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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02352753
Recruitment Status : Active, not recruiting
First Posted : February 2, 2015
Last Update Posted : May 21, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

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.

Condition or disease Intervention/treatment Phase
Osteogenesis Imperfecta Drug: Denosumab Phase 3

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)

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 153 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 24, 2015
Estimated Primary Completion Date : January 14, 2022
Estimated Study Completion Date : January 14, 2022


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.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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)

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02352753


Locations
Show Show 49 study locations
Sponsors and Collaborators
Amgen
Investigators
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Study Director: MD Amgen
Additional Information:
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02352753    
Other Study ID Numbers: 20130173
2014-000184-40 ( EudraCT Number )
First Posted: February 2, 2015    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: May 2020
Individual Participant Data (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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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
Keywords provided by Amgen:
Amgen, OI, Bone
Additional relevant MeSH terms:
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Osteogenesis Imperfecta
Osteochondrodysplasias
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Genetic Diseases, Inborn
Collagen Diseases
Connective Tissue Diseases
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs