Conditions: Osteogenesis Imperfecta
Keywords: Amgen, OI, Bone
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 153
Healthy volunteers: no

Brief summary:
This is a prospective, multicenter, single-arm study in children 2 to 17 years of age with OI to evaluate efficacy and safety of denosumab.

Detailed description:
To evaluate the effect of denosumab in lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in children 2 to 17 years of age (at the time of screening) on a 3-Month Dosing Regimen with osteogenesis imperfecta (OI)

Arms:
arm 1: Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.

Early efficacy and PK data from Q6M dosing supported adjustment of the dosing regimen from Q6M to every 3 months (Q3M). Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.

Interventions: intervention 1: Denosumab
Intervention descriptions: intervention 1: Subcutaneous (SC) injection.

Protocol document:
Prot_000.pdf: 
Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
Page 1 of 108 
CONFIDENTIAL 
 
 
Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and 
Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta 
Amgen Protocol Number (AMG 162) 20130173 
EudraCT number 2014-000184-40 
NCT Number:  
 
Clinical Study Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA  91320, USA 
Tel:  1 (805) 447-1000 
Key Sponsor Contact(s): 
 
Amgen, Inc. 
One Amgen Center Drive, 
Thousand Oaks, CA 91320, USA 
Email:  
 
 
 
Date: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
14 April 2014 
25 July 2014 
28 August 2014 
11 February 2015 
Amendment 4: 
24 March 2016 
Amendment 5: 
11 March 2020 
Amendment 6: 
19 November 2020 
Superseding Amendment 6: 
14 January 2021 
Amendment 7 
22 October 2021 
Superseding Amendment 7 26 November 2021 
 
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 (International 
Council for Harmonisation [ICH] E6). 
 
NCT02352753


Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
Page 2 of 108 
CONFIDENTIAL 
 
 
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; Amgen’s general number in the US (1-805-447-1000).  


Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
Page 3 of 108 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled Prospective, Multicenter, Single-arm Study to 
Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With 
Osteogenesis Imperfecta, dated 26 November 2021, and agree to abide by all 
provisions set forth therein.  
I agree to comply with the International Conference on 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 subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one 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:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
Page 4 of 108 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and 
Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta 
Study Phase:  3 
Indication:  Treatment of osteogenesis imperfecta (OI) in children 2 to 17 years of age  
Primary Objective:  To evaluate the effect of denosumab in lumbar spine bone mineral density 
(BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in 
children 2 to 17 years of age (at the time of screening) on a 3-Month Dosing Regimen with OI.  
Secondary Objective(s):  To evaluate denosumab in children 2 to 17 years of age (at the time of 
screening) with OI on a 3-Month Dosing Regimen with respect to:   
 
Change in lumbar spine BMD Z-score, as assessed by DXA, at 6 months 
 
Change in proximal femur BMD Z-score, as assessed by DXA, at 6 and 12 months (in 
subjects 5 years of age and older) 
 
Incidence of X-ray confirmed long bone and new and worsening vertebral fractures from 
last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed new and worsening vertebral fractures from last 12 months 
on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed new vertebral fractures from last 12 months on 6-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed improving vertebral fractures from baseline of 3-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of vertebral and nonvertebral fractures from last 12 months on 6-Month Dosing 
Regimen to 12 months on 3-Month Dosing Regimen (in subjects 5 years of age or older) 
 
Change in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary 
score at 12 months 
 
Change in CHQ-PF-50 Psychological Summary score at 12 months 
 
Change in Childhood Health Assessment Questionnaire (CHAQ) Disability Index score at 
12 months 
 
Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 months 
 
Change in growth velocity (determined by calculating age-adjusted Z-scores for height, 
weight, and body mass index [BMI]) at 12 months 
 
Serum denosumab concentration and bone turnover markers (BTM) collected at 1, 10, 
30, and 60 days after the first dose of 3-Month Dosing Regimen and every 3 months in all 
subjects  
Exploratory Objectives:  
 
Safety Objectives: 
To evaluate denosumab in children 2 to 17 years of age (at the time of screening) with OI on a 
3-Month Dosing Regimen or 6-Month Dosing Regimen with respect to: 
 
Adverse events and serious adverse events 
 
Laboratory parameters 
 
Vital signs 
 
Antidenosumab antibodies 
 
Metaphyseal index 
 
Molar eruption and mandibular shaping 
 
Hypercalcemia 


Product:  AMG 162 
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CONFIDENTIAL 
 
 
Hypotheses:  The hypothesis of the study is that the change from baseline in lumbar spine BMD 
Z-score following 12 months of denosumab treatment with 3-Month Dosing Regimen in children 
2 to 17 years of age (at the time of screening) with OI will be greater than that from historical 
control (ie, placebo or untreated subjects) (Letocha et al, 2005; Rauch et al, 2009; Ward et 
al, 2011) which was estimated to be 0.01 (95 CI: -0.17, 0.18). 
Primary Endpoint:  Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, 
at 12 months in subjects receiving the 3-Month Dosing Regimen 
Secondary Endpoint(s):   
 
Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 6 months 
in subjects receiving the 3-Month Dosing Regimen 
 
Change from baseline in proximal femur BMD Z-score, as assessed by DXA, at 6 and 
12 months (in subjects 5 years of age and older) in subjects receiving the 3-Month 
Dosing Regimen 
 
Incidence of X-ray confirmed long bone and new and worsening vertebral fractures from 
last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed new and worsening vertebral fractures from last 12 months 
on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed new vertebral fractures from last 12 months on 6-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Subject incidence of improving vertebral fractures from baseline of 3-Month Dosing 
Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of vertebral and nonvertebral fractures from last 12 months on 6-Month Dosing 
Regimen to 12 months on 3-Month Dosing Regimen (in subjects 5 years of age or older) 
 
Change from baseline in CHQ-PF-50 Physical Summary score at 12 months in subjects 
receiving the 3-Month Dosing Regimen 
 
Change from baseline in CHQ-PF-50 Psychological Summary score at 12 months in 
subjects receiving the 3-Month Dosing Regimen 
 
Change from baseline in CHAQ Disability Index score at 12 months in subjects receiving 
the 3-Month Dosing Regimen 
 
Change from baseline in WBFPRS at 12 months in subjects receiving the 3-Month 
Dosing Regimen 
 
Change from baseline in growth velocity (determined by calculating age-adjusted 
Z-scores for height, weight and BMI) at 12 months in subjects receiving the 3-Month 
Dosing Regimen 
 
Serum concentration of denosumab and serum BTM on days 1, 10, 30, 60, and every 3 
months in subjects on 3-Month Dosing Regimen  
Exploratory Endpoints: 
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 
 
Subject incidence of metaphyseal index Z-score above age-appropriate normal range  
 
Subject incidence of abnormal molar eruption  
 
Subject incidence of abnormal mandibular shaping 
 
Subject incidence of hypercalcemia 


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CONFIDENTIAL 
 
 
Study Design Update:   
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, subjects on 
study who had not completed their End of Study (EOS) visit were immediately 
discontinued from IP, and will be followed for safety for 24 weeks following the last dose 
of IP per the updated Schedule of Assessments (Table 7-5).  The last dose of IP will be 
considered week 0.  Subjects who have been on alternative therapy for more than 
6 months or whose last dose of IP was greater than 24 weeks, no additional 24-week safety 
follow-up is required.  These subjects can follow the previous protocol (protocol 
amendment 6) and complete the EOS Case Report Form (CRF).  Subjects whose last dose 
was between 12 and 24 weeks ago can complete the EOS assessments at week 24 per the 
updated Schedule of Assessments (Table 7-5).   
6-Month Dosing Regimen  
This is a prospective, multicenter, single-arm study in children 2 to 17 years of age with OI.  
Approximately 150 subjects will be enrolled including at least 30 subjects less than 7 years of age 
(at time of initial enrollment).  All subjects will receive denosumab 1 mg/kg (up to a maximum of 
60 mg) given subcutaneously every 6 months for 36 months.  Enrollment will be gated as below: 
1. Five subjects 11 to 17 years of age (sentinel cohort) will be initially enrolled in the trial.  
After they complete 14 days of mineral homeostasis monitoring, enrollment will be open 
to the remainder of the 11 to 17 years-of-age cohort.   
2. After the first 5 subjects 11 to 17 years of age enrolled have been treated for 12 months, 
enrollment will be opened to children 7 to 10 years of age 
3. After the first 5 subjects 7 to 10 years of age enrolled have been treated for 6 months, 
enrollment will be opened to children 2 to 6 years of age 
At least 30 subjects less than 7 years of age (at time of initial enrollment) will be enrolled. 
3-Month Dosing Regimen  
Sixty previously enrolled subjects were transitioned to a 3-Month Dosing Regimen, among them 
approximately 20 subjects younger than 7 years of age (at time of initial enrollment).  Per urgent 
safety measure, a decision has been made to stop treatment and subjects will continue a 
24-week safety follow up period.  Following implementation of this urgent safety measure 
and requirement for subjects to follow up for 24 weeks after last dose of denosumab, the 
maximum duration of this regimen could be up to 51 months (84 weeks).  
Sample Size:  Approximately 153 subjects have been enrolled.  No additional subjects will be 
enrolled into this study.  Prior to the implementation of the urgent safety measure, subjects 
who previously ended treatment but remained on study were eligible to transition to the 3-Month 
Dosing Regimen unless they ended treatment due to an adverse event.  Subjects also had the 
option to either consent to the 3-Month Dosing Regimen or to end study participation.   
Sixty subjects have been transitioned to a 3-Month dosing regimen.  Starting from 
30 September 2021, all dosing has been stopped. 
Summary of Subject Eligibility Criteria:  No further subjects were enrolled.  Eligibility criteria 
relates to initial enrollment into this study (6-Month Dosing Regimen).  Subjects reconsenting to a 
3-Month Dosing Regimen will not repeat eligibility assessments; however, any subjects who 
previously ended investigational product (IP) who are receiving alternative therapies must 
discontinue these before resuming treatment with denosumab. 
Inclusion Criteria 
 
Informed consent (to be provided by parent or legal guardian) and informed 
assent (to be provided by subjects when age-appropriate). 
 
Children 2 to 17 years of age inclusive at screening 
 
Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI as 
determined by presence of expected phenotype (examples include:  facial shape, 
voice, blue sclera, dentinogenesis imperfecta, typical radiographic features, 


Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
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CONFIDENTIAL 
 
 
fracture pattern) and lack of additional features unrelated to type I-IV OI 
(eg, blindness, mental retardation, neuropathy, craniosynostosis, premature 
exfoliation of deciduous teeth) 
- 
If familial, also must be autosomal dominant 
 
Clinical severity of OI as defined by 
- 
2 or more prevalent vertebral compression fractures; OR 
- 
1 prevalent vertebral compression fracture and 1 or more nonvertebral 
fractures within the previous 2 years; OR  
- 
3 or more fractures within the previous 2 years 
Exclusion Criteria 
Subjects meeting any of the following criteria at screening are not eligible for enrollment: 
 
Inability or unwillingness to comply with the requirements for frequent calcium 
and phosphorus monitoring for 14 days after the first dose of denosumab 
(only applies to the first 5 subjects 11 to 17 years of age enrolled in the study and 
the first 5 subjects of any age meeting the criteria for increased bone turnover, 
see Section 2.3.2.1) 
 
Currently unhealed fracture or osteotomy as defined by orthopedic opinion 
 
Osteotomy within 5 months prior to screening 
 
Evidence of untreated oral cavities or oral infections 
 
Recent or planned invasive dental procedure 
 
Surgical tooth extraction which has not healed by screening 
 
History of an electrophoresis pattern inconsistent with type I to IV OI  
 
History of known mutation in a gene other than collagen type I alpha 1/collagen 
type I alpha 2 (COL1A1/COL1A2) causing OI or other metabolic bone disease 
 
Abnormalities of the following per central laboratory reference ranges at 
screening: 
- 
Serum albumin-corrected calcium  lower limit of normal (LLN)  
- 
Serum vitamin D  20 ng/mL; rescreening for Vitamin D level  20 ng/mL 
will be allowed, after adequate supplementation  
- 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) 
 1.5 x upper limit of normal (ULN)  
- 
Total bilirubin (TBL)  1.5 x ULN (subjects with Gilbert syndrome are 
eligible) 
- 
Serum phosphorus  LLN  
- 
Serum alkaline phosphatase  20 above the ULN or  20 below the 
LLN  
 
Estimated glomerular filtration rate (eGFR)  60 mL/min/1.73 m2 (calculated by 
the Schwartz equation at screening) 
 
Evidence of any of 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 
- 
Current, uncontrolled hypercalcemia (albumin-corrected serum 
Ca  10 ULN) 
- 
History of osteomalacia or rickets (chart review) 
- 
Other bone diseases that affect bone metabolism (eg, osteoporosis 
pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, 
hypophosphatasia)  
- 
History of autoimmune disease  
- 
History of malabsorption (in children with serum albumin  LLN, 
malabsorption should be clinically ruled out by the investigator to confirm 
eligibility) 


Product:  AMG 162 
Protocol Number:  20130173 
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CONFIDENTIAL 
 
 
- 
History of rare hereditary problems of fructose intolerance 
- 
History of long QT syndrome 
- 
History of non-healing osteotomy 
- 
History of malignancy 
- 
History of alcohol or drug abuse  
- 
History of any solid organ or bone marrow transplant 
- 
Contraindicated or poorly tolerant of denosumab therapy  
 
Positive blood screen for human immunodeficiency virus (HIV) -1 or -2 antibody 
 
Positive blood screen for hepatitis B surface antigen or hepatitis C antibody 
 
Currently pregnant or planning a pregnancy during the study and for an 
additional 5 months after the last dose of IP (denosumab) 
 
Currently breastfeeding or planning on breastfeeding during the study and for an 
additional 5 months after the last dose of IP (denosumab) 
 
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 IP 
(denosumab) 
 
Received other osteoporosis treatment or bone active treatment with the 
following guidelines: 
- 
Prior treatment with 
▪ 
denosumab  
▪ 
fluoride or strontium for bone disease (fluoride taken for routine 
dental care is permitted) 
▪ 
parathyroid hormone (PTH) or PTH derivatives within 12 months 
prior to screening 
▪ 
zoledronic acid within 6 months prior to screening 
▪ 
oral bisphosphonates or intravenous bisphosphonates other than 
zoledronic acid if the first dose of denosumab would be before 
their next scheduled bisphosphonate dose would have been 
given 
- 
Administration of systemic glucocorticoids ( 5.0 mg prednisone 
equivalents/day for more than 10 days) within 3 months prior to 
screening.  Topical and inhaled glucocorticoids will be allowed 
- 
Administration of any of the following treatment within 3 months prior to 
screening: 
▪ 
Growth hormone (subjects on stable dose of growth hormone for 
at least 3 months prior to screening will be allowed) 
▪ 
Calcitonin 
▪ 
Cathepsin K inhibitor 
▪ 
Other bone active drugs including anticonvulsants (except 
gabapentin and benzodiazepines) and heparin 
▪ 
Chronic systemic ketoconazole, androgens, adrenocorticotropic 
hormone (ACTH), cinacalcet, aluminum, lithium, protease 
inhibitors, gonadotropin-releasing hormone agonists 
 
Received Immunosuppressant therapy other than glucocorticoids  
 
Anticipated major skeletal surgery (eg, rodding surgery, spinal surgery) within the 
next 12 months from day 1 
 
Symptoms associated with skull abnormalities such as basilar invagination, 
basilar impression or Chiari malformation (eg, headache induced by coughing or 
straining for stool, or parasthesias or weakness) 
 
Rodding surgery within 5 months prior to screening or not yet healed per 
orthopedic surgeon  
 
Spinal fusion surgery within 5 months prior to screening or not yet healed per 
orthopedic surgeon 
 
Inability to consume milk  
 
Planned orthopedic surgery that, in the opinion of the principal investigator, 
would require missing any dose of IP in year 1 or 2 or more doses thereafter 


Product:  AMG 162 
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CONFIDENTIAL 
 
 
 
Currently receiving treatment in another investigational drug study, or less than 
30 days since ending treatment on another investigational drug study(s), or 
current or planned participation in a clinical trial that would preclude compliance 
with study requirements 
 
Other investigational procedures while participating in this study are excluded 
 
Known intolerance to calcium or vitamin D supplements 
 
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’s  safety or interfere with the study evaluation, 
procedures or completion 
 
Subject will not be available for protocol-required study visits, 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 
For a full list of eligibility criteria, please refer to Section 4.1.  
Investigational Product 
Amgen Investigational Product Dosage and Administration:  See Section 6.2.1  
Denosumab at a dose of 1 mg/kg (up to a maximum dose of 60 mg) will be administered 
subcutaneously once every 3 months in the 3-Month Dosing Regimen. 
Non-investigational Product 
Non-Amgen Non-investigational Product Dosage and Administration:  All subjects will 
receive daily supplements.  Recommended dose of calcium in this population is 30-50 mg/kg per 
day to a maximum of 1000 mg elemental calcium.  Sites will monitor for potential hypercalcemia 
and hypercalciuria and other intolerance to supplements and may change dose at investigator 
discretion.  At least 800 IU vitamin D is recommended for the duration of the study with 
investigator discretion as above. 
Procedures:  Procedures conducted at baseline, day 1, 3-Month Dosing Regimen day 1, and 
periodic intervals throughout the study include collection of demographic information and medical 
and medication history.  Dual-energy X-ray absorptiometry assessment of lumbar spine and 
proximal femur; X-ray radiographic assessment of the spine (thoracic and lumbar); X-ray 
radiographic assessment of the knees in those with open growth plates who do not have bilateral 
hardware; dental X-ray (cephalogram and panoramic radiograph); X-ray assessment of 
unerupted molars; and administration of subject questionnaires (CHQ-PF-50, CHAQ disability 
score and WBFPRS).  Blood will be collected for routine chemistry, hematology, serology, serum 
25 (OH) vitamin D, serum concentration of denosumab, BTM (BSAP and sCTX) and 
antidenosumab antibody assessments.  Serum calcium levels will be monitored more frequently 
in the first 5 subjects enrolling in the study, as well as in the first 5 subjects of any age who meet 
pre-defined criteria for high bone turnover.  During 3-Month Dosing Regimen serum and urine 
calcium are monitored as per Schedule of Assessments. 
Potential events of osteonecrosis of the jaw (ONJ) will be adjudicated by an independent 
adjudication committee.  An external, independent Data Monitoring Committee (DMC) will be 
used to oversee the 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 
all study data in order to monitor safety results to protect subjects, as specified in the DMC 
charter.  Responses to additional ad hoc requests also will be provided.  To minimize the 
potential introduction of bias, the DMC members will not have any direct contact with the study 
site personnel or subjects. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Section 7.1).   
Statistical Considerations:  Descriptive statistics will be provided for baseline characteristics, 
efficacy, patient-reported outcomes (PROs), and safety data.  Descriptive statistics on continuous 


Product:  AMG 162 
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CONFIDENTIAL 
 
 
measurements will include means, medians, standard deviations, and ranges, while categorical 
data will be summarized using counts and percentages.  Subgroup analysis may be conducted 
depending on the number of subjects in each subgroup.  For the primary endpoint, change from 
baseline of 3-Month Dosing Regimen in lumbar spine BMD Z-score at 12 months will be analyzed 
based on all subjects with baseline and at least 1 postbaseline assessment and with validated 
normative ranges, using repeated measures analysis with visit, age, and baseline BMD Z-score 
as fixed effects.  The visit will be treated as a categorical variable, and there will be no imputation 
for missing data.  
This estimated least squares (LS) mean change at 12 months will be presented with a 95 CI 
and will be compared to weighted estimated mean (SE) of 0.01 (0.09) from historical controls 
(Letocha et al, 2005; Rauch et al, 2009; Ward et al, 2011) using a 1-sample two-sided t-test.  
The incidence of fractures will be summarized for 12 months prior to and after 3-Month Dosing 
Regimen denosumab administration for vertebral and nonvertebral fractures).  
Descriptive statistics will be provided for other secondary endpoints (CHQ-PF-50 score, WBFPR 
scale and growth velocity). 
The 6-Month Dosing Regimen safety analysis set will include all enrolled subjects who receive 
 1 dose of IP.  The 3-Month Dosing Regimen safety analysis set will include all subjects in the 
full analysis set (FAS) who received  1 dose of IP under the 3-Month Dosing Regimen.  The 
3-Month Dosing Regimen safety analysis set and 6-Month Dosing Regimen safety analysis set 
will be used for the analysis of all safety endpoints.  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 IP and 
treatment-emergent adverse events of interest will also be provided.  The incidence rate (number 
of events and exposure-adjusted rate) will be summarized.  In addition, subject incidences of 
metaphyseal index Z-score above age-appropriate normal range, severe or symptomatic 
hypocalcemia, ONJ, abnormal molar eruption, abnormal mandibular shaping, and hypercalcemia 
will be summarized. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 4.0 31 October 2013     


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CONFIDENTIAL 
 
 
Study Design and Treatment Schema for 6-Month Dosing Regimen 
 
 
 
B. Sentinel Cohort 
Mineral Homeostasis monitoring schedule 
 
 


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Study Design and Treatment Schema for 3-Month Dosing Regimen 
 


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CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ACTH 
adrenocorticotropic hormone 
ADT 
androgen deprivation therapy 
AFF 
atypical femoral fracture 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AP 
anteroposterior 
AST 
aspartate aminotransferase 
 
 
BMD 
bone mineral density 
BMI 
body mass index 
BSAP 
bone-specific alkaline phosphatase 
BTM 
bone turnover markers 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CHAQ  
Childhood Health Assessment Questionnaire  
CHQ-PF-50 
Child Health Questionnaire – Parent Form-50 
CTCAE 
Common Terminology Criteria for Adverse Events 
COL1A1 
collagen type I alpha 1 gene 
COL1A2 
collagen type I alpha 2 gene 
CRF 
case report form 
DILI 
drug-induced liver injury  
DMC 
Data Monitoring Committee 
DXA 
dual-energy X-ray absorptiometry 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End of Study 
eGFR 
estimated glomerular filtration rate 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
EMA 
European Medicines Agency  
End of Study (end of trial) defined as the date when the last subject across all sites is last 
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 Treatment (ET) 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 


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Abbreviation or Term 
Definition/Explanation 
EU 
European Union 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
Interactive Voice 
Response System (IVRS) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.  
Interactive Web 
Response System 
(IWRS) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information.  
IP 
investigational product 
IPIM 
investigational product instruction manual 
IRB 
institutional review board 
LLN 
lower limit of normal 
LS 
least squares 
IUD 
intrauterine device 
IUS 
intrauterine hormonal releasing system 
OI 
osteogenesis imperfecta 
ONJ 
osteonecrosis of the jaw 
PD 
pharmacodynamic 
PI 
principal investigator 
PTH 
parathyroid hormone 
PK 
pharmacokinetic 
PRO 
patient-reported outcomes 
SC 
subcutaneous 
sCTX 
serum type I collagen C-telopeptide 
SE 
standard error 
SFU 
safety follow-up 
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. 


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Abbreviation or Term 
Definition/Explanation 
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 
ULN 
upper limit of normal 
US 
United States 
WBFPRS 
Wong-Baker Faces Pain Rating Scale 
3 Month Dosing day 1 
Defined as the first date that protocol- specified investigational 
product(s)/protocol-required therapies at 3-Month Dosing Regimen is 
administered to the subject 


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Table of Contents 
Protocol Synopsis ............................................................................................................ 4 
Study Design and Treatment Schema for 6-Month Dosing Regimen ............................. 11 
Study Design and Treatment Schema for 3-Month Dosing Regimen ............................. 12 
Study Glossary .............................................................................................................. 13 
Table of Contents .......................................................................................................... 16 
1. 
OBJECTIVES ....................................................................................................... 21 
1.1 
Primary ..................................................................................................... 21 
1.2 
Secondary ................................................................................................. 21 
1.3 
Exploratory ................................................................................................ 21 
1.4 
Safety ........................................................................................................ 22 
2. 
BACKGROUND AND RATIONALE ...................................................................... 22 
2.1 
Disease ..................................................................................................... 22 
2.2 
Amgen Investigational Product Background .............................................. 23 
2.3 
Pediatric Risk Assessment ........................................................................ 24 
2.3.1 
Pharmacokinetics/Pharmacodynamics (BTM) ........................... 24 
2.3.2 
Safety ........................................................................................ 24 
2.3.2.1 
Hypocalcemia.......................................................... 26 
2.3.2.2 
Hypercalcemia ........................................................ 27 
2.3.2.3 
Osteopetrosis .......................................................... 28 
2.3.2.4 
Tooth Eruption ......................................................... 29 
2.3.2.5 
Osteonecrosis of the Jaw (ONJ) .............................. 29 
2.3.2.6 
Atypical Femoral Fracture ....................................... 30 
2.4 
Rationale ................................................................................................... 30 
2.5 
Clinical Hypotheses ................................................................................... 32 
3. 
EXPERIMENTAL PLAN ........................................................................................ 32 
3.1 
Study Design ............................................................................................. 32 
3.1.1 
6-Month Dosing Regimen .......................................................... 33 
3.1.2 
3-Month Dosing Regimen .......................................................... 34 
3.2 
Number of Sites ........................................................................................ 34 
3.3 
Number of Subjects ................................................................................... 34 
3.4 
Replacement of Subjects .......................................................................... 35 
3.5 
Estimated Study Duration .......................................................................... 35 
3.5.1 
Study Duration for Subjects ....................................................... 35 
3.5.2 
End of Study .............................................................................. 35 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 35 
4.1 
Inclusion and Exclusion Criteria ................................................................ 36 
4.1.1 
Inclusion Criteria ........................................................................ 36 


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4.1.2 
Exclusion Criteria ...................................................................... 36 
5. 
SUBJECT ENROLLMENT .................................................................................... 39 
5.1 
Enrollment into 6-Month Dosing Regimen ................................................. 40 
5.2 
Transition to 3-Month Dosing Regimen ..................................................... 41 
6. 
TREATMENT PROCEDURES .............................................................................. 41 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 42 
6.2 
Investigational Product .............................................................................. 42 
6.2.1 
Amgen Investigational Product Denosumab .............................. 42 
6.2.2 
Dosage, Administration, and Schedule ...................................... 42 
6.2.3 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 43 
6.2.3.1 
6-Month Dosing Regimen ........................................ 43 
6.2.3.2 
3-Month Dosing Regimen ........................................ 44 
6.3 
Other Protocol-required Therapies ............................................................ 44 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 44 
6.4.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 44 
6.4.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 45 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 46 
6.5 
Concomitant Therapy ................................................................................ 46 
6.6 
Product Complaints ................................................................................... 46 
6.7 
Excluded Treatments and/or Procedures During Study Period .................. 47 
6.8 
Contraceptive Requirements ..................................................................... 47 
6.8.1 
Female Subjects ........................................................................ 47 
6.8.2 
Male Subjects ............................................................................ 48 
6.8.3 
Unacceptable Methods of Birth Control for Male and 
Female Subjects ....................................................................... 48 
7. 
STUDY PROCEDURES ....................................................................................... 48 
7.1 
Schedule of Assessments ......................................................................... 48 
7.2 
General Study Procedures ........................................................................ 57 
7.2.1 
Screening and Enrollment ......................................................... 59 
7.2.1.1 
Enrollment in IVRS/IWRS 
System/Rescreening ............................................... 59 
7.2.2 
Transition to 3-Month Dosing Regimen...................................... 61 
7.2.3 
Treatment .................................................................................. 61 
7.2.4 
Study Procedures ...................................................................... 62 
7.2.5 
Safety Follow-up Visit(s)/End of Study Visit ............................... 71 
7.3 
Antibody Testing Procedures .................................................................... 71 


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7.4 
Sample Storage and Destruction ............................................................... 72 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 73 
8.1 
Subjects’ Decision to Withdraw ................................................................. 73 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 74 
8.3 
Reasons for Removal From Treatment, or Study ...................................... 75 
8.3.1 
Reasons for Removal From Treatment ...................................... 75 
8.3.2 
Reasons for Removal From Study ............................................. 76 
8.4 
Lost to Follow-up ....................................................................................... 76 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 76 
9.1 
Definition of Safety Events ........................................................................ 76 
9.1.1 
Adverse Events ......................................................................... 76 
9.1.2 
Serious Adverse Events ............................................................ 77 
9.2 
Safety Event Reporting Procedures .......................................................... 78 
9.2.1 
Adverse Events ......................................................................... 78 
9.2.1.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 78 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 79 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 80 
9.3 
Method of Detecting Adverse Events and Serious Adverse 
Events ....................................................................................................... 80 
9.4 
Safety Monitoring Plan .............................................................................. 81 
9.5 
Pregnancy and Lactation Reporting .......................................................... 81 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 82 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 82 
10.1.1 
Study Endpoints ........................................................................ 82 
10.1.2 
Analysis Sets ............................................................................. 83 
10.1.2.1 
Full Analysis Set ...................................................... 83 
10.1.2.2 
DXA Analysis Set .................................................... 83 
10.1.2.3 
Vertebral Fracture Analysis Set ............................... 83 
10.1.2.4 
PRO Analysis Set .................................................... 83 
10.1.2.5 
Growth Velocity Analysis Set ................................... 84 
10.1.2.6 
Metaphyseal Analysis Set ....................................... 84 
10.1.2.7 
6-Month Dosing Regimen Safety Analysis 
Set .......................................................................... 84 
10.1.2.8 
3-Month Dosing Regimen Safety Analysis 
Set .......................................................................... 84 
10.1.2.9 
PK Analysis Set ....................................................... 84 
10.1.2.10 PK Substudy Analysis Set ....................................... 84 
10.1.2.11 BTM Analysis Set .................................................... 84 


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10.1.2.12 BTM Substudy Analysis Set .................................... 84 
10.1.3 
Covariates and Subgroups ........................................................ 85 
10.1.3.1 
Covariates ............................................................... 85 
10.1.3.2 
Subgroups ............................................................... 85 
10.2 
Sample Size Considerations ..................................................................... 85 
10.2.1 
6-Month Dosing Regimen .......................................................... 85 
10.2.2 
3-Month Dosing Regimen .......................................................... 85 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 86 
10.4 
Planned Analyses ..................................................................................... 86 
10.4.1 
Primary Analysis ........................................................................ 86 
10.4.2 
Data Monitoring Committee ....................................................... 86 
10.5 
Planned Methods of Analysis .................................................................... 86 
10.5.1 
General Considerations ............................................................. 86 
10.5.2 
Primary Efficacy Endpoint .......................................................... 86 
10.5.3 
Secondary Efficacy Endpoint(s) ................................................. 87 
10.5.3.1 
Other Changes From Baseline in BMD 
Z-score by DXA ....................................................... 87 
10.5.3.2 
New and Worsening Fractures, and 
Vertebral and Nonvertebral Fractures ..................... 87 
10.5.3.3 
Improved Vertebral Fracture .................................... 87 
10.5.3.4 
Patient-reported Outcomes ..................................... 87 
10.5.3.5 
Growth Velocity ....................................................... 88 
10.5.3.6 
Serum Denosumab Concentrations ......................... 88 
10.5.3.7 
Bone Turnover Markers ........................................... 88 
10.5.4 
Safety Endpoints ....................................................................... 88 
10.5.4.1 
Adverse Events ....................................................... 88 
10.5.4.2 
Clinical Laboratory Measurements .......................... 89 
10.5.4.3 
Vital Signs ............................................................... 89 
10.5.4.4 
Antidenosumab Antibodies ...................................... 89 
11. 
REGULATORY OBLIGATIONS ............................................................................ 90 
11.1 
Informed Consent ...................................................................................... 90 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 92 
11.3 
Subject Confidentiality ............................................................................... 92 
11.4 
Investigator Signatory Obligations ............................................................. 93 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 94 
12.1 
Protocol Amendments and Study Termination .......................................... 94 
12.2 
Study Documentation and Archive ............................................................ 94 
12.3 
Study Monitoring and Data Collection ....................................................... 95 
12.4 
Investigator Responsibilities for Data Collection ........................................ 96 
12.5 
Language .................................................................................................. 96 
12.6 
Publication Policy ...................................................................................... 97 


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12.7 
Compensation ........................................................................................... 97 
13. 
REFERENCES ..................................................................................................... 98 
14. 
APPENDICES .................................................................................................... 101 
List of Tables 
Table 6-1.  List of Proscribed Therapy ........................................................................... 47 
Table 7-1.  Schedule of Assessments for 6-Month Dosing Regimen ............................. 49 
Table 7-2.  6-Month Dosing Regimen Additional Schedule of Assessments for 
Subjects in Sentinel Cohort and the First 5 Subjects Who Have 
Increased Bone Turnover as Defined in Section 3.1 ............................... 52 
Table 7-3.  6-Month Dosing Regimen Additional Schedule of Assessments for 
Subjects in Sentinel Cohort  as Defined in Section 3.1 ........................... 52 
Table 7-4.  Schedule of Assessments for 3-Month Dosing Regimen ............................. 53 
Table 7-5.  Schedule of Assessments Following Implementation of Urgent 
Safety Measure ...................................................................................... 56 
Table 7-6.  Blood Sample Analyte Listing ...................................................................... 69 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 102 
Appendix B.  Sample Serious Adverse Event Report Form ......................................... 103 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 106 


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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the effect of denosumab in lumbar spine bone mineral density (BMD) 
Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in 
children 2 to 17 years of age (at the time of screening) on a 3-Month Dosing Regimen 
with osteogenesis imperfecta (OI). 
1.2 
Secondary 
To evaluate denosumab in children 2 to 17 years of age (at the time of screening) with 
OI on a 3-Month Dosing Regimen with respect to:   
 
Change in lumbar spine BMD Z-score, as assessed by DXA, at 6 months 
 
Change in proximal femur BMD Z-score, as assessed by DXA, at 6 and 12 months 
(in subjects 5 years of age and older) 
 
Incidence of X-ray confirmed long bone and new and worsening vertebral fractures 
from last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing 
Regimen 
 
Incidence of X-ray confirmed new and worsening vertebral fractures from last 
12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed new vertebral fractures from last 12 months on 6-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed improving vertebral fractures from baseline of 3-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen  
 
Incidence of vertebral and nonvertebral fractures from last 12 months on 6-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen (in subjects 5 years of 
age or older)  
 
Change in Child Health Questionnaire – Parent Form-50 (CHQ – PF-50) Physical 
Summary Score at 12 months 
 
Change in CHQ-PF-50 Psychological Summary Score at 12 months 
 
Change in Childhood Health Assessment Questionnaire (CHAQ) Disability Index 
Score at 12 months 
 
Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 months  
 
Change in growth velocity (determined by calculating age-adjusted Z-scores for 
height, weight and body mass index [BMI]) at 12 months 
 
Serum denosumab concentration and bone turnover markers (BTM) collected at 1, 
10, 30, and 60 days after the first dose of 3-Month Dosing Regimen and every 
3 months in all subjects  
1.3 
Exploratory 


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1.4 
Safety 
To evaluate denosumab in children 2 to 17 years of age (at the time of screening) with 
OI on a 3-Month Dosing Regimen or 6-Month Dosing Regimen with respect to: 
 
Adverse events and serious adverse events 
 
Laboratory parameters 
 
Vital signs 
 
Antidenosumab antibodies 
 
Metaphyseal index 
 
Molar eruption and mandibular shaping 
 
Hypercalcemia 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Osteogenesis imperfecta is a group of genetic skeletal disorders characterized by 
increased bone fragility, low bone mass (Rauch and Glorieux, 2004), and increased 
bone turnover (Rauch et al, 2009).  Osteogenesis imperfecta is the most common form 
of primary osteoporosis in children with an estimated incidence of 1 per 25,000 live 
births (Byers, 2000).  
At least twelve types of OI have been identified based on clinical phenotype and 
underlying genetic defect (Forlino and Marini, 2016; Marini and Blissett, 2013).  The 
majority of individuals with OI are heterozygous for mutations in the type I collagen 
genes COL1A1 or COL1A2 that lead to quantitative and/or qualitative defects in collagen 
synthesis and negatively impact bone strength (van Dijk et al, 2012).   
The clinical features of OI may include fractures, short stature, hyperlaxity of ligaments 
and skin, hearing loss, blue sclera, and dentinogenesis imperfecta (Marini et al 2017; 
Steiner et al, 2005).  The clinical severity of OI caused by dominantly inherited collagen 
mutations varies from mild, non-deforming to perinatal lethal; most children with OI 
experience recurrent fractures, with or without progressive deformity, disability, and pain 
(Rauch and Glorieux, 2004).  
The medical management of pediatric OI includes the orthopedic prevention and 
treatment of fractures, bowing, and scoliosis.  Currently, there are no approved 
medicinal products for the treatment of OI, except for neridronate, which is only 
approved for the treatment of OI in Italy.  Clinicians have been using bisphosphonates in 


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children with moderate to severe OI to reduce osteoclast activity and increase bone 
mass (even though abnormal collagen is usually present [Byers, 2000]) with the aim of 
reducing fractures (Rauch and Glorieux, 2004).  Clinical trials of bisphosphonate 
treatment in pediatric OI have consistently shown increases in BMD, with variable effects 
on fracture reduction, bone pain, and quality of life (Castillo et al, 2009).  Recent 
meta-analyses confirm the variable effect of bisphosphonates on fracture reduction 
(Dwan et al, 2016; Hald et al, 2015).  Thus, an unmet need remains in children with OI. 
Rationale for Dose Change 
The change to 3-Monthly dosing stems from early findings that a significant number of 
subjects met BMD Z-score decline of more than 0.5 units.  This decline was associated 
with a lower than anticipated increase in lumbar spine BMD from baseline in the whole 
population as compared to published studies on oral bisphosphonates.  However, it 
should be noted that overall there was an upward trend.  In addition, preliminary study 
data indicate that after administration of 1 mg/kg denosumab, pharmacokinetic (PK) 
exposures are cleared within 3 months and sCTx levels recover back to near baseline by 
3 months.  This is likely due to a faster rate of bone turnover in the pediatric OI 
population (Rauch et al, 2000; Baron et al, 1983) and to higher RANKL target expression 
in subjects with pediatric OI compared to normal children (Brunetti et al, 2016).  These 
data support that adjustment of the dose regimen from 6-Month Dosing Regimen to 
3-Month Dosing Regimen is appropriate for evaluation in pediatric OI subjects. 
2.2 
Amgen Investigational Product Background 
Denosumab is a fully human monoclonal antibody that binds with high affinity 
(dissociation equilibrium constant [Kd] 3 x 10-12 M) and specificity to RANKL and 
neutralizes the activity of RANKL, preventing activation of its receptor, RANK, on the 
surface of osteoclast precursors and osteoclasts.  Denosumab has an approximate 
molecular weight of 147 kDa and is produced in genetically engineered mammalian 
Chinese hamster ovary cells.  It consists of 2 heavy chains of the immunoglobulin (Ig)G2 
subclass and 2 light chains of the kappa subclass.  The heavy and light chains are 
covalently linked through disulfide bonds. 
Denosumab, by inhibiting RANK ligand, has the potential to treat diseases characterized 
by increased osteoclast-mediated bone loss and increased fracture risk.  In children with 
OI, denosumab may have benefit due to its unique mechanism of action, reversible PK, 
and ease of administration.  In a mouse model of moderate to severe OI, both RANKL 


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inhibition (via RANK-Fc) and alendronate significantly reduced fracture incidence when 
treatment was started in neonatal animals (Bargman et al, 2012). 
Denosumab is currently indicated for:  treatment of postmenopausal women with 
osteoporosis; treatment of men with osteoporosis; treatment of bone loss in men 
receiving androgen deprivation therapy (ADT) for prostate cancer, treatment of bone 
loss in women receiving aromatase inhibitor therapy for breast cancer, and treatment of 
adult glucocorticoid-induced osteoporosis.  Additional information is provided in the 
Denosumab Investigator’s Brochure. 
2.3 
Pediatric Risk Assessment 
Although denosumab has been studied in an adolescent population in the oncology 
setting of Giant Cell Tumor of Bone, it has not been studied in the setting of skeletal 
fragility in children.  Several aspects will be investigated and are further considered in 
Section 7. Volumes of blood withdrawn for analysis in association with clinical monitoring 
will be minimized as appropriate for this pediatric population based on body weight 
(EU Ethical Considerations, 2008). 
Preliminary study data indicate that after administration of 1 mg/kg denosumab, PK 
exposures are cleared within 3 months and sCTx levels recover back to near baseline by 
3 months.  This is likely due to higher RANKL target expression levels and a faster rate 
of bone turnover in the pediatric OI population (Brunetti et al, 2016; Rauch et al, 2000; 
Baron et al, 1983).  
Recently, life threatening events of hypercalcemia were reported on denosumab 
1 mg/kg Q3M regimen in the pediatric OI subjects within this study.  Amgen 
considers that the overall benefit:risk profile of Prolia (denosumab) (Q3M/Q6M) is 
not favorable in the OI pediatric patient population based on the data observed.   
2.3.1 
Pharmacokinetics/Pharmacodynamics (BTM) 
Pharmacokinetic/PD analysis will be performed on all subjects on 3-Month Dosing 
Regimen to further evaluate the impact of 3-Month Dosing in this pediatric population 
with OI to add to the data obtained during the trial during the 6-Month Dosing Regimen.   
2.3.2 
Safety 
 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 ADT 
for prostate cancer (Study 20040138) or aromatase inhibitor therapy for breast cancer 


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(Study 20040135); and men with osteoporosis (Study 20080098) and glucocorticoid-
induced osteoporosis (Study  20101217).  In addition, denosumab also 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 in adults 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 reported in every study evaluated to 
date.  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 (ONJ), atypical femoral fracture ([AFF] reported 
rarely in patients treated with denosumab and not evaluable in subjects with OI); eczema 
(including dermatitis, allergic dermatitis, atopic dermatitis, and contact dermatitis), pain in 
the extremity, musculoskeletal pain, and multiple vertebral fractures following 
discontinuation of denosumab treatment.  Additionally, hypercalcemia following 
denosumab discontinuation is an important potential risk in patients with growing 
skeletons.  There may be a possibility hypercalcemia can occur at the end of the dosing 
interval when a subject is still receiving investigational product (IP).   
As of 20 April 2020 with the every 6 months dosing regimen in Study 20130173, 
153 subjects had received IP. 
As of 03 August 2021, 60 subjects had received at least 1 dose of Prolia at the 
1 mg/kg Q3M dosing regimen. 
Of the 153 subjects who had received IP, 149 (97.4) had at least 1 treatment-emergent 
adverse event; 121 (79.1) subjects, 57 (37.3) subjects, and 1 (0.7) subjects had 
grade 2, 3, and 4 adverse events, respectively.  A total of 47 (30.7) subjects had a 
serious adverse event, and 5 (3.3) subjects had an adverse event leading to 
withdrawal of IP.  There were no fatal adverse events.   
In the Q6M dosing regimen, hypercalcemia events including events of calcium ionized 
increased and blood calcium increased have been reported in 24 (15.7) study 
subjects.  No serious adverse events of hypercalcemia have been reported.  The 
majority of hypercalcemia adverse events were grade 1 in severity.  Three subjects had 
events grade 2 in severity including the following verbatim events:  asymptomatic 


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increased level of ionized calcium reported on day 29; calcium blood 
increased - nonsymptomatic, underlying diagnosis unknown on day 30; and a report of 
hypercalcemia (no clinical consequences) beginning as a grade 1 hypercalcemia 
12 days following the previous dose.  The severity grade was increased to 2 on day 85 
and the event resolved on day 180 following the previous dose.   
Twelve subjects reported events of hypercalcemia  30 days from the most recent dose.  
Six subjects reported events 31 to 90 days following the most recent dose.  
Five subjects reported events  90 days to 180 days following the most recent dose.  
One subject reported hypercalcemia  180 days (day 196) following the most recent 
dose.  Overall, the events of hypercalcemia reported to date have not been clinically 
significant.  The majority of the events resolved and no action was taken with IP.   
In the combined Q3M/Q6M dosing cohorts, treatment-emergent adverse events of 
hypocalcemia have been reported in 19 (12.4) of study subjects.  There have been no 
cases of positively adjudicated osteonecrosis of the jaw.  
In a substudy assessment of urine calcium, deoxypyridinoline/creatinine (DPD/creat) 
ratio, and urine N-telopeptide (NTX) for each treatment cycle shows the following trends:   
 
Urine calcium/creatinine ratio declines in first 2 weeks following IP administration 
and increases to slightly above baseline in weeks 12-18 
 
Absolute value and DPD/ creatinine ratio decreases within the first 2 weeks 
following dosing and subsequently increases by week 8 and returns to or slightly 
above baseline between 12-18 weeks following IP administration 
 
Urine NTX similarly decreases within first 2 weeks, increasing by week 8 and 
is back to baseline levels by 18 weeks 
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.   
2.3.2.1 
Hypocalcemia 
Skeletal turnover rates vary by age and are higher in children than adults.  These higher 
bone turnover rates expected at baseline in children with OI 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 other than OI (eg, fibrous 
dysplasia and juvenile Paget’s disease) have described disturbances in mineral 


Product:  AMG 162 
Protocol Number:  20130173 
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metabolism, including hypocalcemia and hypophosphatemia (Boyce et al, 2012; 
Grasemann et al, 2013).  
To minimize such risk, the following strategies will be employed: 
 
calcium and vitamin D supplementation will be given and serum calcium and 
phosphorus concentrations will be monitored throughout the study on a regular 
basis.  
 
at all study visits, signs and symptoms of hypocalcemia will be assessed and 
subjects reminded of importance of taking calcium and vitamin D.   
 
occurrence of severe or symptomatic hypocalcemia will prompt discontinuation of 
study medication and institution of appropriate medical treatment. 
 
enrollment in the study will be gated by age group, as described in Section 3.1.1.  
 
mineral homeostasis will be monitored more frequently over 14 days after 
administration of the first dose of denosumab in a sentinel cohort comprised of 
first 5 subjects enrolled in the 11-17 year age group to permit adaptation of 
subsequent mineral homeostasis assessments for all study subjects, as appropriate.  
A similar approach will be employed in the first 5 subjects of any age who have 
increased bone turnover defined as meeting 2 of the 3 following criteria: 
(1) untreated with bisphosphonates for 4 years prior to entry in the trial; (2) Type 3 OI 
with the following characteristics:  height  3rd percentile and bowed extremities (or 
saber shins); or (3) Tanner stage 3 or 4. 
 
subjects will not be eligible to participate who have evidence of hypocalcemia or 
diseases that increase the risk of hypocalcemia, including, but not limited to, 
malabsorption and kidney disease, as well as subjects with additional risk factors for 
detrimental effects of hypocalcemia, eg, a history of long QT syndrome. 
2.3.2.2 
Hypercalcemia 
As of 7 September 2021, a total of 56 events of hypercalcemia were reported in the 
pediatric studies 20130173 and 20170534. Of these 56 events, 5 events of severe 
hypercalcemia grade 4 (n  2) and grade 3 (n  3) were reported in study 20130173. 
The remaining 51 hypercalcemia events were of grade 1 (n  47) and grade 2 
(n  4).  
Thirteen events, including 5 events of severe hypercalcemia ( grade 3) occurred 
in subjects receiving Q3M dosing in studies 20130173 (n  12) and 20170534 
(n  1). These events occurred in 12 subjects between age of 5 years and 13 years. 
Three events were serious and the remaining 10 events were non serious.  Nine 
(69) of these events occurred after the subjects had received 3 or 4 doses of 
denosumab.  Twelve events occurred toward the end of dosing regimen between 
60 and 99 days after the prior dose.  The severe life-threatening adverse events of 
hypercalcemia have been reported at or near the end of the denosumab 1 mg/kg 


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Q3M dosing period ( 60 days from the previous dose) in Study 20130173. Two 
subjects had hypercalcemia grade 4 and both required hospitalization and are 
described below.  
 
In one 13-year-old male subject, the grade 4 event occurred 77 days after the 
most recent dose and was life threatening. He was treated with intravenous 
normal saline. The event resolved.   
 
In one 7-year old male subject, the grade 4 event occurred 91 days after the 
most recent dose. The subject presented with severe dehydration, reduced 
glomerular filtration rate (GFR) and seizures resulting in sedation, intubation 
and assisted ventilation. Rescue medication (IV Zoledronic Acid) was required 
to stabilize the subject. 
There were 43 events reported in 31 subjects receiving Q6M dosing in the studies 
20130173 (n  41) and 20170534 (n  2).  These events occurred in subjects 
between the ages of 2 and 16 years.  There were 40 events of grade 1 
hypercalcemia and 3 events of grade 2 hypercalcemia. 
The higher bone turnover rates expected at baseline in children with OI appears to 
increase the risk for rebound hypercalcemia in the latter part of the dosing interval due to 
a rapid release of bone turnover marker inhibition.  In addition, recent clinical reports of 
denosumab administration in pediatric patients with disorders of high bone turnover 
other than OI (eg, fibrous dysplasia and juvenile Paget’s disease) have described the 
occurrence of rebound hypercalcemia (Boyce et al, 2012; Grasemann et al, 2013). 
Based on the benefit:risk profile of denosumab in pediatric OI study, Amgen made 
the decision to stop further dosing of denosumab in this study and subjects will 
be followed for safety for 24 weeks from the last dose of denosumab. 
2.3.2.3 
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 modeled 
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 


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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  2 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 minimizes 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 on 3-Month Dosing Regimen 
throughout the study in subjects with open growth plates who do not have 
bilateral hardware only, as only in subjects with open growth plates who do not 
have bilateral hardware does the potential risk exist of an abnormal rate of 
increase in metaphyseal width.  
 
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 consistent with local institutional guidelines, will prompt 
discontinuation of study medication and institution of appropriate follow-up. 
2.3.2.4 
Tooth Eruption 
RANKL plays an important role in tooth eruption.  In nonclinical studies conducted in 
neonatal rats, OPG-Fc and alendronate administration impaired the eruption of 2nd and 
3rd molars and also reduced incisor growth.  These findings were at least partially 
reversible within 10 weeks of discontinuing OPG-Fc.  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. 
2.3.2.5 
Osteonecrosis of the Jaw (ONJ) 
Cases of ONJ have been reported in association with antiresorptive use.  ONJ may be 
associated with pain and/or infection of the jaw bone, teeth or gums resulting in a 
non-healing area of exposed bone in the mouth.  How this happens is poorly 
understood.  One hypothesized mechanism involves interference with bone remodeling 
as a result of decreased osteoclast activity.  In this study, all events reported as ONJ, or 


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those coded to prespecified terms potentially indicative of ONJ, will be reviewed by an 
independent adjudication committee.   
To minimize this risk, the following strategies will be employed:  Potential infection of jaw 
bone, tooth, or gum infections will be monitored with oral visual inspection as part of the 
scheduled physical examinations (including after molar eruption) and X-ray assessments 
when indicated. 
2.3.2.6 
Atypical Femoral Fracture 
Cases of AFF have been reported in patients with osteoporosis in association with 
antiresorptive use.  Some case series have reported a possible association between 
AFF and long-term alendronate therapy (Odvina et al, 2010; Lenart et al, 2009; 
Odvina et al, 2005), while others have not (Abrahamsen et al, 2009). Osteogenesis 
imperfecta is characterized by increased bone fragility and resulting frequent fractures 
that are often precipitated by minimal trauma.  The most frequent fracture site in patients 
with OI includes the femur (Folkestad et al, 2017). The major defining features of AFF 
include a fracture that is associated with minimal or no trauma, a subtrochanteric or 
femoral shaft location, and a fracture line that is transverse in orientation.  This definition 
however, does not apply to pathological fractures associated with primary or metastatic 
bone tumors and certain bone diseases (eg, Paget’s disease, fibrous dysplasia) (Shane 
et al, 2014).  The increased rate of femoral fractures in OI is likely related to the 
brittleness of bones and the femoral fractures in OI tend to resemble AFF.  Earlier data 
suggested an increased risk of AFF-like femur with antiresorptive (bisphosphonate) use 
(Nicolaou et al, 2012), but more recent studies suggest that the atypical features of 
femur fractures were likely related to severity of OI and not bisphosphonate use (Trejo et 
al, 2017; Vuorimies et al, 2017). 
To minimize this risk, the following strategies will be employed: 
 
Subjects will be seen no less frequently than every 3 months and can have hip 
X-rays where clinically suspected.  All femur fractures will be reviewed by the study 
team and site investigator to determine if change in treatment is required. 
In alignment with the Study 20130173 Data Monitoring Committee (DMC) terminology, 
all femur fractures will be reviewed as typical OI femur fractures (TOIFF). 
2.4 
Rationale 
This study is part of a Pediatric Investigation Plan for denosumab (Prolia) that was 
agreed upon with the European Medicines Agency (EMA).  The purpose of this study is 
to evaluate the efficacy, safety, and PK of denosumab (1 mg/kg, up to a maximum of 


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60 mg, administered subcutaneously once every 3 months) in children with OI.  Change 
from baseline of 3-Month Dosing Regimen in lumbar spine BMD, as assessed by 
Z-score, will be calculated and compared to age- and sex-comparable historical data 
from 3 published, randomized, controlled trials in pediatric subjects with OI and to the 
3-Month Dosing Regimen baseline.   
The 3-Month primary endpoint is based on comparison with 3-Month baseline which is at 
the end of 6 month dosing.  Including subjects with 6 month exposure prior to 3 Month 
dosing will likely attenuate the effect size to be observed for the 3-Month primary 
endpoint.  Thus this is a more conservative approach to show statistical significance.  In 
addition, the 6 Month exposure will be used as a covariate to account for its effect on 
3 Month primary endpoint.   
The subject incidence of fractures also will be summarized for  6-Month and 3-month 
Dosing Regimen.  It is expected that the change in lumbar spine BMD Z-score following 
12 months of denosumab treatment using 3-Month Dosing Regimen will be greater than 
historical controls.  Safety of subjects during study conduct will be monitored by the 
study team and a DMC.  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.  
Rationale for Stopping Denosumab Administration 
The independent DMC convened on 24 September 2021 to review efficacy and 
safety data on Study 20130173.  After reviewing the data, the DMC determined that 
the benefit observed with Q3M dosing in the OI study does not outweigh the 
potentially life-threatening events of the observed severe hypercalcemia events 
(Section 2.3.2.2). 
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, 
subjects on study who had not completed their EOS visit were immediately 
discontinued from IP, and will be followed for safety for 24 weeks following the 
last dose of IP per the updated Schedule of Assessments (Table 7-5).  The last 
dose of IP will be considered week 0.  Subjects who have been on alternative 
therapy for more than 6 months or whose last dose of IP was greater than 
24 weeks, no additional 24-week safety follow-up is required.  These subjects can 
follow the previous protocol (protocol amendment 6) and complete the EOS CRF.  
Subjects whose last dose was between 12 and 24 weeks ago can complete the 


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EOS assessments at week 24 per the updated Schedule of Assessments (Table 
7-5).   
2.5 
Clinical Hypotheses 
The hypothesis of the study is that the change from baseline in lumbar spine BMD 
Z-score following 12 months of denosumab treatment with 3-Month Dosing Regimen in 
children 2 to 17 years of age (at the time of screening) with OI will be greater than that 
from historical controls (ie, placebo or untreated subjects) (Letocha et al, 2005; Rauch et 
al, 2009; Ward et al, 2011) which was estimated to be 0.01 (95 CI: -0.17, 0.18). 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a single-arm, multicenter, phase 3 study to demonstrate the superiority of 
denosumab administration compared with historical controls as measured by change 
from baseline in lumbar spine BMD Z-score at 12 months and to evaluate the safety, 
efficacy, and PK in children with OI.  The effect of denosumab administered every 
3 months will be evaluated based on comparison in BMD Z-score change from baseline 
of 3-Month Dosing Regimen to 12 months with historical controls derived from published 
randomized, controlled trials (Letocha et al, 2005; Rauch et al, 2009; Ward et al, 2011). 
BMD, fracture, growth velocity, and other efficacy and safety data also will be collected.  
Questionnaires will be administered to subjects and their parents to evaluate 
patient-reported outcomes (PROs).  Blood samples will be collected to measure serum 
blood levels of denosumab.  For a female who has a Tanner stage 2 or greater, or has 
had menarche, a urine pregnancy test will be performed prior to IP administration at 
every visit and End of Study (EOS). 
Radiographic assessments will be performed to monitor skeletal impact of denosumab 
treatment during the 3-Month Dosing Regimen, including:  metaphyseal modeling, 
mandibular shape, and unerupted molars.  Treatment with denosumab will be stopped 
for subjects in the following situations: 
 
decline in BMD Z-score by at least 0.5 units at any 6-month assessment compared 
to the 3-Month Dosing Regimen baseline  
 
4 or more new long bone and/or vertebral fractures in any 6-month period (additional 
spine X-rays should be obtained if clinically indicated)   
 
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 consistent with local institutional guidelines 
 
severe or symptomatic hypocalcemia 


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 
severe or symptomatic hypercalcemia, which requires the use of a rescue 
medication for management 
 
ONJ 
 
dental abnormalities requiring invasive dental procedures, as determined by 
investigator and/or treating dentist and within the local institutional practice 
guidelines 
 
Denosumab administration should be withheld 30 days prior to an invasive dental 
procedure and until complete mucosal healing is observed and documented 
(refer to Section 6.2.3 for guidance on restarting IP) 
 
pregnancy 
 
Potential events of ONJ will be adjudicated by an independent adjudication 
committee using pre-defined criteria.  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 all data in order to monitor safety results to protect 
subjects.  To minimize the potential introduction of bias, the DMC members will not 
have any direct contact with the site personnel, or subjects.  
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.1.1 
6-Month Dosing Regimen 
Approximately 150 subjects between 2 to 17 years of age will be enrolled, including at 
least 30 subjects younger than 7 years of age (at time of initial enrollment).  All subjects 
will receive denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 
6 months for 36 months, and all subjects will receive age appropriate calcium and 
vitamin D (Study Design and Treatment Schema are provided at end of protocol 
synopsis section).  Subjects meeting eligibility criteria will be enrolled in the study to 
receive treatment with denosumab.  Although enrollment in the study will not be 
stratified, it will be gated as follows: 
 
Older children (11 to 17 years of age) will be enrolled first because they will be the 
most skeletally mature and are more verbal and cognizant to describe adverse 
events. 
 
The first 5 subjects enrolled in the 11 to 17 years-of-age cohort (sentinel cohort) will 
undergo intensive mineral homeostasis monitoring for the first 14 days after 
administration of IP, to permit adaptation of subsequent mineral homeostasis 
assessments for all study subjects, as appropriate.  Once these 5 subjects have 
completed 14 days of mineral homeostasis monitoring, enrollment will be open to the 
remainder of the 11 to 17 years-of-age cohort.   
 
When the first 5 subjects in the 11 to 17 years-of-age cohort have been treated for 
12 months, enrollment will be open to the next age group (7 to 10 years of age).   


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 
Enrollment will be open to children 2 to 6 years of age after the first 5 subjects 
between 7 to 10 years of age have been treated for 6 months.   
At least 30 subjects younger than 7 years of age (at time of initial enrollment) will be 
enrolled.   
Calcium and vitamin D supplementation will be given to all study subjects and serum 
calcium and phosphorus concentrations will be monitored throughout the study on a 
regular basis.  Mineral homeostasis will be monitored more frequently over 14 days after 
administration of the first dose of denosumab in a sentinel cohort comprised of the 
first 5 subjects enrolled in the 11 to 17 years-of-age group to permit adaptation of 
subsequent mineral homeostasis assessments for all study subjects, as appropriate.  A 
similar approach will be employed in the first 5 subjects of any age who have increased 
bone turnover, defined as meeting 2 of the 3 following criteria:  (1) untreated with 
bisphosphonates for 4 years prior to entry in the trial; (2) Type 3 OI with the following 
characteristics:  height  3rd percentile and bowed extremities (or saber shins); or 
(3) Tanner stage 3 or 4.  The first 5 subjects meeting the criteria for increased bone 
turnover must undergo frequent mineral homeostasis monitoring for the first 14 days 
after denosumab administration according to the above schedule.  If a subject within the 
first 5 meeting the criteria for increased bone turnover is not willing to comply with these 
requirements, then he/she cannot be enrolled until the first 5 subjects have completed 
these required assessments and the regular monitoring schedule can be safely 
implemented.   
3.1.2 
3-Month Dosing Regimen 
Sixty previously enrolled subjects were transitioned to a 3-Month Dosing Regimen, 
among them, approximately 20 subjects were younger than 7 years of age (at time 
of initial enrollment).  Based on the life-threatening events of hypercalcemia 
observed, Amgen evaluated that benefit:risk profile of denosumab is not 
favorable.  Per DMC recommendation and Amgen decision, an urgent safety 
measure was issued to stop IP with the EOS visit 24 weeks after the last dose of 
IP.  See Section 3.5.2. 
3.2 
Number of Sites 
Approximately 40 sites in North America, Europe, and Australia may participate in this 
study.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.”   


