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临床试验/NCT02304367
NCT02304367已完成2 期

A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23, an Antibody to FGF23, in Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)-Associated Osteomalacia

Kyowa Kirin, Inc.14 个研究点 分布在 1 个国家目标入组 17 人开始时间: 2015年3月24日最近更新:
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适应症

试验速览

阶段
2 期
状态
已完成
入组人数
17
试验地点
14
主要终点
Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS)
研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

The primary objectives of this study are to evaluate the effect of burosumab treatment on:

  • Increasing serum phosphorus levels in adults with TIO or ENS-associated osteomalacia
  • Improvement in TIO/ENS-associated osteomalacia as determined by osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), osteoid volume/bone volume (OV/BV) and mineralization lag time (MLt).

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
18 Years 至 —（Adult, Older Adult）
性别
All
接受健康志愿者
否

入选标准

  • •Have a clinical diagnosis of TIO/ENS-associated osteomalacia based on evidence of excessive fibroblast growth factor 23 (FGF23) that was not amenable to cure by surgical excision of the underlying tumor/lesion (documented by Investigator).
  • •Be ≥ 18 years of age
  • •Have a fasting serum phosphorus level < 2.5 mg/dL
  • •Have an FGF23 level ≥ 100 pg/mL by Kainos assay
  • •Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) < 2.5 mg/dL
  • •Have an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using Cockcroft-Gault formula). Subjects with eGFR ≥ 30 but < 60 mL/min will be considered eligible as long as in the opinion of the investigator the decline in renal function is not related to nephrocalcinosis.
  • •Have a corrected serum calcium level < 10.8 mg/dL
  • •Females of child-bearing potential must have a negative urine pregnancy test at Screening and Baseline and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have not experienced menarche, are post-menopausal (defined as having no menses for at least 12 months without an alternative medical cause) or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
  • •Be willing to use 2 forms of effective methods of contraception while participating in the study (sexually active subjects) and for 12 weeks after last dose of study drug.
  • •Be willing to provide access to prior medical records to determine eligibility including imaging, biochemical, and diagnostic, medical, and surgical history data
  • •Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
  • •Be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments (in the opinion of the investigator)

排除标准

  • •Have a prior diagnosis of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C
  • •Have a history of recurrent infection, a predisposition to infection, or a known immunodeficiency
  • •Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or partner) at any time during the study
  • •Have participated in an investigational drug or device trial within 30 days prior to Screening or are currently enrolled in another study of an investigational product or device
  • •Have used a therapeutic monoclonal antibody (mAb), including KRN23, within 90 days prior to Screening or have a history of allergic or anaphylactic reactions to any mAb
  • •Have or a have a history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
  • •Have used a pharmacologic vitamin D metabolite or its analog (e.g., calcitriol, doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) within 2 weeks prior to Screening or during the study
  • •Have used medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening
  • •Have a history of malignancy within 5 years of study entry with the exception of phosphaturic mesenchymal tumors (PMTs) of the mixed connective tissue type or non-melanoma skin cancers such as basal cell skin cancer
  • •Have donated blood or blood products within 60 days prior to Screening
  • •Have a history of allergic reaction to or have shown adverse reactions to a tetracycline (e.g., tetracycline hydrochloride [HCl] and demeclocycline), benzodiazepines, fentanyl or lidocaine
  • •Have any condition, which in the opinion of the investigator and sponsor, could present a concern for either subject safety or difficulty with data interpretation

结局指标

主要结局

Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS)

时间窗: Baseline, Week 48

Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid surface/bone surface is expressed as the percentage of bone surface covered in osteoid.

Change From Baseline to Week 48 in Mineralization Lag Time (MLt)

时间窗: Baseline, Week 48

Mineralization lag time is a dynamic modeling parameter representing the mean time interval between the formation of osteoid and its subsequent mineralization which can be measured using histomorphometry with double tetracycline labeling. Mlt was calculated by dividing the osteoid width by the mineralizing apposition rate (MAR; the average rate at which new bone mineral is being added on any actively forming surface). If Mlt could not be calculated directly due to low tetracycline uptake, Mlt was imputed according to the following: Mlt = O.Th/(MAR\*MS/OS), where O.Th = osteoid thickness, MAR is imputed as 0.3 μm/day, MS/OS=mineralizing surface/osteoid surface, each measured at the same visit.

Change From Baseline to Week 48 in Osteoid Thickness

时间窗: Baseline, Week 48

Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid thickness is the mean thickness of osteoid seams.

Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV)

时间窗: Baseline, Week 48

Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid volume/bone volume is expressed as the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).

Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24

时间窗: Mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22 [there was no study visit at Week 18])

The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL \[0.81 mmol/L\]) at the mid-point of the dose interval (2 weeks after dosing), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).

次要结局

  • Change From Baseline Over Time in Sit-to-Stand (STS) Test(Baseline and Weeks 24 and 48)
  • Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP)(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Percent Change From Baseline Over Time in CTx(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24(Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22))
  • Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24(Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22))
  • Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24(Baseline and Weeks 4, 8, 12, 16, 20, and 24)
  • Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24(Pre-dose on Day 1 and at Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 21, 22, and 24)
  • Change From Baseline Over Time in 24-hour Urinary Phosphorus(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP)(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Percent Change From Baseline Over Time in P1NP(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Osteocalcin(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24(End of each dose interval from Baseline to Week 24 (Weeks 4, 8, 12, 16, 20, and 24))
  • Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP)(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24(Baseline and Weeks 4, 8, 12, 16, 20, and 24)
  • Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR)(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP)(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Percent Change From Baseline Over Time in BALP(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx)(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Percent Change From Baseline Over Time in Osteocalcin(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements(Baseline and Weeks 24 and 48)
  • Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements(Baseline and Weeks 24 and 48)
  • Change From Baseline Over Time in Weighted Arm Lift (WAL) Test(Baseline and Weeks 24 and 48)
  • Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Six-Minute Walk Test (6MWT)(Baseline and Weeks 24 and 48)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score(Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (14)

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