A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Historical Control Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Children With Hypophosphatasia (HPP)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 13
- 试验地点
- 4
- 主要终点
- Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale
研究概览
简要总结
This clinical trial studied the safety and efficacy of asfotase alfa in children with HPP compared to a historical control group.
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 no approved disease-modifying treatments for patients with this disease. There is also limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
Efficacy analyses were prospectively defined in the protocol with a comparison to historical controls. The historical control group came from patients whose characteristics matched as closely as possible the entry criteria for the trial. The control group included all patients who had x-rays within the age range defined by the inclusion criteria of this study (5 to 12 years of age, inclusive, with open growth plates).
The pre-specified plan for analysis was to combine the two asfotase alfa treated groups (asfotase alfa 2 mg/kg subcutaneous (SC) injection three times per week or 3 mg/kg subcutaneous (SC) injection three times per week) and compare them to historical controls.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent from parent or legal guardian prior to participation
- •Patients > 5 and < 12 years of age with open growth plates at time of enrollment
- •Tanner stage of 2 or less indicating pre-pubescence
- •Documented history of HPP, as evidenced by:
- •Presence of HPP-related rickets on skeletal radiographs of the wrist and knee
- •Serum alkaline phosphatase (ALP) below age-adjusted normal range
- •Plasma PLP at least twice the upper limit of normal
- •25(OH) vitamin D level > 20 ng/mL
- •Ability of patient and parent/guardian to comply with study requirements
排除标准
- •Serum calcium or phosphorus below age-adjusted normal range
- •History of sensitivity to any study drug constituent
- •Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities
- •Treatment with an investigational drug within 1 month before start of study drug
- •Current enrollment in any other study involving an investigational new drug, device, or treatment for HPP (e.g., bone marrow transplantation)
- •Current evidence of a treatable form of rickets
- •Prior treatment with bisphosphonates
- •Bone fracture or orthopedic surgery within the past 12 months that, in the opinion of the Investigator would interfere with the ability of study patient to comply with study protocol
- •Major congenital abnormality other than those associated with HPP
结局指标
主要结局
Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale
时间窗: Baseline and Week 24
A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings.
次要结局
- Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy)(Baseline and Week 24)
- Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy)(Baseline and Week 24)
- Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi)(Baseline and Week 24)
- Change in Height (Z-scores)(Baseline and Week 24)
- Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP)(Baseline and Week 24)
- Time at Maximum Serum Concentration of Asfotase Alfa (Tmax).(Study Week 6 (0 to 48 hours post-dose))
- Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy)(Baseline and Week 24)
- Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)(Study Week 1 (0 to 48 hours post-dose))
- Maximum Serum Concentration of Asfotase Alfa (Cmax).(Study Week 6 (0 to 48 hours post-dose))
- Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)(Study Week 6 (0 to 48 hours post-dose).)