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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02352753
Registration number
NCT02352753
Ethics application status
Date submitted
28/01/2015
Date registered
2/02/2015
Date last updated
28/12/2022
Titles & IDs
Public title
Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
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Scientific 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
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Secondary ID [1]
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2014-000184-40
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Secondary ID [2]
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20130173
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Universal Trial Number (UTN)
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Trial acronym
OI
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Osteogenesis Imperfecta
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Condition category
Condition code
Musculoskeletal
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Other muscular and skeletal disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Injuries and Accidents
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Fractures
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Denosumab
Experimental: Denosumab - Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.
Early efficacy and PK data from Q6M dosing supported adjustment of the dosing regimen from Q6M to every 3 months (Q3M). Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
Treatment: Drugs: Denosumab
Subcutaneous (SC) injection.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and 12 months
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Secondary outcome [1]
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Change From Baseline in Lumbar Spine BMD Z-score at 6 Months
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and 6 months
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Secondary outcome [2]
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Change From Baseline in Proximal Femur BMD Z-score at 6 and 12 Months
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline, 6 and 12 months
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Secondary outcome [3]
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Percentage of Participants With at Least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture
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Assessment method [3]
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Timepoint [3]
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Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
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Secondary outcome [4]
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Percentage of Participants With at Least 1 X-ray Confirmed New and Worsening Vertebral Fracture
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Assessment method [4]
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Timepoint [4]
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Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
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Secondary outcome [5]
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Percentage of Participants With at Least 1 X-ray Confirmed New Vertebral Fracture
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Assessment method [5]
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Timepoint [5]
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Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
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Secondary outcome [6]
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Percentage of Participants Wth at Least 1 X-ray Confirmed Improving Vertebral Fracture
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Assessment method [6]
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Timepoint [6]
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Q3M Dosing Regimen: Baseline up to 12 months
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Secondary outcome [7]
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Percentage of Participants With at Least 1 Vertebral and Nonvertebral Fracture
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Assessment method [7]
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Timepoint [7]
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Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
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Secondary outcome [8]
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Change From Baseline in Child Health Questionnaire-Parent Form Physical Summary Score (CHQ-PF-50) at 12 Months
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Assessment method [8]
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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.
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Timepoint [8]
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Baseline and 12 months
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Secondary outcome [9]
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Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12 Months
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Assessment method [9]
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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.
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Timepoint [9]
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Baseline and 12 months
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Secondary outcome [10]
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Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12 Months
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Assessment method [10]
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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.
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Timepoint [10]
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Baseline and 12 months
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Secondary outcome [11]
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Change From Baseline in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 Months
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Assessment method [11]
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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.
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Timepoint [11]
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Baseline and 12 months
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Secondary outcome [12]
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Serum Concentration of Denosumab
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Assessment method [12]
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Timepoint [12]
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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)
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Secondary outcome [13]
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Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide
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Assessment method [13]
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Timepoint [13]
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Baseline and Days 10 and 30, and Months 3, 6, 9, 12, 15 and 18
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Secondary outcome [14]
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BTM - Bone-specific Alkaline Phosphatase (BSAP)
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Assessment method [14]
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Timepoint [14]
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Baseline and Days 10 and 30, and Months 3, 6, 9, 12, and 15
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Secondary outcome [15]
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Change From Baseline in Growth Velocity at 12 Months
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Assessment method [15]
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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.
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Timepoint [15]
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Baseline and 12 months
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Eligibility
Key inclusion 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
• 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.
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Minimum age
2
Years
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Maximum age
17
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Other
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
24/06/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
26/03/2022
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Sample size
Target
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Accrual to date
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Final
153
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Recruitment in Australia
Recruitment state(s)
NSW,WA
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Recruitment hospital [1]
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Research Site - Westmead
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Recruitment hospital [2]
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Research Site - Subiaco
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Recruitment postcode(s) [1]
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2145 - Westmead
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Recruitment postcode(s) [2]
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6008 - Subiaco
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Recruitment outside Australia
Country [1]
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United States of America
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California
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United States of America
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Colorado
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United States of America
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Connecticut
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United States of America
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Delaware
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United States of America
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Georgia
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Indiana
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United States of America
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Iowa
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United States of America
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Maryland
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United States of America
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Massachusetts
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Nebraska
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Tennessee
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Texas
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Belgium
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Bruxelles
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Belgium
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Gent
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Belgium
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Leuven
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Bulgaria
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Sofia
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Bulgaria
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Varna
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Canada
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Ontario
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Canada
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Hradec Kralove
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Czechia
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Pardubice
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Plzen
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Czechia
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Praha 4
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Czechia
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Zlin
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France
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Bordeaux Cedex
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France
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Paris Cedex 15
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France
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Paris
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France
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Saint Priest en Jarez
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France
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Toulouse Cedex 9
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Germany
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Köln
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Hungary
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Budapest
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Italy
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Roma
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Italy
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Verona
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Poland
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Bialystok
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Lodz
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Poland
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Rzeszow
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Poland
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Warszawa
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Spain
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Cataluña
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Spain
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Comunidad Valenciana
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Spain
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Madrid
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Birmingham
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Bristol
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Glasgow
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United Kingdom
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Sheffield
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Amgen
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Address
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02352753
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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MD
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Address
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Amgen
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02352753
Download to PDF