Clinical trial NCT05768854: Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
Official title: An Open-label, Randomized, Active-Controlled, Phase 3 Study of Setrusumab Compared With Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta Types I, III or IV
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Osteogenesis Imperfecta
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2023-03-14
Enrollment: 69
Sex: ALL
Minimum age (years): 2
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to evaluate the effect of setrusumab vs intravenous bisphosphonates (IV-BP) on reduction in fracture rate, including morphometric vertebral fractures in pediatric participants.

Detailed description: Participants will be randomized 1:1 to receive either setrusumab or IV-BP. Following randomization, participants will receive setrusumab or IV-BP for up to 24 months during the Active-controlled Period. At the end of the Active-controlled Period all participants will enter the Extension Period and participants assigned to IV-BP will transition to setrusumab. During the Extension Period, all participants will receive setrusumab for a minimum of 12 months or until setrusumab becomes commercially available in their respective country or the study is discontinued. The use of any bisphosphonate is prohibited throughout the Extension Period.

Eligibility criteria: Inclusion Criteria:

* Male or female 2 to \< 7 years of age at time of informed consent
* Clinical diagnosis of OI Types I, III, or IV confirmed by identification of genetic mutation in COL1A1 or COL1A2
* History of ≥ 1 fracture in the past 12 months, ≥ 2 fractures in the past 24 months, or ≥ 1 femur, tibia, or humerus fracture in the past 24 months
* Any prior exposure to, or currently receiving, IV-bisphosphonate therapy for treatment of OI
* Serum 25-hydroxyvitamin D level ≥ 20 ng/mL at the Screening visit. If 25-hydroxyvitamin D levels are below 20 ng/mL, the subject may be rescreened after a minimum of 14 days of vitamin D supplementation as directed by the Investigator

Exclusion Criteria:

* Contraindication for the use of IV bisphosphonates based on clinical judgment of the Investigator
* History of skeletal malignancies or bone metastases at any time
* History of neural foraminal stenosis (except if due to scoliosis)
* Clinical manifestations of Chiari malformation or basilar invagination. Presence of any other neurologic disease that has been clinically unstable within past 2 years requires review by the Medical Monitor.
* History of or current uncontrolled concomitant diseases that may impact bone metabolism, such as hypo/hyperparathyroidism, abnormal thyroid function, nephrotic syndrome, or Stage IV/V renal disease
* Any skeletal condition (other than OI) leading to bone deformity and/or increased risk of fractures, such as rickets, osteopetrosis, idiopathic juvenile osteoporosis, or skeletal dysplasia
* History of known cardiovascular disease such as coronary artery anomaly, Kawasaki disease, myocarditis, cardiomyopathy, myocardial infarction, stroke, or thromboembolic disease. Individuals with other congenital or acquired cardiovascular disease necessitating echocardiogram require Medical Monitor review. Investigators should consider whether the potential benefits of treatment outweigh the potential risks in patients with cardiovascular risk factors such as confirmed arterial hypertension.
* Hypocalcemia, defined as serum calcium levels below the age-adjusted normal limit reference ranges after a recommended ≥ 4 hour fast, at Screening
* Estimated glomerular filtration rate \<=35 mL/min/1.73 m2 at Screening
* Prior treatment with growth hormone, denosumab, anti-sclerostin antibody, or other anabolic or anti-resorptive medications impacting the bone (other than bisphosphonates) at any time
* History of external radiation therapy
* Known hypersensitivity to setrusumab or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects
* Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results
* Use of any investigational product or investigational medical device within 4 weeks or 5 half-lives (whichever is longer) of investigational drug prior to Screening, or during the study (per discretion of the Investigator in consultation with the Medical Monitor)
* Concurrent participation in another clinical study without prior approval from the study Medical Monitor

Primary outcomes:
measure: Annualized Rate of All Radiographically-Confirmed Fractures, Including Morphometric Vertebral Fractures at the Primary Analysis
timeFrame: Up to 24 Months
Secondary outcomes:
measure: Annualized Rate of Radiographically-Confirmed Fractures, Excluding Morphometric Vertebral Fractures at the Primary Analysis
timeFrame: Up to 24 Months
measure: Change from Baseline in Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI) Sports/Physical Functioning and Pain/Comfort Subscale Scores at the Primary Analysis
timeFrame: Baseline, Up to 12 Months
measure: Change from Baseline in DXA BMD Z-score at the Lumbar Spine at the Primary Analysis
timeFrame: Up to 24 Months
measure: Percent Change from Baseline in DXA BMD at the Lumbar Spine at the Primary Analysis
timeFrame: Up to 24 Months
measure: Serum Setrusumab Concentration
timeFrame: Up to 24 Months
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
timeFrame: Up to 24 Months
measure: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies
timeFrame: Up to 24 Months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Childrens Hospital LA
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Wilmington
country: United States
facility: Nemours/ Alfred i. duPoint Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Hospital DC
state: District of Columbia
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Shriners Hospitals for Children Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Missouri-Kansas City (UMKC) Medical School - Children's Mercy Hospitals & Clinics (CMHC)
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill (UNC)
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center (VUMC)
state: Tennessee
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre (HCPA)
state: Rio Grande Do Sul
city: London
country: Canada
facility: Children's Hospital at London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Childrens Hospital Of Eastern Ontario Research Institute, University Of Ottawa
city: Paris
country: France
facility: Institut Imagine
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Umberto I
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht (UMCU) - Wilhelmina Kinderziekenhuis
city: Łódź
country: Poland
facility: Uniwersytet Medyczny w Lodzi - Klinika Endokrynologii i Chorob Metabolicznych
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References: