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Study of KRN23 in Adults With X-linked Hypophosphatemia (XLH)

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ClinicalTrials.gov Identifier: NCT02526160
Recruitment Status : Active, not recruiting
First Posted : August 18, 2015
Last Update Posted : October 17, 2018
Sponsor:
Collaborator:
Kyowa Hakko Kirin Co., Ltd
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Brief Summary:
The primary efficacy objective of this study is to establish the effect of KRN23 treatment compared with placebo on increasing serum phosphorus levels in adults with XLH.

Condition or disease Intervention/treatment Phase
X-linked Hypophosphatemia Biological: KRN23 Other: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 134 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study With Open-Label Extension to Assess the Efficacy and Safety of KRN23 in Adults With X-linked Hypophosphatemia (XLH)
Study Start Date : October 2015
Actual Primary Completion Date : December 22, 2016
Estimated Study Completion Date : November 30, 2018


Arm Intervention/treatment
Experimental: KRN23 1 mg/kg
KRN23 1 mg/kg administered subcutaneously (SC) every 4 weeks, for the duration of the study.
Biological: KRN23
solution for SC injection
Other Names:
  • UX023
  • burosumab
  • Crysvita

Placebo Comparator: Placebo
Placebo administered SC every 4 weeks through Week 24, followed by KRN23 1 mg/kg, for the duration of the study.
Biological: KRN23
solution for SC injection
Other Names:
  • UX023
  • burosumab
  • Crysvita

Other: Placebo
saline solution for SC injection




Primary Outcome Measures :
  1. Proportion of Participants Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]

