Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta

A Phase 3, Open-Label, Multicenter, Randomized Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta

The primary objective of this study is to evaluate the effect of romosozumab treatment for 12-months compared with bisphosphonate(s) on the number of clinical fractures at 12-months; the number of any fractures at 12-months and change in lumbar spine bone mineral density (BMD) Z-score at 6-months.

Study Overview

• Status: Recruiting
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Drug: Romosozumab; Drug: Bisphosphonate

• Study Type: Interventional
• Enrollment (Estimated): 106
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Amgen Call Center; Phone Number: 866-572-6436; Email: medinfo@amgen.com

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Recruiting
      • Monash Childrens Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6909
      • Recruiting
      • Perth Childrens Hospital
• Austria
  • Linz, Austria, 4020
    • Recruiting
    • Kepler Universitaetsklinikum GmbH
• Belgium
  • Leuven, Belgium, 3000
    • Recruiting
    • Universitair Ziekenhuis Leuven - Campus Gasthuisberg
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Recruiting
      • Centre Hospitalier Universitaire Sainte Justine
• France
  • Paris Cedex 15, France, 75743
    • Recruiting
    • Hôpital Necker Enfants Malades
• Hungary
  • Budapest, Hungary, 1094
    • Recruiting
    • Semmelweis Egyetem
• Japan
  • Okayama
    • Okayama-shi, Okayama, Japan, 700-8558
      • Recruiting
      • Okayama University Hospital
    • Okayama-shi, Okayama, Japan, 700-0013
      • Recruiting
      • Okayama Saiseikai Outpatient Center Hospital
  • Osaka
    • Izumi-shi, Osaka, Japan, 594-1101
      • Recruiting
      • Osaka Womens and Childrens Hospital
• Poland
  • Lodz, Poland, 93-338
    • Recruiting
    • Instytut Centrum Zdrowia Matki Polki
  • Lodz, Poland, 91-738
    • Recruiting
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Centralny Szpital Kliniczny UMeds
• Slovakia
  • Bratislava, Slovakia, 833 40
    • Recruiting
    • Narodny ustav detskych chorob
• Spain
  • Madrid, Spain, 28009
    • Recruiting
    • Hospital Universitario Infantil Niño Jesus
  • Cataluña
    • Esplugues De Llorbregat, Cataluña, Spain, 08950
      • Recruiting
      • Hospital Sant Joan de Deu
  • Madrid
    • Getafe, Madrid, Spain, 28905
      • Recruiting
      • Hospital Universitario de Getafe
  • País Vasco
    • Baracaldo, País Vasco, Spain, 48903
      • Recruiting
      • Hospital de Cruces
• Switzerland
  • Lausanne, Switzerland, 1011
    • Recruiting
    • Centre Hospitalier Universitaire Vaudois
• Turkey
  • Ankara, Turkey, 06500
    • Recruiting
    • Gazi Universitesi Tip Fakultesi
  • Istanbul, Turkey, 34890
    • Recruiting
    • Marmara Universitesi Tip Fakultesi Hastanesi
  • Trabzon, Turkey, 61080
    • Recruiting
    • Karadeniz Teknik Universitesi Hastanesi
• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic Childrens Center
  • Tennessee
    • Nashville, Tennessee, United States, 37212-3157
      • Recruiting
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant has provided informed consent/assent prior to initiation of any study specific activities/procedures.

OR

• Participant's legally authorized representative has provided informed consent when the participant is legally too young to provide informed consent and the participant has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
• Ambulatory male and female children and adolescents, age 5 to <18 years, including ambulatory with assistance as defined in the pediatric osteogenesis imperfecta (OI) population.

• Clinical diagnosis of OI, defined as clinical history consistent with type I, III, or IV OI as determined by presence of expected phenotype (examples include: facial shape, voice, blue sclera, dentinogenesis imperfecta, typical radiographic features, fracture pattern) and lack of additional features unrelated to type I, III, or IV OI (eg, blindness, mental retardation, neuropathy, and craniosynostosis).

  o If familial, also must be autosomal dominant.

• Meets at least one of the following:

  • 3 or more fractures within the previous 2 years, or
  • 1 or more nonvertebral fracture(s) within the previous 2 years and at least 1 prevalent vertebral fracture, or
  • 2 or more prevalent vertebral fractures.
• Lumbar spine Z-score of ≤-1.0.

Exclusion Criteria:

Disease Related

• History of an electrophoresis pattern inconsistent with type I, III or IV OI.
• History of known mutation in a gene other than collagen type I alpha 1/collagen type I alpha 2 (COL1A1/COL1A2) causing OI or other metabolic bone disease.
• History of congenital dislocation of the radial head, interosseous membrane calcification, or exuberant callus formation.

Other Medical Conditions

• History of osteomalacia or rickets.
• Body weight less than 14 kg or greater than 90 kg.
• History of other bone diseases that affect bone metabolism (e.g., but not limited to osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, hypophosphatasia).
• History of Kawasaki disease, rheumatic myocarditis, ischemic cardiomyopathy, inherited cardiomyopathies, nephrotic syndrome, familial hypercholesterolemia, stroke, or any thromboembolic disorder.
• Evidence of untreated or unhealed oral infections.
• Unhealed or planned invasive dental or tooth procedure as determined by treating dentist; removal of baby teeth is acceptable and not considered an invasive dental procedure.
• Unhealed fracture as defined by orthopedic opinion.
• Osteotomy, rodding surgery or spinal fusion surgery within 5-months prior to screening, or not yet healed per orthopedic surgeon.
• History of clinically significant valvular heart disease previously documented with local echocardiogram results.

• Evidence of any of the following:

  • Current hyper- or hypoparathyroidism (parathyroid hormone outside the normal range).

  • Renal disease: Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2 (calculated by the bedside Schwartz equation at screening) eGFR (mL/min/1.73 m^2) = 0.413 X (height/serum creatinine)

    1. (Height is in centimeters, and serum creatinine is in mg/dL).

  • Current hypocalcemia (albumin-adjusted serum calcium <lower limit of normal [LLN]) or hypercalcemia (albumin-adjusted serum calcium > upper limit of normal [ULN] of the laboratory's reference range).
  • Serum vitamin D <20 ng/mL; rescreening for Vitamin D level < 20 ng/mL will be allowed, after adequate supplementation.
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 x ULN.
  • Total bilirubin (TBL) >1.5 x ULN (participants with Gilbert syndrome are eligible).
  • Serum phosphorus < LLN for age.
• Symptoms associated with skull abnormalities such as basilar invagination, basilar impression or Chiari malformation (e.g., headache induced by coughing or straining for stool, visual disturbances, paresthesias or weakness).
• History of malabsorption (in children with serum albumin <LLN, malabsorption should be clinically ruled out by the investigator to confirm eligibility).
• History of long QT syndrome.
• History of malignancy.
• History of any solid organ or bone marrow transplant.
• History of hyper- or hypothyroidism, unless participant is on stable therapy > 6-months and has supporting laboratory documentation within 6-months prior to or at screening indicating normal serum thyroid-stimulating hormone (TSH) value.
• Known intolerance to calcium or vitamin D supplements.
• History of osteonecrosis of the jaw (ONJ).

Prior/Concomitant Therapy

• Prior treatment with:
• Romosozumab or other anti-sclerostin antibody within 12-months prior to screening.
• Fluoride or strontium for bone disease.
• Parathyroid hormone (PTH) or PTH derivatives within 12-months prior to screening.
• Denosumab within 12-months after the last injection prior to first dose of romosozumab.
• Administration of any of the following treatments within 3-months prior to screening:
• Systemic glucocorticoids (≥ 5.0 mg prednisone equivalent/day for more than 10 days) within 3-months prior to screening. Topical and inhaled glucocorticoids will be allowed.
• Growth hormone (participants on stable dose of growth hormone for at least 3-months prior to screening will be allowed).
• Calcitonin.
• Other bone active drugs including anticonvulsants (except gabapentin and benzodiazepines) and heparin (unless low molecular weight heparin).
• Chronic systemic ketoconazole, androgens (except participants who have received testosterone therapy for physiologic replacement in the setting of documented hormonal deficiency), adrenocorticotropic hormone (ACTH), cinacalcet, aluminum, lithium, protease inhibitors, gonadotropin-releasing hormone agonists.
• Use of concomitant medications that may prolong the corrected QT interval (eg, ondansetron, albuterol, sotalol, amiodarone, erythromycin, or clarithromycin). Refer to CredibleMeds.org for the complete list of medications which can impact QT interval.

Prior/Concurrent Clinical Study Experience

- Currently receiving treatment in another investigational device or drug study, or less than 2 years since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.

Other Exclusions

• Positive blood screen for hepatitis B surface antigen (HbsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody (HepCAb).
• Participants with symptomatic human immunodeficiency virus (HIV) with bone involvement or those that have been in a serious clinical condition.
• Less than 2 evaluable vertebrae by dual-energy x-ray absorptiometry evaluation in the region of interest, L1-L4, as confirmed by the central imaging laboratory.
• Any planned major surgery, including skeletal surgery (eg, rodding surgery, spinal surgery) within the next 12-months from Day 1 that would interfere with study procedures or would require missing of any investigational product
• Female participants of childbearing potential unwilling to use a highly effective method of contraception during treatment and for an additional 3-months after the last dose of investigational product or non-investigational product.
• Female participants who are breastfeeding or who plan to breastfeed while on study through 3-months after the last dose of investigational product or non-investigational product.
• Female participants planning to become pregnant or donate eggs while on study through 3-months after the last dose of investigational product or non-investigational product.
• Female participants of childbearing potential with a positive pregnancy test assessed at Screening and/or Day 1 by a highly sensitive urine or serum pregnancy test.
• Male participants with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 3-months after the last dose of investigational product or non-investigational product.
• Male participants unwilling to abstain from donating sperm during treatment and for an additional 3-months after the last dose of investigational product or non-investigational product.
• Participant has known sensitivity to any of the products to be administered during dosing.
• Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the participant and investigator's knowledge.
• 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 participant safety or interfere with the study evaluation, procedures or completion

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Romosozumab; Participants will receive romosozumab once a month (QM) for 12 months.	Drug: Romosozumab; Subcutaneous (SC) injection; Other Names: EVENITY®
Active Comparator: Standard of Care Bisphosphonate; Participants will receive bisphosphonates per local standard of care treatment regimens, as determined by the investigator for 12 months.	Drug: Bisphosphonate; Administration determined by investigator according to the local standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Clinical Fractures	Clinical fractures include clinical vertebral fractures and nonvertebral fractures.	12 months
Number of Any Fractures	Fractures include new and worsening vertebral compression fractures, whether clinically silent or manifest, and nonvertebral fractures.	12 months
Change from Baseline to 6 Months in Lumbar Spine BMD Z-score		Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline to 12 Months in Lumbar Spine BMD Z-score		Baseline and 12 months
Change from Baseline to 6 Months in Total Hip BMD Z-score		Baseline and 6 months
Change from Baseline to 12 Months in Total Hip BMD Z-score		Baseline and 12 months
Change from Baseline to 6 Months in Femoral Neck BMD Z-score		Baseline and 6 months
Change from Baseline to 12 Months in Femoral Neck BMD Z-score		Baseline and 12 months
Number of Participants with Any Fractures		12 months
Number of Participants with Clinical Fractures		12 months
Number of Participants with New or Worsening Vertebral Fractures		12 months
Number of Participants with Nonvertebral Fractures		12 months
Number of New or Worsening Vertebral Fractures		12 months
Number of Nonvertebral Fractures		12 months
Number of Long Bone Fractures		12 months
Change from Baseline in Child Health Questionnaire - Parent Version (CHQ-PF-50) Physical Summary Score	The CHQ-PF-50 measures how a child's condition affects their ability to function in daily life. The CHQ-PF-50 measures 50 items in the following domains: physical functioning, role/social limitations - physical, general health perceptions, bodily pain/discomfort, family activities, role/social limitations - emotional/behavioral, parent impact - time, parent impact - emotion, self-esteem, mental health, behavior, family cohesion, change in health. Each item is rated on a scale from "without any difficulty" to "unable to do". Total scores for each item are transformed to 0 - 100 scale, with lower scores indicating worse health states. Higher change from baseline scores indicate better or more positive health states.	Baseline and 12 months
Change from Baseline in Childhood Health Assessment Questionnaire (CHAQ-CV) Disability Score	The CHAQ-CV measures how a child's condition affects their ability to function in daily life. The CHAQ-CV measures 50 items in the following domains: physical functioning, role/social limitations - physical, general health perceptions, bodily pain/discomfort, family activities, role/social limitations emotional/behavioral, self-esteem, mental health, behavior, family cohesion, change in health. Each item is rated on a scale from "without any difficulty" to "unable to do". Total scores for each item are transformed to 0 - 100 scale, with lower scores indicating worse health states. Higher change from baseline scores indicate better or more positive health states.	Baseline and 12 months
Change from Baseline in the Wong-Baker Faces Pain Rating Scale	The Wong-Baker Faces Pain Rating Scale is a horizontal pain scale that consists of six hand-drawn faces that range from a smiling "no hurt" face with a score of 0 to a crying "hurts worst" face with a score of 10. Greater change from baseline scores indicate greater pain experienced by the participant.	Baseline and 12 months
Serum Concentration of Romosozumab		Day 1 to Month 12
Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) at 12 Months	Any clinically signification change from baseline in laboratory values and vital signs after first dose will be recorded as a TEAE.	12 months
Number of Participants with Anti-romosozumab Antibodies at 12 Months		12 months
Number of Participants who Experience TEAEs from Month 12 to Month 15	Any clinically signification change from baseline in laboratory values and vital signs after first dose will be recorded as a TEAE.	Month 12 to Month 15
Number of Participants with Anti-romosozumab Antibodies from Month 12 to Month 15		Month 12 to Month 15
Number of Participants who Experience TEAEs at 15 Months	Any clinically signification change from baseline in laboratory values and vital signs after first dose will be recorded as a TEAE.	15 months
Number of Participants with Anti-romosozumab Antibodies at 15 Months		15 months
Number of Participants with a Narrowing from Baseline to 6 Months in the Intracranial Nerve Tract in the Cranium and Vault of the Skull	Measured in a subset of participants who receive cranial nerve computerized tomography (CT) scans.	Baseline and 6 months
Number of Participants with a Narrowing from Baseline to 12 Months in the Intracranial Nerve Tract in the Cranium and Vault of the Skull	Measured in a subset of participants who receive cranial nerve CT scans.	Baseline and 12 months

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2024
• Primary Completion (Estimated): June 7, 2027
• Study Completion (Estimated): September 10, 2027

Study Registration Dates

• First Submitted: July 24, 2023
• First Submitted That Met QC Criteria: July 24, 2023
• First Posted (Actual): August 2, 2023

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Bisphosphonates; Osteogenesis Imperfecta; Romosozumab; EVENITY®
• 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; Diphosphonates
• Other Study ID Numbers: 20200105; 2023-503294-37 (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; SAP; ICF; 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