A Retrospective Observational Study of the Effect of Dosing Regimen of Burosumab on Biochemical Control of Serum Phosphate Levels in Patients With X-linked Hypophosphataemia (XLH)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 2
- 主要终点
- The proportion of patients who achieved biochemical control (serum phosphate above the lower limit of the local reference range) on a dose of less than 0.8 mg/kg per dose of Burosumab.
研究概览
简要总结
X-linked hypophosphataemia (XLH) is a rare, hereditary condition. The genetic defect leads to low blood phosphate levels and vitamin D suppression. Phosphate is required for strong bones and teeth and to store energy in cells. Low phosphate leads to soft bones (rickets). Patients experience bowed legs, short stature, bone pain and dental pain.
Prior to Burosumab, conventional treatment of XLH previously consisted of two medications. On this regimen, patients take oral phosphate supplements 4-6 times a day and an active form of vitamin D daily. This treatment can leave patients with residual symptoms. They report significant disabilities and reduced quality of life.
Burosumab (Crysvita, Kyowa Kirin) is now the standard paediatric treatment for XLH. It is given once a fortnight by injection under the skin. Early studies used a starting dose of 0.4mg/kg per dose. NICE recommends a starting dose of 0.4mg/kg, a normal maintenance dose of 0.8mg/kg and a maximum of 2mg/kg (up to 90mg). The British National Formulary for Children (BNFC) gives the same advice.
However, the European Medicines Agency recommends a starting dose of 0.8mg/kg per dose which is, therefore, the standard starting dose now. Some patients achieve symptom and biochemical control on less than 0.8 mg/kg per dose. They may be exposed to higher doses than necessary.
To date, approximately 200 patients have started on Burosumab in England. They are all managed by specialist centres. The rare status of XLH means there are relatively few patients in each centre. Treatment effects and trends can only be described by collating data from multiple centres.
The investigators will undertake a review across multiple English centres of the doses of Burosumab. The review will only collect data already in the patients' health records. It will look at factors affecting the starting dose. The investigators will assess the association between dose, blood markers and growth.
详细描述
X-linked hypophosphatemia (XLH) is a rare, lifelong genetic disorder caused by inactivating mutations in the PHEX gene, leading to elevated levels of fibroblast growth factor 23 (FGF23), which induces renal phosphate wasting. The resultant hypophosphataemia disrupts bone mineralisation, causing rickets, skeletal deformities, growth failure, and chronic pain.
Historically, treatment has relied on oral phosphate and activated vitamin D analogues, which are burdensome and only partially effective. Burosumab (Crysvita), a monoclonal antibody that targets and neutralizes FGF23, is a transformative therapy for XLH. It has been shown to normalise serum phosphate levels, improve growth parameters, and reduce rickets severity. However, real-world data on optimal dosing regimens remain limited.
This study is a multi-centre, pragmatic, retrospective observational analysis conducted across paediatric metabolic bone centres in England. The objective is to assess whether a starting dose of less than 0.8 mg/kg of Burosumab is effective in achieving biochemical control and to characterise dosing variation and outcomes across centres. The current standard dose recommended by the European Medicines Agency (EMA) is 0.8 mg/kg every two weeks, but clinical experience and historical trial data suggest that a proportion of patients may achieve biochemical control on lower doses.
This study will review data from paediatric patients with a diagnosis of XLH who have received at least 12 months of continuous Burosumab treatment under paediatric dosing criteria. Patients will be included regardless of whether they subsequently transitioned to adult dosing, provided their data under paediatric treatment can be clearly delineated.
Data will be extracted from existing clinical records by each participating centre. These records form part of routine care and include biochemistry (serum phosphate, calcium, alkaline phosphatase, creatinine, parathyroid hormone; and urinary calcium, phosphate, and creatinine), auxology (height, weight, sitting height), treatment timelines, imaging findings (notably nephrocalcinosis), and documented adverse effects. Data will be submitted in pseudonymised form through a secure portal hosted by the University of Nottingham.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A diagnosis of x-linked hypophosphataemia (XLH) including genetic confirmation of a PHEX mutation.
- •Has received at least 12 months of continuous Burosumab treatment under paediatric criteria (given Burosumab is not started till a child is 12 months old in England, the minimum age will, therefore, be 2 years old) prior to their 18th birthday.
排除标准
- •Burosumab received under adult criteria (patients who have received both Burosumab under paediatric arrangements and, subsequently, adult arrangements, can have data obtained during paediatric dosing included).
结局指标
主要结局
The proportion of patients who achieved biochemical control (serum phosphate above the lower limit of the local reference range) on a dose of less than 0.8 mg/kg per dose of Burosumab.
时间窗: During study period, up to 1 year
The proportion of patients who achieved biochemical control (serum phosphate above the lower limit of the local reference range) on a dose of less than 0.8 mg/kg per dose of Burosumab.
时间窗: During study period, up to 1 year
次要结局
- Comparison of patients with a raised baseline PTH (prior to initiation of Burosumab) to those with a normal PTH - time to control(12 months following first dose of Burosumab)
- Comparison of patients with a raised baseline PTH (prior to initiation of Burosumab) to those with a normal PTH - change in height SDS(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - time to biochemical control(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - change in height SDS(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - dose difference(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - cost difference(12 months following first dose of Burosumab)
- Comparison of patients with a raised baseline PTH (prior to initiation of Burosumab) to those with a normal PTH - dose difference(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - time to biochemical control(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - change in height SDS(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - dose difference(12 months following first dose of Burosumab)
- Comparison of outcomes for patients started on Burosumab at a dose of less than 0.8 mg/kg per dose with those started on a dose of 0.8 mg/kg per dose and above - cost difference(12 months following first dose of Burosumab)
- Comparison of patients with a raised baseline PTH (prior to initiation of Burosumab) to those with a normal PTH - dose difference(12 months following first dose of Burosumab)
- Comparison of patients with a raised baseline PTH (prior to initiation of Burosumab) to those with a normal PTH - time to control(12 months following first dose of Burosumab)
- Comparison of patients with a raised baseline PTH (prior to initiation of Burosumab) to those with a normal PTH - change in height SDS(12 months following first dose of Burosumab)
- Factors influencing dosing regimen in patients on Burosumab(At baseline, first dose of Burosumab)
- Description of progression and monitoring following the initiation of Burosumab - PTH(From first dose of Burosumab to 12 months later)
- Description of progression and monitoring following the initiation of Burosumab - nephrocalcinosis(From first dose of Burosumab to 12 months later)
- Description of progression and monitoring following the initiation of Burosumab - urinary calcium & phosphate(From first dose of Burosumab to 12 months later)
- Description of progression and monitoring following the initiation of Burosumab - adverse events(From first dose of Burosumab to 12 months later)