Conditions: Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis
Keywords: Denosumab Pediatric GIOP Glucocorticoid-induced Osteoporosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
To evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) Z-score as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in children 5 to 17 year of age with Glucocorticoid (GC)-induced osteoporosis (GiOP).

Detailed description:

Arms:
arm 1: SC Q6M placebo arm 2: 1 mg/kg BW (up to a maximum of 60 mg) SC Q6M

Interventions: intervention 1: Denosumab intervention 2: Placebo
Intervention descriptions: intervention 1: 1mg/kg BW (up to a maximum of 60 mg) SC Q6M intervention 2: SC Q6M placebo

Protocol document:
Prot_000.pdf: 
Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 1 of 94 
CONFIDENTIAL 
 
 
Title:  A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group 
Study to Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects 
With Glucocorticoid-induced Osteoporosis 
Amgen Protocol Number (Denosumab/Prolia) 20140444 
EudraCT number 2016-003083-39 
NCT number NCT03164928 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone:  1-805-447-1000 
Key Sponsor Contact(s): 
, MD 
Clinical Research Medical Director 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 
Email:  
 
Date: 
Amendment 1: 
17 August 2016 
14 February 2017 
Amendment 2 
25 May 2018 
Amendment 3 
20 April 2021 
Amendment 4 
10 July 2023 
 
This protocol was developed, reviewed, and approved in accordance with 
Amgen’s standard operating procedures.  This format and content of this protocol 
is aligned with Good Clinical Practice:  Consolidated Guidance (ICH E6). 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; for all other countries Amgen’s general number in the US (1-805-447-
1000).  


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 2 of 94 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 3 Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study to Evaluate the Safety and Efficacy of 
Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis, dated 
10 July 2023, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my sub investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
At the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 3 of 94 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Study to 
Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With 
Glucocorticoid-induced Osteoporosis 
Study Phase:  3 
Indication:  Glucocorticoid-induced Osteoporosis 
Primary Objective:  To evaluate the effect of denosumab on lumbar spine bone mineral density 
(BMD) Z-score as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in children 
5 to 17 years of age with Glucocorticoid (GC)-induced osteoporosis (GiOP). 
Secondary Objective(s):  To evaluate the effect of denosumab in children 5 to 17 years of age 
with GiOP with respect to: 
 
Change in lumbar spine BMD Z-score as assessed by DXA from baseline to 6, 18, 24, 
and 36 months 
 
Change in proximal femur BMD Z-score as assessed by DXA from baseline to 6, 12, 18, 
24, and 36 months 
 
Incidence of X-ray confirmed long-bone fractures and new and worsening vertebral 
fractures during 12, 24, and 36 months  
 
Incidence of improving vertebral fractures at 12, 24, and 36 months compared to 
baseline  
 
Incidence of new and worsening vertebral and nonvertebral fractures during 12, 24, 
and 36 months  
 
Change in Childhood Health Questionnaire – Parent Form-50 (CHQ-PF-50) Physical 
Summary Score at 12, 24, and 36 months 
 
Change in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months 
 
Change in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 
12, 24, and 36 months 
 
Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12, 24, and 36 months 
 
Change in growth velocity, determined by calculating age-adjusted Z-scores for height, 
weight, and body mass index (BMI), at 12, 24, and 36 months 
 
Serum concentration of denosumab at 1 and 10 days, and 6, 12, and 18 months 
(additional serum denosumab pharmacokinetics [PK] samples to be collected at day 30 
and month 3 in a PK/
substudy of up to 15 subjects) 
Hypotheses:  The hypothesis of this study is that the change from baseline in lumbar spine BMD 
Z-score following 12 months of denosumab treatment in children 5 to 17 years of age with GiOP 
will be greater than placebo. 
Primary Endpoint:  Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 
12 months 
Secondary Endpoint(s):   
 
Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 6, 18, 24, 
and 36 months 
 
Change from baseline in proximal femur BMD Z-score as assessed by DXA at 6, 12, 18, 
24, and 36 months 
 
Subject incidence of X-ray confirmed long-bone fractures and new and worsening 
vertebral fractures during 12, 24, and 36 months  
 
Subject incidence of improving vertebral fractures at 12, 24, and 36 months compared to 
baseline 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 4 of 94 
CONFIDENTIAL 
 
 
 
Subject incidence of new and worsening vertebral and nonvertebral fractures during 12, 
24, and 36 months 
 
Change from baseline in CHQ-PF-50 Physical Summary Score at 12, 24, and 36 months 
 
Change from baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 
36 months 
 
Change from baseline in CHAQ Disability Index Score at 12, 24, and 36 months 
 
Change from baseline WBFPRS at 12, 24, and 36 months 
 
Change from baseline in growth velocity, determined by calculating age-adjusted 
Z-scores for height, weight, and BMI, at 12, 24, and 36 months 
 
Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, 12, and 18 months 
Exploratory Endpoint(s):   
Study Design:  This is a phase 3 multicenter, randomized, double-blind, placebo-controlled, 
parallel group study in pediatric subjects, age 5 to 17 years, with GiOP.  Twenty-four subjects 
including at least 16 evaluable subjects for the primary analysis will be enrolled.  Subjects will be 
randomized in a 2:1 (active:placebo) allocation ratio to receive either denosumab 1 mg/kg body 
weight (BW) (up to a maximum of 60 mg) subcutaneous (SC) every 6 months (Q6M) or matching 
placebo SC Q6M.  Up to 15 subjects at selected sites will be given the opportunity to participate 
in a PK/
 substudy.  The study is comprised of 2 periods, a 24-month treatment period 
(including a 12-month placebo-controlled period and a 12-month open-label period) and a 12-
month off-treatment observation period.  At the end of the first 12 months of the placebo-
controlled treatment period, all subjects will receive open-label denosumab Q6M for 12 months.  
Upon completion of the 24-month treatment period, the 12-month observation period will begin.  
Daily supplements of calcium and vitamin D will be given to all subjects during the 24-month 
treatment period.  Daily supplements of calcium and vitamin D may also be given to subjects 
during the 12-month observation period, if deemed medically warranted by the investigator.  The 
planned length of participation in the study for an individual subject is approximately 3 years, 
which includes screening (up to 35 days), treatment phase (24 months), and off-treatment 
observation period (12 months).  The anticipated dropout rate is approximately 10 in the first 
year.   
Treatment Period 
The treatment period will last for 24 months including 12-month double-blind and 12-month 
open-label treatment.  During the first 12 months of the treatment period, subjects will receive 
either denosumab 1 mg/kg BW (up to a maximum of 60 mg) SC Q6M or matching placebo SC 
Q6M.  At the end of the first 12 months of the treatment period, all subjects will receive open-label 
denosumab Q6M for 12 months.  The last dose of study medication will be administered at 
month 18. 
Observation Period 
The observation period will start immediately after the 24-month treatment period and last 
12 months, during which study subjects will receive no investigational product.  Study subjects 
are to be followed up during the 12-month observation period according to the following 
guidelines: 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 5 of 94 
CONFIDENTIAL 
 
 
 
Subjects who are currently on systemic GC for the treatment of the underlying 
non-malignant condition(s) at the month 24 visit should discontinue investigational 
product and transition to another osteoporosis treatment per local standard of care, 
according to the medical judgment of the investigator, for an additional 12 months or until 
systemic GC treatment is discontinued (see Section 2.3.6) 
 
Subjects who are no longer on systemic GC for the treatment of the underlying 
non-malignant condition(s) at the month 24 visit should discontinue investigational 
product and be followed up for an additional 12 months off treatment; however, subjects 
who, during the 12-month observation period, resume systemic GC therapy, experience a 
worsening of their osteoporosis, or require osteoporosis therapy based on the medical 
judgment of the investigator may resume osteoporosis treatment per local standard of 
care at the discretion of the investigator 
Sample Size:  A total of 24 subjects will be randomized into the study (approximately 16 to 
denosumab and 8 to placebo). 
Summary of Subject Eligibility Criteria:   
Inclusion criteria will include the following: 
 
Subject’s legally acceptable representative has provided informed consent when the subject 
is legally too young to provide informed consent and the subject has provided assent based 
on local regulations and/or guidelines prior to any study-specific activities/procedures being 
initiated 
 
Male or female subjects, age 5 to 17 years, inclusive, at the time of informed consent. 
 
Clinical diagnosis of GiOP as defined by the following (and consistent with the International 
Society for Clinical Densitometry definition of osteoporosis in children and adolescents 
[Bishop et al, 2014])  
 
A confirmed diagnosis of non-malignant condition(s) requiring treatment with systemic 
GC (including, but not limited to, chronic rheumatologic, gastrointestinal, neurologic, 
respiratory, and/or nephrological conditions) 
o 
Subjects who are on systemic GC only as replacement therapy for adrenal 
insufficiency are not eligible for the study 
 
Treatment with systemic GC (intravenous or oral) of any duration for the underlying 
non-malignant condition(s) within the 12 months prior to screening 
o 
Prepubertal children should be expected to require significant GC use during the 
study, per investigator opinion  
 
Evidence of at least 1 vertebral compression fracture of Genant grade 1 or higher, as 
assessed by the central imaging vendor on lateral spine X-rays performed at screening or 
within 2 months prior to screening; or, in the absence of vertebral compression fractures, 
presence of both clinically significant fracture history (ie,  2 long-bone fractures by age 
10 years or  3 long-bone fractures at any age up to 17 years) and lumbar spine BMD 
Z-score  -2.0, as assessed by the central imaging vendor 
Exclusion criteria will include the following: 
 
Current hyperthyroidism (unless well controlled on stable antithyroid therapy) 
 
Current clinical hypothyroidism (unless well controlled on stable thyroid replacement therapy) 
 
History of hyperparathyroidism 
 
Current hypoparathyroidism 
 
Any causes of primary or secondary osteoporosis (other than GC use), or previous exposure 
to non-GC medications, which the investigator considers to have been a major factor 
contributing to the patient’s fracture(s) 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 6 of 94 
CONFIDENTIAL 
 
 
 
Current adrenal insufficiency as the sole indication for GC therapy 
 
Duchenne muscular dystrophy with symptomatic cardiac abnormality 
 
Current malabsorption (in children with serum albumin  lower limit of normal [LLN], 
malabsorption should be clinically ruled out by the investigator to confirm eligibility) 
 
Known intolerance to calcium or vitamin D supplements 
 
Active infection or history of infections, defined as follows: 
 
Any active infection for which systemic anti-infectives were used within 4 weeks prior to 
screening 
 
Serious infection, defined as requiring hospitalization or intravenous anti-infectives within 
8 weeks prior to screening 
 
Recurrent or chronic infection or other active infection that, in the opinion of the 
investigator, might compromise the safety of the subject 
 
History of malignancy 
 
History of any solid organ or bone marrow transplant 
 
Evidence of untreated oral cavities or oral infections 
 
Recent or planned invasive dental procedure 
 
Surgical tooth extraction which has not healed by screening 
 
Currently unhealed fracture or osteotomy, as defined by orthopedic opinion 
 
Osteotomy within 5 months prior to screening 
 
Spinal fusion surgery within 5 months prior to screening or not yet healed (per orthopedic 
surgeon) 
 
Rodding surgery within 5 months prior to screening or not yet healed (per orthopedic 
surgeon) 
 
Anticipated major skeletal surgery (eg, rodding surgery, spinal surgery) within the next 
12 months from day 1 
 
Planned orthopedic surgery that, in the opinion of the investigator, would require missing any 
dose of investigational product in year 1 or 2 or more doses thereafter 
 
History of rare hereditary problems of fructose intolerance 
 
History of long QT syndrome 
 
History of alcohol or drug abuse 
 
History or evidence of any other clinically significant disorder, condition, or disease that, in 
the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject 
safety or interfere with the study evaluation, procedures, or completion 
 
Serum albumin-corrected calcium  LLN or  10 above upper limit of normal (ULN) at 
screening 
 
Serum vitamin D  20 ng/mL at screening (rescreening for vitamin D level  20 ng/mL will be 
allowed, after adequate supplementation) 
 
Serum phosphorus  LLN at screening 
 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)  1.5 x ULN (or 
 5 x ULN in subjects with dystrophinopathies) at screening (see Section 4.1.2 for further 
details) 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 7 of 94 
CONFIDENTIAL 
 
 
In subjects with dystrophinopathies, AST or ALT elevation  5 x ULN may not be exclusionary 
if 
o 
It is associated with serum creatine phosphokinase (CPK) elevation 
AND 
o 
Serum total bilirubin, alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), 
and prothrombin time/international normalized ratio (PT/INR) are  ULN, and serum 
albumin is  LLN 
AND 
o 
There are no symptoms or signs of hepatic inflammation, such as nausea, vomiting, right 
upper quadrant pain or tenderness, jaundice, fever, with no other immediately apparent 
possible cause (eg, gastroenteritis or constipation) 
 
Serum total bilirubin  1.5 x ULN at screening (subjects with Gilbert syndrome are eligible) 
 
Positive blood screen for human immunodeficiency virus (HIV)-1 or -2 antibody 
 
Positive blood screen for hepatitis B surface antigen or hepatitis C antibody 
 
Estimated glomerular filtration rate  60 mL/min/1.73 m2 at screening (calculated by the 
bedside Schwartz equation) 
 
Less than 2 evaluable vertebrae by DXA evaluation in the region of interest L1-L4, as 
confirmed by the central imaging laboratory 
 
Prior treatment for bone disease with any of the following at any time: 
 
Denosumab 
 
Strontium 
 
Fluoride 
 
Recent Bisphosphonate (BP) treatment, according to the following guidelines: 
 
Zoledronic acid (ZA) within 6 months prior to screening (subjects are eligible if 6 months 
will have elapsed, since the previous ZA dose, by the time of first dose of investigational 
product) 
 
Oral BP or intravenous BP (other than ZA), if the first dose of investigational product 
would be before their next scheduled BP dose (subjects are eligible if at least 1 BP 
dosing interval will have elapsed at time of the first dose of investigational product) 
 
Administration of any of the following treatment within 3 months prior to screening: 
 
Growth hormone (unless on stable dose for at least 3 months prior to screening) 
 
Calcitonin 
 
Cathepsin K inhibitor 
 
Other bone active drugs including anti-convulsants (except gabapentin and 
benzodiazepines) and heparin 
 
Chronic systemic ketoconazole, androgens (except subjects who have received 
testosterone therapy for physiologic replacement in the setting of documented hormonal 
deficiency), cinacalcet, aluminum, lithium, protease inhibitors, gonadotropin releasing 
hormone agonists 
 
Initiation of any of the following biologic agents within 4 weeks prior to screening:   
 
Anti-alpha 4 integrin antibody (eg, natalizumab)  
 
Anti-CD4/CD8 T-cells (eg, alefacept) 
 
Anti-IL-12/IL-23 (eg, ustekinumab) 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 8 of 94 
CONFIDENTIAL 
 
 
 
CTLA4 inhibitor (eg, abatacept) 
 
IL1 receptor antagonist (eg, anakinra) 
 
IL6 inhibitor (eg, tocilizumab) 
 
Monoclonal antibody to CD20 (eg, rituximab) 
 
Tumor necrosis factor antagonist (eg, adalimumab, certolizumab, golimumab, etanercept, 
infliximab) 
 
Current treatment with  1 biologic agent for underlying inflammatory disease 
 
Currently pregnant or planning a pregnancy during the study and for an additional 5 months 
after the last dose of investigational product 
 
Currently breastfeeding or planning on breastfeeding during the study and for an additional 
5 months after the last dose of investigational product 
 
For sexually active girls: refusal to use highly effective methods of contraception and to 
continue this practice for 5 months after the last injection of investigational product 
 
Subject likely to not be available to complete all protocol-required study visits or procedures, 
and/or to comply with all required study procedures to the best of the subject and 
investigator’s knowledge 
 
Subject’s parent or legal representative has any kind of disorder that, in the opinion of the 
investigator, may compromise the ability to give written parental permission for informed 
consent 
 
Currently receiving treatment in another investigational device or drug study, or  30 days 
since ending treatment on another investigational device or drug study(ies).  Other 
investigational procedures while participating in this study are excluded   
For a full list of eligibility criteria, please refer to Section 4.1.1 and Section 4.1.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Subjects will be randomized to 
receive denosumab or placebo every 6 months in a 2:1 allocation ratio for the first 12 months.  At 
the end of the initial 12-month period, all subjects will receive open-label denosumab Q6M for a 
further 12 months.  All subjects will receive investigational product through month 18.  
Denosumab will be administered at a dose of 1 mg/kg BW (up to a maximum of 60 mg).   
Denosumab and placebo will be manufactured and packaged by Amgen Inc.  Denosumab will be 
presented as a 70 mg/mL solution containing 1.7 mL in a 3 mL vial.  Placebo will be presented as 
a solution identical in appearance to denosumab, without the active ingredient.  All subjects will 
receive a SC injection of investigational product every 6 months for 24 months (last injection to be 
administered at month 18).  All SC injections must be administered by authorized site personnel.  
The injection should not be administered in the same arm from which blood is drawn.  
Investigational product should be administered only after all other study visit procedures have 
been completed.  If a subject misses a scheduled dose of denosumab during a study visit, then 
he/she should return to the clinic to receive the missed dose within the visit window allowed for 
that particular visit.  The clinical monitor should be contacted for specific instructions if a subject 
cannot receive his/her dose within the allowed visit window. 
Procedures:  Key procedures for this study involve various imaging techniques.  Bone 
densitometry assessments of the lumbar spine and proximal femur performed by DXA, lateral 
radiographs of the thoracic and lumbar spine, anteroposterior (AP) radiographs of both knees (to 
calculate the metaphyseal index Z-score of each knee), and dental radiographs will be used to 
assess GiOP in this pediatric population.  Subjects will also undergo a visual inspection of the 
oral cavity to look for the presence of unerupted molars.   
Several instruments will be used to assess the subject’s health-related quality of life, physical 
functioning, and pain intensity:  the CHQ-PF-50, CHAQ, and the WBFPRS.   


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 9 of 94 
CONFIDENTIAL 
 
 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2).   
Statistical Considerations:   
Sample Size Considerations: 
The study will enroll 24 subjects.  Assuming that approximately 10 of subjects will not be 
evaluable at month 12 for the primary efficacy endpoint due to dropout, the analysis set for the 
primary efficacy endpoint will include approximately 20 subjects.   
Analyses: 
The primary analysis will be conducted at the time of the final analysis.  The final analysis for the 
study, including the analysis of the primary endpoint, will be performed when all enrolled subjects 
have had the opportunity to complete the 36-month follow-up. 
The primary efficacy endpoint will be the change from baseline in lumbar spine BMD Z-score at 
12 months and will be analyzed based on the primary DXA analysis set using an analysis of 
covariance (ANCOVA) model including treatment (denosumab vs placebo), baseline age (age at 
informed consent), and baseline BMD Z-score.  Missing baseline and postbaseline BMD Z-scores 
will not be imputed.  The superiority of denosumab compared to placebo for the primary efficacy 
endpoint will be estimated from the 12-month least-squares (LS) mean of the treatment difference 
(denosumab – placebo) and the corresponding 95 confidence interval.  
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version(s) 5: 20 March 2015   
 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 10 of 94 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
* In the event of rescreening, an additional 42 days will be allowed.


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 11 of 94 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AP 
Anteroposterior 
AST 
Aspartate aminotransferase 
BMD 
Bone mineral density 
BMI 
Body mass index 
BP 
Bisphosphonate 
BW 
Body weight 
CHAQ  
Childhood Health Assessment Questionnaire  
CHQ-PF-50 
Childhood Health Questionnaire – Parent Form-50 
CPK 
Creatine phosphokinase 
CPRD 
Clinical Practice Research Datalink 
CRF 
Case report form 
DILI 
Drug-induced liver injury  
DMC 
Data Monitoring Committee 
DXA 
Dual-energy X-ray absorptiometry 
EDC 
Electronic data capture 
Electronic Source Data 
(eSource)  
Source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a study 
End of Follow-up 
Defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study (end of trial) Defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit), 
following any additional parts in the study (eg, long-term follow-up), 
as applicable 
End of Study (primary 
completion) 
Defined as the date when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint(s), If there are multiple primary endpoint(s) this would be 
the date of last primary endpoint assessment. 
End of Study for 
Individual Subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Treatment 
Defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
eSAE 
electronic Serious Adverse Event 
Exposure-Response  
Analysis 
Mechanism-based modeling and simulation and statistical analyses 
based on individual PK exposure (eg, population pharmacokinetic 
modeling) and response, which may include biomarkers, 
pharmacodynamic effects, efficacy and safety endpoints 
FAS 
Full analysis set 
GC 
Glucocorticoid 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 12 of 94 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
GCP 
Good Clinical Practice 
Page 1 of 2 
Abbreviation or Term 
Definition/Explanation 
GGT 
Gamma-glutamyltransferase 
GiOP 
Glucocorticoid-induced osteoporosis 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy  
ICF 
Informed consent form 
ICH 
International Conference for Harmonisation 
IEC 
Independent ethics committee  
INR 
International normalized ratio 
IVR 
Interactive Voice Response – telecommunication technology that is 
linked to a central computer in real time as an interface to collect and 
process information.  
IWR 
Interactive Web Response – web-based technology that is linked to a 
central computer in real time as an interface to collect and process 
information.  
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
LLN 
Lower limit of normal 
LS 
Least-squares 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
Q3M 
Every 3 months  
Q6M  
Every 6 months 
RANK 
Receptor activator of nuclear factor kappa 
RANKL 
Receptor activator of nuclear factor kappa-B ligand  
SC 
Subcutaneous 
Source Data 
Information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies) (ICH 
Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
Study Day 1 
Defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
Total bilirubin 
UK 
United Kingdom 
ULN 
Upper limit of normal 
US 
United States 
WBFPRS 
Wong-Baker Faces Pain Rating Scale 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 13 of 94 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
ZA 
Zoledronic acid 
Page 2 of 2 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  10 July 2023 
Page 14 of 94 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ........................................................................... 10 
Study Glossary .............................................................................................................. 11 
1. 
OBJECTIVES ....................................................................................................... 19 
1.1 
Primary ..................................................................................................... 19 
1.2 
Secondary ................................................................................................. 19 
1.3 
Safety ........................................................................................................ 19 
1.4 
Exploratory ................................................................................................ 20 
2. 
BACKGROUND AND RATIONALE ...................................................................... 20 
2.1 
Disease ..................................................................................................... 20 
2.2 
Amgen Investigational Product Background .............................................. 21 
2.3 
Pediatric Risk Assessment ........................................................................ 21 
2.3.1 
Hypocalcemia ............................................................................ 22 
2.3.2 
Hypercalcemia in Pediatric Subjects Receiving 
Denosumab and After Discontinuation of Denosumab .............. 22 
2.3.3 
Osteopetrosis ............................................................................ 23 
2.3.4 
Tooth Eruption ........................................................................... 24 
2.3.5 
Serious Infections ...................................................................... 24 
2.3.6 
Multiple Vertebral Fractures Following Treatment 
Discontinuation .......................................................................... 25 
2.4 
Rationale ................................................................................................... 26 
2.5 
Clinical Hypotheses ................................................................................... 27 
3. 
EXPERIMENTAL PLAN ........................................................................................ 27 
3.1 
Study Design ............................................................................................. 27 
3.2 
Number of Sites ........................................................................................ 29 
3.3 
Number of Subjects ................................................................................... 29 
3.4 
Replacement of Subjects .......................................................................... 29 
3.5 
Estimated Study Duration .......................................................................... 29 
3.5.1 
Study Duration for Subjects ....................................................... 29 
3.5.2 
End of Study .............................................................................. 29 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 30 
4.1 
Inclusion and Exclusion Criteria ................................................................ 30 
4.1.1 
Inclusion Criteria ........................................................................ 30 
4.1.2 
Exclusion Criteria ...................................................................... 31 
5. 
SUBJECT ENROLLMENT .................................................................................... 34 
5.1 
Screening .................................................................................................. 35 
5.2 
Randomization .......................................................................................... 35 
5.3 
Site Personnel Access to Individual Treatment Assignments .................... 35 


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6. 
TREATMENT PROCEDURES .............................................................................. 35 
6.1 
Classification of Products .......................................................................... 36 
6.2 
Amgen Investigational Product .................................................................. 36 
6.2.1 
Dosage, Administration, and Schedule ...................................... 36 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 37 
6.3 
Non-Amgen Non-investigational Product(s) ............................................... 38 
6.3.1 
Non-Amgen Non-investigational Product:  Calcium ................... 39 
6.3.2 
Non-Amgen Non-investigational Product:  Vitamin D ................. 39 
6.3.3 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 39 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 40 
6.4.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies Due to Potential 
Hepatotoxicity............................................................................ 40 
6.4.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 42 
6.5 
Concomitant Therapy ................................................................................ 42 
6.6 
Product Complaints ................................................................................... 42 
6.7 
Excluded Treatments and/or Procedures During Study Period .................. 42 
6.8 
Contraceptive Requirements ..................................................................... 43 
6.8.1 
Female Subjects ........................................................................ 44 
6.8.2 
Male Subjects ............................................................................ 44 
6.8.3 
Unacceptable Methods of Birth Control for Female 
Subjects .................................................................................... 45 
7. 
STUDY PROCEDURES ....................................................................................... 45 
7.1 
Schedule of Assessments ......................................................................... 45 
7.2 
General Study Procedures ........................................................................ 49 
7.2.1 
Screening .................................................................................. 49 
7.2.2 
Rescreening .............................................................................. 50 
7.2.3 
Day 1 ......................................................................................... 51 
7.2.4 
Treatment Period ....................................................................... 52 
7.2.4.1 
Study Days 10 and 30 ............................................. 52 
7.2.4.2 
Study Months 3, 6, 12, 18, and 24 
(Month 24 is Also Considered the Start of 
the Observation Period) .......................................... 53 
7.2.5 
Observation Period (Months 30 and 36) .................................... 54 
7.3 
Study Procedures ...................................................................................... 55 
7.3.1 
Data Collection .......................................................................... 55 
7.3.2 
Medical History .......................................................................... 55 
7.3.3 
Medication History ..................................................................... 55 
7.3.4 
Concomitant Medications .......................................................... 55 


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7.3.5 
Laboratory Assessments ........................................................... 56 
7.3.6 
Physical Examination ................................................................ 56 
7.3.7 
Physical Measurements ............................................................ 56 
7.3.8 
Vital Signs ................................................................................. 57 
7.3.9 
Pregnancy Testing..................................................................... 57 
7.3.10 
Dual-energy X-Ray Absorptiometry (DXA) ................................. 57 
7.3.11 
Spine Radiographs .................................................................... 58 
7.3.12 
Radiographs for Assessment of Long-bone Fractures ............... 58 
7.3.13 
Knee Radiograph ...................................................................... 58 
7.3.14 
Dental Radiograms .................................................................... 58 
7.3.15 
Oral Visual Inspection ................................................................ 59 
7.3.16 
Patient-reported Outcomes (PROs) ........................................... 59 
7.3.17 
Pharmacokinetic (PK) Samples ................................................. 60 
7.4 
Antibody Testing Procedures .................................................................... 60 
7.5 
Optional Substudies .................................................................................. 61 
7.6 
Early Termination ...................................................................................... 61 
7.7 
Sample Storage and Destruction ............................................................... 61 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 62 
8.1 
Subjects’ Decision to Withdraw ................................................................. 62 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 63 
8.3 
Reasons for Removal From Study............................................................. 63 
8.3.1 
Reasons for Removal From Treatment ...................................... 63 
8.3.2 
Reasons for Removal From Study ............................................. 64 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 65 
9.1 
Definition of Safety Events ........................................................................ 65 
9.1.1 
Adverse Events ......................................................................... 65 
9.1.2 
Serious Adverse Events ............................................................ 65 
9.2 
Safety Event Reporting Procedures .......................................................... 66 
9.2.1 
Adverse Events ......................................................................... 66 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 66 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 67 
9.2.1.3 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 69 
9.2.1.4 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 69 
9.2.1.5 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 69 
9.3 
Pregnancy and Lactation Reporting .......................................................... 69 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 70 


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10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 70 
10.1.1 
Study Endpoints ........................................................................ 70 
10.1.1.1 
Primary Endpoint ..................................................... 70 
10.1.1.2 
Secondary Endpoint(s) ............................................ 70 
10.1.1.3 
Exploratory Endpoint(s) ........................................... 71 
10.1.1.4 
Safety Endpoints ..................................................... 71 
10.1.2 
Analysis Sets ............................................................................. 71 
10.1.2.1 
Full Analysis Set ...................................................... 71 
10.1.2.2 
Primary DXA Analysis Set ....................................... 71 
10.1.2.3 
DXA Analysis Set .................................................... 72 
10.1.2.4 
Vertebral Fracture Analysis Set ............................... 72 
10.1.2.5 
Nonvertebral Fracture Analysis Set ......................... 72 
10.1.2.6 
PRO Analysis Set .................................................... 72 
10.1.2.7 
Growth Velocity Analysis Set ................................... 72 
10.1.2.8 
Safety Analysis Sets................................................ 72 
10.1.2.9 
PK Analysis Set ....................................................... 73 
10.1.3 
Covariates and Subgroups ........................................................ 73 
10.1.3.1 
Covariates ............................................................... 73 
10.1.4 
Handling of Missing and Incomplete Data .................................. 73 
10.2 
Sample Size Considerations ..................................................................... 73 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 73 
10.4 
Planned Analyses ..................................................................................... 74 
10.4.1 
Interim Analyses ........................................................................ 74 
10.4.2 
Data Monitoring Committee (DMC) ............................................ 74 
10.4.3 
Primary Analysis ........................................................................ 74 
10.4.4 
Final Analysis ............................................................................ 74 
10.5 
Planned Methods of Analysis .................................................................... 75 
10.5.1 
General Considerations ............................................................. 75 
10.5.2 
Primary Efficacy Endpoint .......................................................... 75 
10.5.3 
Secondary Efficacy Endpoint(s) ................................................. 75 
10.5.3.1 
Other Change From Baseline in BMD 
Z-score by DXA ....................................................... 75 
10.5.3.2 
New and Worsening Vertebral Fractures, 
and Nonvertebral Fractures ..................................... 76 
10.5.3.3 
Improved Vertebral Fracture .................................... 76 
10.5.3.4 
Patient Reported Outcomes .................................... 76 
10.5.3.5 
Growth Velocity ....................................................... 76 
10.5.3.6 
Serum Denosumab Concentrations ......................... 76 
10.5.4 
Safety Endpoints ....................................................................... 76 
10.5.4.1 
Adverse Events ....................................................... 76 


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10.5.4.2 
Clinical Laboratory Measurements .......................... 77 
10.5.4.3 
Vital Signs ............................................................... 77 
10.5.4.4 
Antidenosumab Antibodies ...................................... 77 
11. 
REGULATORY OBLIGATIONS ............................................................................ 77 
11.1 
Informed Consent ...................................................................................... 77 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 78 
11.3 
Subject Confidentiality ............................................................................... 79 
11.4 
Investigator Signatory Obligations ............................................................. 79 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 80 
12.1 
Protocol Amendments and Study Termination .......................................... 80 
12.2 
Study Documentation and Archive ............................................................ 80 
12.3 
Study Monitoring and Data Collection ....................................................... 81 
12.4 
Investigator Responsibilities for Data Collection ........................................ 82 
12.5 
Language .................................................................................................. 82 
12.6 
Publication Policy ...................................................................................... 83 
12.7 
Compensation ........................................................................................... 83 
13. 
REFERENCES ..................................................................................................... 85 
14. 
APPENDICES ...................................................................................................... 87 
List of Tables 
Table 1.  List of Proscribed Therapy .............................................................................. 43 
Table 2.  Schedule of Assessments ............................................................................... 46 
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 88 
Appendix B.  Sample Electronic Serious Adverse Event Contingency Report 
Form ....................................................................................................... 90 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 93 


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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) 
Z-score as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in 
children 5 to 17 years of age with glucocorticoid (GC)-induced osteoporosis (GiOP). 
1.2 
Secondary 
To evaluate the effect of denosumab in children 5 to 17 years of age with GiOP with 
respect to: 
 
Change in lumbar spine BMD Z-score as assessed by DXA from baseline to 6, 18, 
24, and 36 months 
 
Change in proximal femur BMD Z-score as assessed by DXA from baseline to 6, 12, 
18, 24, and 36 months 
 
Incidence of X-ray confirmed long-bone fractures and new and worsening vertebral 
fractures during 12, 24, and 36 months  
 
Incidence of improving vertebral fractures at 12, 24, and 36 months compared to 
baseline  
 
Incidence of new and worsening vertebral and nonvertebral fractures during 12, 
24, and 36 months 
 
Change in Childhood Health Questionnaire – Parent Form-50 (CHQ-PF-50) Physical 
Summary Score at 12, 24, and 36 months 
 
Change in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months 
 
Change in Childhood Health Assessment Questionnaire (CHAQ) Disability Index 
Score at 12, 24, and 36 months 
 
Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12, 24, and 
36 months 
 
Change in growth velocity, determined by calculating age-adjusted Z-scores for 
height, weight, and body mass index (BMI), at 12, 24, and 36 months 
 
Serum concentration of denosumab at 1 and 10 days, and 6, 12, and 18 months 
(additional serum denosumab pharmacokinetics [PK] samples to be collected at 
day 30 and month 3 in a PK
 substudy of up to 
15 subjects) 
1.3 
Safety 
To evaluate the effect of denosumab in children 5 to 17 years of age with GiOP with 
respect to: 
 
Adverse events and serious adverse events 
 
Laboratory parameters 
 
Vital signs 
 
Antidenosumab antibodies 


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1.4 
Exploratory 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Glucocorticoid (GC)-induced osteoporosis (GiOP) is the most common condition of 
medication-induced bone loss in children (Ward et al, 2010).  Glucocorticoid -induced 
osteoporosis is the result of profound effects of GCs on bone cells, which include 
inhibition of osteoblastogenesis and promotion of osteoblast apoptosis, resulting in 
significant reductions in bone formation, as well as increase in osteoclast-mediated bone 
resorption (Leonard, 2007; Ward, 2005; Canalis et al, 2004; Bianchi, 2002; 
Weinstein et al, 1998).  Decreased BMD has been described in various pediatric 
disorders that require GCs, such as asthma, juvenile rheumatoid arthritis, inflammatory 
bowel disease, systemic lupus erythematosus, and organ transplantation 
(Burnham and Leonard, 2004; Daniels et al, 2003; Leonard and Zemel, 2002; 
Boot et al, 1997).  Some of the detrimental bone effects attributed to GCs may be 
caused by the underlying inflammatory disease being treated with GCs.  Inflammatory 
cytokines, such as tumor necrosis factor-, known to be increased in rheumatoid 
arthritis, systemic lupus erythematosus, and inflammatory bowel disease, suppress bone 
formation and promote bone resorption (Parfitt et al, 1996).  The GC-induced decrease 
in bone mass is associated with an increase in fracture risk.  A population-based study 
reported increased fracture risk (adjusted odds ratio: 1.32; 95 confidence interval:  
1.03, 1.69) in children who required  4 courses of glucocorticoids (van Staa et al, 2003). 
There are currently no widely accepted guidelines for or approaches to the treatment of 
osteoporosis in the pediatric population.  Bisphosphonates (BP) are not licensed for the 
treatment of osteoporosis in children, but they have been evaluated in exploratory 
clinical studies in the setting of childhood osteoporosis.  Most BP studies in pediatric 
GiOP have shown significant increases in either BMD Z-scores (Inoue et al, 2008; 
Acott et al, 2005) or lumbar spine BMD (Simm et al, 2011; Bianchi et al, 2000).  


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However, based on a 2010 Cochrane review, there is not sufficient evidence to support 
BP use as standard therapy for pediatric GiOP (Ward et al, 2010).  Thus, an unmet need 
remains in children with GiOP. 
2.2 
Amgen Investigational Product Background 
Denosumab is a fully human monoclonal antibody that binds with high affinity and 
specificity to and neutralizes the activity of the receptor activator of nuclear factor 
kappa- B ligand (RANKL), preventing activation of its receptor, RANK, on the surface of 
osteoclast precursors and osteoclasts.  Denosumab is currently indicated for the 
treatment of postmenopausal women with osteoporosis, treatment of men with 
osteoporosis, treatment of bone loss in men receiving androgen deprivation therapy for 
prostate cancer, and treatment of bone loss in women receiving aromatase inhibitor 
therapy for breast cancer. 
2.3 
Pediatric Risk Assessment 
This pediatric study involves greater than minimal risk, but presents the prospect of 
direct benefit to the subject.  Pediatric subjects treated with denosumab in this study are 
expected to have a risk profile comparable to that observed in adults.  Additional 
information on specific risks in this pediatric population is provided in Sections 2.3.1 
through 2.3.6.  The extensive denosumab clinical development program includes pivotal 
phase 3 studies in bone loss settings in adults, ie postmenopausal women with 
osteoporosis (Study 20030216) or low bone mass (Study 20040132); bone loss 
associated with androgen deprivation therapy for prostate cancer (Study 20040138) or 
aromatase inhibitor therapy for breast cancer (Study 20040135); men with osteoporosis 
(Study 20080098), and in adult subjects with GiOP (Study 20101217 [Saag et al, 2018]).  
There is an ongoing study in pediatric subjects with osteogenesis imperfecta 
(Study 20130173).  In addition, denosumab has been studied in adolescent subjects with 
giant cell tumor of bone at a dose of 120 mg every 4 weeks (Study 20062004). 
In clinical studies to date, there has been a comparable incidence of adverse events 
overall between the denosumab and placebo or active-comparator treatment groups and 
a low incidence of treatment-related adverse events, serious adverse events, 
withdrawals due to adverse events, and deaths.  Most adverse events have been mild to 
moderate in severity, transient, and considered unrelated to denosumab.  Adverse 
reactions to denosumab include hypocalcemia; hypersensitivity; skin infections, 
predominantly cellulitis, leading to hospitalization; osteonecrosis of the jaw; atypical 
femoral fracture; eczema (including dermatitis, allergic dermatitis, atopic dermatitis, and 


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contact dermatitis); cataracts in males with prostate cancer receiving androgen 
deprivation therapy; pain in the extremities; and musculoskeletal pain.  Multiple vertebral 
fractures and hypercalcemia may occur following discontinuation of denosumab 
treatment.  
In the bone loss setting, denosumab use is contraindicated in pregnancy, in patients with 
hypocalcemia, and in patients with hypersensitivity to the active substance or to any of 
the excipients.  
Volumes of blood withdrawn for analysis in association with clinical monitoring will be 
minimized as appropriate for this pediatric population based on body weight (BW) 
(European Union Ethical Considerations, 2008). 
2.3.1 
Hypocalcemia 
Skeletal turnover rates vary by age and are higher in children than adults.  These higher 
bone turnover rates expected at baseline in children may increase the risk for 
hypocalcemia and hypophosphatemia resulting from denosumab-mediated reduction of 
bone turnover.  In addition, recent clinical reports of denosumab administration in 
pediatric patients with disorders of high bone turnover (eg, fibrous dysplasia and juvenile 
Paget’s disease) have described disturbances in mineral metabolism, including 
hypocalcemia and hypophosphatemia (Grasemann et al, 2013; Boyce et al, 2012).  
To minimize such risk, the following strategies will be employed: 
 
Calcium and vitamin D supplementation will be given to all study subjects 
 
Serum calcium and phosphorus concentrations will be monitored throughout the 
study on a regular basis 
 
Subjects will not be eligible to participate if they have evidence of hypocalcemia; 
diseases that increase the risk of hypocalcemia, including, but not limited to, 
malabsorption and chronic kidney disease (as defined by an estimated glomerular 
filtration rate  60 mL/min/1.73 m2); or additional risk factors for detrimental effects of 
hypocalcemia, eg, a history of long QT syndrome 
 
Occurrence of severe or symptomatic hypocalcemia will prompt discontinuation of 
study medication and institution of appropriate medical treatment 
2.3.2 
Hypercalcemia in Pediatric Subjects Receiving Denosumab and 
After Discontinuation of Denosumab 
In the clinical trial and postmarketing setting, clinically significant cases of 
hypercalcemia requiring hospitalization have been observed in patients, including those 
with developing skeletons, at the end of every 3 months (Q3M) dosing period or in 
those who had previously received off-label denosumab.  These incidents of 


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hypercalcemia have presented with severe vomiting with or without acute renal failure, 
and have occurred in patients who had used denosumab at higher doses and/or 
frequencies than those being used by the patient population in this study.  In pediatric 
patients with osteogenesis imperfecta, severe life-threatening adverse events of 
hypercalcemia have been reported at or near the end of the denosumab 1 mg/kg 
Q3M dosing period (> 60 days from the previous dose) in Study 20130173.  In 
ongoing XGEVA Study 20062004 (in subjects with giant cell tumor of bone), a 19-year-
old subject developed clinically significant hypercalcemia approximately 8 months after 
the discontinuation of XGEVA dosing (denosumab 120 mg every 4 weeks).  Therefore, 
hypercalcemia, including off-treatment hypercalcemia, is a potential risk in this 
pediatric population receiving Prolia. 
2.3.3 
Osteopetrosis 
In children, osteoclast activity is necessary to remove the cartilaginous anlagen of bone.  
Genetic deficiency in RANKL leads to osteopetrosis, a disorder of poor bone quality, 
retained cartilage, frequent fractures, and a high bone mass typified by poorly modelled 
bones with widened, club-shaped metaphyses.  Significant reduction of this 
resorption-based modeling can lead to osteopetrosis-like changes with a similar 
abnormal geometry (Whyte et al, 2003).  In nonclinical studies of denosumab, the 
severity of phenotypic changes observed in the growth plate and bone was consistent 
with the rate of longitudinal growth in the bone, with limited and reversible effects in the 
adolescent monkey.  The most rapid increase in stature in humans occurs during the 
first 9 or 12 months of life, and head circumference continues to increase sharply over 
the first 2 years of life (Centers for Disease Control and Prevention, 2011).  Based on 
these data, the potential for significant alterations of skeletal growth and morphology is 
lower in children  5 years of age, who will be enrolled in this study.  The limited and 
reversible bone effects of denosumab in the adolescent monkey (the second most rapid 
growth phase), lack of negative biomechanical consequences seen in the infant mice, 
and the radiographic monitorability minimize the risk of denosumab administration in 
pediatric patients whose growth rates approximate that of adolescent monkeys. 
Strategies to assess changes to the skeleton include the following: 
 
Physical examination and radiographic assessments will be performed on a regular 
basis throughout the study to monitor for possible detrimental skeletal changes; such 
assessment will also include evaluation of metaphyseal index via knee X-ray to be 
performed every 6 months throughout the study in subjects with open growth plates 
only, as only in subjects with open growth plates does the potential risk exist of an 
abnormal rate of increase in metaphyseal width 


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 
Changes in growth plate morphology as observed in the 6 months monitoring 
considered by the investigator to be unexpected and having an adverse clinical 
impact for the subject during the study will prompt discontinuation of study 
medication and institution of appropriate follow-up 
2.3.4 
Tooth Eruption 
RANKL plays an important role in tooth eruption.  In non-clinical studies conducted in 
neonatal rats, osteoprotegerin-immunoglobulin Fc segment complex and alendronate 
administration impaired the eruption of second and third molars and also reduced incisor 
growth.  These findings were at least partially reversible within 10 weeks of discontinuing 
osteoprotegerin-immunoglobulin Fc segment complex.  In infant monkeys exposed in 
utero to denosumab, there was no effect on tooth eruption, although altered bone shape 
and jaw length led to tooth dysplasia and malalignment.  Such findings were not 
observed in adolescent cynomolgus monkeys.  These data suggest that the use of 
denosumab in the rapidly growing skeleton carries potential risk for impaired tooth 
eruption.  
To minimize this risk, molar eruption and mandibular shaping will be monitored using 
visual inspection and X-ray assessments. 
2.3.5 
Serious Infections 
RANKL is expressed on activated T and B lymphocytes and in lymph nodes.  Therefore, 
RANKL inhibition may theoretically increase the risk of infection.  In a clinical trial of over 
7800 women with postmenopausal osteoporosis, the overall incidence of infections, 
including opportunistic infections, was similar between the denosumab and placebo 
groups.  However, serious skin infections leading to hospitalization were reported more 
frequently in the denosumab group than in the placebo group.  Subjects on concomitant 
immunosuppressant agents, such as GCs, may be at increased risk of serious 
infections. 
While the completed clinical study of denosumab in adult GiOP 
(Study 20101217 [Saag et al, 2018]) has not shown an excess risk for serious infection 
associated with denosumab use, strategies have been implemented in this pediatric 
study to minimize the risk for serious infections and include the following: 
 
Subjects who have initiated a biologic agent for the treatment of underlying 
inflammatory disease 4 weeks prior to screening or are on  1 biologic agent for 
the treatment of underlying inflammatory disease will not be eligible for study 
participation 
 
Any subject who develops a serious opportunistic infection will permanently 
discontinue study medication 


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 
Any subject who develops a serious infection during the study and is receiving a 
biologic agent for the treatment of underlying inflammatory disease will permanently 
discontinue study medication 
2.3.6 
Multiple Vertebral Fractures Following Treatment Discontinuation 
Multiple vertebral fractures may occur following discontinuation of denosumab treatment, 
particularly in subjects with a history of vertebral fracture.  Among postmenopausal 
women with osteroporosis who discontinued denosumab during the placebo-controlled 
FREEDOM trial and its open-label active-treatment extension, the incidence of new 
vertebral fracture was higher than in subjects who remained on treatment, but similar to 
the incidence in subjects who discontinued placebo, ie, had never been treated.  Among 
subjects who experienced off-treatment new vertebral fractures, a greater percentage of 
those who discontinued denosumab than placebo sustained multiple new vertebral 
fractures.  Prior vertebral fracture before or during treatment was the strongest predictor 
of off-treatment new vertebral fracture, including multiple vertebral fractures. 
The current study includes a 12-month off-treatment observation period following the 
24-month treatment period.  The intent of the observational period was to evaluate 
clinical outcomes after investigational product discontinuation.  Discontinuation of 
osteoporosis treatment for subjects who continue to administer systemic GCs for the 
underlying non-malignant condition(s) at the end of the treatment period may be 
inconsistent with standard of care, particularly as subjects were required to have a 
clinically significant fracture history to participate.   
With the identified risk for multiple vertebral fractures after denosumab cessation in a 
setting where study subjects are at high risk for fracture, the mandated observation 
period will be managed as follows:  to minimize the risk of multiple vertebral fractures 
following treatment discontinuation, subjects who currently are administering systemic 
GC therapy for the underlying non-malignant condition(s) upon completing the 24-month 
treatment period should transition to osteoporosis treatment per local standard of care 
for an additional 12 months or until systemic GC treatment is discontinued.  Local 
standard of care for pediatric subjects with GiOP may include BP use.  It is recognized 
that BPs are not approved for the treatment of pediatric GiOP, and BP use is considered 
off-label in this setting.  However, BP therapy is often recommended in children with 
clinically significant fracture history and ongoing risk factors, eg, systemic GC therapy 
(Ward et al, 2016).  Therefore, the decision to use BP in these subjects will be left to the 
medical judgment of the investigator, and BP use would not be proscribed by the 
protocol in this situation. 


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2.4 
Rationale 
A non-clinical study in skeletally mature (8-month-old) human RANKL knock-in mice 
challenged with subcutaneous (SC) slow-release prednisolone pellets showed that 
denosumab treatment fully prevented the reductions in BMD and strength of lumbar 
vertebrae observed in vehicle-treated mice and was associated with significant 
reductions in bone resorption parameters.  These findings indicate that denosumab can 
prevent loss of bone mass and strength secondary to GC therapy. 
Clinical data currently available with denosumab that are relevant to GiOP include a 
subset of adult subjects with rheumatoid arthritis who were receiving GCs in the 
denosumab phase 2 Study 20040144, in which administration of denosumab 60 mg or 
180 mg every 6 months (Q6M) led to increased BMD at lumbar spine and total hip 
(Dore et al, 2010).  In addition, denosumab has been investigated in a clinical trial of 
adults with GiOP (Study 20101217 [Saag et al, 2018]). 
This study is part of a Pediatric Investigation Plan for denosumab (Prolia) that was 
agreed upon with the European Medicines Agency.  The purpose of this study is to 
evaluate the efficacy, safety, and PK of denosumab (1 mg/kg BW, up to a maximum of 
60 mg, administered SC Q6M) in pediatric subjects with GiOP.  The selection of the 
1 mg/kg BW Q6M dose is based on the following considerations: 
 
The pharmacodynamic effects of denosumab were similar in neonatal and 
adolescent animal models 
 
The pharmacodynamic effect of denosumab on inhibition of bone resorption in 
clinical studies in adult subjects is maintained over the 6-month dosing interval 
 
The PK profile of monoclonal antibodies, such as cetuximab 
(Erbitux prescribing information, 2012), bevacizumab (Glade Bender et al, 2008; 
Gordon et al, 2001), and infliximab (Fasanmade et al, 2011), is similar in pediatric 
and adult populations 
 
The PK of denosumab is not affected by age across all populations studied, with an 
age range of 28 to 87 years (Sutjandra et al, 2011) 
Based on these data, the PK and pharmacodynamics of denosumab are expected to be 
similar between the adult and pediatric populations, thus supporting selection of the 
1 mg/kg BW Q6M dose.  This dose is equivalent to the approved 60 mg adult dose for 
denosumab (assuming a 60 kg subject), which was also the dose investigated in the 
adult GiOP trial (Study 20101217 [Saag et al, 2018]).  In addition, denosumab PK will be 
assessed throughout the study to further characterize exposure/response relationship in 
the pediatric GiOP population. 


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A feasibility analysis of the study sites has shown difficulties in identifying appropriate 
per protocol patients that meet the diagnostic criteria of GiOP (International Society for 
Clinical Densitometry [ISCD], 2019; Bishop et al, 2014) with a specific inclusion criterion 
for evidence of at least 1 vertebral compression fracture of Genant grade 1 or higher, 
OR presence of both clinically significant fracture history and lumbar spine BMD Z-score 
 -2.0.  This inclusion criteria is the primary reason for a screen failure rate of 70 to 
75 in this study. 
In addition, trends in pediatric GiOP over time using real-world data from 3 different 
databases:  1) United States (US) MarketScan, 2) United Kingdom (UK) Clinical Practice 
Research Datalink (CPRD), and 3) Germany Electronic Medical Records (EMR) 
supported the findings in the feasibility analysis. 
Based on agreement with regulatory agencies, sample size for this study will be reduced 
to 24 subjects including at least 16 evaluable subjects for the primary analysis. 
This study will be conducted per local regulatory and ethics committee/investigation 
review board requirements/guidelines, and data from this study may be used to seek 
modification of regional denosumab prescribing information. 
2.5 
Clinical Hypotheses 
The hypothesis of this study is that the change from baseline in lumbar spine BMD 
Z-score following 12 months of denosumab treatment in children 5 to 17 years of age 
with GiOP will be greater than placebo. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
This is a phase 3 multicenter, randomized, double blind, placebo-controlled, parallel 
group study in pediatric subjects, age 5 to 17 years, with GiOP.  Twenty-four subjects 
will be enrolled with at least 16 evaluable subjects for the primary analysis.  Subjects will 
be randomized in a 2:1 (active:placebo) allocation ratio to receive either denosumab 
1 mg/kg BW (up to a maximum of 60 mg) SC Q6M or matching placebo SC Q6M.  Up to 
15 subjects at selected sites will be given the opportunity to participate in a PK
substudy.  The study is comprised of 2 periods, a 24-month treatment period (including a 
12-month placebo-controlled period and a 12-month open-label period) and a 12-month 
observation period.  At the end of the first 12 months of the placebo-controlled treatment 


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period, all subjects will receive open-label denosumab Q6M for 12 months.  Upon 
completion of the 24-month treatment period, the 12-month observation period will 
begin.  Daily supplements of calcium and vitamin D will be given to all subjects during 
the 24-month treatment period.  Daily supplements of calcium and vitamin D may also 
be given to subjects during the 12-month observation period, if deemed medically 
warranted by the investigator.  The planned length of participation in the study for an 
individual subject is approximately 3 years, which includes screening (up to 35 days), 
treatment phase (24 months), and off-treatment observation period (12 months).  The 
anticipated dropout rate is approximately 10 in the first year. 
Treatment Period  
The treatment period will last for 24 months, including 12-month double-blind and 
12-month open-label treatment.  During the first 12 months of the placebo-controlled 
treatment period, subjects will receive either denosumab 1 mg/kg BW (up to a maximum 
of 60 mg) SC Q6M or matching placebo SC Q6M.  At the end of the first 12 months of 
the treatment period, all subjects will receive open-label denosumab Q6M for 12 months.  
The last dose of study medication will be administered at month 18. 
Observation Period 
The observation period will start immediately after the 24-month treatment period and 
last 12 months, during which study subjects will receive no investigational product.  
Study subjects are to be followed up during the 12-month observation period according 
to the following guidelines: 
 
Subjects who are currently on systemic GC for the treatment of the underlying 
non-malignant condition(s) at the month 24 visit should discontinue investigational 
product and transition to another osteoporosis treatment per local standard of care, 
according to the medical judgment of the investigator, for an additional 12 months or 
until systemic GC treatment is discontinued (see Section 2.3.6) 
 
Subjects who are no longer on systemic GC for the treatment of the underlying 
non-malignant condition(s) at the month 24 visit should discontinue investigational 
product and be followed up for an additional 12 months off treatment; however, 
subjects who, during the 12-month observation period, resume systemic GC therapy, 
experience a worsening of their osteoporosis, or require osteoporosis therapy based 
on the medical judgment of the investigator may resume osteoporosis treatment per 
local standard of care at the discretion of the investigator 
The study endpoints are defined in Section 10.1.1. 


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3.2 
Number of Sites 
The study will be conducted in approximately 40 sites in North America, Europe, South 
America, Asia, and The Middle East.   
Sites that do not enroll subjects within 6 months of site initiation may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Twenty-four subjects will be enrolled with at least 16 evaluable subjects for the primary 
analysis.  Subjects will be randomized in a 2:1 (active:placebo) allocation ratio.  Up to 
15 enrolled subjects (at selected sites) will be given the opportunity to participate in a 
PK
substudy. 
Refer to Section 10.2 for additional information regarding the determination of the 
sample size. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The planned length of participation in the study for an individual subject is approximately 
3 years, which includes screening (up to 42 days), treatment phase (24 months), and 
off-treatment observation period (12 months).  The anticipated dropout rate is 
approximately 10 in the first year.  After signing the informed consent form (ICF), 
subjects should be randomized within 35 days. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), whether the study concluded as planned in the protocol or was 
terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for month 12.   
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 


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End of Study:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up), as applicable. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
(IVR)/Interactive Web Response (IWR) system. 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).  In addition to written informed consent from a 
legally acceptable representative, the assent of the child also must be obtained, as 
appropriate if requested by the institutional review board/independent ethics committee 
(IRB/IEC). 
If the subject reaches the age of consent during the duration of the study, once the 
subject reaches the age of maturation (usually 18 years), the previously acquired 
parental consent is no longer applicable and the participant’s consent must be obtained.  
Per International Conference for Harmonisation (ICH) E11 (R1), during clinical studies 
there is a requirement for obtaining adequate informed consent for continued 
participation from pediatric participants once a child reaches the age of legal consent.  
Local regulations related to confidentiality and privacy of pediatric participants must be 
followed. 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 
Subject’s legally acceptable representative has provided informed consent when 
the subject is legally too young to provide informed consent and the subject has 
provided assent based on local regulations and/or guidelines prior to any 
study-specific activities/procedures being initiated 
102 
Male or female subjects, age 5 to 17 years, inclusive, at the time of informed 
consent 
Clinical diagnosis of GiOP as defined by the following (and consistent with the 
International Society for Clinical Densitometry definition of osteoporosis in children and 
adolescents [Bishop et al, 2014]):  
103 
A confirmed diagnosis of non-malignant condition(s) requiring treatment with 
systemic GC (including, but not limited to, chronic rheumatologic, 
gastrointestinal, neurologic, respiratory, and/or nephrological conditions) 


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 
Subjects who are on systemic GC only as replacement therapy for 
adrenal insufficiency are not eligible for the study 
104 
Treatment with systemic GC (intravenous or oral) of any duration for the 
underlying non-malignant condition(s) within the 12 months prior to screening 
 
Prepubertal children should be expected to require significant GC use 
during the study, per investigator opinion 
105 
Evidence of at least 1 vertebral compression fracture of Genant grade 1 or 
higher, as assessed by the central imaging vendor on lateral spine X-rays 
performed at screening or within 2 months prior to screening; or, in the absence 
of vertebral compression fractures, presence of both clinically significant fracture 
history (ie,  2 long-bone fractures by age 10 years or  3 long-bone fractures at 
any age up to 17 years) and lumbar spine BMD Z-score  -2.0, as assessed by 
the central imaging vendor 
4.1.2 
Exclusion Criteria 
201 
Current hyperthyroidism (unless well controlled on stable antithyroid therapy) 
202 
Current clinical hypothyroidism (unless well controlled on stable thyroid 
replacement therapy) 
203 
History of hyperparathyroidism 
204 
Current hypoparathyroidism 
205 
Any causes of primary or secondary osteoporosis (other than GC use), or 
previous exposure to non-GC medications, which the investigator considers to 
have been a major factor contributing to the patient’s fracture(s) 
206 
Current adrenal insufficiency as the sole indication for GC therapy 
207 
Duchenne muscular dystrophy with symptomatic cardiac abnormality 
208 
Current malabsorption (in children with serum albumin  lower limit of normal 
[LLN], malabsorption should be clinically ruled out by the investigator to confirm 
eligibility) 
209 
Known intolerance to calcium or vitamin D supplements 
Active infection or history of infections, defined as follows: 
210 
Any active infection for which systemic anti-infectives were used within 4 weeks 
prior to screening 
211 
Serious infection, defined as requiring hospitalization or intravenous 
anti-infectives within 8 weeks prior to screening 
212 
Recurrent or chronic infections or other active infection that, in the opinion of the 
investigator, might compromise the safety of the subject 
213 
History of malignancy 
214 
History of any solid organ or bone marrow transplant 
215 
Evidence of untreated oral cavities or oral infections 
216 
Recent or planned invasive dental procedure 
217 
Surgical tooth extraction which has not healed by screening 
218 
Currently unhealed fracture or osteotomy, as defined by orthopedic opinion 


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219 
Osteotomy within 5 months prior to screening 
220 
Spinal fusion surgery within 5 months prior to screening or not yet healed (per 
orthopedic surgeon) 
221 
Rodding surgery within 5 months prior to screening or not yet healed (per 
orthopedic surgeon) 
222 
Anticipated major skeletal surgery (eg, rodding surgery, spinal surgery) within the 
next 12 months from day 1 
223 
Planned orthopedic surgery that, in the opinion of the investigator, would require 
missing any dose of investigational product in year 1 or 2 or more doses 
thereafter 
224 
History of rare hereditary problems of fructose intolerance 
225 
History of long QT syndrome 
226 
History of alcohol or drug abuse 
227 
History or evidence of any other clinically significant disorder, condition, or 
disease that, in the opinion of the investigator or Amgen physician, if consulted, 
would pose a risk to subject safety or interfere with the study evaluation, 
procedures, or completion 
228 
Serum albumin-corrected calcium  LLN or  10 above upper limit of normal 
(ULN) at screening 
229 
Serum vitamin D  20 ng/mL at screening (rescreening for vitamin D level 
 20 ng/mL will be allowed, after adequate supplementation) 
230 
Serum phosphorus  LLN at screening 
231 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
 1.5 x ULN (or  5 x ULN in subjects with dystrophinopathies) at screening 
In subjects with dystrophinopathies, AST or ALT elevation  5 x ULN may not be 
exclusionary if 
i. 
It is associated with serum creatine phosphokinase (CPK) elevation 
AND 
ii. 
Serum total bilirubin, alkaline phosphatase (ALP), 
gamma-glutamyltransferase (GGT), and prothrombin time/international 
normalized ratio (PT/INR) are  ULN, and serum albumin is  LLN 
AND 
iii. 
There are no symptoms or signs of hepatic inflammation, such as nausea, 
vomiting, right upper quadrant pain or tenderness, jaundice, fever, with no 
other immediately apparent possible cause (eg, gastroenteritis or 
constipation) 
232 
Serum total bilirubin  1.5 x ULN at screening (subjects with Gilbert syndrome 
are eligible) 
233 
Positive blood screen for human immunodeficiency virus (HIV)-1 or -2 antibody 
234 
Positive blood screen for hepatitis B surface antigen or hepatitis C antibody 


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235 
Estimated glomerular filtration rate  60 mL/min/1.73 m2 at screening (calculated 
by the bedside Schwartz equation) 
236 
Less than 2 evaluable vertebrae by DXA evaluation in the region of interest 
L1-L4, as confirmed by the central imaging laboratory 
Prior treatment for bone disease with any of the following at any time: 
237 
Denosumab 
238 
Strontium 
239 
Fluoride  
Recent BP treatment, according to the following guidelines: 
240 
Zoledronic acid (ZA) within 6 months prior to screening (subjects are eligible if 
6 months will have elapsed, since the previous ZA dose, by the time of first dose 
of investigational product) 
241 
Oral BP or intravenous BP (other than ZA), if the first dose of investigational 
product would be before their next scheduled BP dose (subjects are eligible if at 
least 1 BP dosing interval will have elapsed at time of the first dose of 
investigational product) 
Administration of any of the following treatment within 3 months prior to screening: 
242 
Growth hormone (unless on stable dose for at least 3 months prior to screening) 
243 
Calcitonin 
244 
Cathepsin K inhibitor 
245 
Other bone active drugs including anti-convulsants (except gabapentin and 
benzodiazepines) and heparin 
246 
Chronic systemic ketoconazole, androgens (except subjects who have received 
testosterone therapy for physiologic replacement in the setting of documented 
hormonal deficiency), cinacalcet, aluminum, lithium, protease inhibitors, 
gonadotropin releasing hormone agonists 
Initiation of any of the following biologic agents within 4 weeks prior to screening:   
247 
Anti-alpha 4 integrin antibody (eg, natalizumab)  
248 
Anti-CD4/CD8 T-cells (eg, alefacept) 
249 
Anti-IL-12/IL-23 (eg, ustekinumab) 
250 
CTLA4 inhibitor (eg, abatacept) 
251 
IL1 receptor antagonist (eg, anakinra) 
252 
IL6 inhibitor (eg, tocilizumab) 
253 
Monoclonal antibody to CD20 (eg, rituximab) 
254 
Tumor necrosis factor antagonist (eg, adalimumab, certolizumab, golimumab, 
etanercept, infliximab) 
255 
Current treatment with  1 biologic agent for underlying inflammatory disease 


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256 
Currently pregnant or planning a pregnancy during the study and for an 
additional 5 months after the last dose of investigational product 
257 
Currently breastfeeding or planning on breastfeeding during the study and for an 
additional 5 months after the last dose of investigational product 
258 
For sexually active girls:  refusal to use highly effective methods of contraception 
and to continue this practice for 5 months after the last injection of investigational 
product 
259 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
260 
Subject’s parent or legal representative has any kind of disorder that, in the 
opinion of the investigator, may compromise the ability to give written parental 
permission for informed consent 
261 
Currently receiving treatment in another investigational device or drug study, or 
 30 days since ending treatment on another investigational device or drug 
study(ies).  Other investigational procedures while participating in this study are 
excluded   
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written IRB/IEC approval of the protocol, ICF, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
legally acceptable representatives must personally sign and date the ICF, and subjects 
should sign the subject assent form as applicable by local law before commencement of 
study specific activities/procedures. 
A subject is considered enrolled when the investigator confirms that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as when the 
informed consent and subject assent forms are duly signed) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned by an IVRS/IWRS.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 


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5.1 
Screening 
After signing the informed consent, and assent if applicable, subjects will be screened in 
order to assess their eligibility for study participation.  The screening window is up to 
35 days.  If a subject has not met all eligibility criteria during or by the end of the 
screening window, the subject will be registered as a screen failure.  Subjects who 
screen fail may be eligible to rescreen per Section 7.2.2. 
5.2 
Randomization 
Subjects will be randomized in a 2:1 allocation ratio to receive either denosumab or 
placebo respectively, in a double-blind manner.  The randomization will be performed by 
IVR/IWR system.  The randomization date is to be documented in the subject’s medical 
record and on the enrollment CRF. 
5.3 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The investigator is strongly encouraged to contact the Amgen Clinical Manager before 
unblinding any subject’s treatment assignment, but must do so within 1 working day after 
the event. 
6. 
TREATMENT PROCEDURES 
Subjects will be randomized to receive denosumab or placebo every 6 months in a 
2:1 allocation ratio for the first 12 months.  At the end of the initial 12-month period, all 
subjects will receive open-label denosumab Q6M for 12 months.  Denosumab 
administered at a dose of 1 mg/kg BW (up to a maximum of 60 mg) and matching 
placebo are considered to be IPs in this study.  A manual containing detailed information 
regarding the storage, preparation, and administration of investigational product are 
provided separately in the Investigational Product Instruction Manual (IPIM). 
All subjects will receive a SC injection of investigational product Q6M for the first 
12 months.  At the end of the initial 12-month placebo-controlled period, all subjects will 
receive open-label denosumab Q6M for 12 months (last injection to be administered at 
month 18).  All SC injections must be administered by authorized site personnel.  The 
injection should not be administered in the same arm from which blood is drawn.  
Investigational product should be administered only after all other study visit procedures 
have been completed.  If a subject misses a scheduled dose of investigational product 
during a study visit, then he/she should return to the clinic to receive the missed dose 


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within the visit window allowed for that particular visit (see Section 7).  The clinical 
monitor should be contacted for specific instructions if a subject cannot receive his/her 
dose within the allowed visit window. 
The total volume of investigational product, start date/time, and box number of 
investigational product are to be recorded on each subject's CRF. 
Overdose with this product has not been reported.  The highest dose tested in clinical 
trials is 210 mg SC Q6M.  It is possible that an overdose may result in hypocalcemia.  
Hypocalcemia, if severe, should be managed by oral or parenteral calcium replacement, 
as clinically indicated. 
6.1 
Classification of Products 
The Amgen investigational product and/or placebo (except if required by local regulation) 
used in this study include:  denosumab, placebo.   
The non-Amgen non-investigational products used in this study include:  calcium, 
vitamin D.  
The IPIM, a document external to this protocol, contains detailed information regarding 
the storage, preparation, destruction, and administration of denosumab.  
6.2 
Amgen Investigational Product 
Denosumab and placebo will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  Denosumab will be 
presented as a 70 mg/mL solution containing 1.7 mL in a 3 mL vial.  Placebo will be 
presented as a solution identical in appearance to denosumab, without the active 
ingredient. 
6.2.1 
Dosage, Administration, and Schedule 
All subjects will receive a SC injection of investigational product Q6M for 24 months (last 
injection to be administered at month 18).  Each subject will receive a total of 
2 double-blind, randomized doses (either denosumab or placebo) over the first 
12 months (given at the day 1 and month 6 visits) and a total of 2 open-label denosumab 
doses over the following 12 months (given at the month 12 and month 18 visits).  All 
SC injections must be administered by authorized site personnel.  The injection should 
not be administered in the same arm from which blood is drawn.  Investigational product 
should be administered only after all other study visit procedures have been completed.  


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The total volume of investigational product, start date/time, and box number of 
investigational product are to be recorded on each subject's CRF.  
Overdose with this product has not been reported.  The highest dose tested in clinical 
trials is 210 mg SC Q6M.  It is possible that an overdose may result in hypocalcemia.  
Hypocalcemia, if severe, should be managed by oral or parenteral calcium replacement, 
as clinically indicated. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
There are no dose adjustments for the Amgen investigational product.  If a subject 
misses a scheduled dose of denosumab during a study visit, then he/she should return 
to the clinic to receive the missed dose within the visit window allowed for that particular 
visit (see Section 7).  The clinical monitor should be contacted for specific instructions if 
a subject cannot receive his/her dose within the allowed visit window. 
Administration of Amgen investigational product will be stopped for subjects in the 
following situations: 
1. Subject request   
2. Safety concern due to:   
a. Ineligibility determined 
b. Protocol deviation 
c. Noncompliance 
d. Requirement for alternative therapy 
e. Adverse event (but not limited to): 
 
Severe or symptomatic hypocalcemia 
- 
Subjects who are removed from treatment as a result of severe or 
symptomatic hypocalcemia should receive treatment according to 
local standard of care, at the discretion of the treating physician 
and should be closely followed up until resolution of the adverse 
event 
 
Osteonecrosis of the jaw 
 
Serious opportunistic infection 
3. Decision by sponsor (other than subject request or safety concern) 
4. Death 
5. Lost to follow-up 
6. Pregnancy 


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7. Other protocol-specified criteria:   
a.  4 new fractures in 6 months 
b.  2 new long-bone fractures in 6 months 
c. Decline in lumbar spine BMD Z-score by 0.5 units or more in 6 months  
 
Subjects who are removed from treatment as a result of criterion a, b, 
or c (above) should be followed up and treated, if applicable, 
according to local standard of care, at the discretion of the treating 
physician 
d. Changes in growth plate morphology, as observed in the 6-month 
monitoring, considered by the investigator to be unexpected and having 
an adverse clinical impact for the subject 
e. Disease flare requiring treatment not allowed in the protocol 
f. Dental abnormalities requiring invasive dental procedures 
g. Serious infection, if the subject is receiving a biologic agent for the 
treatment of underlying inflammatory disease 
 
Serious infection is defined as a serious adverse event of infection 
that is complicated by multiple organ involvement or sepsis 
 
Sepsis is defined by the presence of infection and a severe 
systemic inflammatory response 
If a subject discontinues Amgen investigational product, the investigator is to discuss 
with the subject the appropriate processes for discontinuation and the options for 
continuation of the Schedule of Assessments and collection of data, including endpoints 
and adverse events, as applicable.  The investigator must document the change to the 
Schedule of Assessments and the level of follow up that is agreed to by the subject 
(eg, in person, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, from review of the medical 
records). 
6.3 
Non-Amgen Non-investigational Product(s)  
Non-Amgen non-investigational product(s) including calcium and vitamin D supplements 
will also be used in this study.  These therapies are commercially available and are not 
provided by Amgen (except if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these protocol-required therapies and will be 
reimbursed. 
The dose, start date, stop date, and frequency for calcium and vitamin D are to be 
recorded on each subject’s CRF.  At screening, the investigator or designee will instruct 
subjects on daily calcium and vitamin D supplementation. 


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Additional details regarding the product(s) are provided in the IPIM. 
The below clarifies use of the activated form of 1-25 OH vitamin D (Calcitriol): 
Calcitriol is allowed for use when in cases where medically indicated and no other 
exclusionary medical history is present.  Recommended doses in the pediatric 
population are: 
 
Children under 1 year:  0.04-0.08 mcg/kg orally once/day. 
 
Children 1-5 years:  0.25-0.75 mcg orally once/day. 
 
Children over 6 years:  0.5-2 mcg orally once/day. 
Calcitriol may not be used as an adjuvant treatment for osteoporosis and rationale for 
use must be documented in the CRF. 
6.3.1 
Non-Amgen Non-investigational Product:  Calcium  
All subjects are required to take daily supplements of 30 to 50 mg/kg BW and not to 
exceed 1000 mg elemental calcium during the 24-month treatment phase of the study.  
6.3.2 
Non-Amgen Non-investigational Product:  Vitamin D  
All subjects are required to take daily supplements of at least 800 IU vitamin D during 
the 24-month treatment phase of the study.  
6.3.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
If a subject becomes hypercalcemic over the course of the study, the calcium and/or 
vitamin D supplementation may be discontinued until the serum calcium concentration 
has returned to the normal range.  If a subject becomes hypocalcemic over the course of 
the study, the calcium and/or vitamin D supplementation may be increased, per medical 
judgment of the investigator. 
In instances where a subject is experiencing tolerability issues with daily elemental 
calcium, the subject should be instructed to try different calcium salt formulations.  If this 
strategy fails, the investigator may document that only a lower calcium supplementation 
dose is tolerated by the subject or that dietary supplementation is required and this will 
be allowed.  Tolerability issues for vitamin D should be managed using the same 
approach as outlined for calcium above. 
The reason for dose change of calcium and/or vitamin D supplementation is to be 
recorded on each subject’s CRF. 


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6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, ALT, TBL) and/or INR 
and/or signs/symptoms of hepatitis (as described below) may meet the criteria for 
withholding or permanent discontinuation of Amgen investigational product or other 
protocol-required therapies as specified in the Guidance for Industry Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation, July 2009. 
6.4.1 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due 
to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified. 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, Herpes 
Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
 
Right-sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia. 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic Fatty Liver Disease including Steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
Amgen investigational product and other protocol-required therapies, as appropriate, 
should be withheld pending investigation into alternative causes of Drug Induced Liver 
Injury (DILI).  If investigational product(s) is/are withheld, the subject is to be followed for 
possible DILI.  Rechallenge may be considered if an alternative cause for impaired liver 
tests (ALT, AST, ALP) and/or elevated TBL, is discovered and the laboratory 
abnormalities resolve to normal or baseline. 


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Permanent discontinuation of investigational product is recommended if all of the 
following apply: 
 
TBL  2 x ULN or INR  1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below:   
Baseline AST or ALT value 
AST or ALT elevation 
 ULN 
 3 x ULN 
 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent (eg, hepatobiliary tract disease, viral hepatitis, right-sided heart 
failure, hypotension or any cause of hypoxia to the liver causing ischemia, etc) 
Conditional withholding of investigational medicinal product or other protocol-required 
therapies is recommended if all of the following apply: 
 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation 
Any 
 8 x ULN at any time 
Any 
 5 x ULN but  8 x ULN for  2 weeks 
Any 
 5 x ULN but  8 x ULN and unable to adhere to 
enhanced monitoring schedule 
Any 
 3 x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, and jaundice). 
 
OR:  TBL  3 x ULN at any time 
 
OR:  ALP  8 x ULN at any time 
In subjects with dystrophinopathies, given the well-known occurrence of serum 
transaminase elevation of muscular origin (McMillan et al, 2011), conditional withholding 
of investigational medicinal product or other protocol-required therapies is recommended 
if the above elevations in AST or ALT are: 
 
Not accompanied by corresponding CPK elevations 
OR 
 
Accompanied by concomitant TBL, ALP, GGT, or PT/INR elevation and/or symptoms 
or signs of hepatic inflammation, such as nausea, vomiting, right upper quadrant pain 
or tenderness, jaundice, or fever, with no other immediately apparent possible cause 
(eg, gastroenteritis or constipation) 


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6.4.2 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, the subject’s legally acceptable representative, investigator, 
and Amgen. 
If signs or symptoms recur with rechallenge, then denosumab should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 6.4.1) should never be rechallenged. 
6.5 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.7. 
Concomitant therapies are to be collected from informed consent through the end of 
study.  Collect therapy name, indication, dose, unit, frequency, route, start date, and stop 
date. 
6.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s) or device(s) provisioned and/or repackaged/modified 
by Amgen.  Drug(s) or device(s) includes investigational product. 
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.7 
Excluded Treatments and/or Procedures During Study Period 
All medications listed in the exclusion criteria, those shown in Table 1 below, or any 
other medication that is known or suspected to have activity on bone metabolism (except 
for GCs, calcium, and vitamin D) will not be allowed during the study. 


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Table 1.  List of Proscribed Therapy 
 
Aluminum 
 
Anabolic steroids 
 
Androgensa 
 
Anticonvulsants 
(gabapentin and 
benzodiazepines are 
allowed) 
 
Any investigational 
agents for bone loss 
other than 
investigational 
product 
 
Aromatase inhibitors 
 
 1 biologic agent for 
the treatment of 
underlying 
inflammatory disease  
 
Bisphosphonates 
(a cumulative dose of 
 30 days)b 
 
Calcitonin 
 
Calcium chelators 
 
Chemotherapeutics 
(except for 
methotrexate, 
azathioprine, 
6-mercaptopurine, 
thioguanine, 
leflunomide, and 
cyclosporine) 
 
Chronic heparin use 
( 7 days) 
 
Cinacalcet 
 
Citrated products 
 
Fluoride 
 
Gonadotropin-releasing 
hormone agonists 
 
Growth hormone 
(unless stable for at 
least 3 months prior to 
screening) 
 
Lithium 
 
Parathyroid 
hormone (or a 
derivative) 
 
Progestins, when 
used as 
monotherapy 
 
Protease inhibitors 
 
Strontium 
 
Tibolone 
Footnote is defined on next page 
a Except subjects who are receiving testosterone therapy for physiologic replacement in the setting of 
documented hormonal deficiency 
b Bisphosphonates are not proscribed medications if prescribed per local standard of care, according to the 
medical judgement of the investigator, after investigational product discontinuation during the, 1) 24-month 
treatment period (see Section 6.2.2) or, 2) 12-month observation period (see Sections 2.3.6 and 3.1) 
6.8 
Contraceptive Requirements 
Female of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females are considered of childbearing potential if they have had menarche or are 
Tanner stage 2 or higher.  Female subjects who have had menarche or are Tanner 
stage 2 or higher will need to have pregnancy testing. 
Females in the following categories are not considered of child bearing potential: 
1. Premenopausal female with 1 of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 


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Note:  Site personnel documentation from the following sources is 
acceptable:  1) review of subject medical records, 2) subject medical 
examination, or 3) subject medical history interview. 
2. Premenarchal female (unless of Tanner Stage 2 or higher) 
3. Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle-stimulating hormone level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single 
follicle-stimulating hormone measurement is insufficient. 
b. Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
6.8.1 
Female Subjects  
Female subjects of childbearing potential must agree to use 1 highly effective method of 
contraception (as described in the table below) during treatment and for an additional 
5 months after the last dose of protocol-required therapies.   
Highly Effective Contraceptive Methods for Female Subjects 
Failure rate of  1 per year when used consistently and correctly. 
 
Combined (estrogen and progestogen) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, or transdermal) 
 
Intrauterine device 
 
Intrauterine hormonal-releasing system 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female subject 
of childbearing potential and that the vasectomized partner has received medical assessment 
of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments.  The reliability of sexual abstinence must 
be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the subject.) 
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed.   
6.8.2 
Male Subjects 
Male subjects are not required to use birth control during exposure to denosumab. 


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6.8.3 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to fetus if they become pregnant during treatment and for 
5 months after the last dose of investigational product.   
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
Screening assessments and study procedures required for each visit are outlined in this 
section and the Schedule of Assessments (Table 2).  The informed consent, and assent 
if applicable, must be obtained prior to performing any screening or study procedures.  
All subjects randomized to denosumab will have samples assayed for binding and, if 
positive, neutralizing antibodies. 
 


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Table 2.  Schedule of Assessments 
 
Screening Period 
Treatment Period 
Observation Period 
Procedures 
Study Day -35a to -1 
Study Day 
Study Month 
1 
10 
30 
3 
6 
12 
18 
24 
30 
36/ETb 
 
 
 
3-day 
window 
 7-day window 
Informed consent and assent form (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
Medical and medication history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Tanner stage 
X 
 
 
 
 
Xc 
X 
Xc 
X 
Xc 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Arm span  
X 
 
 
 
 
 
X 
 
X 
 
X 
DXA (lumbar spine)d 
Xe 
 
 
 
 
X 
X 
X 
X 
 
X 
DXA (proximal femur)d,f 
 
Xe 
 
 
 
X 
X 
X 
X 
 
X 
X-ray (lateral thoracic, lumbar spine)d 
Xg 
 
 
 
 
 
X 
 
X 
 
X 
X-ray – AP kneesd,h,i 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Dental X-ray (cephalogram and panoramic 
radiograph)d 
 
X 
 
 
 
 
 
 
 
 
X 
Oral visual inspection 
 
 
 
 
 
 
X 
 
X 
 
 
Dental X-ray (molars)d,j 
 
 
 
 
 
 
X 
 
X 
 
 
Hematology 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
Serology for HIV, hepatitis B, and hepatitis C 
X 
 
 
 
 
 
 
 
 
 
 
Serum CPK, GGT, and PT/INRl,m 
X 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnote defined on last page of the table 


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Date:  10 July 2023 
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Table 2.  Schedule of Assessments 
 
Screening Period 
Treatment Period 
Observation Period 
Procedures 
Study Day -35a to -1 
Study Day 
Study Month 
1 
10 
30 
3 
6 
12 
18 
24 
30 
36/ETb 
 
 
 
3-day 
window 
 7-day window 
25(OH) vitamin D level 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine dipstick method)n 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
SC injection of investigational product 
(denosumab/placebo)o 
 
X 
 
 
 
X 
X 
X 
 
 
 
Dispensation of calcium and vitamin D 
 
X 
 
 
 
X 
X 
X 
 
 
 
Antidenosumab antibody assay 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK (serum denosumab) 
 
X 
X 
Xp 
Xp 
X 
X 
X 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
Serious adverse eventsq 
 
 
 
 
 
 
 
 
 
 
 
Product complaints 
 
 
 
 
 
 
 
 
 
 
 
Clinical fracture recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of:  
 
 
 
 
 
 
 
 
 
 
 
CHQ-PF-50 
 
X 
 
 
 
 
X 
 
X 
 
X 
CHAQ Disability Score 
 
X 
 
 
 
 
X 
 
X 
 
X 
Wong-Baker Faces Pain Scale 
 
X 
 
 
 
 
X 
 
X 
 
X 
Page 2 of 2 
Footnote defined on next page 


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Protocol Number:  20140444 
Date:  10 July 2023 
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ALT  Alanine aminotransferase; AP  Anteroposterior; AST  Aspartate aminotransferase;
 CPK  Creatine phosphokinase, DILI  Drug-induced liver injury; DXA  Dual-energy X-ray absorptiometry, CHAQ  Childhood Health Assessment 
Questionnaire, CHQ-PF-50  Childhood Health Questionnaire-Parent Form-50, ET  Early termination; GGT  gamma-glutamyltransferase, HIV  Human 
immunodeficiency virus; INR  International normalized ratio; PK  Pharmacokinetic, PT  Prothrombin time; Q6M  every 6 months; SC  Subcutaneous, 
 ULN  Upper limit of normal; WBFPRS  Wong-Baker Faces Pain Scale. 
a Day -42 for rescreening only 
b If the subject discontinues the study prior to the month 36 visit, a safety follow-up visit will occur within 30 days following the last protocol-required therapy 
c Tanner stage to be conducted at months 6, 18, and 30 only in female subjects to determine the need to perform a pregnancy urine dipstick test at these visits 
d All images/reports (as applicable) to be sent to the central imaging vendor 
e To be performed in duplicate at this visit only 
f May be performed at screening to facilitate subject scheduling 
g For subjects who have qualified based on long-bone fracture criteria, the baseline lateral spine radiograph may be obtained on day 1 instead 
h To be performed only in children with open growth plates who do not have bilateral hardware 
i Only the knee with the highest metaphyseal index Z-score on the day 1 bilateral knee X-ray should be X-rayed post day 1 
j To be performed based on oral visual inspection 
k On study day 30, blood collection may be performed by a qualified individual at the subject’s home, in lieu of a site visit, except for subjects participating in the 
PK/
substudy.  In addition, when blood collection is performed at the subject’s home, the investigator must ensure that concomitant medications and adverse 
events, if any, are appropriately recorded. 
l To be performed in subjects with dystrophinopathies only 
m PT/INR to be performed at screening only in subjects with dystrophinopathies who have AST or ALT  5 x ULN and at subsequent visits in any subjects for the 
purpose of DILI ascertainment, as applicable (see Section 6.4) 
n To be performed in female subjects who have had menarche or those who are Tanner stage 2 or higher 
o At month 12, all subjects will receive open-label denosumab Q6M for 12 months 
q After the protocol required reporting period or after end of study, serious adverse events will be reported to Amgen.  Please refer to Section 9.2.1.5 for 
additional details. 
 


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Refer to the applicable supplemental manuals (eg, laboratory, imaging) for detailed 
collection and handling procedures. 
7.2 
General Study Procedures  
All on-study visits and dosing should be scheduled from day 1.  It is important to perform 
study assessments and obtain samples at the time points outlined in the Schedule of 
Assessments (Table 2). 
When it is not possible to perform the study visit at the specified time point, the visit may 
be performed within the visit window noted in the Schedule of Assessments (Table 2).  If 
a study visit is missed, subsequent visits should resume on the original visit schedule.  
Missed assessments at prior visits should not be duplicated at subsequent visits. 
With the exception of screening or rescreening visits, all study procedures for a visit 
must be completed on the same day. 
It is the responsibility of the investigator to ensure that all procedures are performed 
according to the protocol. 
Details regarding each type of procedure are provided in Section 7.3. 
7.2.1 
Screening 
Screening and day 1 visit cannot occur on the same day.  The day 1 visit needs to occur 
within 35 days of the screening date (unless the subject is rescreened).   
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Table 2): 
 
Confirmation that the ICF and Assent form (if applicable) have been signed 
 
Demographic data including sex, date of birth, age, race, and ethnicity will be 
collected in order to study their possible association with subject safety and 
treatment effectiveness.  Additionally demographic data will be used to study the 
impact biomarker variability and PK of the protocol-required therapies. 
 
Registration in IVR/IWR system 
 
Medical and medication history 
 
Physical examination as per standard of care.   Physical examination findings should 
be recorded on the appropriate CRF (eg, medical history) 
 
Tanner stage 
 
Vital signs 
 
Height 
 
Weight 
 
Arm span 


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 
DXA (lumbar spine) (To be performed in duplicate at this visit only.  All 
images/reports [as applicable] to be sent to the central imaging vendor.)  
 
X-ray (lateral thoracic spine) (For subjects who have qualified based on long-bone 
fracture criteria, the baseline lateral spine radiograph may be obtained on day 1 
instead.  All images/reports [as applicable] to be sent to the central imaging vendor) 
 
Hematology 
 
Serum chemistry 
 
Serology for HIV, hepatitis B, and hepatitis C 
 
Serum CPK, GGT, and PT/INR (to be performed at screening only in subjects with 
dystrophinopathies who have AST or ALT  5 x ULN) 
 
25(OH) vitamin D level 
 
Pregnancy test (urine dipstick method) (to be performed in female subjects who have 
had menarche or those who are Tanner stage 2 or higher) 
 
Serious adverse events/fractures  
7.2.2 
Rescreening 
Rescreening will be allowed as follows.  A new ICF must be signed unless it has been 
 30 days since the previous ICF signature was obtained.  Subjects may be rescreened 
only once for each of the 2 conditions below (rescreening for serum 25 [OH] vitamin D 
and/or full rescreening for other reasons of screen failure).  Sites will be notified, near 
the end of enrollment for the study, when subjects can no longer be rescreened.  After 
this notification, subjects who do not qualify based on their initial tests will be screen 
failed. 
Rescreening for Serum 25(OH) Vitamin D 
For subjects with an initial screening serum 25(OH) vitamin D level  20 ng/mL, 
rescreening will be performed as follows:  
 
Enter the subject as a screen failure into the IVRS/IWRS and enter him/her as a 
rescreen.  Subjects not entered into IVRS/IWRS as a rescreen will not be eligible to 
participate in the study. 
 
A new 42-day screening window will commence at this time.  
 
The subject must be repleted for vitamin D, as confirmed by a serum vitamin D level 
 20 ng/mL obtained by the central laboratory prior to the day 1 visit, to meet subject 
eligibility requirements. 
Full Rescreening 
Full rescreening will be allowed for any subject who has previously failed screening if, in 
the opinion of the investigator, the reason for the initial screen failure has been resolved 
or is no longer applicable. 


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Full rescreening will be performed according to the following procedure: 
 
Reassess only the procedure(s) that did not meet screening standards initially in 
subjects who are rescreened within 84 days of screen failure 
 
Reassess all the screening procedures, except for radiologic procedures and 
serology for HIV, hepatitis B virus, and hepatitis C virus, in subjects who are 
rescreened  84 days, but  6 months, after screen failure 
 
Reassess all the screening procedures in subjects who are rescreened  6 months 
after screen failure 
 
Subjects must be enrolled within the new 42-day rescreening window  
 
A new ICF must be signed unless it has been  30 days since the previous ICF 
signature was obtained 
7.2.3 
Day 1 
At the completion of the screening period, when the subject has met all eligibility criteria, 
sites will need to complete the randomization call in the IVR/IWR system.  The initial 
dose of investigational product is to be administered within 3 days of confirming 
randomization.  The date that the initial procedures are performed postrandomization will 
be considered day 1.  All subsequent study visits will be scheduled based on the day 1 
date. 
 
Physical examination as per standard of care.   Physical examination findings should 
be recorded on the appropriate CRF (eg, medical history) 
 
Vital signs 
 
Height 
 
Weight 
 
DXA (proximal femur) (To be performed in duplicate at this visit only.  All 
images/reports [as applicable] to be sent to the central imaging vendor.)  (Note:  this 
may be done at screening in order to facilitate subject scheduling) 
 
X-ray (anterioposterior [AP] knees) (To be performed only in children with open 
growth plates who do not have bilateral hardware.  All images/reports [as applicable] 
to be sent to the central imaging vendor.) 
 
Dental X-ray (cephalogram and panoramic radiograph) (All images/reports [as 
applicable] to be sent to the central imaging vendor.) 
 
Hematology 
 
Serum chemistry 
 
Pregnancy test (urine dipstick method) (To be performed in female subjects who 
have had menarche or those who are Tanner stage 2 or higher.) 
 
Dispensation of calcium and vitamin D 
 
Antidenosumab antibody assay 
 
Concomitant medications 


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 
PK (serum denosumab) 
 
 
 
Adverse events 
 
Serious adverse events 
 
Product complaints 
 
Clinical fracture recording 
 
Administration of: 
 
CHQ-PF-50 
 
CHAQ Disability Score 
 
WBFPRS 
 
SC injection of investigational product (denosumab/placebo) 
7.2.4 
Treatment Period 
7.2.4.1 
Study Days 10 and 30 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 2).  These study visits will occur 
 3 days.  The following procedures and assessments will be completed at the times 
designated in the Schedule of Assessment (Table 2) and recorded on the CRF: 
 
Vital signs 
 
Serum chemistry (On study day 30, blood collection may be performed by a qualified 
individual at the subject’s home, in lieu of a site visit, except for subjects participating 
in the PK/
substudy.  In addition, when blood collection is performed at the 
subject’s home, the investigator must ensure that concomitant medications and 
adverse events, if any, are appropriately recorded.)  
 
Concomitant medications 
 
PK (serum denosumab) (Serum denosumab concentrations will be collected at 
day 30 only in a PK
substudy of up to 15 subjects [additional consent for the 
substudy must be obtained].) 
 
 
Antidenosumab antibody assay (days 1 and 30 only) 
 
Adverse events 
 
Serious adverse events 
 
Product complaints 
 
Clinical fracture recording 


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7.2.4.2 
Study Months 3, 6, 12, 18, and 24 (Month 24 is Also Considered the 
Start of the Observation Period) 
These study visits will occur  7 days.  The following procedures and assessments will 
be completed at the times designated in the Schedule of Assessment (Table 2) and 
recorded on the CRF: 
 
Physical examination as per standard of care.   Physical examination findings should 
be recorded on the appropriate CRF (eg, medical history). 
 
Tanner stage (months 12 and 24 in all subjects, and months 6 and 18 in female 
subjects only to determine the need to perform a pregnancy urine dipstick test) 
 
Vital signs 
 
Height (months 6, 12, 18, and 24 only) 
 
Weight (months 6, 12, 18, and 24 only) 
 
Arm Span (months 12 and 24 only) 
 
DXA (lumbar spine) (All images/reports [as applicable] to be sent to the central 
imaging vendor) (months 6, 12, 18, and 24 only) 
 
DXA (proximal femur) (All images/reports [as applicable] to be sent to the central 
imaging vendor) (months 6, 12, 18, and 24 only) 
 
X-ray (lateral thoracic, lumbar spine) (All images/reports [as applicable] to be sent to 
the central imaging vendor) (months 12 and 24 only) 
 
X-ray (AP knees) (All images/reports [as applicable] to be sent to the central imaging 
vendor) (months 6, 12, 18, and 24 only) 
 
Oral visual inspection (months 12 and 24 only) 
 
Dental X-ray (molars) (To be performed based on oral visual inspection.  All 
images/reports [as applicable] to be sent to the central imaging vendor) (months 12 
and 24 only) 
 
Hematology 
 
Serum chemistry 
 
Pregnancy test (urine dipstick method) (To be performed in female subjects who 
have had menarche or those who are Tanner stage 2 or higher.) (months 6, 12, 18, 
and 24 only) 
 
Dispensation of calcium and vitamin D (months 6, 12, and 18 only) 
 
Antidenosumab antibody (months 3, 6, 12 and 24 only) 
 
Concomitant medications 
 
PK (serum denosumab) (To be collected at month 3 only in a PK
substudy of 
up to 15 subjects [additional consent for the substudy must be obtained].)  (months 
6, 12, and 18 only) 
 
Adverse events 


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 
Serious adverse events 
 
Product complaints 
 
Clinical fracture recording 
 
Administration of: 
 
CHQ-PF-50 (months 12 and 24 only) 
 
CHAQ Disability Score (months 12 and 24 only) 
 
WBFPRS (months 12 and 24 only) 
 
SC injection of investigational product (denosumab or placebo at month 6, 
denosumab at months 12 and 18) 
7.2.5 
Observation Period (Months 30 and 36) 
These study visits will occur  7 days.  The following procedures and assessments will 
be completed at the times designated in the Schedule of Assessment (Table 2) and 
recorded on the CRF: 
 
Physical examination as per standard of care.   Physical examination findings should 
be recorded on the appropriate CRF (eg, medical history) 
 
Tanner stage (month 36 in all subjects, and month 30 in female subjects only to 
determine the need to perform a pregnancy urine dipstick test) 
 
Vital signs 
 
Height (months 30 and 36 only) 
 
Weight 
 
Arm Span (month 36 only) 
 
DXA (lumbar spine) (All images/reports [as applicable] to be sent to the central 
imaging vendor) (month 36 only) 
 
DXA (proximal femur) (All images/reports [as applicable] to be sent to the central 
imaging vendor) (month 36 only) 
 
X-ray (lateral thoracic, lumbar spine) (All images/reports [as applicable] to be sent to 
the central imaging vendor) (month 36 only) 
 
X-ray (AP knees) (All images/reports [as applicable] to be sent to the central imaging 
vendor) 
 
Dental X-ray (cephalogram and panoramic radiograph) (month 36 only) 
 
Hematology 
 
Serum chemistry 
 
Pregnancy test (urine dipstick method) (To be performed in female subjects who 
have had menarche or those who are Tanner stage 2 or higher.)  
 
Concomitant medications 
 
 
 
Adverse events 
 
Serious adverse events 


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 
Clinical fracture recording 
 
Administration of: 
 
CHQ-PF-50 (month 36 only) 
 
CHAQ Disability Score (month 36 only) 
 
WBFPRS (month 36 only) 
7.3 
Study Procedures 
7.3.1 
Data Collection 
All laboratory values will be electronically transferred from the central laboratory to the 
Amgen database.  The central imaging vendor will collect DXA and radiographic imaging 
and will electronically transfer the data to the Amgen database.  All other data will be 
captured on the eCRF.  Demographic data collection including sex, age, race, and 
ethnicity will be collected in order to study their possible association with subject safety 
and treatment effectiveness. 
7.3.2 
Medical History 
The investigator or designee will complete a general medical/surgical history collected 
from 5 years prior to enrollment up to the time of enrollment and will be recorded on the 
eCRF.  Medical history will include information on the subject’s concurrent medical 
conditions.  Fracture history and the condition for which GCs are/were administered 
must be recorded regardless of time frame. 
7.3.3 
Medication History 
Medication history will be collected from 5 years prior to enrollment up to the time of 
enrollment and will be recorded on the eCRF. 
7.3.4 
Concomitant Medications 
All concomitant medications, including over-the-counter products and vitamins 
administered while the subject is on the study, must be recorded on the eCRF.  The 
generic name, indication, dose, frequency, and start and stop dates will be recorded.   


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7.3.5 
Laboratory Assessments 
Central 
Laboratory 
Chemistry 
Central 
Laboratory 
Coagulation 
Central 
Hematology 
Serology 
Other 
assessments 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
25(OH) vitamin D 
Calciuma 
Adjusted calciuma 
Magnesium 
Phosphorusa 
Glucose 
BUN 
Creatinine 
Total bilirubin 
Alk phosa 
AST (SGOT) 
ALT (SGPT) 
GGTb 
CPKb 
PT/INRc 
 
RBC 
Hemoglobin 
Platelets 
WBC 
Differential 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Neutrophils 
HIV-1, -2 antibody 
HBsAg 
Hep C Ab 
Serum 
denosumaba 
Anti denosumab 
antibodya 
 
ALT  Alanine aminotransferase; AST  Aspartate aminotransferase;
 BUN  Blood urea nitrogen; CPK  Creatine phosphokinase; DILI  Drug-induced liver injury; 
GGT  Gamma-glutamyltransferase; HBsAg  Hepatitis B surface antigen; Hep C Ab  Hepatitis C antibody; 
HIV  Human immunodeficiency virus; INR  International normalized ratio; PT  Prothrombin time; 
RBC  Red blood cell;
 ULN  Upper limit of normal; 
WBC  White blood cell. 
a Results of post-day 1 assessments will be blinded to any study-related personnel (including the sites) 
except for serum calcium, albumin-adjusted calcium, phosphorus, or ALP in the event of a panic value 
b To be performed only in subjects with dystrophinopathies at screening and at subsequent visits for the 
purpose of DILI ascertainment (if applicable) 
c To be performed at screening only in subjects with dystrophinopathies who have AST or ALT  5 x ULN 
and at subsequent visits in any subjects for the purpose of DILI ascertainment, as applicable 
(see Section 6.4) 
7.3.6 
Physical Examination 
Physical examination will also include assessment of Tanner stage.  A pelvic, breast, or 
rectal examination is not required unless a specific evaluation is warranted.   
7.3.7 
Physical Measurements 
Physical measurements include height and weight.  Height (in centimeters) and weight 
(in kilograms) should be measured without shoes.  Height measurements will be 
performed in the standing position unless it is not possible to do so.  Measurement of 


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standing height should be made using a wall-mounted stadiometer (calibrated within the 
previous 4 hours), and recorded to the nearest 10th of a centimeter (Food and Drug 
Administration Guidance for Industry, 2007).  In instances where standing height cannot 
be measured, measurement of recumbent height will be allowed. 
Body Mass Index should be calculated using the following formula:  
BMI (kg/m2)  weight (kg)/[height (cm)/100]2. 
7.3.8 
Vital Signs 
Vital signs will include temperature, respiration rate, blood pressure, and heart rate 
obtained in the sitting position after the subject has been sitting quietly for at least 
5 minutes.  The temperature location selected for a subject should be the same that is 
used throughout the study and documented on the vital signs CRF. 
7.3.9 
Pregnancy Testing 
Pregnancy tests will be performed from urine samples to be collected at screening, on 
day 1, and at months 6, 12, 18, 24, 30, and 36 in all female subjects who are at Tanner 
stage 2 (or higher) or have had menarche.  A negative pregnancy test must be 
confirmed prior to administration of study medication at all scheduled visits 
(as applicable). 
7.3.10 
Dual-energy X-Ray Absorptiometry (DXA) 
All subjects will undergo bone densitometry assessments of the lumbar spine and 
proximal femur performed by DXA at all applicable visits.  DXA assessments of the 
lumbar spine and proximal femur are to be performed in duplicate only at screening and 
day 1, respectively.  All DXA scans will be submitted to a central imaging vendor for 
analysis. 
Only General Electric Lunar or Hologic bone densitometers will be allowed for this study.  
The same DXA machine must be used for all study procedures for a particular subject.  
The left side should be used for proximal femur, unless prohibited (eg, hip implant).  If 
the right side must be used or is inadvertently used at screening, then it must be used 
consistently throughout the study.  Lumbar spine scans should include L1 through L4.  
At least 2 lumbar vertebrae from L1-L4 must be evaluable by DXA.  
After analysis of the scans by the central imaging vendor, the study site may be asked to 
re-acquire a scan, because of poor positioning or other technical reasons.  The 
investigator sites must comply with the requests from the central imaging vendor.  


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Detailed instructions for scan acquisition will be in a separate manual provided by the 
central imaging vendor. 
7.3.11 
Spine Radiographs 
Lateral radiographs of the thoracic and lumbar spine will be obtained at scheduled 
time-points to determine morphometric fractures.  Baseline lateral spine radiographs will 
be obtained at screening for all subjects, unless an adequate lateral spine radiograph 
has been obtained within the 2 months prior to screening day; in this case the 
radiograph must still be sent to the central imaging vendor.  All available radiographic 
assessments for evaluation of potential fracture from screening until end of study will be 
submitted to the central imaging vendor for final analysis.  The results from the central 
imaging vendor analysis of the scan data will be used for determination of eligibility and 
analysis of the final dataset.   
7.3.12 
Radiographs for Assessment of Long-bone Fractures 
Long-bone fractures which occurred within 2 years prior to screening should be 
substantiated by radiographs, where available, or with a medical report, in the event of 
unavailable radiographs.  Images and/or radiologic/medical reports for potential 
long-bone fractures will be submitted to the central imaging vendor for reading and 
evaluation.   
7.3.13 
Knee Radiograph 
Anteroposterior (AP) radiographs of both knees (unless prohibited by the presence of 
hardware such as implants) will be used to calculate the metaphyseal index Z-score of 
each knee; the score will then be based on the knee with the higher Z-score.  The knee 
for assessment of metaphyseal index during the study should be the 1 with the higher 
Z-score at day 1, unless prohibited by presence of hardware, in which case an 
AP radiograph of the contralateral knee may be obtained.  Knee radiographs will be 
submitted to the central imaging vendor for reading and evaluation.   
7.3.14 
Dental Radiograms 
Lateral Cephalogram 
The lateral cephalogram is a profile X-ray of the skull and soft tissues and is used to 
assess the relation of the teeth in the jaws, the relation of the jaws to the skull, and the 
relation of the soft tissues to the teeth and jaws.  Lateral cephalogram will be performed 
to enable assessment of mandibular shaping. 


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Panoramic Radiogram 
The panoramic radiogram is a panoramic scanning dental X-ray of the upper and lower 
jaw, which shows a 2-dimensional view of a half-circle from ear to ear.  Panoramic 
radiogram will be performed to monitor molar eruption at day 1 and end of the study. 
Other Dental Radiograms 
Reflex radiographic assessment (eg, panoramic, bitewing, or periapical view) may be 
performed in the event a subject is referred to a dentist due to suspicion of unerupted 
molar(s), based on visual inspection.  The choice of technique/view for this reflex 
radiographic assessment (eg, panoramic, bitewing, or periapical view) will be determined 
by the dentist based on his/her professional judgment.  All films resulting from these 
assessments should be submitted to the central reader. 
7.3.15 
Oral Visual Inspection 
Each subject will undergo a visual inspection under natural light for the presence of 
molars.  Since third molar eruption normally occurs after age 21, evaluation of third 
molar eruption will not be carried out. 
Oral visual inspection should be performed at the month 12 and 24 visits to assess the 
risk for unerupted molars.  The subject should be referred to a dentist to perform 
radiographic assessment of the unerupted molar(s) if: 
 
A subject is 7 years of age or older and less than 13 years of age and appears to 
have an unerupted upper or lower first molar (ie, all 4 first molars should be 
visible/detectable)  
 
A subject is 13 years of age or older and appears to have an unerupted upper or 
lower (first or) second molar (ie, all 4 first molars and all 4 second molars should be 
visible/detectable) 
7.3.16 
Patient-reported Outcomes (PROs) 
The subject’s health-related quality of life, physical functioning, and pain intensity will be 
assessed using the CHQ-PF-50, CHAQ, and the WBFPRS.  
The CHQ-PF-50 is a generic health-related quality-of-life instrument that is used to 
measure 14 unique physical and psychosocial domains for children from 5 to 18 years of 
age; the parent-reported version of the questionnaire is to be used in this study, as 
summary scoring and norms are not available for the child-reported version.  The CHAQ 
has been developed to measure the physical functioning in children 6 months to 
18 years of age.  The WBFPRS is a horizontal pain scale for children from 3 to 18 years, 


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which consists of 6 hand-drawn faces that range from a smiling “no hurt” face with a 
score of 0 to a crying “hurts most” face with a score of 10.   
7.3.17 
Pharmacokinetic (PK) Samples 
All subjects receiving denosumab will have PK samples assessed.  Blood sample(s) for 
PK testing are to be collected for the measurement of pharmacokinetic concentrations.   
7.4 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected for the measurement of 
antidenosumab binding antibodies.  Samples testing positive for binding antibodies will 
also be tested for neutralizing antibodies and may be further characterized for 
quantity/titer, isotype, affinity, and presence of immune complexes.  Additional blood 
samples may be obtained to rule out antidenosumab antibodies during the study.   
Sites will be notified of any positive neutralizing antibody results to denosumab or 
protocol-required therapies.  If results are not provided, no neutralizing antibodies to 
denosumab or protocol-required therapies have been detected. 
Subjects who test positive for neutralizing antibodies to denosumab (eg, Amgen or 
non-Amgen IPs) or protocol-required therapies at the final scheduled study visit will be 
asked to return for additional follow-up testing.  This testing is to occur approximately 
every 3 months starting from when the site has been notified of the positive result, until:  
(1) neutralizing antibodies are no longer detectable or (2) the subject has been followed 
for a period of at least 1 year ( 4 weeks) postadministration of denosumab (eg, Amgen 
or non-Amgen IPs) or protocol-required therapies.  All follow-up results, both positive 
and negative will be communicated to the sites.  More frequent testing (eg, every month) 
or testing for a longer period of time may be requested in the event of safety-related 
concerns.  Follow-up testing is not required where it is established that the subject did 
not receive denosumab or protocol-required therapies. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-denosumab (eg, Amgen or 
non-Amgen IPs) or protocol-required therapies antibody response may also be asked to 
return for additional follow-up testing.  Refer to the Schedule of Assessments (Table 2), 
as applicable, for specific time points and the laboratory manual for detailed collection 
and handling instructions. 


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7.5 
Optional Substudies 
7.6 
Early Termination  
If the subject discontinues the study prior to the month 36 visit, a safety follow-up visit 
will occur within 30 days following the last protocol-required therapy. 
All procedures outlined for the month 36 visit will be performed during this visit with the 
following exception: 
 
Procedures involving radiation exposure other than DXA assessment may not be 
performed if  3 months have elapsed since the previous radiographic assessment 
 
DXA scans will only be performed if  30 days have elapsed since the previous 
assessment 
 
Administration of PROs may not be performed if  1 month has elapsed since the 
previous assessment 
7.7 
Sample Storage and Destruction  
Any blood PK sample collected according to the Schedule of Assessments (Table 2) can 
be analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If permitted by local law and informed consent is provided by the subject’s legally 
acceptable representative(s), Amgen can do additional testing on remaining samples 
(ie, residual and back-up) to investigate and better understand GiOP, the dose response 
and/or prediction of response to denosumab, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of other exploratory studies are not placed in the subject’s 


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medical record and are not to be made available to the subject, members of the family, 
the personal physician, or other third parties, except as specified in the informed 
consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Assessments 
(Table 2) including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints and adverse 
events.  Subjects who have discontinued investigational product and/or protocol-required 
therapies or procedures should not be automatically removed from the study.  Whenever 


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safe and feasible it is imperative that subjects remain on-study to ensure safety 
surveillance and/or collection of outcome data.  The investigator must document the 
level of follow-up that is agreed to by the subject.   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Section 8.3.1 and Section 8.3.2. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Study  
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
1. Subject request 
2. Safety concern due to: 
a. Ineligibility determined 
b. Protocol deviation 
c. Noncompliance 
d. Requirement for alternative therapy 


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e. Adverse event (but not limited to): 
 
Severe or symptomatic hypocalcemia 
 
Subjects who are removed from treatment as a result of severe or 
symptomatic hypocalcemia should receive treatment according to 
local standard of care, at the discretion of the treating physician 
and should be closely followed up until resolution of the adverse 
event 
 
Osteonecrosis of the jaw 
 
Serious opportunistic infection 
3. Decision by sponsor (other than subject request or safety concern) 
4. Death 
5. Lost to follow-up 
6. Pregnancy 
7. Other protocol-specified criteria: 
a. 
 4 new fractures in 6 months 
b. 
 2 new long-bone fractures in 6 months 
c. 
Decline in lumbar spine BMD Z-score by 0.5 units or more in 6 months  
 
Subjects who are removed from treatment as a result of criterion a, b, 
or c (above) should be followed up and treated, if applicable, 
according to local standard of care, at the discretion of the treating 
physician 
d. Changes in growth plate morphology, as observed in the 6-month 
monitoring, considered by the investigator to be unexpected and having 
an adverse clinical impact for the subject 
h. Disease flare requiring treatment not allowed in the protocol 
i. 
Dental abnormalities requiring invasive dental procedures 
j. 
Serious infection, if the subject is receiving a biologic agent for the 
treatment of underlying inflammatory disease 
 
Serious infection is defined as a serious adverse event of infection 
that is complicated by multiple organ involvement or sepsis 
 
Sepsis is defined by the presence of infection and a severe 
systemic inflammatory response 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor  
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 


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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
If the severity of an adverse event worsens from onset to resolution, a single event for 
each increased level of severity should be recorded on the Events eCRF.  
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
 
Fatal 
 
Life threatening (places the subject at immediate risk of death) 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect 
 
Other medically important serious event 


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An adverse event would meet the criterion of “requires hospitalization,” if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event.”  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of investigational 
product through the end of study are reported using the Events CRF. 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Did the event start prior to first dose of investigational product, other 
protocol-required therapies; 
 
Assessment of seriousness; 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to investigational product or other protocol-required 
therapies;  
 
Action taken; and  
 
Outcome of event 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events.  The grading scale used in this study is described in Appendix A.  If the 
severity of an adverse event worsens from onset to resolution, record a single event for 
each increased level of severity. 
The investigator must assess whether the adverse event is possibly related to the 
investigational product(s) and/or other protocol-required therapies.  This relationship is 
indicated by a “yes” or “no” response to the question:  Is there a reasonable possibility 


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that the event may have been caused by the investigational product(s) and/or other 
protocol-required therapies?   
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, and/or procedure (including any screening procedures).  This relationship is 
indicated by a “yes” or “no” response to the question:  “Is there a reasonable possibility 
that the event may have been caused by a study activity (eg, administration of 
investigational product, protocol-required therapies, and/or procedure)”?  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last day of the dosing interval or end of study, 
whichever is a longer period, are recorded in the subject’s medical record and are 
submitted to Amgen.  All serious adverse events must be submitted to Amgen within 
24 hours following the investigator’s knowledge of the event via the Events CRF.   
If the electronic data capture (EDC) system is unavailable for more than 24 hours to the 
site staff to report the serious adverse event, the information is to be reported to Amgen 
via a paper-based Serious Adverse Event Contingency Report Form (also referred to as 
the electronic Serious Adverse Event [eSAE] Contingency Report Form) within 24 hours 
of the investigator’s awareness of the event.  See Appendix B for a sample of the 
electronic Serious Adverse Event Contingency Report Form.  For EDC studies where 
the first notification of a serious adverse event is reported to Amgen via the eSerious 


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Adverse Event Contingency Report Form, the data must be entered into the EDC 
system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product and/or other protocol-required therapies.  This relationship is 
indicated by a “yes” or “no” response to the question:  Is there a reasonable possibility 
that the event may have been caused by the investigational product and/or other 
protocol-required therapies?  Relatedness means that there are facts or reasons to 
support a relationship between investigational product and the event. 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Serious adverse event(s) should be reported to Amgen (regardless of causality) if the 
investigator becomes aware of a serious adverse event.   
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice (GCP).  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 


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9.2.1.3 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.1.4 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 
9.2.1.5 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period (as defined in Section 9.2.1.1) or after end of 
study.  However, these serious adverse events should be reported to Amgen (regardless 
of causality) if the investigator becomes aware of them.  In some countries (eg, 
European Union member states), investigators are required to report serious adverse 
events that they become aware of after end of study.  If serious adverse events are 
reported, the investigator is to report them to Amgen within 24 hours following the 
investigator’s knowledge of the event.  The investigator should use the paper-based 
Serious Adverse Event Contingency Report Form to report the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking denosumab report the pregnancy to Amgen Global Patient Safety as 
specified below. 


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In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur within 5 months after the last dose of Amgen 
investigational product.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, stillbirth, 
or neonatal death or there is a fetal or neonatal congenital anomaly) the investigator will 
report the event as a serious adverse event.  
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 12 months. 
10.1.1.2 
Secondary Endpoint(s) 
 
Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 6, 18, 
24, and 36 months 
 
Change from baseline in proximal femur BMD Z-score as assessed by DXA at 6, 12, 
18, 24, and 36 months 
 
Subject incidence of X-ray confirmed long-bone fractures and new and worsening 
vertebral fractures during 12, 24, and 36 months  


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 
Subject incidence of improving vertebral fractures at 12, 24, and 36 months 
compared to baseline 
 
Subject incidence of new and worsening vertebral and nonvertebral fractures 
during 12, 24, and 36 months 
 
Change from baseline in CHQ-PF-50 Physical Summary Score at 12, 24, and 
36 months 
 
Change from baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 
36 months 
 
Change from baseline in CHAQ Disability Index Score at 12, 24, and 36 months 
 
Change from baseline WBFPRS at 12, 24, and 36 months 
 
Change from baseline in growth velocity, determined by calculating age-adjusted 
Z-scores for height, weight, and BMI, at 12, 24, and 36 months 
 
Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, 12, and 
18 months 
10.1.1.3 
Exploratory Endpoint(s) 
10.1.1.4 
Safety Endpoints 
 
Subject incidence of adverse events and serious adverse events 
 
Change from baseline in laboratory values 
 
Change from baseline in vital signs 
 
Subject incidence of antidenosumab antibodies 
10.1.2 
Analysis Sets 
10.1.2.1 
Full Analysis Set 
The full analysis set (FAS) is defined according to the intent-to-treat analysis to include 
all subjects enrolled into the study. 
10.1.2.2 
Primary DXA Analysis Set 
The primary DXA analysis set includes all subjects in the FAS with baseline and will ≥ 1 
post‑baseline lumbar spine provided by the central imaging vendor during the 
first 12 months and only be used to analyze the change from baseline in lumbar spine 
BMD Z-score as assessed by DXA at 12 months, as the primary analysis for the primary 
efficacy endpoint.  Subjects will be analyzed according to their randomized treatment 
group. 


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10.1.2.3 
DXA Analysis Set 
The DXA analysis set for each endpoint of interest (lumbar spine, total hip or 
femoral neck) includes all subjects in the FAS with baseline and ≥ 1 post baseline 
valid DXA assessments as provided by the central imaging vendor for the relevant 
endpoint at or before the timepoint under consideration (6, 12, 18, 24 or 36 
months).  Subjects will be analyzed according to their randomized treatment 
group. 
10.1.2.4 
Vertebral Fracture Analysis Set 
For each time point of interest (at 12, 24 and 36 months), the vertebral analysis set 
includes all subjects in the FAS who have a non-missing baseline and  1 non-missing 
postbaseline X-ray vertebral evaluation as provided by the central imaging vendor, on or 
before the time point under consideration.  This analysis set will be used to analyze 
incidence of vertebral fracture. 
10.1.2.5 
Nonvertebral Fracture Analysis Set 
The nonvertebral fracture analysis set includes all subjects in the FAS, and will be used 
to analyze the subject incidence of nonvertebral fracture endpoints.  All fractures will be 
identified or confirmed by the central imaging vendor. 
10.1.2.6 
PRO Analysis Set 
For each PRO (CHQ-PF-50, CHAQ disability index score and WBFPRS), the PRO 
analysis set includes all subjects in the FAS with baseline and at least 1 postbaseline 
valid PRO response for the appropriate PRO at the time point under consideration.  
Note that this subset could potentially be different from endpoint to endpoint, and from 
time point to time point, due to missing data.   
10.1.2.7 
Growth Velocity Analysis Set 
For each growth velocity endpoint (weight-for-age, height-for-age, and BMI-for-age 
Z-scores) and time point (12, 24 and 36 months), the analysis set includes all subjects in 
the FAS who have the relevant data (age in total months, weight, height, and BMI, 
respectively) at baseline, and on or before the time point of interest. 
10.1.2.8 
Safety Analysis Sets 
The safety analysis set for the treatment phase includes all subjects in the FAS who 
received  1 dose of investigational product.  The safety analysis set for the observation 
period includes all subjects who completed the treatment phase and remain in the 
observation phase. 


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10.1.2.9 
PK Analysis Set 
The PK analysis set includes all subjects in the FAS who have  1 serum denosumab 
reported result. 
10.1.3 
Covariates and Subgroups 
10.1.3.1 
Covariates 
The following covariates are assumed to have prognostic value with respect to the 
lumbar spine BMD Z-score as assessed by DXA.  The covariate’s association with the 
primary endpoint might be investigated. 
 
Sex (Male/Female) 
 
Race (White, non-White) 
 
Age (years) 
 
Baseline lumbar spine BMD Z-score 
 
Baseline glucocorticoid dose 
10.1.4 
Handling of Missing and Incomplete Data  
Subjects may have missing specific data points for a variety of causes.  In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a specific clinical measurement at its planned clinical visit.  Missing 
data will not be imputed for this study. 
10.2 
Sample Size Considerations 
The study will enroll 24 subjects.  Assuming that approximately 10 of subjects will not 
be evaluable at month 12 for the primary efficacy endpoint due to dropout, the analysis 
set for the primary efficacy endpoint will include approximately 20 subjects.   
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded at the final analysis.  Unblinding and potentially unblinding information 
should not be distributed to the study team, investigators or subjects prior to the study 
being formally unblinded at the final analysis, except as specified (eg, Section 5.3 and 
Section 9.2.1.2).  


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Individual subject treatment assignments will be maintained by the IVRS/IWRS.  Any 
unplanned unblinding occurring during the study period will be documented and reported 
in the final clinical study report.  The Independent Data Monitoring Committee (DMC) 
members and the Independent Biostatistical Group will have access to the treatment 
assignments and subject level data from the clinical trial database.  Amgen staff 
members who are involved in randomization, biological sample management, performing 
PK and anti-denosumab antibody assay analysis will have treatment assignment 
information but will not have access to the subject level data from the clinical database. 
10.4 
Planned Analyses 
10.4.1 
Interim Analyses 
No interim analysis is planned for the study. 
10.4.2 
Data Monitoring Committee (DMC) 
An external, independent DMC will be used to oversee progress of the study and make 
recommendations relating to early closure/extension or alteration of the study based on 
ongoing monitoring of the study data.  The DMC will be comprised of members external 
to Amgen.  The DMC members will have access to treatment assignments in order to 
monitor safety and efficacy results to protect subjects.  To minimize the potential 
introduction of bias, the DMC members will not have any direct contact with the study 
team, site personnel, or subjects.  An independent statistical service provider will 
generate unblinded reports for review by the DMC.  If at any time there are safety 
concerns, the DMC will communicate the concerns to a representative from Amgen 
senior management.  A charter specifying the DMC functions will be written with the 
agreement of the DMC members.  Last DMC was in March 2022 as all subjects have 
completed 12-month double blind treatment period of the study.   
10.4.3 
Primary Analysis 
The primary analysis will be conducted at the time of the final analysis.   
10.4.4 
Final Analysis  
The final analysis for the study, including the analysis of the primary endpoint, will be 
performed when all enrolled subjects have had the opportunity to complete the 36-month 
follow-up. 


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10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Descriptive statistics will be provided for demographics and subject characteristics, 
efficacy, PROs, and safety data.  Descriptive statistics of continuous measurements will 
include means, medians, standard deviations, and ranges, while categorical data will be 
summarized using counts and percentages. 
10.5.2 
Primary Efficacy Endpoint 
The change from baseline in lumbar spine BMD Z-score at 12 months will be analyzed 
based on the primary DXA analysis set using an analysis of covariance (ANCOVA) 
model including treatment (denosumab vs placebo), baseline age (age at informed 
consent), and baseline BMD Z-score.  Missing baseline and postbaseline BMD Z-scores 
will not be imputed.  The superiority of denosumab compared to placebo for the primary 
efficacy endpoint will be estimated from the 12-month least-squares (LS) mean of the 
treatment difference (denosumab – placebo) and the corresponding 95 confidence 
interval.   
A sensitivity analysis of the primary efficacy endpoint will be conducted in the 
DXA analysis set, in subjects with baseline and ≥ 1 postbaseline valid DXA 
assessments, using a repeated measures analysis.  Treatment (denosumab vs 
placebo), study visit (6, and 12 months), baseline age, baseline BMD Z-score, will 
be included as fixed effects, and treatment-by-visit included as an interaction.  
Study visit will be treated as a categorical variable.  The 12-month LS mean of the 
treatment difference (denosumab – placebo) and the corresponding 95% 
confidence interval and associated p-value will be estimated.  Unstructured 
variance–covariance structure will be used for estimation in the repeated 
measures analysis.  Other variance-covariance structure may be substituted if 
convergence problem arises.  
10.5.3 
Secondary Efficacy Endpoint(s) 
Secondary efficacy endpoints will be assessed without multiplicity adjustment. 
10.5.3.1 
Other Change From Baseline in BMD Z-score by DXA 
For each skeletal site (lumbar spine, total hip, and femoral neck), change from baseline 
in BMD Z-score will be analyzed using the same repeated measures analysis as 
described for the sensitivity analysis of the primary efficacy endpoint in Section 10.5.2.  


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10.5.3.2 
New and Worsening Vertebral Fractures, and Nonvertebral Fractures 
The subject incidence of new and worsening vertebral fractures, and nonvertebral 
fractures will be summarized by treatment group. 
10.5.3.3 
Improved Vertebral Fracture 
The proportion of subjects with improved vertebral fracture will be summarized at each 
time point based on the vertebral fracture analysis set. 
10.5.3.4 
Patient Reported Outcomes 
Patient reported outcomes (CHQ-PF-50, CHAQ disability index score, and WBFPRS) 
and their changes from baseline will be summarized at 12, 24, and 36 months based on 
their respective PRO analysis set.  There is no imputation for missing baseline or 
postbaseline data. 
10.5.3.5 
Growth Velocity 
Change from baseline in age-adjusted growth velocity endpoints will be summarized at 
12, 24, and 36 months based on the growth velocity analysis set.  There is no imputation 
for missing data. 
10.5.3.6 
Serum Denosumab Concentrations 
Individual serum denosumab concentration-time data will be tabulated and presented 
graphically based on the PK analysis set.  A mean concentration-time profile will also be 
provided.  There will be no imputation for missing values. 
10.5.4 
Safety Endpoints 
All safety endpoints will be analyzed separately for the 12-month double-blind period, 
24-month treatment period and overall study period (36-month). 
10.5.4.1 
Adverse Events 
All adverse events will be summarized based on the respective safety analysis set.  
Subject incidence of all treatment-emergent adverse events and serious adverse events 
will be tabulated by system organ class and preferred term.  Tables of fatal adverse 
events, adverse events leading to withdrawal from investigational product and 
treatment-emergent adverse events of interest will also be provided. 


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10.5.4.2 
Clinical Laboratory Measurements 
Actual values and changes from baseline in each parameter will be descriptively 
summarized at each visit.  For serum albumin-adjusted calcium, phosphorus, and ALP, 
summary of the percent change from baseline also will be provided. 
Shifts in laboratory parameters between baseline and the most extreme postbaseline 
values will be assessed based on the Common Terminology Criteria for Adverse Events  
v 4.0. 
All laboratory analyses will be based on the safety analysis set.  Subjects with missing 
data for a scheduled visit will not contribute to the tabulation for that time point 
(no imputation). 
10.5.4.3 
Vital Signs 
Descriptive statistics of the actual values and changes from baseline in vital signs (heart 
rate, respiration rate, temperature) will be presented by visit based on the safety analysis 
set.  Subjects with missing data for a scheduled visit will not contribute to the tabulation 
for that time point (no imputation). 
10.5.4.4 
Antidenosumab Antibodies 
The incidence and percentage of subjects who develop antidenosumab antibodies 
(binding and, if positive, neutralizing) at any time will be tabulated based on the safety 
analysis set. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen Clinical Manager to the investigator.  The written ICF 
is to be prepared in the language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational product(s) is/are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study.   


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The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  The original signed ICF is to be retained in accordance with institutional 
policy, and a copy of the signed consent form is to be provided to the subject or legally 
acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood. 
In this study, obtaining assent from the child and consent from the parents or legally 
authorized representative, except if the child is very young, as defined by local law will 
apply.  A child is defined as a person who has not attained the legal age for consent for 
treatments or procedures involved in clinical investigations, under the applicable law of 
the jurisdiction in which the clinical investigation will take place.  The local IRB/IEC will 
determine the process for obtaining and documenting the assent process for pediatric 
subject, but should follow the guidelines established by the Department of Health and 
Human Services Office of Human Research Protections guidelines, which state an 
explanation of the procedures involved in the study should be made in a language 
appropriate to the child’s age, experience, maturity, and condition. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  A 
copy of the written approval of the protocol and ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 


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The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of signing of informed consent.   
 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with governmental/International Conference on Harmonisation GCP 
Guidelines, it is required that the investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IRB/IEC direct 
access to review the subject’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 


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 
A recognized expert in the therapeutic area 
 
An investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IVR/IWR system captures the following data points and these are 
considered source data:  subject identification number, randomization date, 
randomization number, and treatment group assignment.  


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CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data).  In this study, PROs 
may be considered as source documents.  
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
Clinical Monitor is to have access to subject medical records and other study-related 
records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the Clinical Monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with International Conference on Harmonisation GCP and the sponsor’s 
audit plans, this study may be selected for audit by representatives from Amgen’s Global 
Research & Development Compliance and Audit function (or designees).  Inspection of 
site facilities (eg, pharmacy, protocol-required therapy storage areas, laboratories) and 
review of study-related records will occur to evaluate the study conduct and compliance 
with the protocol, International Conference on Harmonisation GCP, and applicable 
regulatory requirements. 
Data capture for this study is planned to be electronic: 


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 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
 
Updates to CRFs will be automatically documented through the software’s “audit 
trail.” 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the CRF, the data queries, and agrees with the 
content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database.  Self-evident corrections will be documented in the CRF Standard 
Instructions and the CRF Specific Instructions, both of these will be available through the 
EDC system.  Examples of obvious data errors that may be corrected by Amgen 
(or designee) include deletion of obvious duplicate data (ie, the same results sent twice 
with the same date with different visit, [eg, week 4 and early termination]) and updating a 
specific response if the confirming datum is provided in the “other, specify” field (eg, for 
race, reason for ending study).  
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 2), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
CRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language.   
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   


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12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, 3 and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
Additional information on the current guidelines for publications can be found at the 
following location:  http://www.icmje.org/. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 


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Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
During the study, the subjects may be reimbursed for reasonable expenses associated 
with the study (eg, transportation), if permitted under applicable regional laws or 
regulatory guidelines.  These arrangements for compensation are described in the 
Informed Consent that is available as a separate document. 


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13. 
REFERENCES 
Acott PD, Wong JA, Lang BA, Crocker JF. Pamidronate treatment of paediatric fracture 
patients on chronic steroid therapy. Pediatr Nephrol. 2005;20:368-373. 
Bianchi ML, Cimaz R, Bardare M, et al. Efficacy and safety of alendronate for the 
treatment of osteoporosis in diffuse connective tissue diseases in children:  a 
prospective multicenter study. Arthritis Rheum. 2000;43:1960-1966. 
Bianchi ML. Glucocorticoids and bone:  some general remarks and some special 
observations in paediatric patients. Calcif Tissue Int. 2002;70:384-390. 
Bishop N, Arundel P, Clark E, et al.  International Society of Clinical Densitometry. 
Fracture prediction and the definition of osteoporosis in children and adolescents:  the 
ISCD 2013 Pediatric Official Positions. J Clin Densitom. 2014;17(2):275-280. 
Boot AM, de Jongste JC, Verberne AA, Pols HA, de Muinck Keizer-Schrama SM. Bone 
mineral density and bone metabolism of prepubertal children with asthma after long-term 
treatment with inhaled corticosteroids. Pediatr Pulmonol. 1997;24:379-384. 
Boyce AM, Chong WH, Yao J, et al. Denosumab treatment for fibrous dysplasia. J Bone 
Miner Res. 2012;27:1462-1470. 
Burnham JM, Leonard MB. Bone disease in pediatric rheumatologic disorders. Curr 
Rheumatol Rep. 2004;6:70-78. 
Canalis E, Bilezikian JP, Angeli A, et al.  Perspectives on glucocorticoid-induced 
osteoporosis. Bone. 2004;34:593-598. 
Centers for Disease Control and Prevention. Overview of the CDC growth charts. 2011. 
http://www.cdc.gov/nccdphp/dnpa/growthcharts/training/modules/module2/text/module2p
rint.pdf  
Daniels MW, Wilson DM, Paguntalan HG, Hoffman AR, Bachrach LK. Bone mineral 
density in pediatric transplant recipients. Transplantation. 2003;76:673-678. 
Dore RK, Cohen SB, Lane NE, et al.  Effects of denosumab on bone mineral density and 
bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids of 
bisphosphonates. Ann Rheum Dis. 2010;69:872-875. 
Erbitux Package Insert. ImClone LLC, 2012. 
EU Ethical Considerations. Ethical considerations for clinical trials on medicinal products 
conducted with the paediatric population. 2008. 
ftp://ftp.cordis.europa.eu/pub/fp7/docs/ethical-considerations-paediatrics_en.pdf. 
Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. Pharmacokinetic properties 
of infliximab in children and adults with Crohn’s disease:  a retrospective analysis of data 
from 2 phase III clinical trials. Clin Ther. 2011;33:946-964. 
Food and Drug Administration Guidance for Industry - Orally Inhaled and Intranasal 
Corticosteroids:  Evaluation of the Effects on Growth in Children. 2007 
(http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-
4359b1_02_03_FDA20Corticosteroid20Guidance.pdf). 
Glade Bender JL, Adamson PC, Reid JM, et al. Phase I trial and pharmacokinetic study 
of bevacizumab in pediatric patients with refractory solid tumors. J Clin Oncol. 
2008;26:399-405. 


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Gordon MS, Margolin K, Talpaz M, et al.  Phase I safety and pharmacokinetic study of 
recombinant human anti-vascular endothelial growth factor in patients with advanced 
cancer. J Clin Oncol. 2001;19:843-850. 
Grasemann C, Schundeln MM, Hovel M, et al.  Effects of RANK-ligand antibody 
(denosumab) treatment on bone turnover markers in a girl with juvenile Paget's disease. 
J Clin Endocrinol Metab. 2013;98:3121-3126. 
Inoue Y, Shimojo N, Suzuki S, et al.  Efficacy of intravenous alendronate for the 
treatment of glucocorticoid-induced osteoporosis in children with autoimmune diseases. 
Clin Rheumatol. 2008;27:909-912. 
International Society for Clinical Densitometry, 2019. 
Leonard MB, Zemel BS. Current concepts in pediatric bone disease. Pediatr Clin North 
Am. 2002;49:143-173. 
Leonard MB. Glucocorticoid-induced osteoporosis in children:  impact of the underlying 
disease. Pediatrics. 2007;119 (suppl):166-174. 
McMillan HJ, Gregas M, Darras BT, Kang PB.  Serum transaminase levels in boys with 
Duchenne and Becker muscular dystrophy. Pediatrics. 2011;127(1):e132-136 
Parfitt AM, Mundy GR, Roodman GD, Hughes DE, Boyce BF.  A new model for the 
regulation of bone resorption, with particular reference to the effects of bisphosphonates. 
J Bone Miner Res. 1996;11:150-159. 
Saag KG, Wagman RB, Geusens P, et al.  Denosumab versus risedronate in 
glucocorticoid-induced osteoporosis:  a multicentre, randomised, double-blind, 
active-controlled, double-dummy, non-inferiority study. Lancet Diabetes Endocrinol 
(published online). 06 April 2018. 
Simm PJ, Johannesen J, Briody J, et al. Zoledronic acid improves bone mineral density, 
reduces bone turnover and improves skeletal architecture over 2 years of treatment in 
children with secondary osteoporosis. Bone. 2011;49:939-943. 
Sutjandra L, Rodriguez RD, Doshi S, Ma M, Peterson MC, Jang GR, Chow AT, 
Pérez-Ruixo JJ. Clin Pharmacokinet. 2011;50(12):793-807. 
van Staa TP, Cooper C, Leufkens HG, Bishop N.  Children and the risk of fractures 
caused by oral corticosteroids. J Bone Miner Res. 2003;18:913-918. 
Ward LM. Osteopetrosis due to glucocorticoid use in children with chronic illness. Horm 
Res. 2005;64:209-221. 
Ward LM, Tricco A, Phuong PN, et al. Bisphosphonate therapy for children and 
adolescents with secondary osteoporosis (Review). Cochrane Database of Systematic 
Reviews. 2010, Issue 7. 
Ward LM, Konji VN, Ma J. The management of osteoporosis in children. Osteoporos Int.  
2016;27(7):2147-79. 
Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and 
promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids:  potential 
mechanisms of their deleterious effects on bone. J Clin Invest. 1998;102:  274-282. 
Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced 
osteopetrosis. N Engl J Med. 2003;349:457-463. 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events is available at the following 
location:   
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.4 require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate CRF (eg, Events eCRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen. 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1.3. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI (Section 6.4.1) or who 
experience AST or ALT elevations  3 x ULN (except for subjects with 
dystrophinopathies) are to undergo a period of “close observation” until abnormalities 
return to normal or to the subject’s baseline levelsAssessments that are to be 
performed during this period include: 
 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR as clinically necessary 
until laboratory abnormalities improve. 
 
Obtain pediatric gastroenterologist or pediatric hepatologist consult 
 
The diagnostic approach (including blood tests) to investigate alternative causes 
for abnormal liver tests is to be determined in consultation with a pediatric 
gastroenterologist or hepatologist. 
 
The “close observation” is to continue until all laboratory abnormalities return to 
baseline or normalize and subject’s clinical condition improves. 


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The potential DILI event and additional information such as medical history, concomitant 
medications, clinical presentation, and laboratory results must be captured in 
corresponding eCRFs. 


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Appendix B.  Sample Electronic Serious Adverse Event Contingency Report Form 
 
  


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Safety and Efficacy of Denosumab in 
Pediatric Subjects With Glucocorticoid-induced Osteoporosis 
 
Amgen Protocol Number:  20140444 
NCT Number:  NCT03164928 
 
Amendment Date: 
10 July 2023 
 
Rationale: 
The protocol has been amended to remove specific endpoints that will not be met for 
end of study and to align with European Medicines Agency/Paediatric Committee 
(EMA/PDCO) Modification Summary Report provided by the EMA.  Changes including, 
but not limited to, the following are being incorporated into the protocol: 
 
Updated secondary objectives and endpoints: 
o Replaced “from pre-treatment to post-treatment” with “compared to 
baseline” to clarify that the determination of improving vertebral fracture is 
to compare with baseline spine X-ray. 
o Removed language ‘overall among subjects with clinical fracture 
reduction, and among subjects with clinical fracture increase’ as it is not 
statistically meaningful to perform a subgroup analysis in a study that has 
only enrolled globally 24 subjects. 
o Updated language to clarify that new and worsening vertebral and 
nonvertebral fractures will be used to evaluate the effect of denosumab in 
children with Glucocorticoid (GC)-induced osteoporosis (GiOP). 
 
Updated Section 1.3:  Safety to delete the evaluation of metaphysical index and 
Molar eruption and mandibular shaping. 
 
Added footnote q stating that after the protocol required reporting period or after 
end of study, serious adverse events will be reported to Amgen. 
 Added language to Section 2.3.2 to clarify that pediatric patients with 
osteogenesis imperfecta, severe life threatening adverse events of 


Product:  Denosumab 
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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
hypercalcemia have been reported at or near the end of the denosumab 1 mg/kg 
Q3M dosing period (> 60 days from the previous dose) in Study 20130173. 
 Updated language in Section 10.4.2 to clarify that the last data management 
committee was in March 2022 as all subjects have completed 12-month double 
blind treatment period of the study. 
 Updated language in Section 10.5.2 to add additional language on sensitivity 
analysis of the primary efficacy endpoint. 
 Updated language in Section 10.5.4: Safety endpoints to clarify that safety 
endpoints will be analyzed for the 12-month double-blind period, 24-month 
treatment period and overall study period (36-month). 
 Removed Abnormal Metaphyseal Index Z score, Abnormal Molar Eruption, and 
Abnormal Mandibular Shaping Section 10.5.4.5. 
 Administrative, typographical, abbreviations, and formatting changes were made 
throughout the protocol. 


Product:  Denosumab 
Protocol Number:  20140444 
Date:  20 April 2021 
Page 1 of 18 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Safety and Efficacy of Denosumab in 
Pediatric Subjects With Glucocorticoid-induced Osteoporosis 
 
Amgen Protocol Number (Denosumab/Prolia) 20140444 
EudraCT number 2016-003083-39 
NCT number NCT03164928 
Amendment Date: 
20 April 2021 
 
Rationale: 
The following changes were made to the protocol dated 20 April 2021. 
 
Updated the number of subjects enrolled in the study. 
 
The study was initially designed to enroll 150 patients, to attain at least 
100 evaluable patients for the primary analysis and has been running since 
June 2017; however, as of December 2020, only 24 patients have been enrolled 
at 36 clinical sites activated globally. 
 
Following agreement from the Food and Drug Administration (FDA) and the 
European Medicines Agency (EMA), Amgen made a decision to end enrollment 
into this study.  The primary reason to request FDA and EMA agreement for early 
discontinuation is that there are too few children with the disease or condition to 
study, and this is not due to safety or efficacy concerns.  In order to maximize the 
value of the data from this study in this rare pediatric population, subjects who 
have been enrolled in the study will be allowed to complete the study, as defined 
in the protocol (ie, to last visit at 36 months).  As of January 2021, enrolment of 
subjects into this study has been closed.  The study is anticipated to end when 
the remaining subjects will have reached the 36 months visit. 
 
Aligned the protocol with current Amgen protocol template and safety reporting 
language. 
 
Administrative and editorial changes were completed as part of this amendment. 


Product:  Denosumab 
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Amendment 2 
Protocol Title:  A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Safety and Efficacy of Denosumab in 
Pediatric Subjects With Glucocorticoid-induced Osteoporosis 
Amgen Protocol Number 20140444 
EudraCT number 2016-003083-39 
NCT number NCT03164928 
 
Amendment Date: 
25 May 2018 
Rationale: 
The major purpose of this protocol amendment is to reflect changes in 
protocol 20140444 arising as a result of recommendations from FDA protocol-review in 
conjunction with the Prolia iPSP application, changes to the matching placebo 
formulation, and administrative changes. Revisions include: 
• 
Protocol synopsis edited to increase clarity and align with changes to the main 
protocol sections 
• 
Asia and the Middle East were added as study site continents to assist patient 
enrollment 
• 
Language added to clarify the meaning of exclusion criteria 240 and 241 
• 
Eligibility criteria 205 added in response to FDA suggestion 
• 
Schedule of assessments updated to include blood sampling for immunogenicity 
assessments at months 1, 3, and 6 
• 
Detailed instructions provided for height measurement added, at FDA suggestion 
• 
Rescreening period without re-consent requirement changed to 30 days throughout 
for consistency 
• 
Changes in rules for adverse event reporting if the severity changes, to align with TA 
program conventions 
• 
Updates to Pregnancy and Lactation reporting section per new regulatory 
requirements 
• 
Clarify age recording rules in the CRF demographics page 
• 
Add description of additional sensitivity analysis to asses impact of short stature on 
BMD Z-scores in response to FDA comments 
• 
Decription of placebo was changed to reflect the fact that with the new XGEVA 
formulation, the placebo will no longer be identical in composition 
• 
Text was edited in sections 2.3 and 2.4 to reflect the completion of Study 20101217 
• 
Minor administative changes and clarification was made throughout the document 
Approved 
 
 


Product:  Denosumab 
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CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Safety and Efficacy of Denosumab in 
Pediatric Subjects With Glucocorticoid-induced Osteoporosis 
 
Amgen Protocol Number 20140444 
 
Amendment Date: 
14 February 2017 
 
Rationale: 
The purpose of this protocol amendment is to reflect changes in the design of protocol 
20140444 arising from concerns around the acceptability and feasibility of subject 
exposure to placebo for 24 months. Major changes include: 
• 
Subjects in the placebo arm will transition to open-label denosumab at 12 months 
and continue open-label denosumab for an additional 12 months. 
• 
Secondary objectives and endpoints have been updated to reflect the change in 
placebo duration. 
• 
The study schema has been updated to reflect these revisions. 
Statistical revisions: 
• 
The primary analysis will be conducted at the time of the final analysis. 
• 
To remain in alignment with the key binding elements in the current PIP 
(Decision P/0058/2016), the primary analysis has been updated to use an 
analysis of covariance (ANCOVA) model, replacing the repeated measures 
analysis.  The repeated measures analysis has now been included as a 
sensitivity analysis. 
• 
Following current guidelines on handling of missing data, the protocol has been 
updated to include imputation rules for analysis of the primary endpoint. 
Other revisions: 
• 
Language added to clarify the end of study date. 
• 
Language regarding the reasons for stopping Amgen investigational product has 
been reorganized to ensure the reasons are mutually exclusive. 
Approved 
 
 


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• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) has been removed from the list of acceptable forms 
of contraception as it is a prohibited medication for the study. 
• 
Language regarding collection of medical and medication history clarified 
• 
Examples of underlying disease types requiring treatment with systemic 
glucocorticoids have been added. 
• 
Minor administrative changes and clarifications have also been incorporated. 
 
Approved 
 
 

SAP_001.pdf: 
Product:  Denosumab 
Statistical Analysis Plan:  20140444 
Date:  12 Nov 2023 
Page 1 
Internal Use Only Medical and Scientific Affairs 
STATISTICAL ANALYSIS PLAN 
A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Study to 
Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With 
Glucocorticoid-induced Osteoporosis 
Protocol Number: 
20140444 
Version: 
Version 4.0 
Date: 
12 NOV 2023 
Authors: 
 
NCT Number: NCT03164928
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Denosumab 
Statistical Analysis Plan:  20140444 
Date:  12 Nov 2023 
Page 2 
Internal Use Only Medical and Scientific Affairs 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
21 Sep 2017 
NA. The first version. 
Amendment 1 (v2.0) 
23 Oct 2018 
This statistical analysis plan (SAP) 
was updated based on the protocol 
amendment 2 for Denosumab 
Study 20140444 dated  25 May 2018. 
Amendment 2 (v3.0) 
30 Aug 2023 
This statistical analysis plan (SAP) 
was updated based on the updates in 
protocol amendment 4 for Denosumab 
Study 20140444 dated 10Jul2023.  
Changes including, but not limited to, 
the following are incorporated: 

Updated the fracture endpoints
and its analysis.

Removed the following safety
endpoints and its analysis:
Metaphysical Index, Molar
eruption, Mandibular shaping.

Made administrative and
editorial changes throughout
the document.
Amendment 3 (v4.0) 
12 Nov 2023 
This statistical analysis plan (SAP) 
was updated to add a sensitivity 
analysis for the primary efficacy 
endpoint (based on a FDA request), 
along with other updated methods. 

Added the definition of age in
months in the Section 6.6.

Added sensitivity analysis of
the primary efficacy endpoint


Product:  Denosumab 
 
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Date:  12 Nov 2023 
Page 3 
 
Internal Use Only Medical and Scientific Affairs 
per the FDA request in Section 
10.5.1.2. 
 
Updated the Sections 6.7.4 
10.5.2.2 to provide detail on the 
nonvertebral and long bone 
fractures consideration. 
 
Updated the Tables A.1.4 - 
A.1.10 in the Appendix A to 
include visit window for 
Screening/Baseline visit. 
 
Updated Table C2 in Appendix 
C for Nonvertebral Fracture 
Locations 
 
Updated Appendix E for the 
CHQ-PF50. 
 
Made administrative and 
editorial changes throughout 
the document. 
 


Product:  Denosumab 
 
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Date:  12 Nov 2023 
Page 4 
 
Internal Use Only Medical and Scientific Affairs 
Table of Contents  
Table of Abbreviations ..................................................................................................... 8 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives ............................................................................................................... 9 
2.1 
Primary ....................................................................................................... 9 
2.2 
Secondary ................................................................................................... 9 
2.3 
Safety ........................................................................................................ 10 
2.4 
Exploratory ................................................................................................ 10 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Sample Size .............................................................................................. 12 
4. 
Study Endpoints and Covariates ........................................................................... 12 
4.1 
Study Endpoints ........................................................................................ 12 
4.1.1 
Primary Efficacy Endpoint .......................................................... 12 
4.1.2 
Secondary Endpoint(s) .............................................................. 12 
4.1.3 
Safety Endpoints ....................................................................... 13 
4.1.4 
Exploratory Endpoint(s) ............................................................. 13 
4.2 
Planned Covariates and Subgroups .......................................................... 13 
4.2.1 
Covariates ................................................................................. 13 
5. 
Hypotheses and/or Estimations ............................................................................ 13 
6. 
Definitions ............................................................................................................. 14 
6.1 
Basic Definitions........................................................................................ 14 
6.2 
Study Points of Reference ......................................................................... 14 
6.3 
Study Dates .............................................................................................. 15 
6.4 
Study Time Intervals ................................................................................. 16 
6.5 
Subject Disposition .................................................................................... 16 
6.6 
Arithmetic Calculations .............................................................................. 17 
6.7 
Study Endpoints ........................................................................................ 17 
6.7.1 
DXA Assessments ..................................................................... 17 
6.7.2 
Fracture-related Trauma Severity Definitions............................. 18 
6.7.3 
Vertebral Fractures .................................................................... 18 
6.7.4 
Nonvertebral Fracture ................................................................ 21 
6.7.5 
Growth Velocity Endpoints ......................................................... 21 
6.7.6 
PRO Questionnaires .................................................................. 22 
6.7.7 
Adverse Events ......................................................................... 23 
7. 
Analysis Subsets .................................................................................................. 23 
7.1 
Full Analysis Set........................................................................................ 23 
7.2 
Primary DXA Analysis Set ......................................................................... 23 
7.3 
Per Protocol DXA Analysis Set .................................................................. 23 


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7.4 
DXA Analysis Set ...................................................................................... 24 
7.5 
Vertebral Fracture Analysis Set ................................................................. 24 
7.6 
Nonvertebral Fracture Analysis Set ........................................................... 24 
7.7 
PRO Analysis Set ...................................................................................... 24 
7.8 
Growth Velocity Analysis Set..................................................................... 24 
7.9 
Safety Analysis Set ................................................................................... 25 
7.9.1 
Safety Analysis Set for 12-month Observation Period ............... 25 
7.10 
PK Analysis Set......................................................................................... 25 
8. 
Interim Analysis and Early Stopping Guidelines .................................................... 25 
8.1.1 
Interim Analyses ........................................................................ 25 
8.1.2 
Data Monitoring Committee (DMC) ............................................ 25 
8.1.3 
Primary Analysis ........................................................................ 26 
8.1.4 
Final Analysis ............................................................................ 26 
9. 
Data Screening and Acceptance ........................................................................... 26 
9.1 
General Principles ..................................................................................... 26 
9.2 
Data Handling and Electronic Transfer of Data ......................................... 26 
9.3 
Handling of Missing and Incomplete Data ................................................. 27 
9.3.1 
Missing Data.............................................................................. 27 
9.3.2 
Incomplete Dates ...................................................................... 27 
9.3.2.1 
Other Incomplete Dates .......................................... 27 
9.4 
Detection of Bias ....................................................................................... 28 
9.5 
Outliers ..................................................................................................... 28 
9.6 
Validation of Statistical Analyses ............................................................... 29 
10. 
Statistical Methods of Analysis.............................................................................. 29 
10.1 
General Principles ..................................................................................... 29 
10.2 
Subject Accountability ............................................................................... 29 
10.3 
Important Protocol Deviations ................................................................... 30 
10.4 
Demographic and Baseline Characteristics ............................................... 30 
10.5 
Efficacy Analyses ...................................................................................... 30 
10.5.1 
Analyses of Primary Efficacy Endpoint ...................................... 33 
10.5.1.1 
Primary Analysis ..................................................... 33 
10.5.1.2 
Sensitivity Analysis .................................................. 33 
10.5.1.3 
Covariate Analysis .................................................. 34 
10.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 34 
10.5.2.1 
Analyses of Other Changes From Baseline 
in BMD Z-score by DXA .......................................... 35 
10.5.2.2 
New and Worsening Vertebral Fractures 
and Nonvertebral Fractures ..................................... 36 
10.5.2.3 
Improved Vertebral Fracture .................................... 36 


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10.5.2.4 
Analyses of Patient Reported Outcomes ................. 36 
10.5.2.5 
Growth Velocity ....................................................... 36 
10.5.2.6 
Denosumab Serum Concentrations ......................... 36 
10.5.3 
Analyses of Exploratory Endpoints ............................................ 37 
10.6 
Safety Analyses ........................................................................................ 37 
10.6.1 
Adverse Events ......................................................................... 38 
10.6.2 
Adverse Events of Interest ......................................................... 38 
10.6.3 
Laboratory Test Results ............................................................ 38 
10.6.4 
Vital Signs ................................................................................. 39 
10.6.5 
Antidenosumab Antibody ........................................................... 39 
10.6.6 
Exposure to Investigational Product .......................................... 39 
10.6.7 
Exposure to Concomitant Medication ........................................ 39 
11. 
Literature Citations / References ........................................................................... 40 
12. 
Changes From Protocol-specified Analyses.......................................................... 40 
13. 
Appendices ........................................................................................................... 41 
 


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List of Tables 
Table 1. Endpoint Summary Table ................................................................................ 30 
Table 2. Summary of Description for Interpretation of LS Mean Difference 
Between Treatment Estimates After 12 Months ...................................... 35 
 
List of Appendices 
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ...................................................... 42 
Appendix B.  Age Conversion in Months ........................................................................ 46 
Appendix C.  Bone Codes for Nonvertebral Fractures ................................................... 47 
Appendix D.  Code Fragments ...................................................................................... 50 
Appendix E.  Patient-reported Outcome Forms/Instruments .......................................... 54 
Appendix F.  Reference Values/Toxicity Grades and Lab Assessments ........................ 62 
Appendix G.  CDC Growth Chart for stature z-scores by sex and age ........................... 63 
 


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Table of Abbreviations  
Term or Abbreviation 
Definition 
AE 
Adverse Event 
BMD 
Bone mineral density 
BMDS 
Biomedical data stewardship standard 
BMI 
Body mass index 
CHAQ 
Childhood Health Assessment Questionnaire 
CHQ-PF 
Child Health Questionnaire - Parent Form 
CT 
Computerized tomography 
DMC 
Data monitoring committee 
DoB 
Date of birth 
DXA 
Dual-energy X-ray absorptiometry 
EC 
Ethics committee 
eCRF 
Electronic case report form 
GiOP 
Glucocorticoid (GC)-induced osteoporosis 
IC 
Informed consent 
IP 
Investigational product 
IVRS 
Interactive voice response system 
MRI 
Magnetic resonance imaging 
NTX 
Cross-linked N-telopeptides of type 1collagen 
PK 
Pharmacokinetic 
SAP 
Statistical analysis plan 
SQ 
Semiquantitative 
SAS 
Statistical Analysis System 
WBFPRS 
Wong-Baker FACES Pain Rating Scale 
 


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1. 
Introduction  
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 4 for denosumab 
Study 20140444, dated 10Jul2023.The scope of this plan includes the final analysis at 
36 months, which will be executed by the Biostatistics department unless otherwise 
specified. 
2. 
Objectives  
2.1 
Primary  
To evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) 
Z-score as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in 
children 5 to 17 years of age with glucocorticoid (GC)-induced osteoporosis (GiOP). 
2.2 
Secondary  
To evaluate the effect of denosumab in children 5 to 17 years of age with GiOP with 
respect to: 
 
Change in lumbar spine BMD Z-score as assessed by DXA from baseline to 6, 18, 
24, and 36 months 
 
Change in proximal femur BMD Z-score as assessed by DXA from baseline to 6, 12, 
18, 24, and 36 months 
 
Incidence of X-ray confirmed long-bone fractures and new and worsening vertebral 
fractures during 12, 24, and 36 months  
 
Incidence of improving vertebral fractures at 12, 24, and 36 months compared to 
baseline   
 
Incidence of new and worsening vertebral and nonvertebral fractures during 12, 24, 
and 36 months  
 
Change in Childhood Health Questionnaire – Parent Form-50 (CHQ-PF-50) Physical 
Summary Score at 12, 24, and 36 months 
 
Change in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months 
 
Change in Childhood Health Assessment Questionnaire (CHAQ) Disability Index 
Score at 12, 24, and 36 months 
 
Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12, 24, and 
36 months 
 
Change in growth velocity, determined by calculating age-adjusted Z-scores for 
height, weight, and body mass index (BMI), at 12, 24, and 36 months.  
 
Serum concentration of denosumab at 1 and 10 days, and 6, 12, and 18 months 
(additional serum denosumab pharmacokinetics [PK] samples to be collected at 
day 30 and month 3 in a PK
substudy of up to 
15 subjects) 


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2.3 
Safety  
To evaluate the effect of denosumab in children 5 to 17 years of age with GiOP with 
respect to: 
 
Adverse events and serious adverse events 
 
Laboratory parameters 
 
Vital signs 
 
Antidenosumab antibodies 
2.4 
Exploratory  
3. 
Study Overview  
3.1 
Study Design  
This is a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel 
group study in pediatric subjects, age 5 to 17 years, with GiOP.  Twenty four subjects 
will be enrolled with at least 16 evaluable subjects for the primary analysis.The study will 
consist of 2 periods, a 24-month treatment period (including a 12-month placebo-
controlled period and a 12-month open-label treatment period) and a 12-month off-
treament observation period.   
Treatment Period 
The treatment period will last for 24 months.  Subjects will be randomized in a 2:1 
(active:placebo) allocation ratio to receive either denosumab 1 mg/kg body weight (BW) 
(up to a maximum of 60 mg) subcutaneous (SC) every 6 months (Q6M) or matching 
placebo SC Q6M for the first 12 months.  At the end of the 12-month placebo-controlled 
treatment period all subjects will receive open-label denosumab 1 mg/kg BW (up to a 
maximum of 60 mg) SC Q6M for 12 months, with the last dose of investigational product 
(IP) being administered at month 18. 


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Observation Period 
The observation period will start immediately after the 24-month treatment period and 
last 12 months, during which subjects will receive no IP.  Subjects will be followed during 
the 12-month observation period according to the following guidelines: 
 
Subjects who are currently on systemic GC for the treatment of the underlying 
non-malignant condition(s) at the month-24 visit should discontinue IP and 
transition to another osteoporosis treatment per local standard of care, according 
to the medical judgment of the investigator, for an additional 12 months or until 
systemic GC treatment is discontinued  
 
Subjects who are no longer on systemic GC for the treatment of the underlying 
non-malignant condition(s) at the month-24 visit should discontinue IP and be 
followed for an additional 12 months off-treatment; however, subjects who, during 
the 12-month observation period, resume systemic GC therapy, experience a 
worsening of their osteoporosis, or require osteoporosis therapy based on the 
medical judgment of the investigator may resume osteoporosis treatment per 
local standard of care at the discretion of the investigator 
Daily supplements of calcium and vitamin D will be given to all subjects during the 
24-month treatment period and if deemed medically warranted by the investigator during 
the 12-month observation period.  The planned length of participation in the study for an 
individual subject is approximately 3 years, which includes screening (up to 35 days), 
treatment period (24 months), and off-treatment observation period (12 months).  The 
anticipated dropout rate is approximately 10 in the first year.  The overall study design 
is described by a study schema in Figure 1. 
Figure 1.  Study Design and Treatment Schema  
 


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3.2 
Sample Size  
A total of 24 subjects will be randomized into the study (approximately 16 to denosumab 
and 8 to placebo). Assuming that approximately 10 of subjects will not be evaluable at 
month 12 for the primary efficacy endpoint due to dropout, the analysis set for the 
primary efficacy endpoint will include approximately 20 subjects. 
4. 
Study Endpoints and Covariates  
4.1 
Study Endpoints  
4.1.1 
Primary Efficacy Endpoint  
Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 12 months 
4.1.2 
Secondary Endpoint(s)  
 
Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 6, 18, 
24, and 36 months 
 
Change from baseline in proximal femur BMD Z-score as assessed by DXA at 6, 12, 
18, 24, and 36 months 
 
Subject incidence of X-ray confirmed long-bone fractures and new and worsening 
vertebral fractures during 12, 24, and 36 months  
 
Subject incidence of improving vertebral fractures at 12, 24, and 36 months 
compared to baseline  
 
Subject incidence of new and worsening vertebral and nonvertebral fractures during 
12, 24, and 36 months  
 
Change from baseline in CHQ-PF-50 Physical Summary Score at 12, 24, and 
36 months 


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 
Change from baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 
36 months 
 
Change from baseline in CHAQ Disability Index Score at 12, 24, and 36 months 
 
Change from baseline WBFPRS at 12, 24, and 36 months 
 
Change from baseline in growth velocity, determined by calculating age-adjusted 
Z-scores for height, weight, and BMI, at 12, 24, and 36 months 
 
Serum concentration of denosumab at 1, 10 and 30 days, and 3, 6, 12, and 
18 months  
4.1.3 
Safety Endpoints  
 
Subject incidence of adverse events and serious adverse events 
 
Change from baseline in laboratory values 
 
Change from baseline in vital signs 
 
Subject incidence of antidenosumab antibodies 
4.1.4 
Exploratory Endpoint(s)  
4.2 
Planned Covariates and Subgroups  
4.2.1 
Covariates  
The following covariates are assumed to have prognostic value with respect to the 
lumbar spine BMD Z-score as assessed by DXA.  The  association between these 
covariates with the primary efficacy endpoint might be investigated. 
 
Sex (Male/Female) 
 
Race (White, non-White) 
 
Age (years) 
 
Baseline lumbar spine BMD Z-score 
 
Baseline glucocorticoid dose 
5. 
Hypotheses and/or Estimations  
The hypothesis of this study is that the change from baseline in lumbar spine BMD 
Z-score following 12 months of denosumab treatment in children 5 to 17 years of age 
with GiOP will be greater than placebo.  


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6. 
Definitions  
6.1 
Basic Definitions  
Investigational Product  
Denosumab 1 mg/kg BW (up to a maximum of 60 mg) SC Q6M or matching placebo SC 
Q6M 
Interactive Voice Response System (IVR System) 
The system used to screen, screen failure, randomize and enroll subjects, provide IP 
box number, and volume administered, as well as to manage denosumab drug supply at 
the site and to track subject study termination data. 
6.2 
Study Points of Reference  
Baseline 
Baseline is the closest recorded measurement before the administration of the first dose 
of IP. If the measurement is done on the same day as the first dose and the exact 
measurement time relative to the first dose is unknown, it will be assumed the 
measurement is done before the administration of the first dose of IP.  If a subject does 
not receive IP, baseline is the closest recorded measurement on or before the 
enrollment date. 
Baseline DXA Assessments 
Baseline DXA assessments of lumbar spine and proximal femur are the latest DXA 
assessments obtained on or before the date of the first IP administration and evaluated 
by the central imaging vendor. If the baseline DXA assessments need to be repeated, 
due to poor quality as determined by the central imaging vendor, then the repeat DXA 
scans obtained within the first 60 Days after the first IP administration may be 
considered as baseline DXA. Because the baseline DXA will be assessed in duplicate, 
the baseline BMD value for analysis purpose will be the average of the BMD values from 
all baseline DXA scans for the same skeletal site.  
Baseline Lateral Spine Radiographs  
Baseline lateral spine radiograph is the latest radiograph obtained on or before the date 
of the first IP administration that is evaluated by the central imaging vendor.  
End of Study  
The end of study date is defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study (ie, last subject last visit), following 
any additional parts in the study (eg, long-term follow-up), as applicable 


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Study Day 1 
The first day of IP administration 
Study Day 
Pre study day 1: Study Day  (date of interest – date of Study Day 1)  
Post study day 1: Study Day  (date of interest – date of Study Day 1)  1 
Analysis Visit Windows 
As specified in the protocol, all tests and procedures scheduled to occur on days 10 and 
30 should be performed within  3 days of the scheduled day, and  7 days for visits at 
Months 3, 6, 12, 18, 24, 30 and 36. However, for analysis purpose the analysis visit 
windows defined in Appendix A will be used to assign evaluations to the most 
appropriate nominal visit. 
6.3 
Study Dates  
Informed Consent (IC) Date 
The date on which the study informed consent form, and subject assent form if 
applicable, is signed.  
Screening Date 
The screening date is the IC date 
Enrollment Date 
The date on which the investigator confirms that the subject has met all eligibility criteria 
and the enrollment call is made using the IVR system. 
Randomization Date 
The date on which the enrollment call is made using IVR system and a randomization 
number is assigned.  
First Dose Date in Double-blind Treatment Period (DBTP) 
The date of administration of first dose of IP following randomization (ie, the first date 
recorded on the IP Administration (IPA) electronic Case Report Form (eCRF) with 
volume  0) during the double-blind treatment period.  This date is defined as Study 
Day 1 for subjects who receive at least dose of IP. 
First Dose Date in Open-label Treament Period (OLTP)  
The date of administration of first dose of open-label IP recorded on the IPA eCRF with 
volume  0 during the OLTP following completion of the double-blind treatment period.  


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Last Dose Date 
The date of administration of last dose of IP (ie, the last date recorded on the IPA eCRF 
with volume  0) 
End of Study Date (i.e End of 36-Month Study Period) 
The date recorded on the End of Study eCRF.  
End of 12-Month Study Period 
The date recorded on the End of Treatment Phase Double Blind eCRF. 
End of 24-Month Study Period 
The date recorded on the End of Treatment Phase Open Label eCRF. 
6.4 
Study Time Intervals  
Screening Period 
The time between the date of informed consent and the enrollment.  
Overall Study Period (0-36 Months) 
The time period between the first dose date and end-of-study date, inclusive 
(approximately 3 years for completers). 
Double-blind Treatment Period (DBTP) 
The time from first dose date to the earlier of 12-month visit date or end-of-study date. 
Treatment Period (0-24 Months) 
The time from first dose date to the earlier of 24-month visit date or end-of-study date.   
Observation Period 
The time from end of treatment period (24-month visit) to end of study.  
6.5 
Subject Disposition  
Enrolled 
Individuals are considered enrolled when an enrollment call is made using IVRS and a 
randomization number is assigned. Enrolled individuals are referred to as ‘subjects’. 
Exposed to IP 
Subjects are defined as exposed to IP if the total amount of IP volume received during 
the study is greater than zero. 
Age at Screening (Informed Consent) (Months) 
Number of months as recorded on the subjects demographic eCRF page.  A table 
showing age conversion from months to years is provided in Appendix B.  


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6.6 
Arithmetic Calculations  
Age (months) at Visit 
Age (months) at visit  Collected age at screening (informed consent) in months  
((visit date – screening date (date of informed consent) 1) / 365.25) * 12 
Age at Screening (Informed Consent) (Years) 
Number of whole years (rounded down) derived from age in months on the subjects 
demographic eCRF page.   
Age (years)  age (months) / 12    
Age at Visit (Years) 
Age at visit in years (rounded down) will be calculated as: 
Age (years) at visit   (date of visit – date of informed consent  1) / 365.25   
                                   (age at screening (informed consent) in months) / 12 
Change from Baseline  
For a given variable, study baseline of interest, and timepoint of interest, subtract the 
endpoint value at the timepoint of interest minus the corresponding baseline value. 
Percent change from baseline  
The change from baseline divided by study baseline value of interest and multiplied by 
100: 
(Change from Baseline/ Baseline) * 100 
6.7 
Study Endpoints  
6.7.1 
DXA Assessments  
Only General Electric Lunar or Hologic bone densitometers will be allowed for this study. 
The same DXA machine must be used for all DXA assessments for a particular subject. 
The left side should be used for proximal femur, unless prohibited (eg, hip implant).  If 
the right side must be used or is inadvertently used at screening, then it must be used 
consistently throughout the study.   
Lumbar spine scans should include L1 through L4. At least 2 lumbar vertebrae from 
L1 to L4 must be evaluable by DXA.  Individual vertebral levels may be excluded due to 
artifact.  A vertebral level excluded from one visit will be excluded from all visits with the 
total lumbar spine BMD calculated based on the evaluable vertebral levels by the central 
imaging vendor.   


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Baseline DXAs will be performed as duplicate scans; DXA assessments at all other visits 
will be performed as single scans. After analysis of the scans by the central imaging 
vendor, the study site may be asked to re-acquire a scan, because of poor positioning or 
other technical reasons.  
6.7.2 
Fracture-related Trauma Severity Definitions  
Low Trauma Severity 
Assessed by the investigator and collected on the Additional Fracture Details eCRF for 
each clinical fracture event with the following trauma severity:   
 
Fall from standing height or less than 20 inches 
 
Minimal or moderate trauma other than a fall from standing height or less than 
20 inches 
 
Unknown/don’t know (including missing) 
High Trauma Severity 
Assessed by the investigator and collected on the Additional Fracture Details eCRF for 
each clinical fracture event with the following trauma severity: 
 
Severe trauma 
Pathologic  
Assessed by the investigator and collected on the Additional Fracture Details eCRF for 
each clinical fracture event with the following trauma severity:   
 
Pathologic fractures 
6.7.3 
Vertebral Fractures  
Lateral radiographs of the thoracic and lumbar spine (T4 through L4) will be obtained at 
times to determine clinical or morphometric vertebral fractures.  
The lateral spine radiographs will be assessed for prevalent, new, worsening and 
improving vertebral fractures using the Genant Semiquantitative (SQ) scoring method: 
 
Grade 0: normal (approximately  20 reduction in anterior, middle, and/or 
posterior height) 
 
Grade 1: mild fracture (approximately 20 - 25 reduction in anterior, 
middle, and/or posterior height) 
 
Grade 2: moderate fracture (approximately 25 - 40 reduction in anterior, 
middle, and/or posterior height) 
 
Grade 3: severe fracture ( 40 reduction in anterior, middle, and/or 
posterior height) 
All vertebral fractures data will be verified by Bioclinica for analysis purpose.  


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Prevalent Vertebral Fracture 
A subject has prevalent vertebral fracture if any thoracic or lumbar vertebrae (T4 to L4) 
evaluated have SQ grade  1 at baseline.  A subject does not have any prevalent 
vertebral fracture when the SQ grades of all evaluated vertebrae are 0 on the baseline 
spinal radiograph. Otherwise, the subject will have an unknown status for prevalent 
vertebral fracture. 
New Vertebral Fractures 
Any thoracic or lumbar vertebrae (T4 to L4) evaluated at a post-baseline visit is deemed 
to have a vertebral fracture when the post-baseline SQ is  1 compared to a baseline 
SQ score of 0.  
A subject is identified as having a new vertebral fracture at a timepoint of interest if at 
least one thoracic or lumbar vertebra from T4 to L4 at the timepoint of interest is deemed 
to have a new vertebral fracture (SQ  1) compared to the baseline SQ score of 0, 
excluding any symptomatic new vertebral fracture associated with high trauma severity 
or a pathologic fracture.  
Because the vertebral fractures in the pediatric population can worsen or improve over 
time, the SQ score of the fractured vertebra may increase or decrease over time, 
respectively.  The vertebral fracture status at a timepoint of interest will always be based 
on the last radiograph assessment on or before the timepoint of interest relative to the 
baseline radiograph assessment.  For example, if a vertebra is assessed as having 0, 2, 
0, and 2 SQ scores at baseline, 12, 24, and 36 months, respectively, then the vertebra 
will be identified as having a new vertebral fracture at the 12- and 36-month timepoints. 
However, the vertebra will not be assessed as having a new vertebral fracture at the 
24-month timepoint.  
Multiple New Vertebral Fractures 
A subject will be identified as having multiple new vertebral fractures when more than 
one thoracic or lumbar vertebra from T4 to L4 is identified as having a new vertebral 
fracture at the timepoint of interest, and the total number of new vertebral fractures will 
be the sum of new vertebral fractures at the timepoint of interest. 
Worsening Vertebral Fractures 
Worsening vertebral fractures occur in vertebrae with prevalent fractures. It is identified 
when a vertebra SQ score increases by more than 1 grade relative to a baseline SQ 
score  1, in any thoracic or lumbar vertebra evaluated, excluding any symptomatic 


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worsening vertebral fracture associated with high trauma severity or a pathologic 
fracture.  
A subject is identified as having a worsening vertebral fracture at a timepoint of interest if 
at least one thoracic or lumbar vertebra from T4 to L4 is assessed as having a 
worsening vertebral fracture compared to the baseline SQ score of  1.  For example, if 
a vertebra is assessed as having SQ scores of 2, 3, 3, and 2 at baseline, 12, 24 and 
36 months, respectively, the vertebra will not be identified as having a worsening 
vertebral fracture at the 36-month timepoint because the SQ score closest to the 
36 months is not greater than the baseline SQ score. However, the vertebra will be 
assessed as having a worsening vertebral fracture at the 12 and 24-month timepoints.  
Multiple Worsening Vertebral Fractures 
A subject will be identified as having multiple worsening vertebral fractures when more 
than one thoracic or lumbar vertebra from T4 to L4 is identified as having a worsening 
vertebral fracture at the timepoint of interest, and the total number of worsening vertebral 
fractures will be the sum of worsening vertebral fractures at the timepoint of interest. 
New or Worsening Vertebral Fracture 
A new and worsening vertebral fracture is identified when there is  1 grade increase 
from the baseline grade in any vertebra from T4 to L4, excluding any symptomatic 
vertebral fracture associated with high trauma severity or a pathologic fracture. 
A subject is identified as having a new or worsening vertebral fracture if at least one 
thoracic or lumbar vertebra from T4 to L4 is assessed as having a new or worsening 
vertebral fracture at the timpoint of interest.  
Multiple New or Worsening Vertebral Fractures 
A subject will be identified as having multiple new or worsening vertebral fractures when 
more than one thoracic or lumbar vertebra is identified as having a new or worsening 
vertebral fracture at the timepoint of interest, and the total number of new or worsening 
vertebral fractures will be the sum of new or worsening vertebral fractures at the 
timepoint of interest. 
Improving Vertebral Fractures 
For each postbaseline timepoint of interest (12, 24 and 36 months), an improvement in a 
prevalent vertebral fracture is identified when the SQ score decreases by at least 
1 grade relative to baseline SQ score, ie, the last SQ score assessment closest to the 
time point of interest is smaller than its baseline SQ score. 


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For each timepoint of interest (12, 24 and 36 months), a subject is identified as having 
an improving vertebral fracture if at least one thoracic or lumbar vertebra from T4 to L4 is 
assessed as an improving vertebral fracture at the timepoint of interest. For example, if a 
vertebra is assessed as having 2, 2, 1, and 1 SQ scores at baseline, 12, 24 and 
36 months, respectively, then the vertebra will be identified as having an improving 
vertebral fracture at the 24- and 36-month timepoints.  
6.7.4 
Nonvertebral Fracture  
Nonvertebral fracture (other than long bone fractures), reported on the Events eCRF 
and Additional Fractures Details eCRF, is defined as any nonvertebral (excluding 
fingers, toes, skull or face) fracture confirmed by the central imaging vendor based on 
a copy of radiographs or other diagnostic images such as computerized tomography 
(CT) or magnetic resonance imaging (MRI), and/or documented in a copy of the 
radiology report, surgical report, or discharge summary, excluding fractures associated 
with high trauma severity or pathologic fractures. See Appendix C  for the list of fracture 
locations. 
Long-bone Fractures 
Long bone fractures are a subset of nonvertebral fractures including the femur, tibia, 
fibula and the humerus, radius, and ulna bones. 
Long bone fractures reported on the Events eCRF, are defined as any long bone 
fracture confirmed by imaging excluding fractures associated with high trauma 
severity or pathologic fractures. 
Any Historical Fracture 
Any fracture recorded on the Subject Fracture History eCRF regardless of trauma 
severity. 
Historical Nonvertebral Fracture 
Any nonvertebral fracture recorded on the Subject Fracture History eCRF and not 
associated with known high trauma severity or pathologic fractures. 
6.7.5 
Growth Velocity Endpoints  
Height-for-age Z-score is defined as the difference between the subject’s height and the 
median height for the population with the same age and gender, divided by the 
population standard deviation: 
𝐻𝑒𝑖𝑔ℎ𝑡−𝑓𝑜𝑟−𝑎𝑔𝑒  𝑍−𝑠𝑐𝑜𝑟𝑒(𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑣𝑎𝑙𝑢𝑒 − 𝑚𝑒𝑑𝑖𝑎𝑛 𝑜𝑓 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛)
𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑑𝑒𝑣𝑖𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛
 


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Growth velocity is given by the change from baseline in height-for-age Z-scores at 12, 24 
and 36 months. During normal growth, the change in growth velocity score should 
equal 0. Growth acceleration is indicated by a positive change, and growth deceleration 
is indicated by a negative change. 
The definitions of growth velocity based on weight and BMI are similarly calculated;  
weight-for-age and BMI-for-age Z-scores will be calculated for each subject. 
To programmatically calculate the Z-scores, the National Center for Health Statistics 
percentiles growth charts, based on the 2000 Center for Disease Control and Prevention 
(CDC) (http://www.cdc.gov/growthcharts/cdc_charts.htm), and the CDC Anthropometric 
Software Package 3.0 Z scores will be used. See details in Appendix D (Code 
Fragment). 
6.7.6 
PRO Questionnaires  
CHQ-PF-50 
The CHQ-PF50 is a 50-item questionnaire to be completed by the parents or guardian of 
children between 5 and 18 years of age. The 50 questions measure 14 domains which 
are summarized as the physical and psychological summary scores. Each domain is 
scored from 0 to 100, with higher score indicating better physical and psychosocial 
health. 
For more information on the contribution of the 50 questions to calculate the CHQ-PF50, 
see Appendix E. 
CHAQ Disability Index Score 
The disability domain (questions 1-54) of the CHAQ is used to measure the subject’s 
assessment of physical functioning or the parent’s assessment of the child’s physical 
functioning. The disability index comprises 8 categories (dressing and grooming, arising, 
eating, walking, hygiene, reaching, gripping, and activities). Scoring ranges from 1 to 5; 
1 is “without any difficulty,” 2 is “with some difficulty,” 3 is “with much difficulty,” and 4 is 
“unable to do.” An answer of “not applicable” is scored as a 5, but is not counted. If a 
child requires assistance from another person or uses an aid or other device for any of 
the 8 categories, the minimum score for that category will be recorded as a 3. The 
CHAQ questions will then be converted to a 0 to 3 scale score. 
Missing values will not be imputed. If any of the domain questions are missing, but the 
aids/device indicator is non-missing, the domain can still be computed. However, if all 
domain questions are missing (or are scored as “not applicable”) and the aids/device 


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indicators are missing, then the domain score is considered missing. The CHAQ score is 
not computed when the subject/parent provides answers in fewer than 6 domains 
(normally coded as “UNK” in the database). 
For more information on the contribution of the 54 questions to calculate the CHAQ, 
see Appendix E. 
WBFPRS 
The WBFPRS is validated for use in children 3 years of age or older.  At each timepoint, 
subjects are asked to choose the face that best describes their own pain. See details in 
Appendix E. 
6.7.7 
Adverse Events  
Treatment-emergent Adverse Events for the 12-month Double-blind Treatment 
Period 
Adverse events with an onset date during the 12-month double-blind treatment period  
Treatment-emergent Adverse Events for the 24-month Treatment Period 
(Double-blind and Open-label) 
Adverse events with an onset date during the 24-month treatment period  
Treatment-emergent Adverse Events for the 36-month Overall Study Period 
Adverse events with an onset date during the 36-month overall study period  
Adverse Events for the 12-month Observation Period 
Adverse events with an onset date during 12-month observation period 
7. 
Analysis Subsets  
7.1 
Full Analysis Set  
The full analysis set (FAS) is defined according to the intent-to-treat analysis to include 
all subjects randomized into the study. 
7.2 
Primary DXA Analysis Set  
The primary DXA analysis set includes all subjects in the FAS with baseline and  1 
post-baseline lumbar spine provided by the central imaging vendor during the first 12 
months and will only be used to analyze the change from baseline in lumbar spine BMD 
Z-score as assessed by DXA at 12 months, as the primary analysis for the primary 
efficacy endpoint.  Subjects will be analyzed according to their randomized treatment 
group. 


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7.3 
Per Protocol DXA Analysis Set  
The per protocol DXA analysis set will only be used to analyze the change from baseline 
in lumbar spine BMD Z-score as assessed by DXA at 12 months, as an additional  
analysis for the primary efficacy endpoint.   
The per protocol DXA analysis set for the primary efficacy endpoint includes subjects 
who are in the primary DXA analysis set, received the planned doses at day 1 and 
month 6, and did not significantly deviate from the protocol through month 12.  Subjects 
will be analyzed according to their randomized treatment group. 
7.4 
DXA Analysis Set  
The DXA analysis set for each endpoint of interest (lumbar spine, total hip or femoral 
neck) includes all subjects in the FAS with baseline and  1 post-baseline valid DXA 
assessments as provided by the central imaging vendor for the relevant endpoint at or 
before the timepoint under consideration (6, 12, 18, 24 or 36 months).  Subjects will be 
analyzed according to their randomized treatment group. 
7.5 
Vertebral Fracture Analysis Set  
For each time point of interest (12, 24 and 36 months), the vertebral analysis set 
includes all subjects in the FAS who have a non-missing baseline and  1 non-missing 
postbaseline X-ray vertebral evaluation as provided by the central imaging vendor, on or 
before the time point under consideration. This analysis set will be used to analyze 
incidence of vertebral fracture. 
7.6 
Nonvertebral Fracture Analysis Set  
The nonvertebral fracture analysis set includes all subjects in the FAS, and will be used 
to analyze the subject incidence of nonvertebral fracture endpoints.  All nonvertebral 
fractures (other than long bone fractures) included in the analysis will be identified or 
confirmed by the central imaging vendor.  Long bone fractures reported on the 
Events eCRF and confirmed by imaging will be included in the analysis. 
7.7 
PRO Analysis Set  
For each PRO (CHQ-PF-50, CHAQ disability index score and WBFPRS), the PRO 
analysis set includes all subjects in the FAS with baseline and at least 1 postbaseline 
valid PRO response for the respective PRO at the time point under consideration.  Note 
that this subset could potentially be different from endpoint to endpoint, and from time 
point to time point, due to missing data.   


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7.8 
Growth Velocity Analysis Set  
For each growth velocity endpoint (weight-for-age, height-for-age, and BMI-for-age 
Z-scores) and time point (12, 24, and 36 months), the analysis set includes all subjects 
in the FAS who have the relevant data (age in total months, weight, height, and BMI, 
respectively) at baseline, and on or before the time point of interest. 
7.9 
Safety Analysis Set  
The safety analysis set includes all subjects in the FAS who received  1 dose of IP.  
This analysis set will also be used to summarize safety data in the 12-month 
double-blind treatment period, 24-month treatment period and the entire 36-month 
overall study period.  These subjects will be analyzed according to their actual treatment 
received during the 12-month double-blind treatment period, where subjects who 
received  1 dose of denosumab will be analyzed in the denosumab treatment group 
regardless of the randomized treatment. 
7.9.1 
Safety Analysis Set for 12-month Observation Period  
The safety analysis set for the 12-month observation period includes all subjects in the 
FAS who received  1 dose of IP, completed the 24-month treatment period, and 
remained in the observation period.  These subjects will be analyzed according to their 
actual treatment received during the 12-month double-blind treatment period, where 
subjects who received  1 dose of denosumab will be analyzed in the denosumab 
treatment group regardless of the randomized treatment.    
7.10 
PK Analysis Set  
The PK analysis set includes all subjects in the FAS who have  1 serum denosumab 
reported result. 
8. 
Interim Analysis and Early Stopping Guidelines  
8.1.1 
Interim Analyses  
No interim analysis is planned for the study. 


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8.1.2 
Data Monitoring Committee (DMC)  
An external, independent DMC will be used to oversee progress of the study and make 
recommendations relating to early closure/extension or alteration of the study based on 
ongoing monitoring of the study data.  The DMC will be comprised of members external 
to Amgen.  The DMC members will have access to treatment assignments in order to 
monitor safety and efficacy results to protect subjects.  To minimize the potential 
introduction of bias, the DMC members will not have any direct contact with the study 
team, site personnel, or subjects.  An independent statistical service provider will 
generate unblinded reports for review by the DMC.  If at any time there are safety 
concerns, the DMC will communicate the concerns to a representative from Amgen 
senior management.  A charter specifying the DMC functions will be written with the 
agreement of the DMC members. Last DMC was in March 2022 as all subjects have 
completed 12-month double blind treatment period of the study.   
8.1.3 
Primary Analysis  
The primary analysis will be conducted at the time of the final analysis.   
8.1.4 
Final Analysis  
The final analysis for the study, including the analysis of the primary efficacy endpoint, 
will be performed when all enrolled subjects have had the opportunity to complete the 
36-month follow-up.  
9. 
Data Screening and Acceptance  
9.1 
General Principles  
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses.  
9.2 
Data Handling and Electronic Transfer of Data  
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses, except for the imaging and 
laboratory data. The central imaging vendor will provide DXA scans, and X-ray (lateral 
thoracic, lumbar spine, knees, molars, cephalogram, and panoramic radiograms or 
radiographic assessment) data to Amgen cumulatively.  
The central laboratory vendor will provide all lab-related data, except for the samples 
analyzed at local laboratories. All laboratory values will be transferred cumulatively from 
the central laboratory.  


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Data screening will be performed periodically during the conduct of the study. The 
objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. Any 
questionable values or situations will be reported to GSO-DM for review or confirmation. 
As part of the data acceptance procedure, all datasets, planned tables, listings, and 
graphs will be generated and reviewed to identify any additional data issues. Any critical 
issues identified must be resolved with GSO-DM before final acceptance of the data. 
Cumulative data from the central vendors and Amgen will be transferred via a secure 
electronic transfer directly to the Independent Biostatistical Group supporting the DMC 
on a monthly basis initially. The frequency may change later during the study. 
This study will use the RAVE database. 
9.3 
Handling of Missing and Incomplete Data  
Subjects may have missing specific data points for a variety of causes.  In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a specific clinical measurement at its planned clinical visit.  
9.3.1 
Missing Data  
Missing data will not be imputed for this study, except for the sensitivity analysis for 
the primary endpoint in which missing data will be imputed based on placebo data 
using a multiple imputation approach incorporating baseline covariates. 
9.3.2 
Incomplete Dates  
NA 
9.3.2.1 
Other Incomplete Dates  
The following data will be imputed using the following algorithm:  
 
Adverse Events  
 
Concomitant Medications  
Imputation Rules for Partial or Missing Start Dates 


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1Impute the date of first dose; 2Impute the first of the month; 3Impute January 1 of the year; 4Impute 
January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date. 
9.4 
Detection of Bias  
The study has been designed to minimize potential bias by allocating subjects randomly 
to treatment groups, assessing endpoints, and handling withdrawals without knowledge 
of the treatment.  Other factors that may bias the results of the study include:  
 
important protocol deviations (IPDs) likely to impact the analysis and 
interpretation of the efficacy endpoints  
 
inadvertent breaking of the blind before formal unblinding  
 
IP dosing non-compliance  
 
the timing of and reasons for early withdrawal from treatment and from study  
The incidence of these factors will be assessed.  IPDs likely to impact the analysis and 
interpretation of the efficacy endpoints will be listed and/or tabulated.  Any breaking of 


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the blind for individual subjects prior to formal unblinding of the study will be 
documented.  The impact of such unblinding on the results observed will be assessed.   
9.5 
Outliers  
Scatter plots will be examined to identify outliers in continuous variables. Frequencies of 
the categorical data will be examined to identify questionable values. Outliers resulting 
from data entry error will be corrected in the database. Outliers that are not due to data 
entry error will be included in the analysis. The validity of any questionable values or 
outliers will be confirmed. No valid measurement will be excluded from descriptive or 
inferential analyses. However, sensitivity analyses may be conducted to evaluate the 
influence of extreme values in the data. These analyses will be documented in the 
clinical study report. 
9.6 
Validation of Statistical Analyses  
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
10. 
 Statistical Methods of Analysis   
10.1 
General Principles  
Descriptive statistics will be provided for demographics and subject characteristics, 
efficacy, PROs, and safety data. Descriptive statistics of continuous measurements will 
include mean, standard deviation, minimum, 25th percentile, median (50th percentile), 
75th percentile, maximum and number of nonmissing observations, while categorical 
data will be summarized using counts and percentages.  Subjects will be analyzed 
according to their randomized treatment group for efficacy endpoints and actual 
treatment received for safety endpoints.  Where appropriate safety data for the 12-month 
double-blind period, 24-month treatment period, 36-month overall study period and 12-
month observation period will be summarized separately.    
Data will be subject to ongoing checks for integrity, completeness and accuracy in 
accordance with the Data Management Plan with the expectation that all outstanding 
data issues are resolved ahead of the final lock.   


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10.2 
Subject Accountability  
The disposition of all enrolled subjects will be tabulated. Disposition for number of 
enrolled subjects participating in the PK/
substudy, disposition for number of 
randomized subjects, successfully completing IP administration during double-blind 
period and 24-month treatment period, completing double-blind period and 24-month 
period and completing the study will be included. The disposition of subjects will also 
include the number of subjects who withdrew from the IP, their reasons for withdrawal 
including protocol specified criteria reasons and the number of subjects who withdrew 
from study and their reasons for withdrawal.  IPDs including eligibility violations will be 
summarized and listed. 
10.3 
Important Protocol Deviations  
IPD categories are defined by the study team before the first subject’s visit and updated 
during the IPD reviews throughout the study prior to database lock.  These definitions of 
IPD categories, sub-category codes, and descriptions will be used during the course of 
the study.  Eligibility deviations are defined in the protocol. Summary table and listing of 
the deviations from eligibility criteria will be generated. 
10.4 
Demographic and Baseline Characteristics  
Subject demographic and baseline disease characteristics will be summarized based on 
FAS. They include the following endpoints: 
 
Race 
 
Ethnicity 
 
Age (in years) 
 
Age (in months) 
 
Gender 
 
Body composition (height [cm], weight [kg], and BMI [kg/m2]) 
 
Growth Velocity (height-for-age, weight-for-age, and BMI-for-age z-scores) 
 
Armspan 
 
Baseline BMD Z-score  
 
Fracture history including any fractures and nonvertebral fractures 
 
Prevalent vertebral fracture at baseline (based on screening spinal radiograph) 
 
Number of prevalent vertebral fractures at baseline (0, 1,  2; based on 
screening spinal radiograph) 
 
Selected Laboratory assessments  


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10.5 
Efficacy Analyses  
Table 1. Endpoint Summary Table  
Endpoint 
Primary Summary and 
Analysis Method 
(Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
Primary Efficacy Endpoint 
Change from baseline in 
lumbar spine BMD Z-score 
as assessed by DXA at 
12 months 
 
Primary DXA Analysis 
Set:  Analysis of 
covariance (ANCOVA) 
model including 
treatment (denosumab 
vs placebo), baseline 
age (age at informed 
consent) and baseline 
BMD Z-score. Missing 
baseline and 
postbaseline BMD Z-
scores will not be 
imputed. 
 
DXA Analysis Set: 
Repeated measures 
model including 
treatment (denosumab 
vs placebo), study visit 
(6 and 12 months), 
baseline age, baseline 
BMD Z-score, and 
treatment-by-visit 
included as an 
interaction with no 
imputation for missing 
data  
 
Full Analysis Set: 
An additional 
sensitivity analysis of 
the primary efficacy 
endpoint will be 
conducted including 
all randomized and 
treated subjects, with 
missing data for the 
primary endpoint 
imputed based on 
placebo data using a 
control-based pattern 
multiple imputation 
approach 


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Endpoint 
Primary Summary and 
Analysis Method 
(Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
incorporating 
baseline covariates .  
This sensitivity 
analysis will be 
performed using an 
ANCOVA model as 
described for the 
primary analysis of 
the primary endpoint. 
 
 
Key Secondary Endpoints 
Change from baseline in 
lumbar spine BMD Z-score 
as assessed by DXA at 6, 
18, 24, and 36 months  
 
DXA Analysis Set:  
Repeated measures 
model as described for 
the primary efficacy 
endpoint 
 
Change from baseline in 
total hip and femoral neck 
BMD Z-score as assessed 
by DXA at 6, 12, 18, 24, 
and 36 months 
 
DXA Analysis Set:  
Repeated measures 
model as described for 
the primary efficacy 
endpoint 
 
Subject incidence of X-ray 
confirmed long-bone 
fractures and new and 
worsening vertebral 
fractures during 12, 24, and 
36 months  
 
 
Full Analysis Set: 
Summary of the 
subject incidence of 
confirmed long-bone 
fractures and new and 
worsening vertebral 
fracture endpoints will 
 


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Endpoint 
Primary Summary and 
Analysis Method 
(Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
be provided for each 
timepoint of interest 
Subject incidence of 
improving vertebral 
fractures at 12, 24, and 36 
months compared to 
baseline  
 
Vertebral Fracture 
Analysis Set: 
Summary of the 
subject incidence of 
improving vertebral 
fracture will be 
provided for each 
timepoint of interest  
 
Subject incidence of new 
and worsening vertebral 
and nonvertebral fractures 
fractures during 12, 24, and 
36 months  
 
Full Analysis Set: 
Summary of the 
subject incidence of 
new and worsening 
vertebral and 
nonvertebral fracture 
endpoints will be 
provided for each 
timepoint of interest 
 
Change from baseline in 
patient reported outcomes 
(CHQ-PF-50, CHAQ 
disability index score, and 
WBFPRS) at 12, 24, and 
36 months 
 
PRO Analysis Set: 
Summary statistics 
without imputation for 
missing data 
 
Change from baseline in 
growth velocity, 
determined by calculating 
age-adjusted Z-scores for 
 
Growth Velocity 
Analysis Set: 
 


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Endpoint 
Primary Summary and 
Analysis Method 
(Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
height, weight, and BMI, at 
12, 24, and 36 months 
Summary statistics 
without imputation for 
missing data 
 
10.5.1 
Analyses of Primary Efficacy Endpoint  
10.5.1.1 
Primary Analysis  
The change from baseline in lumbar spine BMD Z-score at 12 months will be analyzed 
based on the primary DXA analysis set using an analysis of covariance (ANCOVA) 
model including treatment (denosumab vs placebo), baseline age (age at informed 
consent) and baseline BMD Z-score. Missing baseline and postbaseline BMD Z-scores 
will not be imputed.  
The superiority of denosumab compared to placebo for the primary efficacy endpoint will 
be estimated from the 12-month least-squares (LS) mean of the treatment difference 
(denosumab – placebo) and the corresponding 95 confidence interval and associated  
p-value.  See Appendix D (Code Fragment). 
The above primary analysis will be repeated based on the Per Protocol DXA Analysis 
Set, as an additional analysis for the primary efficacy endpoint. 
10.5.1.2 
Sensitivity Analysis  
A sensitivity analysis of the primary efficacy endpoint will be conducted in the DXA 
analysis set, in subjects with baseline and  1 postbaseline valid DXA assessments, 
using a repeated measures analysis. Treatment (denosumab vs placebo), study visit (6, 
and 12, months), baseline age, baseline BMD Z-score, will be included as fixed effects, 
and treatment-by-visit included as an interaction. Study visit will be treated as a 
categorical variable. The 12-month least-squares (LS) mean of the treatment difference 
(denosumab – placebo) and the corresponding 95 confidence interval and associated 
p-value will be estimated. 
Unstructured variance–covariance structure will be used for estimation in the repeated 


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measures analysis. Other variance-covariance structure may be substituted if 
convergence problem arises. 
An additional sensitivity analysis of the primary efficacy endpoint will be 
conducted including all randomized and treated subjects, with missing data for 
the primary endpoint imputed based on placebo data using a control-based 
pattern multiple imputation approach incorporating baseline covariates.  This 
sensitivity analysis will be performed using an ANCOVA model as described for 
the primary analysis of the primary endpoint. 
10.5.1.3 
Covariate Analysis  
The ANCOVA model specified for the primary analysis will be explored to include the 
remaining covariates of interest in Section 4.2.1; summary statistics for the results will 
include 12-month LS mean point estimate of the treatment difference 
(denosumab - placebo) and 2-sided 95 confidence interval.  No imputation will be 
performed for missing data. 
10.5.2 
Analyses of Secondary Efficacy Endpoint(s)  
Secondary efficacy endpoints will be assessed without imputation for missing data and 
without multiplicity adjustment. Due to the lack of a placebo control group after the 
double-blind treatment period, point estimates of the difference in a given endpoint 
between the two treatment groups based on their original randomization after M12 
cannot be interpreted as the treatment effect of denosumab compared with placebo 
anymore. Instead, the correct interpretation at different time points after M12 is listed in 
Table 2 and applicable to the following secondary efficacy endpoints: 
 
Change from baseline in BMD Z-score as assessed by DXA at 6, 18, 24, and 36 
months for each skeletal site (lumbar spine, total hip, and femoral neck). 


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Table 2. Summary of Description for Interpretation of LS Mean Difference Between 
Treatment Estimates After 12 Months  
Time point 
Interpretation of LS mean difference 
Months 18, 24  
M18: Effect of 18 months of denosumab 
treatment vs 12 months of placebo followed 
by 6 months of denosumab treatment. 
M24: Effect of 24 months of denosumab 
treatment vs 12 months of placebo followed 
by 12 months of denosumab treatment. 
Months 36 
M36: Effect of 24 months of denosumab 
followed by 12 months of no treatment versus 
12 months of placebo followed by 12 months 
of denosumab treatment followed by 
12 months of no treatment 
10.5.2.1 
Analyses of Other Changes From Baseline in BMD Z-score by DXA  
For each skeletal site (lumbar spine, total hip, and femoral neck), the change from 
baseline in BMD Z-score will be analyzed using repeated measures analysis with 
original randomized treatment group (denosumab vs placebo), visit (6,12, 18, 24, and 
36 months), baseline age and baseline BMD Z-score as fixed effects and treatment by 
visit included as an interacton term. Visit will be treated as categorical variable. LS mean 
difference between the two treatment groups (denosumab-placebo)  (95 CI) and 
assocaited p-value will be presented for total hip and femoral neck, and for each visit 
excluding the 12-month visit for lumbar spine. However, due to the lack of a placebo 
control group after the double-blind treatment period, all such estimates after month 12 
cannot be interpreted as the treatment effect anymore. Instead, the appropriate 
interpretations of these estimates are listed in Table 2. 
All analyses will be based on the skeletal site specific DXA analysis set at 36 months. 
Missing baseline and post-baseline BMD Z-scores will not be imputed; only subjects with 
baseline and at least one skeleton-specific DXA assessment visit will be included in the 
analysis. 


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10.5.2.2 
New and Worsening Vertebral Fractures and Nonvertebral Fractures  
Fracture analysis will use the data as mentioned below :  
1. Vertebral Fractures : central imaging vendor i.e fractures confirmed by vendor  
2. Nonvertebral Fractures other than long bone fracture : fractures reported on the 
Events eCRF which is confirmed by the central imaging vendor  
3. Long bone Fractures : fractures reported on the Events eCRF i.e fractures 
confirmed by imaging  
Summary of the subject incidence of the confirmed long-bone and new and worsening 
vertebral fractures and new and worsening vertebral and nonvertebral fractures will be 
provided from Baseline to each timepoint of interest (12, 24, and 36 months). 
10.5.2.3 
Improved Vertebral Fracture  
For each timepoint (12, 24, and 36 months), the subject incidence of improving vertebral 
fracture will be summarized based on the vertebral fracture analysis set.  
10.5.2.4 
Analyses of Patient Reported Outcomes  
Patient reported outcomes (CHQ-PF-50, CHAQ disability index score, and WBFPRS) 
and their changes from baseline will be summarized at 12, 24, and 36 months based on 
their respective PRO analysis set. There is no imputation for missing baseline or 
postbaseline data. WBFPRS, CHQ-PF-50  physical and psychological summary scores, 
and CHAQ disability score will be calculated as detailed in the Appendix E. 
10.5.2.5 
Growth Velocity  
For each time point, descriptive statistics of height-for-age, weight-for-age and 
BMI-for-age Z-scores, and the respective changes from baseline at 12, 24, and 
36 months based on the growth velocity analysis set.  There is no imputation for missing 
data.  
10.5.2.6 
Denosumab Serum Concentrations  
Descriptive statistics of denosumab serum concentration by visit (1, 10 and 30 days, and 
3, 6, 12 and 18 months) will be provided based on the PK analysis set. 
10.5.3 
Analyses of Exploratory Endpoints  


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10.6 
Safety Analyses  
Where appropriate safety endpoints will be analyzed separately for the 12-month 
double-blind period, 24-month treatment period and overall study period (36-month), 
Adverse events of hypercalcemia will be presented for 12 month observation period (24-
36 month) separately. 
10.6.1 
Adverse Events  
The Medical Dictionary for Regulatory Activities (MedDRA) version 26.0 or later will be 
used to code all events categorized as adverse events (AEs) to a system organ class 
and a preferred term.  Treatment-emergent AEs will be summarized separately for the 
12-month double-blind treatment period, 24-month treatment period, 36-month overall 


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study period according to the event onset date and based on the respective safety 
analysis set. 
Treatment-emergent AEs of Hypercalcemia events will be summarized during 12-month 
observation period separately under safety analysis set for 12-month observation period.   
The subject incidence of AEs will be summarized for all treatment-emergent AEs, 
serious AEs, AEs leading to withdrawal of investigational product, and fatal AEs by 
system organ class and preferred term in descending order of frequency. 
10.6.2 
Adverse Events of Interest  
Subject incidence of treatment-emergent AEs of interest (EOIs) will also be summarized 
according to their categories.  This tentative list has been based on the EOIs identified 
for denosumab in the osteoporosis indication, and may be revised and changed later on 
to better reflect the GiOP pediatric population. 
 
hypocalcemia  
 
hypercalcemia 
 
hypersensitivity 
 
serious bacterial cellulitis (skin infection)  
 
osteonecrosis of the jaw (ONJ)  
In addition, subject incidence of Hypercalcemia following denosumab during the 12-
month observation period will also be summarized.   
10.6.3 
Laboratory Test Results  
Actual values and changes from baseline in each parameter will be descriptively 
summarized at each visit. For serum calcium, serum albumin-adjusted calcium, 
phosphorus, and alkaline phosphatase, summary of the percent change from baseline 
will also be provided.  Shifts in laboratory parameters between baseline and the most 
extreme postbaseline values will be assessed based on the Common Terminology 
Criteria for Adverse Events v4.0. See Appendix F.   
All laboratory analyses will be based on the safety analysis set for the respective period 
of interest. Subjects with missing data for a scheduled visit will not contribute to the 
tabulation for that timepoint (no imputation). Visit windows will be used for these 
summaries as described in Appendix A.  
Potential Hy’s law cases will be summarized. A listing of liver function tests will be 
produced for the subjects who meet the criteria for potential Hy’s law.   


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10.6.4 
Vital Signs  
Descriptive statistics of the actual values and changes from baseline in vital signs (heart 
rate, respiration rate, temperature) will be presented by visit based on the safety analysis 
set. Subjects with missing data for a scheduled visit will not contribute to the tabulation 
for that time point (no imputation). 
10.6.5 
Antidenosumab Antibody  
Subjects receiving at least 1 dose of denosumab will be tested for antidenosumab 
antibodies. The percentages of subjects who tested positive (binding or neutralizing) for 
antidenosumab antibodies will be descriptively summarized by visit. 
If a subject tests positive for antibodies against denosumab, the relationship between the 
presence of antibodies, adverse events, bone mineral density, and 
 
 will be evaluated. 
Immunogenic response during the study will be described by tabulating the numbers and 
percentages of subjects who tested positive for (binding and neutralizing) 
antidenosumab antibodies based on the safety analysis set. 
10.6.6 
Exposure to Investigational Product  
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group.    
10.6.7 
Exposure to Concomitant Medication  
During the 12-month observation period, bisphosphonate use will be summarized. 


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11. 
Literature Citations / References  
Centers for Disease Control and Prevention, National Center for Health Statistics. CDC 
growth charts: United States. May 2000 http://www.cdc.gov/growthcharts/2000 Centers 
for Disease Control and Prevention Growth Charts for the United States:Methods and 
Development:http: //www.cdc.gov/growthcharts/2000growthchart-us.pdf 
Rudge S, Hailwood S, Horne A, et al. Effects of once-weekly oral alendronate on bone in 
children on glucocorticoid treatment. Rheumatology. 2005;44:813-818. 
Sbrocchi AM, Forget S, Laforte D, et al. Zoledronic acid for the treatment of osteopenia 
in pediatric Crohn’s disease. Pediatrics International. 2010;52:754-761. 
Simm PJ, Johannesen J, Briody J, et al. Zoledronic acid improves bone mineral density, 
reduces bone turnover and improves skeletal architecture over 2 years of treatment in 
children with secondary osteoporosis. Bone. 2011;49:939-943. 
Ward K, Cowell CT and Little DG. Quantification of metaphyseal modeling in children 
treated with bisphosphonates. Bone. 2005; 36: 999-1002 
12. 
Changes From Protocol-specified Analyses  
In response to a FDA request, imputation will be used in an additional sensitivity 
analysis for the primary efficacy endpoint to use a control based multiple 
imputation approach based on placebo data incorporating baseline covariates, as 
described in Section 10.5.1.2.   
  
As described in Section 10.5.2.2, fracture analysis will use the data as mentioned 
below:  
1. Vertebral Fractures : central imaging vendor i.e fractures confirmed by vendor  
2. Nonvertebral Fractures other than long bone fracture : fractures reported on the 
Events eCRF which is confirmed by the central imaging vendor  
3. Long bone Fractures : fractures reported on the Events eCRF i.e fractures 
confirmed by imaging 


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13. 
Appendices  


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Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs  
A.1  Analysis Visit Windows 
Per protocol, all tests and procedures scheduled on Study Day 1, 10 and 30  will be 
performed  3 days of the scheduled day and  7 days for visits at Months 3, 6, 12, 18, 
24, 30, and 36. To allow for variations in scheduling, the following sets of analysis visit 
windows will be used to assign evaluations to a most appropriate nominal visit for  
analysis. Furthermore, there will be no gaps between consecutive analysis visit windows 
in order to include as many data points as possible for summarization. 
Regardless of the width of the analysis visit window, if more than 1 visit falls within the 
defined window, the result from the visit closest to the target day will be used in the 
analysis. If 2 evaluations are of the same distance from the target day, the result from 
the later visit will be used in the analysis.  
Table A.1.1  Lateral Thoracic and Lumbar Spine X-ray,CHQ-PF50, CHAQ Disability 
Score and WBFPS 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
1 
Last evaluation on or before Study Day 1 
Month 12 
365 
Study Day 2  to 548 
Month 24 
731 
Study Day 549 to 913 
Month 36 
1096 
 Study Day 914  
Table A.1.2  DXA  
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline a 
1 
Last evaluation on or before Study Day 1.  
Month 6  
183 
Study Day 2 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
Study Day 642 to 915 
Month 36 
1098 
 Study Day 916  
a If results from baseline DXA are not available, the results from the scan taken on or before Study Day 60 
will be considered as baseline values and not the 6-month values.   


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Table A.1.3  X-ray AP Knees 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
1 
Last evaluation on or before Study Day 1 
Month 6 
183 
Study Day 2 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
Study Day 642 to 824 
Month 30 
915 
Study day 825 to 1007 
Month 36 
1098 
 Study Day 1008  
Table A.1.5  Vital Signs, 
 and Serum Chemistry 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Screening 
-38 
Last evaluation on or before Study Day -1 
Baseline 
1 
Study day 1 to 5 
Study Day 10 
10 
Study day 6 to 20 
Study Day 30 
30 
Study day 21 to 40 
Month 3 
92 
Study day 46 to 138 
Month 6 
183 
Study Day 139 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
Study Day 642 to 824 
Month 30 
915 
Study day 825 to 1007 
Month 36 
1098 
 Study Day 1008  


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Table A.1.6  Physical Examination and Haematology 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Screening 
-38 
Last evaluation on or before Study Day -1 
Baseline 
1 
Last evaluation on or before Study Day 1 
Month 3 
91 
Study day 2 to 137 
Month 6 
183 
Study Day 138 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
Study Day 642 to 824 
Month 30 
915 
Study day 825 to 1007 
Month 36 
1098 
 Study Day 1008  
Table A.1.7  Height and Weight 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Screening 
-38 
Last evaluation on or before Study Day -1 
Baseline 
1 
Last evaluation on or before Study Day 1 
Month 6 
183 
Study Day 2 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
Study Day 642 to 824 
Month 30 
915 
Study Day 825 to 1007 
Month 36 
1098 
 Study Day 916 1008 


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Table A.1.8  Pregnancy Test  
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Screeninga 
-38 
Last evaluation on or before Study Day-1 
Baseline 
1 
On study day 1 
Month 6 
183 
Study Day 2 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
Study Day 642 to 915 
Month 36 
1098 
 Study Day 916 
a Only for Pregnancy Test 
Table A.1.9  Armspan 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
-38 
Last evaluation on or before Study Day 1 
Month 12 
366 
Study Day 2  to 549 
Month 24 
732 
Study Day 550 to 915 
Month 36 
1098 
 Study Day 916 
Table A.1.10  Antidenosumab Antibody Assay 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
1 
On study day 1 
Day 30 
30 
Study Day 2 to 61 
Month 3 
92 
Study Day 62 to 138 
Month 6 
183 
Study Day 139 to 275 
Month 12 
366 
Study Day 276 to 549 
Month 24 
732 
 Study Day 550 
Table A.1.11  Tanner Stage 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
1 
Last evaluation on or before Study Day 1 
Month 6 
183 
2 to 275 
Month 12 
366 
276 to 458 
Month 18 
549 
459 to 641 
Month 24 
732 
642 to 824 
Month 30 
915 
825 to 1007 
Month 36 
1098 
 Study Day 1008 


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Appendix B.  Age Conversion in Months  
Whole-year Age 
Partial-year Age (Months) 
Years Months 
0 to 
 1 
1 to 
 2 
2 to 
 3 
3 to 
 4 
4 to 
 5 
5 to 
 6 
6 to 
 7 
7 to 
 8 
8 to 
 9 
9 to 
 10 
10 to 
 11 
11 to 
 12 
5 
60 
60 
61 
62 
63 
64 
65 
66 
67 
68 
69 
70 
71 
6 
72 
72 
73 
74 
75 
76 
77 
78 
79 
80 
81 
82 
83 
7 
84 
84 
85 
86 
87 
88 
89 
90 
91 
92 
93 
94 
95 
8 
96 
96 
97 
98 
99 
100 101 102 103 104 
105 
106 
107 
9 
108 
108 
109 
110 
111 
112 113 114 115 116 
117 
118 
119 
10 
120 
120 
121 
122 
123 
124 125 126 127 128 
129 
130 
131 
11 
132 
132 
133 
134 
135 
136 137 138 139 140 
141 
142 
143 
12 
144 
144 
145 
146 
147 
148 149 150 151 152 
153 
154 
155 
13 
156 
156 
157 
158 
159 
160 161 162 163 164 
165 
166 
167 
14 
168 
168 
169 
170 
171 
172 173 174 175 176 
177 
178 
179 
15 
180 
180 
181 
182 
183 
184 185 186 187 188 
189 
190 
191 
16 
192 
192 
193 
194 
195 
196 197 198 199 200 
201 
202 
203 
17 
204 
204 
205 
206 
207 
208 209 210 211 212 
213 
214 
215 


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Appendix C.  Bone Codes for Nonvertebral Fractures  
Table C1  Bone Codes for Nonvertebral Fracturesa 
Code 
Name 
 
Code 
Name 
100 
Skull 
 
480 
Acetabulum 
120 
Facial 
 
502 
Femur Neck 
122 
Mandible 
 
503 
Femur Intertrochanter 
210 
Cervical Vertebrae 
 
504 
Femur Subtrochanter 
240 
Sacrum 
 
512 
Femur Midshaft 
250 
Coccyx 
 
513 
Femur Distal 
310 
Ribs 
 
520 
Patella 
320 
Sternum 
 
530 
Fibula 
401 
Clavicle 
 
531 
Fibula Proximal 
402 
Scapula 
 
532 
Fibula Shaft 
410 
Humerus 
 
533 
Fibula Distal 
411 
Humerus Proximal 
 
540 
Tibia 
412 
Humerus Shaft 
 
541 
Tibia Proximal 
413 
Humerus Distal 
 
542 
Tibia Shaft 
420 
Radius 
 
543 
Tibia Distal 
421 
Radius Proximal 
 
550 
Metatarsus 
422 
Radius Shaft 
 
560 
Tarsus 
423 
Radius Distal 
 
570 
Toe Phalanges 
430 
Ulna 
 
620 
Ilium 
431 
Ulna Proximal 
 
630 
Ischium 
432 
Ulna Shaft 
 
640 
Pubis 
433 
Ulna Distal 
 
888 
Other (Specify) 
450 
Carpus 
 
 
 
460 
Metacarpus 
 
 
 
470 
Finger Phalanges 
 
 
 
a From BioClinica Charter for Independent Imaging Assessment 


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Table C2  Mapping Nonvertebral Fracture Locationsa 
Fracture Location Assessed by 
BioClinica 
eCRF Locations 
Acetabulum 
Acetabulum Fracture 
Carpus 
Carpus Fracture  
Cervical Vertebrae 
Cervical Vertebrae Fracture 
Clavicle 
Clavicle Fracture 
Coccyx 
Coccyx Fracture 
Femur Distal 
Femur Distal Fracture 
Femur Intertrochanter 
Femur Intertrochanter Fracture 
Femur Midshaft 
Femur Midshaft Fracture 
Femur Neck 
Femur Neck Fracture 
Femur Subtrochanter 
Femur Subtrochanter Fracture  
 
Fibula 
Fibula Fracture 
Fibula Distal 
Fibula Distal Fracture 
Fibula Proximal 
Fibula Proximal Fracture 
Fibula Shaft 
Fibula Shaft Fracture 
Humerus 
Humerus Fracture 
Humerus Distal 
Humerus Distal Fracture 
Humerus Proximal 
Humerus Proximal Fracture 
Humerus Shaft 
Humerus Shaft Fracture 
Ilium 
Ilium Fracture 
Ischium 
Ischium Fracture 
Mandible 
Mandible Fracture 
Metacarpus 
Metacarpus Fracture 
Metatarsus 
Metatarsus Fracture 
Patella 
Patella Fracture 
Pubis 
Pubis Fracture 
Radius 
Radius Fracture 
Radius Distal 
Radius Distal Fracture 
Radius Proximal 
Radius Proximal Fracture 
Radius Shaft 
Radius Shaft Fracture 
Ribs 
Ribs Fracture 
Sacrum 
Sacrum Fracture 
Scapula 
Scapula Fracture 
Sternum 
Sternum Fracture 
Tarsus 
Tarsus Fracture 
Tibia 
Tibia Fracture 
Tibia Distal 
Tibia Distal Fracture 
Tibia Proximal 
Tibia Proximal Fracture 
Tibia Shaft 
Tibia Shaft Fracture 
.Page 1 of 2 
Footnotes defined on last page of the table 


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Table C2  Mapping Nonvertebral Fracture Locationsa 
Fracture Location Assessed by 
BioClinica 
eCRF Locations 
Ulna 
Ulna Fracture 
Ulna Distal 
Ulna Distal Fracture 
Ulna Proximal 
Ulna Proximal Fracture 
Ulna Shaft 
Ulna Shaft Fracture 
Page 2 of 2 
a From BioClinica Charter for Independent Imaging Assessment and Events eCRF.  Finger, toe, 
skull, and facial fractures are not included for nonvertebral fractures in the study. 


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Appendix D.  Code Fragments  
D.1 Analysis of covariance (ANCOVA) Model for the Change from Baseline in BMD 
Z-score. 
D.2 Repeated-measure Analysis for the Change from Baseline BMD Z-score. 
D.3 Growth Velocity 
D.3.1 Age-adjusted Z-score 
The instructions below are given for the calculation of age-adjusted Z-scores for height 
(also called height-for-age Z-scores). Similar calculations can be performed for 
weight-for-age and BMI-for-age Z-scores. 
Height measurements are normalized for age (given in months) and sex by converting 
them to Z-score (the number of SD above or below the mean for sex and age) using the 
National Center for Health Statistics percentiles based on the 2000 Center for Disease 
Control and Prevention (CDC) growth charts for ages 0 to less than 20 years of age 
(http://www.cdc.gov/growthcharts/cdc_charts.htm). The CDC Anthropometric Software 
Package 3.0. Z scores are calculating as: 


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𝐻𝑒𝑖𝑔ℎ𝑡−𝑓𝑜𝑟−𝑎𝑔𝑒 𝑍−𝑠𝑐𝑜𝑟𝑒  
[(ℎ𝑒𝑖𝑔ℎ𝑡 )
𝑀
)
𝐿
−1 ]
𝑆∗𝐿
 , 
where the age-specific M, S and L values are provided by the CDC growth charts. 
To calculate height-for-age Z-scores follow the steps below: 
Step 1. From site http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm, 
download the SAS program (cdc-source-code.sas) and the reference data file 
(CDCref_d.sas7bdat). Do not alter these files, but move them to a folder (directory) that 
SAS can access. 
Step 2. Create a libname statement in your SAS program to point at the folder location of 
‘CDCref_d.sas7bdat’. 
Step 3. Set your existing dataset containing height, weight, sex, age and other variables 
[ie, subject ID, visit (baseline , 12, 24 and 36 months), cohorts],  into a temporary 
dataset, named mydata. Make sure the following variables are renamed and coded as 
follows: 
MYDATA Variables 
Variable 
Description 
agemos 
Child's age in months; must be present. The program assumes you know the 
number of months to the nearest day based on the dates of birth and 
examination. For example, if a child was born on Oct 1, 2007 and was examined 
on Nov 15, 2011, the child’s age would be 1506 days or 49.48 months, rounded 
to 1 decimal place (ie 49.5 months). In everyday usage, this age would be stated 
as 4 years or as 49 months. However, if 49 months were used as the age of all 
children who were between 49.0 and 50 months in your data, the estimated 
z-scores would be slightly too high because, on average, these children would be 
taller, weigh more, and have a higher BMI than children who are exactly 
49.0 months of age. This bias would be greater if only completed years of age 
were known, and the age of all children between 4 and 5 years was represented 
as 48 months. 
If age is known only as the completed number of months (as is data from 
NHANES 1988-1994 and 1999-2010), consider adding 0.5 so that the maximum 
error would be 15 days. If age is given as the completed number of years, 
multiply by 12 and consider adding 6. 
sex 
Coded as 1 for boys and 2 for girls. 
height 
Height in cm. This is either standing height (for children who are  24 months of 
age or recumbent length (for children  24 months of age); both are input as 
height. If standing height was measured for some children less than 24 months of 
age, you should add 0.8 cm to these values (see page 8 of 


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http://www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf 
). If recumbent length 
was measured for some children who are  24 months of age, subtract 0.8 cm. 
weight 
Weight (kg) 
bmi 
BMI (Weight (kg) /Height (m)2). If your data doesn’t contain BMI, the program 
calculates it. If BMI is present in your data, the program will not overwrite it. 
headcir 
Head circumference (cm) 
Z-scores and percentiles for variables that are not in mydata will be coded as missing (.) 
in the output dataset (named _cdcdata). Sex (coded as 1 for boys and 2 for girls) and 
agemos must be in mydata. It’s unlikely that the SAS code will overwrite other variables 
in your dataset, but you should avoid having variable names that begin with an 
underscore, such as _bmi. 
Step 4. Copy and paste the following line into your SAS program to call for the SAS 
macro; location means the full path to where the macro program was copied:  
include ‘location\CDC-source-code.sas'; run; 
Step 5. Submit the include statement. This will create a dataset, named _cdcdata, 
which contains all of your original variables along with z-scores, percentiles, and flags for 
extreme values. The names and descriptions of these new variables in _cdcdata are in 
the table below. Additional information on the extreme z-scores is given in a separate 
section that follows the “Example SAS Code”. 
Z-Scores, Percentiles, and Extreme Values 
Description 
Variable 
Cutoff for Extreme 
Z-Scores 
Percentile Z-score 
Modified 
Z-score to 
Identify 
Extreme 
Values 
Flag for 
Extreme  
Values 
Low 
z-score 
(Flag 
coded 
as -1) 
High 
z-score 
(Flag 
coded 
as 1) 
Weight-for-age for 
children between 0 and 
239 (inclusive) months of 
age 
wapct 
waz 
_Fwaz 
_bivwt 
 -5 
 5 
Height-for-age for children 
between 0 and 239 
(inclusive) months of age. 
hapct 
haz 
_Fhaz 
_bivht 
 -5 
3 
Weight-for-height for 
children with heights 
between 45 and 121 cm 
(this height range 
whpct 
whz 
_Fwhz 
_bivwh 
 -4 
5 


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approximately covers 
ages 0 to 6 y) a 
BMI-for-age for children 
between 24 and 239 
months of age 
bmipct 
bmiz 
_Fbmiz 
_bivbmi 
 -4 
5 
Head circumference-for-
age for children between 0 
and 35 (inclusive) months 
of age a 
headcpct 
headcz _Fheadcz 
_bivhc 
 -5 
5 
a Not applicable to this study 
Step 6. Examine the new dataset, _cdcdata, with PROC MEANS or some other 
procedure to verify that the z-scores and other variables have been created. If a variable 
in the table was not in your original dataset (eg, head circumference), the output dataset 
will indicate that all values for the percentiles and z-scores of this variable are missing. If 
values for other variables are unexpectedly missing, make sure that you’ve renamed and 
recoded variables as indicated in the table and that your SAS dataset is named mydata. 
The program should not modify your original data, but will add new variables to your 
original dataset. 
Additional Information 
Z-scores are calculated as  
 Z 
((value
M )
L
- 1)
S*L
, 
in which ‘value’ is the child’s height, BMI, weight, etc. The L, M, and S values are in 
CDCref_d.sas7bdat and vary according to the child’s sex and age or according to the 
child’s sex and height. 
Validation of the SAS program (cdc-source-code.sas) will be performed by checking the  
percentiles associated to a subset of the subjects against the CDC percentiles tables 
available at the site. 
D.3.2 Growth Velocity 
Growth velocity at 36 months is then determined by the change from baseline in 
height-for-age Z-scores (haz). Similar calculations are done for weight-for-age (waz) and 
BMI-for-age (bmiz) Z-scores. 


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Appendix E.  Patient-reported Outcome Forms/Instruments  
E.1  Wong-Baker FACES Pain Rating Scale (WBFPRS) 
At each assessment (baseline, 12, 24 and 36 months), subjects are asked to choose a 
face that best describes their own pain; the corresponding number (0, 2, 4, 6, 8, or 10) is 
recorded. 
This rating scale is recommended for subjects age 3 years and older, therefore only 
subjects at the age of 3 or older at baseline will be asked to respond. 
There is no imputation for missing values. 
Change from baseline will be calculates for those subjects with baseline and 
post-baseline assessments at the timepoint of interest (12, 24 or 36 months). 
 
E.2  Child Health Questionnaire – Parent Form 50 
The scales and corresponding items for the CHQ-PF50 are listed below in the order in 
which they appear in the health survey. Specific instructions for their scoring are given in 
the Child Health Questionnaire Scoring and Interpretation Manual , 2013 
HealthActCHQ Inc Boston MA. A summary of those instructions is provided below. 


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Scale/Item Name 
(and abbreviation) 
Questions  
No. of 
Items 
Questionnaire Section 
Global Health (GH) 
1.1 
1 
Your Child’s Global Health (1) 
Physical Functioning (PF) 
2.1.a - 2.1.f   
6 
Your Child’s Physical Activities 
(2) 
Roles/Social Limitations- 
Emotional/Behavioral (REB) 
3.1.a - 3.1c  
3 
Your Child’s Everyday 
Activities (3.1) 
Roles/Social Limitations- 
Physical (RP) 
3.2.a - 3.2.b  
2 
Your Child’s Everyday 
Activities (3.2) 
Bodily Pain/Discomfort (BP) 
4.1, 4.2 
2 
Pain (4) 
Behavior (BE) 
5.1.a - 5.1.e, 5.2 
6 
Behavior (5) 
Mental Health (MH) 
6.1.a - 6.1.e 
5 
Well-Being (6) 
Self Esteem (SE) 
7.1.a - 7.1.f 
6 
Self Esteem (7) 
General Health Perception 
(GH) 
8.1.a - 8.1.e   
5 
Your Child’s Health (8.1) 
Change in health (CH)  
8.2  
1  
Your Child’s Health (8.2)  
Parental Impact – Emotional 
(PE) 
9.1.a - 9.1.c  
3 
You and Your Family (9.1) 
Parental Impact – Time (PT) 
9.2.a - 9.2.c 
3 
You and Your Family (9.2) 
Family Activity (FA)  
9.3a – 9.3 f  
6  
You and Your Family (9.3)  
Family Cohesion (FC)  
9.4  
1  
You and Your Family (9.4)  
Items should be recoded and recalibrated: 
 
Recoding is necessary to ensure that all items are positively scored so that a 
higher score indicates better health. Scores vary from 5 to 1. 
 
Recalibrating is performed for two items (Question 1.1 and 5.2 ) with an 
“excellent to poor” response as given below. 
Table Recalibration 
Response choices 
Precoded Value 
Final Value 
Excellent 
1 
5.0 
Very good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.2 
Poor 
5 
1.0 


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 
Recalibrating is performed for one item (Question 4.1) with a “none to very 
severe” response as given below. 
Response choices 
Precoded Value 
Final Value 
None  
1 
6 
Very mild  
2 
5 
Mild  
3 
4 
Moderate  
4 
3 
Severe  
5 
2 
Very severe  
6 
1 
 
Recalibrating is performed for one item (Question 4.2) with a “none of the time to 
every/almost every day” response as given below. 
Response choices 
Precoded Value 
Final Value 
None of the time  
1 
6 
Once or twice  
2 
5 
A few times  
3 
4 
Fairly often  
4 
3 
Very often  
5 
2 
Every/almost every day  
6 
1 
 
Recalibrating is performed for one item (Question 6.1.e) with an “all of the time to 
none of the time” response as given below. 
Response choices 
Precoded Value 
Final Value 
All of the time  
1 
5 
Most of the time  
2 
4 
Some of the time  
3 
3 
A little of the time  
4 
2 
None of the time  
5 
1 
 
Recalibrating is performed for six items (Question 7.1.a - 7.1.f) with a “very 
satisfied to very dissatisfied” response as given below. 
Response choices 
Precoded Value 
Final Value 
Very satisfied 
1 
5 
Somewhat satisfied 
2 
4 
Neither satisfied nor dissatisfied 
3 
3 
Somewhat dissatisfied 
4 
2 
Very dissatisfied 
5 
1 


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 
Recalibrating is performed for two items (Question 8.1.b, 8.1.d) with a “definitely 
true to definitely false” response as given below. 
Response choices 
Precoded Value 
Final Value 
Definitely true 
1 
5 
Mostly true 
2 
4 
Don't know 
3 
3 
Mostly false 
4 
2 
Definitely false 
5 
1 
 
 
Recalibrating is performed for a item (Question 8.2) with a “Much better now 
than 1 year ago” to “Much worse now than 1 year ago” response as given 
below. 
Response choices 
Precoded Value 
Final Value 
Much better now than 1 year ago 
1 
5 
Somewhat better now than 1 year ago 
2 
4 
About the same now as 1 year ago 
3 
3 
Somewhat worse now than 1 year ago 
4 
2 
Much worse now than 1 year ago 
5 
1 
 
 
Recalibrating is performed for three items (Question 9.1.a - 9.1.c) with a “none at 
all to a lot” response as given below. 
Response choices 
Precoded Value 
Final Value 
None at all  
1 
5 
A little bit  
2 
4 
Some  
3 
3 
Quite a bit  
4 
2 
A lot  
5 
1 
For subjects that complete half or more of the items in each scale, the mean of the scale 
will be calculated based on the available responses by adding all non-missing values 
and divided by the number of non-missing items; otherwise scale is set to missing. Mean 
is provided with 1 decimal place. After calculating the mean for each subject, it will need 
to be standardized usinf the formula as: [(Mean -1)/N]*100. The transformed score 
should be rounded to 0 decimal place.  


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For each of the 10 scales in Table below, from the manual, each subject’s non-missing 
mean is then standardized by using the Mean and SD of the reference population. For 
example, the mean for REB is standardized as: 
REB_Z  (REB - 90.4013015) / 19.5067502 
CHQ-PF50 Scale and Factor Score Coefficients 
CHQ-PF50 
Scale 
No. of 
Completed 
Items* 
N 
Mean 
SD 
Factor Score Coefficients 
PhS 
PsS 
GH 
3 
4 
66.6958379 
19.3564297 
0. 29460 
-0.05547 
PF 
3 
3 
90.8525408 
16.3826344 
0. 37138 
-0. 09243 
REB 
2 
3 
90.4013015 
19.5067502 
-0.01178 
0. 21155 
RP 
1 
3 
91.4951246 
18.9079749 
0. 34493 
-0.06973 
BP 
1 
5 
78.6833515 
20.7355708 
0. 27883 
-0. 05514 
BE 
3 
4 
72.3086051 
17.1447913 
-0.12675 
0. 27911 
MH 
3 
4 
77.2595806 
13.6861999 
-0.08263 
0. 25335 
SE 
3 
4 
79.2555314 
17.8308361 
-0.09480 
0. 24792 
PE 
2 
4 
73.9788476 
21.406013 
0. 06063 
0. 19823 
PT 
2 
4 
83.8816188 
20.2901603 
0. 09113 
0. 16944 
* The raw scores can be created by computing the algebraic mean of items when the respondents who 
completed at least the number of items listed in the table; otherwise both the raw scores and transformed 
scores should be set to missing. 
Values are given with 2 decimal places. 
The aggregate CHQ-PF50 physical summary score (PhS) consists of multiplying each 
CHQ-PF50 scale z-score by its respective physical factor score coefficient (PhS) and 
summing the ten products. Result is given with 6 decimal places and is called PhS_raw. 
The formula of calculating aggregate PhS (PhS_raw) is:  
PhS_raw  (GH_Z * 0.29460)  (PF_Z * 0.37138)  (REB_Z * -0.01178)  (RP_Z * 
0.34493)  (BP_Z * 0.27883)  (BE_Z * -0.12675)  (MH_Z * -0.08263)  (SE_Z * -
0.09480)  (PE_Z * 0.06063)  (PT_Z * 0.09113) 
And finally the transformed physical (PhS) is calculates as: 


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PhS  50  (PhS_raw * 10) 
PhS should be rounded to 1 decimal place. 
Similarly, the aggregate CHQ-PF50 psychological summary score (PsS) consists of 
multiplying each CHQ-PF50 scale z-score by its respective psychological factor score 
coefficient (PsS) and summing the ten products. Result is given with 6 decimal places 
and is called PsS_raw. The formula of calculating aggregate PsS (PsS_raw) is: 
PsS_raw  (GH_Z * -0.05547)  (PF_Z * -0.09243)  (REB_Z * 0.21155)  (RP_Z * -
0.06973)  (BP_Z  * -0.05514)   (BE_Z * 0.27911)  (MH_Z * 0.25335)  (SE_Z * 
0.24792)  PE_Z * 0.19823)  (PT_Z  * 0.16944)  
And finally the transformed physical (PsS) is calculates as: 
PsS   50  (PsS_raw * 10) 
PsS should be rounded to 1 decimal place. 
For each subject, the summary scale scores (PhS and PsS) are set to missing if the 
subject is missing any one of the ten CHQ-PF50. To minimize the number of summary 
scores missing and for a further comparison with original PhS and PsS, each of the 
ten scale scores is calculated if half or more of the items are completed. 
E.3  Childhood Health Assessment Questionnaire (CHAQ) 
The disability domain (questions 1-54) of the CHAQ was used to measure the subject’s 
assessment of physical functioning or the parent’s assessment of the child’s physical 
functioning. The disability index comprises eight categories (dressing and grooming, 
arising, eating, walking, hygiene, reaching, gripping, and activities). Scoring ranged from 
1 to 5; 1 was “Without ANY difficulty,” 2 was “With SOME difficulty,” 3 was “With MUCH 
difficulty,” and 4 was “UNABLE to do”. An answer of “not applicable” was scored as a 5, 
but was not counted. If a child required assistance from another person or used an aid or 
other device for any of the eight categories, the minimum score for that category was to 
be recorded as a 3. The CHAQ questions would then need to be converted to a 0 to 
3 scaled score. 
Afterwards, the CHAQ score using the aids (and/or devices) indicator is computed by 
taking the maximum score of the questions in each domain (range: 0, 3) and whether or 
not aids/devices are used (range: 0, 1): 
A   
max(dressing & grooming domain questions, 2*aids indicator)   


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 max(rising domain questions, 2*aids indicator)  
 max(eating domain questions, 2*aids indicator)  
max(walking domain questions, 2*aids indicator)  
 max(hygiene domain questions, 2*aids indicator)  
 max(reach domain questions, 2*aids indicator)  
 max(grip domain questions, 2*aids indicator)  
 max(usual activities domain questions, 2*aids indicator). 
CHAQ A/(total number of sub-domains with at least 6 non-missing) 
The CHAQ score is given with 2 decimal places. No missing values are imputed. If any of 
the domain questions are missing, but the aids/device indicator is non-missing, the domain 
can still be computed. However, if a domain is missing all domain questions (or is scored 
as “not applicable”) and is missing aids/device indicators, then the domain score is 
considered missing. The CHAQ score is not computed when the subject/parent provides 
answers in fewer than six domains (normally coded as “UNK” in the database). 
The following table shows the contribution of the 54 questions used to calculate the 
CHAQ: 


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CHAQ Domains and Scores 
CHAQ Domains 
Domian Components:  At least 
6 domains must have scores to 
compute the CHAQ. 
CHAQ Component 
Score Definition: 
Domain 
Questions 
Aids/Devices 
Questions 
Dressing/Grooming 1, 2, 3, 4 
16, 20 
First set the Domain 
Component to missing 
if the original 
question  5 for Scale 
Range Questions. 
Then, convert values of 
each question to a 
scale of 0-3 (Without 
ANY difficulty  0, With 
SOME difficulty  1, 
With MUCH 
difficulty  2, UNABLE 
to do  3). If 
Aids/Devices  Yes for 
Yes/No questions, then 
set the minimum CHAQ 
Domain to be equal 
to 2. 
Specific terms are 
mapped to current 
component for question 
19, 53 or 54. 
Set max of the Domain 
Questions and 
Aid/Devices Questions 
as the component 
score. 
Note: 
Questions 19, 53 and 
54 use format to define 
which category. 
Arising 
5, 6 
18, 21 
Eating 
7, 8, 9 
17, 22 
Walking 
10, 11 
12, 13, 14, 15, 23 
Hygiene 
24, 25, 26, 27, 28 43, 44, 46, 48, 49 
Reach 
29, 30, 31, 32 
47, 50 
Grip 
33, 34, 35, 36, 37  45, 51 
Activity 
38, 39, 40, 41, 42 52 


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Appendix F.  Reference Values/Toxicity Grades and Lab Assessments  
Central 
Laboratory 
Chemistry 
Central 
Laboratory 
Coagulation 
Central 
Hematology 
Serology 
Other 
assessments 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
25(OH) vitamin D 
Calciuma 
Adjusted calciuma 
Magnesium 
Phosphorusa 
Glucose 
BUN 
Creatinine 
Total bilirubin 
Alk phosa 
AST (SGOT) 
ALT (SGPT) 
GGTb 
CPKb 
PT/INRc 
 
RBC 
Hemoglobin 
Platelets 
WBC 
Differential 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Neutrophils 
HIV-1, -2 antibody 
HBsAg 
Hep C Ab 
Serum 
denosumaba 
Anti denosumab 
antibodya 
ALT  Alanine aminotransferase; AST  Aspartate aminotransferase;
 BUN  Blood urea nitrogen; CPK  Creatine phosphokinase; DILI  Drug-induced liver 
injury; GGT  Gamma-glutamyltransferase; HBsAg  Hepatitis B surface antigen;  
Hep C Ab  Hepatitis C antibody; HIV  Human immunodeficiency virus; INR  International normalized 
ratio; PT  Prothrombin time; RBC  Red blood cell;
 
ULN  Upper limit of normal; WBC  White blood cell. 
a Results of post-day 1 assessments will be blinded to any study-related personnel (including the sites) 
except for serum calcium, albumin-adjusted calcium, phosphorus, or ALP in the event of a panic value 
b To be performed only in subjects with dystrophinopathies at screening and at subsequent visits for the 
purpose of DILI ascertainment (if applicable). 
c To be performed at screening only in subjects with dystrophinopathies who have AST or ALT  5 x ULN     
and at subsequent visits in any subjects for the purpose of DILI ascertainment. 
Assessment of severity for each adverse event and serious adverse event reported during the study will be 
based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 which is 
available at the following location:  https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_8.5x11.pdf  


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Appendix G.  CDC Growth Chart for stature z-scores by sex and age  
https://www.cdc.gov/growthcharts/data/zscore/zstatage.xls