit completion, and reasons for study termination/study withdrawal 
will be summarized.  The baseline variables for all enrolled patients to be summarized 
include, but are not limited to, demographic and physical characteristics (sex, height, 
and weight), pubertal status, historical laboratory test results, and all other entry criteria.  
Antibody status at baseline will also be summarized.  All enrolled patients will be 
included in these summaries as the intent-to-treat population.  The primary and 
secondary analyses will include all treated patients as described below, except as noted 
for patients who enter puberty.  
6.3 
OUTCOMES ANALYSES 
Descriptive statistics and graphic displays will be provided to summarize data from this 
study.  There are no formal statistical hypothesis tests planned. 
6.3.1 
Primary Endpoint 
The primary endpoint for this study is the proportion of patients who develop anti-GH 
antibodies after initiating treatment with Nutropin AQ v1.1.  
6.3.2 
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
• 
Proportion of patients who exhibit growth attenuation (defined as initial growth 
response greater than pretreatment velocity followed by reduction in growth 
response to below the pretreatment velocity in the subsequent 6-  to 12-month 
treatment period or reaching  ≤ 2 cm per year) 
– 
Cross tabulation between growth attenuation status (i.e., with or without) and 
anti-GH antibody status (i.e., positive or negative) will be provided for any 
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antibody and for neutralizing anti-GH antibody, respectively, at each visit.  
Similar tables will also be provided for patients who had at least one positive 
anti-GH antibody (anti-GH antibody and neutralizing antibody, respectively) at 
any follow-up visit against those who never developed antibody after treatment.  
• 
Proportion of patients with neutralizing antibody among those who had positive 
anti-GH antibody  
– 
This analysis will be summarized by visit, as well as cumulatively, for patients 
who had detectible anti-GH antibody at any post-baseline visit, as well as those 
who remained negative throughout the study.   
• 
Annualized 6- and 12-month growth velocities and height SDS will be summarized 
separately for patients who were anti-GH antibody-positive at any post-baseline 
follow-up visit and those who were anti-GH antibody-negative at all visits (including 
baseline).  Graphic displays of the individual patient growth patterns along with the 
longitudinal antibody profile over the course of the study will be prepared.  Patients 
who enter puberty during the study period will be included up to the last visit at 
which they were determined to be prepubertal. 
 
Additional analyses deemed appropriate for assessing immunogenicity will be described 
in the Statistical Analysis Plan.  
6.4 
SAFETY ANALYSES 
Safety analyses will include all patients who received at least one dose of study drug.  
Adverse events will be summarized by mapped term, appropriate thesaurus level, and 
toxicity grade.  Summaries (or listings, if appropriate), including investigator 
assessments of relationship to study drug, will also be produced for each of the following: 
• 
Serious adverse events 
• 
All events leading to the withdrawal of treatment 
• 
All events by severity 
• 
All events possibly indicative of hypersensitivity  
 
6.5 
HANDLING OF MISSING DATA 
Missing data will not be imputed.  All available assessments will be reported with 
associated number of observations.  If a patient discontinues study drug before the end 
of the 1-year treatment period, growth rate will be computed for the last 3-month interval 
visit and used in the calculation of mean growth for that time interval only. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC through 
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use of eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event 
of discrepant data, the CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data.   
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures.  
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational study site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
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ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC−approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act of 1996 (HIPAA).  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
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under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech, a member of the Roche group, and will be 
managed by Genentech and a CRO.  The CRO will provide clinical operations 
management, project management, monitor study conduct, patient enrollment and 
discontinuation, and medical monitoring for the duration of the study.  
An IWRS will be used to assign patient numbers, monitor enrollment and patient status, 
and to manage study treatment requests and shipments.   
Patient data will be recorded via an EDC system using eCRFs (see Section 7.2). 
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9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
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9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
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10. 
REFERENCES 
Buzi F, Buchanan CR, Morrell DJ, et al. Antigenicity and efficacy of authentic sequence 
recombinant human growth hormone (somatropin): first-year experience in the United 
Kingdom. Clin Endocrinol 1989;30:531−8. 
Cogan JD, Phillips JA. GH1 gene deletions and IGHD type 1A. Pediatr Endocrinol Rev 
2006;3(Suppl 3):480−8. 
Franklin S, Geffner ME. Growth hormone: the expansion of available products and 
indications. Endocrinol Metab Clin North Am 2009;38:587−611. 
NUTROPIN AQ® [somatropin (rDNA origin) injection], Genentech, Inc. 2014 Jun 
[cited 2014 Aug 8]. Available from:  
http://www.gene.com/download/pdf/nutropin_aq_PI.pdf. 
Pirazzoli P, Cacciari E, Mandini M, et al. Follow-up of antibodies to growth hormone in 
210 growth hormone-deficient children treated with different commercial preparations. 
Acta Paediatr 1995;84:1233−6. 
Procter AM, Phillips JA, Cooper DN. The molecular genetics of growth hormone 
deficiency. Hum Genet 1998;103:255−72. 
Schwarz S, Berger P, Frisch H, et al. Growth hormone blocking antibodies in a patient 
with deletion of the GH-N gene. Clin Endocrinol 1987;27 213−24. 
 
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Appendix 1  
Schedule of Assessments 
Assessment 
Screening 
(Day −28 
to Day −1) 
Baseline 
(Day 1) a 
Month 1
(± 3 days)
Month 3 
(± 3 days) 
Month 6
(± 3 days) 
Month 9
(± 3 days)
Month 12 
(± 3 days) b 
Safety 
Follow-Up 
(± 3 days) c 
Early 
Discontinuation d 
Informed consent/assent  
x e 
 
 
 
 
 
 
 
 
Medical history f 
x 
 
 
 
 
 
 
 
 
Eligibility criteria g 
x 
 
 
 
 
 
 
 
 
Demographic data h 
x 
 
 
 
 
 
 
 
 
Limited physical 
examination i 
x 
x 
 
x 
x 
x 
x 
 
x 
Concomitant 
medications j 
x 
x 
 
x 
x 
x 
x 
 
x 
Height and weight 
x 
x 
 
x 
x 
x 
x 
 
x 
Serum sample for serum 
drug concentration and 
immunogenicity 
assessments k 
 
x 
x 
x 
x 
x 
x l 
 
x l 
Optional tests m 
x 
 
 
 
x 
 
x 
 
 
NuSpin instruction/ 
training n 
 
x 
 
 
 
 
 
 
 
Nutropin AQ v1.1 
administration o 
 
x 
x 
x 
x 
x 
x 
 
 
Nutropin AQ v1.1 dose 
compliance p 
 
 
x 
x 
x 
x 
x 
 
x 
Adverse events q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
a All baseline assessments should be performed before the first dose of study drug. 
b The Month 12 visit will serve as the study completion visit.   
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Appendix 1 (cont.)  
Schedule of Assessments 
c The patient will be contacted by phone 28 ± 3 days after the Month 12 visit to collect adverse events. 
d Patients who discontinue from the study early will be asked to return to the clinic within 28 days after the last dose of study drug. 
e Written informed consent/assent must be obtained and documented before any study-specific screening procedure is performed. 
f Includes clinically significant diseases, surgeries, prior height and weight measurements, and all prescription medications used by the patient in 
the 30 days prior to the screening visit. 
g Historical laboratory tests include two GH stimulation tests with GH response < 10 ng/mL (obtained up to 12 months prior to informed 
consent/assent; see Section 4.1.1 for acceptable tests); thyroid function testing (obtained within 12 months prior to informed consent/assent); 
complete blood counts (obtained within 12 months prior to informed consent/assent); and for females, karyotype or SHOX analysis to exclude 
the diagnosis of Turner syndrome (obtained any time prior to informed consent/assent).  Historical radiographic test includes bone age obtained 
within 12 months prior to enrollment.  If results are not available within a specified timeframe, the tests that may be done as part of the 
screening process are CBC and X-ray for bone age. All other tests should be done as part of standard care. 
h Demographic data will include date of birth, sex, and self-reported race/ethnicity. 
i Limited physical examinations should be performed as per the standard of care guidelines for a child with GHD undergoing GH therapy.  
Pubertal status and confirmation of prepubertal status, presence of hip or knee pain, appearance of spine (i.e., appearance of significant 
scoliosis), and routine fundoscopic examination for absence of signs of intracranial pressure must be recorded.  New or worsened clinically 
significant abnormalities after baseline should be recorded as adverse events, if applicable. 
j Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements, medications to manage multiple pituitary-hormone deficits as well as other chronic medications) used by a patient from 7 days 
prior to dosing to the study completion/early discontinuation visit. 
k A single blood sample will be collected at each visit during the treatment period for immunogenicity and drug concentrations.  Process each 
sample for serum and split into four separate tubes for serum drug concentration and immunogenicity assessments (anti-GH antibody screening 
assay, anti-GH neutralizing antibody assay, and anti-GH antibody binding capacity assay).  After baseline, blood samples for immunogenicity 
and serum drug concentration should be taken at least 12 hours after the last dose of Nutropin AQ v1.1 and prior to the next dose.   
l The last blood sample at Month 12 must be drawn at least 12 hours after the last dose of Nutropin AQ v1.1.  In the event of early discontinuation, 
an early discontinuation visit should be scheduled within 28 days after the last dose of Nutropin AQ v1.1 and a blood sample will be collected for 
a final assessment of serum drug concentration and immunogenicity. 
m Optional tests include a serum sample to test CBC at screening (if results are not available within 12 months prior to informed consent) and 
serum samples for IGF-1, which can be drawn at the discretion of the investigator at Month 6 and 12.  All optional samples will be analyzed 
at the local laboratory.  Optional tests also include an X-ray to determine bone age eligibility at screening only if the results are not available 
within 12 months prior to the enrollment date. 
n Nutropin AQ v1.1 will be administered via daily SC injections by the patient or caregiver.  Instruction and training on Nutropin AQ v1.1 
administration with the NuSpin device will be provided by a trained study nurse coordinator. 
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Appendix 1 (cont.)  
Schedule of Assessments 
o The first dose (Day 1, baseline visit) should occur after the patient receives dosing administration instruction in the clinic and after the initial blood 
sample is drawn.  Blood samples scheduled after baseline (Months 1, 3, 6, 9, and Month 12 or early discontinuation) should be taken at least 
12 hours after the last dose of Nutropin v1.1 and prior to the next dose.  
p Assess compliance with daily dosing at each visit after baseline.  Reinstruct patients and caregivers, as needed. 
q After initiation of study drug, all serious adverse events and non-serious adverse events, regardless of relationship to study drug, will be reported 
until 28 days after the last dose of study drug as provided in this study.  After this period, the investigator should report any serious adverse 
events that are believed to be related to study drug.  The Sponsor should be notified if the investigator becomes aware of any serious adverse 
event that occurs after the end of the adverse event reporting period (defined as 28 days after the last dose of study drug), if the event is 
believed to be related to prior study drug treatment. The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort 
should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can 
be reported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
 
Official Title: 
A Phase IV, Multicenter, Open-Label Study of the Immunogenicity of 
Nutropin AQ® V1.1 [Somatropin (rDNA Origin) Injection] 
Administered Daily to Naïve Growth Hormone-Deficient Children 
(iSTUDY) 
NCT Number: 
NCT02311894 
Document Date: 
SAP: 28-Mar-18 
 
 






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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
2.1 
Protocol Synopsis .................................................................... 4 
2.2 
Outcome Measures ................................................................. 4 
2.2.1 
Primary Outcome Measures .................................................... 4 
2.2.2 
Secondary Outcome Measures ............................................... 5 
2.2.3 
Exploratory Efficacy Outcome Measures ................................. 5 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures ........................ 5 
2.2.5 
Safety Outcome Measures ...................................................... 5 
2.3 
Determination of Sample Size ................................................. 5 
2.4 
Analysis Timing ....................................................................... 6 
3. 
STUDY CONDUCT ....................................................................................... 6 
3.1 
Randomization Issues ............................................................. 6 
3.2 
Independent Review Facility .................................................... 6 
3.3 
Data Monitoring ....................................................................... 6 
4. 
STATISTICAL METHODS ............................................................................ 6 
4.1 
Analysis Populations ............................................................... 6 
4.1.1 
Intent-to-Treat (ITT) Population ............................................... 6 
4.1.2 
Per Protocol Population ........................................................... 7 
4.1.3 
Pharmacokinetic-Evaluable Population ................................... 7 
4.1.4 
Safety Population .................................................................... 7 
4.1.5 
Modified Intent-to-Treat (mITT) Population .............................. 7 
4.2 
Analysis of Study Conduct ....................................................... 7 
4.3 
Analysis of Treatment Group Comparability ............................ 7 
4.4 
OUTCOME Analysis ................................................................ 8 
4.4.1 
Primary Outcomes Endpoint .................................................... 9 
4.4.2 
Secondary Outcomes Endpoints ............................................. 9 
4.4.3 
Exploratory Endpoints............................................................ 10 
4.4.4 
Sensitivity Analyses ............................................................... 10 
4.4.5 
Subgroup Analyses ............................................................... 11 
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4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 11 
4.6 
Safety Analyses ..................................................................... 11 
4.6.1 
Exposure of Study Medication ............................................... 11 
4.6.2 
Adverse Events ..................................................................... 11 
4.6.3 
Laboratory Data ..................................................................... 12 
4.6.4 
Vital Signs .............................................................................. 13 
4.6.5 
Previous and Concomitant Medications................................. 13 
4.7 
Missing Data .......................................................................... 13 
4.8 
Interim Analyses .................................................................... 15 
5. 
REFERENCES ........................................................................................... 16 
 
 
LIST OF TABLES 
 
Table 1  
Clopper-Pearson 95% Confidence Intervals for the 
Proportion of Patients Who Are Anti-GH Antibody Positive 
Based on 50 and 60 Patients ........................................................ 6 
Table 2  
Study Windows ............................................................................. 8 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 17 
Appendix 2 
 Schedule of Assessments .......................................................... 22 
Appendix 3 
 Programming Codes for Statistical Analysis .............................. 25 
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1. 
BACKGROUND 
Nutropin [somatropin (rDNA origin) for injection] is a lyophilized form of human growth 
hormone (hGH) produced by recombinant DNA technology. Nutropin AQ is a liquid 
formulation with the chemical structure of somatropin identical to lyophilized Nutropin.  
To use the most advanced methodology and equipment to ensure a continued supply of 
Nutropin AQ, Genentech has updated its manufacturing process while continuing to use 
the same Escherichia coli growth hormone production system. Chemical and biological 
characterization (including potency) has demonstrated comparability of drug substance 
produced by the original and updated manufacturing processes and, based on this, the 
new manufacturing process that is used to produce Nutropin AQ v1.1 has been 
approved by FDA.  
This study, performed in children with growth hormone deficiency (GHD), will assess the 
safety and immunogenicity profile of Nutropin AQ produced by the new manufacturing 
process. 
For further background information please see Section 1 of the protocol. 
This Statistical Analysis Plan (SAP) describes the statistical methods to be used for 
study ML29543. This version of the SAP has been developed using version 2 of the 
study protocol dated 22 April 2015 and revision 1.2 of the CRF dated 26 July 2017. 
2. 
STUDY DESIGN 
This is a Phase IV, multicenter, open-label, single-arm study of somatropin (rDNA origin) 
(Nutropin AQ v1.1) in naïve prepubertal children with GHD. Approximately 80 patients 
will be enrolled at approximately 30 sites in the U.S. and will be treated with daily 
subcutaneous (SC) injections of Nutropin AQ v1.1 at a dose of up to 0.043 mg/kg/day 
(0.3 mg/kg/week, which is the approved and indicated dosage for pediatric GHD; refer to 
the U.S. Prescribing Information [USPI] for Nutropin AQ) for 12 months. Dose 
adjustments may be made at the Month 6 visit for changes in weight and insulin growth 
factor-1 (IGF-1) levels, if measured. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Outcome Measures 
• 
The primary outcome measure for this study is the occurrence of anti-GH antibodies 
in rhGH-naïve, prepubertal GHD children treated with Nutropin AQ v1.1. 
 
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2.2.2 
Secondary Outcome Measures 
• 
The occurrence of functional growth attenuation in association with positive antibody 
formation in patients treated with Nutropin AQ v1.1  
This will be considered in any patient who demonstrates an initial growth response 
greater than pretreatment velocity after treatment with Nutropin AQ v1.1, but then 
slows to below pretreatment velocity in the ensuing 6- to 12-month period (or 
reaches ≤2 cm per year)  
• 
The difference between the annualized 6- and 12-month growth velocities for 
patients who were anti-GH antibody-positive at any post-baseline visit and those who 
were anti-GH antibody-negative at all visits (including baseline)  
• 
The formation of neutralizing antibodies, and the association between the presence 
of neutralizing anti-GH antibodies and growth attenuation. 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
This section is not applicable. 
 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures 
This section is not applicable. 
 
2.2.5 
Safety Outcome Measures 
No specific safety assessments are planned for this study. However, analysis of all 
safety events will be performed. 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
A target enrollment of 80 patients was chosen to allow for a projected 10−15% dropout 
rate and exclusion of growth data for an estimated 10% of patients who might enter 
puberty during the study period and leave sufficient patient numbers to compare to 
previous studies of immunogenicity. This target enrollment was based on enrollment in a 
previous study (L0368) which planned to enroll 60 patients for the assessment of growth 
rate and change in height standard deviation score (SDS). An initial sample size was 
chosen to ensure that at least 50 patients would complete the study (L0368 FR 
30SEP97; Sec 4.8.4). 
This study is expected to yield a minimum of 50 evaluable patients. Given a sample size 
of 50, and an assumed 50% of patients developing anti-GH antibodies, the 95% 
confidence interval (CI) around this proportion will be (35.53%, 64.47%). This interval 
was calculated using Clopper-Pearson methodology. Fluctuations in the proportion of 
patients developing anti-GH antibodies and the increase of evaluable patients will result 
in more precise confidence intervals. The exact confidence intervals for the scenarios for 
sample size of 50 and 60 in combination with the proportion of patients who are anti-GH 
antibody positive of 50% and 20% are listed in Table 1. 
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Table 1 
Clopper-Pearson 95% Confidence Intervals for the Proportion of Patients Who Are 
Anti-GH Antibody Positive Based on 50 and 60 Patients 
N 
Proportion of Patients Who 
Are Anti-GH Antibody Positive 
95% Confidence Interval 
(Lower Limit) 
95% Confidence Interval 
(Upper Limit) 
50 
0.5 
0.3553 
0.6447 
60 
0.5 
0.3681 
0.6319 
50 
0.2 
0.1003 
0.3372 
60 
0.2 
0.1078 
0.3230 
 
2.4 
ANALYSIS TIMING 
No interim analysis is planned. The final analysis will be performed after the completion 
of the study and after the clinical database is locked. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
There is no randomization for this open-label, single arm study. 
3.2 
INDEPENDENT REVIEW FACILITY 
This section is not applicable. 
3.3 
DATA MONITORING 
There is no independent data monitoring committee planned for this study. 
4. 
STATISTICAL METHODS 
Data listings will be produced for all endpoints. Descriptive statistics and graphic 
displays will be provided to summarize data from this study. There are no formal 
statistical hypothesis tests planned. 
Categorical variables will be summarized as the number and percentage of patients or 
occurrences in each response category. Continuous variables will be summarized using 
descriptive statistics (number of observations, mean, standard deviation, median, 
minimum and maximum). 
4.1 
ANALYSIS POPULATIONS 
There are three analysis populations for this study: Intent-to-treat (ITT), Safety and 
Modified ITT. 
4.1.1 
Intent-to-Treat (ITT) Population 
The ITT Population includes all patients enrolled in the study. 
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4.1.2 
Per Protocol Population 
This section is not applicable. 
4.1.3 
Pharmacokinetic-Evaluable Population 
This section is not applicable. 
4.1.4 
Safety Population 
The Safety Population includes all enrolled patients (i.e. ITT population) who received at 
least one dose of study drug. 
4.1.5 
Modified Intent-to-Treat (mITT) Population 
The Modified ITT Population includes all enrolled patients (i.e. ITT population) who 
received at least one dose of study drug and had at least one post-baseline assessment 
(e.g., lab, vital signs, physical exam, concomitant medication, and adverse event). 
4.2 
ANALYSIS OF STUDY CONDUCT 
The number and percentage of patients who have signed informed consent, met 
eligibility criteria, had major protocol deviations, and received treatment will be tabulated. 
Reasons for not completing the study will also be tabulated using numbers and 
percentages. 
A summary of the duration of the patient participation in the study will be produced. 
Duration will be calculated as the date of the last study assessment minus the first study 
drug administration date + 1. 
The number and percentage of patients included and excluded from the analysis 
populations will be tabulated. Reason(s) for exclusion from each population will be 
similarly summarized. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
This is a single-arm study therefore only descriptive statistics will be provided; no 
treatment group comparison will be performed. 
Clinically important demographic and disease characteristics at baseline will be 
summarized overall. Summaries will be produced for the ITT population. 
Continuous variables will be summarized by the number of non-missing observations, 
mean, standard deviation, median, minimum and maximum values. Categorical 
variables will be summarized using numbers and percentages of patients in each 
category; unknown or missing will be included as a separate category. 
The variables to be summarized include but are not limited to the following: 
• 
Demographics: sex, ethnicity, race(s), age (continuous).  
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• 
Baseline characteristics: height, weight, height standard deviation score (SDS) 
(continuous and categorized as ≤ -3, >-3 to ≤ -2, >-2 to ≤ -1, >-1), pre-treatment 
growth velocity, and prepubertal Tanner stage < 1 (yes or no). See Appendix 3 for 
the SAS macros for the calculation of normal height SDS (z-scores) for this study. 
Pre-treatment growth velocity is calculated from the baseline and last historical 
height measurements as: 365.25 × (Baseline height – last historical height)/(date of 
baseline height – date of last historical height) 
• 
Disease-related characteristics: birth weight, bone age, diagnosis of Turner 
syndrome. 
• 
Baseline antibody testing (anti-growth hormone antibody screening assay (ATA), 
anti-growth hormone neutralizing antibody assay (Nab) and anti-growth hormone 
antibody binding capacity assay (ABC). 
• 
Medical history in specific categories. 
• 
Historical Laboratory Results on GH stimulation test (maximum GH level, insulin 
level, L-Dopa level), thyroid function test (free T4, total T4, TSH) in 12 months prior 
to informed consent/assent. 
• 
Screening/Baseline physical examination results, including presence of hip or knee 
pain, fundoscopic examination and appearance of spine. 
Subject listings on demographics, baseline characteristics, medical history, screening 
physical examination and historical laboratory measurements will be provided. 
4.4 
OUTCOME ANALYSES 
Outcome analyses will be performed on the modified ITT population. In the analyses 
related to growth attenuation, growth velocity and height SDS, patients who enter 
puberty during the study period will be included only up to the last visit at which they 
were determined to be prepubertal. 
The study windows listed below in Table 2 (based on visit dates) will be used:  
Table 2 Study Windows 
Visit 
Target Day 
Window 
Screening/Baseline 
Day -28 to -1 
Day -28 to 1 
Month 1 
Day 30 
Day 2 to 60 
Month 3 
Day 90 
Day 61 to 135 
Month 6 
Day 180 
Day 136 to 225 
Month 9 
Day 270 
Day 226 to 315 
Month 12 
Day 360 
Day 316 to 405 
If more than one assessment is measured within the same visit window, then the record 
with the latest visit date (from baseline) will be used for that visit window. 
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4.4.1 
Primary Outcomes Endpoint 
The primary endpoint for this study is the proportion of patients who develop anti-GH 
antibodies (i.e., with positive anti-GH antibody screening assay result) after initiating 
treatment with Nutropin AQ v1.1. 
Among all patients with at least one post-baseline screening assay result, the number 
and percentage of patients who have at least one positive anti-GH antibody screening 
assay result at any post-baseline visit will be presented. The Clopper-Pearson exact 
95% CIs for the percentage will also be provided.  
An anti-GH antibody screening assay result is considered positive if the titer is ≥ 1.0 
mg/L. 
4.4.2 
Secondary Outcomes Endpoints 
The secondary endpoints for this study are as follows:  
• 
Proportion of patients who exhibit growth attenuation is defined as  
(1) initial growth response greater than pretreatment velocity followed by reduction in 
growth response to below the pretreatment velocity in the subsequent 6- to 12-
month treatment period 
or  
(2) reaching ≤ 2 cm per year at any scheduled visit: Month 3, 6, 9, or 12 
Please note that for criteria (1), the initial growth response occurs as early as Month 
3 and growth attenuation status at post-baseline visit will be evaluated at Months 6, 
9, or 12.  
The growth response is based on the annualized growth velocity defined as (height - 
baseline height)/ (date of height assessment – date of baseline)*365.25 at any post-
baseline visit. 
Pretreatment growth velocity is defined as (Baseline height – last historical height) / 
(date of baseline – date of last historical height)*365.25 
Growth attenuation status at post-baseline visit Tk (=Month 6, Month 9 or Month 12 
for k=6, 9, or 12) will be classified as follows: 
Yes: If growth velocity at Tk< pretreatment growth velocity and there is Tj < Tk 
with growth velocity at Tj > pre-treatment growth velocity, for j<k, and k=6, 9, 
or 12  
or  
growth velocity ≤  2 cm per year at any scheduled visit: Month 3, 6, 9, or 12 
No: Otherwise. 
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• 
2x2 cross tabulation (with frequencies and percentages) of growth attenuation status 
(yes or no) and anti-GH antibody status (positive or negative) will be provided for 
each antibody assay at each visit (Month 6, 9, and12).   
Similar tables of growth attenuation status (yes at any visit from Month 6 to Month 12) 
and anti-GH antibody status for those who had a positive antibody assay at any 
follow-up visit (negative at baseline) and those who remained negative throughout 
the study (including baseline) will also be provided.  
• 
Proportion of patients with neutralizing anti-GH antibody (Nab positive) among those 
who had positive anti-GH antibody. This analysis will be summarized by visit, as well 
as cumulatively, for patients who had detectible anti-GH antibody (ATA) at any post 
baseline visit (with negative antibody assay at baseline), as well as those who 
remained negative throughout the study (including baseline).  
• 
Annualized 6- to 12- month growth velocities and height SDS. These variables will 
be summarized separately for patients who were anti-GH antibody-positive at any 
post-baseline follow-up visit (negative at baseline) and those who were anti-GH 
antibody-negative at all visits (including baseline). 
The difference between the annualized 6- and 12- month growth velocities will be 
presented separately for patients who were anti-GH antibody-positive at any post-
baseline visit and those who were anti-GH antibody-negative at all visits (including 
baseline).  
Graphic displays of the individual patient growth patterns (growth velocity); along 
with the longitudinal antibody profile over the course of the study will be prepared.  
For the above analyses, if there is any patient who appears to have positive anti-GH 
antibody at baseline, they will be summarized separately from the other groups. 
4.4.3 
Exploratory Endpoints 
This section is not applicable. 
4.4.4 
Sensitivity Analyses 
Sensitivity analyses will be performed on primary and/or secondary outcome measures 
by excluding patients for the following two types of situations 
• 
Patient 141’s birth weight is too light. Based on safety review query, this patient is 
too small for gestational age. Summary of primary outcome endpoint will be 
conducted by excluding patient 141 from analyses.  
• 
Patient 107 with negative baseline growth velocity because historical height was 
recorded by site as slightly greater than baseline height. The site was already 
permanently closed in 2016 and therefore query couldn’t be responded. Summary of 
secondary outcome endpoints of growth velocity and growth attenuation will be 
conducted by excluding patient 141 from analyses. 
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4.4.5 
Subgroup Analyses 
No subgroup analyses are planned. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
This section is not applicable. 
4.6 
SAFETY ANALYSES 
Safety analyses will be performed on the Safety population.  
4.6.1 
Exposure of Study Medication 
Study medication is open label daily SC injections of Nutropin AQ v1.1 at a dose of up to 
0.043 mg/kg/day (0.3 mg/kg/week) for 12 months. Dose adjustments may be made per 
investigator assessment at the Month 6 visit for changes in weight of at least ± 2 kg from 
baseline or insulin growth factor-1 (IGF 1) levels, if measured.  
The extent of exposure and compliance to study medication for each patient will be 
calculated as follows: 
The extent of exposure to study medication (days) =  
(last study treatment date – date of initial dose) +1.  
Compliance to study drug between visits =  
[1 - number of missed dose / (date of current visit – date of previous visit)] x 100% 
The number and percentage of patients who complete study treatment or discontinue 
prematurely from study treatment will be summarized by reason for discontinuation of 
study medication. Descriptive statistics (mean, standard deviation, median, minimum, 
and maximum) of extent of exposure and compliance to study medication will be 
provided for all patients in the Safety Population. 
Study medication administration data and compliance will also be presented in data 
listings. 
4.6.2 
Adverse Events 
Verbatim descriptions of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA, version 20.1 or newer) preferred terms and System 
Organ Classes. The severity of AEs will be graded (1 - mild, 2 - moderate, 3 - severe, or 
4 - life-threatening) according to Table 1 of the Protocol, and the relationship to study 
medication (yes vs. no) will be assessed by the investigator according to Table 2 of the 
Protocol.  
All adverse events with an onset date on or after Day 1 of study medication until 28 days 
after the last dose of study medication will be summarized (with frequency and 
percentage) by System Organ Class (SOC), preferred term (PT) within SOC, and 
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severity grade. In the adverse event summaries, a patient having the same event more 
than once will be counted only once for that event type. For adverse events of varying 
severity, the highest (worst) grade will be used in the summaries. Missing severity or 
relationship to study drug will not be imputed. 
Summaries of the following adverse events will be provided:  
• 
AEs by SOC and PT 
• 
SAEs by SOC and PT 
• 
AEs by SOC, PT and severity 
• 
AEs by SOC, PT and relationship to study medication 
• 
SAEs by SOC, PT and relationship 
• 
AEs leading to permanently discontinued study medication by relationship to study 
medication 
• 
Death and cause of death (listing) 
• 
AEs possibly indicative of hypersensitivity by relationship to study medication 
All adverse event data will be presented in data listings. 
Adverse Event of Special Interest (AESI) 
ASEIs will be summarized using the following preferred term and MedDRA codes.  
MedDRA Preferred Terms 
MedDRA codes from MedDRA v20.1 
drug-induced liver injury: Drug-induced 
liver injury 
10072268 
suspected transmission of an infectious 
agent via product 
10072754 
transmission of an infectious agent via 
product 
10072753 
 
4.6.3 
Laboratory Data 
Individual serum drug concentration / GH concentration, immunogenicity (anti-GH 
antibody screening, neutralizing anti-GH antibody, and antibody binding capacity) assay 
results will be listed, sorted by patient and visit.   
The GH concentration at each visit will be summarized for patients in modified ITT 
population who have serum blood sample assayed for study drug/GH concentration. 
Descriptive statistics will include the number of observations (n), mean, standard 
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deviation, coefficient of variation, median, minimum, maximum, geometric mean, and 
geometric coefficient of variation. 
The serum concentration-time profiles in semi-logarithmic (log/linear) scales, growth 
velocity time-profile and antibody status (anti-GH antibody, neutralizing anti-GH 
antibodies, antibody binding capacity) for individual patient will be presented. 
Patients who became pregnant during the study will be listed with available pregnancy 
test results. 
4.6.4 
Vital Signs 
Height, weight and their change from baseline values will be summarized in terms of 
mean, standard deviation, median, minimum, and maximum at each visit. The average 
of three measurements of height at each visit will be used for analysis and computation 
of the height SDS and growth velocity. The height and weight data will also be presented 
in a data listing. 
4.6.5 
Previous and Concomitant Medications 
All verbatim terms for medications recorded in the case report form (CRF) will be coded 
by preferred term and an anatomic therapeutic class (ATC) term using International Non-
proprietary Name (INN) drug terms and procedures. Concomitant medications and prior 
medications will be summarized separately, based on the safety population, with number 
(percentage) of patients in each ATC class and preferred drug name. Prior and 
concomitant medications will also be presented in data listings. 
Prior and concomitant medications are defined as follows: 
• 
Prior medication is defined as any medication with start date before the first day of 
study drug, or checked to be prior to first study drug administration date, or 
medication with start date missing. 
• 
Concomitant medication/treatment is any medication/treatment with start date on or 
after the initial dosing of study treatment, whichever occurs first. 
Medication/treatment that started before the first dose and continued during the 
study treatment will also be counted as concomitant medication/treatment. 
4.7 
MISSING DATA 
Missing data will not be imputed for efficacy outcome measures. All available 
assessments will be reported with associated number of observations. If a patient 
discontinues study medication before the end of the 1-year treatment period, their 
growth rate will be computed for the last 3-month interval visit and used in the calculation 
of mean growth for that time interval only. 
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There are two criteria for defining growth attenuation: (1) initial growth response greater 
than pretreatment velocity followed by reduction in growth response to below the 
pretreatment velocity in the subsequent 6- to 12-month treatment period, or (2) reaching 
≤ 2 cm per year at any scheduled visit: Month 3, 6, 9, or 12.  
For criteria (1), if the pretreatment velocity is missing then growth attenuation is missing. 
Otherwise,  
1. If patient discontinued < month 3, the growth attenuation will be missing because 
the initial growth response cannot be determined for criteria (1). 
2. If patient discontinued  ≥ month 3 and < month 6, then:  
a. If the height on Month 3 is missing, the growth attenuation will be missing 
because the initial growth response cannot be determined. 
b. If the height on Month 3 is non-missing, the initial growth response can be 
determined but the growth attenuation cannot be determined because 
there is no Month 6 visit to determine the reduction in growth response to 
below the pretreatment velocity. 
3. If patient discontinued ≥ month 6, the growth attenuation will be calculated based 
on the original definition. 
For safety analyses, incomplete onset dates for adverse events and concomitant 
medications will be imputed according to the following algorithm:  
• 
If the day is missing, the 1st of the month will be used. 
• 
If the day and month are missing, January 1st will be used. 
In cases where the imputation of the start/onset date leads to adverse events or 
concomitant medications occurring before treatment start, the start date will be set to the 
treatment start date. 
Incomplete end dates for non-ongoing adverse events or concomitant medications will 
be imputed according to the following algorithm: 
• 
If the day is missing, the last day of the month will be used.  
• 
If the day and month are missing, December 31st will be used.  
In cases where the imputation of the end date leads to adverse events or concomitant 
medications ending after date of last contact, the end date will be set to the date of last 
contact. 
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4.8 
INTERIM ANALYSES 
No efficacy interim analyses are planned. 
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5. 
REFERENCES 
None. 
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Appendix 1  
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IV, MULTICENTER, OPEN-LABEL STUDY OF THE 
IMMUNOGENICITY OF NUTROPIN AQ V1.1 [SOMATROPIN 
(rDNA ORIGIN) INJECTION] ADMINISTERED DAILY TO NAÏVE 
GROWTH HORMONE-DEFICIENT CHILDREN (iSTUDY) 
PROTOCOL NUMBER: 
ML29543 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
BB IND 39,305 
TEST PRODUCT: 
Nutropin AQ (Somatropin [rDNA origin] injection) (RO6823852) 
PHASE: 
IV 
INDICATION: 
Somatropin-naïve prepubertal growth hormone-deficient children 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
The primary objective for this study is to characterize the immunogenicity profile of 
Nutropin AQ v1.1 when administered as a daily subcutaneous (SC) injection for 12 months 
(per the U.S. Prescribing Information [USPI] for Nutropin AQ). 
The clinical impact of immunogenicity will also be assessed during the course of the study by 
evaluating patients for functional growth attenuation in association with the development of 
anti-growth hormone (GH) antibodies.  
Study Design 
Description of Study 
This is a Phase IV, multicenter, open-label, single-arm study of somatropin (rDNA origin) 
(Nutropin AQ v1.1) in naïve prepubertal children with growth hormone deficiency (GHD).   
Approximately 80 patients will be enrolled at approximately 30 sites in the U.S. and will be 
treated with daily SC injections of Nutropin AQ v1.1 at a dose of up to 0.043 mg/kg/day (0.3 
mg/kg/week, which is the approved and indicated dosage for pediatric GHD; refer to the USPI 
for Nutropin AQ) for 12 months.  Dose adjustments may be made at the Month 6 visit for 
changes in weight and insulin growth factor-1 (IGF-1) levels, if measured. 
Screening will be performed within 28 days prior to Day 1 unless otherwise specified, after 
which eligible patients will initiate study treatment.  Patients who do not meet eligibility criteria 
may be re-screened once for this study.  If during screening a subject is found to have an 
abnormal CBC, this test may be repeated within the same screening period at the discretion of 
the investigator and the subject may be enrolled if the second result is found to be normal per 
investigator assessment. 
Historical laboratory and radiographic tests will be reviewed prior to obtaining informed consent 
and initiation of study drug.  Study assessments will be scheduled at 3-month intervals following 
the baseline visit with an additional visit for the Month 1 blood draw, which can be conducted at 
home with the help of a home health nurse.  Study assessments will include physical 
examinations, height and weight measurements, assessment of pubertal status, and collection 
of serum samples for study-specific laboratory assessments (serum drug concentration and 
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immunogenicity assessments).  Patients will otherwise be treated and followed as determined 
by their health care provider.  
Patients who complete the Month 12 visit will be considered to have completed the study. 
Patients will be contacted by phone 28 (± 3) days after the Month 12 visit to collect adverse 
events.  
Patients who discontinue from the study early will be asked to return to the clinic within 
28 (± 3) days after the last dose of study drug for an early discontinuation visit, which will 
include the collection of serum samples for serum drug concentration and immunogenicity 
assessments. 
Growth response will be monitored throughout the study.  The annualized 6- and 12-month 
growth velocities for prepubertal patients will be analyzed.  Growth velocities of patients who 
enter puberty during the study will not be included in the 6- and 12-month velocity analyses.  
However, these patients will remain in the study and their antibody data will be assessed.   
Safety assessments will consist of monitoring and recording of all serious and non-serious 
adverse events as outlined in Section 5.2. 
Please see Appendix 1 for the schedule of assessments performed during the study. 
Number of Patients 
Approximately 80 patients will be enrolled at approximately 30 sites in the study in the U.S. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent/Assent Form 
– The parent(s)/guardian(s) must be willing to give written informed consent; and 
– The child may be required to give written informed assent (if able, and dependent on 
state/Institutional Review Board requirements). 
• 
Willing to adhere to the visit schedules and meet study requirements 
– For patients below the legal age of consent, both child and parent must be able to 
adhere to dose and visit schedules and meet study requirements.   
• 
Ability to comply with study assessments for the full duration of the study (1 year)  
• 
Male or female age ≥ 3 years and <  14 years.  The patient may be 14 years old exactly on 
the day of the first dose of study treatment. 
• 
Bone age ≤ 9 years (females) or ≤ 11 years (males) as determined by X-ray of the left hand 
and wrist using Greulich and Pyle method and obtained within the 12 months prior to 
enrollment 
• 
Prepubertal (Tanner I) males and females by physical exam 
• 
Diagnosis of GHD (stimulated GH < 10 ng/mL) by two standard pharmacologic tests 
obtained up to 12 months prior to informed consent/assent  
– Acceptable GH stimulation tests include:  insulin tolerance test (considered two tests if 
done sequentially with arginine); arginine stimulation test (considered two tests if done 
sequentially with insulin); glucagon stimulation test; clonidine stimulation test; L-dopa 
stimulation test; L-dopa + inderal stimulation test (considered one test if done together). 
• 
Normal thyroid function test within the 12 months prior to informed consent/assent 
• 
Normal CBC within the 12 months prior to informed consent/assent 
• 
Documentation of prior height and weight measurements, with height standard deviation 
score (SDS) ≤ −1.5 (≤ 5th percentile) for idiopathic isolated GHD patients 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any previous rhGH treatment 
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• 
Short stature etiologies other than GHD (e.g., untreated hypothyroidism, short stature 
associated with GH encoding gene mutations, chromosomal defect associated with short 
stature) 
– Patients with multiple pituitary hormone deficiencies (secondary/tertiary hypothyroidism, 
central adrenal insufficiency, diabetes insipidus) not associated with an intracranial 
tumor or central nervous system irradiation must be controlled on replacement 
medications for ≥ 6 months prior to study entry.  Hormonal treatments, such as 
androgens and estrogens to initiate puberty, are not permitted during the study. 
• 
Acute critical illness or uncontrolled chronic illness, which in the opinion of the investigator 
and Medical Monitor, would interfere with participation in this study, interpretation of the 
data, or pose a risk to patient safety 
• 
Chronic illnesses such as inflammatory bowel disease, celiac disease, heart disease, and 
diabetes 
• 
Bone diseases such as achondroplasia or hypochondroplasia, intracranial tumor, irradiation, 
and traumatic brain injury 
• 
Patients receiving oral or inhaled chronic corticosteroid therapy (> 3 months) for other 
medical conditions other than central adrenal insufficiency 
• 
Patients who require higher (2 × or greater than maintenance) doses of corticosteroids for 
more than 5 days in the 6 months prior to enrollment in the study 
• 
Patients with active malignancy or any other condition that the investigator believes would 
pose a significant hazard to the patient if recombinant human growth hormone (rhGH) were 
initiated   
• 
Females with Turner syndrome (documented with a karyotype or short stature homeobox 
[SHOX] analysis at any time prior to informed consent/assent), regardless of their GH status 
• 
Prader-Willi syndrome regardless of GH status 
• 
Born small for gestational age regardless of GH status 
• 
Presence of scoliosis requiring monitoring 
• 
Previous participation in another clinical trial or investigation of GH, treatment for growth 
failure, or treatment with a biologic agent 
• 
Patients with closed epiphyses 
• 
Patients with a known hypersensitivity to somatropin, excipients, or diluent 
Length of Study/End of Study 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  LPLV 
is expected to occur approximately 12 months after the last patient is enrolled and receives the 
first Nutropin AQ v1.1 injection. 
Outcome Measures 
Primary Outcome Measure 
The primary outcome measure for this study is the occurrence of anti-GH antibodies in 
rhGH-naïve, prepubertal GHD children treated with Nutropin AQ v1.1. 
Secondary Outcome Measures 
The secondary outcome measures for this study are to assess: 
• 
The occurrence of functional growth impairment in association with positive antibody 
formation in patients treated with Nutropin AQ v1.1  
• 
This will be considered in any patient who demonstrates an initial growth response greater 
than pretreatment velocity after treatment with Nutropin AQ v1.1, but then slows to below 
pretreatment velocity in the ensuing 6- to 12-month period (or reaches ≤ 2 cm per year) 
• 
The difference between the annualized 6- and 12-month growth velocities for patients who 
were anti-GH antibody-positive at any post-baseline visit and those who were anti-GH 
antibody-negative at all visits (including baseline)  
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• 
The formation of neutralizing antibodies, and the association between the presence of 
neutralizing anti-GH antibodies and growth attenuation 
Safety Outcome Measures 
No specific safety assessments are planned for this study.  However, analysis of all safety 
events will be performed (see Section 6.4).  
Investigational Medicinal Product 
Test Product 
Nutropin AQ v1.1 will be supplied by the Sponsor as labeled study drug using the 
Nutropin AQ v1.1 NuSpin 10 device for the 1-year duration of this study.  For information on 
the formulation, packaging, and handling of Nutropin AQ v1.1, see the pharmacy manual and 
the USPI for Nutropin AQ. 
Nutropin AQ v1.1 will be provided to the patient and administered at a dose of up to 
0.043 mg/kg/day (0.3 mg/kg/week).  The dose may be adjusted at the Month 6 visit per 
investigator assessment for:  1) a change in body weight of at least ± 2 kg from baseline OR 
2) a change in IGF-1 level (if tested and the investigator deems a change in dose is clinically 
indicated).  The dose of Nutropin AQ v1.1 will be administered via SC injections by the patient 
or caregiver. 
Statistical Methods 
Outcomes Analysis 
Primary Endpoint 
The primary endpoint for this study is the proportion of patients who develop anti-GH antibodies 
after initiating treatment with Nutropin AQ v1.1.  
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
• 
Proportion of patients who exhibit growth attenuation (defined as initial growth response 
greater than pretreatment velocity followed by reduction in growth response to below the 
pretreatment velocity in the subsequent 6- to 12-month treatment period or reaching ≤ 2 cm 
per year) 
– Tables of growth attenuation status (with or without) and anti-GH antibody status 
(positive or negative) will be provided for each antibody assay at each visit.   
– Similar tables of growth attenuation status and anti-GH antibody status for those who 
had a positive antibody assay at any follow-up visit and those who remained negative 
throughout the study  
• 
Proportion of patients with neutralizing antibody among those who had positive anti-GH 
antibody  
– This analysis will be summarized by visit, as well as cumulatively, for patients who had 
detectible anti-GH antibody at any post-baseline visit, as well as those who remained 
negative throughout the study.   
• 
Annualized 6- and 12-month growth velocities and height SDS will be summarized 
separately for patients who were anti-GH antibody-positive at any post-baseline follow-up 
visit and those who were anti-GH antibody-negative at all visits (including baseline).  
Graphic displays of the individual patient growth patterns along with the longitudinal 
antibody profile over the course of the study will be prepared.  Patients who enter puberty 
during the study period will be included up to the last visit at which they were determined to 
be prepubertal. 
Additional analyses deemed appropriate for assessing immunogenicity will be described in the 
Statistical Analysis Plan.  
Safety Analysis 
Safety analyses will include all patients who received at least one dose of study drug.  
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Adverse events will be summarized by mapped term, appropriate thesaurus level, and toxicity 
grade.  Summaries (or listings, if appropriate), including investigator assessments of 
relationship to study drug, will also be produced for each of the following: 
• 
Serious adverse events 
• 
All events leading to the withdrawal of treatment 
• 
All events by severity 
• 
All events possibly indicative of hypersensitivity  
Determination of Sample Size   
A target enrollment of 80 patients was chosen to allow for a projected 10−15% dropout rate and 
exclusion of growth data for an estimated 10% of patients who might enter puberty during the 
study period and leave sufficient patient numbers to compare to previous studies of 
immunogenicity.  This target enrollment was based on enrollment in a previous study (L0368) 
which planned to enroll 60 patients for the assessment of growth rate and change in height SDS.  
An initial sample size was chosen to ensure that at least 50 patients would complete the study 
(L0368 FR 30SEP97; Sec 4.8.4). 
This study is expected to yield a minimum of 50 evaluable patients.  Given a sample size of 50, 
and an assumed 50% of patients developing anti-GH antibodies, the 95% confidence interval 
around this proportion will be (35.53%, 64.47%).  This interval was calculated using 
Clopper-Pearson methodology.  Fluctuations in the proportion of patients developing anti-GH 
antibodies and the increase of evaluable patients will result in more precise confidence intervals.  
The exact confidence intervals for the scenarios for sample size of 50 and 60 in combination 
with the proportion of patients who are anti-GH antibody positive of 50% and 20% are listed in 
the table below. 
 
N 
Proportion of Patients 
Who Are Anti-GH 
Antibody Positive 
95% Confidence 
Interval 
(Lower Limit) 
95% Confidence 
Interval 
(Upper Limit) 
50 
0.5 
0.3553 
0.6447 
60 
0.5 
0.3681 
0.6319 
50 
0.2 
0.1003 
0.3372 
60 
0.2 
0.1078 
0.3230 
 
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Appendix 2 
Schedule of Assessments 
Assessment 
Screening 
(Day −28 
to Day −1) 
Baseline 
(Day 1) a 
Month 1 
(± 3 days) 
Month 3 
(± 3 days) 
Month 6 
(± 3 days) 
Month 9 
(± 3 days) 
Month 12  
(± 3 days) b 
Safety 
Follow-Up 
(± 3 days) c 
Early 
Discontinuation d 
Informed consent/assent  
x e 
 
 
 
 
 
 
 
 
Medical history f 
x 
 
 
 
 
 
 
 
 
Eligibility criteria g 
x 
 
 
 
 
 
 
 
 
Demographic data h 
x 
 
 
 
 
 
 
 
 
Limited physical 
examination i 
x 
x 
 
x 
x 
x 
x 
 
x 
Concomitant 
medications j 
x 
x 
 
x 
x 
x 
x 
 
x 
Height and weight 
x 
x 
 
x 
x 
x 
x 
 
x 
Serum sample for serum 
drug concentration and 
immunogenicity 
assessments k 
 
x 
x 
x 
x 
x 
x l 
 
x l 
Optional tests m 
x 
 
 
 
x 
 
x 
 
 
NuSpin instruction/ 
training n 
 
x 
 
 
 
 
 
 
 
Nutropin AQ v1.1 
administration o 
 
x 
x 
x 
x 
x 
x 
 
 
Nutropin AQ v1.1 dose 
compliance p 
 
 
x 
x 
x 
x 
x 
 
x 
Adverse events q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
a All baseline assessments should be performed before the first dose of study drug. 
b The Month 12 visit will serve as the study completion visit.  All assessments should be performed after the last dose of study drug for that day.    
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c The patient will be contacted by phone 28 ± 3 days after the Month 12 visit to collect adverse events. 
d Patients who discontinue from the study early will be asked to return to the clinic within 28 days after the last dose of study drug. 
e Written informed consent/assent must be obtained and documented before any study-specific screening procedure is performed. 
f Includes clinically significant diseases, surgeries, prior height and weight measurements, and all prescription medications used by the patient in 
the 30 days prior to the screening visit. 
g Historical laboratory tests include two GH stimulation tests with GH response < 10 ng/mL (obtained up to 12 months prior to informed 
consent/assent; see Protocol Section 4.1.1 for acceptable tests); thyroid function testing (obtained within 12 months prior to informed 
consent/assent); complete blood counts (obtained within 12 months prior to informed consent/assent); and for females, karyotype or SHOX 
analysis to exclude the diagnosis of Turner syndrome (obtained any time prior to informed consent/assent).  Historical radiographic test includes 
bone age obtained within 12 months prior to enrollment.  If results are not available within 12 months timeframe, the tests that may be done as 
part of the screening process are CBC and X-ray for bone age. All other tests should be done as part of standard care. 
h Demographic data will include date of birth, sex, and self-reported race/ethnicity. 
i Limited physical examinations should be performed as per the standard of care guidelines for a child with GHD undergoing GH therapy.  
Pubertal status and confirmation of prepubertal status, presence of hip or knee pain, appearance of spine (i.e., appearance of significant 
scoliosis), and routine fundoscopic examination for absence of signs of intracranial pressure must be recorded.  New or worsened clinically 
significant abnormalities after baseline should be recorded as adverse events, if applicable. 
j Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements, medications to manage multiple pituitary-hormone deficits as well as other chronic medications) used by a patient from 7 days 
prior to screening to the study completion/early discontinuation visit. 
k A single blood sample will be collected at each visit during the treatment period for immunogenicity and drug concentrations.  Process each 
sample for serum and split into four separate tubes for serum drug concentration and immunogenicity assessments (anti-GH antibody screening 
assay, anti-GH neutralizing antibody assay, and anti-GH antibody binding capacity assay).  After baseline, blood samples for immunogenicity 
and serum drug concentration should be taken at least 12 hours after the last daily dose of Nutropin AQ v1.1 and prior to the next daily dose of 
Nutropin AQ v1.1.   
l The last blood sample at Month 12 must be drawn at least 12 hours after the last dose of Nutropin AQ v1.1.  In the event of early discontinuation, 
an early discontinuation visit should be scheduled within 28 days after the last dose of Nutropin AQ v1.1 and a blood sample will be collected for 
a final assessment of serum drug concentration and immunogenicity. 
m Optional tests include a serum sample to test CBC at screening (if results are not available within 12 months prior to screening) and serum 
samples for IGF-1, which can be drawn at the discretion of the investigator at Month 6 and 12.  All optional samples will be analyzed at the 
local laboratory.  Optional tests also include an X-ray to determine bone age eligibility at screening only if the results are not available 
within 12 months prior to the enrollment date. 
n Nutropin AQ v1.1 will be administered via daily SC injections by the patient or caregiver.  Instruction and training on Nutropin AQ v1.1 
administration with the NuSpin device will be provided by a trained study nurse coordinator. 
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o The first dose (Day 1, baseline visit) should occur after the patient receives dosing administration instruction in the clinic and after the initial blood 
sample is drawn.  Blood samples scheduled after baseline (Months 1, 3, 6, 9, and Month 12 or early discontinuation) should be taken at least 
12 hours after the last daily dose of Nutropin v1.1 and prior to the next daily dose.  
p Assess compliance with daily dosing at each visit after baseline.  Reinstruct patients and caregivers, as needed. 
q After initiation of study drug, all serious adverse events and non-serious adverse events, regardless of relationship to study drug, will be reported 
until 28 days after the last dose of study drug as provided in this study.  After this period, the investigator should report any serious adverse 
events that are believed to be related to study drug.  The Sponsor should be notified if the investigator becomes aware of any serious adverse 
event that occurs after the end of the adverse event reporting period (defined as 28 days after the last dose of study drug), if the event is 
believed to be related to prior study drug treatment. The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort 
should be made to follow all serious adverse events considered to be related to study drug until or trial-related procedures until a final outcome 
can be reported. 
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***    age = patient age (yr) variable 
***    ht  = patient height (cm) variable 
***  OUTPUT VARIABLES: 
***    htz = patient height SDS variable 
*** 
***  MACROS:        None 
***  INCLUDE CODE:  None 
***  FORMATS:       /NCGS/lib/formats.sct01 
***                  htzml, htzfl, htzmm, htzfm, htzms, and htzfs 
***  AUTHOR:        Ken Dana 
***  DATE WRITTEN:  10/2002 
***  CHANGES:       (None yet) 
********************************************************************; 
 
 %macro htz(sex=,age=,ht=,htz=) ; 
    * reset/initialize temp vars and output parameter, htz ; 
    xzzywwa =.; xzzywwl =.; xzzywwm =.; xzzywws =.; xzzywwi=.; 
    xzzywwa2=.; xzzywwl2=.; xzzywwm2=.; xzzywws2=.; 
    &htz=. ; 
    * check input parameters  based on CDC data table limits ; 
    if (&sex=1 or &sex=2) and &age>=0 and &ht>0 then do ; 
       * calc xzzywwa as age(months) in CDC table just <= macro input age ; 
       * (input parameter, age, is in years) ; 
       * CDC table age (row) index entries are: ; 
       *  half but not whole months, except the limits ; 
       *  0, 0.5, 1.5, 2.5, ...., 237.5, 238.5, 239.5, 240 ; 
       * if the age is not equivalent to a row age, ; 
       *  set xzzywwa to the index just less than age input ; 
       if 0<=&age*12<0.5 then xzzywwa=0 ; 
        else                  xzzywwa=floor(&age*12+0.5)-0.5 ; 
       if &age>=20       then xzzywwa=240 ; 
       * get l, m, and s data from CDC table via format lookups ; 
       *  for either male (sex=1) or female (sex=2) ; 
       if &sex=1 then xzzywwl=input(put(xzzywwa,htzml.),15.) ; 
       if &sex=2 then xzzywwl=input(put(xzzywwa,htzfl.),15.) ; 
       if &sex=1 then xzzywwm=input(put(xzzywwa,htzmm.),15.) ; 
       if &sex=2 then xzzywwm=input(put(xzzywwa,htzfm.),15.) ; 
       if &sex=1 then xzzywws=input(put(xzzywwa,htzms.),15.) ; 
       if &sex=2 then xzzywws=input(put(xzzywwa,htzfs.),15.) ; 
       * if age is not equivalent to an age in the table, interpolate l, m, and s ; 
       if &age*12^=xzzywwa & xzzywwa<240 then do ; 
          * set xzzywwa2 to age in row with age just greater than macro input age ; 
          if 0<=xzzywwa<0.5 then xzzywwa2=0.5 ; 
           else                  xzzywwa2=xzzywwa+1 ; 
          if xzzywwa2>240   then xzzywwa2=240 ; 
          * determine interpolation factor, xzzywwi, between xzzywwa & xzzywwa2 ; 
          xzzywwi=(&age*12-xzzywwa) / (xzzywwa2-xzzywwa) ; 
          * get l, m, and s from next row in table by xzzywwa2 ; 
          *  and interpolate l, m, and s with xzzywwi ; 
          if &sex=1 then xzzywwl2=input(put(xzzywwa2,htzml.),15.) ; 
          if &sex=2 then xzzywwl2=input(put(xzzywwa2,htzfl.),15.) ; 
          xzzywwl= xzzywwl + xzzywwi * (xzzywwl2-xzzywwl) ; 
          if &sex=1 then xzzywwm2=input(put(xzzywwa2,htzmm.),15.) ; 
          if &sex=2 then xzzywwm2=input(put(xzzywwa2,htzfm.),15.) ; 
          xzzywwm= xzzywwm + xzzywwi * (xzzywwm2-xzzywwm) ; 
          if &sex=1 then xzzywws2=input(put(xzzywwa2,htzms.),15.) ; 
          if &sex=2 then xzzywws2=input(put(xzzywwa2,htzfs.),15.) ; 
          xzzywws= xzzywws + xzzywwi * (xzzywws2-xzzywws) ; 
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          end ; 
       * calculate htz according to CDC formulas ; 
       if       xzzywws=0 then &htz=. ; * SAS log() is natural(e) log ; 
        else if xzzywwl=0 then &htz= log(&ht/xzzywwm)             /         xzzywws ; 
         else                  &htz=  (((&ht/xzzywwm)**xzzywwl)-1)/(xzzywwl*xzzywws) ; 
       end ; 
    * extreme limits on output paramter for multivariate input data problems ; 
    if .Z<&htz<-10 or &htz>4 then &htz=. ;   * Ken Attie set 2/1991 ; 
    * ensure temporary variables are not output/kept in the calling data step ; 
    drop xzzywwa  xzzywwl  xzzywwm  xzzywws  xzzywwi 
         xzzywwa2 xzzywwl2 xzzywwm2 xzzywws2 ; 
    %mend htz ; 
 
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