Multicenter,Single-arm Study to Evaluate Efficacy, Safety... | NCT02352753

ID	Type	Description	Link
2014-000184-40	EudraCT Number

Label	Type	Description	Intervention Names
Denosumab	Experimental	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.	Drug: Denosumab

Name	Type	Description	Arm Group Labels	Other Names
Denosumab	Drug	Subcutaneous (SC) injection.	Denosumab

Measure	Description	Time Frame
Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months	Lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA) adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.	Baseline and 12 months

Measure	Description	Time Frame
Change From Baseline in Lumbar Spine BMD Z-score at 6 Months	Lumbar spine BMD was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.	Baseline and 6 months

Eligibility Module

Eligibility Criteria

• 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

Inclusion Criteria:

• Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI Clinical severity of OI as defined by 2 or more prevalent vertebral compression fractures; OR1 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:

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 age 11 to17 enrolled in the study and the first 5 subjects of any age meeting the criteria for increased bone turnover
Currently unhealed fracture or osteotomy as defined by orthopedic opinion
Osteotomy within 5 months of 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 genetic testing results inconsistent with type I to IV OI
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; re-screening 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 bythe 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 rare hereditary problems of fructose intolerance
Positive blood screen for human immunodeficiency virus -1 or -2 antibody
Positive blood screen for hepatitis B surface antigen or hepatitis C antibody
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 of screening.
Topical and inhaled glucocorticoids will be allowed
Administration of any of the following treatment within 3 months of screening:
- Growth hormone (subjects on stable dose of growth hormone for at least 3 months prior to screening will be allowed)
Currently receiving treatment in another investigational drug study, or less than 30 days since ending treatment on another investigational drugstudy(s), or current or planned participation in a clinical trial that would preclude compliance with study requirements Other inclusion/exclusion criteria may apply.

Name	Affiliation	Role
MD	Amgen	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Los Angeles	California	90027	United States
Research Site

Label	URL
AmgenTrials clinical trials website	View source

ID	Title	Description
FG000	Denosumab	Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. 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 transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 26, 2021	Oct 17, 2022

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months

Lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA) adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.

DXA Analysis Set included all participants in the FAS with Baseline and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor.

Posted

Least Squares Mean

Standard Error

Z-score

Baseline and 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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 transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.

Units	Counts
Participants	OG00045

Title

Denominators

Categories

Title	Measurements
	OG0001.009± 0.119

Secondary

Change From Baseline in Lumbar Spine BMD Z-score at 6 Months

Lumbar spine BMD was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.

DXA Analysis Set included all participants in the FAS with Baseline and Month 6 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor.

Posted

Least Squares Mean

Standard Error

Z-score

Baseline and 6 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts
Participants

Secondary

Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months

Proximal femur (total hip and femoral neck) BMD Z-score was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.

DXA Analysis Set included all participants in the FAS with Baseline, Month 6 and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor. Only participants 5 years of age or older are included.

Posted

Least Squares Mean

Standard Error

Z score

Baseline, 6 and 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts

Secondary

Percentage of Participants With at Least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture

Q3M Dosing Regimen Safety Analysis Set: includes all participants in the FAS who received ≥ 1 dose of Q3M dosing regimen.

Posted

Number

Percentage of participants

Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

ID	Title	Description
OG000	Denosumab 6-Month Dosing Regimen	Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.
OG001	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts

Secondary

Percentage of Participants With at Least 1 X-ray Confirmed New and Worsening Vertebral Fracture

The Vertebral Fracture Analysis Set: includes all participants in the FAS who had a readable non-missing baseline and ≥1 non-missing postbaseline X-ray vertebral evaluation on the Q3M dosing regimen as provided by the central imaging vendor.

Posted

Number

Percentage of participants

Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

ID	Title	Description
OG000	Denosumab 6-Month Dosing Regimen	Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.
OG001	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Secondary

Percentage of Participants With at Least 1 X-ray Confirmed New Vertebral Fracture

Posted

Number

Percentage of participants

Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

ID	Title	Description
OG000	Denosumab 6-Month Dosing Regimen	Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.
OG001	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Secondary

Percentage of Participants Wth at Least 1 X-ray Confirmed Improving Vertebral Fracture

Posted

Number

Percentage of participants

Q3M Dosing Regimen: Baseline up to 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts
Participants	OG000

Secondary

Percentage of Participants With at Least 1 Vertebral and Nonvertebral Fracture

Q3M Dosing Regimen Safety Analysis Set: includes all participants in the FAS who received ≥ 1 dose of Q3M dosing regimen. Only participants 5 years of age or older are included.

Posted

Number

Percentage of participants

Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months

ID	Title	Description
OG000	Denosumab 6-Month Dosing Regimen	Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.
OG001	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts

Secondary

Change From Baseline in Child Health Questionnaire-Parent Form Physical Summary Score (CHQ-PF-50) at 12 Months

The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A negative change from Baseline indicates decreased well-being.

Patient Reported Outcomes (PRO) Analysis Set: includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHQ-PF-50. The CHQ-PF-50 analysis set only includes participants 5 years of age and older at screening.

Posted

Mean

Standard Deviation

Score on a scale

Baseline and 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Secondary

Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12 Months

The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A positive change from Baseline indicates improved well-being.

PRO Analysis Set includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHQ-PF-50. The CHQ-PF-50 analysis set only includes participants 5 years of age and older at screening

Posted

Mean

Standard Deviation

Score on a scale

Baseline and 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units

Secondary

Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12 Months

The disability domain (questions 1-54) of the CHAQ was used to measure the participant's assessment of physical functioning or the parent's assessment of the child's physical functioning. The disability index comprised of 8 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 8 categories, the minimum score for that category was recorded as a 3. The CHAQ questions were scored and converted to a total index score ranging from 0 to 3. Negative change from Baseline indicates an improvement.

PRO Analysis Set includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHAQ disability index score.

Posted

Mean

Standard Deviation

Score on a scale

Baseline and 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Secondary

Change From Baseline in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 Months

Participants were asked to report their level of pain by choosing a face that best described their own pain (the corresponding number: 0, 2, 4, 6, 8, 10) were then recorded. The WBFPRS ranged from 0, "no hurt," to 10, "hurts worst". A negative change from baseline indicates an improvement.

Patient Reported Outcomes (PRO) Analysis Set: includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the WBFPRS.

Posted

Mean

Standard Deviation

Score on a scale

Baseline and 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts
Participants

Secondary

Serum Concentration of Denosumab

PK Analysis Set includes all participants in the 3QM dosing regimen safety analysis set who had ≥ 1 serum denosumab reported result on 3QM dosing regimen at any 1 time point.

Posted

Mean

Standard Deviation

ng/mL

Days 1 (predose), 10, 30, and 60, & weeks 12, 24, 36, 48, 60, 72 (end of study visit), early termination visit, & follow-up visit 12 weeks after last dose (average duration of treatment: 231 days)

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts
Participants	OG000

Secondary

Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide

BTM Analysis Set: includes all participants in the 3QM dosing regimen safety analysis set who had baseline and ≥ 1 postbaseline assessment for the BTM endpoint of interest on Q3M dosing regimen.

Posted

Mean

Standard Deviation

ng/L

Baseline and Days 10 and 30, and Months 3, 6, 9, 12, 15 and 18

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts
Participants	OG000

Secondary

BTM - Bone-specific Alkaline Phosphatase (BSAP)

BTM Analysis Set: includes all participants in the 3QM dosing regimen safety analysis set who had baseline and ≥ 1 postbaseline assessment for the BTM endpoint of interest on Q3M dosing regimen.

Posted

Mean

Standard Deviation

μg/L

Baseline and Days 10 and 30, and Months 3, 6, 9, 12, and 15

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Growth Velocity at 12 Months

Change from baseline in growth velocity was determined by calculating age-adjusted Z-scores for height, weight and body mass index (BMI).

Height-for-age Z-score was defined as the difference between the participant's height and the median height for the population with the same age and gender, divided by the population standard deviation.

The definitions of growth velocity based on weight and BMI were analogously calculated. 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/c c_charts.htm), and the CDC Anthropometric Software Package 3.0 Z-scores were used.

During normal growth, the change in z-score for each of the three should equal 0. A positive change in any of the three indicates growth acceleration, whereas a negative change indicates deceleration.

Growth Velocity Analysis Set includes all participants in the FAS with non-missing height, weight, or BMI, as applicable, at Baseline and postbaseline on the Q3M dosing regimen. Only participants with observed data at Baseline and Month 12 are included.

Posted

Mean

Standard Deviation

Z-score

Baseline and 12 months

ID	Title	Description
OG000	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Right ventricular dilatation	Cardiac disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Gastrointestinal pain	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
General physical health deterioration	General disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected153 at risk EG0011 affected60 at risk
Pain	General disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Procedural failure	General disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Gastroenteritis viral	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Concussion	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00015 affected153 at risk EG0012 affected60 at risk
Fibula fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0007 affected153 at risk EG0011 affected60 at risk
Foot fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Humerus fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0008 affected153 at risk EG0010 affected60 at risk
Joint dislocation	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Lumbar vertebral fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0005 affected153 at risk EG0010 affected60 at risk
Patella fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0002 affected153 at risk EG0010 affected60 at risk
Pelvic fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Post-traumatic pain	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Procedural pain	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Radius fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0005 affected153 at risk EG0011 affected60 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Scapula fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0002 affected153 at risk EG0010 affected60 at risk
Thoracic vertebral fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Tibia fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00010 affected153 at risk EG0012 affected60 at risk
Ulna fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0004 affected153 at risk EG0011 affected60 at risk
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0000 affected153 at risk EG0018 affected60 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Haemarthrosis	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Knee deformity	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Limb deformity	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0002 affected153 at risk EG0010 affected60 at risk
Osteochondrosis	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0002 affected153 at risk EG0010 affected60 at risk
Scoliosis	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Tenosynovitis	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Testis cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Complex regional pain syndrome	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Abortion complete	Pregnancy, puerperium and perinatal conditions	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Device dislocation	Product Issues	MedDRA 25.0	Systematic Assessment	EG0004 affected153 at risk EG0010 affected60 at risk
Device failure	Product Issues	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Device loosening	Product Issues	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk
Adnexal torsion	Reproductive system and breast disorders	MedDRA 25.0	Systematic Assessment	EG0001 affected153 at risk EG0010 affected60 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG00013 affected153 at risk EG0010 affected60 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0009 affected153 at risk EG0012 affected60 at risk
Dental caries	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG0009 affected153 at risk EG0011 affected60 at risk
Vomiting	Gastrointestinal disorders	MedDRA 25.0	Systematic Assessment	EG00013 affected153 at risk EG0012 affected60 at risk
Pain	General disorders	MedDRA 25.0	Systematic Assessment	EG00012 affected153 at risk EG0012 affected60 at risk
Pyrexia	General disorders	MedDRA 25.0	Systematic Assessment	EG00018 affected153 at risk EG0011 affected60 at risk
Gastroenteritis	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0008 affected153 at risk EG0010 affected60 at risk
Influenza	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG00013 affected153 at risk EG0010 affected60 at risk
Nasopharyngitis	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG00023 affected153 at risk EG0017 affected60 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 25.0	Systematic Assessment	EG0009 affected153 at risk EG0011 affected60 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00016 affected153 at risk EG0010 affected60 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00025 affected153 at risk EG0016 affected60 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00016 affected153 at risk EG0012 affected60 at risk
Fibula fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0008 affected153 at risk EG0013 affected60 at risk
Foot fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00016 affected153 at risk EG0012 affected60 at risk
Hand fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00015 affected153 at risk EG0011 affected60 at risk
Humerus fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00012 affected153 at risk EG0013 affected60 at risk
Ligament sprain	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00012 affected153 at risk EG0011 affected60 at risk
Lumbar vertebral fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00011 affected153 at risk EG0012 affected60 at risk
Post-traumatic pain	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG0006 affected153 at risk EG0013 affected60 at risk
Radius fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00014 affected153 at risk EG0012 affected60 at risk
Thoracic vertebral fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00010 affected153 at risk EG0013 affected60 at risk
Tibia fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00017 affected153 at risk EG0013 affected60 at risk
Ulna fracture	Injury, poisoning and procedural complications	MedDRA 25.0	Systematic Assessment	EG00016 affected153 at risk EG0012 affected60 at risk
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG00028 affected153 at risk EG00115 affected60 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA 25.0	Systematic Assessment	EG00015 affected153 at risk EG0016 affected60 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG00070 affected153 at risk EG00115 affected60 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG00050 affected153 at risk EG0015 affected60 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG00021 affected153 at risk EG0011 affected60 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG0008 affected153 at risk EG0010 affected60 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 25.0	Systematic Assessment	EG00057 affected153 at risk EG00111 affected60 at risk
Headache	Nervous system disorders	MedDRA 25.0	Systematic Assessment	EG00021 affected153 at risk EG0014 affected60 at risk
Hypercalciuria	Renal and urinary disorders	MedDRA 25.0	Systematic Assessment	EG00049 affected153 at risk EG0015 affected60 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG00013 affected153 at risk EG0012 affected60 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 25.0	Systematic Assessment	EG00011 affected153 at risk EG0012 affected60 at risk

ID	Term
D010009	Osteochondrodysplasias
D001848	Bone Diseases, Developmental
D001847	Bone Diseases
D009140	Musculoskeletal Diseases
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D003095	Collagen Diseases
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Denosumab 6-Month Dosing Regimen	Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.	0	153	52	153	141	153
EG001	Denosumab 3-Month Dosing Regimen	Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and PK data were analyzed. 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 transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.	0	60	12	60	38	60