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

Phase 3

Completed

Conditions: Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With
Glucocorticoid-induced Osteoporosis

Interventions: Other: Placebo
Drug: Denosumab

Registration Number: NCT03164928

Lead Sponsor: Amgen

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	SC Q6M placebo
Denosumab	Denosumab	1 mg/kg BW (up to a maximum of 60 mg) SC Q6M

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Lumbar Spine BMD Z-score as Assessed by Dual-energy X-ray Absorptiometry (DXA) at 12 Months	Baseline and 12 Months	Lumbar spine BMD was assessed by DXA and analyzed by analysis of covariance (ANCOVA) including treatment (denosumab vs placebo), baseline age, and baseline BMD z-score. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Growth Velocity Z-score (Height) at 12, 24, and 36 Months	Baseline and Month 12, 24, and 36	Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and body mass index (BMI). Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity.
Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months	Baseline and Month 12, 24, and 36	Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity.
Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months	Baseline and 6, 12, 18, 24, and 36 Months	Proximal femur (total hip and femoral neck) BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify proximal femur BMD improvement.
Number of Participants With X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months	Month 12, 24, and 36	Number of participants who have at least one long bone fracture or vertebral fracture, and number of participants who have more than one long bone fracture or vertebral fracture.
Number of Participants With Improving Vertebral Fractures at 12, 24, and 36 Months	Month 12, 24, and 36	Number of participants with improving vertebral fractures. An improving fracture is defined as one showing signs of healing/repair from baseline as assessed by X-ray.
Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months	Baseline and Month 12, 24, and 36	The CHAQ was developed to measure the physical functioning in children 6 months to 18 years of age. It consists of 54 questions related to the child's ability to perform various activities of daily living. Depending on the question asked, each question is scored either 0 to 3 based on the level of difficulty experienced by the child or 0-1 based on whether the child required assistance from another person or used an aid or other device. All CHAQ questions were scored and converted to a total index score ranging from 0-3, where higher scores indicate greater disability.
Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months	Baseline and Month 12, 24, and 36	The WBFPRS is a horizontal pain scale for children 3-18 years which consists of 6 faces that range from a smiling "no hurt" face with a score of 0 to a crying "hurts worst" face with a score of 10.
Change From Baseline in Growth Velocity Z-score (Weight) at 12, 24, and 36 Months	Baseline and Month 12, 24, and 36	Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity.
Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months	Baseline and 6, 18, 24, and 36 Months	Lumbar spine BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement.
Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months	Baseline and Month 12, 24, and 36	The CHQ-PF-50 is a 50-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The psychological summary score ranges from 0-100 with higher scores indicating better psychological health.
Number of Participants With New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months	Month 12, 24, and 36	Number of participants who have at least one vertebral fracture or non-vertebral fracture, and number of participants who have more than one vertebral fracture or non-vertebral fracture.
Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months	Baseline and month 12, 24, and 36	The CHQ-PF-50 is a 50-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The physical summary score ranges from 0-100 with higher scores indicating better physical health.
Mean Serum Concentration of Denosumab	Day 1, Day 10, Day 30, Month 3, Month 6, Month 12, and Month 18

Trial Locations

Locations (38): Perth Childrens Hospital
🇦🇺
Nedlands, Western Australia, Australia
FSAI Scientific Center of Childrens Health of MoH of the RF
🇷🇺
Moscow, Russian Federation
Ankara Universitesi Tip Fakultesi
🇹🇷
Ankara, Turkey
AI Dupont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Clinica Angloamericana
🇵🇪
Lima, Peru
Centre Hospitalier Universitaire Sainte Justine
🇨🇦
Montreal, Quebec, Canada
Foscal Internacional-Fundacion Oftalmologica de Santander
🇨🇴
Floridablanca, Santander, Colombia
Center for Clinical and Basic Research Colombia
🇨🇴
Medellin, Antioquia, Colombia
Gandhi Medical College
🇮🇳
Hyderabad, Andhra Pradesh, India
Hospital Nacional Alberto Sabogal Sologuren
🇵🇪
Callao, Peru
KLES Dr Prabhakar Kore Hospital and Medical Research Centre
🇮🇳
Belagavi, Karnataka, India
Centro de Investigacion Ricardo Palma
🇵🇪
Lima, Peru
Instituto Nacional de Salud del Nino
🇵🇪
Brena, Lima, Peru
National Childrens Specialized Hospital OHMATDYT
🇺🇦
Kyiv, Ukraine
Centro Especializado de Enfermedades Neoplasicas
🇵🇪
Arequipa, Peru
Indiana University Hospital
🇺🇸
Indianapolis, Indiana, United States
University of Minnesota Masonic Childrens Hospital Discovery Clinic
🇺🇸
Minneapolis, Minnesota, United States
Metrohealth Medical Center
🇺🇸
Cleveland, Ohio, United States
Nationwide Childrens Hospital
🇺🇸
Columbus, Ohio, United States
Christian Medical College
🇮🇳
Vellore, Tamil Nadu, India
Sir Ganga Ram Hospital
🇮🇳
New Delhi, Delhi, India
Childrens Hospital of Los Angeles
🇺🇸
Los Angeles, California, United States
Cliniques Universtaire Saint Luc Universite Catholique de Louvain
🇧🇪
Bruxelles, Belgium
Medical Centre Synexus Sofia EOOD
🇧🇬
Sofia, Bulgaria
Childrens Hospital of Eastern Ontario
🇨🇦
Ottawa, Ontario, Canada
Azienda Ospedaliera Universitaria Meyer
🇮🇹
Firenze, Italy
Solano y Terront Servicios Medicos Ltda - Unidad Integral de Endocrinologia Uniendo
🇨🇴
Bogota, Cundinamarca, Colombia
Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico
🇮🇹
Milan, Italy
RM Pharma Specialists SA de CV
🇲🇽
Ciudad de Mexico, Mexico
Azienda Ospedaliera Policlinico Umberto I
🇮🇹
Roma, Italy
SBEI of HPE First Moscow state medical university na I M Sechenov of MoH of Russian Federation
🇷🇺
Moscow, Russian Federation
LLC Medical Technologies
🇷🇺
Saint Petersburg, Russian Federation
SBHI of Novosibirsk region City Pediatric Clinical Hospital of Emergency Care
🇷🇺
Novosibirsk, Russian Federation
Marmara Universitesi Pendik Egitim Arastirma Hastanesi
🇹🇷
Istanbul, Turkey
CI Dnipropetrovsk Regional Children Clinical Hospital of Dnipropetrovsk Regional Council
🇺🇦
Dnipro, Ukraine
Ataturk Universitesi Tip Fakultesi
🇹🇷
Erzurum, Turkey
Communal Institution of Healthcare Kharkiv City Clinical Children Hospital 16
🇺🇦
Kharkiv, Ukraine
Ege Universitesi Tip Fakultesi
🇹🇷
Izmir, Turkey