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CompletedNCT02915705Updated Aug 29, 2024Results posted

Efficacy and Safety of Burosumab Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With XLH

A Phase 3 interventional study of burosumab and Oral Phosphate Supplement in X-Linked Hypophosphatemia, sponsored by Kyowa Kirin, Inc.. Completed at 16 sites in 7 countries. Open to participants aged 1 Year to 12 Years. Per ClinicalTrials.gov, last updated 2024-08-29.

Sponsored by Kyowa Kirin, Inc. · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
61
Allocation
Randomized
Ages
1 Year to 12 Years
Sex
All
01

Study 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).

02

Conditions studied

  • X-Linked Hypophosphatemia
03

In context

Familial Hypophosphatemic Rickets

61 studies on the registry are indexed under Familial Hypophosphatemic Rickets; 9 are open to participants now.

This study's enrollment of 61 is above the median of 23 across 35 interventional studies indexed under Familial Hypophosphatemic Rickets.

Browse Familial Hypophosphatemic Rickets studies →

Lead sponsor

Kyowa Kirin, Inc. is the lead sponsor of 36 studies on the registry; 2 are open to participants now.

Of its 7 completed or terminated interventional studies of FDA-regulated products, 3 (43%) have results posted.

Browse Kyowa Kirin Co., Ltd. studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
1 Year to 12 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
61 participants (actual)

Study arms

  • Experimental
    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.

    Biological: burosumab

  • 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). 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.

    Biological: burosumab · Drug: Oral Phosphate Supplement · Drug: active vitamin D

Interventions

  • Biologicalburosumab

    solution for subcutaneous (SC) injection

    Also known as: KRN23, Crysvita ®, UX023

  • DrugOral Phosphate Supplement

    oral tablet; oral solution; oral powder

  • Drugactive vitamin D

    tablet, oral solution

06

What researchers measure

Primary outcomes

  1. Radiographic Global Impression of Change (RGI-C) Global Score at 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).

    Time frame: Week 40

Secondary outcomes

  1. Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at 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).

    Time frame: Week 40

  2. Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at 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).

    Time frame: Week 64

  3. RGI-C Global Score at 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).

    Time frame: Week 64

  4. Change From Baseline in RSS Total Score at 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.

    Time frame: Baseline, Week 40

  5. Change From Baseline in RSS Total Score at 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.

    Time frame: Baseline, Week 64

  6. RGI-C Long Leg Score at 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).

    Time frame: Week 40

  7. RGI-C Long Leg Score at 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).

    Time frame: Week 64

  8. Change From Baseline in Height-For-Age Z-Scores to 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.

    Time frame: Baseline, Week 40

  9. Change From Baseline in Height-For-Age Z-Scores to 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.

    Time frame: Baseline, Week 64

  10. Change in Growth Velocity Z Score From Baseline to 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.

    Time frame: Baseline, Week 40

  11. Change in Growth Velocity Z Score From Baseline to 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.

    Time frame: Baseline, Week 64

  12. Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64

    The GEE model includes change from baseline for serum phosphorous measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

    Time frame: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64

  13. Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112

    Time frame: Baseline, Weeks 66, 68, 76, 88, 100, 112

  14. Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64

    The ANCOVA model includes change in serum phosphorus from baseline to mean post-baseline as the dependent variable, treatment group, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate.

    Time frame: Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64

  15. Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)

    Time frame: 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

  16. Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)

    Time frame: Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140

  17. Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64

    The GEE model includes change from baseline for 1, 25-Dihydroxyvitamin D measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline 1, 25-Dihydroxyvitamin D measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

    Time frame: Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64

  18. Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112

    Time frame: Baseline, Weeks 68, 76, 88, 100, 112

  19. Change From Baseline Over Time in TmP/GFR, up to Week 64

    Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR. The GEE model includes change from baseline for TmP/GFR measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline TmP/GFR measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

    Time frame: Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64

  20. Change From Baseline Over Time in TmP/GFR, Week 68 to 112

    Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR.

    Time frame: Baseline, Weeks 68, 76, 88, 112

  21. Change From Baseline Over Time in Serum ALP, up to Week 64

    The GEE model includes change from baseline for ALP measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline ALP measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

    Time frame: Baseline, Weeks 16, 24, 40, 52, 64

  22. Change From Baseline Over Time in Serum ALP, Week 68 to 112

    Time frame: Baseline, Weeks 68, 76, 88, 100, 112

  23. Percent Change From Baseline Over Time in Serum ALP, up to Week 112

    Decreases indicate improvement.

