Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta

An Open-label, Ascending Multiple-dose Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Romosozumab in Children and Adolescents With Osteogenesis Imperfecta

The primary objective of this study is to evaluate the pharmacokinetics (PK) profile following multiple subcutaneous (SC) doses of romosozumab in children and adolescents with Osteogenesis Imperfecta (OI).

Study Overview

• Status: Completed
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Dietary supplement: Calcium; Dietary supplement: Vitamin D; Drug: Romosozumab

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
    • Kepler Universitaetsklinikum GmbH
• Germany
  • Koeln, Germany, 50937
    • Uniklinik Koln
• Greece
  • Athens, Greece, 11527
    • General Children Hospital Panagioti and Aglaias Kyriakou
• Hungary
  • Budapest, Hungary, 1094
    • Semmelweis Egyetem
• Italy
  • Roma, Italy, 00165
    • IRCCS Ospedale Pediatrico Bambino Gesu
• Spain
  • Cataluña
    • Esplugues de Llobregat, Cataluña, Spain, 08950
      • Hospital Sant Joan de Déu
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Hospital Universitari i Politecnic La Fe
  • Madrid
    • Getafe, Madrid, Spain, 28905
      • Hospital Universitario de Getafe
  • País Vasco
    • Baracaldo, País Vasco, Spain, 48903
      • Hospital de Cruces
• Turkey
  • Ankara, Turkey, 06500
    • Gazi Universitesi Tip Fakultesi
  • Istanbul, Turkey, 34010
    • Koc Universitesi Hastanesi
  • Izmir, Turkey, 35100
    • Ege Universitesi Ilac Gelistirme ve Farmakokinetik Arastirma Uygulama Merkezi (ARGEFAR)
• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Tennessee
    • Nashville, Tennessee, United States, 37212-3157
      • Vanderbilt University Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ambulatory male or female children 5 to less than 18 years of age upon entry into screening
• Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI as determined by presence of expected phenotype and lack of additional features unrelated to type I-IV OI

Exclusion Criteria

• History of an electrophoresis pattern inconsistent with type I to type IV OI
• History of known mutation in a gene other than collagen type I alpha 1/collagen type I alpha 2 (COL1AI/COL1A2) causing OI or other metabolic bone disease
• History of other bone diseases that affect bone metabolism (eg, 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
• Unhealed fracture as defined by orthopedic opinion
• Symptoms associated with skull abnormalities such as basilar invagination, basilar impression or Chiari malformation
• Prior treatment with anti-sclerostin antibody, fluoride or strontium, parathyroid hormone (PTH) within 12 months prior to screening, denosumab within 12 months or zoledronic acid within 6 months prior to first dose
• Less than 2 evaluable vertebrae by DXA evaluation in the region of interest, L1 - L4, as confirmed by the central imaging laboratory.
• Clinically significant valvular heart disease based on local echocardiogram (ECHO) results.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Romosozumab: 12 - < 18 Years of Age; Participants will receive 1 of 3 dose levels of romosozumab. All participants also received calcium and vitamin D.	Dietary supplement: Calcium; All participants will receive daily supplements of elemental calcium.; Dietary supplement: Vitamin D; All participants will receive daily supplementation with vitamin D.; Drug: Romosozumab; Participants will receive multiple doses of romosozumab via a SC injection.
Experimental: Romosozumab: 5 - < 12 Years of Age; Participants will receive 1 of 3 dose levels of romosozumab. All participants also received calcium and vitamin D.	Dietary supplement: Calcium; All participants will receive daily supplements of elemental calcium.; Dietary supplement: Vitamin D; All participants will receive daily supplementation with vitamin D.; Drug: Romosozumab; Participants will receive multiple doses of romosozumab via a SC injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Serum Concentration (Cmax) of Romosozumab	Mean Cmax values following Days 1 and 57 are presented.	Single blood samples were taken on days 1, 8, 15, 29, 57, 64, 71, 85, 113, and 169 (end of study); pre-specified PK analysis took place on Days 1 and 57
Time to Cmax (Tmax) of Romosozumab	Median tmax values following Days 1 and 57 are presented.	Single blood samples were taken on days 1, 8, 15, 29, 57, 64, 71, 85, 113, and 169 (end of study); pre-specified PK analysis took place on Days 1 and 57
Area Under the Serum Concentration Time Curve (AUC) From Time 0 to Day 28 (AUC[0-28]) of Romosozumab	Mean AUC(0-28) values following Days 1 and 57 are presented.	Single blood samples were taken on days 1, 8, 15, 29, 57, 64, 71, and 85; pre-specified PK analysis took place on Days 1 and 57
Accumulation Ratio of Romosozumab	The accumulation ratio was calculated as AUC(0-28) at Day 57/AUC(0-28) at Day 1. Mean accumulation ratio values based on analysis at Days 1 and 57 are presented, as pre-specified.	Single blood samples were taken on days 1, 8, 15, 29, 57, 64, 71, and 85; pre-specified PK analysis took place on Days 1 and 57
Terminal Half-life of Romosozumab	Median terminal half-life values at Day 57 are presented.	Single blood samples were taken on days 1, 8, 15, 29, 57, 64, 71, 85, 113, and 169 (end of study); pre-specified PK analysis took place on Day 57

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	TEAEs were adverse events (AEs) that started on or after first dose of investigational product up to the end of study (up to Day 169). Any clinically significant changes in vital signs, electrocardiogram parameters, physical exam findings, and clinical laboratory parameters were reported as TEAEs. Injection site reactions were events of interest (EOI) for this study.	Day 1 to end of study (up to Day 169); median duration on study was 5.55 months
Number of Participants With Changes From Baseline in Cranial Nerve VII Examination Findings at Day 57, Day 85, and Day 169	Facial nerve (cranial nerve VII) function was assessed clinically by facial symmetry inspection at rest, followed by assessment of the symmetry of specific facial movements: raising eyebrows, closing the eyes, blowing out the cheeks, smiling, pursing and closing the lips. Results of the cranial nerve examination were classed as 0 = Normal; 1 = Abnormal not clinically significant; and 2 = Abnormal clinically significant. An increase from baseline indicates an increase in abnormal clinical findings on the cranial nerve VII examination.	Baseline (Day 1), Day 57, Day 85, and Day 169
Number of Participants With Anti-romosozumab Antibodies	Treatment-boosted anti-romosozumab antibody was defined as binding antibody positive at baseline with a >4 x increase in magnitude post-baseline. Transient results were defined as negative results at the participant's last time point tested within the study period.	Blood samples for anti-romosozumab antibodies were taken Day 1, Day 15, Day 29, Day 85, and Day 169
Percentage Change From Baseline in Serum Concentrations of Serum Type 1 Collagen C-Telopeptide (CTX)	Serum concentrations of the bone turnover marker CTX were determined at pre-specified time points.	Blood samples were taken Days 1 (baseline), 8, 15, 29, 57, 64, 71, 85, 113, and 169
Percentage Change From Baseline in Serum Concentrations of Procollagen Type 1 N-terminal Propeptide (P1NP)	Serum concentrations of the bone turnover marker P1NP were determined at pre-specified time points.	Blood samples were taken Days 1 (baseline), 8, 15, 29, 57, 64, 71, 85, 113, and 169
Percentage Change From Baseline in Bone Mineral Density (BMD) of the Lumbar Spine	BMD was assessed by dual energy X-ray absorptiometry (DXA) scans of the anteroposterior lumbar spine (L1 through L4) and analyzed by a central imaging laboratory. At least 2 lumbar vertebrae from L1 - L4 must be evaluable by DXA.	DXA scans were during screening (baseline) and at Day 85 and Day 169
Percentage Change From Baseline in Bone Mineral Content (BMC) of the Lumbar Spine	BMC was assessed by DXA scans of the anteroposterior lumbar spine (L1 through L4) and analyzed by a central imaging laboratory. At least 2 lumbar vertebrae from L1 - L4 must be evaluable by DXA.	DXA scans were during screening (baseline) and at Day 85 and Day 169
Percentage Change From Baseline in Lumbar Spine Bone Area	Bone area was assessed by DXA scans of the anteroposterior lumbar spine (L1 through L4) and analyzed by a central imaging laboratory. At least 2 lumbar vertebrae from L1 - L4 must be evaluable by DXA.	DXA scans were during screening (baseline) and at Day 85 and Day 169
Mean Change From Baseline in Lumbar Spine BMD Z-Score	Lumbar spine BMD was assessed by DXA scans. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from baseline indicated an improvement in lumbar spine BMD.	DXA scans were during screening (baseline) and at Day 85 and Day 169

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): January 21, 2021
• Primary Completion (Actual): March 30, 2023
• Study Completion (Actual): March 30, 2023

Study Registration Dates

• First Submitted: September 4, 2020
• First Submitted That Met QC Criteria: September 4, 2020
• First Posted (Actual): September 11, 2020

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• 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; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Calcium
• Other Study ID Numbers: 20160227; 2017-004972-74 (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 (or other new use) 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, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. 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
• product manufactured in and exported from the U.S.: Yes