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Completed

NCT Number: NCT02915705

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

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).

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Key information

Conditions

X-linked Hypophosphatemia Avitaminosis Bone Diseases Bone Diseases, Metabolic Calcium Metabolism Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Deficiency Diseases Familial Hypophosphatemic Rickets Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genetic Diseases, Inborn Hypophosphatemia Hypophosphatemia, Familial Kidney Diseases Male Urogenital Diseases Malnutrition Metabolic Diseases Metabolism, Inborn Errors Metal Metabolism, Inborn Errors Musculoskeletal Diseases Nutrition Disorders Nutritional and Metabolic Diseases Phosphorus Metabolism Disorders Renal Tubular Transport, Inborn Errors Rickets Rickets, Hypophosphatemic Urogenital Diseases Urologic Diseases Vitamin D Deficiency

Age range

1 year–12 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

The Children's Hospital at Westmead, Westmead, New South Wales, Australia

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

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

Treatment and study plan

Burosumab

Biological

solution for subcutaneous (SC) injection

Other names: KRN23, Crysvita ®, UX023

Oral Phosphate Supplement

Drug

oral tablet; oral solution; oral powder

active vitamin D

Drug

tablet, oral solution

Primary outcomes

  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 outcomes

  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 Over Time in Serum Phosphorus Concentration, up to Week 64

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

  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

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

  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

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

  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

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

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

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

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

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

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

  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

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

    Decreases indicate improvement.

  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

    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.

  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

    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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

Sponsors and collaborators

Lead sponsor

Kyowa Kirin, Inc.

Industry

Collaborators

  • Kyowa Kirin Co., Ltd.

Registry information

Official study 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)

Important dates

Study start
2016
Primary completion
2018
Study completion
2019
First posted
Sep 27, 2016
Registry last updated
Aug 29, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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