Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta

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

To evaluate long-term safety of denosumab in children/young adults with pediatric osteogenesis imperfecta (OI) who completed the prior study 20130173 (NCT02352753).

Study Overview

• Status: Terminated
• Conditions: Osteogenesis Imperfecta (OI)
• Intervention / Treatment: Drug: Alternative osteoporosis medications; Drug: Denosumab

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • The Childrens Hospital at Westmead
  • Western Australia
    • Nedlands, Western Australia, Australia, 6909
      • Perth Childrens Hospital
• Belgium
  • Bruxelles, Belgium, 1200
    • Universite Catholique de Louvain Cliniques Universitaires Saint Luc
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Childrens Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H4A 0A9
      • Shriners Hospital for Children
• Czechia
  • Plzen, Czechia, 305 99
    • Fakultni nemocnice Plzen
  • Praha 4, Czechia, 140 59
    • Thomayerova nemocnice
• France
  • Bordeaux Cedex, France, 33076
    • Centre Hospitalier Universitaire de Bordeaux - Hopital Pellegrin
  • Paris Cedex 15, France, 75743
    • Hopital Necker Enfants Malades
• Germany
  • Köln, Germany, 50931
    • Uniklinik Köln
• Hungary
  • Budapest, Hungary, 1094
    • Semmelweis Egyetem
• Italy
  • Roma, Italy, 00161
    • Azienda Ospedaliera Policlinico Umberto I
• Poland
  • Lodz, Poland, 91-738
    • SPZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego w Lodzi
• Spain
  • Cataluña
    • Esplugues de Llobregat, Cataluña, Spain, 08950
      • Hospital Sant Joan De Deu
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Hospital Universitari i Politècnic La Fe
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Childrens Hospital
  • Bristol, United Kingdom, BS2 8AE
    • Bristol Royal Hospital for Children
  • Glasgow, United Kingdom, G51 4TF
    • Royal Hospital For Children
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Childrens Hospital
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital of Los Angeles
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University - Riley Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Alternative osteoporosis medications; Alternative osteoporosis medication/s at the discretion of the investigator.
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.	Drug: Denosumab; Solution for injection; Other Names: Prolia
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.	Drug: Denosumab; Solution for injection; Other Names: Prolia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.
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.	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
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.	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
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.	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
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.	Baseline, month 12 and month 24
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.	Baseline, month 12, and month 24
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).	Baseline and month 12 and month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and months 6, 12, and 24
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.	Baseline, months 6, 12, and 24
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.	Baseline and months 6, 12, and 24

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2018
• Primary Completion (Actual): March 28, 2022
• Study Completion (Actual): March 28, 2022

Study Registration Dates

• First Submitted: June 21, 2018
• First Submitted That Met QC Criteria: August 16, 2018
• First Posted (Actual): August 20, 2018

Study Record Updates

• Last Update Posted (Estimate): December 20, 2022
• Last Update Submitted That Met QC Criteria: November 28, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: OI; Bone.
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: 20170534; 2018-000550-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No