    Time frame: Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112

  24. 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

    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.

    Time frame: Baseline, Week 40

  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 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.

    Time frame: Baseline, Week 64

  26. Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at 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.

    Time frame: Baseline, Week 40

  27. Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at 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.

    Time frame: Baseline, Week 64

  28. Change From Baseline in the 6MWT Total Distance at 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.

    Time frame: Baseline, Week 40

  29. Change From Baseline in the 6MWT Total Distance at 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.

    Time frame: Baseline, Week 64

  30. Percent of Predicted Normal in the 6MWT Total Distance at 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.

    Time frame: Baseline, Week 40

  31. Percent of Predicted Normal in the 6MWT Total Distance at 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.

    Time frame: Baseline, Week 64

07

Results

Posted Apr 11, 2019

Participant flow

Treatment Period
Participant flow — Treatment Period
MilestoneActive ControlBurosumab
Started3229
Completed week 403229
Completed week 643229
Completed3229
Not completed00
Long Term Extension Period
Participant flow — Long Term Extension Period
MilestoneActive ControlBurosumab
Started2625
Completed2625
Not completed00

Outcome measures

PrimaryRadiographic Global Impression of Change (RGI-C) Global Score at 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).

Time frame:
Week 40
Reported as:
Least squares mean · score on a scale
Radiographic Global Impression of Change (RGI-C) Global Score at Week 40
score on a scaleActive ControlBurosumab
Radiographic Global Impression of Change (RGI-C) Global Score at Week 400.77 ± 0.1071.92 ± 0.110
Statistical analysis
  • Active Control vs Burosumab · ANCOVA · p = < 0.0001 · Ls mean difference: 1.14 · 95% CI 0.83 to 1.45
SecondaryPercentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at 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).

Time frame:
Week 40
Reported as:
Number · percentage of participants
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 40
percentage of participantsActive ControlBurosumab
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 406.372.4
Statistical analysis
  • Active Control vs Burosumab · Regression, Logistic · p = < 0.0001 (Odds ratio, CI, and 2-sided p-value were per logistic regression model, which included treatment group and baseline age stratification factor as independent variables and baseline RSS score as a continuous covariate.) · Odds ratio (or): 39.1 · 95% CI 7.2 to 211.7
SecondaryPercentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at 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).

Time frame:
Week 64
Reported as:
Number · percentage of participants
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 64
percentage of participantsActive ControlBurosumab
Percentage of Participants With a Mean RGI-C Global Score ≥ +2.0 (Responders) at Week 6418.886.2
Statistical analysis
  • Active Control vs Burosumab · generalized linear mixed model · p = 0.0002 (Odds ratio, CI, and 2-sided p-value were per generalized linear mixed model, which includes treatment, visit, treatment by visit interaction and baseline age stratification factor as factors, baseline RSS total score as a continuous covariate.) · Odds ratio (or): 34.1 · 95% CI 5.6 to 206.3
SecondaryRGI-C Global Score at 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).

Time frame:
Week 64
Reported as:
Least squares mean · score on a scale
RGI-C Global Score at Week 64
score on a scaleActive ControlBurosumab
RGI-C Global Score at Week 641.03 ± 0.1362.06 ± 0.072
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference in ls means: 1.02 · 95% CI 0.72 to 1.33
SecondaryChange From Baseline in RSS Total Score at 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.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · score on a scale
Change From Baseline in RSS Total Score at Week 40
score on a scaleActive ControlBurosumab
Change From Baseline in RSS Total Score at Week 40-0.71 ± 0.138-2.04 ± 0.145
Statistical analysis
  • Active Control vs Burosumab · ANCOVA · p = < 0.0001 (LS mean, SE, CI, and 2-sided p value per ANCOVA model, which included treatment group and baseline age stratification factor as independent variables and baseline RSS score as a continuous covariate.) · Ls mean difference: -1.34 · 95% CI -1.74 to -0.94
SecondaryChange From Baseline in RSS Total Score at 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.

Time frame:
Baseline, Week 64
Reported as:
Least squares mean · score on a scale
Change From Baseline in RSS Total Score at Week 64
score on a scaleActive ControlBurosumab
Change From Baseline in RSS Total Score at Week 64-1.01 ± 0.151-2.23 ± 0.117
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = < 0.0001 (LS mean, SE, CI, and 2-sided p value per GEE model, which included treatment, visit, treatment by visit interaction and baseline age stratification factor as factors, baseline RSS score as a continuous covariate.) · Difference in ls means: -1.21 · 95% CI -1.59 to -0.83
SecondaryRGI-C Long Leg Score at 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).

Time frame:
Week 40
Reported as:
Least squares mean · score on a scale
RGI-C Long Leg Score at Week 40
score on a scaleActive ControlBurosumab
RGI-C Long Leg Score at Week 400.22 ± 0.0800.62 ± 0.153
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0162 (LS mean, SE, CI, and 2-sided p value per GEE model, which included treatment, visit, treatment by visit interaction, and baseline age stratification factor as factors; and baseline RSS score as a continuous covariate.) · Ls mean difference: 0.40 · 95% CI 0.07 to 0.72
SecondaryRGI-C Long Leg Score at 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).

Time frame:
Week 64
Reported as:
Least squares mean · score on a scale
RGI-C Long Leg Score at Week 64
score on a scaleActive ControlBurosumab
RGI-C Long Leg Score at Week 640.29 ± 0.1191.25 ± 0.170
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = < 0.0001 (LS mean, SE, CI, and 2-sided p value per GEE model, which included treatment, visit, treatment by visit interaction, and baseline age stratification factor as factors; and baseline RSS score as a continuous covariate.) · Difference in ls means: 0.97 · 95% CI 0.57 to 1.37
SecondaryChange From Baseline in Height-For-Age Z-Scores to 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.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · Z score
Change From Baseline in Height-For-Age Z-Scores to Week 40
Z scoreActive ControlBurosumab
Change From Baseline in Height-For-Age Z-Scores to Week 400.03 ± 0.0310.16 ± 0.052
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0408 · Ls mean difference: 0.12 · 95% CI 0.01 to 0.24
SecondaryChange From Baseline in Height-For-Age Z-Scores to 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.

Time frame:
Baseline, Week 64
Reported as:
Least squares mean · Z score
Change From Baseline in Height-For-Age Z-Scores to Week 64
Z scoreActive ControlBurosumab
Change From Baseline in Height-For-Age Z-Scores to Week 640.02 ± 0.0350.17 ± 0.066
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0490 · Difference in ls means: 0.14 · 95% CI 0.00 to 0.29
SecondaryChange in Growth Velocity Z Score From Baseline to 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.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · Z score
Change in Growth Velocity Z Score From Baseline to Week 40
Z scoreActive ControlBurosumab
Change in Growth Velocity Z Score From Baseline to Week 400.73 ± 0.3391.76 ± 0.337
Statistical analysis
  • Active Control vs Burosumab · ANCOVA · p = 0.0386 · Difference in ls means: 1.02 · 95% CI 0.06 to 1.99
SecondaryChange in Growth Velocity Z Score From Baseline to 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.

Time frame:
Baseline, Week 64
Reported as:
Least squares mean · Z score
Change in Growth Velocity Z Score From Baseline to Week 64
Z scoreActive ControlBurosumab
Change in Growth Velocity Z Score From Baseline to Week 640.41 ± 0.2651.53 ± 0.264
Statistical analysis
  • Active Control vs Burosumab · ANCOVA · p = 0.0047 · Difference in ls means: 1.12 · 95% CI 0.37 to 1.88
SecondaryChange From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64

The GEE model includes change from baseline for serum phosphorous measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

Time frame:
Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
Reported as:
Least squares mean · mg/dL
Change From Baseline Over Time in Serum Phosphorus Concentration, up to Week 64
mg/dLActive ControlBurosumab
Week 10.22 ± 0.0721.26 ± 0.094
Week 2—1.14 ± 0.098
Week 40.18 ± 0.0611.21 ± 0.102
Week 80.21 ± 0.0640.99 ± 0.074
Week 12—1.01 ± 0.072
Week 160.24 ± 0.0630.87 ± 0.072
Week 240.27 ± 0.0730.78 ± 0.077
Week 320.23 ± 0.0630.93 ± 0.073
Week 33—1.23 ± 0.106
Week 400.20 ± 0.0620.92 ± 0.080
Week 520.30 ± 0.0820.91 ± 0.075
Week 640.21 ± 0.0620.91 ± 0.078
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.04 · 95% CI 0.81 to 1.27Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.03 · 95% CI 0.79 to 1.27Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 0.78 · 95% CI 0.58 to 0.97Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 0.63 · 95% CI 0.44 to 0.81Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 0.51 · 95% CI 0.30 to 0.72Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 0.70 · 95% CI 0.51 to 0.89
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 0.71 · 95% CI 0.51 to 0.91Difference (burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 0.61 · 95% CI 0.39 to 0.82
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 0.69 · 95% CI 0.49 to 0.90
SecondaryChange From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112
Time frame:
Baseline, Weeks 66, 68, 76, 88, 100, 112
Reported as:
Mean · mg/dL
Change From Baseline Over Time in Serum Phosphorus Concentration, Weeks 66-112
mg/dLActive ControlBurosumab
Week 660.05 ± 0.235—
Week 681.17 ± 0.4721.10 ± NA
Week 760.90 ± 0.3240.92 ± 0.324
Week 880.98 ± 0.4331.00 ± 0.576
Week 1000.99 ± 0.4451.00 ± 0.424
Week 1121.26 ± 0.5081.10 ± 0.283
SecondaryChange From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64

The ANCOVA model includes change in serum phosphorus from baseline to mean post-baseline as the dependent variable, treatment group, baseline age and baseline RSS stratification as factors, baseline phosphorous measure as a covariate.

Time frame:
Baseline, Weeks 1, 4, 8, 16, 24, 32, 40, 52, 64
Reported as:
Least squares mean · mg/dL
Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 64
mg/dLActive ControlBurosumab
Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 640.24 ± 0.0580.98 ± 0.061
Statistical analysis
  • Active Control vs Burosumab · ANCOVA · p = < 0.0001 · Difference in ls means: 0.74 · 95% CI 0.58 to 0.91Difference (KRN23 - Oral Phosphate/Active Vitamin D)
SecondaryChange From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)
Time frame:
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
Reported as:
Mean · mg/dL
Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)
mg/dLActive ControlBurosumab
Change From Baseline in Mean Post-Baseline Serum Phosphorus Level to Week 140 (During Treatment With Burosumab)1.05 ± 0.3100.93 ± 0.336
SecondaryPercentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)
Time frame:
Burosumab arm: Baseline, up to Week 140; Active Control arm: Baseline, Week 68 up to Week 140
Reported as:
Number · percentage of participants
Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)
percentage of participantsActive ControlBurosumab
Percentage of Participants Reaching the Normal Range of Serum Phosphorus Concentration (3.2 - 6.1 mg/dL)75.096.6
SecondaryChange From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64

The GEE model includes change from baseline for 1, 25-Dihydroxyvitamin D measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline 1, 25-Dihydroxyvitamin D measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

Time frame:
Baseline, Weeks 1, 2, 4, 8, 12, 16, 24, 32, 33, 40, 52, 64
Reported as:
Least squares mean · pg/mL
Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, up to Week 64
pg/mLActive ControlBurosumab
Week 119.81 ± 2.75868.09 ± 5.251
Week 2—31.78 ± 5.130
Week 412.77 ± 2.99833.86 ± 3.561
Week 815.10 ± 2.52830.85 ± 3.830
Week 12—33.43 ± 3.176
Week 1619.41 ± 3.75732.38 ± 3.032
Week 2417.46 ± 2.90528.35 ± 3.113
Week 3217.25 ± 3.15623.49 ± 2.439
Week 33—31.50 ± 3.423
Week 4018.42 ± 3.59429.63 ± 3.721
Week 528.74 ± 3.86613.75 ± 2.862
Week 641.19 ± 2.7859.89 ± 2.235
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 48.27 · 95% CI 36.53 to 60.02Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 21.09 · 95% CI 12.01 to 30.16Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = 0.0010 · Difference: 15.75 · 95% CI 6.35 to 25.15Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = 0.0078 · Difference: 12.97 · 95% CI 3.41 to 22.53Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = 0.0101 · Difference: 10.89 · 95% CI 2.59 to 19.19Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = 0.1165 · Difference: 6.23 · 95% CI -1.55 to 14.02Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = 0.0317 · Difference: 11.21 · 95% CI 0.98 to 21.44Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = 0.3044 · Difference: 5.01 · 95% CI -4.55 to 14.56Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = 0.0145 · Difference: 8.70 · 95% CI 1.72 to 15.68Difference (Burosumab - Oral Phosphate/Active Vitamin D
SecondaryChange From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112
Time frame:
Baseline, Weeks 68, 76, 88, 100, 112
Reported as:
Mean · pg/mL
Change From Baseline Over Time in 1,25-Dihydroxyvitamin D, Weeks 68 to 112
pg/mLActive ControlBurosumab
Week 6822.12 ± 23.950-9.80 ± NA
Week 7619.05 ± 22.61212.80 ± 20.093
Week 8824.58 ± 17.78711.76 ± 22.874
Week 10033.57 ± 16.59113.25 ± 1.061
Week 11229.94 ± 15.40231.05 ± 33.729
SecondaryChange From Baseline Over Time in TmP/GFR, up to Week 64

Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR. The GEE model includes change from baseline for TmP/GFR measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline TmP/GFR measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

Time frame:
Baseline, Weeks 4, 8, 16, 24, 32, 40, 52, 64
Reported as:
Least squares mean · mg/dL
Change From Baseline Over Time in TmP/GFR, up to Week 64
mg/dLActive ControlBurosumab
Week 4-0.17 ± 0.0651.48 ± 0.173
Week 8-0.20 ± 0.0571.22 ± 0.101
Week 16-0.15 ± 0.0851.00 ± 0.139
Week 24-0.12 ± 0.0720.99 ± 0.134
Week 32-0.10 ± 0.0621.14 ± 0.115
Week 40-0.15 ± 0.0531.20 ± 0.113
Week 52-0.12 ± 0.0691.13 ± 0.124
Week 64-0.09 ± 0.0701.16 ± 0.127
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.65 · 95% CI 1.28 to 2.02Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.42 · 95% CI 1.19 to 1.64Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.16 · 95% CI 0.84 to 1.48
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.11 · 95% CI 0.80 to 1.41Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.24 · 95% CI 0.98 to 1.51
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.35 · 95% CI 1.10 to 1.60Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.26 · 95% CI 0.97 to 1.54Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: 1.25 · 95% CI 0.96 to 1.54Difference (Burosumab - Oral Phosphate/Active Vitamin D)
SecondaryChange From Baseline Over Time in TmP/GFR, Week 68 to 112

Serum phosphorus and TRP measurements were used in the calculation of TmP/GFR.

Time frame:
Baseline, Weeks 68, 76, 88, 112
Reported as:
Mean · mg/dL
Change From Baseline Over Time in TmP/GFR, Week 68 to 112
mg/dLActive ControlBurosumab
Week 681.61 ± 0.7051.65 ± NA
Week 761.18 ± 0.7580.59 ± 0.429
Week 881.33 ± 0.4800.95 ± 0.620
Week 1121.56 ± 0.2331.32 ± 0.233
SecondaryChange From Baseline Over Time in Serum ALP, up to Week 64

The GEE model includes change from baseline for ALP measurement as the dependent variable, treatment group, visit, interaction between treatment group by visit, baseline age and baseline RSS stratification as factors, baseline ALP measure as a covariate, with exchangeable covariance structure. The GEE model included data up to Week 64.

Time frame:
Baseline, Weeks 16, 24, 40, 52, 64
Reported as:
Least squares mean · U/L
Change From Baseline Over Time in Serum ALP, up to Week 64
U/LActive ControlBurosumab
Week 16-5.43 ± 17.885-97.97 ± 11.281
Week 24-22.43 ± 15.074-108.00 ± 16.225
Week 40-34.78 ± 18.132-130.72 ± 12.365
Week 52-50.03 ± 18.641-161.31 ± 11.674
Week 64-28.06 ± 19.980-174.62 ± 13.427
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: -92.53 · 95% CI -131.40 to -53.66Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: -85.57 · 95% CI -126.37 to -44.76Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: -95.95 · 95% CI -136.05 to -55.84Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: -111.28 · 95% CI -152.08 to -70.49Difference (Burosumab - Oral Phosphate/Active Vitamin D)
  • Active Control vs Burosumab · GEE model · p = < 0.0001 · Difference: -146.56 · 95% CI -191.61 to -101.52Difference (Burosumab - Oral Phosphate/Active Vitamin D)
SecondaryChange From Baseline Over Time in Serum ALP, Week 68 to 112
Time frame:
Baseline, Weeks 68, 76, 88, 100, 112
Reported as:
Mean · U/L
Change From Baseline Over Time in Serum ALP, Week 68 to 112
U/LActive ControlBurosumab
Week 68-82.73 ± 83.683-184.00 ± NA
Week 76-106.73 ± 73.316-166.73 ± 87.700
Week 88-146.56 ± 73.120-154.55 ± 48.148
Week 100-83.14 ± 104.675-184.00 ± 48.083
Week 112-104.80 ± 80.350-172.00 ± 26.870
SecondaryPercent Change From Baseline Over Time in Serum ALP, up to Week 112

Decreases indicate improvement.

Time frame:
Baseline, Weeks 16, 24, 40, 52, 64, 68, 76, 88, 100, 112
Reported as:
Mean · percent change
Percent Change From Baseline Over Time in Serum ALP, up to Week 112
percent changeActive ControlBurosumab
Week 160.41 ± 21.021-18.39 ± 10.815
Week 24-3.21 ± 15.827-19.88 ± 17.642
Week 40-6.85 ± 16.493-24.38 ± 13.498
Week 52-8.60 ± 19.027-30.60 ± 11.852
Week 64-4.60 ± 20.711-32.78 ± 13.095
Week 68-14.66 ± 14.760-38.02 ± NA
Week 76-20.49 ± 13.926-31.42 ± 13.422
Week 88-28.77 ± 12.201-32.02 ± 10.610
Week 100-16.06 ± 23.703-39.29 ± 11.460
Week 112-21.00 ± 15.053-36.67 ± 6.868
SecondaryChange 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

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.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · T-score
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
T-scoreActive ControlBurosumab
Pain Interference Domain Score-0.29 ± 1.539-5.31 ± 1.705
Physical Function Mobility Domain Score0.10 ± 0.9662.78 ± 1.336
Fatigue Domain Score-1.05 ± 1.754-4.29 ± 1.709
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0212 · Difference in ls means: -5.02 · 95% CI -9.29 to -0.75
  • Active Control vs Burosumab · GEE model · p = 0.1009 · Difference in ls means: 2.68 · 95% CI -0.52 to 5.89
  • Active Control vs Burosumab · GEE model · p = 0.1676 · Difference in ls means: -3.25 · 95% CI -7.86 to 1.37
SecondaryChange 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

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.

Time frame:
Baseline, Week 64
Reported as:
Least squares mean · T-score
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
T-scoreActive ControlBurosumab
Pain Interference Domain Score-1.29 ± 1.267-3.55 ± 1.873
Physical Function Mobility Domain Score0.92 ± 0.9622.82 ± 1.648
Fatigue Domain Score-2.57 ± 1.547-3.65 ± 2.119
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.3091 · Difference in ls means: -2.26 · 95% CI -6.61 to 2.09
  • Active Control vs Burosumab · GEE model · p = 0.3145 · Difference in ls means: 1.90 · 95% CI -1.80 to 5.59
  • Active Control vs Burosumab · GEE model · p = 0.6810 · Difference in ls means: -1.08 · 95% CI -6.21 to 4.06
SecondaryChange From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at 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.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · units on a scale
Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 40
units on a scaleActive ControlBurosumab
Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 400.02 ± 0.3230.03 ± 0.323
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.9862 · Difference in ls means: 0.01 · 95% CI -0.79 to 0.80
SecondaryChange From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at 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.

Time frame:
Baseline, Week 64
Reported as:
Least squares mean · units on a scale
Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 64
units on a scaleActive ControlBurosumab
Change From Baseline in the FPS-R (For Participants ≥ 5 Years of Age at the Screening Visit) at Week 640.04 ± 0.270-0.01 ± 0.234
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.8786 · Difference in ls means: 0.05 · 95% CI -0.58 to 0.68
SecondaryChange From Baseline in the 6MWT Total Distance at 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.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · meters
Change From Baseline in the 6MWT Total Distance at Week 40
metersActive ControlBurosumab
Change From Baseline in the 6MWT Total Distance at Week 403.65 ± 14.06047.10 ± 15.768
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0514 · Difference in ls means: 43.46 · 95% CI -0.26 to 87.17
SecondaryChange From Baseline in the 6MWT Total Distance at 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.

Time frame:
Baseline, Week 64
Reported as:
Least squares mean · meters
Change From Baseline in the 6MWT Total Distance at Week 64
metersActive ControlBurosumab
Change From Baseline in the 6MWT Total Distance at Week 6429.28 ± 16.83474.83 ± 12.513
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0399 · Difference in ls means: 45.55 · 95% CI 2.09 to 89.02
SecondaryPercent of Predicted Normal in the 6MWT Total Distance at 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.

Time frame:
Baseline, Week 40
Reported as:
Least squares mean · percent of predicted meters
Percent of Predicted Normal in the 6MWT Total Distance at Week 40
percent of predicted metersActive ControlBurosumab
Percent of Predicted Normal in the 6MWT Total Distance at Week 40-1.14 ± 2.2245.59 ± 2.633
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0633 · Difference in ls means: 6.72 · 95% CI -0.37 to 13.82
SecondaryPercent of Predicted Normal in the 6MWT Total Distance at 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.

Time frame:
Baseline, Week 64
Reported as:
Least squares mean · percent of predicted meters
Percent of Predicted Normal in the 6MWT Total Distance at Week 64
percent of predicted metersActive ControlBurosumab
Percent of Predicted Normal in the 6MWT Total Distance at Week 641.88 ± 2.7899.15 ± 2.056
Statistical analysis
  • Active Control vs Burosumab · GEE model · p = 0.0496 · Difference in ls means: 7.27 · 95% CI 0.01 to 14.52

Adverse events

Collected over Up to Week 64 in the Treatment Period and up to Week 140 in the Long Term Extension Period, plus up to 12 weeks ±1 week after the last dose of study drug.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Oral Phosphate/Active Vitamin D (Treatment Period)0/32 (0%)3/32 (9.4%)23/32 (71.9%)
Burosumab (Treatment Period)0/29 (0%)3/29 (10.3%)21/29 (72.4%)
Oral Phosphate/Active Vitamin D->Burosumab (Extension Period)0/26 (0%)0/26 (0%)9/26 (34.6%)
Burosumab->Burosumab (Treatment Period and Extension Period)0/29 (0%)4/29 (13.8%)25/29 (86.2%)
Total Burosumab (Treatment Period and Extension Period)0/55 (0%)4/55 (7.3%)34/55 (61.8%)
Most frequent serious events
Most frequent serious events
EventOral Phosphate/Active Vitamin D (Treatment Period)Burosumab (Treatment Period)Oral Phosphate/Active Vitamin D->Burosumab (Extension Period)Burosumab->Burosumab (Treatment Period and Extension Period)Total Burosumab (Treatment Period and Extension Period)
CraniosynostosisCongenital, familial and genetic disorders1/321/290/261/291/55
PapilloedemaEye disorders0/320/290/261/291/55
Viral InfectionInfections and infestations0/321/290/261/291/55
MigraineNervous system disorders0/321/290/261/291/55
Knee DeformityMusculoskeletal and connective tissue disorders1/320/290/260/290/55
HaematuriaRenal and urinary disorders1/320/290/260/290/55
Most frequent other events
Showing 10 of 66
Most frequent other events
EventOral Phosphate/Active Vitamin D (Treatment Period)Burosumab (Treatment Period)Oral Phosphate/Active Vitamin D->Burosumab (Extension Period)Burosumab->Burosumab (Treatment Period and Extension Period)Total Burosumab (Treatment Period and Extension Period)
PyrexiaGeneral disorders7/3216/297/2617/2924/55
NasopharyngitisInfections and infestations14/3211/296/2615/2921/55
CoughRespiratory, thoracic and mediastinal disorders6/3215/294/2615/2919/55
VomitingGastrointestinal disorders8/3212/295/2614/2919/55
ArthralgiaMusculoskeletal and connective tissue disorders10/3213/293/2613/2916/55
Pain In ExtremityMusculoskeletal and connective tissue disorders10/3211/293/2611/2914/55
Dental CariesGastrointestinal disorders2/329/290/2610/2910/55
HeadacheNervous system disorders6/3210/293/2610/2913/55
Injection Site ErythemaGeneral disorders0/329/296/269/2915/55
Tooth AbscessInfections and infestations3/328/292/269/2911/55

Baseline characteristics

Age, Continuous
Age, Continuous(years)Active ControlBurosumabTotal
Mean6.50 ± 3.2506.01 ± 3.4086.27 ± 3.307
Sex: Female, Male
Sex: Female, Male(Participants)Active ControlBurosumabTotal
Female181634
Male141327
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Active ControlBurosumabTotal
Hispanic or Latino336
Not Hispanic or Latino292655
Unknown or Not Reported000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Active ControlBurosumabTotal
Asian628
White252550
Other (Not Specified)123
Rickets Severity Score (RSS) Total Score
Rickets Severity Score (RSS) Total Score(score on a scale)Active ControlBurosumabTotal
Mean3.19 ± 1.1413.17 ± 0.9753.18 ± 1.057
Height-For-Age Z-Score
Height-For-Age Z-Score(Z score)Active ControlBurosumabTotal
Mean-2.05 ± 0.868-2.32 ± 1.167-2.17 ± 1.018
Growth Velocity Z Score From Pre-Treatment
Growth Velocity Z Score From Pre-Treatment(Z score)Active ControlBurosumabTotal
Mean-2.14 ± 5.571-1.37 ± 1.334-1.75 ± 4.022
Serum Phosphorus
Serum Phosphorus(mg/dL)Active ControlBurosumabTotal
Mean2.30 ± 0.2572.42 ± 0.2442.36 ± 0.256

9 further baseline measures are reported on the registry.

08

Study locations

16 sites
  • Children's Hospital Los Angeles
    Los Angeles, California 90027, United States
  • UCSF
    San Francisco, California 94158, United States
  • Indiana University School of Medicine
    Indianapolis, Indiana 46202, United States
  • Shriners Hospital For Children
    St Louis, Missouri 63110, United States
  • Vanderbilt Children's Hospital
    Nashville, Tennessee 37232, United States
  • The Children's Hospital at Westmead
    Westmead, New South Wales 2145, Australia
  • Children's Hospital of Eastern Ontario (CHEO) Research Institute
    Ottawa, Ontario K1H 8L1, Canada
  • The Hospital for Sick Children
    Toronto, Ontario M5G 1X8, Canada
  • Shriners Hospital for Children - Canada
    Montreal, Quebec H4A 0A9, Canada
  • Kanagawa Children's Medical Center
    Yokohama, Kanagawa 232-8555, Japan
  • Okayama Saiseikai General Hospital
    Okayama, 700-0013, Japan
  • Japan Community Healthcare Organization Osaka Hospital
    Osaka, 553-0003, Japan
  • Seoul National University Hospital
    Seoul, 03080, South Korea
  • Karolinska Institutet and University Hospital
    Stockholm, 17176, Sweden
  • Birmingham Children's Hospital
    Birmingham, B4 6NH, United Kingdom
  • Royal Manchester Children's Hospital - University of Manchester
    Manchester, M13 9WL, United Kingdom
09

References and documents

Publications

  • Portale AA, Ward L, Dahir K, Florenzano P, Ing SW, Jan de Beur SM, Martin RM, Meza-Martinez AI, Paloian N, Ashraf A, Dixon BP, Khan A, Langman C, Chen A, Wang C, Roberts MS, Tandon PK, Bedrosian C, Imel EA. Nephrocalcinosis and kidney function in children and adults with X-linked hypophosphatemia: baseline results from a large longitudinal study. J Bone Miner Res. 2024 Sep 26;39(10):1493-1502. doi: 10.1093/jbmr/zjae127. PubMed 39151033 ↗
  • Imel EA, Glorieux FH, Whyte MP, Portale AA, Munns CF, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Hogler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Chen A, Roberts MS, Ward LM. Burosumab vs Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Subgroup Analysis by Dose Level. J Clin Endocrinol Metab. 2023 Oct 18;108(11):2990-2998. doi: 10.1210/clinem/dgad230. PubMed 37084401 ↗
  • Ward LM, Glorieux FH, Whyte MP, Munns CF, Portale AA, Hogler W, Simmons JH, Gottesman GS, Padidela R, Namba N, Cheong HI, Nilsson O, Mao M, Chen A, Skrinar A, Roberts MS, Imel EA. Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2022 Jul 14;107(8):e3241-e3253. doi: 10.1210/clinem/dgac296. PubMed 35533340 ↗
  • Padidela R, Whyte MP, Glorieux FH, Munns CF, Ward LM, Nilsson O, Portale AA, Simmons JH, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Hogler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Williams A, Nixon A, Sun W, Chen A, Skrinar A, Imel EA. Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia. Calcif Tissue Int. 2021 May;108(5):622-633. doi: 10.1007/s00223-020-00797-x. Epub 2021 Jan 23. PubMed 33484279 ↗
  • Mao M, Carpenter TO, Whyte MP, Skrinar A, Chen CY, San Martin J, Rogol AD. Growth Curves for Children with X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2020 Oct 1;105(10):3243-9. doi: 10.1210/clinem/dgaa495. PubMed 32721016 ↗
  • Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Hogler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019 Jun 15;393(10189):2416-2427. doi: 10.1016/S0140-6736(19)30654-3. Epub 2019 May 16. PubMed 31104833 ↗

Study documents

  • Study protocol · Nov 3, 2017
  • Statistical analysis plan · Jan 2, 2018

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Aug 29, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02915705
Lead sponsor
Kyowa Kirin, Inc.
Collaborators
Kyowa Kirin Co., Ltd.
Responsible party
Sponsor
First posted
Sep 27, 2016
Start date
Sep 8, 2016
Primary completion
Feb 12, 2018
Completion
Jul 15, 2019
Results posted
Apr 11, 2019
Last update
Aug 29, 2024

Study contacts

Medical Director
study director · Ultragenyx Pharmaceutical Inc

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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