Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With, Glucocorticoid-induced Osteoporosis
Conditions
Keywords
Denosumab, Pediatric GIOP, Glucocorticoid-induced, Osteoporosis
Brief summary
To evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) Z-score as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in children 5 to 17 year of age with Glucocorticoid (GC)-induced osteoporosis (GiOP).
Interventions
DRUGDenosumab
1mg/kg BW (up to a maximum of 60 mg) SC Q6M
OTHERPlacebo
SC Q6M placebo
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects, age 5 to 17 years, inclusive, at the time of informed consent. * Clinical diagnosis of GiOP as defined by the following (and consistent with the International Society for Clinical Densitometry definition of osteoporosis in children and adolescents \[Bishop et al, 2014\]) * A confirmed diagnosis of non-malignant condition(s) requiring treatment with systemic GC (including, but not limited to, chronic rheumatologic, gastrointestinal, neurologic, respiratory, and/or nephrological conditions) * Subjects who are on systemic GC only as replacement therapy for adrenal insufficiency are not eligible for the study - Treatment with systemic GC (intravenous or oral) of any duration for the underlying non-malignant condition(s) within the 12 months prior to screening * Evidence of at least 1 vertebral compression fracture of Genant grade 1 or higher, as assessed by the central imaging vendor on lateral spine X-rays performed at screening or within 2 months prior to screening; OR, in the absence of vertebral compression fractures, presence of both clinically significant fracture history (ie, ≥ 2 long-bone fractures by age 10 years or ≥ 3 long-bone fractures at any age up to 17 years) and lumbar spine BMD Z-score ≤ -2.0, as assessed by the central imaging vendor. • Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated * A confirmed diagnosis of non-malignant condition(s) requiring treatment with systemic GC (including, but not limited to, chronic rheumatologic, gastrointestinal, neurologic, respiratory, and/or nephrological conditions) * Subjects who are on systemic GC only as replacement therapy for adrenal insufficiency are not eligible for the study * Treatment with systemic GC (intravenous or oral) of any duration for the underlying non malignant condition(s) within the 12 months prior to screening * Prepubertal children should be expected to require significant GC use during the study, per investigator opinion
Exclusion criteria
will include the following: * Current hyperthyroidism (unless well controlled on stable antithyroid therapy) * Current clinical hypothyroidism (unless well controlled on stable thyroid replacement therapy) * History of hyperparathyroidism * Current hypoparathyroidism * Duchenne muscular dystrophy with symptomatic cardiac abnormality * Current malabsorption * Active infection or history of infections * History of malignancy * Any causes of primary or secondary osteoporosis (other than GC use), or previous exposure to non-GC medications, which the investigator considers to have been a major factor contributing to the patient's fracture(s) * Current adrenal insufficiency as the sole indication for GC therapy * Duchenne muscular dystrophy with symptomatic cardiac abnormality * Current malabsorption (in children with serum albumin -lower limit of normal \[LLN\], malabsorption should be clinically ruled out by the investigator to confirm eligibility) * Known intolerance to calcium or vitamin D supplements * Active infection or history of infections, defined as follows: * Any active infection for which systemic anti-infectives were used within 4 weeks prior to screening * Serious infection, defined as requiring hospitalization or intravenous anti infectives within 8 weeks prior to screening * Recurrent or chronic infection or other active infection that, in the opinion of the investigator, might compromise the safety of the subject
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Lumbar Spine BMD Z-score as Assessed by Dual-energy X-ray Absorptiometry (DXA) at 12 Months | Baseline and 12 Months | Lumbar spine BMD was assessed by DXA and analyzed by analysis of covariance (ANCOVA) including treatment (denosumab vs placebo), baseline age, and baseline BMD z-score. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Baseline and 6, 12, 18, 24, and 36 Months | Proximal femur (total hip and femoral neck) BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify proximal femur BMD improvement. |
| Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 12, 24, and 36 | Number of participants who have at least one long bone fracture or vertebral fracture, and number of participants who have more than one long bone fracture or vertebral fracture. |
| Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months | Month 12, 24, and 36 | Number of participants with improving vertebral fractures. An improving fracture is defined as one showing signs of healing/repair from baseline as assessed by X-ray. |
| Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 12, 24, and 36 | Number of participants who have at least one vertebral fracture or non-vertebral fracture, and number of participants who have more than one vertebral fracture or non-vertebral fracture. |
| Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months | Baseline and month 12, 24, and 36 | The CHQ-PF-50 is a 50-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The physical summary score ranges from 0-100 with higher scores indicating better physical health. |
| Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months | Baseline and Month 12, 24, and 36 | The CHQ-PF-50 is a 50-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The psychological summary score ranges from 0-100 with higher scores indicating better psychological health. |
| Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Baseline and 6, 18, 24, and 36 Months | Lumbar spine BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement. |
| Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months | Baseline and Month 12, 24, and 36 | The WBFPRS is a horizontal pain scale for children 3-18 years which consists of 6 faces that range from a smiling no hurt face with a score of 0 to a crying hurts worst face with a score of 10. |
| Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months | Baseline and Month 12, 24, and 36 | Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and body mass index (BMI). Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity. |
| Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months | Baseline and Month 12, 24, and 36 | Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity. |
| Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months | Baseline and Month 12, 24, and 36 | Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity. |
| Mean Serum Concentration of Denosumab | Day 1, Day 10, Day 30, Month 3, Month 6, Month 12, and Month 18 | — |
| Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months | Baseline and Month 12, 24, and 36 | The CHAQ was developed to measure the physical functioning in children 6 months to 18 years of age. It consists of 54 questions related to the child's ability to perform various activities of daily living. Depending on the question asked, each question is scored either 0 to 3 based on the level of difficulty experienced by the child or 0-1 based on whether the child required assistance from another person or used an aid or other device. All CHAQ questions were scored and converted to a total index score ranging from 0-3, where higher scores indicate greater disability. |
Countries
Australia, Belgium, Bulgaria, Canada, Colombia, India, Italy, Mexico, Peru, Russia, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
This study was conducted at 12 center(s) in Australia, Canada, Columbia, India, Peru, Russia, Turkey, Ukraine, and the United States between May 2018 and December 2023.
Pre-assignment details
Participants were randomized in a 2:1 allocation ratio to receive either denosumab or placebo respectively, in a double-blind manner during the 12-month placebo-controlled double-blind Treatment Period. This was followed by a 12-month denosumab Open-label Treatment Period and a 12-month Off-treatment Observation Period.
Participants by arm
| Arm | Count |
|---|---|
| Denosumab/Denosumab Participants received 1 mg/kg Denosumab by SC injection up to a maximum of 60 mg, Q6M for 24 months during the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period. | 16 |
| Placebo/Denosumab Participants received matching placebo by SC injection Q6M for the first 12 months of the Treatment Period. This was followed by 1 mg/kg Denosumab administered by SC injection, up to a maximum of 60 mg, Q6M for the second 12 months of the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period. | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo/Denosumab | Denosumab/Denosumab |
|---|---|---|---|
| Age, Continuous | 13.4 Years STANDARD_DEVIATION 2.2 | 12.8 Years STANDARD_DEVIATION 2.1 | 13.8 Years STANDARD_DEVIATION 2.3 |
| Bone Mineral Density (BMD) Z-score at Baseline Femoral Neck | -3.79 Z-score STANDARD_DEVIATION 2.25 | -4.78 Z-score STANDARD_DEVIATION 2.8 | -3.35 Z-score STANDARD_DEVIATION 1.91 |
| Bone Mineral Density (BMD) Z-score at Baseline Lumbar Spine | -2.50 Z-score STANDARD_DEVIATION 1.51 | -3.60 Z-score STANDARD_DEVIATION 1.77 | -1.95 Z-score STANDARD_DEVIATION 1.03 |
| Bone Mineral Density (BMD) Z-score at Baseline Total Hip | -3.58 Z-score STANDARD_DEVIATION 1.9 | -4.56 Z-score STANDARD_DEVIATION 2.08 | -3.14 Z-score STANDARD_DEVIATION 1.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 5 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Female | 10 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 14 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 16 | 0 / 8 | 0 / 16 | 0 / 8 | 0 / 16 |
| other Total, other adverse events | 5 / 8 | 11 / 16 | 5 / 8 | 12 / 16 | 5 / 8 | 13 / 16 |
| serious Total, serious adverse events | 1 / 8 | 3 / 16 | 1 / 8 | 3 / 16 | 2 / 8 | 4 / 16 |
Outcome results
Primary
Change From Baseline in Lumbar Spine BMD Z-score as Assessed by Dual-energy X-ray Absorptiometry (DXA) at 12 Months
Lumbar spine BMD was assessed by DXA and analyzed by analysis of covariance (ANCOVA) including treatment (denosumab vs placebo), baseline age, and baseline BMD z-score. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement.
Time frame: Baseline and 12 Months
Population: Primary DXA Analysis Set: all participants in the FAS with baseline and ≥ 1 postbaseline valid DXA assessment of lumbar spine provided by the central imaging vendor during the first 12 months.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by Dual-energy X-ray Absorptiometry (DXA) at 12 Months | 0.23 Z-score |
| Placebo/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by Dual-energy X-ray Absorptiometry (DXA) at 12 Months | 0.11 Z-score |
p-value: 0.6895% CI: [-0.45, 0.673]ANCOVA
Secondary
Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months
The CHQ-PF-50 is a 50-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The physical summary score ranges from 0-100 with higher scores indicating better physical health.
Time frame: Baseline and month 12, 24, and 36
Population: Patient Reported Outcomes (PRO) Analysis Set: all participants in the FAS with baseline and at least one valid CHQ-PF-50 response at post-baseline. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months | Month 12 | 5.26 Scores on a scale | Standard Deviation 8.88 |
| Denosumab/Denosumab | Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months | Month 24 | 5.62 Scores on a scale | Standard Deviation 7.39 |
| Denosumab/Denosumab | Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months | Month 36 | 4.48 Scores on a scale | Standard Deviation 8.89 |
| Placebo/Denosumab | Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months | Month 12 | 8.53 Scores on a scale | Standard Deviation 16.39 |
| Placebo/Denosumab | Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months | Month 24 | 19.88 Scores on a scale | Standard Deviation 15.2 |
| Placebo/Denosumab | Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months | Month 36 | 14.18 Scores on a scale | Standard Deviation 8.14 |
Secondary
Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months
The CHAQ was developed to measure the physical functioning in children 6 months to 18 years of age. It consists of 54 questions related to the child's ability to perform various activities of daily living. Depending on the question asked, each question is scored either 0 to 3 based on the level of difficulty experienced by the child or 0-1 based on whether the child required assistance from another person or used an aid or other device. All CHAQ questions were scored and converted to a total index score ranging from 0-3, where higher scores indicate greater disability.
Time frame: Baseline and Month 12, 24, and 36
Population: PRO Analysis Set: all participants in the FAS with baseline and at least one valid CHAQ response at post-baseline. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months | Month 12 | -0.06 Scores on a scale | Standard Deviation 0.32 |
| Denosumab/Denosumab | Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months | Month 24 | -0.09 Scores on a scale | Standard Deviation 0.33 |
| Denosumab/Denosumab | Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months | Month 36 | -0.12 Scores on a scale | Standard Deviation 0.45 |
| Placebo/Denosumab | Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months | Month 12 | -0.29 Scores on a scale | Standard Deviation 0.44 |
| Placebo/Denosumab | Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months | Month 24 | -0.30 Scores on a scale | Standard Deviation 0.49 |
| Placebo/Denosumab | Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months | Month 36 | -0.43 Scores on a scale | Standard Deviation 0.45 |
Secondary
Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months
The CHQ-PF-50 is a 50-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The psychological summary score ranges from 0-100 with higher scores indicating better psychological health.
Time frame: Baseline and Month 12, 24, and 36
Population: PRO Analysis Set: all participants in the FAS with baseline and at least one valid CHQ-PF-50 response at post-baseline. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months | Month 12 | 0.71 Scores on a scale | Standard Deviation 9.15 |
| Denosumab/Denosumab | Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months | Month 24 | 2.58 Scores on a scale | Standard Deviation 12.58 |
| Denosumab/Denosumab | Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months | Month 36 | 5.20 Scores on a scale | Standard Deviation 10.09 |
| Placebo/Denosumab | Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months | Month 12 | -0.10 Scores on a scale | Standard Deviation 12.52 |
| Placebo/Denosumab | Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months | Month 24 | 1.90 Scores on a scale | Standard Deviation 9.76 |
| Placebo/Denosumab | Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months | Month 36 | 2.00 Scores on a scale | Standard Deviation 9.33 |
Secondary
Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months
Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity.
Time frame: Baseline and Month 12, 24, and 36
Population: Growth Velocity Analysis Set: all participants in the FAS who have non-missing BMI and age in total months at baseline and postbaseline. Only participants with available data for growth velocity (BMI) are included. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months | Month 12 | -0.03 Z-score | Standard Deviation 0.53 |
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months | Month 24 | -0.12 Z-score | Standard Deviation 0.8 |
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months | Month 36 | -0.12 Z-score | Standard Deviation 0.84 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months | Month 12 | -0.14 Z-score | Standard Deviation 0.54 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months | Month 24 | -0.75 Z-score | Standard Deviation 1.02 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months | Month 36 | -0.72 Z-score | Standard Deviation 0.97 |
Secondary
Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months
Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and body mass index (BMI). Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity.
Time frame: Baseline and Month 12, 24, and 36
Population: Growth Velocity Analysis Set: all participants in the FAS who have non-missing height and age in total months at baseline and postbaseline. Only participants with available data for growth velocity (height) are included. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months | Month 12 | -0.18 Z-score | Standard Deviation 0.46 |
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months | Month 24 | -0.11 Z-score | Standard Deviation 0.9 |
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months | Month 36 | -0.33 Z-score | Standard Deviation 0.84 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months | Month 12 | -0.07 Z-score | Standard Deviation 0.84 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months | Month 24 | -0.27 Z-score | Standard Deviation 1.17 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months | Month 36 | 0.01 Z-score | Standard Deviation 1.35 |
Secondary
Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months
Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity.
Time frame: Baseline and Month 12, 24, and 36
Population: Growth Velocity Analysis Set: all participants in the FAS who have non-missing weight and age in total months at baseline and postbaseline. Only participants with available data for growth velocity (weight) are included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months | Month 12 | -0.12 Z-score | Standard Deviation 0.44 |
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months | Month 24 | -0.22 Z-score | Standard Deviation 0.73 |
| Denosumab/Denosumab | Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months | Month 36 | -0.32 Z-score | Standard Deviation 0.9 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months | Month 12 | -0.10 Z-score | Standard Deviation 0.49 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months | Month 24 | -0.68 Z-score | Standard Deviation 0.62 |
| Placebo/Denosumab | Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months | Month 36 | -0.44 Z-score | Standard Deviation 0.6 |
Secondary
Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months
Lumbar spine BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement.
Time frame: Baseline and 6, 18, 24, and 36 Months
Population: DXA Analysis Set: all participants in the FAS with baseline and ≥ 1 postbaseline valid DXA assessment for lumbar spine as provided by the central imaging vendor. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 6 | 0.28 Z-score |
| Denosumab/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 18 | 0.32 Z-score |
| Denosumab/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 24 | 0.37 Z-score |
| Denosumab/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 36 | -0.23 Z-score |
| Placebo/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 36 | 0.57 Z-score |
| Placebo/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 6 | 0.11 Z-score |
| Placebo/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 24 | 0.26 Z-score |
| Placebo/Denosumab | Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months | Month 18 | 0.30 Z-score |
Comparison: Month 6p-value: 0.3495% CI: [-0.194, 0.542]Repeated Measures Model
Comparison: Month 18p-value: 0.9395% CI: [-0.609, 0.661]Repeated Measures Model
Comparison: Month 24p-value: 0.7495% CI: [-0.572, 0.795]Repeated Measures Model
Comparison: Month 36p-value: 0.1295% CI: [-1.848, 0.239]Repeated Measures Model
Secondary
Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months
Proximal femur (total hip and femoral neck) BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify proximal femur BMD improvement.
Time frame: Baseline and 6, 12, 18, 24, and 36 Months
Population: DXA Analysis Set: all participants in the FAS with baseline and ≥ 1 postbaseline valid DXA assessment for total hip and femoral neck as provided by the central imaging vendor.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 18 (Femoral Neck) | 0.85 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 24 (Femoral Neck) | 0.75 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 6 (Total Hip) | 0.22 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 12 (Total Hip) | 0.24 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 18 (Total Hip) | 0.48 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 24 (Total Hip) | 0.52 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 36 (Total Hip) | 0.64 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 6 (Femoral Neck) | 0.42 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 12 (Femoral Neck) | 0.53 Z-score |
| Denosumab/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 36 (Femoral Neck) | 1.00 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 18 (Femoral Neck) | 0.48 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 36 (Total Hip) | 0.73 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 24 (Femoral Neck) | 0.64 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 6 (Total Hip) | 0.64 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 6 (Femoral Neck) | 0.60 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 12 (Total Hip) | 0.30 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 36 (Femoral Neck) | 0.63 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 18 (Total Hip) | 0.75 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 12 (Femoral Neck) | 0.43 Z-score |
| Placebo/Denosumab | Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months | Month 24 (Total Hip) | 0.69 Z-score |
Comparison: Month 12 (Femoral Neck)p-value: 0.8395% CI: [-0.808, 1]Repeated Measures Model
Comparison: Month 36 (Total Hip)p-value: 0.8995% CI: [-1.465, 1.286]Repeated Measures Model
Comparison: Month 6 (Femoral Neck)p-value: 0.6495% CI: [-0.969, 0.614]Repeated Measures Model
Comparison: Month 6 (Total Hip)p-value: 0.1995% CI: [-1.05, 0.223]Repeated Measures Model
Comparison: Month 12 (Total Hip)p-value: 0.8395% CI: [-0.631, 0.515]Repeated Measures Model
Comparison: Month 18 (Total Hip)p-value: 0.5195% CI: [-1.108, 0.565]Repeated Measures Model
Comparison: Month 24 (Total Hip)p-value: 0.6995% CI: [-1.098, 0.746]Repeated Measures Model
Comparison: Month 18 (Femoral Neck)p-value: 0.4895% CI: [-0.697, 1.442]Repeated Measures Model
Comparison: Month 24 (Femoral Neck)p-value: 0.8695% CI: [-1.222, 1.443]Repeated Measures Model
Comparison: Month 36 (Femoral Neck)p-value: 0.6695% CI: [-1.378, 2.13]Repeated Measures Model
Secondary
Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months
The WBFPRS is a horizontal pain scale for children 3-18 years which consists of 6 faces that range from a smiling no hurt face with a score of 0 to a crying hurts worst face with a score of 10.
Time frame: Baseline and Month 12, 24, and 36
Population: PRO Analysis Set: all participants in the FAS with baseline and at least one valid WBFPRS response at post-baseline. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months | Month 12 | -0.7 Scores on a scale | Standard Deviation 3.3 |
| Denosumab/Denosumab | Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months | Month 24 | -0.6 Scores on a scale | Standard Deviation 2.9 |
| Denosumab/Denosumab | Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months | Month 36 | -2.5 Scores on a scale | Standard Deviation 1.8 |
| Placebo/Denosumab | Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months | Month 12 | -0.3 Scores on a scale | Standard Deviation 3.9 |
| Placebo/Denosumab | Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months | Month 24 | -2.4 Scores on a scale | Standard Deviation 0.9 |
| Placebo/Denosumab | Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months | Month 36 | 0.0 Scores on a scale | Standard Deviation 1.4 |
Secondary
Mean Serum Concentration of Denosumab
Time frame: Day 1, Day 10, Day 30, Month 3, Month 6, Month 12, and Month 18
Population: PK Analysis Set: all participants in the FAS who have ≥ 1 denosumab reported result.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denosumab/Denosumab | Mean Serum Concentration of Denosumab | Month 18 | 49 ng/mL | Standard Deviation 154 |
| Denosumab/Denosumab | Mean Serum Concentration of Denosumab | Day 1 | 0.00 ng/mL | Standard Deviation 0 |
| Denosumab/Denosumab | Mean Serum Concentration of Denosumab | Day 10 | 10300 ng/mL | Standard Deviation 7900 |
| Denosumab/Denosumab | Mean Serum Concentration of Denosumab | Day 30 | 6830 ng/mL | Standard Deviation 4770 |
| Denosumab/Denosumab | Mean Serum Concentration of Denosumab | Month 3 | 1100 ng/mL | Standard Deviation 935 |
| Denosumab/Denosumab | Mean Serum Concentration of Denosumab | Month 6 | 141 ng/mL | Standard Deviation 338 |
| Denosumab/Denosumab | Mean Serum Concentration of Denosumab | Month 12 | 157 ng/mL | Standard Deviation 349 |
| Placebo/Denosumab | Mean Serum Concentration of Denosumab | Month 18 | 7.61 ng/mL | Standard Deviation 21.5 |
| Placebo/Denosumab | Mean Serum Concentration of Denosumab | Month 12 | 0.00 ng/mL | Standard Deviation 0 |
Secondary
Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months
Number of participants with improving vertebral fractures. An improving fracture is defined as one showing signs of healing/repair from baseline as assessed by X-ray.
Time frame: Month 12, 24, and 36
Population: Vertebral Fracture Analysis Set: all participants in the FAS who have a non-missing baseline and ≥ 1 non-missing postbaseline X-ray vertebral evaluation as provided by the central imaging vendor, on or before the time point under consideration.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Denosumab/Denosumab | Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months | Month 36 | 1 Participants |
| Denosumab/Denosumab | Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months | Month 12 | 3 Participants |
| Denosumab/Denosumab | Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months | Month 24 | 2 Participants |
| Placebo/Denosumab | Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months | Month 12 | 1 Participants |
| Placebo/Denosumab | Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months | Month 24 | 1 Participants |
| Placebo/Denosumab | Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months | Month 36 | 2 Participants |
Secondary
Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months
Number of participants who have at least one vertebral fracture or non-vertebral fracture, and number of participants who have more than one vertebral fracture or non-vertebral fracture.
Time frame: Month 12, 24, and 36
Population: FAS: all participants randomized into the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Denosumab/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 12 (at least 1 fracture) | 2 Participants |
| Denosumab/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 24 (at least 1 fracture) | 3 Participants |
| Denosumab/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 36 (at least 1 fracture) | 3 Participants |
| Denosumab/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 12 (more than 1 fracture) | 2 Participants |
| Denosumab/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 24 (more than 1 fracture) | 2 Participants |
| Denosumab/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 36 (more than 1 fracture) | 3 Participants |
| Placebo/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 24 (more than 1 fracture) | 0 Participants |
| Placebo/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 12 (at least 1 fracture) | 2 Participants |
| Placebo/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 12 (more than 1 fracture) | 1 Participants |
| Placebo/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 24 (at least 1 fracture) | 3 Participants |
| Placebo/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 36 (more than 1 fracture) | 1 Participants |
| Placebo/Denosumab | Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months | Month 36 (at least 1 fracture) | 3 Participants |
Secondary
Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months
Number of participants who have at least one long bone fracture or vertebral fracture, and number of participants who have more than one long bone fracture or vertebral fracture.
Time frame: Month 12, 24, and 36
Population: FAS: all participants randomized into the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Denosumab/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 24 (at least 1 fracture) | 3 Participants |
| Denosumab/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 12 (more than 1 fracture) | 2 Participants |
| Denosumab/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 24 (more than 1 fracture) | 2 Participants |
| Denosumab/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 12 (at least 1 fracture) | 2 Participants |
| Denosumab/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 36 (more than 1 fracture) | 3 Participants |
| Denosumab/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 36 (at least 1 fracture) | 3 Participants |
| Placebo/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 36 (more than 1 fracture) | 1 Participants |
| Placebo/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 12 (at least 1 fracture) | 2 Participants |
| Placebo/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 24 (at least 1 fracture) | 3 Participants |
| Placebo/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 36 (at least 1 fracture) | 3 Participants |
| Placebo/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 24 (more than 1 fracture) | 0 Participants |
| Placebo/Denosumab | Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months | Month 12 (more than 1 fracture) | 1 Participants |