Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
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| ClinicalTrials.gov Identifier: NCT03638128 |
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Recruitment Status :
Terminated
(The study was stopped earlier than planned due to safety concerns about high levels of calcium in the blood of the participants)
First Posted : August 20, 2018
Results First Posted : December 20, 2022
Last Update Posted : December 20, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Osteogenesis Imperfecta (OI) | Drug: Denosumab Drug: Alternative osteoporosis medications | Phase 3 |
| Study Type : | Interventional |
| Actual Enrollment : | 75 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official 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 |
| Actual Study Start Date : | July 26, 2018 |
| Actual Primary Completion Date : | March 28, 2022 |
| Actual Study Completion Date : | March 28, 2022 |
| Arm | Intervention/treatment |
|---|---|
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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. |
Drug: Alternative osteoporosis medications
Alternative osteoporosis medication/s at the discretion of the investigator. |
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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.
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Drug: Denosumab
Solution for injection
Other Name: Prolia |
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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.
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Drug: Denosumab
Solution for injection
Other Name: Prolia |
- Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest [ 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. ]
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 [ 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 ]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 [ 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 ]
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.
- Number of Participants With Clinically Significant Vital Sign Findings [ 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 ]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 [ Time Frame: 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 [ Time Frame: 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.
- Percent Change From Baseline in Mandibular Shaping Parameters [ Time Frame: 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).
- Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score [ Time Frame: 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.
- Change From Baseline in Total Hip BMD Z-score [ Time Frame: 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 [ Time Frame: 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.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | Child, Adult, Older Adult |
| Sexes Eligible for Study: | All |
| Accepts 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.
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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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03638128
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| Study Director: | MD | Amgen |
Documents provided by Amgen:
| Responsible Party: | Amgen |
| ClinicalTrials.gov Identifier: | NCT03638128 |
| Other Study ID Numbers: |
20170534 2018-000550-21 ( EudraCT Number ) |
| First Posted: | August 20, 2018 Key Record Dates |
| Results First Posted: | December 20, 2022 |
| Last Update Posted: | December 20, 2022 |
| Last Verified: | November 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (CSR) |
| Time Frame: | Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study. |
| Access Criteria: | Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below. |
| URL: | https://www.amgen.com/datasharing |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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OI Bone. |
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Osteogenesis Imperfecta Osteochondrodysplasias Bone Diseases, Developmental Bone Diseases Musculoskeletal Diseases Genetic Diseases, Inborn |
Collagen Diseases Connective Tissue Diseases Denosumab Bone Density Conservation Agents Physiological Effects of Drugs |