Clinical trial NCT02352753: Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Osteogenesis Imperfecta
Keywords: Amgen, OI, Bone
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2015-02-02
Enrollment: 153
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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)

Eligibility 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 (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.

Primary outcomes:
measure: Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months
timeFrame: Baseline and 12 months
Secondary outcomes:
measure: Change From Baseline in Lumbar Spine BMD Z-score at 6 Months
timeFrame: Baseline and 6 months
measure: Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months
timeFrame: Baseline, 6 and 12 months
measure: Percentage of Participants With at Least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture
timeFrame: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
measure: Percentage of Participants With at Least 1 X-ray Confirmed New and Worsening Vertebral Fracture
timeFrame: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
measure: Percentage of Participants With at Least 1 X-ray Confirmed New Vertebral Fracture
timeFrame: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
measure: Percentage of Participants Wth at Least 1 X-ray Confirmed Improving Vertebral Fracture
timeFrame: Q3M Dosing Regimen: Baseline up to 12 months
measure: Percentage of Participants With at Least 1 Vertebral and Nonvertebral Fracture
timeFrame: Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
measure: Change From Baseline in Child Health Questionnaire-Parent Form Physical Summary Score (CHQ-PF-50) at 12 Months
timeFrame: Baseline and 12 months
measure: Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12 Months
timeFrame: Baseline and 12 months
measure: Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12 Months
timeFrame: Baseline and 12 months
measure: Change From Baseline in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 Months
timeFrame: Baseline and 12 months
measure: Serum Concentration of Denosumab
timeFrame: Days 1 (predose), 10, 30, and 60, & weeks 12, 24, 36, 48, 60, 72 (end of study visit), early termination visit, & follow-up visit 12 weeks after last dose (average duration of treatment: 231 days)
measure: Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide
timeFrame: Baseline and Days 10 and 30, and Months 3, 6, 9, 12, 15 and 18
measure: BTM - Bone-specific Alkaline Phosphatase (BSAP)
timeFrame: Baseline and Days 10 and 30, and Months 3, 6, 9, 12, and 15
measure: Change From Baseline in Growth Velocity at 12 Months
timeFrame: Baseline and 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Torrance
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Wilmington
country: United States
facility: Research Site
state: Delaware
city: Decatur
country: United States
facility: Research Site
state: Georgia
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Iowa City
country: United States
facility: Research Site
state: Iowa
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Omaha
country: United States
facility: Research Site
state: Nebraska
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Houston
country: United States
facility: Research Site
state: Texas
city: Westmead
country: Australia
facility: Research Site
state: New South Wales
city: Subiaco
country: Australia
facility: Research Site
state: Western Australia
city: Bruxelles
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Pardubice
country: Czechia
facility: Research Site
city: Plzen
country: Czechia
facility: Research Site
city: Praha 4
country: Czechia
facility: Research Site
city: Zlin
country: Czechia
facility: Research Site
city: Bordeaux Cedex
country: France
facility: Research Site
city: Paris Cedex 15
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Saint Priest en Jarez
country: France
facility: Research Site
city: Toulouse Cedex 9
country: France
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Verona
country: Italy
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Lodz
country: Poland
facility: Research Site
city: Rzeszow
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Esplugues de Llobregat
country: Spain
facility: Research Site
state: Cataluña
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Getafe
country: Spain
facility: Research Site
state: Madrid
city: Birmingham
country: United Kingdom
facility: Research Site
city: Bristol
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: