A Randomized, Open-Label, Phase 3 Study to Assess the Efficacy and Safety of KRN23 Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With X Linked Hypophosphatemia (XLH)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 61
- 试验地点
- 16
- 主要终点
- Radiographic Global Impression of Change (RGI-C) Global Score at Week 40
研究概览
简要总结
The primary objective of this study is to evaluate the effect of KRN23 (burosumab) therapy in improving rickets in children with XLH compared with active control (oral phosphate/active vitamin D).
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
- 1 Year 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged 1 to ≤12 years with radiographic evidence of rickets as determined by central readers
- •Phosphate-regulating endopeptidase homolog, X-linked (PHEX) mutation or variant of uncertain significance in either the patient or in a directly related family member with appropriate X-linked inheritance
- •Biochemical findings associated with XLH: serum phosphorus <3.0 mg/dL (<0.97 mmol/L)
- •Serum creatinine below the age-adjusted upper limit of normal
- •Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit
- •Have received both oral phosphate and active vitamin D therapy for ≥ 12 consecutive months (for children ≥3 years of age) or ≥ 6 consecutive months (for children <3 years of age) 7 days prior to the Randomization Visit
- •Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history
- •Provide written or verbal assent (as appropriate for the subject and region) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.
- •Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments
- •Females who have reached menarche must have a negative pregnancy test at Screening and undergo additional pregnancy testing during the study. Female subjects of childbearing potential must be willing to use a highly effective method of contraception for the duration of the study plus 12 weeks after stopping the study drug. Sexually active male subjects with female partners of childbearing potential must consent to use a condom with spermicide or a highly effective method of contraception for the duration of the study plus 12 weeks after stopping the study drug
排除标准
- •Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, based on physical examination
- •Height percentile > 50th based on country-specific norms
- •Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit
- •Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty
- •Use of growth hormone therapy within 12 months before the Screening Visit
- •Presence of nephrocalcinosis on renal ultrasound grade 4
- •Planned orthopedic surgery, including osteotomy or implantation or removal of staples, 8 plates, or any other hardware, within the first 40 weeks of the study
- •Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
- •Evidence of hyperparathyroidism (parathyroid hormone [PTH] levels 2.5X upper limit of normal [ULN])
- •Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months prior to the Screening Visit
- •Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study.
- •Presence of a concurrent disease or condition that would interfere with study participation or affect safety
- •History of recurrent infection or predisposition to infection, or of known immunodeficiency
- •Use of a therapeutic monoclonal antibody within 90 days prior to the Screening Visit or history of allergic or anaphylactic reactions to any monoclonal antibody
- •Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
- •Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. OR, in Japan, use of any investigational product or investigational medical device within 4 months prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments
研究组 & 干预措施
Burosumab
Burosumab 0.8 mg/kg starting dose, administered Q2W by SC injection during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants continued to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
干预措施: burosumab (Biological)
Active Control
Multiple daily doses of oral phosphate and one or more daily doses of active vitamin D therapy, titrated and individualized by the investigator based on published recommendations during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
干预措施: burosumab (Biological)
Active Control
Multiple daily doses of oral phosphate and one or more daily doses of active vitamin D therapy, titrated and individualized by the investigator based on published recommendations during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
干预措施: Oral Phosphate Supplement (Drug)
Active Control
Multiple daily doses of oral phosphate and one or more daily doses of active vitamin D therapy, titrated and individualized by the investigator based on published recommendations during the Treatment Period (up to Week 64). During the Treatment Extension Period (Week 64 to Week 140), participants crossed over to receive a starting dose of SC burosumab 0.8 mg/kg Q2W. Participants in Japan and Korea did not enter the Treatment Extension Period.
干预措施: active vitamin D (Drug)
结局指标
主要结局
Radiographic Global Impression of Change (RGI-C) Global Score at Week 40
时间窗: Week 40
Changes in the severity of rickets and bowing were assessed using a disease specific qualitative RGI-C scoring system. The RGI-C is a 7-point ordinal scale with possible values: +3 = very much better (complete or near complete healing of rickets), +2 = much better (substantial healing of rickets), +1 = minimally better (i.e., minimal healing of rickets), 0 = unchanged, -1 = minimally worse (minimal worsening of rickets), -2 = much worse (moderate worsening of rickets), -3 = very much worse (severe worsening of rickets).
次要结局
- RGI-C Long Leg Score at Week 64(Week 64)
- Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64(Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64)
- Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40(Week 40)
- RGI-C Long Leg Score at Week 40(Week 40)
- Change From Baseline in Height-For-Age Z-Scores to Week 40(Baseline, Week 40)
- Change From Baseline in Height-For-Age Z-Scores to Week 64(Baseline, Week 64)
- Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112(Baseline, Weeks 66, 68, 76, 88, 100, 112)
- Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64(Week 64)
- RGI-C Global Score at Week 64(Week 64)
- Change in Growth Velocity Z Score From Baseline to Week 64(Baseline, Week 64)
- Change From Baseline in RSS Total Score at Week 40(Baseline, Week 40)
- Change From Baseline in RSS Total Score at Week 64(Baseline, Week 64)
- Change From Baseline Over Time in Serum ALP, up to Week 64(Baseline, Weeks 16, 24, 40, 52, 64)
- Change in Growth Velocity Z Score From Baseline to Week 40(Baseline, Week 40)
- Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64(Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64)
- Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)(Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140)
- Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64(Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64)
- Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112(Baseline, Weeks 68, 76, 88, 100, 112)
- Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)(Burosumab arm: Baseline, Week 1, 4, 8, 16, 24, 32, 40, 52, 64, 66, 68, 76, 88, 100, 112, 124, 140; Active Control arm: Baseline, Week 68, 76, 88, 100, 112, 124, 140)
- Change From Baseline Over Time in TmP/GFR, up to Week 64(Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64)
- Change From Baseline Over Time in TmP/GFR, Week 68 to 112(Baseline, Weeks 68, 76, 88, 112)
- Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40(Baseline, Week 40)
- Change From Baseline in the 6MWT Total Distance at Week 40(Baseline, Week 40)
- Percent of Predicted Normal in the 6MWT Total Distance at Week 40(Baseline, Week 40)
- Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64(Baseline, Week 64)
- Change From Baseline in the 6MWT Total Distance at Week 64(Baseline, Week 64)
- Percent Change From Baseline Over Time in Serum ALP, up to Week 112(Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112)
- Change From Baseline Over Time in Serum ALP, Week 68 to 112(Baseline, Weeks 68, 76, 88, 100, 112)
- Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40(Baseline, Week 40)
- Change From Baseline in the PROMIS Pediatric Pain Interference, Physical Function Mobility and Fatigue Domain Scores (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64(Baseline, Week 64)
- Percent of Predicted Normal in the 6MWT Total Distance at Week 64(Baseline, Week 64)