Evaluation of Romosozumab Versus Bisphosphonates in Pediatric Osteogenesis Imperfecta: A Phase 3, Open-Label, Multicenter, Randomized Study

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, as per FDA guidelines. Additionally, the study aims to assess the number of any fractures at 12 months and the change in lumbar spine BMD Z-score at 12 months, following EMA guidelines. This is clinically relevant as it addresses the efficacy of romosozumab in reducing fracture risk and improving bone mineral density in children and adolescents with **Osteogenesis Imperfecta**, a condition characterized by fragile bones.

Secondary objectives include:

• Evaluating the effect of romosozumab compared with bisphosphonate(s) on changes in lumbar spine and proximal femur BMD Z-score at 6 and 12 months, as assessed by DXA.
• Assessing the impact on new or worsening vertebral fractures, nonvertebral fractures, and long bone fractures through month 12.
• Evaluating changes in function and pain using patient-reported outcomes at 12 months.
• Characterizing serum romosozumab concentration.
• Assessing the effect on any fractures, clinical fractures, and new clinical fractures through month 12.

The clinical trial involves a total of **71 participants** diagnosed with **Osteogenesis Imperfecta** (OI), specifically types I, III, or IV. The study population includes both male and female subjects aged between 5 and less than 18 years. Participants were selected based on a clinical history consistent with the expected phenotype of the specified OI types, such as facial shape, voice, blue sclera, dentinogenesis imperfecta, typical radiographic features, and fracture patterns. The trial includes individuals who have experienced at least three fractures within the previous two years, or at least one nonvertebral fracture and one prevalent vertebral fracture, or two or more prevalent vertebral fractures. The study population is considered vulnerable, and the selection criteria ensure the inclusion of subjects with a significant history of fractures related to their condition. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is a **Phase 3**, open-label, multicenter, randomized study designed to evaluate the efficacy and safety of **romosozumab** compared with bisphosphonates in children and adolescents with **osteogenesis imperfecta**. The trial aims to assess the effect of romosozumab treatment over a 12-month period, focusing on the number of clinical fractures and changes in lumbar spine bone mineral density (BMD) Z-score. The study is structured as a randomized, controlled trial, ensuring that participants are randomly assigned to either the treatment or control group, with neither the participants nor the investigators aware of the group assignments, maintaining the double-blind nature of the study.

The trial duration is estimated to conclude by May 27, 2027, with recruitment starting on March 22, 2024. Participants will be involved in the study for a maximum of 12 months. The study includes several key visits: an initial screening visit to determine eligibility based on inclusion criteria, which include age and clinical history consistent with specific types of osteogenesis imperfecta, and exclusion criteria. Following the screening, participants will undergo regular follow-up visits to monitor treatment effects and safety, with assessments including the number of fractures and changes in BMD. The end-of-study visit will occur at the 12-month mark, where final evaluations will be conducted to assess the primary and secondary endpoints.

Participants are expected to remain in the study for the full 12-month period unless specific conditions necessitate early termination. These conditions may include adverse events, withdrawal of consent, or any other medical reasons deemed significant by the investigators. The study's primary endpoints include the number of clinical fractures and changes in lumbar spine BMD Z-score, while secondary endpoints focus on additional fracture assessments and changes in BMD at other skeletal sites. The trial's methodology and design are structured to provide robust data on the efficacy and safety of romosozumab in the target population, contributing valuable insights into the management of osteogenesis imperfecta.

The clinical trial involves the administration of **romosozumab**, marketed under the brand name EVENITY, which is provided as a 105 mg solution for injection. This experimental medication is available in two pharmaceutical forms: a pre-filled syringe and a pre-filled pen. The solution is administered via **subcutaneous injection**. The dosing regimen involves a maximum daily dose of 7 mg, with a total maximum dose of 2520 mg over a treatment period of 12 months. Romosozumab is a protein-based therapeutic agent, specifically classified under the ATC code M05BX06. The medication is produced by UCB PHARMA S.A. and is not designated as an orphan drug.

In addition to the experimental treatment, the study includes the administration of **ergocalciferol**, a non-experimental auxiliary treatment. Ergocalciferol is provided in tablet form and is administered orally. The maximum daily dose is 50 micrograms, with a total maximum dose of 22,500 micrograms over a 15-month period. Ergocalciferol is a chemical-based substance and is used to support the primary treatment regimen.

Another auxiliary treatment used in the study is **calcium**, also provided in tablet form for oral administration. The maximum daily dose of calcium is 1000 mg, with a total maximum dose of 450,000 mg over a 15-month period. Calcium is a chemical-based substance and is included to complement the primary treatment.

The comparator treatment in the study is **bisphosphonates**, which are administered as a solution for infusion. The maximum daily dose is 0.01 mg, with a total maximum dose of 5 mg over a 12-month period. Bisphosphonates are classified under the ATC code M05BA and serve as the standard-of-care therapy against which the efficacy and safety of romosozumab are evaluated.

The efficacy of the clinical trial will be assessed by evaluating the impact of **romosozumab** treatment compared to bisphosphonates in children and adolescents with Osteogenesis Imperfecta over a 12-month period. The primary endpoints include the number of clinical fractures, encompassing both clinical vertebral and nonvertebral fractures, as well as the number of any fractures, which includes new and worsening vertebral compression fractures, whether clinically silent or manifest, and nonvertebral fractures, all measured through Month 12. Additionally, the change from baseline in lumbar spine Bone Mineral Density (BMD) Z-score at Month 12, as assessed by Dual-energy X-ray Absorptiometry (DXA), will be a key parameter.

Secondary endpoints will further explore changes from baseline in BMD Z-scores at Month 12 for the total hip and femoral neck, also assessed by DXA. The incidence of nonvertebral and long bone fractures, as well as the number of new or worsening vertebral fractures, will be monitored through Month 12. Patient-reported outcomes will be evaluated using changes from baseline in the CHQ-PF-50 Physical Summary score, CHAQ-CV disability score, and Wong-Baker Faces Pain Rating. Serum concentration of **romosozumab** will be measured at Day 1, Month 6, and Month 12 to assess pharmacokinetics.