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Efficacy and Safety of Burosumab (KRN23) Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With X Linked Hypophosphatemia (XLH)

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ClinicalTrials.gov Identifier: NCT02915705
Recruitment Status : Completed
First Posted : September 27, 2016
Results First Posted : April 11, 2019
Last Update Posted : July 30, 2019
Sponsor:
Collaborator:
Kyowa Kirin Co., Ltd.
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
X-Linked Hypophosphatemia Biological: burosumab Drug: oral phosphate Drug: active vitamin D Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 61 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : September 8, 2016
Actual Primary Completion Date : February 12, 2018
Actual Study Completion Date : July 15, 2019


Arm Intervention/treatment
Experimental: Burosumab
Burosumab 0.8 mg/kg starting dose, administered every 2 weeks by subcutaneous injection during the Treatment Period (up to Week 64) and the Treatment Extension Period (up to 140 weeks total study duration).
Biological: burosumab
solution for subcutaneous (SC) injection
Other Names:
  • KRN23
  • Crysvita ®
  • UX023

Active Comparator: 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).

Participants not in Japan or Korea crossover to burosumab receive 0.8 mg/kg starting dose, administered every 2 weeks by subcutaneous injection in the Treatment Extension Period (up to 140 weeks total study duration).

Biological: burosumab
solution for subcutaneous (SC) injection
Other Names:
  • KRN23
  • Crysvita ®
  • UX023

Drug: oral phosphate
Drug: active vitamin D



Primary Outcome Measures :
  1. Radiographic Global Impression of Change (RGI-C) Global Score at Week 40 [ Time Frame: 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).


Secondary Outcome Measures :
  1. Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40 [ Time Frame: Week 40 ]
    RGI-C responders are defined as participants with a mean RGI-C global score >= +2.0. 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).

  2. Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64 [ Time Frame: Week 64 ]
    RGI-C responders are defined as participants with a mean RGI-C global score >= +2.0. 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).

  3. RGI-C Global Score at Week 64 [ Time Frame: Week 64 ]
    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).

  4. Change From Baseline in RSS Total Score at Week 40 [ Time Frame: Baseline, Week 40 ]
    The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, lucency, separation, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees (the total score is the sum of the wrist and knee score). Higher scores indicate greater rickets severity.

  5. Change From Baseline in RSS Total Score at Week 64 [ Time Frame: Baseline, Week 64 ]
    The RSS system is a 10-point radiographic scoring method that was developed to assess the severity of nutritional rickets in the wrists and knees based on the degree of metaphyseal fraying, cupping, and the proportion of the growth plate affected. Scores are assigned for the unilateral wrist and knee X-rays deemed by the rater to be the more severe of the bilateral images. The maximum total score on the RSS is 10 points and the minimum score is 0, with a total possible score of 4 points for the wrists and 6 points for the knees. Higher scores indicate greater rickets severity.

  6. RGI-C Long Leg Score at Week 40 [ Time Frame: Week 40 ]
    Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, 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), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening).

  7. RGI-C Long Leg Score at Week 64 [ Time Frame: Week 64 ]
    Changes in the severity of lower extremity skeletal abnormalities, including genu varum and genu valgus, 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), +2 = much better (substantial healing), +1 = minimally better (i.e., minimal healing), 0 = unchanged, -1 = minimally worse (minimal worsening), -2 = much worse (moderate worsening), -3 = very much worse (severe worsening).

  8. Change From Baseline in Height-For-Age Z-Scores to Week 40 [ Time Frame: Baseline, Week 40 ]
    Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the Centers for Disease Control [CDC] growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.

  9. Change From Baseline in Height-For-Age Z-Scores to Week 64 [ Time Frame: Baseline, Week 64 ]
    Recumbent length/Standing height z scores are measures of height adjusted for a child's age and sex. The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome.

  10. Change in Growth Velocity Z Score From Baseline to Week 40 [ Time Frame: Baseline, Week 40 ]
    A growth velocity Z score was calculated based on Tanner's standard. The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for participants who had data available from within 1.5 years prior to baseline. The Week 64 growth velocity was calculated using data between baseline and Week 64. The mid-point of the age interval was used to locate the closest reference age provided by Tanner's Standard. Children with a mid-point age under 2.25 years were excluded, because younger ages are not available in Tanner's standard. To smoothly transition from recumbent length to standing height, 0·8 cm was subtracted from recumbent length before pooling with standing height. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome.

  11. Change in Growth Velocity Z Score From Baseline to Week 64 [ Time Frame: Baseline, Week 64 ]
    A growth velocity Z score was calculated based on Tanner's standard. The Z score indicates the number of standard deviations away from a reference population (from Tanner's standard) in the same age range and with the same sex. The baseline growth velocity was calculated for participants who had data available from within 1.5 years prior to baseline. The Week 64 growth velocity was calculated using data between baseline and Week 64. The mid-point of the age interval was used to locate the closest reference age provided by Tanner's Standard. Children with a mid-point age under 2.25 years were excluded, because younger ages are not available in Tanner's standard. To smoothly transition from recumbent length to standing height, 0·8 cm was subtracted from recumbent length before pooling with standing height. A Z score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z scores indicate a better outcome.

  12. Change From Baseline in Serum Phosphorus Concentration at Week 40 [ Time Frame: Baseline, Week 40 ]
  13. Change From Baseline in Serum Phosphorus Concentration at Week 64 [ Time Frame: Baseline, Week 64 ]
  14. Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 40 [ Time Frame: Baseline, Week 1, 4, 8, 16, 24, 32, and 40 ]
  15. Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64 [ Time Frame: Baseline, Week 1, 4, 8, 16, 24, 32, 40, 52 and 64 ]
  16. Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL) [ Time Frame: Baseline, up to Week 64 ]
  17. Change From Baseline in 1,25-Dihydroxyvitamin D at Week 40 [ Time Frame: Baseline, Week 40 ]
  18. Change From Baseline in 1,25-Dihydroxyvitamin D at Week 64 [ Time Frame: Baseline, Week 64 ]
  19. Change From Baseline in TmP/GFR to Week 40 [ Time Frame: Baseline, Week 40 ]
    Urinary phosphorus and TRP measurements were used in the calculation of TmP/GFR.

  20. Change From Baseline in TmP/GFR to Week 64 [ Time Frame: Baseline, Week 64 ]
    Urinary phosphorus and TRP measurements were used in the calculation of TmP/GFR.

  21. Change From Baseline in Serum ALP at Week 40 [ Time Frame: Baseline, Week 40 ]
  22. Change From Baseline in Serum ALP at Week 64 [ Time Frame: Baseline, Week 64 ]
  23. Percent Mean Change From Baseline in Serum ALP at Week 40 [ Time Frame: Baseline, Week 40 ]
    Decreases indicate improvement.

  24. Percent Mean Change From Baseline in Serum ALP at Week 64 [ Time Frame: Baseline, Week 64 ]
    Decreases indicate improvement.

  25. 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 [ Time Frame: Baseline, Week 40 ]
    The PROMIS was developed by the National Institutes of Health and uses domain-specific measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue.

  26. 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 [ Time Frame: Baseline, Week 64 ]
    The PROMIS was developed by the National Institutes of Health and uses domain-specific measures to assess patient well-being (Broderick et al. 2013), (NIH 2015). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases indicate less pain, for the Physical Function Mobility Domain, increases indicate greater mobility and for the Fatigue Domain, decreases indicate less fatigue.

  27. Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40 [ Time Frame: Baseline, Week 40 ]
    The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain.

  28. Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64 [ Time Frame: Baseline, Week 64 ]
    The FPS-R is a dimensionless 10 point Likert scale used to assess self-reported pain intensity on a scale from 0 (no pain) to 10 (most pain you can imagine). Greater pain scores are indicative of more severe pain.

  29. Change From Baseline in the 6MWT Total Distance at Week 40 [ Time Frame: Baseline, Week 40 ]
    The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test.

  30. Change From Baseline in the 6MWT Total Distance at Week 64 [ Time Frame: Baseline, Week 64 ]
    The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test.

  31. Percent of Predicted Normal in the 6MWT Total Distance at Week 40 [ Time Frame: Baseline, Week 40 ]
    The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test, and the percent predicted distance based on normative data for age and gender was estimated.

  32. Percent of Predicted Normal in the 6MWT Total Distance at Week 64 [ Time Frame: Baseline, Week 64 ]
    The total distance walked (meters) in a 6-minute period was measured in participants ≥ 5 years of age at the Screening Visit who were able to complete the test, and the percent predicted distance based on normative data for age and gender was estimated.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, aged 1 to ≤12 years with radiographic evidence of rickets as determined by central readers
  2. 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
  3. Biochemical findings associated with XLH: serum phosphorus <3.0 mg/dL (<0.97 mmol/L)
  4. Serum creatinine below the age-adjusted upper limit of normal
  5. Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit
  6. 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
  7. Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history
  8. 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.
  9. 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
  10. 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

Exclusion Criteria:

  1. Tanner stage 4 or higher in any of the following: genitals, breast, or pubic hair, based on physical examination
  2. Height percentile > 50th based on country-specific norms
  3. Use of aluminum hydroxide antacids (eg, Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit
  4. Current or prior use of leuprorelin (eg, Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to delay puberty
  5. Use of growth hormone therapy within 12 months before the Screening Visit
  6. Presence of nephrocalcinosis on renal ultrasound grade 4
  7. 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
  8. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits
  9. Evidence of hyperparathyroidism (parathyroid hormone [PTH] levels 2.5X upper limit of normal [ULN])
  10. Use of medication to suppress PTH (eg, cinacalcet, calcimimetics) within 2 months prior to the Screening Visit
  11. 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.
  12. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
  13. History of recurrent infection or predisposition to infection, or of known immunodeficiency
  14. 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
  15. 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
  16. 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

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): NCT02915705


Locations
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United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
UCSF
San Francisco, California, United States, 94158
United States, Indiana
Indiana University School of Medicine
Indianapolis, Indiana, United States, 46202
United States, Missouri
Shriners Hospital For Children
Saint Louis, Missouri, United States, 63110
United States, Tennessee
Vanderbilt Children's Hospital
Nashville, Tennessee, United States, 37232
Australia, New South Wales
The Children's Hospital at Westmead
Westmead, New South Wales, Australia, 2145
Canada, Ontario
Children's Hospital of Eastern Ontario (CHEO) Research Institute
Ottawa, Ontario, Canada, K1H 8L1
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Shriners Hospital for Children - Canada
Montreal, Quebec, Canada, H4A 0A9
Japan
Kanagawa Children's Medical Center
Yokohama, Kanagawa, Japan, 232-8555
Okayama Saiseikai General Hospital
Okayama, Japan, 700-0013
Japan Community Healthcare Organization Osaka Hospital
Osaka, Japan, 553-0003
Korea, Republic of
Seoul National University Hospital
Seoul, Korea, Republic of, 03080
Sweden
Karolinska Institutet and University Hospital
Stockholm, Sweden, 17176
United Kingdom
Birmingham Children's Hospital
Birmingham, United Kingdom, B4 6NH
Royal Manchester Children's Hospital - University of Manchester
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Ultragenyx Pharmaceutical Inc
Kyowa Kirin Co., Ltd.
Investigators
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Study Director: Medical Director Ultragenyx Pharmaceutical Inc
  Study Documents (Full-Text)

Documents provided by Ultragenyx Pharmaceutical Inc:
Study Protocol  [PDF] November 3, 2017
Statistical Analysis Plan  [PDF] January 2, 2018


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02915705     History of Changes
Other Study ID Numbers: UX023-CL301
First Posted: September 27, 2016    Key Record Dates
Results First Posted: April 11, 2019
Last Update Posted: July 30, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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Familial Hypophosphatemic Rickets
Hypophosphatemia
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
Vitamin D
Ergocalciferols
Vitamins
Antibodies, Monoclonal
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs