Safety and Efficiency of Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis

Study Overview
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Brief Summary
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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).

Official Title
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A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis

Conditions
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Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With, Glucocorticoid-induced Osteoporosis

Intervention / Treatment
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* Drug: Denosumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Placebo<br>SC Q6M placebo | Other: Placebo<br>* SC Q6M placebo<br>|
| Experimental: Denosumab<br>1 mg/kg BW (up to a maximum of 60 mg) SC Q6M | Drug: Denosumab<br>* 1mg/kg BW (up to a maximum of 60 mg) SC Q6M<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 12 months | Change from baseline in lumbar spine BMD Z-score (bone mineral density) as assessed by DXA (dual-energy X-ray absorptiometry) at 12 months. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 6, 18, 24, and 36 months. | Change from baseline in lumbar spine BMD Z-score (bone mineral density) as assessed by DXA (dual-energy X-ray absorptiometry) at 6, 18, 24, and 36 months. | 6, 18, 24, and 36 months | 
| Change from baseline in proximal femur BMD Z-score as assessed by DXA at 6, 12, 18, 24, and 36 months. | Change from baseline in proximal femur BMD Z-score (bone mineral density) as assessed by DXA (dual-energy X-ray absorptiometry) at 6, 12, 18, 24, and 36 months. | 6, 12, 18, 24, and 36 months | 
| Number of participants with X-ray confirmed long-bone fractures and new and worsening vertebral fractures during 12, 24, and 36 months | Number of participants with X-ray confirmed long-bone fractures and new and worsening vertebral fractures during 12, 24, and 36 months compared to pre-treatment | 12, 24, and 36 months | 
| Number of participants with improving vertebral fractures at 12, 24, and 36 months compared to baseline | Number of participants with improving vertebral fractures at 12, 24, and 36 months compared to pre-treatment (overall, among subjects with clinical fracture reduction, and among subjects with clinical fracture increase) | 12, 24, and 36 months | 
| Number of participants with new and worsening vertebral and nonvertebral fractures during 12, 24, and 36 months compared to pre-treatment. | Number of subjects with pre-treatment, post-treatment, and post-withdrawal vertebral and nonvertebral fractures at 12, 24, and 36 months compared to pre-treatment. | 12, 24, and 36 months | 
| Change from baseline in CHQ-PF-50 Physical Summary Score at 12, 24, and 36 months. | Change from baseline in CHQ-PF-50 (Childhood Health Questionnaire - Parent Form-50) Physical Summary Score at 12, 24, and 36 months | 12, 24, 36 months | 
| Change from baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months | Change from baseline in CHQ-PF-50 (Childhood Health Questionnaire - Parent Form-50) Psychological Summary Score at 12, 24, and 36 months | 12, 24, and 36 months | 
| Change from baseline in CHAQ Disability Index Score at 12, 24, and 36 months | Change from baseline in CHAQ (Childhood Health Assessment Questionnaire) Disability Index Score at 12, 24, and 36 months | 12, 24, and 36 months | 
| Change from baseline WBFPRS at 12, 24, and 36 months | Change from baseline WBFPRS (Wong-Baker Faces Pain Rating Scale) at 12, 24, and 36 months | 12, 24, and 36 months | 
| Change from baseline in growth velocity, determined by calculating age-adjusted Z-scores for height, weight, and Body Mass Index at 12, 24, and 36 months | Change from baseline in growth velocity, determined by calculating age-adjusted Z-scores for height, weight, and Body Mass Index at 12, 24, and 36 months | 12, 24, and 36 months | 
| Serum concentration of denosumab on Days 1, 10, and 30, and at 3, 6, 12, and 18 months | Serum concentration of denosumab on Days 1, 10, and 30, and at 3, 6, 12, and 18 months | Days 1, 10, and 30, and at 3, 6, 12, and 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Denosumab, Pediatric GIOP, Glucocorticoid-induced, Osteoporosis