Secondary Outcome Measures :
  1. Change From Baseline to Week 24 in Brief Pain Inventory (BPI) Question 3 (Q3; Worst Pain in Past 24 Hours) Score [ Time Frame: Baseline, 24 weeks ]
  2. Change From Baseline to Week 24 in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Stiffness Score [ Time Frame: Baseline, 24 weeks ]
  3. Change From Baseline to Week 24 in the WOMAC Physical Function Score [ Time Frame: Baseline, 24 weeks ]
  4. Proportion of Participants Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L] at the End of the Dose Cycle (4 Weeks After Dosing), As Averaged Across Dose Cycles [ Time Frame: Baseline, 24 weeks ]
  5. Mean Change From Baseline in Serum Phosphorus at the Mid-Point of Each Dose Cycle, as Averaged Across Dose Cycles [ Time Frame: Baseline, 24 weeks ]
  6. Mean Percentage Change From Baseline in Serum Phosphorus at the End of Each Dose Cycle, as Averaged Across Dose Cycles [ Time Frame: Baseline, 24 weeks ]
  7. Mean Change From Baseline in Serum Phosphorus at the End of Each Dose Cycle, as Averaged Across Dose Cycles [ Time Frame: Baseline, 24 weeks ]
  8. Mean Percent Change From Baseline in Serum Phosphorus at the End of Each Dose Cycle, as Averaged Across Dose Cycles [ Time Frame: Baseline, up to 96 weeks ]
  9. Serum Phosphorus Time-Adjusted Area Under the Curve (AUC) Up to Week 24 [ Time Frame: Up to 24 weeks ]
  10. Change From Baseline to Post-Baseline Visits in Serum Phosphorus [ Time Frame: Baseline, up to 96 weeks ]
  11. Percent Change From Baseline to Post-Baseline Visits in Serum Phosphorus [ Time Frame: Baseline, up to 96 weeks ]
  12. Change From Baseline to Post-Baseline Visits in Serum 1,25(OH)2D [ Time Frame: Baseline, up to 96 weeks ]
  13. Percent Change From Baseline to Post-Baseline Visits in Serum 1,25(OH)2D [ Time Frame: Baseline, up to 96 weeks ]
  14. Change From Baseline to Post-Baseline Visits in Urinary Phosphorus [ Time Frame: Baseline, up to 96 weeks ]
  15. Percent Change From Baseline to Post-Baseline Visits in Urinary Phosphorus [ Time Frame: Baseline, up to 96 weeks ]
  16. Change From Baseline to Post-Baseline Visits in Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate (TmP/GFR) [ Time Frame: Baseline, up to 96 weeks ]
  17. Percent Change From Baseline to Post-Baseline Visits in TmP/GFR [ Time Frame: Baseline, up to 96 weeks ]
  18. Change From Baseline to Post-Baseline Visits in Tubular Reabsorption of Phosphate (TRP) [ Time Frame: Baseline, up to 96 weeks ]
  19. Percent Change From Baseline to Post-Baseline Visits in TRP [ Time Frame: Baseline, up to 96 weeks ]
  20. Change From Baseline to Post-Baseline Visits in Biochemical Marker of Bone Remodeling Procollagen Type 1 N-Propeptide (P1NP) [ Time Frame: Baseline, up to 96 weeks ]
  21. Percent Change From Baseline to Post-Baseline Visits in Biochemical Marker of Bone Remodeling P1NP [ Time Frame: Baseline, up to 96 weeks ]
  22. Change From Baseline to Post-Baseline Visits in Biochemical Marker of Bone Remodeling Carboxy-Terminal Cross-Linked Telopeptide of Type I collagen (CTx) [ Time Frame: Baseline, up to 96 weeks ]
  23. Percent Change From Baseline to Post-Baseline Visits in Biochemical Marker of Bone Remodeling CTx [ Time Frame: Baseline, up to 96 weeks ]
  24. Change From Baseline to Post-Baseline Visits in Biochemical Marker of Bone Remodeling Bone-Specific Alkaline Phosphatase (BALP) [ Time Frame: Baseline, up to 96 weeks ]
  25. Percent Change From Baseline to Post-Baseline Visits in Biochemical Marker of Bone Remodeling BALP [ Time Frame: Baseline, up to 96 weeks ]
  26. Change From Baseline to Post-Baseline Visits in BPI-Q3 (Worst Pain) Score as Averaged From Daily Diary Scores Recorded Over 1 Week and the Study Visit Score [ Time Frame: Baseline, up to 96 weeks ]
  27. Change From Baseline to Post-Baseline Visits in BPI Pain Severity Score as Averaged From Daily Diary Scores Recorded Over 1 Week and the Study Visit Score [ Time Frame: Baseline, up to 96 weeks ]
  28. Change From Baseline to Post-Baseline Visits in BPI Pain Interference Score as Recorded on the Day of the Study Visit [ Time Frame: Baseline, up to 96 weeks ]
  29. Change From Baseline to Post-Baseline Visits in Brief Fatigue Inventory Question 3 (Worst Fatigue in Past 24 Hours; BFI-Q3) Worst Fatigue Score as Averaged From Daily Diary Scores Recorded Over 1 Week and the Study Visit Score [ Time Frame: Baseline, up to 96 weeks ]
  30. Change From Baseline to Post-Baseline Visits in BFI Global Fatigue score, Calculated by Averaging All 9 Items on the BFI as Recorded on the Day of the Study Visit [ Time Frame: Baseline, up to 96 weeks ]
  31. Change From Baseline to Post-Baseline Visits in the WOMAC Stiffness Score [ Time Frame: Baseline, up to 96 weeks ]
  32. Change From Baseline to Post-Baseline Visits in the WOMAC Physical Function Score [ Time Frame: Baseline, up to 96 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, aged 18 - 65 years, inclusive
  2. Diagnosis of XLH supported by classic clinical features of adult XLH (such as short stature or bowed legs) and at least ONE of the following at Screening:

    • Documented phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance
    • Serum intact FGF23 (iFGF23) level > 30 pg/mL by Kainos assay
  3. Biochemical findings consistent with XLH at Screening Visit 2 following overnight fasting (min. 8 hours):

