Conditions: Osteogenesis Imperfecta
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 25
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the pharmacokinetics (PK) profile following multiple subcutaneous (SC) doses of romosozumab in children and adolescents with Osteogenesis Imperfecta (OI).

Detailed description:

Arms:
arm 1: Participants will receive 1 of 3 dose levels of romosozumab. All participants also received calcium and vitamin D. arm 2: Participants will receive 1 of 3 dose levels of romosozumab. All participants also received calcium and vitamin D.

Interventions: intervention 1: Romosozumab intervention 2: Calcium intervention 3: Vitamin D
Intervention descriptions: intervention 1: Participants will receive multiple doses of romosozumab via a SC injection. intervention 2: All participants will receive daily supplements of elemental calcium. intervention 3: All participants will receive daily supplementation with vitamin D.

Protocol document:
Prot_000.pdf: 
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SAP_001.pdf: 
Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 1 of 29 
CONFIDENTIAL 
FORM-008180 v. 16.0, 15 May 2019 
Statistical Analysis Plan 
Protocol Title: 
An Open-label, Ascending Multiple-dose Study to 
Evaluate Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of Romosozumab in Children 
and Adolescents With Osteogenesis Imperfecta 
Short Protocol Title: 
Enter Short Protocol Title 
Protocol Number: 
20160227 
NCT Number: 
N/A 
Authors: 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1979 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
Amendment 1 (v2.0) 
12 August 2020 
15 April 2023 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
12Aug2020 
Amendment 1 (v2.0) 
15Apr2023 
1. Section 6.4: replace the PD analysis
set with BTM analysis set. Subjects
should have least a baseline BTM
measurement of interest and at least
1 post-baseline BTM measurement of
interest.
2. Section 8.3: table 8.1 is removed.
Missing stop date of AE or CM will not
imputed. Imputation for start date of
AE or CM is outlined in Appendix B.


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 2 of 29 
CONFIDENTIAL 
FORM-008180 v. 16.0, 15 May 2019 
3. Section 9.2: The disposition of all
randomized subjects will be tabulated
by cohort is replaced with “The
disposition of all subjects will be
tabulated by cohort”.
4. Section 9.4: unit of BMI is revised to
kg/m2. (Yes, No) is removed from use
of vitamin D and calcium.
Nonvertebral fracture is added for
fracture history and the definition of
historical nonvertebral fractures is
added as well. The error reference
source for section 6.1 is addressed.
5. Section 9.5.2: add reference hyperlink
for Letocha et al, 2005, Rauch et al,
2009 and Ward et al, 2011.
6. Section 9.5.2: Graphs showing
summary statistics (actual value and
change) of BMD Z-score, and percent
change from baseline of BMD at
lumbar spine over time by visit for age
groups will be provided.
7. Section 9.6.1: Subject listing of
treatment-emergent adverse event will
be provided. summary for subject
incidence of adverse event is added.
Serious cardiovascular event will be
identified using cardiac and vascular
SOC in MedDRA and be summarized
as EOI.
8. Section 9.6.2: Graphs depicting
summary statistics (change or percent


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 3 of 29 
CONFIDENTIAL 
FORM-008180 v. 16.0, 15 May 2019 
change from baseline) for each 
parameter over time will be provided. 
9. Section 9.6.6: Shifts in severity grades
of laboratory parameters will not be
assessed. Evaluation for Hy’s Law
and definition is added.
10. Section 9.6.6: Graphs showing central
tendency and dispersion of the
absolute values and percent changes
from baseline by visit will also be
provided for the following laboratory
parameters: calcium corrected by
albumin, phosphorus and alkaline
phosphatase.
11. Section 9.6.8: Descriptive statistics
will be produced to describe the
exposure to IP by cohort is added.
12. Section 10: Shifts in laboratory
parameters between baseline and the
most extreme post baseline values
will be assessed base on Severity
Intensity Scale for Adverse Events.
However, the laboratory abnormality
with clinical significance is considered
as adverse event. Therefore, the
grade shifts in laboratory parameters
will not be conducted.
13. Appendix A: per protocol, nominal visit
Day 8 is added for 12-lead ECG and
the Day 29 in footnote is replaced with
Day 8; Day 61 is removed for vital
sign.


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 4 of 29 
CONFIDENTIAL 
FORM-008180 v. 16.0, 15 May 2019 
14. Appendix B. Handling of Dates,
Incomplete Dates and Missing Dates
is added. The imputation rules for
partial or missing start dates are
outlined.
NCT Number: NCT04545554
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 5 of 29 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
Table of Contents 
Table of Contents ................................................................................................... 5 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 9 
2.1 
Objectives and Endpoints ............................................................................ 9 
2.2 
Hypotheses and/or Estimations ................................................................. 10 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Sample Size .............................................................................................. 12 
3.3 
Adaptive Design ........................................................................................ 12 
4. 
Covariates and Subgroups ................................................................................... 12 
4.1 
Planned Covariates ................................................................................... 12 
4.2 
Subgroups ................................................................................................. 12 
5. 
Definitions ............................................................................................................. 12 
5.1 
Basic Definitions........................................................................................ 12 
5.2 
Study Points of Reference ......................................................................... 12 
5.3 
Study Dates .............................................................................................. 13 
5.4 
Study Time Intervals ................................................................................. 14 
5.5 
Subject Disposition .................................................................................... 14 
5.6 
Arithmetic Calculations .............................................................................. 14 
6. 
Analysis Sets ........................................................................................................ 15 
6.1 
Full Analysis Set........................................................................................ 15 
6.2 
Safety Analysis Set ................................................................................... 15 
6.3 
PK Analysis Set......................................................................................... 15 
6.4 
Bone Turnover Marker Analysis Subset (PD Analysis Set) ........................ 15 
6.5 
Bone Mineral Density (BMD) Analysis Set ................................................. 15 
7. 
Planned Analyses ................................................................................................. 16 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 16 
7.2 
Primary Analysis ....................................................................................... 16 
7.3 
Final Analysis ............................................................................................ 16 
8. 
Data Screening and Acceptance ........................................................................... 16 
8.1 
General Principles ..................................................................................... 16 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 16 
8.3 
Handling of Missing and Incomplete Data ................................................. 16 
8.4 
Detection of Bias ....................................................................................... 17 
8.5 
Outliers ..................................................................................................... 17 
8.6 
Distributional Characteristics ..................................................................... 17 
8.7 
Validation of Statistical Analyses ............................................................... 17 


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 6 of 29 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
9. 
Statistical Methods of Analysis.............................................................................. 18 
9.1 
General Considerations ............................................................................. 18 
9.2 
Subject Accountability ............................................................................... 18 
9.3 
Important Protocol Deviations ................................................................... 18 
9.4 
Demographic and Baseline Characteristics ............................................... 18 
9.5 
PK and Efficacy Analyses ......................................................................... 19 
9.5.1 
Analyses of Primary Endpoint(s)................................................ 19 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 19 
9.6 
Safety Analyses ........................................................................................ 19 
9.6.1 
Adverse Event ........................................................................... 19 
9.6.2 
Bone Turnover Markers ............................................................. 20 
9.6.3 
Vital Signs ................................................................................. 20 
9.6.4 
ECG .......................................................................................... 21 
9.6.5 
Physical Examinations ............................................................... 21 
9.6.6 
Safety Laboratory Tests ............................................................ 21 
9.6.7 
Anti-romosuzomab Antibodies ................................................... 22 
9.6.8 
Exposure to Investigational Product .......................................... 22 
10. 
Changes From Protocol-specified Analyses.......................................................... 22 
11. 
Literature Citations / References ........................................................................... 22 
12. 
Appendices ........................................................................................................... 23 
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ........................................................ 23 
Appendix B.  Handling of Dates, Incomplete Dates and Missing Dates ................. 27 
 
List of Table 
Table 3-1.  Planned Dose Levels ..................................................................................... 7 
Table 9-1.  Safety Laboratory Test Panel ...................................................................... 18 
 
 
List of Figures 
No table of figures entries found. 


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 7 of 29 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase 
BMC 
bone mineral content 
BMD 
bone mineral density 
BP 
bisphosphonate 
BTM 
bone turnover markers 
Cmax 
maximum-observed concentration 
CRF 
case report form 
DILI 
drug-induced liver injury 
DLRM 
DLRT 
dose level review meeting 
dose level review team 
DXA 
dual-energy X-ray absorptiometry 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IP 
investigational product 
iPTH 
Intact Parathyroid Hormone  
Kg 
kilogram 
Mg 
milligram 
P1NP 
procollagen type 1 N-terminal propeptide  
PD 
pharmacodynamic 
PI 
principal Investigator 
PK 
pharmacokinetic 


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 8 of 29 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
SC 
subcutaneous 
sCTX 
Serum type I collagen C-telopeptide 
Source Data 
Information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original 
records or certified copies).  (ICH Guideline (E6)).  Examples of 
source data include Subject identification, Randomization 
identification, and Stratification Value. 
Study Day 1 
defined as the first day that protocol specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
Tmax 
time to Cmax 
 


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 9 of 29 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
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 for study 20160227, Romosozumab  
dated 28 February 2023. The scope of this plan includes the primary analysis that is 
planned and will be executed by the Amgen Global Biostatistical Science department 
unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the pharmacokinetics 
(PK) profile following multiple SC 
doses of romosozumab in children 
and adolescents with OI 
 
Romosozumab serum PK 
parameters maximum-observed 
concentration (Cmax), time to Cmax 
(tmax), area under the curve 
(AUC), and terminal half-life (t1/2) 
Secondary 
 
To evaluate the safety, tolerability, 
and immunogenicity profile 
following multiple SC doses of 
romosozumab in children and 
adolescents with OI 
 
To evaluate the pharmacodynamic 
(PD) profile following multiple SC 
doses of romosozumab in children 
and adolescents with OI 
 
Treatment-emergent adverse 
events, including events of 
injection site reactions and 
changes in cranial nerve function 
 
Vital signs, electrocardiograms, 
physical examinations and safety 
laboratory tests, including serum 
calcium and phosphorous 
 
Incidence of antiromosozumab 
antibodies 
 
Actual value and percent change 
from baseline of bone turnover 
markers including serum P1NP 
and serum CTX measurements 
 
Actual value and percent change 
from baseline of lumbar spine 
BMD, bone mineral content 
(BMC), and bone area 
 
The percent change from baseline 
in BMD Z-score at lumbar spine 
 
 


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 10 of 29 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
2.2 
Hypotheses and/or Estimations 
Romosozumab PK and PD, including the effects on bone mineral density (BMD) and 
bone turnover markers (procollagen type 1 N-terminal propeptide [P1NP] and serum 
collagen type 1 cross-linked C-telopeptide [CTX]), will aid in the selection of the dose for 
the subsequent efficacy and safety study in pediatric subjects with OI.  Romosozumab 
will be safe and well tolerated following multiple SC dose administrations in children and 
adolescents with OI. 
3. 
Study Overview 
3.1 
Study Design 
This is a multicenter, open-label, ascending multiple-dose study to evaluate 
romosozumab in ambulatory children (5 to less than 12 years of age) and adolescents 
(12 to less than 18 years of age) with OI.       
At least 16 subjects will be enrolled into sequential cohorts 1 to 4 (4 per cohort). All 
subjects will receive a total of  SC doses of romosozumab administered every 
 
.  Subjects in cohorts 1 (12 to less than 18 years of age) and 2 (5 to less than 12 
years of age) will be administered romosozumab  mg/kg SC 
  Subjects in cohorts 3 
(12 to less than 18 years of age) and 4 (5 to less than 12 years of age) will receive 
romosozumab  mg/kg SC 
  If the exposure and PD effects are insufficient at  and 
 mg/kg, at least 4 subjects each will enroll into cohorts 5 (12 to less than 18 years of 
age) and 6 (5 to less than 12 years of age) and will receive romosozumab  mg/kg SC 
  All subjects will receive daily supplementation with calcium and vitamin D. 
The planned dose levels and cohorts are described in the below table. 
Table 3-1.  Planned Dose Levels 
Cohort # 
Age Group (years of age) 
Dose* 
Dosing Day 
N (active) 
1 
12 to less than 18 
4 
2 
5 to less than 12 
4 
3 
12 to less than 18 
4 
4 
5 to less than 12 
4 
5 (optional) 
12 to less than 18 
4 
6 (optional) 
5 to less than 12 
4 
* All doses will be administered subcutaneously 
As a precautionary measure consistent with pediatric research, dose cohorts, starting 
with the lowest dose level, will be recruited so that adolescents 12 to less than 18 years 
of age will be enrolled first (n = 4) at each dose level, before children 5 to less than 12 
years of age (n = 4) for the same dose level.   


Product:  Romosozumab 
Protocol Number:  20160227 
Date:  15 April 2023 
Page 11 of 29 
CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
A dose level review meeting (DLRM) will be held to review safety data for the purposes 
of making recommendations before escalation to the next higher dose or expansion to a 
younger age cohort.  The dose level review team (DLRT) will be composed of, at a 
minimum, the investigators actively enrolling subjects at the time of the meeting (ie, have 
subjects in screening or already enrolled), the Amgen Medical Monitor, and Amgen 
Global Safety Officer or designated safety scientist, Amgen Clinical Research Study 
Manager or designee, and biostatistics representative or designee.  Additional members 
may be added as needed (eg, PK scientist).  The DLRT voting members include the 
principal investigator or designee, Amgen Medical Monitor and Amgen Global Safety 
Officer or designee.  The DLRT voting members are responsible for making dosing 
recommendations, which may include escalation to the next planned dose, escalation to 
an intermediate dose (a dose lower than the next planned dose), de-escalation to a 
lower dose; continuation, delay, or termination of dosing; or repetition or expansion of a 
cohort.  Clear stopping rules will be followed, and ad hoc DLRMs will be held if 
necessary.  All available study data, including demographics, medical history, 
concomitant medications, adverse events, electrocardiograms, vital signs, and clinical 
laboratory test results will be reviewed.  The medical monitor will review data on an 
ongoing basis throughout the duration of the study. 
Investigators who are not actively enrolling subjects at the time of the DLRM will not 
participate in the DLRM.  They will be informed of the DLRT recommendations. 
DLRMs will take place at the following time points: 
 
