Osteogenesis Imperfecta (OI)
Conditions
Keywords
OI, Bone.
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).
Detailed description
All participants who completed the prior denosumab study 20130173 (NCT02352753) were offered participation in this study (20170534). Participants could continue to receive denosumab once every 3 months (Q3M) or could receive denosumab once every 6 months (Q6M) or off-treatment observation only at the investigator's discretion. The study design allowed subjects to discontinue denosumab, resume denosumab, initiate alternative osteoporosis medication, discontinue alternative osteoporosis medication, or receive no treatment (observation only) at any time. Therefore results of this study were analyzed according to both baseline treatment and subsequent treatment trajectories.
Interventions
DRUGDenosumab
Solution for injection
DRUGAlternative osteoporosis medications
Alternative osteoporosis medication/s at the discretion of the investigator.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Mandibular Shaping Parameters | Baseline and month 12 and month 24 | 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). |
| Number of Participants With Clinically Significant Vital Sign Findings | 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 | 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. |
| Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Baseline, month 12 and month 24 | 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. |
| Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Baseline, month 12, and month 24 | 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. |
| Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | 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. | 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. |
| Number of Participants With Anti-denosumab Antibodies | 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 | 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. |
| Number of Participants With Clinical Laboratory Toxicities Grade ≥ 3 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Hip BMD Z-score | Baseline, months 6, 12, and 24 | 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. |
| Change From Baseline in Femoral Neck BMD Z-score | Baseline and months 6, 12, and 24 | 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. |
| Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score | Baseline and months 6, 12, and 24 | 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. |
Countries
Australia, Belgium, Canada, Czechia, France, Germany, Hungary, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 22 centers in North America, Europe, and Australia from July 2018 to March 2022. The study was an open-label extension of study 20130173 (NCT02352753). Participants who completed the end of study visit or who withdrew consent or assent to transition to every 3 months (Q3M) dosing regimen in Study 20130173 were offered participation in this study.
Pre-assignment details
Participants who rolled over into Study 20170534 could continue to receive denosumab Q3M or could receive alternative osteoporosis medication, including commercial denosumab every 6 months (Q6M), or off-treatment observation only at the investigator's discretion. At any time during the study, participants could discontinue, resume, or initiate 1 of the above treatments based on the medical judgment of the investigator and per local standard of care.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 21 |
| Denosumab 1 mg/kg Q6M Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) administered by subcutaneous injection, but no Q3M denosumab during this study. | 27 |
| 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. | 27 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Sponsor Decision | 15 | 12 | 19 |
| Overall Study | Withdrawal by Subject | 1 | 7 | 6 |
Baseline characteristics
| Characteristic | Alternative Medications / Observational | Denosumab 1 mg/kg Q6M | Denosumab 1 mg/kg Q3M | Total |
|---|---|---|---|---|
| Age, Continuous | 12.5 years STANDARD_DEVIATION 3.5 | 13.2 years STANDARD_DEVIATION 2.5 | 14.3 years STANDARD_DEVIATION 4.8 | 13.4 years STANDARD_DEVIATION 3.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 27 Participants | 24 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 25 Participants | 23 Participants | 68 Participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 13 Participants | 30 Participants |
| Sex: Female, Male Male | 13 Participants | 18 Participants | 14 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 27 | 0 / 27 |
| other Total, other adverse events | 15 / 21 | 21 / 27 | 13 / 27 |
| serious Total, serious adverse events | 6 / 21 | 5 / 27 | 6 / 27 |
Outcome results
Primary
Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings
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.
Time frame: Baseline, month 12, and month 24
Population: Safety analysis set participants with radiologic assessments at each time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alternative Medications / Observational | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Month 12 | 0 Participants |
| Alternative Medications / Observational | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Baseline | 2 Participants |
| Alternative Medications / Observational | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Month 24 | 1 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Month 12 | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Baseline | 3 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Month 24 | 1 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Baseline | 1 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Month 24 | 0 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings | Month 12 | 2 Participants |
Primary
Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest
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.
Time frame: 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.
Population: The safety analysis set includes all enrolled participants who provided informed consent/assent, had a non-missing enrollment date, and received at least 1 dose of denosumab during Study 20130173.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypocalcemia | 0 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Serious adverse events | 6 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypersensitivity | 0 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypercalcemia | 3 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Any adverse event | 18 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Typical osteogenesis imperfecta femur fractures | 2 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Adverse events of special interest | 5 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Positively adjudicated osteonecrosis of the jaw | 0 Participants |
| Alternative Medications / Observational | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Bacterial cellulitis (skin infection) | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Any adverse event | 22 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Serious adverse events | 5 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Adverse events of special interest | 5 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypocalcemia | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypercalcemia | 4 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypersensitivity | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Bacterial cellulitis (skin infection) | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Typical osteogenesis imperfecta femur fractures | 1 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Positively adjudicated osteonecrosis of the jaw | 0 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Adverse events of special interest | 9 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Any adverse event | 19 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Bacterial cellulitis (skin infection) | 0 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Serious adverse events | 6 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Positively adjudicated osteonecrosis of the jaw | 0 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypercalcemia | 9 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypocalcemia | 1 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Typical osteogenesis imperfecta femur fractures | 2 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest | Hypersensitivity | 0 Participants |
Primary
Number of Participants With Anti-denosumab Antibodies
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.
Time frame: 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
Population: Safety analysis set participants who received at least one dose of denosumab in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alternative Medications / Observational | Number of Participants With Anti-denosumab Antibodies | Anti-denosumab binding antibodies | 0 Participants |
| Alternative Medications / Observational | Number of Participants With Anti-denosumab Antibodies | Anti-denosumab neutralizing antibodies | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Anti-denosumab Antibodies | Anti-denosumab binding antibodies | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Anti-denosumab Antibodies | Anti-denosumab neutralizing antibodies | 0 Participants |
Primary
Number of Participants With Clinical Laboratory Toxicities Grade ≥ 3
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.
Time frame: 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
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alternative Medications / Observational | Number of Participants With Clinical Laboratory Toxicities Grade ≥ 3 | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Clinical Laboratory Toxicities Grade ≥ 3 | 0 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Clinical Laboratory Toxicities Grade ≥ 3 | 0 Participants |
Primary
Number of Participants With Clinically Significant Vital Sign Findings
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.
Time frame: 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
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alternative Medications / Observational | Number of Participants With Clinically Significant Vital Sign Findings | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Clinically Significant Vital Sign Findings | 0 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Clinically Significant Vital Sign Findings | 0 Participants |
Primary
Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range
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.
Time frame: Baseline, month 12 and month 24
Population: The metaphyseal analysis set includes participants with open growth plates and no hardware preventing accurate calculation of MI at baseline, and X-ray of the knee at baseline and postbaseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alternative Medications / Observational | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Month 12 | 2 Participants |
| Alternative Medications / Observational | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Baseline | 2 Participants |
| Alternative Medications / Observational | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Month 24 | 1 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Month 24 | 0 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Baseline | 1 Participants |
| Denosumab 1 mg/kg Q6M | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Month 12 | 1 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Month 12 | 0 Participants |
| Denosumab 1 mg/kg Q3M | Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range | Baseline | 0 Participants |
Primary
Percent Change From Baseline in Mandibular Shaping Parameters
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).
Time frame: Baseline and month 12 and month 24
Population: Safety analysis set participants with radiologic assessments at baseline and each time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | Gonial angle: month 24 | -2.1 percent change | Standard Deviation 3.1 |
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | SNB angle: month 12 | 0.98 percent change | Standard Deviation 1.56 |
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | Gonial angle: month 12 | 0.5 percent change | Standard Deviation 2.4 |
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | ANB angle: month 12 | -81.06 percent change | Standard Deviation 199.39 |
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | SNB angle: month 24 | 1.28 percent change | — |
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | SNA angle: month 12 | 1.38 percent change | Standard Deviation 2.09 |
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | ANB angle: month 24 | -79.69 percent change | — |
| Alternative Medications / Observational | Percent Change From Baseline in Mandibular Shaping Parameters | SNA angle: month 24 | -0.07 percent change | Standard Deviation 0.73 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | ANB angle: month 24 | 15.65 percent change | Standard Deviation 84.75 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | Gonial angle: month 12 | -1.4 percent change | Standard Deviation 1.7 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | Gonial angle: month 24 | -1.4 percent change | Standard Deviation 2.2 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | SNA angle: month 24 | -1.70 percent change | Standard Deviation 1.79 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | SNB angle: month 12 | 1.75 percent change | Standard Deviation 2.36 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | SNB angle: month 24 | -1.60 percent change | Standard Deviation 3.18 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | ANB angle: month 12 | 127.48 percent change | Standard Deviation 312.99 |
| Denosumab 1 mg/kg Q6M | Percent Change From Baseline in Mandibular Shaping Parameters | SNA angle: month 12 | 0.37 percent change | Standard Deviation 2.41 |
| Denosumab 1 mg/kg Q3M | Percent Change From Baseline in Mandibular Shaping Parameters | ANB angle: month 12 | -16.26 percent change | — |
| Denosumab 1 mg/kg Q3M | Percent Change From Baseline in Mandibular Shaping Parameters | SNA angle: month 12 | 0.20 percent change | — |
| Denosumab 1 mg/kg Q3M | Percent Change From Baseline in Mandibular Shaping Parameters | SNB angle: month 12 | 0.70 percent change | — |
| Denosumab 1 mg/kg Q3M | Percent Change From Baseline in Mandibular Shaping Parameters | Gonial angle: month 12 | -1.0 percent change | — |
Secondary
Change From Baseline in Femoral Neck BMD Z-score
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.
Time frame: Baseline and months 6, 12, and 24
Population: The DXA analysis set includes all participants with baseline and ≥ 1 postbaseline valid DXA assessments for the femoral neck as provided by the central imaging vendor.~BMD endpoints were pre-specified to be analyzed for combined treatment groups.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alternative Medications / Observational | Change From Baseline in Femoral Neck BMD Z-score | Month 6 | 0.08 Z-score | Standard Deviation 0.44 |
| Alternative Medications / Observational | Change From Baseline in Femoral Neck BMD Z-score | Month 12 | 0.24 Z-score | Standard Deviation 0.39 |
| Alternative Medications / Observational | Change From Baseline in Femoral Neck BMD Z-score | Month 24 | 0.45 Z-score | Standard Deviation 0.58 |
Secondary
Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score
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.
Time frame: Baseline and months 6, 12, and 24
Population: The DXA analysis set includes all participants with baseline and ≥ 1 postbaseline valid DXA assessments for lumbar spine as provided by the central imaging vendor.~BMD endpoints were pre-specified to be analyzed for combined treatment groups.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alternative Medications / Observational | Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score | Month 6 | -0.11 Z-score | Standard Deviation 0.6 |
| Alternative Medications / Observational | Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score | Month 12 | -0.01 Z-score | Standard Deviation 0.48 |
| Alternative Medications / Observational | Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score | Month 24 | 0.21 Z-score | Standard Deviation 0.49 |
Secondary
Change From Baseline in Total Hip BMD Z-score
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.
Time frame: Baseline, months 6, 12, and 24
Population: The DXA analysis set includes all participants with baseline and ≥ 1 postbaseline valid DXA assessments for the total hip as provided by the central imaging vendor.~BMD endpoints were pre-specified to be analyzed for combined treatment groups.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alternative Medications / Observational | Change From Baseline in Total Hip BMD Z-score | Month 6 | -0.07 Z-score | Standard Deviation 0.4 |
| Alternative Medications / Observational | Change From Baseline in Total Hip BMD Z-score | Month 12 | 0.24 Z-score | Standard Deviation 0.42 |
| Alternative Medications / Observational | Change From Baseline in Total Hip BMD Z-score | Month 24 | 0.50 Z-score | Standard Deviation 0.54 |