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

Osteogenesis Imperfecta Clinical Trial

— 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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02352753
• Other study ID #: 20130173
• Secondary ID: 2014-000184-40
• Status: Terminated
• Phase: Phase 3
• Start date: June 24, 2015
• Est. completion date: March 26, 2022

Study information

• Verified date: November 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 153
• Est. completion date: March 26, 2022
• Est. primary completion date: March 26, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

• 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.

Related Conditions & MeSH terms

• Osteogenesis Imperfecta

Intervention

Drug:
• Denosumab
Subcutaneous (SC) injection.

Locations

Country	Name	City	State
Australia	Research Site	Subiaco	Western Australia
Australia	Research Site	Westmead	New South Wales
Belgium	Research Site	Bruxelles
Belgium	Research Site	Gent
Belgium	Research Site	Leuven
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Hradec Kralove
Czechia	Research Site	Pardubice
Czechia	Research Site	Plzen
Czechia	Research Site	Praha 4
Czechia	Research Site	Zlin
France	Research Site	Bordeaux Cedex
France	Research Site	Paris
France	Research Site	Paris Cedex 15
France	Research Site	Saint Priest en Jarez
France	Research Site	Toulouse Cedex 9
Germany	Research Site	Köln
Hungary	Research Site	Budapest
Italy	Research Site	Roma
Italy	Research Site	Verona
Poland	Research Site	Bialystok
Poland	Research Site	Lodz
Poland	Research Site	Rzeszow
Poland	Research Site	Warszawa
Spain	Research Site	Esplugues de Llobregat	Cataluña
Spain	Research Site	Getafe	Madrid
Spain	Research Site	Valencia	Comunidad Valenciana
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Bristol
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Sheffield
United States	Research Site	Aurora	Colorado
United States	Research Site	Baltimore	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Decatur	Georgia
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Iowa City	Iowa
United States	Research Site	Los Angeles	California
United States	Research Site	Nashville	Tennessee
United States	Research Site	New Haven	Connecticut
United States	Research Site	Omaha	Nebraska
United States	Research Site	Torrance	California
United States	Research Site	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Hungary,  Italy,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months	Lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA) adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.	Baseline and 12 months
Secondary	Change From Baseline in Lumbar Spine BMD Z-score at 6 Months	Lumbar spine BMD was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.	Baseline and 6 months
Secondary	Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months	Proximal femur (total hip and femoral neck) BMD Z-score was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD.	Baseline, 6 and 12 months
Secondary	Percentage of Participants With at Least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture		Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
Secondary	Percentage of Participants With at Least 1 X-ray Confirmed New and Worsening Vertebral Fracture		Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
Secondary	Percentage of Participants With at Least 1 X-ray Confirmed New Vertebral Fracture		Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
Secondary	Percentage of Participants Wth at Least 1 X-ray Confirmed Improving Vertebral Fracture		Q3M Dosing Regimen: Baseline up to 12 months
Secondary	Percentage of Participants With at Least 1 Vertebral and Nonvertebral Fracture		Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
Secondary	Change From Baseline in Child Health Questionnaire-Parent Form Physical Summary Score (CHQ-PF-50) at 12 Months	The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A negative change from Baseline indicates decreased well-being.	Baseline and 12 months
Secondary	Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12 Months	The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A positive change from Baseline indicates improved well-being.	Baseline and 12 months
Secondary	Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12 Months	The disability domain (questions 1-54) of the CHAQ was used to measure the participant's assessment of physical functioning or the parent's assessment of the child's physical functioning. The disability index comprised of 8 categories (dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and activities). Scoring ranged from 1 to 5; 1 was "without any difficulty," 2 was "with some difficulty," 3 was "with much difficulty," and 4 was "unable to do." An answer of "not applicable" was scored as a 5, but was not counted. If a child required assistance from another person or used an aid or other device for any of the 8 categories, the minimum score for that category was recorded as a 3. The CHAQ questions were scored and converted to a total index score ranging from 0 to 3. Negative change from Baseline indicates an improvement.	Baseline and 12 months
Secondary	Change From Baseline in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 Months	Participants were asked to report their level of pain by choosing a face that best described their own pain (the corresponding number: 0, 2, 4, 6, 8, 10) were then recorded. The WBFPRS ranged from 0, "no hurt," to 10, "hurts worst". A negative change from baseline indicates an improvement.	Baseline and 12 months
Secondary	Serum Concentration of Denosumab		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)
Secondary	Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide		Baseline and Days 10 and 30, and Months 3, 6, 9, 12, 15 and 18
Secondary	BTM - Bone-specific Alkaline Phosphatase (BSAP)		Baseline and Days 10 and 30, and Months 3, 6, 9, 12, and 15
Secondary	Change From Baseline in Growth Velocity at 12 Months	Change from baseline in growth velocity was determined by calculating age-adjusted Z-scores for height, weight and body mass index (BMI).; Height-for-age Z-score was defined as the difference between the participant's height and the median height for the population with the same age and gender, divided by the population standard deviation.; The definitions of growth velocity based on weight and BMI were analogously calculated. To programmatically calculate the Z-scores, the National Center for Health Statistics percentiles growth charts, based on the 2000 Center for Disease Control and Prevention (CDC) (http://www.cdc.gov/growthcharts/c c_charts.htm), and the CDC Anthropometric Software Package 3.0 Z-scores were used.; During normal growth, the change in z-score for each of the three should equal 0. A positive change in any of the three indicates growth acceleration, whereas a negative change indicates deceleration.	Baseline and 12 months

External Links

•   AmgenTrials clinical trials website