Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta

Amgen25 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Osteogenesis Imperfecta

Interventions

RomosozumabDRUG

Participants will receive multiple doses of romosozumab via a SC injection.

CalciumDIETARY_SUPPLEMENT

All participants will receive daily supplements of elemental calcium.

Vitamin DDIETARY_SUPPLEMENT

All participants will receive daily supplementation with vitamin D.

Eligibility

Sex: ALLMin age: 5 YearsMax age: 17 Years

Medical Language ↔ Plain English

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.

Locations (15)

Riley Hospital for Children

Indianapolis, Indiana, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Outcomes

Primary Outcomes

Maximum Observed Serum Concentration (Cmax) of Romosozumab

Mean Cmax values following Days 1 and 57 are presented.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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 Outcomes

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.

Data from ClinicalTrials.gov

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The Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Kepler Universitaetsklinikum GmbH

Linz, Austria

Uniklinik Köln

Cologne, Germany

General Children Hospital Panagioti and Aglaias Kyriakou

Athens, Greece

Semmelweis Egyetem

Budapest, Hungary

IRCCS Ospedale Pediatrico Bambino Gesu

Roma, Italy

Hospital de Cruces

Barakaldo, Basque Country, Spain

Hospital Sant Joan de Deu

Esplugues de Llobregat, Catalonia, Spain

...and 5 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: DXA scans were during screening (baseline) and at Day 85 and Day 169