    • Serum phosphorus < 2.5 mg/dL
    • TmP/GFR of < 2.5 mg/dL
  4. Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of ≥ 4 on Brief Pain Inventory (BPI) Questions 3 (Worst Pain) at Screening Visit 1. (Skeletal pain that, in the opinion of the investigator, is attributed solely to causes other than XLH/osteomalacia—for example, back or joint pain in the presence of severe osteoarthritis by radiograph in that anatomical location—in the absence of any skeletal pain likely attributed to XLH/osteomalacia should not be considered for eligibility)
  5. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) or eGFR of 45 60 mL/min at Screening Visit 2 with confirmation that the renal insufficiency is not due to nephrocalcinosis
  6. If taking chronic pain medications (including narcotic pain medications/opioids), must be on a stable regimen for at least 21 days prior to Screening Visit 1, and be willing to maintain medications at the same stable dose(s) and schedule throughout the Placebo-controlled Treatment Period of the study. The dose must not exceed 60 mg oral morphine equivalents/day
  7. Provide written informed consent or if a minor, provide written consent and have a legally authorized representative willing and able to provide written informed consent, after the nature of the study has been explained, and prior to any research-related procedures
  8. Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history
  9. Females of child-bearing potential must have a negative urine pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have been in menopause for at least two years prior to Screening, or have had tubal ligation at least one year prior to Screening, or have had a total hysterectomy or bilateral salpingo-oophorectomy
  10. Participants of child‐bearing potential or with partners of child-bearing potential who have not undergone a bilateral salpingo‐oophorectomy and are sexually active must consent to use an effective method of contraception as determined by the site investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period following the signing of the informed consent through 12 weeks after last dose of study drug
  11. 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
  12. Must have completed at least 4 of 7 days of the patient diaries before the Baseline visit.

Exclusion Criteria:

  1. Use of a pharmacologic vitamin D metabolite or analog (calcitriol, doxercalciferol, and paricalcitol) within 14 days prior to Screening Visit 2
  2. Use of oral phosphate within 14 days prior to Screening Visit 2
  3. Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening Visit 2
  4. Chronic use of systemic corticosteroids defined as more than 10 days in the previous 2 months
  5. Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening Visit 2
  6. Serum intact parathyroid hormone (iPTH) ≥ 2.5 upper limit of normal (ULN) at Screening Visit 1
  7. Use of medication to suppress parathyroid hormone (PTH) (cinacalcet for example) within 60 days prior to Screening Visit 1
  8. Use of oral bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1
  9. Use of denosumab in the 6 months prior to Screening Visit 1
  10. Use of teriparatide in the 2 months prior to Screening Visit 1
  11. Planned or recommended orthopedic surgery within the first 24 weeks of the clinical trial period
  12. History of traumatic fracture or orthopedic surgery within 6 months prior to Screening Visit 1
  13. Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening Visit 1
  14. Use of any investigational product or investigational medical device within 30 days prior to Screening Visit 1, 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.

  15. Pregnant or breastfeeding at Screening /Baseline or planning to become pregnant (self or partner) at any time during the study
  16. Unable or unwilling to withhold prohibited medications throughout the study
  17. Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects.
  18. Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody
  19. History of recurrent infection or predisposition to infection, or of known immunodeficiency
  20. Presence of malignant neoplasm (except basal cell carcinoma)
  21. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
  22. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02526160


  Show 25 Study Locations
Sponsors and Collaborators
Ultragenyx Pharmaceutical Inc
Kyowa Hakko Kirin Co., Ltd

Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02526160     History of Changes
Other Study ID Numbers: UX023-CL303
First Posted: August 18, 2015    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: October 2018

Keywords provided by Ultragenyx Pharmaceutical Inc:
KRN23
Fibroblast growth factor 23 (FGF23)
XLH
X-linked hypophosphatemia
burosumab
Crysvita

Additional relevant MeSH terms:
Hypophosphatemia
Familial Hypophosphatemic Rickets
Phosphorus Metabolism Disorders
Metabolic Diseases
Rickets, Hypophosphatemic
Rickets
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Hypophosphatemia, Familial
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Calcium Metabolism Disorders
Vitamin D Deficiency
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders