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Study of KRN23 in Adult Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02304367
Recruitment Status : Active, not recruiting
First Posted : December 1, 2014
Last Update Posted : February 25, 2020
Sponsor:
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Tracking Information
First Submitted Date  ICMJE November 24, 2014
First Posted Date  ICMJE December 1, 2014
Last Update Posted Date February 25, 2020
Actual Study Start Date  ICMJE March 24, 2015
Actual Primary Completion Date July 27, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2018)
  • Proportion of Participants Achieving Mean Serum Phosphorus Levels Above the Lower Limit of Normal (LLN) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, Week 24 ]
  • Change From Baseline in Osteoid Thickness (O.Th) at Week 48 [ Time Frame: Baseline, Week 48 ]
  • Change From Baseline in Osteoid Surface/Bone Surface (OS/BS) at Week 48 [ Time Frame: Baseline, Week 48 ]
  • Change From Baseline in Osteoid Volume/Bone Volume (OV/BV) at Week 48 [ Time Frame: Baseline, Week 48 ]
  • Change From Baseline in Mineralization Lag Time (MLt) at Week 48 [ Time Frame: Baseline, Week 48 ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 25, 2014)
Incidence, frequency, and severity of adverse events and serious adverse events [ Time Frame: 48 weeks of treatment ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2019)
  • Proportion of Participants Achieving Mean Serum Phosphorus Levels Above the LLN at the End of the Dosing Cycle (4 Weeks After Dosing), as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, Week 24 ]
  • 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 [ Time Frame: Baseline, Week 24 ]
  • 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 [ Time Frame: Baseline, Week 24 ]
  • 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 [ Time Frame: Baseline, Week 24 ]
  • Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24 [ Time Frame: Baseline, Week 24 ]
  • Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Serum Fibroblast growth factor 23 (FGF23) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Alkaline phosphatase (ALP) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Urinary Phosphorus [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Percent Change From Baseline Over Time in BALP [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Percent Change From Baseline Over Time in CTx [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Percent Change From Baseline Over Time in P1NP [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Osteocalcin [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Percent Change From Baseline Over Time in Osteocalcin [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Hand-Held Dynamometry (HHD) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Sit-to-Stand (STS) Test [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Weighted Arm Lift (WAL) Test [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Six-Minute Walk Test (6MWT) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Brief Pain Inventory (BPI) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in Brief Fatigue Inventory (BFI) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
  • Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) [ Time Frame: Baseline, up to Week 300 (or 31 Jan 2021) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2014)
  • PK profile of serum levels of KRN23 to assess KRN23 concentration and possible accumulation [ Time Frame: Baseline (Weeks 0, 2, 4) and 6 months (Weeks 20, 22, 24) ]
  • Change from Baseline in serum FGF23 [ Time Frame: 48 weeks ]
  • Change from Baseline in serum ALP [ Time Frame: 48 weeks ]
  • Change from Baseline in serum 1,25(OH)2D [ Time Frame: 48 weeks ]
  • Change from Baseline in serum and urinary phosphorus [ Time Frame: 48 weeks ]
  • Change from Baseline in TRP and TMP/GFR [ Time Frame: 48 weeks ]
  • Change from Baseline in biomarkers of bone remodeling including BALP, CTx, P1NP, and osteocalcin [ Time Frame: 48 weeks ]
  • Evaluate changes in skeletal disease/osteomalacia through trans-iliac crest bone biopsy [ Time Frame: 48 weeks ]
  • Evaluate changes in skeletal disease/osteomalacia through standard radiographs [ Time Frame: 48 weeks ]
  • Evaluate changes in skeletal disease/osteomalacia through DXA [ Time Frame: 48 weeks ]
  • Evaluate changes in skeletal disease/osteomalacia through 99Tc-labelled bone scan [ Time Frame: 48 weeks ]
  • Evaluate changes in skeletal disease/osteomalacia through XTremeCT [ Time Frame: 48 Weeks ]
  • 6 Minute Walk Test (6MWT) [ Time Frame: 48 Weeks ]
  • Hand Held Dynamometry (HHD) [ Time Frame: 48 Weeks ]
  • Timed Up and Go (TUG) [ Time Frame: 48 Weeks ]
  • Brief Pain Inventory (BPI) [ Time Frame: 48 Weeks ]
  • Short Form Health Survey (SF36) [ Time Frame: 48 Weeks ]
  • Western Ontario and McMaster Universities osteoarthritis index (WOMAC) [ Time Frame: 48 Weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of KRN23 in Adult Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)
Official Title  ICMJE 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
Brief Summary

The primary objectives of this study are to evaluate the effect of KRN23 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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Tumor Induced Osteomalacia (TIO)
  • Epidermal Nevus Syndrome (ENS)
Intervention  ICMJE Biological: KRN23
Solution for SC injection
Other Names:
  • burosumab
  • Crysvita®
  • UX023
Study Arms  ICMJE Experimental: KRN23 0.3 mg/kg
KRN23 starting dose 0.3 mg/kg administered subcutaneously (SC) every 4 weeks (Q4W). Doses may be titrated up to a maximum of 2.0 mg/kg every 2 weeks (Q2W).
Intervention: Biological: KRN23
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 9, 2017)
17
Original Estimated Enrollment  ICMJE
 (submitted: November 25, 2014)
6
Estimated Study Completion Date  ICMJE January 31, 2021
Actual Primary Completion Date July 27, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Have a clinical diagnosis of TIO/ENS based on evidence of excessive FGF23 that is not amenable to cure by surgical excision of the offending tumor/lesion (documented by investigator)
  2. Be ≥18 years of age
  3. Have a fasting serum phosphorus level <2.5 mg/dL
  4. Have an iFGF23 level ≥ 100 pg/mL by Kainos assay
  5. Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) <2.5 mg/dL
  6. 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.
  7. Have a corrected serum calcium level <10.8 mg/dL
  8. 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.
  9. Participants of child‐bearing potential or fertile males with partners of child-bearing potential who are sexually active must consent to use a highly effective method of contraception as determined by the site Investigator from the period following the signing of the informed consent through the final Safety Follow-up TC.
  10. Be willing to provide access to prior medical records to determine eligibility including imaging, biochemical, and diagnostic, medical, and surgical history data
  11. Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
  12. 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)

Exclusion Criteria:

  1. Have a prior diagnosis of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C
  2. Have a history of recurrent infection, a predisposition to infection, or a known immunodeficiency
  3. Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or partner) at any time during the study
  4. 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
  5. Have used a therapeutic monoclonal antibody, including KRN23, within 90 days prior to Screening or have a history of allergic or anaphylactic reactions to any mAb
  6. 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
  7. 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
  8. Have used medication to suppress PTH (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening
  9. Have a history of malignancy within 5 years of study entry with the exception of PMT-MCT (Phosphaturic mesenchymal tumors of the mixed connective tissue type) tumors or non-melanoma skin cancers such as basal cell skin cancer
  10. Have donated blood or blood products within 60 days prior to Screening
  11. Have a history of allergic reaction to or have shown adverse reactions to a tetracycline (e.g., tetracycline HCl and demeclocycline), benzodiazepines, fentanyl or lidocaine
  12. 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02304367
Other Study ID Numbers  ICMJE UX023T-CL201
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ultragenyx Pharmaceutical Inc
Study Sponsor  ICMJE Ultragenyx Pharmaceutical Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Ultragenyx Pharmaceutical Inc
PRS Account Ultragenyx Pharmaceutical Inc
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP