An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy and Pharmacokinetics of Asfotase Alfa (Human Recombinant Tissue-nonspecific Alkaline Phosphatase Fusion Protein) in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 69
- 试验地点
- 23
- 主要终点
- Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
研究概览
简要总结
This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study was to test the safety and efficacy of a study drug called asfotase alfa (human recombinant tissue non-specific alkaline phosphate fusion protein) to see what effects it has on patients 5 years of age or less with HPP.
详细描述
Asfotase alfa was formerly referred to as ENB-0040
Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation that can lead to progressive damage to multiple vital organs, including destruction and deformity of bones, profound muscle weakness, seizures, impaired renal function, and respiratory failure. There are limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Minute 至 5 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must meet all of the following criteria for enrollment in this study:
- •Parent or legal guardian(s) must provide written informed consent prior to any study procedures being performed and must be willing to comply with all study-required procedures. Where appropriate and required by local regulations, patient assent should also be provided prior to any study procedures being performed.
- •Documented diagnosis of HPP as indicated by:
- •Total serum alkaline phosphatase (ALP) below the lower limit of normal for age NOTE: Historical values for ALP may be used to determine patient eligibility.
- •Plasma pyridoxal-5'-phosphate (PLP) above the upper limit of normal (unless patient is receiving pyridoxine for seizures) NOTE: Historical values for PLP may be used to determine patient eligibility.
- •Radiographic evidence of HPP at screening, characterized by:
- •Flared and frayed metaphyses, and
- •Severe, generalized osteopenia, and
- •Widened growth plates, and
- •Areas of radiolucency or sclerosis
- •Two or more of the following HPP-related findings:
- •History or presence of: i) Nontraumatic post-natal fracture or ii) Delayed fracture healing
- •Nephrocalcinosis or history of elevated serum calcium
- •Functional craniosynostosis
- •Respiratory compromise or rachitic chest deformity
- •Vitamin B6-responsive seizures
- •Failure to thrive
- •Onset of symptoms prior to 6 months of age
- •Chronological age or adjusted age for premature infants born ≤ 37 weeks gestation of ≤ 5 years
- •Otherwise medically stable in the opinion of the Investigator and/or Sponsor
- •Exclusion criteria:
- •Patients will be excluded from enrollment in this study if they meet any of the following exclusion criteria:
- •Clinically significant disease that precludes study participation, in the opinion of the Investigator and/or Sponsor
- •Serum calcium or phosphate levels below the normal range
- •Current evidence of treatable form of rickets
- •Prior treatment with bisphosphonates
- •Treatment with an investigational drug within 1 month prior to the start of asfotase alfa treatment
- •Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
- •Intolerance to the investigational product (IP) or any of its excipients
- •Previous participation in the same study
- •Family relative of the Investigator
排除标准
- 未提供
研究组 & 干预措施
Asfotase alfa
A total of 6 mg/kg/week of asfotase alfa administered by SC injection (either 1 mg/kg asfotase alfa 6 times per week, or 2 mg/kg asfotase alfa 3 times per week)
干预措施: asfotase alfa (Drug)
结局指标
主要结局
Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)
时间窗: From Baseline to Week 24
The effect of asfotase alfa treatment on skeletal manifestations of HPP (i.e., change in rickets severity) was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale. Skeletal radiographs obtained at Week 24 were compared with skeletal radiographs obtained before initiation of treatment. The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets).
Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa
时间窗: Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).
Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients was assessed by the number of patients with 1 or more treatment-emergent adverse event.
次要结局
- Effect of Asfotase Alfa Treatment on Respiratory Function(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)(Up to 72 Months or regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline to Last Obtained Value(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 312)(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Pharmacokinetic (PK) Properties of Asfotase Alfa (AUCt)(PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose)
- Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline to Last Obtained Value(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Effect of Asfotase Alfa on Biomarkers - Plasma Inorganic Pyrophosphate (PPi) Change From Baseline to Last Obtained Value(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Effect of Asfotase Alfa Treatment on Tooth Loss(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Effect of Asfotase Alfa on Biomarkers - Plasma Pyridoxal-5' Phosphate (PLP) Change From Baseline to Last Obtained Value(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Effect of Asfotase Alfa on Serum Parathyroid Hormone (PTH) - Change From Baseline to Last Obtained Value(Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).)
- Pharmacokinetic (PK) Properties of Asfotase Alfa (Tlast)(PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose)
- Pharmacokinetic (PK) Properties of Asfotase Alfa (Cmax)(PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose)
- Pharmacokinetic (PK) Properties of Asfotase Alfa (Tmax)(PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose)