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

• ClinicalTrials.gov Identifier: NCT03164928
• Recruitment Status: Active, not recruiting
• First Posted: May 24, 2017
• Last Update Posted: December 8, 2022
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: May 8, 2017
• First Posted Date: May 24, 2017
• Last Update Posted Date: December 8, 2022
• Actual Study Start Date: May 7, 2018
• Estimated Primary Completion Date: December 13, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 22, 2017)

Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 12 months [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 1, 2021)

• Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 6, 18, 24, and 36 months. [ Time Frame: 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.
• Change from baseline in proximal femur BMD Z-score as assessed by DXA at 6, 12, 18, 24, and 36 months. [ Time Frame: 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.
• Number of participants with X-ray confirmed long-bone fractures and new and worsening vertebral fractures at 12, 24, and 36 months compared to pre-treatment [ Time Frame: 12, 24, and 36 months ]
  Number of participants with X-ray confirmed long-bone fractures and new and worsening vertebral fractures at 12, 24, and 36 months compared to pre-treatment
• Number of participants with improving vertebral fractures at 12, 24, and 36 months compared to pre-treatment [ Time Frame: 12, 24, and 36 months ]
  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)
• Number of participants with pre-treatment, post-treatment, and post-withdrawal vertebral and nonvertebral fractures at 12, 24, and 36 months compared to pre-treatment. [ Time Frame: 12, 24, and 36 months ]
  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.
• Change from baseline in CHQ-PF-50 Physical Summary Score at 12, 24, and 36 months. [ Time Frame: 12, 24, 36 months ]
  Change from baseline in CHQ-PF-50 (Childhood Health Questionnaire - Parent Form-50) Physical Summary Score at 12, 24, and 36 months
• Change from baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months [ Time Frame: 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
• Change from baseline in CHAQ Disability Index Score at 12, 24, and 36 months [ Time Frame: 12, 24, and 36 months ]
  Change from baseline in CHAQ (Childhood Health Assessment Questionnaire) Disability Index Score at 12, 24, and 36 months
• Change from baseline WBFPRS at 12, 24, and 36 months [ Time Frame: 12, 24, and 36 months ]
  Change from baseline WBFPRS (Wong-Baker Faces Pain Rating Scale) 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 [ Time Frame: 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
• Serum concentration of denosumab on Days 1, 10, and 30, and at 3, 6, 12, and 18 months [ Time Frame: 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

Original Secondary Outcome Measures (submitted: May 22, 2017)

• Change from baseline in lumbar spine BMD Z-score as assessed by DXA at 6, 18, 24, and 36 months. [ Time Frame: 6 - 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.
• Change from baseline in proximal femur BMD Z-score as assessed by DXA at 6, 12, 18, 24, and 36 months. [ Time Frame: 6 - 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.
• Subject incidence of X-ray confirmed long-bone fractures and new and worsening vertebral fractures at 12, 24, and 36 months compared to pre-treatment [ Time Frame: 12, 24, and 36 months ]
  Subject incidence of X-ray confirmed long-bone fractures and new and worsening vertebral fractures at 12, 24, and 36 months compared to pre-treatment
• Subject incidence of improving vertebral fractures at 12, 24, and 36 months compared to pretreatment [ Time Frame: 12, 24, and 36 months ]
  Subject incidence of improving vertebral fractures at 12, 24, and 36 months compared to pretreatment (overall, among subjects with clinical fracture reduction, and among subjects with clinical fracture increase)
• Subject incidence of vertebral and nonvertebral fractures at 12, 24, and 36 months compared to pretreatment. [ Time Frame: 6 - 36 months ]
  Number of subjects with vertebral and nonvertebral fractures at 12, 24, and 36 months compared to pretreatment.
• Change from baseline in CHQ-PF-50 Physical Summary Score at 12, 24, and 36 months. [ Time Frame: 6 - 36 months ]
  Change from baseline in CHQ-PF-50 (Childhood Health Questionnaire - Parent Form-50) Physical Summary Score at 12, 24, and 36 months
• Change from baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months [ Time Frame: 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
• Change from baseline in CHAQ Disability Index Score at 12, 24, and 36 months [ Time Frame: 12, 24, and 36 months ]
  Change from baseline in CHAQ (Childhood Health Assessment Questionnaire) Disability Index Score at 12, 24, and 36 months
• Change from baseline WBFPRS at 12, 24, and 36 months [ Time Frame: 12, 24, and 36 months ]
  Change from baseline WBFPRS (Wong-Baker Faces Pain Rating Scale) 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 [ Time Frame: 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
• Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, 12, and 18 months [ Time Frame: Days 1, 10, and 30, and months 3, 6, 12, and 18. ]
  Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, 12, and 18 months

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficiency of Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis
• Official Title: 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
• 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).

Detailed Description

Title: 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

Study Phase: 3 Indication: Glucocorticoid-induced Osteoporosis

Primary Objective: 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 years of age with Glucocorticoid (GC)-induced osteoporosis (GiOP).

Secondary Objective(s): To evaluate the effect of denosumab in children 5 to 17 years of age with GiOP with respect to:

• Change in lumbar spine BMD Z-score as assessed by DXA from baseline to 6, 18, 24, and 36 months
• Change in proximal femur BMD Z-score as assessed by DXA from baseline to 6, 12, 18, 24, and 36 months
• Number of participants with X-ray confirmed long-bone fractures and new and worsening vertebral fractures from pre-treatment to posttreatment at 12, 24, and 36 months
• Number of participants with improving vertebral fractures from pre-treatment to posttreatment at 12, 24, and 36 months (overall, among subjects with clinical fracture reduction, and among subjects with clinical fracture increase)
• Number of participants with pre-treatment, post-treatment, and post-withdrawal vertebral and nonvertebral fractures at 12, 24, and 36 months
• Change in Childhood Health Questionnaire - Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 months
• Change in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 months
• Change in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 months
• Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12, 24, and 36 months
• Change in growth velocity, determined by calculating age-adjusted Z-scores for height, weight, and body mass index (BMI), at 24 and 36 months
• Serum concentration of denosumab at 1 and 10 days, and 6, 12, and 18 months (additional serum denosumab pharmacokinetics [PK] samples to be collected at day 30 and month 3 in a PK/bone turnover marker [BTM] substudy of up to 15 subjects) Hypotheses: The hypothesis of this study is that the change from baseline in lumbar spine BMD Z-score following 12 months of denosumab treatment in children 5 to 17 years of age with GiOP will be greater than placebo.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Double-blind

Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Denosumab
  1mg/kg BW (up to a maximum of 60 mg) SC Q6M
• Other: Placebo
  SC Q6M placebo

Study Arms

• Placebo
  SC Q6M placebo
  Intervention: Other: Placebo
• Experimental: Denosumab
  1 mg/kg BW (up to a maximum of 60 mg) SC Q6M
  Intervention: Drug: Denosumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 11, 2021): 24
• Original Estimated Enrollment (submitted: May 22, 2017): 150
• Estimated Study Completion Date: December 13, 2023
• Estimated Primary Completion Date: December 13, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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
  • 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
• 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

  • 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
  • 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Bulgaria, Canada, Colombia, India, Italy, Mexico, Peru, Russian Federation, Turkey, Ukraine, United States
• Removed Location Countries: Korea, Republic of

Administrative Information

• NCT Number: NCT03164928
• Other Study ID Numbers: 20140444; 2016-003083-39 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• URL: https://www.amgen.com/datasharing

• Current Responsible Party: Amgen
• Original Responsible Party: Same as current
• Current Study Sponsor: Amgen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: December 2022