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

NCT03638128 | Terminated Phase 3 Results FDA Drug

• 2 other identifiers: 201705342018-000550-21
• Study Type: interventional
• Target: 75
• Locations: 12 countries
• Sites: 22

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).

Conditions

Osteogenesis Imperfecta (OI)

Keywords

OI; Bone.

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (3)

• Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score

  Baseline and months 6, 12, and 24

• Change From Baseline in Total Hip BMD Z-score

  Baseline, months 6, 12, and 24

• Change From Baseline in Femoral Neck BMD Z-score

  Baseline and months 6, 12, and 24

Study Arms (3)

Alternative Medications / Observational

OTHER

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

Denosumab 1 mg/kg Q6M

EXPERIMENTAL

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

Denosumab 1 mg/kg Q3M

EXPERIMENTAL

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

Interventions

Denosumab DRUG

Solution for injection

Also known as: Prolia

Denosumab 1 mg/kg Q3M; Denosumab 1 mg/kg Q6M

Alternative osteoporosis medications DRUG

Alternative osteoporosis medication/s at the discretion of the investigator.

Alternative Medications / Observational

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Amgen: lead

Study Sites (22)

Childrens Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

Indiana University - Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

The Childrens Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Perth Childrens Hospital

Nedlands, Western Australia, 6909, Australia

Location

Universite Catholique de Louvain Cliniques Universitaires Saint Luc

Brussels, 1200, Belgium

Location

Childrens Hospital of Eastern Ontario

Ottawa, Ontario, K1H 8L1, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Shriners Hospital for Children

Montreal, Quebec, H4A 0A9, Canada

Location

Fakultni nemocnice Plzen

Pilsen, 305 99, Czechia

Location

Thomayerova nemocnice

Prague, 140 59, Czechia

Location

Centre Hospitalier Universitaire de Bordeaux - Hopital Pellegrin

Bordeaux, 33076, France

Location

Hopital Necker Enfants Malades

Paris, 75743, France

Location

Uniklinik Köln

Cologne, 50931, Germany

Location

Semmelweis Egyetem

Budapest, 1094, Hungary

Location

Azienda Ospedaliera Policlinico Umberto I

Roma, 00161, Italy

Location

SPZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego w Lodzi

Lodz, 91-738, Poland

Location

Hospital Sant Joan de Deu

Esplugues de Llobregat, Catalonia, 08950, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, Valencia, 46026, Spain

Location

Birmingham Childrens Hospital

Birmingham, B4 6NH, United Kingdom

Location

Bristol Royal Hospital for Children

Bristol, BS2 8AE, United Kingdom

Location

Royal Hospital for Children

Glasgow, G51 4TF, United Kingdom

Location

Sheffield Childrens Hospital

Sheffield, S10 2TH, United Kingdom

Location

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Osteogenesis Imperfecta

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Osteochondrodysplasias; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2018
• First Posted: August 20, 2018
• Study Start: July 26, 2018
• Primary Completion: March 28, 2022
• Study Completion: March 28, 2022
• Last Updated: December 20, 2022
• Results First Posted: December 20, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

ES (2); US (2); GB (4); CA (3); CZ (2); IT (1); PL (1); DE (1); AU (2); HU (1); BE (1); FR (2)