DLRM 1 
o After 2 subjects in cohort 1 complete 6 weeks on study 
o DLRM 1 will enable enrollment into cohorts 2 and 3 
 
DLRM 2a 
o May be conducted if escalation to the  mg/kg dose level is deemed necessary 
based on available PK and PD data from cohorts 1 and 3   
o If necessary, DLRM 2a will be conducted after 2 subjects in cohort 3 complete 6 
weeks on study 
o DLRM 2a will enable enrollment into cohort 5 
 
DLRM 2b  
o After 2 subjects in both cohorts 2 and 3 complete 6 weeks on study 
o DLRM 2b will enable enrollment into cohort 4 
 
DLRM 3 
o May be conducted if escalation to the  mg/kg dose level is deemed necessary 
based on available PK and PD data from cohorts 1 through 4 


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o If necessary, DLRM 3 will be conducted after 2 subjects in both cohorts 4 and 5 
complete 6 weeks on study  
o 
DLRM 3 will enable enrollment in cohort 6 
3.2 
Sample Size 
The sample size is based on practical considerations. At least 16 subjects (or 24 depending on 
emerging results) will be enrolled into the study. 
3.3 
Adaptive Design 
Adaptive design is not applied in the study. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
No covariate is planned in the study. 
4.2 
Subgroups 
No subgroup analysis is planned. 
5. 
Definitions 
5.1 
Basic Definitions 
Treatment-emergent Adverse Events (TEAE)  
Adverse Events (AEs) starting on or after first dose of investigational product as 
determined by the flag indicating if the adverse event started prior to the first dose on the 
Adverse Events eCRF and up to the end of study date. 
Treatment-emergent Serious Adverse Event (TESAE) 
Treatment-emergent adverse events indicated as serious on the Events eCRF 
5.2 
Study Points of Reference 
Baseline  
The baseline measurement is defined as the last measurement prior to the first dose of 
IP. If the measurement is taken on the same day as the first dose and the exact 
measurement time relative to the first dose is unknown, it will be assumed to have been 
taken prior to the first dose of IP. If a subject does not receive IP, baseline is the closest 
recorded measurement on or prior to the enrollment date.  
Note: If baseline result from DXA assessment is not available, the results assessed on 
or before Study Day 14 will be considered baseline. 


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Study Day 1 
Day 1 is defined as the first day that investigational product is administered to the 
subject. The day before Day 1 is referenced as Day -1. 
Study Day 
Post day of dose: study day= (study date - date of study Day 1) +1 
Pre day of dose: study day= (study date – date of study Day 1) 
The day prior to the first investigational product dosing is Day -1 while the day of 
the first investigational product dose is Day 1. 
Analysis Visit 
To allow for variations in scheduling study visits, the analysis visit windows defined in 
Appendix A will be used to assign evaluations to the most appropriate nominal visit for 
analysis and summarization. 
5.3 
Study Dates 
Informed Consent Date 
The date on which a subject signed the informed consent. 
Enrollment Date 
The date of enrollment in eCRF. 
First Dose Date 
The date of administration of the first dose of IP. 
Last Dose Date 
The date of administration of last dose of IP 
End of the 
 Treatment Period Date 
The end of the 
 treatment period date is defined as the date of the last 
assessment at the 
 visit.  For subjects who discontinue from the study before 
completing the 
 visit, the end of study date is used for the end of the 
 
treatment period end date.  For those subjects who missed the 
 visit but did not 
terminate the study early, the target day 
 plus 3 days will be used as the end of 
the 
 treatment period date. 


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Start of the Follow-up Period Date 
The start of the follow-up period date is defined as the end of the 
 treatment 
period date plus one day. 
End of the Follow-up Period Date 
For subjects with non-missing start of the follow-up period date, the end of the follow-up 
period date is defined as the end of study date as recorded on the electronic case report 
form (eCRF). 
End of Study Date 
The date recorded on the End of Study electronic case report form (eCRF) 
5.4 
Study Time Intervals 
Screening Period 
The time period between the date of informed consent and first dose of IP. 
On-Study Period  
The time period from the enrollment date to the end of study date, inclusive. 
Treatment Period 
The time period from the first dose date to the end of the 
 treatment period date 
Inclusive. 
Follow-up Period 
For subjects entering in the 
 follow-up period: the time period from the start of 
follow-up period date to the end of study date, inclusive. 
5.5 
Subject Disposition 
Enrolled 
Individuals are considered enrolled when the investigator confirms that the subject has 
met all eligibility criteria (both screening and day 1 pre-dose assessments).  Enrolled 
individuals are referred to as “subjects”. 
Exposed to IP 
Subjects are considered exposed to IP if they have a value for the sum of IP volume that 
exceeds zero. 


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5.6 
Arithmetic Calculations 
Change from Baseline 
The arithmetic difference between a post-baseline value and the baseline value: 
Change (absolute) from Baseline = (post-baseline value – baseline value) 
Change (percent) from Baseline = [(post-baseline value – baseline value) / 
baseline value] x 100 
Body Mass Index (BMI) 
Body Mass Index will be calculated using the following formula: 
BMI (kg/m2) = weight (kg) / [height (cm)/100]2 
Subject Incidence for AEs 
The subject incidence for a given event in a given time period is defined as the number 
of subjects with at least 1 reported occurrence of the event divided by the number of 
subjects who are at risk for having the event at the beginning of the given time period.  
For subjects with multiple occurrences of the same event, the event will only be counted 
once per subject. 
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 
The safety analysis set (SAS) includes all subjects in the FAS who received as least 
one (1) dose of investigational product. 
6.3 
PK Analysis Set 
The PK analysis set will consist of all subjects for whom at least one (1) PK parameter or 
endpoint can be adequately estimated. 
6.4 
Bone Turnover Marker Analysis Subset (PD Analysis Set) 
The bone turnover marker analysis set will consist of all subjects for whom at 
least a baseline BTM measurement of interest and at least 1 post-baseline BTM 
measurement of interest. 


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6.5 
Bone Mineral Density (BMD) Analysis Set 
The bone mineral density (BMD) analysis set includes subjects in the FAS who have a 
baseline lumbar spine DXA BMD measurement and at least 1 post-baseline lumbar 
spine DXA BMD measurement.  
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis is planned; however, Amgen, in consultation with the investigators, 
will review all available accumulating data before making dose escalation 
recommendations. Once the data becomes available, dose-aggregate and per subject 
PK data will also be reviewed, but it will be ensured that results do not reveal individual 
treatment assignments. 
7.2 
Primary Analysis 
Please refer to Section 7.3. 
7.3 
Final Analysis 
The final analysis will occur after all subjects have completed the study. The objective of 
the final analysis is to evaluate the safety and PK data and the final analysis will be 
performed at the end of the trial. All data will be cleaned and a database lock will occur. 
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.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
The following imputation for missing or incomplete data will be performed if required: 
Non-pharmacokinetic measurements (e.g., biomarker data) that are below the lower limit 
of quantification will be considered equal to half of the lower limit of quantification for all 
analyses unless specified otherwise.  
Serum PK concentrations below the lower limit of quantifications will be set to zero for 
the estimation of the PK parameters for each subject and for the calculation of the 


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summary statistic for each time point. However, missing PK concentrations will not be 
imputed. 
No imputation will be done on incomplete stop date of an AE or a concomitant 
medication.  
Missing and incomplete start dates of an adverse event or concomitant 
medication taken will be imputed as outlined in Appendix B.  
 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort. 
Other factors that may bias the results of the study include  
 
Important protocol deviations likely to impact the tolerability, safety analysis and 
interpretation of the endpoints as well 
 
Detection of adverse events and/or serious adverse events likely to impact the 
safety analysis 
 
The timing of and reasons for early withdrawal from treatment and from study 
8.5 
Outliers 
Pharmacokinetic (PK) serum concentration data will be evaluated for outliers by visual 
inspection and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. Histograms will be examined to identify 
outliers in any of the continuous variables used in the analyses. Unexpected and/or 
unexplained values in categorical data will be identified by utilizing frequency tables. 
Outliers due to data entry errors will be corrected by the study team before final 
database lock. The validity of any questionable values or outliers will be confirmed. 
Outliers or any questionable values with confirmed validity will be included in the 
analyses. All confirmed outlier data will be included in the analyses presented in this 
statistical analysis plan unless there is sufficient scientific justification (e.g., important 
protocol deviation leading to invalid data) to exclude them. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations will be utilized. 
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.   


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Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected subject disposition, demographics, 
safety, PK, and PD end points.  Descriptive statistics on continuous measurements will 
include means, medians, standard deviations, quartiles (Q1, Q3) and minimum and 
maximum, while categorical data will be summarized using frequency counts and 
percentages. Data will be presented and summarized by cohort and visit as appropriate. 
Graphical summaries of the data may also be presented. When data are summarized by 
visit, the values recorded against the scheduled visits listed in the protocol will be used. 
When assessing minimum/maximum increases or decreases over the study, all 
assessments, including unscheduled assessments will be used. In general, data listings 
will be sorted by, dose, subject and visit unless specified otherwise. 
9.2 
Subject Accountability 
The disposition of all subjects will be tabulated by cohort. The subjects who 
received investigational product, completed investigational product, discontinued 
investigational product and reasons for discontinuing, completed study and discontinued 
study and reasons for discontinuing will be summarized in number and percentage.  
Key study dates for the first subject enrolled, last subject enrolled, last subject end of 
investigational product and the last subject end of study will be presented. 
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. 
9.4 
Demographic and Baseline Characteristics 
Demographic (ie, collected age (years), sex, race, ethnicity (Hispanic, non-Hispanic), 
body composition (height [cm], weight [kg], BMI [kg/m2])) and baseline disease 


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characteristics (ie, lumbar spine BMD, bone mineral content (BMC), bone area, and 
BMD Z-score, bone turnover markers (sCTX, P1NP), laboratory parameters (calcium 
corrected by albumin, phosphorus, creatinine, serum 25-OH vitamin D, eGFR), iPTH, 
fracture history (Any historical fracture (Yes, No), nonvertebral fracture), baseline use 
of vitamin D, baseline use of calcium, prior osteoporosis medication use (Yes, No), type 
of OI (I, II, III, and IV) will be summarized by cohort using descriptive statistics based on 
the Full Analysis Set defined in Section 6.1. 
Historical nonvertebral fractures are as reported on fracture history eCRF, 
excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar 
vertebrae, metacarpus, finger phalanges, and toe phalanges and fractures 
associated with high trauma or pathologic fractures. 
 
9.5 
PK and Efficacy Analyses 
 
9.5.1 
Analyses of Primary Endpoint(s) 
Serum romosozumab concentrations will be determined using a validated assay. 
Individual serum concentration-nialtime plots for romosozumab will be presented for 
each subject as well as mean concentration-time plots for each dose cohort. PK 
parameters will be estimated using non-compartmental methods. Actual dosing and 
sampling times will be used for calculation of PK parameters. Summary statistics will be 
generated for each PK parameter for each dose cohort. The PK analysis set will be used 
to for these analyses. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Actual value and percent change from baseline in BMD, BMC and bone area at the AP 
lumbar spine will be descriptively summarized at each visit for each dose cohort. The 
change from baseline in BMD Z-score at lumbar spine will be checked against weighted 
estimated mean (SE) of 0.01 (0.09) (95CI: -017, 0.18) based on meta-analysis from 
historical controls (Letocha et al, 2005; Rauch et al, 2009; Ward et al, 2011). Graphs 
showing summary statistics (actual value and change from baseline) of BMD Z-
score, and percent change from baseline of BMD at lumbar spine over time by 
visit for age groups will be provided. The results from the historical controls will 
contextualize the observed BMD results at the dose level review meeting. The BMD 
analysis set will be used to for these analyses. 


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9.6 
Safety Analyses 
9.6.1 
Adverse Event 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term.  
The subject incidence of adverse events will be summarized for all treatment-
emergent adverse events, serious adverse events, adverse events leading to 
withdrawal of 
investigational product, fatal adverse events, and adverse events of interest. The 
severity grade of all treatment-emergent 
adverse events will be summarized based on Severity Intensity Scale for Adverse 
Events. 
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of investigational product, and fatal adverse events 
will be tabulated by system organ class and preferred term in descending order of 
frequency. Subject listing of all treatment-emergent adverse events will also be provided. 
Subject incidence of events of interest (EOI; standardized MedDRA queries and/or 
Amgen customized queries) will also be summarized according to their categories and 
preferred term. Events of interest of hypersensitivity and malignancy will be identified 
using a narrow search/scope in standardized MedDRA queries (SMQ). Event of interest 
of hypocalcemia, injection site reaction, hyperostosis and osteoarthritis will be identified 
using Amgen-defined MedDRA search strategies. Serious cardiovascular adverse 
events will be identified using cardiac and vascular system organ class (SOC) in 
MedDRA. Adjudicated-positive adverse events of osteonecrosis of the jaw (ONJ) will 
also be summarized as EOIs. 
The number and percentage of subjects reporting adverse events will be evaluated for 
each dose cohort, across dose cohorts, and will also be tabulated by relationship to 
study drug. In addition, summary of cranial nerve examination at each visit and the result 
change from entry exam over time for each cohort will be tabulated. 
9.6.2 
Bone Turnover Markers 
Actual values and percent changes from baseline in each parameter (P1NP and sCTX) 
will be descriptively summarized for each dose cohort at each visit. Graphs depicting 


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summary statistics (change or percent change from baseline) for each parameter 
over time will be provided. The PD analysis set will be used to for the analyses. 
9.6.3 
Vital Signs 
Vital signs will be reviewed for each subject. Depending on the size and scope of 
changes, summaries of vital sign data over time and/or changes from baseline over time 
may be provided. The safety analysis set will be used to for the analyses. 
9.6.4 
ECG 
ECG data will be listed and reviewed for each subject. Depending on the size and scope 
of changes, summaries of ECG data over time and/or changes from baseline over time 
may be provided. 
9.6.5 
Physical Examinations 
Height and weight data will be reviewed for each subject.  Individual subject results will 
be examined in relation to baseline recordings.  Depending on the size and scope of 
changes in data, summaries of physical examinations data over time and/or changes 
from baseline may be provided. 
9.6.6 
Safety Laboratory Tests 
Actual values and changes from baseline in each parameter will be descriptively 
summarized each dose cohort at each visit.  For serum calcium, phosphorous, and 
magnesium, the percent change from baseline also will be provided. All laboratory 
analyses will be based on the safety analysis set. 
Graphs showing central tendency and dispersion of the absolute values and 
percent changes from baseline by visit will also be provided for the following 
laboratory parameters: calcium corrected by albumin, phosphorus and alkaline 
phosphatase. 


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Table 9-1.  Safety Laboratory Test Panel 
Laboratory: Chemistry 
Laboratory: Hematology 
albumin 
alkaline phosphatase (ALP) 
ALT (SGOT) 
AST (SGPT) 
bicarbonate (HCO3) 
direct bilirubin 
total bilirubin 
blood urea nitrogen 
creatinine 
creatine kinase 
chloride 
magnesium 
phosphorous 
potassium 
Sodium 
total protein 
glucose 
25-OH vitamin D 
iPTH 
calcium 
albumin-corrected calcium 
red blood cells  
Hemoglobin  
Hematocrit  
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH) 
mean corpuscular hemoglobin concentration 
(MCHC) 
platelet count 
white blood cells 
• total neutrophils 
• eosinophils 
• basophils 
• lymphocytes 
• monocytes 
Drug-induced liver injury will be assessed by evaluating subjects for Hy’s Law. 
Hy’s law laboratory criteria are defined as aspartate transaminase or alanine 
transaminase > 3 times upper limit of normal (ULN), total bilirubin > 2 times ULN, 
and alkaline phosphatase < 2 times ULN assessed within 7 days. 
9.6.7 
Anti-romosuzomab Antibodies 
Immunogenic response during the study will be described by tabulating the numbers and 
percentages of subjects who tested positive for (binding and neutralizing) 
anti-romosuzomab antibodies based on the safety analysis set.  
9.6.8 
Exposure to Investigational Product 
Subject listing of manufacturing lot numbers and a separate listing of unique 
manufacturing lot numbers used in this study will be provided. Details for each 
romosuzomab administration will be listed for every subject.  
Descriptive statistics will be produced to describe the exposure to IP by cohort. 


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10. 
Changes From Protocol-specified Analyses 
According to Section 10.4.3.6 in protocol version superseding amendment 3 dated 28 
February 2023, shifts in laboratory parameters between baseline and the most 
extreme post baseline values will be assessed base on the Severity Intensity 
Scale for Adverse Events. However, the laboratory abnormality with clinical 
significance is considered as adverse event. Therefore, the grade shifts in 
laboratory parameters will not be conducted.   


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11. 
Literature Citations / References 
Letocha AD, Cintas HL, Troendle JF et al. Controlled trial of pamidronate in children with 
type III and IV osteogenesis imperfecta confirms vertebral gains but not short-term 
functional improvement. Clin Trial. 2005; 20(6): 977-86. 
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(2):355-364. 


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12. 
Appendices 
Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
For the baseline assessment (excluding DXA), regardless of the width of the visit 
window, if there are multiple records within a Baseline window, the record that is the 
closest to and on or prior to Study Day 1 will be considered as the baseline value.  
For the post-baseline assessment, 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. If more 
than one evaluation on the same date, the average of the results will be used. Only 
laboratory results collected from the central laboratory will be averaged in the case of 
duplicate results. 
To allow for variations in scheduling, the following visit windows will be used to assign 
evaluations to a most appropriate nominal visit for analysis and summarization. 
Furthermore, there will be no gaps between visit windows in order to include as many 
data points as possible for summarization.  
Spine DXA Scans 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea 
1 
Last evaluation prior to or on Study Day 1 
Day 85 
85 
Study Day 2 to 127 
EOS 
169 
Study Day 128 to End of Study 
aIf results from baseline DXA are not available, the results from scans taken on or before Study Day 14 will 
be considered baseline values and not the Day 85 values.   
Physical Examination and Facial Nerve Examination 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last ealuation prior to or on Study Day 1  
Day 57 
57 
Study Day 2 to 71 
Day 85 
85 
Study Day 72 to 127 
EOS  
169 
Study Day 128 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 57.  
12-lead ECG 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to Study Day 1  
Day 8 
8 
Study Day 2 to 18 


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Day 29 
29 
Study Day 19 to 99 
EOS  
169 
Study Day 100 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 8  
Laboratory Assessments (Chemistry) 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to or on Study Day 1  
Day 8 
8 
Study Day 2 to 18 
Day 29 
29 
Study Day 19 to 43 
Day 57  
57 
Study Day 44 to 60 
Day 64 
64 
Study Day 61 to 74 
Day 85 
85 
Study Day 75 to 99 
Day 113 
113 
Study Day 100 to 141 
EOS 
169 
Study Day 142 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 8.  
Laboratory Assessments (iPTH) 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea 
1 
Last evaluation prior to or on Study Day 1  
Day 8 
8 
Study Day 2 to 18 
Day 29 
29 
Study Day 19 to 43 
Day 57  
57 
Study Day 44 to 71 
Day 85 
85 
Study Day 72 to 99 
Day 113 
113 
Study Day 100 to 141 
EOS 
169 
Study Day 142 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 8.  
Laboratory Assessments (Hematology) 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to or on Study Day 1  
Day 29 
29 
Study Day 2 to 43 
Day 57  
57 
Study Day 44 to 71 
Day 85 
85 
Study Day 72 to 127 
EOS 
169 
Study Day 128 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 29.  


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Weight 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to or on Study Day 1  
Day 29 
29 
Study Day 2 to 43 
Day 57  
57 
Study Day 44 to 113 
EOS 
169 
Study Day 114 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 29.  
Height 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to or on Study Day 1  
EOS 
169 
Study Day 2 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 169.  
Vital Signs 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to or on Study Day 1  
Day 29 
29 
Study Day 2 to 43 
Day 57  
57 
Study Day 44 to 60 
Day 64 
64 
Study Day 61 to 67 
Day 71 
71 
Study Day 68 to 78 
Day 85 
85 
Study Day 79 to 99 
Day 113 
113 
Study Day 100 to 141 
EOS 
169 
Study Day 142 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 29.  
Serum PK and BTMs (sCTX and P1NP)  
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to or on Study Day 1  
Day 8 
8 
Study Day 2 to 11 
Day 15 
15 
Study Day 12 to 22 
Day 29 
29 
Study Day 23 to 43 
Day 57  
57 
Study Day 44 to 60 
Day 64 
64 
Study Day 61 to 67 
Day 71 
71 
Study Day 68 to 78 
Day 85 
85 
Study Day 79 to 99 
Day 113 
113 
Study Day 100 to 141 
EOS 
169 
Study Day 142 to End of Study 
aAny assessment done on Study Day 1 but after the administration of the investigational product will be 
classified into Day 8.  


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Antiromosozumab Antibody Assessments 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baselinea  
1 
Last evaluation prior to or on Study Day 1  
Day 15 
15 
Study Day 2 to 22 
Day 29 
29 
Study Day 23 to 57 
Day 85 
85 
Study Day 58 to 127 
EOS 
169 
Study Day 128 to End of Study 
aAny antibody assessment done on Study Day 1 but after the administration of the investigational product 
will be classified into Day 15.  


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CONFIDENTIAL  
FORM-008180 v. 16.0, 15 May 2019 
 
Appendix B.  Handling of Dates, Incomplete Dates and Missing Dates 
Imputation Rules for Partial or Missing Start Dates 
The reference date for the following rules is the date of first dose of study drug. 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1=Impute the date of first dose; 2=Impute the first of the month; 3=Impute January 1 of the year; 4=Impute 
January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Death Dates 
Incomplete or missing death dates will not be imputed.