Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI

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

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

Official Title
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To Evaluate the Effect of Denosumab in Lumbar Spine Bone Mineral Density (BMD) Z-score at 12 Months, as Assessed by Dual-energy X-ray Absorptiometry (DXA), in Children 2 to 17 Years of Age (at the Time of Screening) on a 3-Month Dosing Regimen With OI

Conditions
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Osteogenesis Imperfecta

Intervention / Treatment
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* Drug: Denosumab


Participation Criteria
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Eligibility Criteria
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• 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.

Ages Eligible for Study
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Minimum Age: 2 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br>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<br>* Subcutaneous (SC) injection.<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 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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. | Baseline, 6 and 12 months | 
| Percentage of Participants With at Least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture |  | Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months | 
| Percentage of Participants With at Least 1 X-ray Confirmed New and Worsening Vertebral Fracture |  | Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months | 
| Percentage of Participants With at Least 1 X-ray Confirmed New Vertebral Fracture |  | Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months | 
| Percentage of Participants Wth at Least 1 X-ray Confirmed Improving Vertebral Fracture |  | Q3M Dosing Regimen: Baseline up to 12 months | 
| Percentage of Participants With at Least 1 Vertebral and Nonvertebral Fracture |  | Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months | 
| 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. | Baseline and 12 months | 
| 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. | Baseline and 12 months | 
| 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. | Baseline and 12 months | 
| 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. | Baseline and 12 months | 
| Serum Concentration of Denosumab |  | 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) | 
| Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide |  | Baseline and Days 10 and 30, and Months 3, 6, 9, 12, 15 and 18 | 
| BTM - Bone-specific Alkaline Phosphatase (BSAP) |  | Baseline and Days 10 and 30, and Months 3, 6, 9, 12, and 15 | 
| 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. | Baseline and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amgen, OI, Bone