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

• ClinicalTrials.gov Identifier: NCT02352753
• Recruitment Status: Active, not recruiting
• First Posted: February 2, 2015
• Last Update Posted: December 10, 2020
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: January 28, 2015
• First Posted Date: February 2, 2015
• Last Update Posted Date: December 10, 2020
• Actual Study Start Date: June 24, 2015
• Estimated Primary Completion Date: January 9, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 20, 2020)

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

Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 12 months in subjects receiving the 3-Month Dosing Regimen

Original Primary Outcome Measures (submitted: January 28, 2015)

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

Change in lumbar spine BMD Z-score, as assessed by DXA,

Current Secondary Outcome Measures (submitted: May 20, 2020)

• Change in lumbar spine BMD Z-score, as assessed by DXA, at 6 months [ Time Frame: 6 months ]
  Change in lumbar spine BMD Z-score, as assessed by DXA, at 6 months in subjects receiving the 3-Month Dosing Regimen
• Change in proximal femur BMD Z-score, as assessed by DXA [ Time Frame: 6 and 12 months ]
  Change in proximal femur BMD Z-score, as assessed by DXA, at 6 and 12 months (in subjects 5 years of age and older) in subjects receiving the 3-Month Dosing Regimen
• Incidence of new and worsening fractures (X-ray confirmed long bone and vertebral [ Time Frame: 12 months ]
  Incidence of X-ray confirmed long bone and new and worsening vertebral fractures from pretreatment (on 6-Month Dosing Regimen to post-treatment on 3-Month Dosing Regimen at 12 months)
• Incidence of improving vertebral fractures from pre-treatment to post-treatment [ Time Frame: 12 months ]
  Subject incidence of improving vertebral fractures from pretreatment on 6-Month Dosing Regimen to post-treatment on 3-Month Dosing Regimen at 12 months
• Incidence of pre-treatment compared with post-treatment vertebral and nonvertebral [ Time Frame: 12 months ]
  Incidence of vertebral and nonvertebral fractures from pretreatment on 6-Month Dosing Regimen to post-treatment on 3-Month Dosing Regimen at 12 months
• Change in Child Health Questionnaire (CHQ)-Parent Form (PF)-50 Physical Summary [ Time Frame: 12 months ]
  Change from baseline in CHQ-PF-50 Physical Summary score at 12 months in subjects receiving the 3-Month Dosing Regimen
• Change in CHQ-PF-50 Psychological Summary score [ Time Frame: 12 months ]
  Change from baseline in CHQ-PF-50 Psychological Summary score at 12 months in subjects receiving the 3-Month Dosing Regimen
• Childhood Health Assessment Questionnaire (CHAQ) Disability Index score [ Time Frame: 12 Months ]
  Change from baseline in CHAQ Disability Index score at 12 months in subjects receiving the 3-Month Dosing Regimen
• Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) [ Time Frame: 12 months ]
  Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 months in subjects receiving the 3-Month Dosing Regimen
• Serum concentration of denosumab [ Time Frame: 10, 30, and 60 days and every 3 months ]
  Serum concentration of denosumab and serum bone turnover markers on days 1, 10, 30, 60, and every 3 months in subjects on 3-Month Dosing Regimen
• Change in growth velocity at 12 months [ Time Frame: 12 months ]
  Change from baseline in growth velocity (determined by calculating age-adjusted Z-scores for height, weight and body mass index [BMI]) at 12 months in subjects receiving the 3-Month Dosing Regimen
• Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, and 9 months [ Time Frame: 1, 10, and 30 days, and 3, 6, and 9 months ]
  Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, and 9 months (PK/BTM substudy; 6-Month Dosing Regimen)

Original Secondary Outcome Measures (submitted: January 28, 2015)

• Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 6, 18, 24, [ Time Frame: 6.18,24,36 months ]
  Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 6, 18, 24, and 36 months
• Change in proximal femur BMD Z-score, as assessed by DXA [ Time Frame: 6, 12, 18, 24, and 36 months ]
  Change in proximal femur BMD Z-score, as assessed by DXA, at 6, 12, 18, 24, and 36 months
• Incidence of new and worsening fractures (X-ray confirmed long bone and vertebral [ Time Frame: 12, 24, and 36 months ]
  Incidence of new and worsening fractures (X-ray confirmed long bone and vertebral fractures) from pre-treatment to post-treatment at 12, 24, and 36 months
• Incidence of improving vertebral fractures from pre-treatment to post-treatment [ Time Frame: 12, 24, and 36 months ]
  Incidence of improving vertebral fractures from pre-treatment to post-treatment at 12, 24, and 36 months (overall, among subjects with clinical fracture reduction, and among subjects with clinical fracture increase)
• Incidence of pre-treatment compared with post-treatment vertebral and nonvertebral [ Time Frame: 12, 24, and 36 months ]
  Incidence of pre-treatment compared with post-treatment vertebral and nonvertebral fractures at 12, 24, and 36 months
• Change in Child Health Questionnaire (CHQ)-Parent Form (PF)-50 Physical Summary [ Time Frame: 12, 24, and 36 months ]
  Change in Child Health Questionnaire (CHQ)-Parent Form (PF)-50 Physical Summary score at 12, 24, and 36 months
• Change in CHQ-PF-50 Psychological Summary score [ Time Frame: 12, 24, and 36 months ]
  Change in CHQ-PF-50 Psychological Summary score at 12, 24, and 36 months
• Childhood Health Assessment Questionnaire (CHAQ) Disability Index score [ Time Frame: 12, 24, and 36 Months ]
  Childhood Health Assessment Questionnaire (CHAQ) Disability Index score at 12, 24, and 36 months
• Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) [ Time Frame: 12, 24, and 36 months ]
  Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12, 24, and 36 months
• Serum concentration of denosumab [ Time Frame: 1 and 10 days and 6, 12, 18, 24, 30, and ]
  Serum concentration of denosumab at 1 and 10 days and 6, 12, 18, 24, 30, and 36 months in all subjects (additional serum denosumab pharmacokinetics [PK] samples to be collected at day 30 and month 3 in a PK/bone turnover markers (BTM) substudy of approximately 50 subjects).

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 28, 2015)

Subject incidence of adverse events and serious adverse events [ Time Frame: 36 months ]

Subject incidence of adverse events and serious adverse events

Descriptive Information

• Brief Title: Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
• Official Title: 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
• Brief Summary: 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: 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)
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Osteogenesis Imperfecta

Intervention

Drug: Denosumab

All subjects who remain on-study (have not previously completed Month 36/End of Study (EOS) under the 6-Month Dosing Regimen) will be eligible to transition to the 3-Month Dosing Regimen.Approximately 150 subjects will be enrolled. Approximately 120 subjects will transition to the 3-Month Dosing Regimen. No additional subjects will be enrolled into this study. All subjects will receive denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 3 months for a minimum of 12 months, and all subjects will receive appropriate calcium and vitamin D.

Study Arms

Experimental: Denosumab

Single Arm Study

Intervention: Drug: Denosumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 28, 2019): 153
• Original Estimated Enrollment (submitted: January 28, 2015): 150
• Estimated Study Completion Date: January 9, 2022
• Estimated Primary Completion Date: January 9, 2022 (Final data collection date for primary outcome measure)

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
  • § 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 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, Czechia, France, Germany, Hungary, Italy, Poland, Spain, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02352753
• Other Study ID Numbers: 20130173; 2014-000184-40 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

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 (or other new use) 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, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. 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 URL below.
• URL: https://www.amgen.com/datasharing

• Responsible Party: Amgen
• Study Sponsor: Amgen
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: December 2020