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

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With; Glucocorticoid-induced Osteoporosis	Drug: Denosumab; Other: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blind
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 7, 2018
• Estimated Primary Completion Date: December 13, 2023
• Estimated Study Completion Date: December 13, 2023

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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
4. 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)
5. 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.
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, California

Childrens Hospital of Los Angeles

Los Angeles, California, United States, 90027

United States, Delaware

AI Dupont Hospital for Children

Wilmington, Delaware, United States, 19803

United States, Indiana

Indiana University Hospital

Indianapolis, Indiana, United States, 46202

United States, Minnesota

University of Minnesota Masonic Childrens Hospital Discovery Clinic

Minneapolis, Minnesota, United States, 55454

United States, Ohio

Metrohealth Medical Center

Cleveland, Ohio, United States, 44109

Nationwide Childrens Hospital

Columbus, Ohio, United States, 43205

Australia, Western Australia

Perth Childrens Hospital

Nedlands, Western Australia, Australia, 6909

Belgium

Cliniques Universtaire Saint Luc Universite Catholique de Louvain

Bruxelles, Belgium, 1200

Bulgaria

Medical Centre Synexus Sofia EOOD

Sofia, Bulgaria, 1784

Canada, Ontario

Childrens Hospital of Eastern Ontario

Ottawa, Ontario, Canada, K1H 8L1

Canada, Quebec

Centre Hospitalier Universitaire Sainte Justine

Montreal, Quebec, Canada, H3T 1C5

Colombia

Center for Clinical and Basic Research Colombia

Medellin, Antioquia, Colombia, 050021

Solano y Terront Servicios Medicos Ltda - Unidad Integral de Endocrinologia Uniendo

Bogota, Cundinamarca, Colombia, 110221

Foscal Internacional-Fundacion Oftalmologica de Santander

Floridablanca, Santander, Colombia, 681004

India

Gandhi Medical College

Hyderabad, Andhra Pradesh, India, 500 025

Sir Ganga Ram Hospital

New Delhi, Delhi, India, 110 022

KLES Dr Prabhakar Kore Hospital and Medical Research Centre

Belagavi, Karnataka, India, 590010

Christian Medical College

Vellore, Tamil Nadu, India, 632 004

Italy

Azienda Ospedaliera Universitaria Meyer

Firenze, Italy, 50139

Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico

Milan, Italy, 20145

Azienda Ospedaliera Policlinico Umberto I

Roma, Italy, 00161

Mexico

RM Pharma Specialists SA de CV

Ciudad de Mexico, Mexico, 03100

Peru

Instituto Nacional de Salud del Nino

Brena, Lima, Peru, Lima 5

Centro Especializado de Enfermedades Neoplasicas

Arequipa, Peru, 040001

Hospital Nacional Alberto Sabogal Sologuren

Callao, Peru, Callao 2

Clinica Angloamericana

Lima, Peru, Lima 27

Centro de Investigacion Ricardo Palma

Lima, Peru, Lima27

Russian Federation

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

Moscow, Russian Federation, 119991

SBHI of Novosibirsk region City Pediatric Clinical Hospital of Emergency Care

Novosibirsk, Russian Federation, 630007

LLC Medical Technologies

Saint Petersburg, Russian Federation, 191025

Turkey

Ankara Universitesi Tip Fakultesi

Ankara, Turkey, 06590

Ataturk Universitesi Tip Fakultesi

Erzurum, Turkey, 25240

Marmara Universitesi Pendik Egitim Arastirma Hastanesi

Istanbul, Turkey, 34890

Ege Universitesi Tip Fakultesi

Izmir, Turkey, 35100

Ukraine

CI Dnipropetrovsk Regional Children Clinical Hospital of Dnipropetrovsk Regional Council

Dnipro, Ukraine, 49100

Communal Institution of Healthcare Kharkiv City Clinical Children Hospital 16

Kharkiv, Ukraine, 61075

National Childrens Specialized Hospital OHMATDYT

Kyiv, Ukraine, 01025

Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Additional Information:

AmgenTrials clinical trials website 

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03164928
• Other Study ID Numbers: 20140444; 2016-003083-39 ( EudraCT Number )
• First Posted: May 24, 2017
• Last Update Posted: December 8, 2022
• Last Verified: December 2022

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 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

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

Keywords provided by Amgen:

Denosumab; Pediatric GIOP; Glucocorticoid-induced; Osteoporosis

Additional relevant MeSH terms:

Osteoporosis; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Denosumab; Bone Density Conservation Agents; Physiological Effects of Drugs