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Approximately 150 subjects 2 to 17 years of age will participate in the study of which at 
least 30 subjects will be less than 7 years of age (at time of initial enrollment). 
Sixty subjects transitioned to the 3-Month Dosing Regimen.  Those subjects who do not 
consent to the 24-week safety follow up will end the study.   
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 
Each subject duration may vary between 36 to 51 months.  The maximum duration of 
trial for each subject could be 51 months (84 weeks). 
3.5.2 
End of Study 
An individual subject is considered to have completed the study if he/she has completed 
at least 12 months of 3-Month Dosing Regimen and a minimum of 36 months on study.  
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, 
subjects on study who had not completed their EOS visit were immediately 
discontinued from IP, and will be followed for safety for 24 weeks following the 
last dose of IP per the updated Schedule of Assessments (Table 7-5).  Subjects 
who have been on alternative therapy for more than 6 months or whose last dose 
of IP was greater than 24 weeks, no additional 24-week safety follow-up is 
required.  These subjects can follow the previous protocol (protocol amendment 
6) and complete the EOS CRF.  Subjects whose last dose was between 12 and 
24 weeks ago can complete the EOS assessments at week 24 per the updated 
Schedule of Assessments (Table 7-5). 
End of Study (End of Trial):  the end of the study/trial is defined as the date when the last 
subject across all sites is last 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). 
Before any study-specific activities/procedures related to this amendment, and in 
addition to the appropriate written informed consent from a legally acceptable 


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representative, the assent of the child also must be obtained, as appropriate to the age 
of the subject and/or based on local regulations where approved (see Section 11.1).  
Subjects who remain on study (have not previously completed Month 36/EOS on 
6-Month Dosing Regimen) will be reconsented at their next visit, and transition to a 
3-Month Dosing Regimen.  Subject eligibility will not be re-assessed at time of transition 
to 3-Month Dosing Regimen.  Refer to Section 7.1 for Schedule of Assessments at time 
of dose transition.  Subjects who do not reconsent to a 3-Month Dosing Regimen will be 
discontinued from IP as withdrawn consent and withdrawn from this study.  Subjects 
who do not reconsent will be given the opportunity to transition to Study 20170534. 
4.1 
Inclusion and Exclusion Criteria  
Eligibility criteria relates to initial enrollment into this study.  Subjects reconsenting to a 
3-Month Dosing Regimen will not repeat eligibility assessments; however, any subjects 
who previously ended IP who are receiving alternative therapies must discontinue these 
before resuming treatment with denosumab. 
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 written assent based on local regulations and/or guidelines prior to any 
study-specific activities/procedures being initiated 
102. 
Children 2 to 17 years of age inclusive at screening 
103. 
Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI as 
determined by presence of expected phenotype (examples include:  facial shape, 
voice, blue sclera, dentinogenesis imperfecta, typical radiographic features, 
fracture pattern) and lack of additional features unrelated to type I-IV OI 
(eg, blindness; mental retardation, neuropathy, craniosynostosis; premature 
exfoliation of normal appearing deciduous teeth) 
 
If familial, also must be autosomal dominant 
104. 
Clinical severity of OI as defined by 
 
2 or more prevalent vertebral compression fractures; OR 
 
1 prevalent vertebral compression fracture and 1 or more nonvertebral 
fractures within the previous 2 years; OR  
 
3 or more fractures within the previous 2 years 
4.1.2 
Exclusion Criteria 
Subjects meeting any of the following criteria at screening are not eligible for enrollment: 
201. 
Inability or unwillingness to comply with the requirements for frequent calcium 
and phosphorus monitoring for 14 days after the first dose of denosumab (only 
applies to the first 5 subjects 11 to 17 years of age enrolled in the study and the 


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first 5 subjects of any age meeting the criteria for increased bone turnover 
(see Section 2.3.2.1) 
202. 
Currently unhealed fracture or osteotomy, as defined by orthopedic opinion 
203. 
Osteotomy within 5 months prior to screening 
204. 
Evidence of untreated oral cavities or oral infections 
205. 
Recent or planned invasive dental procedure 
206. 
Surgical tooth extraction which has not healed by screening 
207. 
History of an electrophoresis pattern inconsistent with type I to IV OI  
208. 
History of known mutation in a gene other than COL1A1/COL1A2 causing OI or 
other metabolic bone disease 
Abnormalities of the following per central laboratory reference ranges at screening 
209. 
Serum albumin-corrected calcium  lower limit of normal (LLN)  
210. 
Serum vitamin D  20 ng/mL; rescreening for vitamin D level  20 ng/mL will be 
allowed, after adequate supplementation  
211. 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT)  1.5 x upper 
limit of normal (ULN)  
212. 
Total bilirubin (TBL)  1.5 x ULN (subjects with Gilbert syndrome are eligible) 
213. 
Serum phosphorus  LLN  
214. 
Serum alkaline phosphatase  20 above the ULN or  20 below the LLN  
215. 
Estimated glomerular filtration rate (eGFR)  60 mL/min/1.73 m2 (calculated by 
the Schwartz equation at screening) 
Evidence of any of the following: 
216. 
Current hyperthyroidism (unless well-controlled on stable antithyroid therapy) 
217. 
Current clinical hypothyroidism (unless well-controlled on stable thyroid 
replacement therapy) 
218. 
History of hyperparathyroidism  
219. 
Current hypoparathyroidism 
220. 
Current, uncontrolled hypercalcemia (albumin-corrected serum Ca  10 ULN) 
222. 
History of osteomalacia or rickets (chart review) 
223. 
Other bone diseases that affect bone metabolism (eg, osteoporosis 
pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, 
hypophosphatasia) (chart review) 
224. 
History of autoimmune disease 
225. 
History of malabsorption (in children with serum albumin  LLN, malabsorption 
should be clinically ruled out by the investigator to confirm eligibility) 


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226. 
History of rare hereditary problems of fructose intolerance 
227. 
History of long QT syndrome 
228. 
History of non-healing osteotomy 
229. 
History of malignancy 
230. 
History of alcohol or drug abuse  
231. 
History of any solid organ or bone marrow transplant 
232. 
Contraindicated or poorly tolerant of denosumab therapy  
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   
235. 
Currently pregnant or planning a pregnancy during the study and for an 
additional 5 months after the last dose of IP (denosumab) 
236. 
Currently breastfeeding or planning on breastfeeding during the study and for an 
additional 5 months after the last dose of IP (denosumab) 
237. 
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 IP 
(denosumab) (See Section 6.8.1) 
Received other osteoporosis treatment or bone active treatment with the following 
guidelines: 
238. 
Prior treatment with 
 
denosumab  
 
fluoride or strontium for bone disease (fluoride taken for routine dental care is 
permitted) 
 
parathyroid hormone (PTH) or PTH derivatives within 12 months prior to 
screening 
 
zoledronic acid within 6 months prior to screening 
 
oral bisphosphonates or intravenous bisphosphonates other than zoledronic 
acid, if the first dose of denosumab would be before their next scheduled 
bisphosphonate dose would have been given 
239. 
Administration of systemic glucocorticoids ( 5.0 mg prednisone equivalents/day 
for more than 10 days) within 3 months prior to screening.  Topical and inhaled 
glucocorticoids will be allowed. 
240. 
Administration of any of the following treatment within 3 months prior to 
screening: 
 
Growth hormone (subjects on stable dose of growth hormone for at least 
3 months prior to screening will be allowed) 
 
Calcitonin 
 
Cathepsin K inhibitor 


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 
Other bone active drugs including anti-convulsants (except gabapentin and 
benzodiazepines) and heparin 
 
Chronic systemic ketoconazole, androgens, adrenocorticotropic hormone 
(ACTH), cinacalcet, aluminum, lithium, protease inhibitors, 
gonadotropin-releasing hormone agonists 
241. 
Received immunosuppressant therapy other than glucocorticoids 
242. 
Anticipated major skeletal surgery (eg rodding surgery, spinal surgery) within the 
next 12 months from day 1 
243. 
Symptoms associated with skull abnormalities such as basilar invagination, 
basilar impression or Chiari malformation (eg, headache induced by coughing or 
straining for stool, or parasthesias or weakness)  
244. 
Rodding surgery within 5 months prior to screening or not yet healed per 
orthopedic surgeon  
245. 
Spinal fusion surgery within 5 months prior to screening or not yet healed per 
orthopedic surgeon 
246. 
Inability to consume milk 
247. 
Planned orthopedic surgery that, in the opinion of the principal investigator (PI), 
would require missing any dose of denosumab in year 1 or 2 or more doses 
thereafter 
248. 
Currently receiving treatment in another investigational drug study, or less than 
30 days since ending treatment on another investigational drug study(s), or 
current or planned participation in a clinical trial that would preclude compliance 
with study requirements 
249. 
Other investigational procedures while participating in this study are excluded 
250. 
Known intolerance to calcium or vitamin D supplements 
251. 
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’s safety or interfere with the study evaluation, 
procedures or completion 
252. 
Subject will not be available for protocol-required study visits, to the best of the 
subject and investigator’s knowledge 
253. 
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 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 


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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. 
5.1 
Enrollment into 6-Month Dosing Regimen 
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 Interactive Voice Response 
System/Interactive Web Response System (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 enrollment number 
assigned for the study.  
Enrollment/Treatment Assignment 
After completing all screening procedures and meeting all eligibility criteria, subjects will 
be enrolled in the study to receive a subcutaneous (SC) injection of denosumab.  
Enrollment will be gated as follows: 
 
Older children (11 to 17 years of age) will be enrolled first because they will be the 
most skeletally mature and are more verbal and cognizant to describe adverse 
events.   
 
The first 5 subjects enrolled in the 11 to 17 years-of-age cohort (sentinel cohort) will 
undergo intensive mineral homeostasis monitoring for the first 14 days after 
administration of IP, to permit adaptation of subsequent mineral homeostasis 
assessments for all study subjects, as appropriate.  Once these 5 subjects have 
completed 14 days of mineral homeostasis monitoring, enrollment will be open to the 
remainder of the 11 to 17 years-of-age cohort.   
 
When the first 5 subjects in this age group have been treated for 12 months, 
enrollment will be open to the next age group (7 to 10 years of age).   
 
Enrollment will be open to children 2 to 6 years of age after the first 5 subjects 
between 7 to 10 years of age have been treated for 6 months.   


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At least 30 subjects younger than 7 years of age (at time of initial enrollment) will be 
enrolled. 
A subject will be considered enrolled once he/she meets eligibility criteria and an 
enrollment call is placed in IVRS/IWRS.  It is therefore very important to place the 
enrollment call only after the subject’s eligibility and willingness to participate has been 
confirmed, as the subject cannot be ‘unenrolled’. 
The IVRS/IWRS will be utilized to complete the enrollment of each subject that is ready 
to be enrolled.  Specific details regarding enrollment and treatment assignment 
procedures will be provided separately by the IVRS vendor. 
5.2 
Transition to 3-Month Dosing Regimen 
Due to the life-threatening risk of hypercalcemia, an urgent safety measure has 
been implemented to stop all treatment with IP with the EOS visit 24 weeks after 
the last dose of IP.  See Section 3.1.2. 
Before subjects can transition to a 3-Month Dosing Regimen, Amgen requires a copy of 
the site’s written IRB/IEC approval of the protocol amendment and re-consent form.  All 
legally acceptable representatives must personally sign and date the re-consent form 
and subjects should sign the subject assent form as applicable by local law before 
commencement of 3-Month Dosing Regimen/procedures. 
A subject call will be placed in the IVRS/IWRS at time of re-consent and transition to the 
3-Month Dosing Regimen.  The investigator is to document this decision, and date of 
dosing schedule change, in the subject’s medical record. 
All subjects who remain on study (have not previously completed Month 36/EOS under 
the 6-Month Dosing Regimen) will be eligible to transition to the 3-Month Dosing 
Regimen, unless they ended treatment due to an adverse event.  Subjects may be 
consented and transition to the 3-Month Dosing Regimen up to and including the date 
they attend for a Month 36 visit under the 6-Month Dosing Regimen. 
Should a subject decide not to re-consent, subject will discontinue IP and study.  See 
Section 8.3 for additional guidance. 
6. 
TREATMENT PROCEDURES 
Denosumab administered at a dose of 1 mg/kg (up to a maximum of 60 mg) is 
considered to be an IP in this study.  A manual containing detailed information regarding 
the storage, preparation and administration of IP and brief information about other 


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protocol-required drugs will be provided separately in the modular Investigational 
Product Instruction Manual (IPIM). 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen IP used in this study includes denosumab.   
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care.   
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.   
The modular IPIM, a document external to this protocol, contains detailed information 
regarding the storage, preparation, and administration of denosumab.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product Denosumab 
Denosumab 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.  All subjects will receive a SC 
injection of denosumab every 6 months during the 6-Month Dosing Regimen.  Subjects 
who transition to the 3-Month Dosing Regimen will receive an injection of denosumab 
every 3 months.  All SC injections must be administered by authorized site personnel.  
The denosumab SC injection should be administered as the last procedure after all other 
study visit procedures have been completed.  The injection should not be administered 
in the same arm from which blood is drawn. 
6.2.2 
Dosage, Administration, and Schedule 
Each site will be supplied with denosumab such that each box will contain 1 vial of 
70 mg/mL denosumab.  There is no experience of overdosage with denosumab. 
The site personnel will call IVRS/IWRS to obtain the appropriate box numbers at each 
scheduled dosing visit.  The call to enroll the subject and to receive the day 1 injection 
should only be made after the subject has been determined to be eligible for the study.  
Denosumab will be administered at a dose of 1 mg/kg body weight, but the total dose 
must not exceed 60 mg per subject at any visit.  Please refer to specific instructions 
provided by the IVRS/IWRS vendor for additional information.  


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6.2.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Denosumab will be administered as a weight-based dose determined based on each 
subject’s weight assessed at the time of dosing.  There are no additional dose 
adjustments for the SC IP.  
Blood draws and safety assessments on day 1 of the 3-Month Dosing Regimen should 
be performed before denosumab administration.  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. 
Serum calcium and phosphorus concentrations will be closely monitored during the 
study.   
Dosing may be delayed if a subject has bone surgery scheduled.  Dosing with 
denosumab can be continued after the surgery at the investigator’s discretion. 
6.2.3.1 
6-Month Dosing Regimen 
In order to better evaluate and characterize the risk for hypocalcemia and 
hypophosphatemia, more frequent monitoring of mineral homeostasis after the first dose 
of denosumab for 14 days will be implemented in the first 5 subjects enrolled in the 
study.  Serum calcium and phosphorus concentrations will be checked daily at the local 
and central laboratories for the first 3 days after administration of the first dose of 
denosumab and every other day thereafter for a total of 14 days in this 5-subject sentinel 
cohort.  
If no concerns arise from dosing of the sentinel cohort over 14 days after the first 
administration of denosumab that warrant adaptation of the mineral homeostasis 
assessment schedule, enrollment will be opened for the remainder of the subjects in the 
first age cohort, and monitoring of serum calcium and phosphorus will continue 
according to the planned schedule, ie, days 1, 10, and 30, and months 3, 6, 12, 18, 24, 
30, and 36, thereafter.  
Dosing may be delayed if a subject has bone surgery scheduled.  Dosing with 
denosumab can be continued after the surgery at the investigator’s discretion. 


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6.2.3.2 
3-Month Dosing Regimen 
Serum calcium to be measured at day 10 and day 30 after the week 12 and week 24 
doses. 
6.3 
Other Protocol-required Therapies 
All other protocol-required supplements, including calcium and vitamin D, that are 
commercially available are not provided or reimbursed by Amgen (except if required by 
local regulation).  The investigator will be responsible for obtaining supplies of these 
drugs.   
All subjects are recommended to take daily supplements of 30-50 mg/kg and not to 
exceed 1000 mg elemental calcium and at least 800 IU vitamin D during the study.  If a 
subject becomes hypercalcemic, hypercalciuric or has other intolerance over the course 
of the study, the calcium and/or vitamin D supplementation may be modified or 
discontinued at investigator discretion and site will manage supplementation to maintain 
normal serum and urine calcium.  Similarly, 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. 
Alternative therapy for OI is at investigator discretion and consistent with local 
standard of care and clinical practice guidelines. 
Additional details regarding these supplements are provided in the IPIM. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, TBL) and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis 
(as described below) may meet the criteria for withholding or permanent discontinuation 
of Amgen IP 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 Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Denosumab and other protocol-required therapies, as appropriate, should be 
discontinued permanently and the subject should be followed according to the 
recommendations in Appendix A (Additional Safety Assessment Information) for possible 
drug-induced liver injury (DILI), if ALL of the criteria below are met:  
 
TBL  2x ULN or INR  1.5 


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 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
 ULN 
 3x ULN 
 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; 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 (NASH)  
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
6.4.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following rules are recommended for withholding of denosumab and other 
protocol-required therapies:  
 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
 8x ULN at any time 
Any 
 5x ULN but  8x ULN for  2 weeks 
Any 
 5x ULN but  8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
 3x ULN with clinical signs or symptoms that are consistent 
with hepatitis (such as right upper quadrant pain/tenderness, 
fever, nausea, vomiting, jaundice).   
 
OR:  TBL  3x ULN at any time 
 
OR:  ALP  8x ULN at any time 


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Denosumab and other protocol-required therapies, as appropriate, should be withheld 
pending investigation into alternative causes of DILI.  If IP(s) is withheld, the subject is to 
be followed according to recommendations in Appendix A 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 (Section 6.4.3).   
6.4.3 
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 and other 
protocol-required therapies, as appropriate 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. 
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, combination product, or device after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors and partners for 
whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts. 
This includes any investigational products described above provisioned and/or 
repackaged/modified by Amgen. 
Any product complaint associated with products described above and supplied by 
Amgen are to be reported according to the instructions provided in the modular IPIM. 


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6.7 
Excluded Treatments and/or Procedures During Study Period  
All medications listed in the exclusion criteria, shown in Table 6-1 below, or any other 
medication that is known or suspected to have activity on bone metabolism (except, 
calcium and vitamin D) will not be allowed during the study while the subject is on IP. 
Table 6-1.  List of Proscribed Therapy 
Aluminum 
Anabolic steroids 
Androgens 
Anticonvulsants (gabapentin 
and benzodiazepines are 
allowed) 
Any investigational agents for 
bone loss other than study 
drug 
Aromatase inhibitors 
Biologics (except for insulins 
and vaccines) 
Bisphosphonates 
Calcitonin 
Calcium chelators 
Chemotherapeutics 
Chronic heparin use 
( 7 days) (LMWH are 
permitted)a 
Cinacalcet 
Citrated products 
Fluorideb 
Gonadotropin-releasing 
hormone agonists 
Growth hormone (unless 
stable for at least 3 months 
prior to screening) 
Immunosuppressants 
Lithium 
Parathyroid hormone (or a 
derivative) 
Progestins, other than when 
used as monotherapy for 
contraception 
Prolonged glucocorticoid 
therapy at a prednisone 
equivalent dose of 
 5.0 mg/day (tapering 
glucocorticoid courses of 
 1 month duration are 
permitted regardless of dose; 
inhaled or topical 
glucocorticoids are permitted) 
Protease inhibitors 
Strontium 
Tibolone 
LMWH  low molecular weight heparin  
a Low molecular weight heparin does not have the same effect on bone density or fracture, and thus is not 
prohibited. 
b Fluoride taken for routine dental care is permitted. 
6.8 
Contraceptive Requirements 
6.8.1 
Female Subjects 
Female subjects of childbearing potential must agree to practice true sexual abstinence 
(refrain from heterosexual intercourse) or use a highly effective method of contraception 
during treatment and for an additional 5 months after the last dose of denosumab. 
Contraceptive methods that achieve a failure rate of less than 1 per year when used 
consistently and correctly are considered highly effective and may include:  Hormonal 
(combined estrogen and progestogen or progestogen-only) contraception associated 
with inhibition of ovulation (oral, injectable, implantable, intravaginal, or transdermal 
route); intrauterine device (IUD); intrauterine hormonal releasing system (IUS); bilateral 
tubal occlusion; vasectomized partner (provided that partner is the sole sexual partner of 
the female participant and the vasectomized partner has received medical assessment 
of the surgical success); true sexual abstinence when this is in line with the preferred 


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and usual lifestyle of the subject.  The reliability of sexual abstinence must be evaluated 
by the investigator and be the preferred and usual lifestyle of the subject.  
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 urine pregnancy testing prior to their IP administration 
at every visit and EOS. 
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. 
6.8.3 
Unacceptable Methods of Birth Control for Male and 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 amenorrhoea method. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
 


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Table 7-1.  Schedule of Assessments for 6-Month Dosing Regimen 
 
Screening Phase 
Treatment Phase 
Procedures 
Screening 
Study Day 
Study Months 
1 
10 
30 
3 
6 
12 
18 
24 
30 
36/ETg 
 
 
 3 day window 
These visits will have a  7 day window 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Tanner stage 
X 
 
 
 
 
Xj 
X 
Xj 
X 
Xj 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
X 
 
X 
 
X 
Weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Armspan  
X 
 
 
 
 
 
X 
 
X 
 
X 
DXA (AP lumbar spine)k 
 
Xa 
 
 
 
X 
X 
X 
X 
 
X 
DXA (proximal femur – total hip and femoral neck in 
subjects  5 years of age at screening)k 
 
Xa 
 
 
 
X 
X 
X 
X 
 
X 
X-ray (lateral thoracic, lumbar spine)k 
 
Xl 
 
 
 
 
X 
 
X 
 
X 
X-ray – AP kneesb,k 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Dental X-ray (cephalogram and panoramic 
radiograph)k 
 
X 
 
 
 
 
 
 
 
 
X 
Oral visual inspection 
 
 
 
 
 
 
X 
 
X 
 
 
Dental X-ray (molars)c,k 
 
 
 
 
 
 
X 
 
X 
 
 
Hematology 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
Serology for HIV, hepatitis B and hepatitis Ch 
X 
 
 
 
 
 
 
 
 
 
 
25(OH) vitamin D level 
X 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on last page of the table 


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Table 7-1.  Schedule of Assessments for 6-Month Dosing Regimen 
 
Screening Phase 
Treatment Phase 
Procedures 
Screening 
Study Day 
Study Months 
1 
10 
30 
3 
6 
12 
18 
24 
30 
36/ETg 
 
 
 3 day window 
These visits will have a  7 day window 
Pregnancy test (urine dipstick method)d 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
SC injection of denosumab (1 mg/kg) 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Dispensation of calcium and vitamin D 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Antidenosumab antibody assay 
 
X 
 
 
 
 
X 
 
X 
 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK (serum denosumab)e 
 
X 
X 
Xe 
Xe 
X 
X 
X 
X 
X 
X 
BTM (BSAP, sCTX)e 
 
X 
X 
Xe 
Xe 
X 
X 
X 
X 
X 
X 
Safety data collection/ recording/reportingf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical fracture recording 
 
 
 
 
 
 
 
 
 
 
 
Administration of:  
 
 
 
 
 
 
 
 
 
 
 
CHQ-PF-50 
 
X 
 
 
 
 
X 
 
X 
 
X 
CHAQ Disability Score 
 
X 
 
 
 
 
X 
 
X 
 
X 
WBFPRS 
 
X 
 
 
 
 
X 
 
X 
 
X 
Page 2 of 2 
Footnotes defined on next page 


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AP  anteroposterior; BSAP  bone-specific alkaline phosphatase; BTM  bone turnover markers; CHAQ  Childhood Health Assessment Questionnaire; 
CHQ-PF-50  Child Health Questionnaire-Parent Form-50; DXA  dual-energy X-ray absorptiometry; EOS  End of Study; ET  end of treatment; HIV  human 
immunodeficiency virus; PI  principal investigator; PK  pharmacokinetic; SC  subcutaneous; sCTX  serum type I collagen C-telopeptide; WBFPRS  Wong-Baker 
Faces Pain Rating Scale 
a To be performed in duplicate at this visit only 
b To be performed only in children with open growth plates who do not have bilateral hardware 
c To be performed only if a delay in molar eruption is suspected by the PI 
d To be performed in female subjects who have had menarche or those who are Tanner stage 2 or higher 
e Serum denosumab concentrations and BTM (BSAP and sCTX) levels will be collected at day 30 and month 3 only in a PK/BTM substudy of approximately 
50 subjects 
f Only serious adverse events will be collected at screening visit.  Both serious and nonserious adverse events will be collected at study day 1 visit and later 
g See Section 7.2.5 for details on EOS visit. 
h Serology for HIV and hepatitis B and C should be performed on a separate day from the other non-fasting blood draws for screening in subjects with body weight  
 11 kg 
iOn 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/BTM 
sub-study.  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. 
j Tanner stage to be conducted in female subjects only at months 6, 18, and 30 to determine the need to perform a pregnancy urine dipstick test at these visits. 
k All images/reports (as applicable) to be sent to the central imaging vendor.  Additional spine x-rays should be obtained if clinically indicated. 
l For subjects who have not otherwise qualified based on fracture criteria, the baseline lateral spine radiograph may be obtained at the screening visit. 
m Subjects will have 1 EOS visit, either at the end of 6-Month Dosing Regimen or at the end of 3-Month Dosing Regimen.  All subjects who remain on study (have not 
previously completed Month 36/EOS under the 6-Month Dosing Regimen) will be eligible to transition to the 3-Month Dosing Regimen.  Subjects may be consented 
and transition to the 3-Month Dosing Regimen up to and including the date they attend for a Month 36 visit under the 6-Month Dosing Regimen. For subjects who 
have completed Month 30 on the 6-Month Dosing Regimen, an EOS will not be performed if the subject re-consents to the 3-Month Dosing Regimen.   
 


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Table 7-2.  6-Month Dosing Regimen Additional Schedule of Assessments for Subjects in Sentinel Cohort and the First 
5 Subjects Who Have Increased Bone Turnover as Defined in Section 3.1 
Procedures 
Day 2 
Day 3 
Day 4 
Day 6 
Day 8 
Day 12 
Day 14 
Serum calcium and phosphorusa  
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Safety data collection/recording/reporting 
X 
X 
X 
X 
X 
X 
X 
a Blood collection may be performed by a qualified individual at the subject’s home in lieu of a site visit; If blood collection is performed at the subject’s home on day 2 
through day 14, it should occur at no more than 2 consecutive visits at a time.  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. 
Table 7-3.  6-Month Dosing Regimen Additional Schedule of Assessments for Subjects in Sentinel Cohort  
as Defined in Section 3.1 
Procedures 
Study Month 
4.5 
10 
16 
22 
28 
34 
Serum calcium  
X 
X 
X 
X 
X 
X 
BTM (BSAP and sCTX) 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Safety data collection/recording/reporting  
X 
X 
X 
X 
X 
X 
BSAP  bone-specific alkaline phosphatase; BTM  bone turnover markers; sCTX  serum type I collagen C-telopeptide 
 


Product:  AMG 162 
Protocol Number:  20130173 
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Page 53 of 108 
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Table 7-4.  Schedule of Assessments for 3-Month Dosing Regimen  
 
 
Treatment Phase 
Procedures 
Q3M 
Day 
1a 
Study Day 
Study Weeks 
Q3M 
D10 
Q3M 
D30 
Q3M 
D60 
Q3M
W12 
D10 
D30 
Q3M 
W24 
D10 
D30 
Q3M 
W36 
Q3M 
W48b 
Additional 
Dosingc 
EOS/ 
ETd 
 
 3 day window 
Day visits have a  3 day window; week visits have a  7 day window 
Re-consent to Q3M 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Tanner stage 
X 
 
 
 
Xe 
 
 
Xe 
 
 
Xe 
Xe 
Xe 
Xe 
Vital signs 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Height 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Armspan  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
DXA (AP lumbar spine)f 
Xg 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
DXA (proximal femur – total hip and 
femoral neck in subjects  5 years of 
age at screening)f 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X-ray (lateral thoracic, lumbar spine)f 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X-ray – AP kneesf, h 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
Dental X-ray (cephalogram and 
panoramic radiograph)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Oral visual inspection 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Dental X-ray (molars)f, i 
X 
Hematology 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
 
X 
Xj,l 
Xj,l 
X 
Xj,l 
Xj,l 
X 
X 
X 
X 
25(OH) vitamin D level 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on the last page of the table 


Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
Page 54 of 108 
CONFIDENTIAL 
 
 
 
Table 7-4.  Schedule of Assessments for 3-Month Dosing Regimen  
 
 
Treatment Phase 
Procedures 
Q3M 
Day 
1a 
Study Day 
Study Weeks 
Q3M 
D10 
Q3M 
D30 
Q3M 
D60 
Q3M 
W12 
D10 
D30 
Q3M 
W24 
D10 
D30 
Q3M 
W36 
Q3M 
W48b 
Additional 
Dosingc 
EOS/ 
ETd 
 
 3 day window 
Day visits have a  3 day window; week visits have a  7 day window 
Urine calcium 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Pregnancy test (urine dipstick method)k 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
SC injection of denosumab (1 mg/kg) 
Xl 
 
 
 
Xl 
 
 
Xl 
 
 
Xl 
Xl,m 
Xl 
 
Dispensation of calcium and vitamin D 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Antidenosumab antibody assay 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
PK (serum denosumab) 
X 
Xl 
Xl 
Xl 
X 
 
 
X 
 
 
X 
X 
X 
X 
BTM (BSAP, sCTX)n 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Safety data collection/ recording/reporting 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Clinical fracture recording 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Administration of:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CHQ-PF-50 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
CHAQ Disability Score 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
WBFPRS 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Page 2 of 2 
Footnotes defined on next page 


Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
Page 55 of 108 
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AP  anteroposterior; BSAP  bone-specific alkaline phosphatase; BTM  bone turnover markers; CHAQ  Childhood Health Assessment Questionnaire; 
CHQ-PF-50  Child Health Questionnaire-Parent Form-50; D  day; DXA  dual-energy X-ray absorptiometry; EOS  End of Study; ET  end of treatment; 
PI  principal investigator; PK  pharmacokinetic; Q3M  every 3 months (every 12 weeks); SC  subcutaneous; sCTX  serum type I collagen C-telopeptide; 
W  week; WBFPRS  Wong-Baker Faces Pain Rating Scale 
a The 3-Month Dosing Regimen day 1 is defined as the date of reconsent and the first dose of denosumab on the 3-Month Dosing Regimen. All subjects who remain on 
study (have not previously completed Month 36/EOS under the 6-Month Dosing Regimen) will be eligible to transition to the 3-Month Dosing Regimen unless they 
ended treatment due to an adverse event.  Subjects may be consented and transition to the 3-Month Dosing Regimen up to and including the date they attend for a 
Month 36 visit under the 6-Month Dosing Regimen. 
b Week 48 will be EOS for all subjects who are at or beyond M24 of 6-Month Dosing Regimen at time of transition to 3-Month Dosing Regimen.  End of Study will be 
delayed for subjects at M18 of 6-Month Dosing Regimen at time of transition to 3-Month Dosing Regimen.  These subjects will complete additional Dosing visits at 
W48 and W60.  End of Study will be delayed until W72.  End of study may be extended for some subjects until week 84 due to 24 weeks of safety follow-up 
following the last dose of IP due to urgent safety measure.   
c Performed only for subjects at M18 of 6-Month Dosing Regimen at time of transition to 3-Month Dosing Regimen, and who will not have completed a minimum of 
144 weeks (Month 36) on study if EOS is scheduled 3 months after week 48. These subjects will receive additional dosing at W48 and W60 so that EOS occurs at 
week 144 (W72 on 3-Month Dosing Regimen).  All other subjects will perform EOS at W48.  End of study may be extended for some subjects until week 84 due 
to 24 weeks of safety follow-up following the last dose of IP due to urgent safety measure.   
d See Section 7.2.5 for details on EOS visit. Week 48 will be EOS for all subjects who are at or beyond M24 of 6-Month Dosing Regimen at time of transition to 3-Month 
Dosing Regimen. All W48 and EOS procedures will be performed during this visit. No IP will be administered.  End of Study will be delayed for subjects at M18 of 
6-Month Dosing Regimen at time of transition to 3-Month Dosing Regimen.  These subjects will complete additional Dosing visits at W48 and W60.  End of Study will 
be delayed until W72.  End of study may be extended for some subjects until week 84 due to 24 weeks of safety follow-up following the last dose of IP due 
to urgent safety measure.   
e Tanner stage to be conducted in female subjects at every dosing visit and EOS to determine the need to perform a pregnancy urine dipstick test.  For a female who 
has a Tanner stage 2 or greater, or has had menarche, a pregnancy test will be performed prior to IP administration at every visit and EOS.  
f All images/reports (as applicable) to be sent to the central imaging vendor, including any unscheduled images taken during the study.  Additional spine x-rays should 
be obtained if clinically indicated. 
g To be performed in duplicate on Day 1 of 3-Month Dosing Regimen. 
h To be performed only in children with open growth plates who do not have bilateral hardware. 
i To be performed only if a delay in molar eruption is suspected by the PI. 
j Serum calcium to be performed on days 10 and 30 following week 12 and week 24 doses.  Blood collection may be performed by a qualified individual at the subject’s 
home, in lieu of a site visit. 
k To be performed in female subjects who have had menarche or those who are Tanner stage 2 or higher. 
l At all study visits signs and symptoms of hypocalcemia will be assessed and subjects reminded of importance of taking calcium and vitamin D. 
m Week 48 denosumab administration performed only for subjects who will not have completed a minimum of 144 weeks (Month 36) on study. Applies to subjects who 
were at M18 of 6-Month Dosing Regimen at time of transition to 3-Month Dosing Regimen. 
n On days 10, 30, and 60, blood collection may be performed by a qualified individual at the subject’s home for these visits, in lieu of a site visit. In addition, when blood 
collection is performed at the subject’s home, the investigator must ensure that concomitant medications, clinical fractures, and adverse events, if any, are 
appropriately recorded. 
 
