Phase 3 Evaluation of Setrusumab Versus Bisphosphonates in Pediatric Osteogenesis Imperfecta Types I, III, and IV: A Randomized, Open-label, Active-controlled Study
- Trial ID
- 2023-504196-24-00
- Protocol
- UX143-CL314
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **setrusumab** compared to intravenous bisphosphonates (IV-BP) on the reduction in fracture rate, including morphometric vertebral fractures, in pediatric subjects with **osteogenesis imperfecta** types I, III, or IV. This is clinically relevant as reducing fracture rates can significantly improve patient outcomes and quality of life in individuals with this condition.
Secondary objectives include:
- Evaluating the effect of setrusumab versus IV-BP on the reduction in fracture rate, excluding morphometric vertebral fractures.
- Assessing the systemic exposure of setrusumab.
- Evaluating the safety profile of setrusumab.
- Assessing the immunogenicity of setrusumab.
- Evaluating the effect of setrusumab versus IV-BP on health-related quality of life as reported by caregivers.
- Evaluating the effect of setrusumab versus IV-BP on bone mineral density (BMD).
Participants
The clinical trial involves a total of **41 participants** diagnosed with **osteogenesis imperfecta**. The study population includes both male and female subjects aged between 2 to less than 7 years. Participants are required to have a clinical diagnosis of Osteogenesis Imperfecta Types I, III, or IV, confirmed by a genetic mutation in COL1A1 or COL1A2. The trial population was selected based on a history of fractures, with specific criteria regarding the number and type of fractures experienced in the past 12 to 24 months. All participants have had prior exposure to or are currently receiving intravenous bisphosphonate therapy for the treatment of osteogenesis imperfecta. Additionally, a serum 25-hydroxyvitamin D level of at least 20 ng/mL is required at the screening visit, with the possibility of rescreening after vitamin D supplementation if initial levels are below this threshold. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, given the young age of the participants.
Plans and Procedures
The clinical trial is designed as an open-label, randomized, active-controlled, Phase 3 study to evaluate the efficacy of **setrusumab** compared to intravenous bisphosphonates in pediatric subjects with **osteogenesis imperfecta** Types I, III, or IV. The primary objective is to assess the reduction in fracture rate, including morphometric vertebral fractures. The trial is expected to commence recruitment on August 1, 2023, and conclude by June 1, 2026. Participants will be randomly assigned to receive either setrusumab or a bisphosphonate, with the treatment administered via intravenous or subcutaneous routes.
The trial will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the screening visit, eligibility criteria will be confirmed, including age, clinical diagnosis, fracture history, and serum vitamin D levels. Participants will be monitored throughout the study with follow-up visits scheduled to assess treatment efficacy and safety, including the collection of serum setrusumab concentrations and monitoring for treatment-emergent adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, such as changes in fracture rates and bone mineral density.
Participant involvement is expected to last up to 12 months, depending on the treatment group assignment. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent. The study will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable insights into the management of osteogenesis imperfecta in pediatric populations.
Treatment
The clinical trial involves the administration of **Setrusumab**, a fully human immunoglobulin G subclass 2 (IgG2) lambda anti-sclerostin neutralizing monoclonal antibody. Setrusumab is provided as a solution for infusion and can be administered either intravenously (IV) or subcutaneously (SC). The maximum daily and total dose is 20 mg/kg, with a treatment period extending up to 12 months. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
**Pamidronate Disodium** is utilized in various formulations, including Pamidronate disodique Hospira 3 mg/ml and 9 mg/ml solutions for infusion, and PAMIFOS-30, 60, and 90 mg powders for infusion preparation. These are administered via infusion, with a maximum daily and total dose of 60 mg/h, over a treatment period of up to 12 months. Compliance is monitored through infusion records and participant follow-up.
**Zoledronic Acid** is administered in formulations such as Zoledronate EG 4 mg/100 ml and 5 mg/100 ml solutions for infusion, and Aclasta 5 mg solution for infusion. The administration route is infusion, with a maximum daily and total dose of 5 mg, and a treatment period of up to 12 months. Participant adherence is tracked through infusion logs and regular clinical evaluations.
**Neridronate Sodium** is provided as NERIXIA 25 mg solution for injection and NERIXIA 100 mg concentrate for infusion solution. The administration is via infusion, with a maximum daily and total dose of 25 mg, over a 12-month treatment period. Compliance is ensured through monitoring of infusion schedules and participant check-ins.
These treatments are compared against each other in the context of the trial, with the primary objective being the evaluation of the effect of Setrusumab versus intravenous bisphosphonates on the reduction in fracture rate, including morphometric vertebral fractures, in pediatric subjects with Osteogenesis Imperfecta Types I, III, or IV. The trial is designed to ensure rigorous monitoring of dosing schedules and participant compliance to maintain the integrity of the study outcomes.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the annualized rate of radiographically-confirmed fractures, including morphometric vertebral fractures, at the primary analysis. Secondary endpoints include the annualized rate of radiographically-confirmed fractures, excluding morphometric vertebral fractures, and changes from baseline in the 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. Additionally, serum **setrusumab** concentration will be measured at scheduled time points, and the frequency, severity, and relationship to treatment of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will be recorded. The incidence of binding and neutralizing anti-setrusumab antibodies will also be assessed at scheduled time points. Changes from baseline in DXA BMD z-score at the lumbar spine and percent change from baseline in DXA BMD at the lumbar spine will be evaluated at the primary analysis.
Inclusion and Exclusion 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Aug 2023 | 5 |
 Germany | Not Recruiting | 01 Aug 2023 | 5 |
 Italy | Not Recruiting | 01 Aug 2023 | 5 |
 The Netherlands | Not Recruiting | 01 Aug 2023 | — |
 Poland | Not Recruiting | 01 Aug 2023 | 7 |
| Netherlands | — | — | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zoledronate EG 5 mg/100 ml solution pour perfusion | Comparator | SOLUTION POUR PERFUSION | INFUSION | 5 | 24 | PRD5769278 |
PAMIFOS-60, 60 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji | Comparator | PROSZEK I ROZPUSZCZALNIK DO SPORZADZANIA ROZTWORU DO INFUZJI | INFUSION | 60 | 24 | PRD2773207 |
PAMIFOS-30, 30 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji | Comparator | PROSZEK I ROZPUSZCZALNIK DO SPORZADZANIA ROZTWORU DO INFUZJI | INFUSION | 5 | 24 | PRD2773206 |
PAMIFOS-90, 90 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji | Comparator | PROSZEK I ROZPUSZCZALNIK DO SPORZADZANIA ROZTWORU DO INFUZJI | INFUSION | 60 | 24 | PRD2697807 |
Pamidronate disodique Hospira 3 mg / ml solution à diluer pour perfusion | Comparator | SOLUTION À DILUER POUR PERFUSION | INFUSION | 5 | 24 | PRD1167573 |
Aclasta 5 mg solution for infusion | Comparator | SOLUTION FOR INFUSION | INFUSION | 5 | 24 | PRD10109489 |
Pamidronate disodique Hospira 9 mg / ml solution à diluer pour perfusion | Comparator | SOLUTION À DILUER POUR PERFUSION | INFUSION | 60 | 24 | PRD1167576 |
Zoledronate EG 5mg/100ml Infusionslösung | Comparator | INFUSIONSLÖSUNG | INFUSION | 5 | 24 | PRD4881390 |
NERIXIA 100 mg concentrato per soluzione per infusione | Comparator | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INFUSION | 25 | 24 | PRD375819 |
Zoledronate EG 4 mg/100 ml solution pour perfusion | Comparator | SOLUTION POUR PERFUSION | INFUSION | 5 | 24 | PRD5781028 |