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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/NCT03638128
Registration number
NCT03638128
Ethics application status
Date submitted
21/06/2018
Date registered
20/08/2018
Date last updated
20/12/2022
Titles & IDs
Public title
Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
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Scientific title
Multicenter, Single-arm Open-label Extension Study to Assess Long-term Safety and Efficacy of Current or Prior Treatment With Denosumab in Children/Young Adults With Osteogenesis Imperfecta
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Secondary ID [1]
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2018-000550-21
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Secondary ID [2]
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20170534
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Osteogenesis Imperfecta (OI)
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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
Treatment: Drugs - Alternative osteoporosis medications
Other: Alternative Medications / Observational - Participants who received non-denosumab alternative therapy during the study or who were not receiving any medication at baseline.
Alternative osteoporosis medication(s) were determined at the investigator's discretion and per standard of care and local guidelines.
Experimental: Denosumab 1 mg/kg Q6M - Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) by subcutaneous injection, but no Q3M denosumab during this study.
Experimental: Denosumab 1 mg/kg Q3M - Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.
Treatment: Drugs: Denosumab
Solution for injection
Treatment: Drugs: Alternative osteoporosis medications
Alternative osteoporosis medication/s at the discretion of the investigator.
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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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Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest
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Assessment method [1]
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A Serious Adverse Event is defined as any untoward medical occurrence that met at least 1 of the following serious criteria:
Resulted in death (fatal)
Immediately life-threatening
Required in-patient hospitalization or prolongation of existing hospitalization
Resulted in persistent or significant disability/incapacity
Was a congenital anomaly/birth defect
Other medically important serious event that may have jeopardized the participant or require medical or surgical intervention to prevent 1 of the outcomes listed above.
Adverse events of special interest included hypocalcemia, hypersensitivity, bacterial cellulitis, osteonecrosis of the jaw (ONJ), hypercalcemia, and typical osteogenesis imperfecta (OI) femur fractures.
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Timepoint [1]
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From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months.
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Primary outcome [2]
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Number of Participants With Anti-denosumab Antibodies
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Assessment method [2]
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Blood samples were collected (from denosumab treated participants only) for the measurement of anti-denosumab binding antibodies. Samples positive for anti-denosumab binding antibodies were further tested for neutralizing antibodies.
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Timepoint [2]
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From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months
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Primary outcome [3]
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Number of Participants With Clinical Laboratory Toxicities Grade = 3
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Assessment method [3]
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Laboratory abnormalities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The grades refer to the severity of the finding:
Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening consequences, urgent intervention indicated.
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Timepoint [3]
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From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months
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Primary outcome [4]
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Number of Participants With Clinically Significant Vital Sign Findings
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Assessment method [4]
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Vital sign measurements included systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. The investigator assessed vital sign results and determined whether any abnormal changes represented a clinically significant change from the participant's baseline values.
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Timepoint [4]
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From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months
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Primary outcome [5]
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Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range
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Assessment method [5]
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Anteroposterior radiographs of both knees (unless prohibited by the presence of hardware such as implants) were used to calculate the metaphyseal index Z-score of each knee in participants with open growth plates; the knee selected for assessment during the study was the knee with the higher Z-score at baseline. The metaphyseal index (MI) was calculated by the central imaging vendor as the ratio of femoral width over distal femoral growth plate width, and the Z-score for each participant, relative to the participant's age as:
MI Z-score = (participant value - mean)/SD, where mean and standard deviation (SD) are the corresponding values based on a reference population for the participant's age group at the time of the assessment.
Metaphyseal index Z-score above age-appropriate normal range is defined as a MI Z-score > 2.
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Timepoint [5]
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Baseline, month 12 and month 24
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Primary outcome [6]
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Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings
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Assessment method [6]
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Participants underwent a visual inspection under natural light for the presence of the first and second molars. Participants were referred to a dentist to perform radiographic assessment of the unerupted molar(s) if:
A participant was age 7 to 12 years and appeared to have an unerupted upper or lower first molar (ie, not all 4 first molars were visible/detectable).
A participant was age 13 years or older and appeared to have an unerupted upper or lower (first or) second molar (ie, not all 4 first molars and all 4 second molars were visible/detectable).
Abnormal molar eruptions includes the number of participants 7 to 12 years of age with 1st unerupted or partially erupted molars and participants 13 years of age or older with 2nd unerupted or partially erupted molars.
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Timepoint [6]
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Baseline, month 12, and month 24
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Primary outcome [7]
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Percent Change From Baseline in Mandibular Shaping Parameters
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Assessment method [7]
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Lateral cephalogram was performed to enable assessment of mandibular shaping. The lateral cephalogram is a profile X-ray of the skull and soft tissues and is used to assess the relation of the teeth in the jaws, the relation of the jaws to the skull, and the relation of the soft tissues to the teeth and jaws.
The following anatomical angles and dimensions were measured to evaluate the correct proportions of the mandible and its position relative to the skull/maxilla: Gonial angle; Sella-Nasion-A Point Angle (SNA angle); Sella-Nasion-B Point Angle (SNB angle); and A Point - Nasion-B Point Angle (ANB Angle).
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Timepoint [7]
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Baseline and month 12 and month 24
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Secondary outcome [1]
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Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score
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Assessment method [1]
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Bone densitometry assessments of the lumbar spine were performed using dual X-ray absorptiometry (DXA).
The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in lumbar spine BMD.
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Timepoint [1]
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Baseline and months 6, 12, and 24
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Secondary outcome [2]
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Change From Baseline in Total Hip BMD Z-score
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Assessment method [2]
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Bone densitometry assessments of the hip were performed using dual X-ray absorptiometry (DXA).
The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in total hip BMD.
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Timepoint [2]
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Baseline, months 6, 12, and 24
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Secondary outcome [3]
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Change From Baseline in Femoral Neck BMD Z-score
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Assessment method [3]
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Bone densitometry assessments of the femoral neck were performed using dual X-ray absorptiometry (DXA).
The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in femoral neck BMD.
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Timepoint [3]
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Baseline and months 6, 12, and 24
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Eligibility
Key inclusion criteria
- Subject has provided informed consent/assent prior to initiation of any Study 20170534
specific activities/procedures. 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 written assent based on local regulations and/or
guidelines prior to any study-specific activities/procedures being initiated.
- Subject is currently/was enrolled in Study 20130173 and
- completed the 20130173 End of Study (EOS) visit (regardless of completing or
ending investigational product early) OR
- did not reconsent/reassent to transition to 3-month dosing regimen on Study
20130173 OR
- early terminated from Study 20130173 as a result of meeting bone mineral density
(BMD) Z-score investigational product stopping criteria.
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Minimum age
No limit
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Maximum age
No limit
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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
- Treatment with any prohibited proscribed medications while receiving denosumab.
Eligibility into study treatment with alternative osteoporosis medication/s of
investigator's choice, follow guidelines per the specific alternative osteoporosis
medication/s selected. For subjects off-treatment (observation only), no prohibited
medications apply.
- Subjects currently receiving treatment in another investigational device or drug study
other than Study 20130173. Other investigational procedures while participating in
this study are excluded.
- For subjects expected to receive investigational product (denosumab) at study day 1:
Female subject is pregnant or breastfeeding or planning to become pregnant or
breastfeed during treatment and for an additional 5 months after the last dose of
denosumab. Females of childbearing potential (Tanner Stage greater than or equal to 2)
should only be included in the study after a negative highly sensitive urine or serum
pregnancy test. For study treatment with alternative osteoporosis medication/s of
investigator's choice, follow guidelines per the specific alternative osteoporosis
medication/s selected. For Subjects off-treatment (observation only), no exclusion
applies.
- For subjects expected to receive investigational product (denosumab) at study day 1:
Female subjects of childbearing potential unwilling to practice true sexual abstinence
(refrain from heterosexual intercourse) or use 1 highly effective method of
contraception during treatment and for an additional 5 months after the last dose of
investigational product (denosumab). For study treatment with alternative osteoporosis
medication/s of investigator's choice, follow contraception guidelines per the
specific alternative osteoporosis medication/s selected. For subjects not receiving
any investigational product (observation only), no contraception required.
- History or evidence of any other clinically significant disorder, condition or disease
(with the exception of those outlined above) that, in the opinion of the investigator
or Amgen physician, if consulted, would pose a risk to subject safety or interfere
with the study evaluation, procedures or completion.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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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
Parallel
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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
26/07/2018
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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
28/03/2022
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Sample size
Target
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Accrual to date
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Final
75
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Recruitment in Australia
Recruitment state(s)
NSW,WA
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Recruitment hospital [1]
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The Childrens Hospital at Westmead - Westmead
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Recruitment hospital [2]
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Perth Childrens Hospital - Nedlands
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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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6909 - Nedlands
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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United States of America
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Indiana
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Belgium
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Bruxelles
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Canada
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State/province [4]
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Ontario
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Canada
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State/province [5]
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Quebec
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Country [6]
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Czechia
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State/province [6]
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Plzen
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Country [7]
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Czechia
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State/province [7]
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Praha 4
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Country [8]
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France
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State/province [8]
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Bordeaux Cedex
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Country [9]
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France
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State/province [9]
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Paris Cedex 15
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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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Poland
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Lodz
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Spain
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State/province [14]
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Cataluña
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Spain
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State/province [15]
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Comunidad Valenciana
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Country [16]
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United Kingdom
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State/province [16]
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Birmingham
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Country [17]
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United Kingdom
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State/province [17]
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Bristol
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Country [18]
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United Kingdom
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State/province [18]
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Glasgow
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Country [19]
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United Kingdom
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State/province [19]
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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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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
To evaluate long-term safety of denosumab in children/young adults with pediatric
osteogenesis imperfecta (OI) who completed the prior study 20130173 (NCT02352753).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03638128
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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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Country
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Phone
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Fax
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Email
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Contact person for public queries
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Address
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03638128
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