 


Product:  AMG 162 
Protocol Number:  20130173 
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Page 56 of 108 
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Table 7-5.  Schedule of Assessments Following Implementation of Urgent Safety Measure  
(For Subjects on 3-Month Dosing Still On Study as of 30 September 2021) 
Weeks after last dose of denosumab (Week 0)a 
Week 12b 
Week 24/EOSc 
Physical examination 
X 
X 
Tanner stage 
X 
Xe 
Vital signs 
X 
X 
Height 
X 
X 
Weight 
X 
X 
Armspan  
 
X 
DXA (AP lumbar spine)d 
 
X 
DXA (proximal femur – total hip and femoral neck in subjects  5 years of age at screening)d 
 
X 
X-ray (lateral thoracic, lumbar spine)d 
 
X 
X-ray – AP kneesd, e 
 
X 
Dental X-ray (cephalogram and panoramic radiograph)d 
 
X 
Oral visual inspection 
X 
X 
Dental X-ray (molars)d, f 
X 
X 
Hematology 
X 
X 
Serum chemistryg 
X 
X 
Page 1 of 2 
Footnotes defined on last page of table 
 


Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
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Table 7-5.  Schedule of Assessments Following Implementation of Urgent Safety Measure 
(For Subjects on 3-Month Dosing Still On Study as of 30 September 2021) 
Weeks after last dose of denosumab (Week 0)a 
Week 12b 
Week 24/EOSc 
Urine calcium 
X 
X 
Pregnancy test (urine dipstick method)h 
X 
X 
Dispensation of calcium and vitamin Di 
X 
X 
Antidenosumab antibody assay 
X 
X 
Concomitant medications 
X 
X 
PK (serum denosumab) 
X 
X 
BTM (BSAP, sCTX) 
X 
X 
Safety data collection/ recording/reporting 
X 
X 
Clinical fracture recording 
X 
X 
Administration of:  
 
 
CHQ-PF-50j 
 
X 
CHAQ Disability Scorej 
 
X 
WBFPRSj 
 
X 
Page 2 of 2 
Footnotes defined on next page. 


Product:  AMG 162 
Protocol Number:  20130173 
Date:  26 November 2021 
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CONFIDENTIAL 
 
 
 
AP  anteroposterior; BSAP  bone-specific alkaline phosphatase; BTM  bone turnover markers; CHAQ  Childhood Health Assessment Questionnaire; 
CHQ-PF-50  Child Health Questionnaire-Parent Form-50; D  day; DXA  dual-energy X-ray absorptiometry; PK  pharmacokinetic; (every 12 weeks); 
sCTX  serum type I collagen C-telopeptide; W  week; WBFPRS  Wong-Baker Faces Pain Rating Scale 
a No IP will be administered.  Subjects who have been on alternative therapy for more than 6 months, subjects whose last dose was between 12 and 24 
weeks ago, and subjects whose last dose of IP was greater than 24 weeks ago should complete their EOS visit, and no 24-week safety follow-up is 
required.  These subjects can follow the current protocol and complete the EOS CRF. 
b Not to be completed for subjects who have already completed 24 weeks post IP. 
c End of study may be extended for some subjects until week 84 due to the 24 weeks of safety follow-up following the last dose of IP due to urgent safety 
measure.   
d All images/reports (as applicable) to be sent to the central imaging vendor, including any unscheduled images taken during the study.  Additional spine x 
rays should be obtained if clinically indicated.  Assessment may not be performed if less than 3 months have elapsed since previous radiographic 
assessment. 
e To be performed only in children with open growth plates who do not have bilateral hardware. 
f To be performed only if a delay in molar eruption is suspected by the PI. 
g If the 12-week visit occurs after any of the first 3 injections of IP, serum calcium should be obtained at day 10 and day 30 after that visit. 
h To be performed in female subjects who have had menarche or those who are Tanner stage 2 or higher. 
i Per investigator discretion. 
j Administration of PROs may not be performed if less than 1 month has elapsed since the previous assessment.


Product:  AMG 162 
Protocol Number:  20130173 
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7.2 
General Study Procedures  
Study tests and procedures will be performed only after written informed consent and 
subject assent (as applicable by local law) is obtained.  During the study, every effort 
should be made to keep subjects on the study schedule of procedures.  Tests and 
procedures will be performed as per the schedule provided in Section 7.1.  
All subjects enrolled in the trial will have samples assayed for antidenosumab binding 
and if positive, neutralizing antibodies. 
The injectable IP administration should be the last procedure performed at each visit 
after all other study procedures have been completed. 
Specific details of all tests and procedures are outlined below 
Study Visit Definitions 
6-Month Dosing Regimen: 
 
The screening date is defined as the date the informed consent/subject assent is 
signed. 
 
Enrollment date is defined as the date of enrollment call is made using 
IVRS/IWRS. 
 
Day 1 visit must occur within 35 days of screening or 42 days of the rescreening 
date.  
 
Day 1 is defined as the day that the initial dose of IP is administered to the 
subject.  All subjects should receive their first dose of the IP on the day of 
enrollment.  If this is not possible, day 1 must occur within 72 hours of 
enrollment. 
3-Month Dosing Regimen: 
 
3-Month Dosing Regimen day 1 should occur at the next study visit following all 
regulatory and ethics approval of protocol Amendment 5 dated 11 March 2020. 
 
3-Month Dosing Regimen day 1 visit is defined as the day that the initial dose of 
IP for 3-Month Dosing Regimen is administered to the subject. 
 
3-Month Dosing Regimen will be defined as 12 weeks per dose period. 
If a subject’s visit is delayed, his/her subsequent visit dates should not be shifted, but 
always calculated based on the day 1 visit date. 
Visit Schedule following Urgent Safety Measure: 
Following implementation of the Urgent Safety Measure, subsequent visits are 
calculated from last dose of IP. 


Product:  AMG 162 
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Study Visit Windows 
6-Month Dosing Regimen: (Note:  Per urgent safety measure, all dosing should be 
stopped). 
 
All tests and procedures scheduled for day 1 must occur within 35 days of the 
screening date or 42 days of the rescreening date. 
 
All tests and procedures scheduled for the day 10 and day 30 visits must be 
performed within  3 days of the scheduled visit date. 
 
All tests and procedures scheduled for the month 3, 6, 12, 18, 24, 30, and 
36 visits must be performed within  7 days of the scheduled visit date. 
 
All tests and procedures for the additional visits for the sentinel cohort must be 
performed on the day of the scheduled visit date. 
3-Month Dosing Regimen:  (Note:  all 3-Month dosing has been stopped even if 
subjects have not met the study duration.) 
 
All tests and procedures scheduled for the day 10, day 30, and day 60 visits must 
be performed within  3 days of the scheduled visit date. 
 
All tests and procedures scheduled for the week 12, 24, 36, 48 visit and any 
additional dosing months must be performed within  7 days of the scheduled 
visit date. 
 
3-Month Dosing Regimen will continue for 12-months of dosing, or longer for any 
subjects who would not meet the minimum of week 144 (Month 36) at time of 
EOS. 
Any missed visits, tests not done, and examinations not conducted must be reported as 
such on the electronic case report forms (eCRFs).   
Study procedures for a specific visit may be completed on multiple days as long as all of 
the procedures are completed within the visit window.  However, the IP should be 
administered last. 
7.2.1 
Screening and Enrollment 
Screening and Enrollment applies only to the 6-Month Dosing Regimen and initial 
enrollment into this study.  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; see below).   
Before obtaining informed consent/subject assent, the investigator should discuss 
alternative therapies that may be available. 
The following procedures are to be completed during the timepoints designated in the 
Schedule of Assessments (Section 7.1).  


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 
Confirmation that the ICF and the Assent Form 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 
 
Physical examination as per standard of care (including medical/surgical history and 
fracture history)  
 
Tanner stage 
 
Height in centimeters measured without shoes 
 
Weight 
 
Armspan 
 
Vital signs (ie, pulse, respiration rate, temperature, systolic and diastolic blood 
pressure) 
 
Laboratory assessments hematology, serum chemistry, serology for HIV, hepatitis B 
and hepatitis C, and 25 (OH) vitamin D level 
 
Serology for HIV and hepatitis B and C should be performed on a separate day 
from the other non-fasting blood draws for screening in subjects with body weight 
 11 kg  
 
Urine pregnancy test 
 
Documentation of medication history 
7.2.1.1 
Enrollment in IVRS/IWRS System/Rescreening 
Rescreening applies only to the 6-Month Dosing Regimen and initial enrollment into this 
study.  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 either of the 
2 conditions below.  Sites will be notified, near to 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. 
7.2.1.1.1 
Rescreening for Serum 25 (OH) Vitamin D 
Rescreening applies only to the 6-Month Dosing Regimen and initial enrollment into this 
study.  Rescreening will be allowed for subjects with an initial screening serum 25 (OH) 
vitamin D level of  20 ng/mL ( 49.9 nmol/L).  Rescreening, if needed for serum 
vitamin D level, will be performed as follows:  
 
Enter the subject as a screen failure into the IVRS/IWRS System and immediately 
enter him/her as a rescreen.  Subjects not entered into IVRS/IWRS System 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 ( 49.9 nmol/L) obtained by the central laboratory prior to day 1 visit. 


Product:  AMG 162 
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 
Subjects must restart a new 42-day rescreening window.  Repletion treatment and a 
confirmatory lab result must be obtained within this 42-day window to meet subject 
eligibility requirements.  
 
Subjects may be rescreened only once for either vitamin D or full rescreening 
(defined below).  
Sites will be notified, near to 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 test for serum vitamin D levels will be screen failed. 
7.2.1.1.2 
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 not applicable anymore. 
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, and hepatitis C, in subjects who are rescreened more 
than 84 days of screen failure. 
 
Subjects must be enrolled within the new 42-day rescreening window.  
Subjects may be rescreened only once for either vitamin D or full rescreening. 
7.2.2 
Transition to 3-Month Dosing Regimen 
Subjects who already transitioned will immediately follow the Schedule of 
Assessments for Urgent Safety Measure as outlined in Table 7-5. 
7.2.3 
Treatment 
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, 
subjects on study who had not completed their EOS visit were immediately 
discontinued from IP, and will be followed for safety for 24 weeks following the 
last dose of IP per the updated Schedule of Assessments (Table 7-5).  The last 
dose of IP will be considered week 0.  Subjects who have been on alternative 
therapy for more than 6 months or whose last dose of IP was greater than 
24 weeks, no additional 24-week safety follow-up is required.  These subjects can 
follow the previous protocol (protocol amendment 6) and complete the EOS CRF.  
Subjects whose last dose was between 12 and 24 weeks ago can complete the 
EOS assessments at week 24 per the updated Schedule of Assessments 
(Table 7-5).  The following procedures will be completed during the treatment period at 


Product:  AMG 162 
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Page 63 of 108 
CONFIDENTIAL 
 
 
the times designated in the Schedule of Assessments (Section 7.1).  Denosumab 
(1 mg/kg and up to a maximum of 60 mg) should be administered last during each visit 
that it is required. 
 
Physical examination as per standard of care  
 
Tanner stage 
 
Height in centimeters measured without shoes 
 
Weight 
 
Armspan 
 
Vital signs (ie, pulse, respiration rate, temperature, systolic and diastolic blood 
pressure) 
 
Laboratory assessments hematology, serum chemistry, and urine calcium 
 
Assessment of antidenosumab antibodies 
 
Assessment of serum denosumab levels 
 
BTM (sCTX and BSAP) 
 
DXA Assessments of the lumbar spine and proximal femur, conducted every 
6 months 
 
Urine pregnancy test must be performed for female subjects with a Tanner stage 2 or 
greater, or have had menarche prior to IP administration and EOS 
 
X-ray radiograph of the spine, conducted every 12 months 
 
X-ray radiograph of the knees, conducted every 6 months 
 
Oral visual inspection (dental X-ray may be obtained if a delay in molar eruption is 
suspected by the PI) 
 
Dental X-ray (cephalogram, panoramic) 
 
Concomitant medication recording 
 
Clinical fracture recording 
 
Adverse event collection/recording/reporting 
 
Serious adverse event collection/recording/reporting 
 
Administration of PROs (CHQ-PF-50, CHAQ, WBFPRS) 
 
Dispense calcium and vitamin D 
 
SC injection of denosumab 
7.2.4 
Study Procedures 
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, 
subjects on study who had not completed their EOS visit were immediately 
discontinued from IP, and will be followed for safety for 24 weeks following the 
last dose of IP per the updated Schedule of Assessments (Table 7-5).  The last 
dose of IP will be considered week 0.  Subjects who have been on alternative 


Product:  AMG 162 
Protocol Number:  20130173 
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Page 64 of 108 
CONFIDENTIAL 
 
 
therapy for more than 6 months or whose last dose of IP was greater than 
24 weeks, no additional 24-week safety follow-up is required.  These subjects can 
follow the previous protocol (protocol amendment 6) and complete the EOS CRF.  
Subjects whose last dose was between 12 and 24 weeks ago can complete the 
EOS assessments at week 24 per the updated Schedule of Assessments 
(Table 7-5).   
Data Collection 
All laboratory values will be electronically transferred from the central laboratory to the 
Amgen database.  The central imaging vendor will collect DXA data and radiographic 
imaging and will electronically transfer the data to the Amgen database.  All other data 
will be captured on the eCRF. 
Medical and Medication History 
Medical and medication history will be obtained prior to enrollment and will be recorded 
on the eCRF. 
Physical Examination 
The physical examination will include height and weight.  A pelvic, breast, or rectal 
examination is not required unless a specific evaluation is warranted.  Height 
measurements (in centimeters without shoes) will be performed in the standing position 
unless it is not possible to do so.  In instances where standing height cannot be 
measured, measurement of recumbent height will be allowed.   
Vital Signs 
The following measurements should be performed:  systolic and diastolic blood pressure 
(if clinically acceptable by the investigator), pulse, respiratory rate, and temperature.  
Subject should be in a supine position in a rested and calm state for at least 5 minutes 
before pulse assessments are conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The position 
selected for a subject should be the same that is used throughout the study and 
documented on the vital sign CRF.  The temperature location selected for a subject 
should be the same that is used throughout the study and documented on the vital signs 
CRF.  Record all measurements on the vital signs CRF.   
Armspan 
The arm span is measured with the child leaning against a flat surface (eg, wall) with the 
arms outstretched (or extended to the best of the child’s ability) parallel to the ground at 


Product:  AMG 162 
Protocol Number:  20130173 
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CONFIDENTIAL 
 
 
shoulder height, and between the tip of the middle fingers of the left and right hands.  
The flat surface should have a fixed point against which the child places 1 middle finger 
and a mark should be made on the surface for the opposite middle finger.  The child 
then steps away and the distance between the fixed point and the new mark is 
measured and recorded.  
Pregnancy Test 
Pregnancy tests will be performed from urine samples to be collected at screening, on 
day 1, at every IP administration visit (prior to denosumab injection), and EOS 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). 
Radiographic Assessments 
Lateral spine radiographs obtained within the past 2 years prior to screening can be 
submitted for verification of prevalent vertebral compression fracture.  Nonvertebral 
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.  Baseline lateral spine radiographs will be obtained on day 1 for all enrolled 
subjects unless an adequate lateral spine radiograph has been obtained within the past 
2 months prior to screening day.  For subjects who have not otherwise qualified based 
on fracture criteria, the baseline lateral spine radiograph may be obtained at the 
screening visit.  
For the purposes of this study, fractures related to OI are not considered pathological 
fractures, however pathological will relate to fractures in this disease of interest.  Lateral 
spine radiographs will be obtained at the day 1 visit for 3-Month Dosing Regimen, and 
every 12 months. 
All available radiographic assessments for evaluation of potential fracture from screening 
until EOS, including any unscheduled assessments, will be submitted to 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.   
3-Month Dosing Regimen assessments will be compared to data from 6-Month Dosing 
Regimen as pretreatment. 


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Dual-energy X-Ray Absorptiometry Assessments 
All subjects will undergo bone densitometry assessments of the lumbar spine and 
subjects 5 years of age or older at screening will undergo bone densitometry 
assessments of the proximal femur (for total hip and femoral neck) performed by DXA 
per the schedule outlined in Section 7.1. 
.Scans will be performed every 6 months. 
A DXA should be performed at day 1 visit (in duplicate) of the 3-Month Dosing Regimen, 
and then every 6-months. 
Only General Electric Lunar or Hologic bone densitometers will be allowed for this study.  
The same DXA machine will be used for all study procedures for a particular subject.  
Any changes to DXA machines should follow the requirements specified in the Imaging 
Manual.  The left side should be used for proximal femur, unless prohibited (eg, hip 
implant).  If another side must be used or is inadvertently used during Day 1, 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.  
Detailed instructions for scan acquisition will be in a separate manual provided by the 
central imaging vendor. 
Spine Radiographs 
Lateral radiographs of the thoracic and lumbar spine will be obtained to determine 
morphometric fractures. 
Knee Radiograph  
In subjects with open growth plates, 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 one with the higher Z-score at day 1 of 6-Month Dosing 
Regimen, unless prohibited by presence of hardware, in which case an AP radiograph of 
the contralateral knee may be obtained. 


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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. 
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, 3-Month Dosing 
Regimen day 1 visit, and end of the study (to be performed only if a delay in molar 
eruption is suspected by the PI). 
Other Dental Radiograms 
As indicated below (see “Oral Visual Inspection”), 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 assessment should be submitted 
to the central reader. 
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 all visits for the 3-Month Dosing Regimen 
to assess the risk for unerupted molars.  The subject should be referred to a dentist to 
perform radiographic assessment of the unerupted molar(s) (see above “Other Dental 
Radiograms”) if: 
 
A subject is 7 years of age or older 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). 


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Blood and Serum Assessments 
All blood samples will be obtained by venipuncture before IP administration.  The 
average volume of blood drawn per visit will be approximately 5.0 mL.   
6-Month Dosing Regimen: 
In subjects undergoing intensive serum calcium and phosphorus monitoring on days 2, 
3, 4, 6, 8, 10, 12, and 14 after study drug administration, the blood volume drawn per 
visit for these assessments will be approximately 2.2 mL. 
Blood will be obtained for the following assessments (Table 7-7) at the timepoints 
outlined in the Schedule of Assessments (Section 7.1)  The date and time of blood 
collection will be recorded in the subjects’ medical records.  
Given the lack of denosumab PK data in pediatric patients, denosumab PK will be 
collected in all subjects in this study in order to adequately characterize denosumab 
exposure and variability within the different age cohorts, as specified below.   
6-Month Dosing Regimen:  serum denosumab concentration 
 
Samples for serum denosumab concentration levels will be obtained on days 1 
and 10, and months 6, 12, 18, 24, 30, and 36 in all subjects, with additional 
serum PK samples to be collected at day 30 and month 3 in a PK/BTM substudy 
of approximately 50 subjects, as outlined on the Schedule of Assessments 
(Section 7.1) 
3-Month Dosing Regimen:  serum denosumab concentration  
 
Samples for serum denosumab concentration levels will be obtained at predose 
on day 1 of the 3-Month Dosing Regimen and on days 10, 30, and 60, and every 
3 months (ie, W12, W24, W36, W48, etc.) until EOS, as outlined on the Schedule 
of Assessments (Table 7-4). 
Laboratory Assessments 
All blood samples will be processed and sent to the central laboratory.  The central 
laboratory will be responsible for completing assays and shipping samples to Amgen for 
performance of other assays.  Additional analyte test results may be reported by the 
local or central laboratory, in accordance with standard laboratory procedures 
(eg, components of a hematology panel).   
6-Month Dosing Regimen: 
 
In addition, blood samples collected from the sentinel cohort for assessment of 
serum calcium and phosphorus in the first 14 days after denosumab 
administration will be sent to the local laboratory and the central laboratory.  In 


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addition, blood samples collected from the sentinel cohort for assessment of 
serum calcium at months 4.5, 10, 16, 22, 28 and 34 after denosumab 
administration will be sent to central laboratory.  Blood samples collected for 
assessment of serum calcium and phosphorus in the first 14 days after 
denosumab administration from the first 5 subjects of any age who have 
increased bone turnover, as defined in Section 3.1.1, will be sent to the local 
laboratory and central laboratory on days 2, 3, 4, 6, 8, 12, and 14, if body weight 
is  11 kg, but only to the local laboratory for subjects whose body weight is 
 11 kg. 
 
Collection of blood samples may be performed at the subject’s home at visits 
occurring on days 2, 3, 4, 6, 8, 12, 14, and 30, as applicable.  House visits 
between days 2 and 30, if performed, should occur at no more than two 
consecutive visits at a time.  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.  Collection of blood 
samples may not be performed at the subject’s home on day 30 in subjects 
participating in the PK/BTM substudy.  The collection of blood samples may not 
be performed at the subject’s home either at months 4.5 and 10, due to the 
collection requirements for the BTM samples obtained during these visits. 
3-Month Dosing Regimen  
 
Serum chemistry should be collected at Day 10 and Day 30 following first 
administration in 3-Month Dosing Regimen.  Additional assessments of serum 
calcium will be performed on day 10 and day 30 after the week 12 and week 24 
doses.  Blood collection may be performed by a qualified individual at the 
subject’s home, in lieu of a site visit. 
 
PK and BTM will be collected at days 10, 30, and 60 and every 3 months. 
 
Blood collection may be performed by a qualified individual at the subject’s 
home, in lieu of a site visit, on days 10, 30, and 60.  When blood collection is 
performed at the subject’s home, the investigator must ensure that concomitant 
medications, clinical fractures, and adverse events, if any, are appropriately 
recorded.   
The central laboratory will be responsible for all serum chemistry, vitamin D, hematology 
as well as serology assessments and will also conduct assessments of sCTX and serum 
BSAP.  Amgen will be responsible for antidenosumab antibody assessments.  The 
central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all serum samples. 
All samples will be obtained by venipuncture before IP administration, when applicable.  
The date and time of blood collection will be recorded in the subject’s medical record.   
Table 7-7 outlines the specific analytes for the serum chemistry and hematology 
assessments, as well as other assessments to be conducted on blood samples.  


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Table 7-7.  Blood Sample Analyte Listing 
Serum Chemistry  
Hematology 
Other Assessments 
Sodium 
Red blood cells  
samples for antidenosumab 
antibody assay 
Potassium 
Hemoglobin 
25 (OH) vitamin D 
Chloride 
Platelets 
sCTX 
Bicarbonate  
White blood cells  
BSAP 
Total protein 
Differential 
Serum denosumab 
concentrations 
Albumin 
Neutrophils 
Urine calcium 
Calciuma,b 
Eosinophils 
Urine or serum pregnancy test 
Albumin-corrected calcium 
Basophils 
 
Magnesium 
Lymphocytes 
 
Phosphorusa 
Monocytes 
 
Glucose 
 
 
BUN 
Serology 
  
Creatinine 
HIV-1, -2 antibody 
 
Total Bilirubin 
Hepatitis B surface antigen 
 
Alkaline phosphatase 
Hepatitis C antibody 
 
AST (SGOT) 
 
 
ALT (SGPT) 
 
 
ALT (SGPT)  alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)  aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); BSAP  bone-specific alkaline 
phosphatase; BUN  blood urea nitrogen; HIV  human immunodeficiency virus; sCTX  serum type I 
collagen C-telopeptide. 
a (6-Month Dosing Regimen) will be measured in local and central laboratory for the first 14 days in the 
sentinel cohort; will be measured in local and central laboratory (as applicable) for the first 14 days in the 
first 5 subjects of any age who have increased bone turnover, as defined in Section 3.1.1. 
b (6-Month Dosing Regimen) will be measured at the central laboratory at months 4.5, 10, 16, 22, 28, and 34 
in the sentinel cohort 
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 or trade name, indication, quantity administered (dose and frequency) and 
date(s) of administration will be recorded.  For other concomitant therapies being taken, 
data collection may be limited to generic drug name/treatment, indication and dates of 
administration. 
Additional Procedures Conducted in Sentinel Cohort Only (6-Month Dosing 
Regimen) 
Intensive mineral homeostasis assessment:  Serum calcium and phosphorus 
concentrations will be closely monitored during the study.  In order to better evaluate and 
characterize the risk for hypocalcemia and hypophosphatemia, intensive monitoring of 


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mineral homeostasis will be implemented in the first 5 subjects enrolled in the study.  
Serum calcium and phosphorus concentrations will be checked daily at the local 
laboratory for the first 3 days after administration of the first dose of denosumab and 
every other day thereafter for a total of 14 days in this 5-subject sentinel cohort. 
If no safety concerns arise from dosing of the sentinel cohort over the first 14 days after 
the first administration of denosumab, enrollment will be opened for the remainder of the 
subjects in the study, and monitoring of serum calcium and phosphorus will continue 
according to the planned schedule, ie, days 1, 10, and 30, and months 3, 6, 12, 18, 24, 
30, and 36, thereafter.  However, based on the results from the sentinel cohort, serum 
calcium and/or phosphorus monitoring may be performed more frequently in the 
remainder of the subjects enrolled in the study, if warranted. 
A similar approach will be employed in the first 5 subjects of any age who have 
increased bone turnover, defined as meeting 2 of the 3 following criteria: (1) untreated 
with bisphosphonates for 4 years prior to entry in the trial; (2) Type 3 OI with the 
following characteristics:  height  3rd percentile and bowed extremities (or saber shins); 
or (3) Tanner stage 3 or 4. 
Furthermore in order to better characterize the theoretical risk of rebound hypercalcemia 
during the latter part of the dosing interval, additional monitoring of serum calcium also 
will be implemented in the first 5 subjects enrolled in the study (sentinel cohort).  Serum 
calcium concentrations will be checked at months 4.5, 10, 16, 22, 28, and 34 in the 
5-subject sentinel cohort.  Based on these results from the sentinel cohort, serum 
calcium monitoring may be performed similarly in the remainder of the subjects enrolled 
in the study, if warranted. 
Patient-reported Outcomes 
The subject’s health-related quality of life, physical functioning, and pain intensity will be 
assessed using the CHQ, CHAQ, and WBFPRS.  
The CHQ 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 CHQ (CHQ-PF-50) will 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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The scale 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.   
Safety Data 
Subjects will be evaluated for safety events at each study visit through EOS.  If the 
subject is removed from IP, every effort should be made to continue evaluating safety 
events through his/her last study visit.  See Section 8.4 for details regarding safety data 
collection/recording/reporting. 
7.2.5 
Safety Follow-up Visit(s)/End of Study Visit 
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, 
subjects on study who had not completed their EOS visit were immediately 
discontinued from IP, and will be followed for safety for  24 weeks following the 
last dose of IP per the updated Schedule of Assessments (Table 7-5).  The last 
dose of IP will be considered week 0.  Subjects who have been on alternative 
therapy for more than 6 months or whose last dose of IP was greater than 
24 weeks, no additional 24-week safety follow-up is required.  These subjects can 
follow the previous protocol (protocol amendment 6) and complete the EOS CRF.  
Subjects whose last dose was between 12 and 24 weeks ago can complete the 
EOS assessments at week 24 per the updated Schedule of Assessments 
(Table 7-5).   
All procedures outlined for the EOS visit will be performed during this visit with the 
following exception: 
 
Procedures involving X-ray radiation other DXA assessment may not be performed if 
less than 3 months have elapsed since the previous radiographic assessment 
 
Administration of PROs may not be performed if less than 1 month has elapsed 
since the previous assessment 
7.3 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected at day 1, annually and 
EOS/early termination (ET) (Schedule of Assessments, Section 7.1) 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.   


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7.4 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Section 7.1) 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 informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
biology of OI, the dose response and/or prediction of response to denosumab to 
characterize antibody response (if any), and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from these analyses 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 such exploratory studies are not placed in the subject’s 
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 


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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 IP 
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 IP or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule 
of Assessments (Section 7.1) 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). 
Ongoing subjects as of 30 September 2021 who have been discontinued from IP 
(denosumab) as a result of the urgent safety measure, and subjects who have 
previously discontinued IP and/or other protocol-required therapies or procedures 
should not be automatically removed from the study.  Whenever safe and feasible, it is 
imperative that subjects remain on study to ensure safety surveillance, 
collection/reporting of serious adverse events, and/or collection of outcome data.  
Following implementation of the urgent safety measure, subjects should be 
followed for 24 weeks for safety following the last dose of IP.  If a subject withdraws 
from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must notify Amgen accordingly (see Section 7.4 for further details). 
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, publicly available data 


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can be included after withdrawal of consent.  The investigator is to discuss with the 
subject/subjects parent or legal guardian 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 IP and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
prior to study completion.  Following identification of a life-threatening risk of 
hypercalcemia, a decision has been made to stop all IP administration and 
subjects will be followed for safety for 24 weeks. 


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8.3 
Reasons for Removal From Treatment, or Study  
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following: 
 
subject request   
 
adverse event 
 
decision by sponsor 
 
death 
 
lost to follow-up 
 
other protocol-specified criteria: 
 
pregnancy 
 
disease flare requiring treatment not allowed in the protocol (eg, colitis, asthma) 
 
decline in lumbar spine BMD Z-score by at least 0.5 units at any 6-month 
assessment compared to the 3-Month Dosing Regimen baseline 
 
4 or more new long bone and/or vertebral fractures in any 6 month period 
(additional spine x rays should be obtained if clinically indicated) 
 
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 consistent with local institutional guidelines 
 
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.  
 
severe or symptomatic hypercalcemia, which requires the use of a rescue 
medication for management 
 
dental abnormalities requiring invasive dental procedures, as determined by 
investigator and/or treating dentist and within the local institutional practice 
guidelines 
 
Denosumab administration should be withheld 30 days prior to an 
invasive dental procedure and until complete mucosal healing is 
observed and documented (refer to Section 6.2.3 for guidance on 
restarting IP) 
 
ONJ 


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8.3.2 
Reasons for Removal From Study 
Reasons for removal from protocol-required IP or procedural assessments include any 
of the following: 
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
 
decision by sponsor 
8.4 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.   
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:   
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study.   
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record.   
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.   
For subjects who are lost to follow-up, the investigator can search publicly 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.   
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 


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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.   
A single event should be reported for each increased level of severity on the adverse 
event 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 
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. 


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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 or subject’s legally acceptable representative that 
occur after first dose of IP (denosumab) through the safety follow-up (SFU)/EOS are 
reported using the applicable eCRF (eg, Adverse Event Summary). 
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), 
 
Severity [and/or toxicity per protocol], 
 
Assessment of relatedness to the IP (denosumab) or other protocol-required 
therapies or any study procedures/study activity, and 
 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in 
Appendix A.  The criteria for grade 4 in the CTCAE grading scale differs from the 
regulatory criteria for serious adverse events.  It is left to the investigator’s judgment to 
report these grade 4 abnormalities as serious adverse events.   
The investigator must assess whether the adverse event is possibly related to the IP 
(denosumab) and/or other protocol-related 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 IP (denosumab)?”  
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of IP, protocol-required therapies, and/or 
procedure (including any screening procedure(s)).  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, 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 


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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, or subject’s legally acceptable representative, 
that occur after signing of the informed consent through 30 days after the last dose of IP 
or SFU/EOS, whichever is later, 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 applicable CRF.   
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an Electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge 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 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 IP (denosumab) 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 IP (denosumab) and/or other 
protocol-related therapies?”  
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 record.  Information 


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provided about the serious adverse event must be consistent with that recorded on the 
applicable CRF (eg, Adverse Event Summary CRF). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
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. 
Adverse events that are adjudicated as positive for ONJ will be categorized as serious 
adverse events and will follow the serious adverse events reporting as noted above.  
9.2.1.3 
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 or after EOS.  However, these serious adverse 
events can be reported to Amgen.  In some countries (eg, European Union [EU] member 
states), investigators are required to report serious adverse events that they become 
aware of after EOS.  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. 
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.  If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study. 
9.3 
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 obtain information about adverse event 
occurrence. 


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9.4 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety 
surveillance and signal management processes.  
9.5 
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. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of denosumab through an additional 
5 months.  
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 will 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 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. 
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. 
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur 5 months after the last dose of protocol-required therapies. 
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 will be requested. 


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10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoint:   
 
Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 
12 months in subjects receiving the 3-Month Dosing Regimen 
Secondary Endpoint(s):   
 
Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 
6 months in subjects receiving the 3-Month Dosing Regimen 
 
Change from baseline in proximal femur BMD Z-score, as assessed by DXA, at 
6 and 12 months (in subjects 5 years of age and older) in subjects receiving the 
3-Month Dosing Regimen 
 
Incidence of X-ray confirmed long bone and new and worsening vertebral fractures 
from last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing 
Regimen 
 
Incidence of X-ray confirmed new and worsening vertebral fractures from last 
12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of X-ray confirmed new vertebral fractures from last 12 months on 6-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of improving vertebral fractures from baseline of 3-Month Dosing 
Regimen to 12 months on 3-Month Dosing Regimen 
 
Incidence of vertebral and nonvertebral fractures from last 12 months on 6-Month 
Dosing Regimen to 12 months on 3-Month Dosing Regimen (in subjects 5 years of 
age or older) 
 
Change from baseline in CHQ-PF-50 Physical Summary score at 12 months in 
subjects receiving the 3-Month Dosing Regimen 
 
Change from baseline in CHQ-PF-50 Psychological Summary score at 12 months in 
subjects receiving the 3-Month Dosing Regimen 
 
Change from baseline in CHAQ Disability Index score at 12 months in subjects 
receiving the 3-Month Dosing Regimen 
 
Change from baseline in WBFPRS at 12 months in subjects receiving the 3-Month 
Dosing Regimen 
 
Change from baseline in growth velocity (determined by calculating age-adjusted 
Z-scores for height, weight and BMI) at 12 months in subjects receiving the 3-Month 
Dosing Regimen 
 
Serum concentration of denosumab and serum BTM on days 1, 10, 30, 60, and 
every 3 months in subjects on 3-Month Dosing Regimen  
 
Exploratory Endpoints: 


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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 
 
Subject incidence of metaphyseal index Z-score above age-appropriate normal 
range  
 
Subject incidence of abnormal molar eruption 
 
Subject incidence of abnormal mandibular shaping  
 
Subject incidence of hypercalcemia 
10.1.2 
Analysis Sets 
10.1.2.1 
Full Analysis Set 
The full analysis set (FAS) is defined according to intent-to-treat analysis to include all 
subjects enrolled into the study.  
10.1.2.2 
DXA Analysis Set 
The DXA analysis set includes all subjects in the FAS with baseline and  1 postbaseline 
DXA assessment on 3-Month Dosing Regimen for the endpoint of interest (lumbar spine 
and proximal femur) as provided by the central imaging vendor. 
10.1.2.3 
Vertebral Fracture Analysis Set 
The vertebral fracture analysis set includes all subjects in the FAS who have a readable 
non-missing baseline and  1 non-missing postbaseline X-ray vertebral evaluation on 
3-Month Dosing Regimen as provided by the central imaging vendor.  This analysis set 
will be used to analyze incidence of vertebral fracture endpoints.  
10.1.2.4 
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  1 postbaseline valid 
PRO response on 3-Month Dosing Regimen for the appropriate PRO.  Moreover, the 
CHQ-PF-50 analysis set will only include subjects 5 years of age and older at screening; 
the questionnaire has not been validated in younger children (4 years of age or 
younger), and so this subgroup will not be included in the CHQ-PF-50 analysis set.  


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10.1.2.5 
Growth Velocity Analysis Set  
The analysis set includes all subjects in the FAS who have evaluable data (age in total 
months, and weight, height, and BMI) at baseline and  1 post baseline assessment for 
each growth velocity endpoint (weight-for-age, height-for-age, and BMI-for-age 
Z-scores).  
10.1.2.6 
Metaphyseal Analysis Set 
This analysis set includes all subjects in the 3-month dosing safety analysis set with 
open growth plates (and no hardware preventing accurate calculation of metaphyseal 
index) at baseline and X-ray of the knee at baseline and post-baseline. 
10.1.2.7 
6-Month Dosing Regimen Safety Analysis Set 
The safety analysis set includes all subjects in the FAS who received  1 dose of IP. 
10.1.2.8 
3-Month Dosing Regimen Safety Analysis Set 
The 3-Month Dosing Regimen safety analysis set includes all subjects in the FAS who 
received  1 dose of 3-Month Dosing. 
10.1.2.9 
PK Analysis Set 
The PK analysis set includes all subjects in the 3-Month Dosing Regimen safety analysis 
set who have  1 serum denosumab reported result 3-Month Dosing Regimen.  
10.1.2.10 
PK Substudy Analysis Set 
The subset includes all subjects in the 6-Month Dosing Regimen safety analysis set who 
enroll in the PK/BTM substudy and have  1 serum denosumab reported result.  
10.1.2.11 
BTM Analysis Set 
The BTM analysis set includes all subjects in the 3-Month Dosing Regimen safety 
analysis set who have baseline and  1 postbaseline assessments for the endpoint of 
interest on 3-Month Dosing Regimen. 
10.1.2.12 
BTM Substudy Analysis Set 
The subset includes all subjects in the safety analysis set who enroll in the PK/BTM 
substudy and have baseline and  1 postbaseline assessments for the endpoint of 
interest on 6-Month Dosing Regimen. 


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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 will be investigated.  
 
Age (years) at the time of transition to 3-Month Dosing Regimen 
 
Baseline lumbar spine BMD Z-score of 3-Month Dosing Regimen 
10.1.3.2 
Subgroups 
The following subgroups will be explored for the change from baseline of 3-Month 
Dosing Regimen in lumbar spine BMD Z-score as assessed by DXA at 12 months.  
 
Gender (females vs males) 
 
Age at the time of screening (2 to 4, 5 to 10, 11 to 17 years) 
 
OI severity subgroups  
10.2 
Sample Size Considerations 
10.2.1 
6-Month Dosing Regimen 
A study sample size of 150 subjects will be enrolled to collect adequate efficacy and 
safety information for the ad hoc analysis at 12 months.  Assuming that 20 of subjects 
will not be evaluable at month 12 for the ad hoc efficacy endpoint due to dropout, the 
analysis set for the ad hoc efficacy endpoint will include at least 120 subjects.  
10.2.2 
3-Month Dosing Regimen 
Sixty previously enrolled subjects were previously transitioned to a 3-Month Dosing 
Regimen.  Approximately 60 previously enrolled subjects were to transition to a 3-Month 
Dosing Regimen.   
This sample size will provide more than 95 power to demonstrate that the difference in 
the change from baseline lumbar spine BMD Z-score at month 12 between denosumab 
and historical control is significantly greater than zero using 1-sample 2-sided t-test with 
a significance level of 0.05 based on the following assumptions: 
 
Mean change in lumbar spine BMD Z-score at 12 months for denosumab is 1.31 
(SD  0.91), which represents the lower bound of the 95 CI for the effect of a 
bisphosphonate (zoledronic acid) (EMA assessment report for Zometa Procedure no 
EMEA/H/C/000336/II/0031)  
 
Weighted mean (SE) change in lumbar spine BMD Z-score at 12 months for 
historical control is 0.01(0.09) (95 CI: -0.17, 0.18), estimated using meta-analysis 


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based on data from the placebo or control of 3 studies in children with OI 
(Ward et al, 2011; Rauch et al, 2009; Letocha et al, 2005). 
Assuming the sample size will provide at least 10 of the subjects evaluable for the 
primary efficacy endpoint in most subgroups of interest, the effect of denosumab on 
lumbar spine BMD Z-score also may be summarized descriptively in these subgroups. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Not applicable; this is an open-label single-arm study. 
10.4 
Planned Analyses 
10.4.1 
Primary Analysis 
The primary analysis (or final analysis since there is only 1 milestone analysis for this 
study) will occur after the last subject completes the 24-week safety follow up visit 
following the last dose of IP.  
10.4.2 
Data Monitoring Committee  
Safety of the subjects during study conduct will be monitored by the study team and a 
DMC in an ongoing manner.  A charter specifying the DMC functions will be written with 
the agreement of the DMC members.  Independent experts may be invited to Open 
Sessions to support in DMC review, as needed. 
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 of 3-Month Dosing Regimen in BMD Z-score at 12 months in 
subjects on 3-Month Dosing Regimen will be analyzed based on the DXA analysis set 
using repeated measures analysis with visit (6 and 12 months), baseline age, and 
baseline BMD Z-score as fixed effects.  Visit will be treated as a categorical variable.  
Missing baseline and postbaseline BMD Z-scores will not be imputed.  The estimated 
12-month least squares (LS) mean will be presented with a 95 CI.  The estimated 
12-month LS mean will be compared to weighted estimated mean (SE) of 0.01 (0.09) 
from historical controls (Ward et al, 2011; Rauch et al, 2009; Letocha et al, 2005) using a 
1-sample 2-sided t-test. 


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Summary statistics will be provided by the subgroups defined in Section 10.1.3.2.  
10.5.3 
Secondary Efficacy Endpoint(s) 
10.5.3.1 
Other Changes From Baseline in BMD Z-score by DXA 
For each skeletal site (lumbar spine, total hip, and femoral neck), change from baseline 
of 3-Month Dosing Regimen in BMD Z-score in subjects on 3-Month Dosing Regimen 
will be analyzed using repeated measures analysis with visit (6 and 12 months), baseline 
age, and baseline BMD Z-score as fixed effects.  Visit will be treated as a categorical 
variable.  Missing baseline and postbaseline BMD Z-scores will not be imputed.  LS 
mean and 95 CI will be presented for each visit. 
All analyses will be based on the DXA analysis set corresponding to the skeletal site of 
interest.  Total hip and femoral neck summaries will include only subjects 5 years of age 
and older at screening.   
10.5.3.2 
New and Worsening Fractures, and Vertebral and Nonvertebral 
Fractures 
On-treatment fracture rates in subjects on 3-Month and 6-Month Dosing Regimen will 
be summarized.  Pretreatment data includes 12 months prior to 3-Month Dosing 
Regimen denosumab administration for vertebral and nonvertebral fractures.  Subgroup 
analyses may be conducted depending on the number of subjects in each subgroup.   
Exposure-adjusted Incidence rate (EAIR) for fractures pre and post 3-Month Dosing 
Regimen will be provided. 
The incidence of vertebral fractures will be summarized based on the vertebral fracture 
analysis set and the incidence of nonvertebral fractures will be summarized based on 
the FAS with the fracture assessment provided by the central imaging vendor. 
The incidence of long bone and new and worsening fractures and vertebral and 
nonvertebral fractures in subjects on 3-Month Dosing Regimen will be summarized 
based on the FAS with the fracture assessment provided by the central imaging vendor. 
10.5.3.3 
Improved Vertebral Fracture  
The proportion of subjects with improved vertebral fracture from baseline of 3-Month 
Dosing Regimen will be summarized at each timepoint based on the vertebral fracture 
analysis set on 3-Month Dosing Regimen.  
10.5.3.4 
Patient-reported Outcomes  
Patient-reported outcomes (CHQ-PF-50, CHAQ disability index score and WBFPRS) 
and their changes from 3-Month Dosing Regimen will be summarized at month 12 based 


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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 of 3-Month Dosing Regimen in age-adjusted growth velocity 
endpoints will be summarized at 12 months based on the growth velocity analysis set.  
There is no imputation for missing data. 
10.5.3.6 
Serum Denosumab Concentrations 
Serum denosumab concentrations will be summarized by visit based on PK analysis set 
on 3-Month Dosing Regimen for all subjects and on 6-Month Dosing Regimen for the 
PK/BTM substudy.  There will be no imputation for missing values.  
10.5.3.7 
Bone Turnover Markers  
Actual values and percent changes from baseline of 3-Month Dosing Regimen in each 
parameter (BSAP and sCTX) will be descriptively summarized at each visit based on the 
BTM analysis set for the parameter of interest.  There will be no imputation for missing 
values. 
Similar analyses also including day 30 and month 3 will be performed based on the BTM 
substudy analysis set based on 6-Month Dosing Regimen. 
10.5.4 
Safety Endpoints 
All safety endpoints will be summarized for all subjects on 6-Month Dosing Regimen and 
subjects who received  1 dose of 3-Month Dosing Regimen separately. 
10.5.4.1 
Adverse Events 
All adverse events will be summarized based on the 3-Month Dosing Regimen safety 
analysis set and 6-Month Dosing Regimen 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 IP and treatment-emergent adverse events of interest will 
also be provided.  In addition, the exposure-adjusted subject incidence on the 3-Month 
Dosing Regimen safety analysis set and 6-Month Dosing Regimen safety analysis set 
respectively will be summarized. 
In addition, the following selected adverse events will be summarized: 
 
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 


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 
Severe or symptomatic hypocalcemia 
 
ONJ 
 
Abnormal molar eruption 
 
Abnormal mandibular shaping 
 
Hypercalcemia 
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 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 CTCAE v4.03. 
All laboratory analyses will be based on the 3-Month Dosing Regimen safety analysis set 
and 6-Month Dosing Regimen safety analysis set.  Subjects with missing data for a 
scheduled visit will not contribute to the tabulation for that timepoint (no imputation). 
10.5.4.3 
Vital Signs 
Descriptive statistics of the actual values and changes from baseline in vital signs (pulse, 
respiration rate, temperature, systolic and diastolic blood pressure) will be presented by 
visit based on the 3-Month Dosing Regimen safety analysis set and 6-Month Dosing 
Regimen safety analysis set.  Subjects with missing data for a scheduled visit will not 
contribute to the tabulation for that timepoint (no imputation). 
10.5.4.4 
Antidenosumab Antibodies 
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 3-Month Dosing Regimen safety analysis set 
and 6-Month Dosing Regimen safety analysis set. 


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11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
Investigators should have communicated the Urgent Safety Measure findings and 
actions to all ongoing subjects by phone or in-person within 3 days of the receipt 
of the Dear Investigator Letter, and documented this contact in the subject’s 
medical records.  A written consent/assent will be provided to subjects, following 
approval by the IRB/IEC, and subjects will be asked to sign this written 
consent/assent form.   
An initial sample ICF and pediatric subject assent form is provided for the investigator to 
prepare the informed consent document and subject assent to be used at his or her site.  
Updates to the template are to be communicated formally in writing from the Amgen 
Clinical Study Manager to the investigator.  The written informed consent and subject 
assent documents are 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 IP(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.  If the subject reaches the age of consent 
during the duration of the study, once the subject reaches the age of maturation (usually 
18), the previously acquired parental consent is no longer applicable and the 
participant’s consent must be obtained.  Per International Conference on 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.   
The investigator also is responsible for obtaining written assent from the pediatric 
subject as applicable by local law, before any protocol-specific screening procedures or 
any IP(s) is/are administered. 
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 


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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. 
For this study, assent from the child and consent from the parents or legally authorized 
representatives must be obtained, except if the child is a neonate, an infant, a toddler or 
very young as defined by local law.  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.  Country-specific requirements should be followed for specific local information.   
Where permitted according to country regulation, the ICF will contain a separate section 
that addresses the use of remaining mandatory samples for optional future research.  
The investigator or authorized designee will explain to each subject the objectives of the 
future research.  Subjects will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate signature will be required to document a subject’s agreement to allow any 
remaining specimens to be used for future research.  Subjects who decline to participate 
will not provide this separate signature.   
A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date.   


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11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, subject assent form, 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, ICF and subject assent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen IP. 
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 
that Amgen distributes to the site.  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.   
During the course of the study, if new information becomes available that alters the 
benefit:risk of the study or the study drug, Amgen will follow applicable regulations to 
notify investigators, the IRB/IEC, and regulatory authorities, as appropriate. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
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 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the US Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
The subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  


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On the CRF demographics page, in addition to the unique subject identification number, 
include the age at time of enrollment. 
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 age (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. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, as described below. 
In compliance with Federal regulations/ICH 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. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the sponsor’s systems.  The 
sponsor uses access-controlled systems to house, review and analyze subject data.  
These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline.   
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 


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The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
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 
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, 
subjects on study who had not completed their EOS visit were immediately 
discontinued from IP, and will be followed for safety for  24 weeks following the 
last dose of IP per the updated Schedule of Assessments (Table 7-5).  Subjects 
who have been on alternative therapy for more than 6 months or whose last dose 
of IP was greater than 24 weeks, no additional 24-week safety follow-up is 
required.  These subjects can follow the previous protocol (protocol amendment 
6) and complete the EOS CRF.  Subjects whose last dose was between 12 and 24 
weeks ago can complete the EOS assessments at week 24 per the updated 
Schedule of Assessments (Table 7-5). 
If Amgen amends the protocol, agreement from the investigator must be obtained.  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 to Amgen. 
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 study contract.  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.   
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 eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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. 


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In this study, the IVRS/IWRS captures the following data points and these are 
considered source data:  subject identification number and enrollment number. 
eCRF entries may be considered source data if the eCRF is the site of the original 
recording (ie, there is no other written or electronic record of data).  In this study, PRO 
CRFs can be used 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.   
Elements to include: 
 
Subject files containing completed eCRFs, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Denosumab Investigator’s 
Brochure, copies of prestudy documentation, and all correspondence to and from the 
IRB/IEC and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
In addition, all original source documents supporting entries in the eCRFs 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, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen clinical monitor is responsible for verifying the eCRFs 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 eCRFs. 
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 eCRFs, are resolved. 


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In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing 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, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available. 
 
Updates to eCRFs 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 and/or site notifications 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.  
This signature indicates that investigator inspected or reviewed the data on the 
eCRF, the data queries, and the site notifications, and agrees with the content. 
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 (Section 7.1). 
the investigator can search publicly 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 
eCRFs 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 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) 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. 
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 
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. 
If permitted under applicable regional laws or regulatory guidelines, subjects may be 
compensated for other inconveniences not associated with study-related injuries 
(eg, travel costs). 


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13. 
REFERENCES 
Denosumab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Abrahamsen B, Eiken P, and Eastell R.  Subtrochanteric and Diaphyseal Femur 
Fractures in Patients Treated With Alendronate: A Register-Based National Cohort 
Study.  J Bone Miner Res.  2009;24:1095-1102. 
Bargman R, Posham R, Boskey AL, DiCarlo E, Raggio C, Pleshko N.  Comparable 
outcomes in fracture reduction and bone properties with RANKL inhibition and 
alendronate treatment in a mouse model of osteogenesis imperfecta.  Osteoporos Int.  
2012;23:1141-1150. 
Baron R, Gertner JM, Lang R, et al.  Increased Bone Turnover with Decreased Bone 
Formation by Osteoblasts in Children with Osteogenesis Imperfecta Tarda.  Pediatr Res.  
1983;17:204-207. 
Boyce AM, Chong WH, Yao J, et al.  Denosumab treatment for fibrous dysplasia.  
J Bone Miner Res.  2012;27:1462-1470. 
Brunetti G, Papadia F, Tummola A, et al.  Impaired bone remodeling in children with 
osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, 
RANKL, and TNF-.  Osteoporos Int.  2016;27:2355-2365. 
Byers PH.  Osteogenesis imperfecta: perspectives and opportunities.  Curr Opin Pediatr. 
2000;12:603-609. 
Castillo H, Samson-Fang L, American Academy for Cerebral P, Developmental Medicine 
Treatment Outcomes Committee Review P.  Effects of bisphosphonates in children with 
osteogenesis imperfecta: an AACPDM systematic review.  Dev Med Child Neurol.  
2009;51:17-29. 
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 (website accessed March 23, 2014. 
Dwan K, Phillipi CA, Steiner RD, et al.  Bisphosphonate therapy for osteogenesis 
imperfecta.  Cochrane Database Syst Rev.  2016;10:CD005088. 
EMA assessment report for Zometa Procedure no EMEA/H/C/000336/II/0031.  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Assessment_Report_-_Variation/human/000336/WC500074897.pdf (website accessed 
March 23, 2014) 
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 (website 
accessed 23 March 2014) 
Folkestad L, Hald JD, Ersboll AK, et al.  Fracture Rates and Fracture Sites in Patients 
With Osteogenesis Imperfecta: A Nationwide Register-Based Cohort Study.  J Bone 
Miner Res.  2017;32:125-134. 
Forlino A and Marini JC.  Osteogenesis imperfecta.  Lancet.  2016;387:1657-1671. 
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. 


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Hald JD, Evangelou E, Langdahl BL, et al.  Bisphosphonates for the Prevention of 
Fractures in Osteogenesis Imperfecta: Meta-Analysis of Placebo-Controlled Trials.  
J Bone Miner Res.  2015;5:929-933.  
International Committee of Medical Journal Editors.  Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals.  2013. 
http://www.icmje.org/ 
Lenart BA, Neviaser AS, Lyman S, et al.  Association of low-energy femoral fractures 
with prolonged bisphosphonate use: a case control study.  Osteoporos Int.  
2009;20:1353-1362. 
Letocha AD, Cintas HL, Troendle JF, et al.  Controlled trial of pamidronate in children 
with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term 
functional improvement.  J Bone Miner Res.  2005;20:977-986. 
Marini JC, Forlino A, Bachinger HP, et al.  Osteogenesis imperfecta.  Nat Rev Dis 
Primers.  2017;3:17052. 
Marini JC, Blissett AR.  New Genes in Bone Development: What's New in Osteogenesis 
Imperfecta.  J Clin Endocrinol Metab.  2013;98:3095-3103. 
Nicolaou N, Agrawal Y, Padman M, et al.  Changing pattern of femoral fractures in 
osteogenesis imperfecta with prolonged use of bisphosphonates.  J Child Orthop.  
2012;6:21-27. 
Odvina CV, Levy S, Rao S, Zerwekh JE, Rao DS.  Unusual mid-shaft fractures during 
long-term bisphosphonate therapy.  Clin Endocrinol (Oxf).  2010;72:161-168. 
Odvina CV, Zerwekh JE, Rao DS, et al.  Severely Suppressed Bone Turnover: A 
Potential Complication of Alendronate Therapy.  J Clin Endocrinol Metab.  
2005;90:1294-301. 
Rauch F, Glorieux FH.  Osteogenesis imperfecta.  Lancet.  2004;363:1377-1385. 
Rauch F, Munns CF, Land C, Cheung M, Glorieux FH.  Risedronate in the Treatment of 
Mild Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study.  
J Bone Miner Res.  2009;24:1282-1289. 
Rauch F, Travers R, Parfitt AM, et al.  Static and dynamic bone histomorphometry in 
children with osteogenesis imperfecta.  Bone.  2000;26:581-589. 
Shane E, Burr D, Abrahamsen B, et al.  Atypical Subtrochanteric and Diaphyseal 
Femoral Fractures: Second Report of a Task Force of the American Society for Bone 
and Mineral Research.  J Bone Miner Res.  2014;29:1-23. 
Steiner RD, Adsit J, Basel D.  COL1A1/2-Related Osteogenesis imperfecta.  In: Pagon 
RA, Adam M.P., Bird T.D., et al., ed.  GeneReviews: University of Washington, Seattle; 
2005 
Trejo P, Fassier F, Glorieux FH, et al.  Diaphyseal Femur Fractures in Osteogenesis 
Imperfecta: Characteristics and Relationship With Bisphosphonate Treatment.  J Bone 
Miner Res.  2017;32:1034-1039. 
van Dijk FS, Byers PH, Dalgleish R, et al.  EMQN best practice guidelines for the 
laboratory diagnosis of osteogenesis imperfecta.  Eur J Hum Genet . 2012;20:11-19. 
Vuorimies I, Mayranpaa MK, Valta H, et al.  Bisphosphonate Treatment and the 
Characteristics of Femoral Fractures in Children With Osteogenesis Imperfecta.  J Clin 
Endocrinol Metab.  2017;102:1333-1339. 


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Ward LM, Rauch F, Whyte MP, et al.  Alendronate for the treatment of pediatric 
osteogenesis imperfecta: a randomized placebo-controlled study.  J Clin Endocrinol 
Metab.  2011;96:355-364. 
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 
CTCAE (Adverse Event Grading Scale) 
Drug-induced Liver Injury Reporting & 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, Adverse Event 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 9.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product (IP)(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Sections 6.4.1 and 6.4.2 or who experience AST or ALT elevations  3 x ULN 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.  
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 Serious Adverse Event Report Form 
 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Amendment 7 
Protocol Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, 
Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis 
Imperfecta 
 
Amgen Protocol Number AMG 162 20130173 
NCT Number:  NCT03638128 
 
Amendment Date: 
22 October 2021 
Superseding Amendment 
Date 
26 November 2021 
 
Rationale: 
This protocol is being amended to: 
 
Address Risk Level 1 safety concern of hypercalcemia.  Per Amgen decision 
based on the Data Monitoring Committee (DMC) recommendation and urgent 
safety measure, the protocol has been updated to stop treatment and subjects 
will continue to a 24-week safety follow up period.   
 
Update risks and benefits to reflect that the benefit of AMG 162 does not 
outweigh the risks 
 
Add language that all subjects will discontinue study treatment and be followed 
for safety for 24 weeks 
 
Add Schedule of Assessments for safety follow-up period 
 
Administrative and editorial updates 
On 26 November 2021, the protocol amendment 7 was superseded to: 
 
Add week 12 visits for oral visual inspection, sample collection for hematology 
and serum chemistry, and clinical fracture recording. 
 
Remove the administration of the Child Health Questionnaire-Parent Form-50 
(CHQ-PF-50), Childhood Health Assessment Questionnaire (CHAQ) Disability 
Score and Wong-Baker Faces Pain Rating Scale (WBFPRS) at week 12. 


Product:  AMG 162 
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Page 1 of 35 
Amendment 7 
Protocol Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, 
Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis 
Imperfecta 
 
Amgen Protocol Number AMG 162 20130173 
NCT Number:  NCT03638128 
 
Amendment Date: 
22 October 2021 
 
Rationale: 
This protocol is being amended to: 
 
Address Risk Level 1 safety concern of hypercalcemia.  Per Amgen decision 
based on the Data Monitoring Committee (DMC) recommendation and urgent 
safety measure, the protocol has been updated to stop treatment and subjects 
will continue to a 24-week safety follow up period.   
 
Update risks and benefits to reflect that the benefit of AMG 162 does not 
outweigh the risks 
 
Add language that all subjects will discontinue study treatment and be followed 
for safety for 24 weeks 
 
Add Schedule of Assessments for safety follow-up period 
 
Administrative and editorial updates 
 


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Page 2 of 37 
 
Clarify inconsistencies in BTM endpoints 
 
Make minor administrative and editorial changes 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020, Version:6.0 
Superseding Amendment 6 
Protocol Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, 
Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis 
Imperfecta 
 
Amgen Protocol Number (AMG162) 20130173 
EudraCT Number:  2014-000184-40 
 
Amendment Date: 
19 November 2020 
Superseding Amendment Date: 
14 January 2021 
 
Superseding Amendment 6 Summary of Changes: 
Rationale: 
Protocol amendment 6 is being superseded to correct inconsistencies introduced into the 
document during amendment 6.  Additionally, administrative, typographical, and formatting 
changes were made throughout the protocol.   


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020, Version:6.0 
Amendment 6 
Protocol Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, 
and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta 
 
Amgen Protocol Number (AMG162) 20130173 
EudraCT Number:  2014-000184-40 
 
Amendment Date: 
19 November 2020 
 
Rationale: 
The protocol is being amended to harmonize content with protocol 20170534 and to address 
FDA feedback received.  In addition, this amendment is intended to optimize study procedures 
to improve the operational efficiency of the protocol following team feedback.   
Changes include, but are not limited to: 
 
Additional blood samples at days 10 and 30 following investigational product dosing at 
weeks 12 and 24. 
 
Administrative changes from previously written memos. 
 
Analyte table updated. 
 
Statistical Analysis section updated. 
 
Administrative, typographical and formatting changes were made throughout the 
protocol.  Updates have been implemented to align with the current template.   


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Amendment 5 
Protocol Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, 
Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis 
Imperfecta 
 
Amgen Protocol Number (AMG 162 [Denosumab]) 20130173 
 
Amendment Date: 
11 March 2020 
Rationale: 
The main purpose of this protocol amendment is to adjust the dose regimen from 
6-Month Dosing Regimen to 3-Month Dosing Regimen for evaluation in paediatric OI 
subjects. 
Approved 
 
 


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Amendment 4 
Protocol Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, 
Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis 
Imperfecta 
 
Amgen Protocol Number (AMG 162) 20130173 
EudraCT Number: 2014-000184-40 
Amendment Date: 
24 March 2016 
Rationale: 
The protocol is being amended to: 
• 
Update secondary objectives and endpoints and exclusion criteria language to reflect 
approved modifications to the Paediatric Investigation Plan  
• 
Eliminate all occurrences of “randomization” in the study procedures as it does not 
apply to the protocol design 
• 
Update rescreening language to clarify requirements and rescreening guidelines 
• 
Update pregnancy and lactation reporting language to align with recent changes to 
the protocol template and Core Risk and Discomforts form, and replace sample 
reporting forms with current versions 
• 
Update safety language to adhere to recent changes to the protocol template, and 
replace sample electronic serious adverse event reporting forms with current 
versions 
• 
Correct typographic, grammatical, and formatting errors throughout the protocol. 


Product:  AMG 162 
Protocol Number:  20130173 
Date:  11 February 2015 
Page 1 of 12 
CONFIDENTIAL 
 
 
Amendment 3 
Title:  Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and 
Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta 
 
Amgen Protocol Number (AMG 162) 20130173 
 
 
Amendment Date: 
11 February 2015 
 
Rationale: 
The protocol is being amended to:  
• 
update visit schedules for enabling assessment of serum calcium  
The higher bone turnover rates expected at baseline in children with osteogenesis 
imperfect (OI) may increase the risk for rebound hypercalcemia in the latter part of the 
denosumab dosing interval due to release of bone turnover inhibition.  Additional visits at 
months 4.5,10, 16, 22, 28 and 34 will be conducted in the first 5 subjects enrolled in the 
sentinel cohort in order to assess the effect of denosumab on serum calcium 
homeostasis and to permit adaptation of subsequent mineral homeostasis assessments 
for all study subjects as appropriate.   
Minor administrative changes and clarifications have also been incorporated. 
Additions are noted in bold text.


Product:  AMG 162 
Protocol Number:  20130173 
Date:  28 August 2014 
Page 1 of 12 
 
Amendment 2 
Protocol Title:  Prospective, Multicenter, Single-arm 
Study to Evaluate Efficacy, Safety, and 
Pharmacokinetics of Denosumab in Children With 
Osteogenesis Imperfecta 
 
Amgen Protocol Number (AMG 162) 20130173 
 
 
Amendment Date: 
 28 August 2014 
Rationale: 
The protocol is being amended to:  
• 
update the exclusion criteria  regarding serum vitamin D levels at screening and 
duration of prior use of PTH or PTH derivatives 
• 
remove blood pressure measurement as a required procedures 
• 
add the potential of some visits being conducted by sending qualified personnel 
to obtain blood samples 
The exclusion criteria are being amended to modify the requirement for serum vitamin D 
in order to make it consistent with other protocols in the denosumab program and to 
clarify duration of exposure to PTH or PTH derivatives. 
Blood pressure monitoring is being removed as a required procedure since it may 
expose the subjects to the risk of fracturing their bone during assessment. 
To reduce the burden on the subject of having to visit the clinic site too often, some of 
the visits over the first 30 days after denosumab injection may be performed by sending 
qualified personnel to the subject. 
Typographic and administrative changes were made throughout the document as 
needed. 


Product:  AMG 162 
Protocol Number:  20130173 
Date:  25 July 2014 
Page 1 of 5 
 
 
Amendment 1 
Protocol Title:  Prospective, Multicenter, Single-arm Study to Evaluate 
Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With 
Osteogenesis Imperfecta 
 
Amgen Protocol Number (AMG 162) 20130173 
 
Amendment Date: 
25 July 2014 
Rationale: 
The protocol is being amended to conform to feedback received from the Voluntary 
Harmonization Process of regulatory agencies in Europe 
• 
update the exclusion criteria  
• 
add serological tests at screening visit 
• 
clarify follow up of subjects with incident severe or symptomatic hypocalcemia 
• 
clarify that pregnancy is a stand-alone criteria for discontinuation of study drug 
• 
enumerate the acceptable methods of contraception 
The exclusion criteria is being amended to add an item to make it consistent with the 
summary of product characteristics (SPC) in effect in the European Union (EU). 
Serological tests for HIV and Hepatitis B and Hepatitis C are being added to be 
consistent with exclusion criteria outlined in the protocol.  
The protocol also is being amended to clarify treatment and follow up of subjects who 
discontinue study drug as a result of severe or symptomatic hypocalcemia; to state that 
pregnancy is an independent reason for discontinuation of study drug. 
Acceptable methods of contraception are being outlined in the protocol and are 
consistent with those listed in the informed consent form. 

SAP_001.pdf: 
Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 1 of 79 
CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020 
 
Statistical Analysis Plan 
Protocol Title: 
Prospective, Multicenter, Single-arm Study to 
Evaluate Efficacy, Safety, and Pharmacokinetics of 
Denosumab in Children With Osteogenesis 
Imperfecta 
Short Protocol Title: 
Prospective, Multicenter, Single-arm Study to 
Evaluate Efficacy, Safety, and Pharmacokinetics of 
Denosumab in Children With Osteogenesis 
Imperfecta 
Protocol Number: 
20130173 
NCT Number: 
 
Authors: 
 
Sponsor: 
AMGEN, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA  91320, USA 
Tel: +1 (805) 447-1000 
SAP Date: 
Document Version 
Date 
Amendment 4 (v5.0) 
27 Apr 2022 
NCT02352753


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 2 of 79 
CONFIDENTIAL  
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Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
23 Oct 2015 
NA. The first version. 
Amendment 1 (v2.0) 
13 Feb 2020 
This statistical analysis plan (SAP) was 
updated 
based 
on 
the 
protocol 
amendment 
4 
for 
Denosumab 
Study 20130173 dated  24 March 2016 
and 
the 
German 
country 
specific 
substudy protocol supplement dated 06 
August 2015 to perform primary analysis  
of Denosumab in lumbar spine bone 
mineral density at 12 months on a 6-
month dosing regimen. 
Amendment 2 (v3.0) 
13 Apr 2020 
The following changes  are made in 
version 2 of the SAP. 
Section 2.2- Secondary objectives related 
to incidence fractures were updated. 
Section 
4.1- 
Secondary 
efficacy 
endpoints related to incidence fractures 
were updated.  
Section 7- The DXA analysis set and non-
vertebral fracture analysis set were 
updated. 
Amendment 3 (v4.0) 
12 Nov 2021 
This statistical analysis plan (SAP) is 
updated 
based 
on 
the 
protocol 
amendment 
7 
for 
Denosumab 
study 20130173 dated 22 October 2021 
and 
the 
German 
country 
specific 
substudy protocol supplement dated 28 
October 2021 to perform final analysis.  
Superseding 
amendment 3 (V4.1) 
18 Feb 2022 
This statistical analysis plan (SAP) is 
updated to remove by age cohort 
summary 
except 
for 
hypercalcemia 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 3 of 79 
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adverse event and to remove the pooled 
adverse 
events 
summary 
for 
the 
combined dosing regimen. Also its 
updated to provide the listings for 3-
month dosing regimen german subjects 
Amendment 4 (V5.0) 
27 Apr 2022 
The following changes  are made in 
version 5 of the SAP. 
Section 6.4.8- Added the definition for 
German substudy safety analysis set.   
Section 
5.1- 
The 
definition 
for 
treatment emergent adverse event for 
6-month dosing regimen is updated to 
include all the adverse events.  
Section 5.7.4 and 9.5.2.2- Provided the 
details for source data of non-vertebral 
fractures and long bone fractures to 
include 
the 
maximum 
fractures. 
Appendix C- Updated the upper bound 
for renal laboratory in visit window. 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 4 of 79 
CONFIDENTIAL  
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Table of Contents 
1. 
Introduction ........................................................................................ 10 
2. 
Objectives, Endpoints and Hypotheses .............................................. 10 
2.1 
Objectives and Endpoints ....................................................... 10 
2.2 
Hypotheses and/or Estimations .............................................. 14 
3. 
Study Overview ................................................................................. 14 
3.1 
Study Design .......................................................................... 14 
3.2 
Sample Size ........................................................................... 15 
3.2.1 
6-month dosing regimen ......................................... 15 
3.2.2 
3-month dosing regimen ......................................... 15 
4. 
Covariates and Subgroups ................................................................ 16 
4.1 
Planned Covariates ................................................................ 16 
4.2 
Subgroups .............................................................................. 16 
5. 
Definitions .......................................................................................... 17 
5.1 
Basic Definitions..................................................................... 17 
5.2 
Study Points of Reference ...................................................... 18 
5.3 
Study Dates ........................................................................... 20 
5.4 
Study Time Intervals .............................................................. 21 
5.5 
Subject Disposition ................................................................. 21 
5.6 
Arithmetic Calculations ........................................................... 21 
5.7 
Study Endpoints ..................................................................... 22 
5.7.1 
Fracture-related Trauma Severity Definitions.......... 22 
5.7.2 
DXA Assessments .................................................. 23 
5.7.3 
Vertebral Fractures ................................................. 23 
5.7.4 
Nonvertebral Fracture ............................................. 26 
5.7.5 
Growth Velocity Endpoints ...................................... 27 
5.7.6 
PRO Questionnaires ............................................... 27 
5.7.7 
Metaphyseal Index Z-score of the Distal Femur ...... 28 
5.7.8 
Mandibular Shaping ................................................ 29 
5.7.9 
Molar Eruption ........................................................ 29 
6. 
Analysis Sets ..................................................................................... 29 
6.1 
Full Analysis Set..................................................................... 29 
6.2 
Safety Analysis Set ................................................................ 29 
6.2.1.1 
6-Month Dosing Regimen Safety Analysis 
Set ....................................................... 29 
6.2.1.2 
3-Month Dosing Regimen Safety Analysis 
Set ....................................................... 30 
6.3 
 PK Analysis set ..................................................................... 30 
6.4 
Study-specific Analysis Sets................................................... 30 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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6.4.1 
DXA Analysis Set ................................................... 30 
6.4.2 
Vertebral Fracture Analysis set ............................... 30 
6.4.3 
PRO Analysis set ................................................... 30 
6.4.4 
Growth Velocity Analysis set .................................. 30 
6.4.5 
Metaphyseal Analysis set ....................................... 31 
6.4.6 
BTM Analysis set .................................................... 31 
6.4.7 
DXA Per Protocol Analysis Set ............................... 31 
6.4.8 
German Substudy Safety Analysis Set ................... 31 
6.4.9 
PK Substudy Analysis Set ...................................... 31 
6.4.10 
BTM Substudy Analysis Set ................................... 31 
7. 
Planned Analyses .............................................................................. 31 
7.1 
Interim Analysis and Early Stopping Guidelines ..................... 31 
7.2 
Primary Analysis .................................................................... 32 
7.3 
Final Analysis ......................................................................... 32 
8. 
Data Screening and Acceptance ........................................................ 32 
8.1 
General Principles .................................................................. 32 
8.2 
Data Handling and Electronic Transfer of Data ...................... 32 
8.3 
Handling of Missing and Incomplete Data .............................. 33 
8.3.1 
Missing Data........................................................... 33 
8.3.2 
Incomplete Dates ................................................... 33 
8.3.3 
Other Incomplete Dates .......................................... 33 
8.4 
Detection of Bias .................................................................... 34 
8.5 
Outliers .................................................................................. 34 
8.6 
Distributional Characteristics .................................................. 35 
8.7 
Validation of Statistical Analyses ............................................ 35 
9. 
Statistical Methods of Analysis........................................................... 35 
9.1 
General Considerations .......................................................... 35 
9.2 
Subject Accountability  ........................................................... 35 
9.3 
Important Protocol Deviations ................................................ 36 
9.4 
Demographic and Baseline Characteristics ............................ 36 
9.5 
Efficacy Analyses ................................................................... 37 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) ............... 44 
9.5.1.1 
Primary Analysis .................................. 44 
9.5.1.2 
Per Protocol Analysis ........................... 44 
9.5.1.3 
Subgroup Analysis ............................... 44 
9.5.1.4 
Sensitivity Analysis ............................... 44 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s)........... 45 
9.5.2.1 
 Other Changes From Baseline in BMD Z-
score by DXA ....................................... 45 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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9.5.2.2 
New and Worsening Vertebral Fractures, 
and Vertebral and Nonvertebral Fractures
 ............................................................. 45 
9.5.2.3 
Incidence of Improving Vertebral 
Fractures .............................................. 45 
9.5.2.4 
PRO Measurements ............................. 46 
9.5.2.5 
Growth Velocity .................................... 46 
9.5.2.6 
Denosumab Serum Concentration ....... 46 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) .......... 46 
 46 
 46 
 46 
 46 
9.6 
Safety Analyses ..................................................................... 47 
9.6.1 
Analyses of Primary Safety Endpoint(s) .................. 47 
9.6.2 
Adverse Events ...................................................... 48 
9.6.2.1 
Adverse Events of Special Interest ....... 49 
9.6.2.2 
Other Safety Endpoints ........................ 50 
9.6.3 
Laboratory Test Results ......................................... 50 
9.6.3.1 Renal Clinical Laboratory Test Results 
(German substudy only) ....................... 50 
9.6.4 
Vital Signs .............................................................. 51 
9.6.5 
 Antidenosumab Antibodies .................................... 51 
9.6.6 
Exposure to Investigational Product ....................... 51 
9.6.7 
Exposure to Non-investigational Product ................ 51 
9.6.8 
Exposure to Other Protocol-required Therapy ........ 51 
9.6.9 
Exposure to Concomitant Medication ..................... 51 
9.7 
Other Analyses ...................................................................... 51 
9.7.1 
Pharmacokinetic/Pharmacodynamic Analysis ......... 52 
9.7.2 
Analyses of Clinical Outcome Assessments ........... 52 
9.7.3 
Analyses of Health Economic Endpoints ................ 52 
9.7.4 
Analyses of Biomarker Endpoints ........................... 52 
10. 
Changes From Protocol-specified Analyses....................................... 52 
11. 
Literature Citations / References ........................................................ 53 
12. 
Prioritization of Analyses.................................................................... 53 
13. 
Data Not Covered by This Plan.......................................................... 53 
14. 
Appendices ........................................................................................ 54 
 
List of Table 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Table A Primary Efficacy Endpoint Summary Table.................................... 38 
Table B Secondary Efficacy Endpoint Summary Table ............................... 38 
Table C Exploratory Efficacy Endpoint Summary Table .............................. 42 
Table D Safety Endpoint Summary Table ................................................... 47 
 
List of Appendices 
Appendix A. Reference Values/Toxicity Grades ......................................... 54 
Appendix B.Health Economic Forms/Instruments ....................................... 55 
Appendix C.Analytical Windows ................................................................. 63 
Appendix D.Bone Codes for Non-vertebral Fractures ................................. 71 
Appendix E.Code Fragment ....................................................................... 74 
 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
Adverse Event 
BMC 
Bone mineral content  
BMD 
Bone mineral density 
BMDS 
Biomedical data stewardship standard 
BMI 
Body mass index 
BSAP 
Bone-specific alkaline phosphatase 
BTM 
Bone turnover marker 
CHAQ 
Childhood Health Assessment Questionnaire 
CHQ-PF 
Child Health Questionnaire - Parent Form 
CT 
Computerized tomography 
DMC 
Data monitoring committee 
DoB 
Date of birth 
DPN 
Deoxypridinoline 
DXA 
Dual-energy X-ray absorptiomet 
DPD 
Deoxypyridinoline 
EC 
Ethics committee 
eCRF 
Electronic case report form 
IC 
Informed consent 
IP 
Investigational product 
IVRS 
Interactive voice response system 
MRI 
Magnetic resonance imaging 
OI 
Osteogenesis imperfecta 
NTX 
Cross-linked N-telopeptides of type 1collagen 
NA    
Not Applicable 
PK 
Pharmacokinetic 
PKDM 
Pharmacokinetic and drug metabolism 
Q6M 
6-month dosing regimen 
Q3M 
3-month dosing regimen 
SAP 
Statistical analysis plan 
sCTX 
Serum type I collagen C-telopeptide 
SQ 
Semiquantitative 
SAS 
Statistical Analysis System 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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WBFPRS 
Wong-Baker FACES Pain Rating Scale 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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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 7 for Denosumab 
study 20130173  dated 22 October 2021 and the German country specific sub study 
protocol supplement dated 28 October 2021. The scope of this plan includes the final 
analysis and will be executed by the Biostatistics department unless otherwise 
specified.  
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To evaluate the effect of denosumab in 
lumbar spine bone mineral density (BMD) 
Z-score at 12 months, as assessed by 
dual-energy X-ray absorptiometry (DXA), 
in children 2 to 17 years of age (at the 
time of screening) on a 3-month dosing 
regimen with Osteogenesis Imperfecta 
 Change from baseline in lumbar spine 
BMD Z-score, as assessed by DXA, at 
12 months in subjects receiving the 3-
month dosing regimen 
Secondary  
To evaluate denosumab in children 2 to 17 years of age (at the time of screening) 
with OI on a 3-Month Dosing Regimen with respect to: 
Change in lumbar spine BMD Z-score, as 
assessed by DXA, at 6 months 
 
Change from baseline in lumbar spine 
BMD Z-score, as assessed by DXA, at 6 
months in subjects receiving the 3-month 
dosing regimen 
Change in proximal femur BMD Z-score, 
as assessed by DXA, at 6 and 12 months 
(in subjects 5 years of age and older) 
 
Change from baseline in proximal femur 
BMD Z-score, as assessed by DXA, at 6 
and 12 months (in subjects 5 years of 
age and older) in subjects receiving the 
3-month dosing regimen 
Incidence of X-ray confirmed long bone 
and new and worsening vertebral 
Incidence of X-ray confirmed long bone 
and new and worsening vertebral 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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fractures from last 12 months on 6-month 
dosing regimen to 12 months on 3-month 
dosing regimen 
fractures from last 12 months on 6-month 
dosing regimen to 12 months on 3-month 
dosing regimen 
Incidence of X-ray confirmed new and 
worsening vertebral fractures from last 
12 months on 6-month dosing regimen to 
12 months on 3-month dosing regimen 
Incidence of X-ray confirmed new and 
worsening vertebral fractures from last 
12 months on 6-month dosing regimen to 
12 months on 3-month dosing regimen 
Incidence of X-ray confirmed new 
vertebral fractures from last 12 months 
on 6-month dosing regimen to 12 months 
on 3-month dosing regimen 
Incidence of X-ray confirmed new 
vertebral fractures from last 12 months 
on 6-month dosing regimen to 12 months 
on 3-month dosing regimen 
Incidence of X-ray confirmed improving 
vertebral fractures from baseline of 
3-Month Dosing Regimen to 12 months 
on 3-Month Dosing Regimen 
Incidence of X-ray confirmed improving 
vertebral fractures from baseline of 
3-Month Dosing Regimen to 12 months 
on 3-Month Dosing Regimen 
Incidence of vertebral and non-vertebral 
fractures from last 12 months on 6-month 
dosing regimen to 12 months on 3-month 
dosing regimen (in subjects 5 years of 
age or older) 
Incidence of vertebral and non-vertebral 
fractures from last 12 months on 6-month 
dosing regimen to 12 months on 3-month 
dosing regimen (in subjects 5 years of 
age or older) 
Change in Child Health 
Questionnaire-Parent Form-50 (CHQ-PF-
50) Physical Summary score at 12 
months 
Change from baseline in CHQ-PF-50 
Physical Summary score at 12 months in 
subjects receiving the 3-month dosing 
regimen 
Change in CHQ-PF-50 Psychological 
Summary score at 12 months 
Change from baseline in CHQ-PF-50 
Psychological Summary score at 12 
months in subjects receiving the 3-month 
dosing regimen 
Change in Childhood Health Assessment 
Questionnaire (CHAQ) Disability Index 
score at 12 months 
Change from baseline in CHAQ Disability 
Index score at 12 months in subjects 
receiving the 3-month dosing regimen 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Change in Wong-Baker Faces Pain 
Rating Scale (WBFPRS) at 12 months 
Change from baseline in WBFPRS at 12 
months in subjects receiving the 3-month 
dosing regimen 
Change in growth velocity (determined by 
calculating age-adjusted Z-scores for 
height, weight, and body mass index 
[BMI]) at 12 months 
 
Change from baseline in growth velocity 
(determined by calculating age-adjusted 
Z-scores for height, weight and BMI) at 
12 months in subjects receiving the 3-
month dosing regimen 
Serum denosumab concentration and 
bone turnover markers (BTM) collected 
at 1(pre-dose),10, 30, and 60 days after 
the first dose of 3-month dosing regimen 
and every 3 months(pre-dose) in all 
subjects  
Serum concentration of denosumab and 
serum BTM on days 1(pre-dose), 10, 30, 
60 after the first dose and every 3 
months(pre-dose), in subjects on 3-
month dosing regimen 
 
 
Exploratory 
 


Product:  AMG162 (Denosumab)  
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Safety 
To evaluate denosumab in children 2 to 17 years of age (at the time of screening) 
with OI on a 3-Month Dosing Regimen or 6-Month Dosing Regimen with respect to: 
Adverse events and serious adverse 
events 
Subject incidence of adverse events and 
serious adverse events 
Laboratory parameters  
 
Change from baseline in laboratory 
values 
Vital signs 
Change from baseline in vital signs 
Antidenosumab antibodies  
 
Subject incidence of antidenosumab 
antibodies 
Metaphyseal index 
Subject incidence of metaphyseal index 
Z-score above age-appropriate normal 
range 
Molar eruption and mandibular shaping 
Subject incidence of abnormal molar 
eruption and Subject incidence of 
abnormal mandibular shaping 
Hypercalcemia 
Subject incidence of hypercalcemia 
 


Product:  AMG162 (Denosumab)  
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2.2 
Hypotheses and/or Estimations 
The hypothesis of the study is that the change from baseline in lumbar spine BMD Z-
score following 12 months of denosumab treatment with 3-month dosing regimen in 
children 2 to 17 years of age (at the time of screening) with OI will be greater than that 
from historical control (ie, placebo or untreated subjects) (Letocha et al, 2005; Rauch et 
al, 2009; Ward et al, 2011) which was estimated to be 0.01 (95 CI: -0.17, 0.18). 
3. 
Study Overview 
3.1 
Study Design 
This is a prospective, single-arm, multicenter, phase 3 study to demonstrate the 
superiority of denosumab administration compared with historical controls as measured 
by change from baseline in lumbar spine BMD Z-score at 12 months and to evaluate 
the safety, efficacy, and pharmacokinetics in children with OI. The effect of denosumab 
administered every 3 months will be evaluated based on comparison in BMD Z-score 
change from baseline of 3-month dosing regimen to 12 months with historical controls 
derived from published randomized, controlled trials (Letocha et al, 2005; Rauch et al, 
2009; Ward et al, 2011). 
6-month dosing regimen 
Approximately 150 subjects between age 2 to 17 will be enrolled, including at least 
30 subjects younger than 7 years old. All subjects will receive denosumab 1 mg/kg (up 
to a maximum of 60 mg) subcutaneously every 6 months for 36 months, and all 
subjects will receive appropriate calcium and vitamin D (study design and treatment 
schema are provided at end of protocol synopsis section). Subjects meeting eligibility 
criteria will be enrolled in the study to receive treatment with denosumab. Although 
enrollment in the study will not be stratified, it will be gated as follows: 
Older children (11 to 17 years) will be enrolled first because they will be the most 
skeletally mature and are more verbal and cognizant to describe adverse events. 
The first 5 subjects enrolled in the age 11 to 17 year cohort (sentinel cohort) will 
undergo intensive mineral homeostasis monitoring for the first 14 days after 
administration of investigational product, to permit adaptation of subsequent mineral 
homeostasis assessments for all study subjects, as appropriate. Once these 5 subjects 
have completed 14 days of mineral homeostasis monitoring, enrollment will be open to 
the remainder of the age 11 to 17 year cohort. 


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When the first 5 subjects in the age 11 to 17 cohort have been treated for 12 months, 
enrollment will be open to the next age cohort (7 to 10 years). 
Enrollment will be open to children 2 to 6 years old after the first 5 subjects between 7 
to 10 years old have been treated for 6 months. 
 
3-month dosing regimen 
Sixty previously enrolled subjects will transition to a 3-month dosing regimen, among 
them approximately 20 subjects younger than 7 years of age (at time of initial 
enrollment).  All subjects will receive denosumab 1 mg/kg (up to a maximum of 60 mg) 
subcutaneously every 3 months for a minimum of 12 months, and all subjects will 
receive age appropriate calcium and vitamin D. 
All subjects who remain on study (have not previously completed month 36/EOS under 
the 6-month dosing regimen) will be eligible to transition to the 3-month dosing regimen 
unless they ended treatment due to an adverse event.  Subjects may be consented and 
transition to the 3-month dosing regimen up to and including the date they attend for a 
month 36 visit under the 6-month dosing regimen. Subjects who previously ended 
treatment but remain on study will be eligible to transition to the 3-month dosing 
regimen unless they ended treatment due to an adverse event. Subjects will have the 
option to either consent to the 3-month dosing regimen or to end study participation. 
Based on the life-threatening events of hypercalcemia observed, Amgen evaluated that 
benefit/risk profile of denosumab is not favorable. Per DMC recommendation and 
Amgen decision, an urgent safety measure was issued to stop IP with the EOS visit 24 
weeks after the last dose of IP.  
3.2 
Sample Size 
3.2.1 
6-month dosing regimen 
A study sample size of 150 subjects will be enrolled to collect adequate efficacy and 
safety information for the ad hoc analysis at 12 months.  Assuming that 20 of subjects 
will not be evaluable at month 12 for the ad hoc efficacy endpoint due to dropout, the 
analysis set for the ad hoc efficacy endpoint will include at least 120 subjects.  
3.2.2 
3-month dosing regimen 
Sixty previously enrolled subjects were previously transitioned to a 3-Month Dosing 
Regimen. Approximately 60 previously enrolled subjects were to transition to a 3-Month 
Dosing Regimen.  


Product:  AMG162 (Denosumab)  
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This sample size will provide more than 95 power to demonstrate that the difference 
in the change from baseline lumbar spine BMD Z-score at month 12 between 
denosumab and historical control is significantly greater than zero using 1-sample 2-
sided t-test with a significance level of 0.05 based on the following assumptions: 
 
Mean change in lumbar spine BMD Z-score at 12 months for denosumab is 1.31 
(SD  0.91), which represents the lower bound of the 95 CI for the effect of a 
bisphosphonate (zoledronic acid) (EMA assessment report for Zometa Procedure 
no EMEA/H/C/000336/II/0031).  
 
Weighted mean (SE) change in lumbar spine BMD Z-score at 12 months for 
historical control is 0.01(0.09) (95 CI: -0.17, 0.18), estimated using meta-analysis 
based on data from the placebo or control of 3 studies in children with OI 
(Ward et al, 2011; Rauch et al, 2009; Letocha et al, 2005). 
Assuming the sample size will provide at least 10 of the subjects evaluable for the 
primary efficacy endpoint in most subgroups of interest, the effect of denosumab on 
lumbar spine BMD Z-score also may be summarized descriptively in these subgroups. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The following covariates are assumed to have prognostic value with respect to the 
lumbar spine BMD Z-score as assessed by DXA.   
 
Age (years) at the time of transition to 3-month dosing regimen 
 
Baseline lumbar spine BMD Z-score of 3-month dosing regimen 
The covariate’s association with the primary endpoint will be investigated. 
4.2 
Subgroups 
The following subgroups will be used to analyze the change from baseline of 3-month 
dosing regimen in lumbar spine BMD Z-score as assessed by DXA at 12 month. 
Selected subgroups may be used to analyze other endpoints.  
 
Age cohorts at the time of screening (2 to 6, 7 to 10, 11 to 17 years) 
 
Gender (females or males) 
 
Baseline OI severity (Level 1, Level 2 or Level 3) 
o Severity level 1: blue sclera, normal height (3-97percentile) at 
screening, and does not meet the required criteria for greater 
severity (see below). 


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o Severity level 2: blue or grey sclera, >2 fractures/year averaged 
over lifetime, height <50 percentile for age at screening and does not 
meet the required criteria for greater severity (see below). 
o Severity level 3: fractures in utero or at birth, saber shins and/or 
significant bowing, typical for type III per investigator, dentinogenesis 
imperfecta,  >2 fractures/year averaged over lifetime, and height <25 
percentile for age at screening. 
If there are < 10 subjects within a subgroup,  this subgroups analysis will not be 
provided. 
5. 
Definitions 
5.1 
Basic Definitions 
Investigational Product 
Denosumab (1 mg/kg, up to a maximum of 60 mg). 
Interactive Voice Response System (IVRS) 
The system used to screen, screen failure and enroll subjects, provide investigational 
product (IP) box number, and volume administered, as well as to manage the cohorts 
and denosumab drug supply at the site and to track subject study termination data. 
Exposure-adjusted subject incidence rate (EAIR) 
Exposure-adjusted subject incidence rate (EAIR) for fractures during last 12 
months on 6- month dosing regimen will be calculated as the number of subjects 
with a fracture divided by the total time at risk for the fracture. Time at risk will be 
calculated as sum of the total time to first fracture or total exposure of last 12 months on 
Q6M if no event across all subject. 
Exposure-adjusted subject incidence rate (EAIR) for fractures during12 months 
on 3-month dosing regimen will be calculated as the number of subjects with a 
fracture divided by the total time at risk for the fracture. Time at risk will be calculated as 
the sum of total time to first fracture or total exposure of 12 month or the end of study 
whichever earlier if no event across all subjects.   
Exposure-adjusted subject incidence rate (EAIR) will be displayed per 100 subjects-
years. 
Exposure-adjusted event rate (EAER) 


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Exposure-adjusted event rate (EAER) for fractures during last 12 months on 6- month 
dosing regimen will be calculated as the number of fractures divided by the total time at 
risk for the fracture. Time at risk will be calculated as Sum of subjects years of exposure 
on last 12 months on Q6M. 
Exposure-adjusted event rate (EAER) for fractures during 12 months on 3-month 
dosing regimen will be calculated as the number of fractures divided by the total time at 
risk for the fracture. Time at risk will be calculated as sum of total time from first dose of 
Q3M to month 12 or to the end of study whichever earlier across all subjects.  
Exposure-adjusted Event rate (EAER) will be displayed per 100 subjects-years. 
Treatment-emergent adverse event (TEAE) for 6-month dosing regimen 
 
Subject who did not transition to 3-months dosing regimen and 
discontinued the study early; Treatment-emergent adverse event are 
events categorized as Adverse Events (AEs) starting on or after first dose 
of investigational product as determined by “Did event start before first 
dose of investigational product” equal to “No” or missing on the Events 
eCRF  up to end of study.  
 
Subject who transition to 3-months dosing regimen Treatment-emergent 
adverse event are events categorized as Adverse Events (AEs) starting on 
or after first dose of investigational product as determined by “Did event 
start before first dose of investigational product” equal to “No” or missing 
on the Events eCRF up to the day before first dose of 3-month dosing 
regimen . 
Treatment-emergent adverse event (TEAE) for 3-month dosing regimen 
Treatment-emergent adverse event are events categorized as Adverse Events (AEs) 
starting on or after first dose of investigational product on 3-month dosing regimen and 
up to the end of study.   
5.2 
Study Points of Reference 
Baseline for 3-month dosing regimen 
Baseline for 3-month dosing regimen will be Day 1 of 3-month dosing regimen. 
Baseline for 6-month dosing regimen 


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Baseline for 6-month dosing regimen will be the closest recorded measurement before 
the administration of the first dose of 6-month dosing regimen. 
Baseline for Vertebral Fractures  
Baseline for vertebral fractures will be the x-rays obtained on day 1 of 3-month dosing 
regimen. 
Baseline DXA Assessments 
Baseline DXA will be performed at day 1 visit (in duplicate) of the 3-month dosing 
regimen. Because the baseline DXA will be assessed in duplicate, the baseline 
BMD/BMC value for analysis purpose will be the average of the BMD/BMC values from 
all baseline DXA scans for the same skeletal site. 
If the baseline (before first dose of 3-month dosing regimen) DXA assessment is 
missing, only then the DXA scans obtained after the first 3-month dosing regimen but 
no more than 60 days from the first 3-month dosing regimen may be considered as 
baseline DXAs. 
Baseline for fractures occurred during last 12 months on 6-month dosing 
regimen. 
Day x to day 1 of Q3M dosing regimen where “x” is the day of the assessment closest 
to the previous 12 months in 6-month dosing. 
Study Day 1 for 3-month dosing regimen. 
3-month dosing regimen day 1 is defined as the day that the initial dose of IP for 3-
month dosing regimen is administered to the subject.  
Study Day 1 for 6-month dosing regimen. 
6-month dosing regimen day 1 is defined as the day that the initial dose of IP for 6-
month dosing regimen is administered to the subject.  
Study Day 
The number of days from Study Day 1 of respective dosing regimen, inclusive: 
Study Day = (Date of Interest – Date of Study Day 1) + 1 
End of Treatment (EOT) 
End of Treatment (EOT) defined as “the last assessment for the protocol-specified 
treatment phase of the study for an individual subject.”  


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EOS for subject who did not transition to 3-month dosing regimen 
The date recorded on the End of Study eCRF and no record of 3-month dosing regimen 
in Investigational Product Administration eCRF with volume > 0.   
EOS for Subject who did transition to 3-month dosing regimen: 
The date recorded on the End of Study eCRF and has record of 3-month dosing 
regimen in Investigational Product Administration eCRF with volume > 0 
As of 30 September 2021, due to the life-threatening risk of hypercalcemia, subjects on 
study who had not completed their EOS visit were immediately discontinued from IP, 
and will be followed for safety for 24 weeks following the last dose of IP per the updated 
Schedule of Assessments. For subjects who have been on alternative therapy for more 
than 6 months or whose last dose of IP was greater than 24 weeks, no additional 24-
week safety follow-up is required. These subjects can follow the previous protocol 
(protocol amendment 6) and complete the EOS CRF. Subjects whose last dose was 
between 12 and 24 weeks ago can complete the EOS assessments at week 24 per the 
updated Schedule of Assessments. 
Visit Windows 
For analysis purpose the analysis visit windows defined in Appendix C will be used to 
assign evaluations to the most appropriate nominal visit. 
Ad-hoc analysis 
Analysis based on all subjects who completed 12 months on 6-month dosing regimen 
based on as-is snapshot data referred as ad hoc analysis. 
5.3 
Study Dates 
Informed Consent (IC) Dates for 6-month dosing regimen 
The date on which the study informed consent forms, and subject assent form if 
applicable, is signed.  
Screening Date 
The screening date is the informed consent (IC) for 6-month dosing regimen / subject 
assent date. 
Enrollment Date 
The date on which the enrolment call is made using IVRS. 


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First Dose Date For 3-month dosing regimen 
The date of administration of first dose of IP for 3-month dosing regimen will be day 1 of 
3-month dosing regimen (ie, the first date recorded on the Investigational Product 
Administration eCRF with volume > 0).  
Last Dose Date 
The date of administration of last dose of IP (ie, the last date recorded on the 
Investigational Product Administration eCRF with volume > 0). 
End of Study Date  
The date recorded on the End of Study eCRF. 
5.4 
Study Time Intervals 
Screening Period 
The time between the date of informed consent and the enrolment.  
Study Period 
The time period between the first dose date and the end of study date, inclusive. 
Last 12 months on 6- month dosing regimen for fracture endpoints is the 12 months 
prior to first dose date of 3-month dosing regimen.  
12 months on 3-month dosing regimen for fracture endpoints starts at first dose date of 
3 months dosing regimen and ends at months 12 or end of study date for 3-month 
dosing regimen, whichever comes first. 
5.5 
Subject Disposition 
Enrolled 
Individuals are considered enrolled when an enrollment call is made using IVRS. 
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. 
5.6 
Arithmetic Calculations 
Age at Screening (Years) 
Age as collected on screening period based on screen date, and to allocate subjects to 
the appropriate cohort (11 to 17, 7 to 10, or 2 to 6 years) at enrollment. 


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Age at Screening (months) 
Age in months is derived as collected age on screening period in years multiplied by 
number of months in year.  
Age at Visit  
Age at visit in years is derived as –  
((visit date  - Date of Birth)+1) / 365.25 
If Date of birth is incomplete then use below formula, 
Collected age at screening period in years + (visit date - screening date) / 365.25 
Age at visit in months is derived as –  
((visit date  - Date of Birth)+1) / 30.4375 
If Date of birth is incomplete then use below formula, 
Collected age at screening period in months + (visit date - screening date) / 30.4375 
Age at the time of transition to 3-month dosing regimen in years is derived as- 
((Day 1 visit  date of 3-month dosing regimen - Date of Birth )+1) / 365.25 
If Date of birth is incomplete then use below formula, 
Collected age at screening period in years +(Day 1 visit date of 3-month dosing 
regimen  - screening date) / 365.25 
Age at the time of transition to 3-month dosing regimen in months is derived as- 
((Day 1 visit  date of 3-month dosing regimen - Date of Birth)+1) / 30.4375 
If Date of birth is incomplete then use below formula, 
Collected age at screening period in months + (Day 1 visit  date of 3-month dosing 
regimen - screening date) / 30.4375 
5.7 
Study Endpoints 
5.7.1 
Fracture-related Trauma Severity Definitions 
Low Trauma Severity 
Assessed by the investigator and collected on the Clinical Fracture Summary eCRF for 
each clinical fracture event and includes: 
▪ 
Fall from standing height or less than 20 inches 


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▪ 
Minimal or Moderate  trauma other than a fall from standing height or less than 
20 inches 
▪ 
Unknown/don’t Know 
High Trauma Severity 
Assessed by the investigator and collected on the Clinical Fracture Summary 
eCRF for each clinical fracture event and includes 
 
Severe trauma other than a fall 
Pathologic Fracture 
Assessed by the investigator and collected on the Clinical Fracture Summary eCRF for 
each clinical fracture event and includes: 
 
Pathologic fractures 
5.7.2 
DXA Assessments 
Only GE 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 another 
side must be used or is inadvertently used during screening, then the same side must 
be used consistently throughout the study. 
Lumbar spine scans should include L1 through L4. 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. 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. 
5.7.3 
Vertebral Fractures 
Lateral radiographs of the thoracic and lumbar spine 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) 


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▪ 
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.  
Prevalent Vertebral Fracture 
A subject has prevalent vertebral fracture if any vertebra from T4 to L4 has a grade of ≥ 
1 at baseline. A subject does not have prevalent vertebral fracture when all 13 grades 
from T4 to L4 are 0 on the first evaluable spinal radiograph collected during the study.  
Otherwise, the subject will have an unknown status for prevalent vertebral fracture.   
Any vertebra(e) with a missing grade at baseline can be assumed having a grade of 0 if 
the subsequent x-ray shows a grade of 0 for the same vertebra(e). 
New Vertebral Fractures 
A new vertebral fracture is identified when there is ≥ 1 grade increase from the baseline 
grade of 0 in any vertebra from T4 to L4, excluding any symptomatic new vertebral 
fracture associated with high trauma severity or a pathologic fracture Because the 
vertebral fractures can improve in the OI population, the SQ score of the fractured 
vertebra should remain ≥ 1 at the last assessment on or before the timepoint of interest. 
So for example, if a vertebra is assessed as having  0, 2 SQ scores at baseline and 12 
months, respectively, then the vertebra will be identified as having a new vertebral 
fracture at the 12-month assessment because the SQ score remained > 0 at 12 
months.   
A subject will be identified as having multiple new vertebral fractures when more than 
one thoracic or lumbar vertebra is identified as having a new vertebra fracture at the 
timepoint of interest, and the total number of new vertebral fractures will be the sum of  
new vertebra fractures at the timepoint of interest. 
Worsening Vertebral Fractures 
A worsening vertebral fracture is identified when there is ≥ 1 grade increase from the 
baseline grade of ≥ 1 in any vertebra from T4 to L4, excluding any symptomatic 
worsening vertebral fracture associated with high trauma severity or a pathologic 


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fracture.  For example, if a vertebra is assessed as having  SQ scores of 2, 3 at 
baseline and 12 months respectively the vertebra will be assessed as having a 
worsening vertebral fracture at the 12-month assessments.  
A subject will be identified as having multiple worsening vertebral fractures when more 
than one thoracic or lumbar vertebra is identified as having a worsening vertebra 
fracture at the timepoint of interest, and the total number of new vertebral fractures will 
be the sum of  worsening vertebral fractures at the timepoint of interest. 
New or Worsening Incident 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 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 
vertebra fracture at the timepoint of interest, and the total number of new or worsening 
vertebral fractures will be the sum of new or worsening vertebra fractures at the 
timepoint of interest. 
Improving Vertebral Fractures 
At 12 months (an improvement in a prevalent vertebral fracture is identified when the 
SQ grade decreases by at least 1 relative to baseline SQ score, ie the last SQ score 
assessment in the period of interest is smaller than its baseline SQ score. 
At 12 months a subject is identified as having an improving vertebral fracture if at least 
one thoracic or lumbar vertebra is assessed as an improving vertebral fracture at the 
visit of interest, and the vertebra SQ score remains < baseline SQ at the last 
assessment on or before the timepoint of interest. For example, if a vertebra is 
assessed as having  2, 1 SQ scores at baseline and 12 months respectively, then the 
vertebra will be identified as having an improving vertebral fracture at the 12 month 
assessments. 
Clinical Vertebral Fractures 
Clinical vertebral fracture is any new or worsening vertebral fracture assessed at either 
a scheduled or unscheduled study visit, and associated with any signs and/or 
symptoms indicative of a fracture on the Clinical Fracture Summary eCRF, excluding 


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any fracture associated with high trauma severity or a pathologic fracture. Clinical 
vertebral fracture is also called symptomatic vertebral fracture. 
5.7.4 
Nonvertebral Fracture 
Nonvertebral fracture (other than long bone fractures), reported on the Clinical 
Fracture Summary eCRF, is defined for post-treatment period as any nonvertebral 
(excluding cervical vertebrae, thoracic vertebrae and lumbar vertebrae) 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.  
Long bone fractures are subset of nonvertebral fractures including the femur, humerus, 
radius, ulna, tibia and fibula bone. 
Long Bone fractures reported on the Clinical Fracture Summary eCRF, is defined 
for post-treatment period as any long bone fracture confirmed by imaging 
excluding fractures associated with high trauma severity or pathologic fractures. 
See Appendix D for the list of nonvertebral fracture locations. 
Historical Fracture 
All historical fractures are defined based on the fracture locations listed on the Subject 
Fracture History eCRF. Nonvertebral fractures should be substantiated by radiographs 
where available or with a medical report in the event of unavailable radiographs. 
Subject fracture history eCRF page will be used for the classification of nonvertebral 
fractures for last 12 months on 6- month dosing regimen  excluding spine fracture, 
ankle fracture, facial bone fracture, skull fractures and for the classification of long bone 
fractures exclude forearm fracture, lower leg (Not knee or ankle) fracture, upper arm 
fracture and upper leg (Not hip) fracture. 
Any Historical Fracture 
Any fracture recorded on the Subject Fracture History eCRF regardless of trauma 
severity. 
Historical Nonvertebral Fracture 


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Any nonvertebral fracture recorded on the Subject Fracture History eCRF and not 
associated with known high trauma severity or pathologic fractures. 
5.7.5 
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
 
Growth velocity is given by  the change from baseline in height-for-age Z-scores at 12 
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 analogously 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 E. 
5.7.6 
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. 
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 


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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 
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 B. 
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 B.  
5.7.7 
Metaphyseal Index Z-score of the Distal Femur 
To assess a subject’s eligibility at screening, AP radiographs of both knees (unless 
prohibited by the presence of hardware such as implants) is to be used to calculate the 
metaphyseal index Z-score of each knee; the knee for assessment during the study at 6 
and 12 months should be the one with the higher Z-score at day 1 of 6-month dosing 
regimen, unless prohibited by presence of hardware, in which case an AP radiograph of 
the contralateral knee may be obtained. Subject incidences of metaphyseal index Z-
score above age-appropriate normal range (ie, metaphyseal index Z-score > +2) will be 
provided at each timepoint.  The metaphyseal index (MI) will be calculated by the 
central imaging vendor as the ratio of the femoral width (W) over the distal femoral 
growth plate width (GPW), and the Z-score for each subject, relative to the subject’s 
age as: 
MI Z-score = (subject value – mean)/ SD,  
where mean and standard deviation (SD) are the corresponding values based on 
Ward et al database, (Ward, 2005), for the subject’s age group at the time of the 
assessment. 


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5.7.8 
Mandibular Shaping 
Lateral cephalogram will be performed to enable assessment of mandibular shaping at 
Day 1 of 6-month dosing regimen, Day 1 of 3-month dosing regimen and EOS. 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.  
The following anatomical angles will be measured to evaluate the correct proportions of 
the mandible and its position relative to the skull/maxilla:  
▪ 
Gonial angle 
▪ 
SNA angle 
▪ 
SNB angle 
▪ 
ANB Angle = SNA - SNB. 
5.7.9 
Molar Eruption 
Radiographic assessment of molars will be performed at all visits for the 3-month 
dosing regimen and 6-month dosing regimen to assess the risk for unerupted molars.  
In addition, each subject will undergo a visual inspection under natural light for the 
presence of the first and second molars. The subject should be referred to a dentist to 
perform radiographic assessment of the unerupted molar(s) if: 
 
A subject is age 7 to 12 years and appears to have an unerupted upper or 
lower first molar (ie, not all 4 first molars are visible/detectable). 
 
A subject is age 13 years or older and appears to have an unerupted upper 
or lower (first or) second molar (ie, not all 4 first molars and all 4 second 
molars are visible/detectable).  
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The full analysis set (FAS) is defined according to intent-to-treat analysis to include all 
subjects enrolled into the study. 
6.2 
Safety Analysis Set 
6.2.1.1 
6-Month Dosing Regimen Safety Analysis Set 
The 6-month dosing regimen safety analysis set includes all subjects in the FAS who 
received  1 dose of IP. 


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6.2.1.2 
3-Month Dosing Regimen Safety Analysis Set 
The 3-month dosing regimen safety analysis set includes all subjects in the FAS who 
received  1 dose of 3-month dosing regimen. 
6.3 
 PK Analysis set 
The PK analysis set includes all subjects in the 3-month dosing regimen safety analysis 
set who have  1 serum denosumab reported result on 3-month dosing regimen. 
6.4 
Study-specific Analysis Sets 
6.4.1 
DXA Analysis Set 
The DXA analysis set includes all subjects in the FAS with baseline and  1 
postbaseline DXA assessment on 3-month dosing regimen for the endpoint of interest 
(lumbar spine and proximal femur) as provided by the central imaging vendor. 
6.4.2 
Vertebral Fracture Analysis set 
The vertebral fracture analysis set includes all subjects in the FAS who have a readable 
non-missing baseline and  1 non-missing postbaseline X-ray vertebral evaluation on 3-
month dosing regimen as provided by the central imaging vendor.  This analysis set will 
be used to analyze incidence of vertebral fracture endpoints.  
6.4.3 
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  1 postbaseline valid 
PRO response on 3-month dosing regimen for the appropriate PRO.  Moreover, the 
CHQ-PF-50 analysis set will only include subjects 5 years of age and older at the time 
of transition to 3-month dosing regimen; the questionnaire has not been validated in 
younger children (4 years of age or younger), and so this subgroup will not be included 
in the CHQ-PF-50 analysis set. 
6.4.4 
Growth Velocity Analysis set  
The analysis set includes all subjects in the FAS who have evaluable data (age in total 
months, and weight, height, and BMI) at baseline and  1 post baseline assessment on 
3-month dosing regimen for each growth velocity endpoint (weight-for-age, height-for-
age, and BMI-for-age Z-scores).  


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6.4.5 
Metaphyseal Analysis set  
This analysis set includes all subjects in the 3-month dosing safety analysis set with 
open growth plates (and no hardware preventing accurate calculation of metaphyseal 
index) at baseline and X-ray of the knee at baseline and post-baseline. 
6.4.6 
BTM Analysis set  
The BTM analysis set includes all subjects in the 3-month dosing regimen safety 
analysis set who have baseline and  1 postbaseline assessments for the endpoint of 
interest on 3-month dosing regimen. 
6.4.7 
DXA Per Protocol Analysis Set 
The DXA per protocol analysis set includes all subjects in the FAS with baseline and 
month 12 DXA assessment on 3-month dosing regimen for lumbar spine as provided by 
the central imaging vendor. 
6.4.8 
German Substudy Safety Analysis Set 
6.4.9 
PK Substudy Analysis Set 
The subset includes all subjects in the 6-Month Dosing Regimen safety analysis set 
who enroll in the PK/BTM substudy and have  1 serum denosumab reported result. 
6.4.10 
BTM Substudy Analysis Set 
The subset includes all subjects in the safety analysis set who enroll in the PK/BTM 
substudy and have baseline and  1 postbaseline assessments for the endpoint of 
interest on 6-Month Dosing Regimen. 
7. 
Planned Analyses 
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. 
7.1 
Interim Analysis and Early Stopping Guidelines 
Not applicable for the study. 


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7.2 
Primary Analysis 
The primary analysis (or final analysis since there is only 1 milestone analysis for this 
study) will occur after the last subject completes the 24-week safety follow up visit 
following the last dose of IP.  
7.3 
Final Analysis 
The final analysis is primary analysis for this study.  
8. 
Data Screening and Acceptance 
8.1 
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. 
8.2 
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. This study will use the RAVE database. The central imaging vendor will 
provide DXA scans, and X-ray (lateral thoracic, knees, lateral 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.  
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 Clinical Data Management (CDM) 
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 CDM 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 on the study. 


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8.3 
Handling of Missing and Incomplete Data 
Subjects may have missing specific data points for a variety of causes. The general 
procedures outlined below describe what will be done when data point is missing or 
incomplete. 
8.3.1 
Missing Data 
Missing baseline or post-baseline endpoints will not be imputed, unless otherwise 
specified. 
8.3.2 
Incomplete Dates 
NA 
8.3.3 
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 
     
 
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 
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. 
Note:  
1. The above imputation rule will apply to the subject respective dosing regimen 
during which the event has started. 


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2. If the imputation leads to an overlap of the imputation rules with respect to Q3M 
or Q6M, imputation rules will be applied in the following order. 
 
If a subject's transition happened during a month from Q6M to Q3M and AE 
start date is partial, check the end date of AE if it is before the Q3M 
administration start date, then the AE start date imputation should be as per the 
Q6M administration start date. 
 
If the AE end date is missing, the AE start date imputation should be as per the 
Q3M administration start date. 
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. 
 
8.4 
Detection of Bias 
Given the open-label nature of the study, changes to the study conduct and statistical 
analyses should be kept to a minimum to avoid undermining the study credibility. Any 
change to the protocol that is data driven should be avoided, except for safety related 
events and changes related to inclusion/exclusion criteria to speed up enrollment, if 
needed. 
8.5 
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 study report. 


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8.6 
Distributional Characteristics 
The assumption of normality underlying the primary analysis is considered quite robust 
with this sample size, nonetheless the normality of the denosumab sample will be 
tested.  
8.7 
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 safety analysis set System 
version 9.2 or later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for demographics and subject characteristics, 
efficacy, patient reported outcomes 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. 
Nominal and ordinal categorical variables will be summarized using counts and 
percentages. 
The primary endpoint will be compared with historical control (Ward et al, 2011; Rauch 
et al, 2009; Letocha et al, 2005) using a one-sample t-test, with a significance level of 
0.05. This is the only pre-planned comparison in this single-arm study. 
9.2 
Subject Accountability  
The disposition of all subjects who enrolled in this study and who transitioned to 3-
month dosing regimen  will be tabulated . Disposition, for successfully completing IP 
administration, and completing the study will be included. The disposition of subjects 
will also include the number of subjects who withdrew from the IP and their reasons for 
withdrawal and the number of subjects who withdrew from study and their reasons for 
withdrawal. The number of subjects enrolled within each region and country will be 
summarized. The number of transitioned subjects participating in each of the sub 
studies will be summarized. 


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9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory 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 for the subjects who received 3-month dosing regimen.  
9.4 
Demographic and Baseline Characteristics 
Subject demographic and baseline disease characteristics will be summarized based 
on FAS.  
Below characteristics are collected at the time of initial screening : 
 
Race 
 
Ethnicity 
 
Gender  
 
Type and details of Osteogenesis Imperfecta  
Below characteristics are based on baseline of 6-month dosing regimen 
 
 
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 
 
Vital signs (pulse, respiration rate, temperature) 
 
Selected laboratory assessments  
 
 
 
DXA assessments of the lumbar spine and proximal femur (these DXAs will be 
performed as duplicate scans at baseline only) 
 
Fracture history including any fractures, vertebral fractures, and nonvertebral 
fractures 


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 
Prevalent vertebral fracture at pre-treatment (based on screening spinal 
radiograph) 
 
Number of prevalent vertebral fractures (0, 1, ≥ 2; based on screening spinal 
radiograph) 
Subject demographic and baseline disease characteristics will be summarized based 
on 3-Month Dosing Regimen Safety Analysis Set .  
 
Age (in years) at the time of transition to 3-month dosing regimen 
 
Age (in months) at the time of transition to 3-month dosing regimen 
 
Age cohorts (2 to 6, 7 to 10, and 11 to 17) at the time of screening 
 
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 
 
Vital signs (pulse, respiration rate, temperature, systolic and diastolic blood 
pressure) 
 
Selected laboratory assessments  
 
 
 
DXA assessments of the lumbar spine and proximal femur (these DXAs will be 
performed as duplicate scans at baseline only)  
 
Fracture history including any fractures, vertebral fractures, and nonvertebral 
fractures from last 12 months on 6-month dosing regimen  
 
Number of Prevalent vertebral fracture (based on Day 1 of 3-month dosing 
regimen spinal radiograph) 
9.5 
Efficacy Analyses 
Most analyses will be descriptive given the lack of a comparator in this study as well as 
lack of historical comparator data for many endpoints. In addition, the magnitude of any 
natural change in most efficacy endpoints is unknown. However, for the primary 
endpoint of change from baseline in lumbar spine BMD Z-score at 12 months in 
subjects on 3-month dosing regimen, comparison with a weighted estimate of historical 


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controls will be performed at the 5% significance level based on a 2-sided test (see 
Section 9.5.1.1). The weighted mean change in lumbar spine BMD Z-score at 12 
months from historical controls is 0.01 (95% CI: -0.17, 0.18). This suggests that the 
natural progression over 12 months with respect to the primary efficacy endpoint is 
minimal, and any bias in estimating the treatment effect, if exist, will likely to be trivial. 
All descriptive statistics will be provided by visit based on the observed values, with no 
imputation for missing values. Analysis visit windows are defined in Appendix C for 
each endpoint. 
Categorical endpoints will be summarized using the number and percentage in each 
category, and continuous endpoints will be summarized using descriptive statistics 
including mean, standard deviation, minimum, 25th percentile, median (50th percentile), 
75th percentile, maximum, and number of nonmissing observations (n). 
Table A Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
Change from baseline 
in lumbar spine BMD 
Z-score, as assessed 
by DXA, at 12 months 
in subjects receiving 
the 3-month dosing 
regimen 
The change from baseline of 3-
month dosing regimen in BMD Z-
score at 12 months in subjects on 
3-month dosing regimen will be 
analyzed based on the DXA 
analysis 
set 
using 
repeated 
measures analysis with visit (6 
and 12 months), baseline age, 
and baseline BMD Z-score as 
fixed effects.   
 
The primary analyses  
will be repeated 
substituting baseline 
age with baseline 
height to the fixed 
effects in the model.  
 
The DXA per protocol 
analysis set will be used 
in this analysis. 
 
Table B Secondary Efficacy Endpoint Summary Table 


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Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
Change from baseline 
in lumbar spine BMD 
Z-score, as assessed 
by DXA, at 6 months 
in subjects receiving 
the 3-month dosing 
regimen 
 
The change from baseline of 3-
month dosing regimen in lumbar 
spine BMD Z-score in subjects 
on 3-month dosing regimen will 
be analyzed based on the DXA 
analysis 
set 
using 
repeated 
measures analysis with visit (6 
and 12 months), baseline age, 
and baseline BMD Z-score as 
fixed effects. Visit will be treated 
as a categorical variable. 
 
Change from baseline 
in 
proximal 
femur 
BMD 
Z-score, 
as 
assessed by DXA, at 
6 and 12 months (in 
subjects 5 years of 
age and older) in 
subjects receiving the 
3-month 
dosing 
regimen 
The change from baseline of 3-
month 
dosing 
regimen 
in 
proximal femur BMD Z-score in 
subjects on 3-month dosing 
regimen will be analyzed based 
on the DXA analysis set using 
repeated measures analysis with 
visit (6 and 12 months), baseline 
age, and baseline BMD Z-score 
as fixed effects. Visit will be 
treated as a categorical variable. 
 
Incidence of X-ray 
confirmed long bone 
and 
new 
and 
worsening 
vertebral 
fractures from last 12 
months on 6- month 
dosing regimen to 12 
Exposure 
adjusted 
subject 
incidence rate and exposure 
adjusted event rate of long bone 
and new and worsening vertebral 
fractures will be summarized 
based on the 3-month dosing 
regimen safety analysis set.  
 


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Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
months on 3-month 
dosing regimen 
Incidence of X ray 
confirmed new and 
worsening 
vertebral 
fractures from last 12 
months on 6-month 
dosing regimen to 12 
months on 3-month 
dosing regimen 
Exposure 
adjusted 
subject 
incidence rate and exposure 
adjusted event rate of new and 
worsening vertebral fractures will 
be summarized based on the 
vertebral fracture analysis set 
 
Incidence of X ray 
confirmed 
new 
vertebral 
fractures 
from last 12 months 
on 6-month dosing 
regimen to 12 months 
on 3-month dosing 
regimen 
Exposure 
adjusted 
subject 
incidence rate and exposure 
adjusted event rate of new 
vertebral 
fractures 
will 
be 
summarized 
based 
on 
the 
vertebral fracture analysis set. 
 
Subject incidence of 
improving 
vertebral 
fractures 
from 
baseline of 3-Month 
Dosing Regimen to 
12 
months 
on 
3-
month 
dosing 
regimen 
The proportion of subjects with 
improved vertebral fracture from 
baseline 
of 
3-month 
dosing 
regimen will be summarized at 
each timepoint based on the 
vertebral fracture analysis set. 
 
Incidence of vertebral 
and 
nonvertebral 
fractures from last 12 
months on 6-month 
Exposure 
adjusted 
subject 
incidence rate and exposure 
adjusted event rate of vertebral 
and nonvertebral fractures will be 
  
 


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Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
dosing regimen to 12 
months on 3-month 
dosing regimen (in 
subjects 5 years of 
age or older) 
summarized based on the 3-
month dosing regimen safety 
analysis set. 
Change from baseline 
in 
CHQ-PF-50 
Physical 
Summary 
score at 12 months in 
subjects receiving the 
3-month 
dosing 
regimen 
Patient-reported 
outcomes 
(CHQ-PF-50,) and their changes 
from 3-month dosing regimen will 
be summarized at month 12 
based on their respective PRO 
analysis set. 
 
Change from baseline 
in 
CHQ-PF-50 
Psychological 
Summary score at 12 
months in subjects 
receiving the 3-month 
dosing regimen 
Patient-reported 
outcomes 
(CHQ-PF-50) and their changes 
from 3-month dosing regimen will 
be summarized at month 12 
based on their respective PRO 
analysis set. 
 
Change from baseline 
in CHAQ Disability 
Index score at 12 
months in subjects 
receiving the 3-month 
dosing regimen 
Change from baseline in CHAQ 
Disability Index score at 12 
months in subjects receiving the 
3-month dosing regimen will be 
summarized at month 12 based 
on their respective PRO analysis 
 
Change from baseline 
in WBFPRS at 12 
months in subjects 
receiving the 3-month 
dosing regimen 
Patient-reported 
outcomes 
(WBFPRS) and their changes 
from 3-month dosing regimen will 
be summarized at month 12 
 


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Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if 
FAS is Not Used) 
Sensitivity Analysis 
based on their respective PRO 
analysis set. 
Change from baseline 
in 
growth 
velocity 
(determined 
by 
calculating 
age-
adjusted Z scores for 
height, weight and 
BMI) at 12 months in 
subjects receiving the 
3-month 
dosing 
regimen 
Change from baseline of 3-month 
dosing regimen in age-adjusted 
growth velocity endpoints will be 
summarized at 12 months based 
on the growth velocity analysis 
set. 
 
Serum concentration 
of 
denosumab 
on 
days 1(pre-dose), 10, 
30, 60 and every 3 
months (pre-dose) in 
subjects on 3-month 
dosing regimen 
Serum 
denosumab 
concentrations 
will 
be 
summarized by visit based on PK 
analysis set  
 
Serum BTM on days 
1(pre-dose), 10, 30, 
60, 
and 
every 
3 
months (pre-dose), in 
subjects on 3-month 
dosing regimen 
Serum BTM will be summarized 
by visit based on BTM analysis 
set  
 
Table C Exploratory Efficacy Endpoint Summary Table 


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9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
9.5.1.1 
Primary Analysis 
The change from baseline of 3-month dosing regimen in lumbar spine BMD Z-score at 
12 months in subjects on 3-month dosing regimen will be analyzed based on the DXA 
analysis set using repeated measures analysis with visit (6 and 12 months), baseline 
age, and baseline BMD Z-score as fixed effects. Visit will be treated as a categorical 
variable. Missing baseline and post-baseline BMD Z-scores will not be imputed; only 
subjects with baseline and at least one lumbar spine DXA assessment at 6-month or 
12-month visit will be included in the analysis. The estimated 12-month least squares 
(LS) mean will be presented with a 95% confidence interval (CI). See Appendix E 
(Code Fragment). 
The LS mean will be compared to weighted estimated mean (SE) of 0.01 (0.09) from 
historical controls (Ward et al, 2011; Rauch et al, 2009; Letocha et al, 2005) using one 
sample t test with the historical mean used as the null hypothesis with a significance 
level of 0.05. See Appendix E for details. 
All analyses will be based on the site-specific DXA analysis set.  
9.5.1.2 
Per Protocol Analysis 
The above analyses will be repeated for the primary endpoint based on the DXA Per 
Protocol analysis set. 
9.5.1.3 
Subgroup Analysis 
Summary statistics will be provided by the subgroups defined in Section 4.2.  
9.5.1.4 
Sensitivity Analysis 
The primary analyses above will be repeated substituting baseline age with baseline 
height to the fixed effects in the model. The DXA Per Protocol analysis set will be used 
in this analysis. 


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9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
9.5.2.1 
 Other Changes From Baseline in BMD Z-score by DXA 
Similarly as above, for each skeletal site (lumbar spine, total hip and femoral neck), the 
change from baseline of 3-month dosing regimen in BMD Z-score in subjects on 3-
month dosing regimen will be analyzed using repeated measure analysis with visit (6, 
12 months), baseline age, and baseline BMD Z-score as fixed effects. Visit will be 
treated as categorical variable.LS mean (95% CI) will be presented for total hip and 
femoral neck, and for each visit excluding the 12-month visit for lumbar spine. 
All analyses will be based on the skeletal site specific DXA analysis set. 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. 
9.5.2.2 
New and Worsening Vertebral Fractures, and Vertebral 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 Clinical Fracture Summary eCRF which is confirmed by the central 
imaging vendor 
3. Long bone Fractures : fractures reported on the Clinical Fracture Summary 
eCRF i.e fractures confirmed by imaging 
Summary of the incidence of fractures for each endpoint (new and worsening vertebral 
fractures, vertebral and nonvertebral fractures , long bone and vertebral fracture) will be 
provided for 12 month.Exposure-adjusted incidence rate (EAIR) and exposure-adjusted 
event rate (EAER) for fractures occurred during last 12 months on 6- month dosing 
regimen  and 12 months on 3-month dosing regimen  will be summarized during the 12 
months interval. 
For details on the analysis code see Appendix E.  
9.5.2.3 
Incidence of Improving Vertebral Fractures 
The proportion of subjects with improved vertebral fracture from baseline of 3-month 
dosing regimen will be summarized at month 12 based on the vertebral fracture 
analysis set on 3-month dosing regimen. 


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9.5.2.4 
PRO Measurements 
Patient-reported outcomes (CHQ-PF-50, CHAQ disability index score and WBFPRS) 
and their changes from 3-month dosing regimen will be summarized at month 12 based 
on their respective PRO analysis set. There is no imputation for missing baseline or 
post baseline data. 
WBFPRS, CHQ-PF-50 physical and psychological summary scores, and CHAQ 
disability score will be calculated as detailed in the Appendix B. 
9.5.2.5 
Growth Velocity  
Descriptive statistics of height-for-age, weight-for-age and BMI-for-age Z-scores, and 
the respective changes from baseline at 12 months will be summarized for 3-month 
dosing regimen. There is no imputation for missing baseline or postbaseline data. 
9.5.2.6 
Denosumab Serum Concentration  
Descriptive statistics of denosumab serum concentration by visit (days 1 (pre-dose), 10, 
30 ,60 and every 3 months (pre-dose) in subjects on 3-month dosing regimen ) will be 
provided and may be evaluated by cohort based on the PK analysis set. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 


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9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Table D Safety Endpoint Summary Table 
All safety endpoints will be summarized for all subjects on 6-Month Dosing Regimen 
and subjects who received ≥ 1 dose of 3-Month Dosing Regimen separately.  
Endpoint 
Primary Summary and Analysis Method 
(Specify Analysis Set if Safety Analysis Set 
is Not Used) 
Sensitivity 
Analysis 
Subject 
incidence 
of 
adverse 
events 
and 
serious adverse events 
All TEAEs will be summarized for all 
subjects on 6-Month Dosing Regimen using 
6-Month Dosing Regimen Safety Analysis 
Set and subjects who received ≥ 1 dose of 
3-Month Dosing Regimen separately using 
3-Month Dosing Regimen Safety Analysis 
Set. 
 
Change from baseline in 
laboratory values 
Descriptive statistics of the actual values 
and changes from baseline in laboratory 
values will be presented by visit. 
 
Change from baseline in 
vital signs 
Descriptive statistics of the actual values 
and changes from baseline in vital signs 
(pulse, respiration rate, temperature) will be 
presented by visit. In addition, systolic and 
diastolic blood pressure will be summarized 
for 3-Month Dosing Regimen. 
 
Subject 
incidence 
of 
antidenosumab 
antibodies 
The percentages of subjects who tested 
positive 
(binding 
or 
neutralizing) 
for 
antidenosumab 
antibodies 
will 
be 
descriptively summarized. 
 


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9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. All TEAEs will be summarized for all subjects on 6-Month Dosing 
Regimen using 6-Month Dosing Regimen Safety Analysis Set and subjects who 
received ≥ 1 dose of 3-Month Dosing Regimen separately using 3-Month Dosing 
Regimen Safety Analysis Set.  
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events with CTCAE grades, serious adverse events, adverse events leading to 
discontinuation of investigational product, fatal adverse events ,treatment-related 
adverse events with CTCAE grades, treatment-related serious adverse events, 
treatment-related fatal adverse events and treatment-related adverse events leading to 
withdrawal of IP. 
Subject incidence of all treatment-emergent adverse event related to investigator 
product (IP) (including all treatment-emergent AEs, serious AEs and AEs leading to 
withdrawal of investigational product) will also be summarized by SOC and PT in 
descending order of frequency.  
Subject 
incidence 
of 
metaphyseal index Z-
score 
above 
age-
appropriate normal range 
Subject incidence of the metaphyseal index 
Z-score above age-appropriate normal 
range safety events will be tabulated. 
 
Subject 
incidence 
of 
abnormal molar eruption 
Subject incidence of the abnormal molar 
eruption safety events based on 
radiological findings will be tabulated.  
 
Subject 
incidence 
of 
abnormal 
mandibular 
shaping 
Descriptive summary statistics for 
mandibular shaping parameters  will be 
tabulated. 
 
Subject 
incidence 
of 
hypercalcemia 
Subject incidence of hypercalcemia will be 
summarized per baseline age cohort and 
overall. 
 


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Summaries of treatment-emergent and serious AEs occurring in at least 5% of the 
subjects by preferred term will be provided in descending order of frequency in the 
overall group. 
The exposure-adjusted subject incidence will be summarized for all subjects on 6-
Month Dosing Regimen using 6-Month Dosing Regimen Safety Analysis Set and 
subjects who received ≥ 1 dose of 3-Month Dosing Regimen separately using 3-Month 
Dosing Regimen Safety Analysis Set. 
9.6.2.1 
Adverse Events of Special Interest 
Subject incidence of following adverse events of interest will be summarized based on 
6-Month Dosing Regimen using 6-Month Dosing Regimen Safety Analysis Set and 
subjects who received ≥ 1 dose of 3-Month Dosing Regimen separately using 3-Month 
Dosing Regimen Safety Analysis Set.  
This tentative list has been based on the events of interest (EOI) identified for 
denosumab in the osteoporosis indication, and may be revised and changed later on to 
better reflect the OI population. 
Event of Special Interest 
Search Strategy 
Narrow or 
Broad Search? 
Hypocalcemia 
Hypocalcemia AMQ 
Narrow 
Hypercalcemia 
Hypercalcemia AMQ 
Narrow 
Positively adjudicated 
osteonecrosis of the jaw 
(ONJ) 
Positively adjudicated 
cases in the database 
NA 
Hypersensitivity 
Hypersensitivity SMQ 
Narrow  
Bacterial Cellulitis (skin 
infection) 
Bacterial cellulitis AMQ 
with serious criteria of 
“hospitalization” 
Narrow 
Typical OI Femur 
Fractures (TOIFF) 
Atypical femoral fractures 
AMQ 
Narrow 
In addition, Subject incidence for each adverse event of interest (EOI) will be presented 
by PT except for Positively adjudicated ONJ. Subject incidence of hypercalcemia will be 
summarized per baseline age cohort and overall. Listing of Positively adjudicated ONJ 
and typical OI femur fractures (TOIFF) will be presented. 


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9.6.2.2 
Other Safety Endpoints 
The subject incidence of the following safety events will be tabulated for all subjects on 
6-Month Dosing Regimen using 6-Month Dosing Regimen Safety Analysis Set and 
subjects who received ≥ 1 dose of 3-Month Dosing Regimen separately using 3-Month 
Dosing Regimen Safety Analysis Set.:  
 
Metaphyseal index Z-score above age-appropriate normal range 
(ie, metaphyseal index Z-score > +2) 
 
Severe or symptomatic hypocalcemia (ie. serious hypocalcemia) 
 
Abnormal molar eruption of the first or second molars 
 
Abnormal mandibular shaping 
9.6.3 
Laboratory Test Results 
Actual values and changes from baseline in each parameter will be descriptively 
summarized at each visit. For serum calcium, phosphorus and alkaline phosphatase, 
summary of the percent change from baseline will be provided as well. Shifts in 
laboratory parameters between baseline and the most extreme post-baseline values will 
be assessed based on the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE). See Appendix A. Graphical representations of serum calcium, BSAP, sCTX, 
Urine calcium may also be presented. 
All laboratory analyses will be summarized for all subjects on 6-Month Dosing Regimen 
using 6-Month Dosing Regimen Safety Analysis Set and subjects who received ≥ 1 
dose of 3-Month Dosing Regimen separately using 3-Month Dosing Regimen Safety 
Analysis Set.  
Listings of actual values, change from baseline and percent change from baseline for 
serum calcium, phosphorus and alkaline phosphatase will be provided as well for 
German substudy safety analysis set. 
Visit windows will be used for these summaries as described in Appendix C.  
9.6.3.1 Renal Clinical Laboratory Test Results (German substudy only) 
For 24-hour urine calcium and 24-hour urine phosphate the mean of all values during 
the 24-hour period will be calculated and used for analysis. 
Listing will be presented for urine calcium, including spot urine calcium-to-creatinine 
ratio and, if applicable, 24-hour urine calcium at each visit. Change from baseline and 


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percent change from baseline will also be listed for German substudy safety analysis 
set. 
Nephrocalcinosis grade and shifts from baseline, if applicable, will be listed by visit 
based on the German substudy safety analysis set. 
Visit windows will be used for these summaries as described in Appendix C. 
9.6.4 
Vital Signs 
Descriptive statistics of the actual values and changes from baseline in vital signs 
(pulse, respiration rate, temperature) will be presented by visit for all subjects on 6-
Month Dosing Regimen using 6-Month Dosing Regimen Safety Analysis Set and 
subjects who received ≥ 1 dose of 3-Month Dosing Regimen separately using 3-Month 
Dosing Regimen Safety Analysis Set. In addition, systolic and diastolic blood pressure 
will be summarized during 3-Month Dosing Regimen. 
9.6.5 
 Antidenosumab Antibodies 
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 for all subjects on 6-Month 
Dosing Regimen using 6-Month Dosing Regimen Safety Analysis Set and subjects who 
received ≥ 1 dose of 3-Month Dosing Regimen separately using 3-Month Dosing 
Regimen Safety Analysis Set.  
9.6.6 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational 
product using 3-Month Dosing Regimen Safety Analysis Set.. 
9.6.7 
Exposure to Non-investigational Product  
Not Applicable for this study 
9.6.8 
Exposure to Other Protocol-required Therapy 
Not Applicable for this study 
9.6.9 
Exposure to Concomitant Medication 
Not Applicable for this study 
9.7 
Other Analyses 
Not applicable for this study 


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9.7.1 
Pharmacokinetic/Pharmacodynamic Analysis 
The subgroups described in Section 4.2 will be used to descriptively summarize the 
serum denosumab concentrations by scheduled visit. Graphs of summary statistics by 
scheduled visit will also be produced.  
Serum denosumab concentration and bone turnover marker data collected from the PK 
substudy may be used in combination with data from other clinical studies with 
denosumab in a population PK or pharmacokinetic and pharmacodynamic (PKPD) 
analyses. The results of the analysis, if conducted, and details regarding objectives, 
data handling, and methodology will be provided in a separate population PK or PKPD 
analysis plan. 
9.7.2 
Analyses of Clinical Outcome Assessments 
Not applicable for this study 
9.7.3 
Analyses of Health Economic Endpoints 
Not applicable for this study 
9.7.4 
Analyses of Biomarker Endpoints 
Not applicable for this study 
10. 
Changes From Protocol-specified Analyses 
Removed the German substudy analysis set from section 6.4.8 as this definition 
was applicable to efficacy endpoints considering baseline and post baseline 
information for endpoint of interest. However to analyze the safety endpoints 
related German substudy the new definition is added as below in section 6.4.8, 
German substudy safery analysis set - “The subset includes all subjects in the 3-
month dosing regimen safety analysis set who enroll in the German substudy.” 
Instead of Subject incidence of abnormal mandibular shaping, we will provide 
descriptive summary statistics for mandibular shaping parameters. 
To provide the maximum incidence of fractures the Section 9.5.2.2 updated as 
follows, 
Fracture analysis will use the data as mentioned below : 
 
Vertebral Fractures : central imaging vendor i.e fractures confirmed by vendor  
 
Nonvertebral Fractures other than long bone fractures: fractures reported on 
the Clinical Fracture Summary eCRF which is confirmed by the central 
imaging vendor 


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 
Long bone Fractures : fractures reported on the Clinical Fracture Summary 
eCRF i.e fractures confirmed by imaging 
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 
Letocha AD, Cintas HL, Troendle JF, et al. Controlled trial of pamidronate in children 
with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-
term functional improvement. J Bone Miner Res. 2005;20:977-986. 
Rauch F, Munns CF, Land C, Cheung M, Glorieux FH Risedronate in the Treatment of 
Mild Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study. J 
Bone Miner Res. 2009;24:1282-1289. 
Ward LM, Rauch F, Whyte MP, et al. Alendronate for the treatment of pediatric 
osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol 
Metab. 2011;96:355-364. 
Ward K, Cowell CT and Little DG. Quantification of metaphyseal modeling in children 
treated with bisphosphonates. Bone 2005; 36: 999-1002 
12. 
Prioritization of Analyses 
Not applicable for this study 
13. 
Data Not Covered by This Plan 
Analysis for denosumab concentrations and additional pharmacokinetic analyses will 
not be described or analyzed under this plan. Pharmacokinetic and Drug metabolism 
(PKDM) group will provide a separate report for those analyses. The PKDM group will 
perform summary statistics on the serum denosumab PK samples collected in this 
study. 


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14. 
Appendices 
Appendix A. Reference Values/Toxicity Grades 
The Common Terminology Criteria for Adverse Events (CTCAE) are available at the 
following link:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03/CTCAE 4.03 2010-06-
14 QuickReference 5x7.pdf  
 
 




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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,  
6 
Behavior (5.1) 
Global Behavior Item (GBE) 
5.2 
1 
Behavior (5.2) 
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. 
 
 
 


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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 
 
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 
 


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 
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 
 
 
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 




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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: 
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. 
B.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 




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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 C.Analytical Windows 
Per protocol, all tests and procedures scheduled on Study Day 10, 30 and 60  will be 
performed ± 3 days of the scheduled day and ± 7 days for visits at Months 3, 6, 9,12 
and EOS. To allow for variations in scheduling, the following sets of visit windows will 
be used to assign evaluations to a most appropriate nominal visit for analysis. 
Furthermore, there will be no gaps between visit windows in order to include as many 
data points as possible for summarization. 
Regardless of the width of the 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. If 2 evaluations 
are of the same distance from the target day, the result from the later visit will be used. 
Results not included for analysis will be included in listings.  
Study day 1 is defined as the day of initial dose of IP administration during the 
respective dosing regimen. 
Visit Windows of 3-month dosing regimen 
Table C.1.1  Lateral Thoracic and Lumbar Spine X-ray,CHQ-PF50, CHAQ Disability 
Score, Non-vertebral Fractures, WBFPS and Armspan 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Q3M Baseline 
1 
Study Day 1 
Q3M Month 12 
366 
Study Day 2 to 458 
Q3M Month 18 
549 
After Study Day of 458 
Table C.1.2  DXA, AP Knees 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Q3M Baseline 
1 
Study Day 1 
Q3M Month 6 
183 
Study Day 2 to 275 
Q3M Month 12 
366 
Study Day 276 to 458 
Q3M Month 18 
549 
After Study Day of 458 


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Table C.1.3  Tanner stage, Physical Examination, Oral Visual Inspection, Dental 
Xray (molars), Haematology, Height, Weight, Pregnancy Test, Urine calcium, 
Denosumab Administration and Dispensation of calcium and vitamin D 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Q3M Baseline 
1 
Study Day 1 
Q3M Month 3 
92 
Study Day 2 to 138 
Q3M Month 6 
183 
Study Day 139 to 229 
Q3M Month 9 
 275 
Study Day 230 to 321 
Q3M Month 12 
366 
Study Day 322 to 412 
Q3M Month 15 
458 
Study Day 413 to 504 
Q3M Month 18a 
549 
After Study Day of 504 
aThis visit is not for Denosumab Administration and Dispensation of calcium and vitamin 
Table C.1.4 Vital Signs, Bone Turnover Marker 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Q3M Baseline 
1 
Study day 1  
Q3M Day 10 
10 
Study Day 2 to 20 
Q3M Day 30 
  
30             
Study Day 21 to 45 
Q3M Day 60 
60 
Study Day  46 to 76 
Q3M Month 3 
92 
Study Day  77 to 138 
Q3M Month 6 
183 
Study Day 139 to 229 
Q3M Month 9 
             275 
Study Day 230 to 321 
Q3M Month 12 
366 
Study Day 322 to 412 
Q3M Month 15 
458 
Study Day 413 to 504 
Q3M Month 18 
             549 
After Study Day of 504 
Table C.1.5 Serum Chemistry 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Q3M Baseline 
1 
Study day 1  
Q3M Day 10 
10 
Study Day 2 to 20 
Q3M Day 30      
30           
Study Day 21 to 61 
Q3M Month 3 
92 
Study Day  62 to 97 
Q3M Month 3 Day 10         
102 
Study Day  98 to 112 
Q3M Month 3 Day 30 
122 
Study Day 113 to 153 
Q3M Month 6 
183 
Study Day 154 to 188 
Q3M Month 6  Day 10        
193 
Study Day 189 to 203 


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Nominal Visit 
Target Day 
Window Definition (Study Day) 
Q3M Month 6  Day 30 
213 
Study Day 204 to 244 
Q3M Month 9 
            275 
Study Day 245 to 321 
Q3M Month 12 
366 
Study Day 322 to 412 
Q3M Month 15 
458 
Study Day 413 to 504 
Q3M Month 18 
             549 
After Study Day of 504 
Table C.1. 6  Cephalogram and Panoramic Radiograph 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Q3M Baseline  
1 
Last evaluation on or before Study Day 1 
Q3M Month 12 
366 
After Study Day of 2 
Table C.1.7  Renal laboratory value 
Nominal Visit                               
Target Day          
 Window Definition (Study Day) 
Q3M Baseline  
1 
Study Day 1 
Q3M Week 6 
42 
Study Day 2 to 49 
Q3M Week 8 
56 
Study Day 50 to 63 
Q3M Week 10 
70 
Study Day 64 to 77  
Q3M Week 12 
84 
Study Day 78 to 109  
Q3M Month 3 Week 6                     
134 
Study Day 110  to 141 
Q3M Month 3 Week 8 
148 
Study Day 142 to 155 
Q3M Month 3 Week 10 
162 
Study Day 156  to 169 
Q3M Month 3 Week 12 
176 
Study Day 170  to 201 
Q3M Month 6 Week 6 
225 
Study Day 202 to 232 
Q3M Month 6 Week 8 
239 
Study Day 233  to 246 
Q3M Month 6 Week 10 
253 
Study Day 247  to 260 
Q3M Month 6 Week 12 
267 
Study Day 261  to 292 
Q3M Month 9 Week 6 
317 
Study Day 293 to 324 
Q3M Month 9 Week 8 
331 
Study Day 325 to 338 
Q3M Month 9 Week 10 
345 
Study Day 339 to 352 
Q3M Month 9 Week 12 
359 
Study Day 353 to 384 
Q3M Month 12 Week 6 
408 
Study Day 385 to 415 
Q3M Month 12 Week 8 
422 
Study Day 416 to 429 
Q3M Month 12 Week 10 
436 
Study Day 430 to 443 
Q3M Month 12 Week 12 
450 
Study Day 444 to 500 
Q3M Month 18 
549 
After Study Day of 500 
 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Visit Windows of 6-month dosing regimen 
The below visit windows are applicable only for the assessments collected during 6-
month dosing regimen. For subjects transitioned to 3-month dosing regimen the upper 
bound (UB) of last visit on 6-month dosing regimen will be assigned as below. There 
will not be subsequent visits on 6-month dosing regimen for the transitioned subjects.  
UB for Month xx  minimum(UB of month xx defined in table C.2.x, (first dose date of 3-
month dosing regimen - first dose date of 6-month dosing regimen  1)). 
Table C.2.1  Lateral Thoracic and Lumbar Spine X-ray,CHQ-PF50, CHAQ Disability 
Score, Non-vertebral Fractures ,WBFPS, Oral Visual Inspection and Dental X-ray , 
Cephalogram and Panoramic Radiograph 
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 to 1278 
Table C.2.2  DXA 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline a 
1 
Last evaluation on or before Study Day 60 
Month 6 
183 
Study Day 61 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 to 1281 
a only applicable when baseline (before first dose) is missing. 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Table C.2.3  Tanner stage and X-ray AP Knees 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
-38 
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 to 1190 
Table C.2.4  Bone Turnover Marker  
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
1 
Study day 1 to 5 
Study Day 10 
10 
Study day 6 to 20 
Month 6 
183 
Study Day 21 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 to 1190 
Table C.2.5  Vital Signs, Bone Turnover Marker Substudy 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 61 
Month 3 
92 
Study day 62 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 to 1190 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Table C.2.6  Physical Examination and Haematology 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Screening 
-38 
Last evaluation on or before Study Day-1 
Baseline 
1 
Study day 1 to 5 
Month 3 
91 
Study day 6 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 to 1190 
Table C.2.7  Weight 
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 
Month 6 
183 
Study Day 6 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
Month 30 
732 
915 
Study Day 642 to 824 
Study Day 825 to1007 
Month 36 
1098 
Study Day 1008 to 1190 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Table C.2.8  Pregnancy Test,  Denosumab Administration  
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 
Month 30 
732 
915 
Study Day 642 to 824  
Study Day 825 to 1007 
 
 
  
a Only for Pregnancy Test 
Table C.2.9  Height and Armspan 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Screening 
-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 to 1190 
Table C.2.10 Renal laboratory value 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline 
-38 
Last evaluation on or before Study Day 1 
Week 6 
42 
Study Day 2  to 49 
Week 8 
56 
Study Day 50 to 63 
Week 10 
70 
Study Day 64 to 77 
Week 12 
84 
Study Day 78 to 155 
Month 6 Week 6 
225 
Study 156 to 232 
Month 6 Week 8 
239 
Study 233 to 246 
Month 6 Week 10 
253 
Study 247 to 260 
Month 6 Week 12 
267 
Study 261 to 338 
Month 12 Week 6 
408 
Study 339 to 415 
Month 12 Week 8 
422 
Study 416 to 429  
Month 12 Week 10 
436 
Study 430 to 443 
Month 12 Week 12 
450 
Study 444 to 521 
Month 18 Week 6 
591 
Study 522 to 598 
Month 18 Week 8 
605 
Study 599 to 612 
Month 18 Week 10 
619 
Study 613 to 626 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Month 18 Week 12 
633 
Study 627 to 704 
Month 24 Week 6 
774 
Study 705 to 781 
Month 24 Week 8 
788  
Study 782 to 795 
Month 24 Week 10 
802 
Study 796 to 809 
Month 24 Week 12 
816 
Study 810 to 887 
Month 30 Week 6 
957 
Study 888 to 964 
Month 30 Week 8 
971 
Study 965 to 978 
Month 30 Week 10 
985 
Study 979 to 992 
Month 30 Week 12 
999 
Study 993 to 1070 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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Appendix D.Bone Codes for Non-vertebral Fractures 
Table D1 Bone Codes for Non-vertebral 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 
 
 
 
aFrom BioClinica Charter for Independent Imaging Assessment 
 
 
 
 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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CONFIDENTIAL  
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Table D2.  Mapping Nonvertebral Fracture Locationsa 
BioClinica Location 
eCRF Locations 
Carpus 
FRACTURED CARPAL  
Cervical Vertebrae 
CERVICAL VERTEBRAL 
Clavicle 
CLAVICLE FRACTURE 
Coccyx 
FRACTURED COCCYX  
Facial 
FACIAL BONES FRACTURE 
Femur Distal 
FEMUR DISTAL FRACTURE 
Femur Intertrochanter 
FEMUR INTERTROCHANTER FRACTURE 
Femur Midshaft 
FEMUR SHAFT FRACTURE 
Femur Neck 
FEMORAL NECK FRACTURE 
Femur Subtrochanter 
FEMUR FRACTURE SUBTROCHANTERIC  
 
Fibula 
FIBULA FRACTURE 
Fibula Distal 
Fibula Proximal 
Fibula Shaft 
Finger Phalanges 
FRACTURED FINGER  
Humerus 
HUMERUS FRACTURE 
Humerus Distal 
Humerus Proximal 
Humerus Shaft 
Ilium 
ILIUM FRACTURE 
Ischium 
FRACTURED ISCHIUM  
Mandible 
FRACTURED MANDIBLE  
Metacarpus 
FRACTURED METACARPAL  
Metatarsus 
FRACTURED METATARSAL  
Other (Specify) 
-  
Patella 
PATELLA FRACTURE  
Pubis 
PUBIS FRACTURE  
Radius 
RADIUS FRACTURE  
Radius Distal 
Radius Proximal 
Radius Shaft 
Ribs 
RIB FRACTURE  
Sacrum 
FRACTURED SACRUM  
Scapula 
SCAPULA FRACTURE  
Skull 
SKULL FRACTURE  
Sternum 
STERNAL FRACTURE  
Tarsus 
FOOT FRACTURE  


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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BioClinica Location 
eCRF Locations 
Tibia 
TIBIA FRACTURE 
Tibia Distal 
Tibia Proximal 
Tibia Shaft 
Toe Phalanges 
FRACTURED TOE  
Acetabulum 
ACETABULUM   
Ulna 
ULNA FRACTURE  
Ulna Distal 
Ulna Proximal 
Ulna Shaft 
Wrist 
aFrom BioClinica Charter for Independent Imaging Assessment and eCRF Clinical 
Fracture 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
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CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020 
 
Appendix E.Code Fragment 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 75 of 79 
CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 76 of 79 
CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 77 of 79 
CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 78 of 79 
CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020 
 


Product:  AMG162 (Denosumab)  
Protocol Number:  20130173 
Date:  27 Apr 2022 
Page 79 of 79 
CONFIDENTIAL  
FORM-008180 v. 17.0, 29 April 2020