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

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

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.

Study Overview

• Status: Completed
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Drug: 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
• Enrollment (Actual): 153
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Research Site
  • Western Australia
    • Subiaco, Western Australia, Australia, 6008
      • Research Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Bulgaria
  • Sofia, Bulgaria, 1784
    • Research Site
  • Sofia, Bulgaria, 1606
    • Research Site
  • Varna, Bulgaria, 9010
    • Research Site
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Research Site
    • Toronto, Ontario, Canada, M5G 1X8
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H4A 0A9
      • Research Site
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Pardubice, Czechia, 532 03
    • Research Site
  • Plzen, Czechia, 305 99
    • Research Site
  • Praha 4, Czechia, 140 59
    • Research Site
  • Zlin, Czechia, 762 75
    • Research Site
• France
  • Bordeaux Cedex, France, 33076
    • Research Site
  • Paris, France, 75012
    • Research Site
  • Paris Cedex 15, France, 75743
    • Research Site
  • Saint Priest en Jarez, France, 42270
    • Research Site
  • Toulouse Cedex 9, France, 31059
    • Research Site
• Germany
  • Köln, Germany, 50931
    • Research Site
• Hungary
  • Budapest, Hungary, 1094
    • Research Site
• Italy
  • Roma, Italy, 00161
    • Research Site
  • Verona, Italy, 37126
    • Research Site
• Poland
  • Bialystok, Poland, 15-274
    • Research Site
  • Lodz, Poland, 91-738
    • Research Site
  • Rzeszow, Poland, 35-301
    • Research Site
  • Warszawa, Poland, 04-730
    • Research Site
• Spain
  • Cataluña
    • Esplugues de Llobregat, Cataluña, Spain, 08950
      • Research Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Research Site
  • Madrid
    • Getafe, Madrid, Spain, 28905
      • Research Site
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Research Site
  • Bristol, United Kingdom, BS2 8AE
    • Research Site
  • Glasgow, United Kingdom, G51 4TF
    • Research Site
  • Sheffield, United Kingdom, S10 2TH
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Research Site
    • Torrance, California, United States, 90502
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Research Site
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Research Site
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Research Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Denosumab; Single Arm Study

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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in lumbar spine BMD Z-score, as assessed by DXA, at 6 months	Change in lumbar spine BMD Z-score, as assessed by DXA, at 6 months in subjects receiving the 3-Month Dosing Regimen	6 months
Change in proximal femur BMD Z-score, as assessed by DXA	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	6 and 12 months
Incidence of X-ray confirming long bone and new and worsening vertebral fractures	Incidence of X-ray confirmed long bone and new and worsening vertebral fractures from last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen	Up to 24 months
Incidence of X-ray confirmed new and worsening vertebral fractures	Incidence of X-ray confirmed new and worsening vertebral fractures from last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen	Up to 24 months
Incidence of X-ray confirming new vertebral fractures	Incidence of X-ray confirmed new vertebral fractures from last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen	Up to 24 months
Incidence of improving vertebral fractures	Subject incidence of improving vertebral fractures from baseline of 3-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen	Up to 12 months
Incidence of vertebral and nonvertebral fractures	Incidence of vertebral and nonvertebral fractures from last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen (in subjects 5 years of age or older)	Up to 24 months
Change in Child Health Questionnaire (CHQ)-Parent Form (PF)-50 Physical Summary	Change from baseline in CHQ-PF-50 Physical Summary score at 12 months in subjects receiving the 3-Month Dosing Regimen	12 months
Change in CHQ-PF-50 Psychological Summary score	Change from baseline in CHQ-PF-50 Psychological Summary score at 12 months in subjects receiving the 3-Month Dosing Regimen	12 months
Childhood Health Assessment Questionnaire (CHAQ) Disability Index score	Change from baseline in CHAQ Disability Index score at 12 months in subjects receiving the 3-Month Dosing Regimen	12 Months
Change in Wong-Baker Faces Pain Rating Scale (WBFPRS)	Change in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 months in subjects receiving the 3-Month Dosing Regimen	12 months
Serum concentration of denosumab	Serum concentration of denosumab on days 1, 10, 30, 60, and every 3 months in all subjects	Days 1, 10, 30, and 60 and every 3 months (up to approximately 24 months)
Change in Bone Turnover Marker (BTM) Values	Change in BTM values on days 1, 10, 30, 60, and every 3 months in all subjects	Days 1, 10, 30, and 60 and every 3 months (up to approximately 24 months)
Actual BTM Values	Actual BTM values on days 1, 10, 30, 60, and every 3 months in all subjects	Days 1, 10, 30, and 60 and every 3 months (up to approximately 24 months)
Change in growth velocity at 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	12 months

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2015
• Primary Completion (Actual): March 26, 2022
• Study Completion (Actual): March 26, 2022

Study Registration Dates

• First Submitted: January 28, 2015
• First Submitted That Met QC Criteria: January 28, 2015
• First Posted (Estimate): February 2, 2015

Study Record Updates

• Last Update Posted (Actual): April 5, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Amgen, OI, Bone
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: 20130173; 2014-000184-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)