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

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

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).

Study Overview

• Status: Completed
• Conditions: Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With; Glucocorticoid-induced Osteoporosis
• Intervention / Treatment: Other: Placebo; Drug: Denosumab

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
• Enrollment (Actual): 24
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Nedlands, Western Australia, Australia, 6909
      • Perth Childrens Hospital
• Belgium
  • Bruxelles, Belgium, 1200
    • Cliniques Universtaire Saint Luc Universite Catholique de Louvain
• Bulgaria
  • Sofia, Bulgaria, 1784
    • Medical Centre Synexus Sofia EOOD
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Childrens Hospital of Eastern Ontario
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte Justine
• Colombia
  • Antioquia
    • Medellin, Antioquia, Colombia, 050021
      • Center for Clinical and Basic Research Colombia
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia, 110221
      • Solano y Terront Servicios Medicos Ltda - Unidad Integral de Endocrinologia Uniendo
  • Santander
    • Floridablanca, Santander, Colombia, 681004
      • Foscal Internacional-Fundacion Oftalmologica de Santander
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500 025
      • Gandhi Medical College
  • Delhi
    • New Delhi, Delhi, India, 110 022
      • Sir Ganga Ram Hospital
  • Karnataka
    • Belagavi, Karnataka, India, 590010
      • KLES Dr Prabhakar Kore Hospital and Medical Research Centre
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632 004
      • Christian medical college
• Italy
  • Firenze, Italy, 50139
    • Azienda Ospedaliera Universitaria Meyer
  • Milan, Italy, 20145
    • Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico
  • Roma, Italy, 00161
    • Azienda Ospedaliera Policlinico Umberto I
• Mexico
  • Ciudad de Mexico, Mexico, 03100
    • RM Pharma Specialists SA de CV
• Peru
  • Arequipa, Peru, 040001
    • Centro Especializado de Enfermedades Neoplasicas
  • Callao, Peru, Callao 2
    • Hospital Nacional Alberto Sabogal Sologuren
  • Lima, Peru, Lima 27
    • Clinica Angloamericana
  • Lima, Peru, Lima27
    • Centro de Investigacion Ricardo Palma
  • Lima
    • Brena, Lima, Peru, Lima 5
      • Instituto Nacional de Salud del Nino
• Russian Federation
  • Moscow, Russian Federation, 119991
    • FSAI Scientific Center of Childrens Health of MoH of the RF
  • Moscow, Russian Federation, 119991
    • SBEI of HPE First Moscow state medical university na I M Sechenov of MoH of Russian Federation
  • Novosibirsk, Russian Federation, 630007
    • SBHI of Novosibirsk region City Pediatric Clinical Hospital of Emergency Care
  • Saint Petersburg, Russian Federation, 191025
    • LLC Medical Technologies
• Turkey
  • Ankara, Turkey, 06590
    • Ankara Universitesi Tip Fakultesi
  • Erzurum, Turkey, 25240
    • Ataturk Universitesi Tip Fakultesi
  • Istanbul, Turkey, 34890
    • Marmara Universitesi Pendik Egitim Arastirma Hastanesi
  • Izmir, Turkey, 35100
    • Ege Universitesi Tip Fakultesi
• Ukraine
  • Dnipro, Ukraine, 49100
    • CI Dnipropetrovsk Regional Children Clinical Hospital of Dnipropetrovsk Regional Council
  • Kharkiv, Ukraine, 61075
    • Communal Institution of Healthcare Kharkiv City Clinical Children Hospital 16
  • Kyiv, Ukraine, 01025
    • National Childrens Specialized Hospital OHMATDYT
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital of Los Angeles
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • AI Dupont Hospital for Children
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota Masonic Childrens Hospital Discovery Clinic
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Childrens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

• 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

  • 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Placebo; SC Q6M placebo	Other: Placebo; SC Q6M placebo
Experimental: Denosumab; 1 mg/kg BW (up to a maximum of 60 mg) SC Q6M	Drug: Denosumab; 1mg/kg BW (up to a maximum of 60 mg) SC Q6M

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 at 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.	12 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2018
• Primary Completion (Actual): December 13, 2021
• Study Completion (Actual): December 20, 2023

Study Registration Dates

• First Submitted: May 8, 2017
• First Submitted That Met QC Criteria: May 22, 2017
• First Posted (Actual): May 24, 2017

Study Record Updates

• Last Update Posted (Actual): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Osteoporosis; Denosumab; Pediatric GIOP; Glucocorticoid-induced
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: 20140444; 2016-003083-39 (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 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. 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No