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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Osteogenesis Imperfecta

Intervention / Treatment
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* Drug: Romosozumab
* Drug: Bisphosphonate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteogenesis Imperfecta, Romosozumab, EVENITY®, Bisphosphonates